MR-guided focused ultrasound pallidotomy for Parkinson's disease: Safety and feasibility

Abstract

OBJECTIVE
Stereotactic radiofrequency pallidotomy has demonstrated improvement in motor fluctuations in patients with Parkinson’s disease (PD), particularly levodopa (L-dopa)–induced dyskinesias. The authors aimed to determine whether or not unilateral pallidotomy with MR-guided focused ultrasound (MRgFUS) could safely improve Unified Dyskinesia Rating Scale (UDysRS; the primary outcome measure) scores over baseline scores in patients with PD.

METHODS
Twenty patients with PD and L-dopa responsiveness, asymmetrical motor signs, and motor fluctuations, including dyskinesias, participated in a 1-year multicenter open-label trial of unilateral MRgFUS ablation of the globus pallidus internus.

RESULTS
The sonication procedure was successfully completed in all 20 enrolled patients. MRgFUS-related adverse neurological events were generally mild and transient, including visual field deficit (n = 1), dysarthria (n = 4, 2 mild and 2 moderate), cognitive disturbance (n = 1), fine motor deficit (n = 2), and facial weakness (n = 1). Although 3 adverse events (AEs) were rated as severe (transient sonication-related pain in 2, nausea/vomiting in 1), no AE fulfilled US FDA criteria for a Serious Adverse Effect. Total UDysRS, the primary outcome measure, improved 59% after treatment (baseline mean score 36.1, 95% CI 4.88; at 3 months 14.2, 95% CI 5.72, p < 0.0001), which was sustained throughout the study (at 12 months 20.5, 95% CI 7.39, 43% improvement, p < 0.0001). The severity of motor signs on the treated side (Movement Disorder Society version of the United Parkinson’s Disease Rating Scale [MDS-UPDRS] part III) in the “off” medication state also significantly improved (baseline mean score 20.0, 95% CI 2.4; at 3 months 10.6, 95% CI 1.86, 44.5% improvement, p < 0.0001; at 12 months 10.4, 95% CI 2.11, 45.2% improvement, p > 0.0001). The vast majority of patients showed a clinically meaningful level of improvement on the impairment component of the UDysRS or the motor component of the UPDRS, while 1 patient showed clinically meaningful worsening on the UPDRS at month 3.

CONCLUSIONS
This study supports the feasibility and preliminary efficacy of MRgFUS pallidotomy in the treatment of patients with PD and motor fluctuations, including dyskinesias. These preliminary data support continued investigation, and a placebo-controlled, blinded trial is in progress.
Clinical trial registration no.: NCT02263885 (clinicaltrials.gov)

Full text

CLINICAL ARTICLE
J Neurosurg 135:792–798, 2021
Stereotactic surgery targeting the globus pallidus in-
ternus (GPi) has been shown to benet motor symp-
toms of Parkinson’s disease (PD).1–3 Radiofrequency
pallidotomy results in a particularly substantial decrease
in involuntary movements known as dyskinesias, induced
by long-term treatment with carbidopa/levodopa (L-dopa)
(L-dopa–induced dyskinesias).4,5 Cardinal motor signs of
PD such as tremor, bradykinesia, and rigidity are also im-
proved contralateral to a pallidotomy, specically in the
“off” L-dopa state in patients with a uctuating response
to L-dopa.6–8
Deep brain stimulation (DBS) of the GPi was intro-
ABBREVIATIONS AE = adverse event; DBS = deep brain stimulation; FGATIR = fast gray matter acquisition T1 inversion recovery; GPi = globus pallidus internus; L-dopa
= levodopa; MDS-UPDRS = Movement Disorder Society version of the UPDRS; MRgFUS = MR-guided focused ultrasound; PD = Parkinson’s disease; SAE = Serious
Adverse Effect; UDysRS = Unified Dyskinesia Rating Scale; UPDRS = United Parkinson’s Disease Rating Scale.
SUBMITTED October 11, 2019. ACCEPTED June 29, 2020.
INCLUDE WHEN CITING Published online November 27, 2020; DOI: 10.3171/2020.6.JNS192773.
MR-guided focused ultrasound pallidotomy for
Parkinson’s disease: safety and feasibility
Howard M. Eisenberg, MD,1 Vibhor Krishna, MD, SM,2 W. Jeffrey Elias, MD,3
G. Rees Cosgrove, MD,4 Dheeraj Gandhi, MD,5 Charlene E. Aldrich, RN, MSN,1 and
Paul S. Fishman, MD, PhD6
Departments of 1Neurosurgery, 5Diagnostic Radiology and Nuclear Medicine, and 6Neurology, University of Maryland School
of Medicine, Baltimore, Maryland; 2Department of Neurosurgery, Ohio State University Medical Center, Columbus, Ohio;
3Department of Neurosurgery, University of Virginia Health Sciences Center, Charlottesville, Virginia; and 4Department of
Neurosurgery, Brigham and Women’s Hospital, Boston, Massachusetts
OBJECTIVE Stereotactic radiofrequency pallidotomy has demonstrated improvement in motor uctuations in patients
with Parkinson’s disease (PD), particularly levodopa (L-dopa)–induced dyskinesias. The authors aimed to determine
whether or not unilateral pallidotomy with MR-guided focused ultrasound (MRgFUS) could safely improve Unied Dyski-
nesia Rating Scale (UDysRS; the primary outcome measure) scores over baseline scores in patients with PD.
METHODS Twenty patients with PD and L-dopa responsiveness, asymmetrical motor signs, and motor uctuations,
including dyskinesias, participated in a 1-year multicenter open-label trial of unilateral MRgFUS ablation of the globus
pallidus internus.
RESULTS The sonication procedure was successfully completed in all 20 enrolled patients. MRgFUS-related adverse
neurological events were generally mild and transient, including visual eld decit (n = 1), dysarthria (n = 4, 2 mild and
2 moderate), cognitive disturbance (n = 1), ne motor decit (n = 2), and facial weakness (n = 1). Although 3 adverse
events (AEs) were rated as severe (transient sonication-related pain in 2, nausea/vomiting in 1), no AE fullled US
FDA criteria for a Serious Adverse Effect. Total UDysRS, the primary outcome measure, improved 59% after treatment
(baseline mean score 36.1, 95% CI 4.88; at 3 months 14.2, 95% CI 5.72, p < 0.0001), which was sustained throughout
the study (at 12 months 20.5, 95% CI 7.39, 43% improvement, p < 0.0001). The severity of motor signs on the treated
side (Movement Disorder Society version of the United Parkinson’s Disease Rating Scale [MDS-UPDRS] part III) in the
“off” medication state also signicantly improved (baseline mean score 20.0, 95% CI 2.4; at 3 months 10.6, 95% CI 1.86,
44.5% improvement, p < 0.0001; at 12 months 10.4, 95% CI 2.11, 45.2% improvement, p > 0.0001). The vast majority of
patients showed a clinically meaningful level of improvement on the impairment component of the UDysRS or the motor
component of the UPDRS, while 1 patient showed clinically meaningful worsening on the UPDRS at month 3.
CONCLUSIONS This study supports the feasibility and preliminary efcacy of MRgFUS pallidotomy in the treatment of
patients with PD and motor uctuations, including dyskinesias. These preliminary data support continued investigation,
and a placebo-controlled, blinded trial is in progress.
Clinical trial registration no.: NCT02263885 (clinicaltrials.gov)
https://thejns.org/doi/abs/10.3171/2020.6.JNS192773
KEYWORDS MR-guided focused ultrasound; MRgFUS; pallidotomy; Parkinson’s disease; dyskinesia; functional
neurosurgery
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Eisenberg et al.
duced in part to reduce the neurological complications
of radiofrequency pallidotomy, such as weakness, imbal-
ance, cognitive abnormalities, and visual eld defects.9–14
Benecial effects of GPi DBS that are similar to those
of pallidotomy are well documented using this strategy,
which employs high-frequency stimulation rather than a
destructive brain lesion to ameliorate motor symptoms
of PD.15–18 DBS is still an open surgical procedure, and
similar to radiofrequency, pallidotomy shares the risk of
intracranial bleeding and infection.19,20 Another limitation
of DBS is that some appropriate patients nd this form of
open brain surgery, with the permanent implantation of its
associated hardware, unacceptable.21
MR-guided focused ultrasound (MRgFUS) is an in-
cisionless method that can create a highly targeted brain
ablation. MRgFUS of the ventral intermediate nucleus of
the thalamus was initially FDA approved for the treat-
ment of medically refractory essential tremor, and very
recently for tremor-predominant PD as well. MRgFUS
has also been utilized in the treatment of other motor as-
pects of PD, including dyskinesias.22–25 An initial patient
report of successful unilateral lesioning of the GPi was
followed by a small open-label study of PD patients with
dose uctuation including dyskinesia, which showed simi-
lar results to radiofrequency pallidotomy.26,27 On the basis
of previous experience with radiofrequency pallidotomy
and MRgFUS for PD and related movement disorders,
we initiated a trial of MRgFUS unilateral pallidotomy for
patients with asymmetrical motor signs and functionally
interfering motor uctuations, including bothersome dys-
kinesias.
Methods
Study Population and Criteria
Patients with a diagnosis of PD in the study had the
following inclusion criteria: age between 40 and 80 years,
and L-dopa–responsive PD with at least a 30% difference
in motor score severity on part III of the Movement Dis-
order Society version of the United Parkinson’s Disease
Rating Scale (MDS-UPDRS) between “on” and “off”
medication states. Patients had a minimum severity in the
“off” state with a motor score of at least 30 on part III
of the MDS-UPDRS. This study was registered with the
ClinicalTrials.gov database (http://clinicaltrials.gov), and
its registration no. is NCT02263885.
PD motor symptoms were either unilateral or markedly
asymmetrical, with predominant disability from one side
of the body to the extent that the investigator felt there was
a likelihood of improvement with unilateral treatment. All
patients had functionally interfering motor uctuations
with dyskinesia on optimal and stable medical therapy
with a score of at least 3 in response to question 4.2 of the
MDS-UPDRS.
Exclusion criteria included suspicion of another related
neurodegenerative disease (such as progressive supranu-
clear palsy, multisystem atrophy, or dementia with Lewy
bodies); impaired cognition with a Montreal Cognitive
Assessment score of less than 21; impairment of speech or
swallowing (score of 3 or 4 on question 5 of part II of the
MDS-UPDRS); impairment of balance with a score of 3
or greater on the Hoehn and Yahr scale; poorly controlled
depression (Beck Depression Inventory score > 14); and
signicant medical or psychiatric comorbidities. Patients
with vascular or structural lesions on MRI, a skull density
ratio (i.e., the ratio of density of cortical bone to density of
cancellous bone) of 0.40 or less, claustrophobia, or inabil-
ity to lie at were also excluded.
Evaluation and Testing
Preprocedure evaluations included physical and neuro-
logical examinations, comprehensive neuropsychological
testing, formal visual eld testingS-UPDRS in both “on”
and “off” states, and the Unied Dyskinesia Rating Scale
(UDysRS).
Imaging evaluation obtained prior to the procedure in-
cluded a noncontrast head CT scan as well as MRI of the
brain. CT images reconstructed using a C-lter in bone
windows were utilized for skull density measurements,
identifying and marking calcications, and procedural
planning. Multiplanar MRI was performed for procedural
planning. The following sequences were used for target-
ing and preplanning purposes: fast gray matter acquisi-
tion T1 inversion recovery (FGATIR) in 15 patients, 3D
T1-weighted gradient echo in 3 patients, and T2-weighted
fast spin echo in 2 patients. The axial images were refor-
matted or obtained in the commissural (anterior commis-
sure–posterior commissure) plane.
MRgFUS Pallidotomy Procedure
MRgFUS pallidotomy was performed using the In-
Sightec ExAblate 4000 Transcranial System interfaced
with a 3T GE Medical System MRI machine. The patient’s
head was shaved on the day of the procedure. After ad-
ministration of local anesthetic, an Integra CRW stereo-
tactic frame was placed on the patient’s head. A silicone
membrane bag was placed around the head and connected
to a circulating degassed and cooled water bath to create
an air-free interface between the transducers and the head.
The patient was placed supine and the head was afxed to
the focused ultrasound device throughout the procedure.
Intraoperative MRI of the brain was performed, and the
intraoperative images were coregistered with the preopera-
tive planning study. Targeting was performed using a com-
bination of standard stereotactic coordinates for the GPi
(20 mm lateral of midline, 3–4 mm anterior of midpoint,
and 3 mm interior of the intercommissural line) and direct
imaging of the GPi (Fig. 1 left). In 12 patients, direct im-
aging of the GPi using FGATIR MRI sequences as well
as tractography of the corticospinal tract was utilized to
adjust the ablation location. Initially, low-energy sonica-
tions were delivered to the target GPi, contralateral to the
side of the desired treatment effect. As has been previously
described, focused ultrasound lesioning was performed by
initially heating an approximately 2-mm-diameter volume
of tissue with short low-energy sonications generating a
40°C–45°C target temperature.23 The energy delivered
was gradually increased, progressing incrementally to
higher ablative temperatures, with each therapeutic sonica-
tion followed by patient evaluation for both improvement
of motor symptoms of PD (rigidity, tremor, bradykinesia,
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Eisenberg et al.
J Neurosurg Volume 135 • September 2021794
and dystonia, because patients were treated in the “off”
medication state) and potential off-target adverse effects
such as dysarthria, weakness, or vision changes. Transient
improvement without off-target adverse effects with sub-
lethal sonications was followed by sonications with in-
creased energy to reach target temperatures greater than
56°C. The size and location of the ablative zone were also
continuously monitored using MR thermometry.
Multiple lesions (typically 2–3), usually contiguous,
were created guided by the boundaries of the GPi on
MRI and the clinical response of the patient. Patients
were awake during the procedure but were medicated as
needed for procedure-related pain and nausea. Following
the treatment session, the stereotactic frame was removed.
The patients were observed overnight and discharged
from the hospital the following day. A postprocedure MRI
of the brain was acquired prior to discharge to evaluate
the location and size of the lesion within the pallidum. Not
all patients attained the target temperature of 56°C, but
all treated patients had a lesion detectable by MRI im-
mediately after the procedure and at least one sonication
greater than 51° (Fig. 1).
Adverse Events
The severity of adverse events (AEs) was predened
as mild (minor inconvenience, not affecting daily routine
activities), moderate (bothersome, interferes with routine
daily activities), or severe (incapacitating, cannot per-
form activities of daily living). The severity rating (mild,
moderate, or severe) reects the maximal severity of the
occurrence at any time. Serious Adverse Effects (SAEs)
fullled the FDA denition of serious, which is an injury
or illness that 1) is life-threatening; 2) results in perma-
nent impairment of a body function or permanent damage
to a body structure; or 3) necessitates medical or surgi-
cal intervention to preclude permanent impairment of a
body function or permanent damage to a body structure.
Permanent means irreversible impairment or damage to a
body structure or function, excluding trivial impairment
or damage.
Results
Patient Demographics
Of 34 patients initially screened, 20 were enrolled and
treated in the study. These patients included 13 men and 7
women, of whom 18 were White and 2 were Hispanic, with
a mean age of 56.4 years (range 35–74 years). The mean
time from diagnosis was 9.9 years, and the mean daily L-
dopa equivalent of therapy was 1039 ± 601 mg (Table 1).
All 20 of the treated patients completed the 3-month visit.
One patient withdrew following the 3-month visit for per-
sonal reasons. Nineteen patients were expected to attend
the 6-month visit; 1 was unable to attend but continued
participation. One patient withdrew following the 6-month
visit to have an alternative treatment. For the 12-month
visit, 18 patients were expected to attend but 1 was un-
able to attend. All patient and visit data are included in the
analysis and gures.
MRgFUS Treatment Characteristics
Patients received a mean of 15 ± 3 sonications during
treatment with a mean power of 605.6 ± 164.9 W. The
mean maximum sonication power was 1045.1 ± 233.3 W.
Clinical Outcomes: Efcacy
The primary efcacy outcome measure, the total
UDysRS score at 3 months, signicantly improved from a
baseline score of 36.1 ± 11.12 (95% CI 4.88) to 14.2 ± 13.06
FIG. 1. Axial FGATIR sequence at day 1 (left) and 6 months (right)
after treatment. The lesion (large arrow in both panels) is demonstrated
as hyperintensity conned to the ventral lateral aspect of the GPi, with
a smaller size of the T2 hyperintense lesions and resolution of the per-
ilesional edema noted later on the follow-up image (right). The smaller
arrow in the left panel indicates the internal lamina between the external
and internal segments of the globus pallidus.
TABLE 1. Demographics and baseline characteristics
Variable Value
Sex (n = 20)
Men
Women 13
7
Race (n = 20)
White
Black
Hispanic
Other
18
0
2
0
Age, yrs (n = 20)
Mean
SD
Max
Min
56.4
11.3
73.9
34.5
Yrs since diagnosis (n = 6)
Mean
SD
Max
Min
9.9
6.4
19.7
2.7
Daily L-dopa equivalents (n = 19), mg
Mean
SD
Max
Min
1039.4
601.3
2500
200
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Eisenberg et al.
(95% CI 5.72), an improvement of 59% (p < 0.0001 using a
paired t-test). This improvement continued throughout the
duration of the study with a mean total UDysRS score at
12 months of 20.5 ± 15.99 (95% CI 7.39), a 43% improve-
ment (p < 0.0001; Fig. 2A).
Similar improvement was seen in part III of the
UDysRS, which is the examiner rating of dyskinesia in-
tensity, with a reduction from a mean of 10.2 ± 6.17 (95%
CI 2.0) to 4.5 ± 4.87 (95% CI 2.14) at 3 months, an im-
provement of 56.4%. This improvement also persisted,
with a mean value of 4.4 ± 5.17 at 12 months (95% CI
2.39), for a reduction of 68.6% (Fig. 2B).
The efcacy of the treatment of motor signs of PD was
assessed through the motor examination section (part III)
of the MDS-UPDRS for those portions related to the treat-
ed side (9 items for arm and leg) in the “off” medication
state. There was a signicant reduction of scores from a
baseline of 20.0 ± 5.62 (95% CI 2.46) to 10.6 ± 4.24 (95%
CI 1.86) at 3 months after treatment, representing a 44.5%
improvement (p < 0.0001). This signicant reduction was
sustained at 12 months after treatment, with a mean score
of 10.4 ± 4.57 (95% CI 2.11), representing a 45.2% reduc-
tion from the baseline value (p < 0.0001; Fig. 2C).
Motor complications of PD were assessed with part IV
of the MDS-UPDRS capturing data regarding duration and
functional impact of both dyskinesias and “off” periods.
After treatment there was a signicant and persistent im-
provement in scores on this measure. The baseline pretreat-
ment mean value of 11.1 ± 5.61 (95% CI 2.46) improved to
6.4 ± 4.15 (95% CI 1.82, p = 0.007) by 3 months and was
maintained at this value (6.4 ± 4.31, 95% CI 1.99) at 12
months, representing a 42% improvement (Fig. 2D). No dif-
ference in results could be discerned between centers; how-
ever, the study was not powered to detect such differences.
In these patients with asymmetrical motor signs, even
the unilateral treatment provided resulted in signicant
improvement in motor aspects of experiences of daily liv-
ing as assessed by part II of the MDS-UPDRS. Treatment
was followed by a signicant reduction in mean score
from 14.0 ± 7.53 (95% CI 3.30) at baseline to 7.4 ± 5.04
(95% CI 2.21, p = 0007) at 3 months, an improvement of
47%. This group change was not sustained, worsening to
12.1 ± 6.5 (95% CI 2.99) by 12 months after baseline.
Individual Patient Therapeutic Benet or Worsening:
Responder Analyses
To obtain a measure of individual patient treatment suc-
cess or failure, responder analysis was performed. Although
most patients tolerate a dyskinetic state better than the bra-
dykinesia state, there is individual patient variation as to
the relative importance of improving cardinal Parkinsonian
signs over the dyskinetic state. Achieving either of these out-
comes may be important depending on the patient’s treat-
ment objectives. For this responder analysis, a responder is a
patient with a minimal clinically important improvement on
FIG. 2. Clinical outcome measures following unilateral MRgFUS pallidotomy. Mean UDysRS total scores (A), part III scores (B),
part III (motor) scores for the treated extremities (C), and part IV (motor complications) scores (D) at baseline and at 1, 3, 6, and 12
months after treatment. B = baseline. Figure is available in color online only.
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Eisenberg et al.
J Neurosurg Volume 135 • September 2021796
either the UDysRS part III impairment score (2.32 points,
while worsening scores are 2.76) or the MDS-UPDRS part
III motor examination (3.25 points, while worsening scores
are 4.63), as dened in previous studies.30–32
The majority of patients were responders at all post-
procedure evaluations, based on the UDysRS part III im-
pairment scores, suggesting a meaningful clinical benet
in reduction in dyskinesias (70% at 3 months, 68% at 6
months, 76% at 12 months). The majority of patients were
also responders at all postprocedure evaluations based on
the MDS-UPDRS part III motor examination scores, sug-
gesting clinically meaningful relief of cardinal signs of
PD, including tremor, bradykinesia, and rigidity (80% at
3 months, 68% at 6 months, 76% at 12 months). The vast
majority of patients had clinically important levels of im-
provement at all postprocedure evaluations on at least one
of these two outcome measures (90% at 3 months, 95% at
6 months, 94% at 12 months). One patient had a clinically
important level of worsening at only the 3-month evalua-
tion, based on the MDS-UPDRS part III.
In this study, screening scores were also used as baseline
scores, so that follow-up scores for all outcome measures
were compared to this single time point. In this setting it
is possible that the initial single score may represent an
atypically severe patient state and that improvement seen in
follow-up scores may be inuenced by the regression to the
mean phenomenon. We feel that this phenomenon did not
substantively inuence the signicant improvement seen in
this study because improvement was noted in multiple out-
come measures over multiple follow-up time points. A trend
of diminishing improvement over time in the UDysRS
score would be expected with disease progression.
Safety and Tolerability
A total of 61 AEs were reported by 17 patients (3 pa-
tients reported no AEs). Twenty-ve of these AEs (41%)
were reported to be unrelated to the procedure, although
4 AEs (all mild) were considered to be related to place-
ment of the stereotactic frame (headache, facial edema).
Ten AEs were considered to be PD related.
Of the 36 procedure-related AEs, the most common
were nausea/vomiting (n = 3), headache (n = 3), and sonica-
tion-related head pain (n = 7). Seventeen of the AEs were
transient, which included the only severe AEs (2 with tran-
sient sonication-related head pain, 1 with transient nausea
and vomiting, 5% of total). Neurological AEs related to the
procedure included visual eld decit (1 mild, transient),
dysarthria (4 total, 2 mild and 2 moderate), cognitive dis-
turbance (1 mild), ne motor decit (2 mild), facial weak-
ness (1 mild), and balance difculties (1 moderate).
Twenty AEs persisted and continue to be followed, in-
cluding ne motor difculties (1 mild), dysarthria (1 mild,
2 moderate), and balance difculties (1 mild), none of
which were rated as severe. No AEs fullled FDA criteria
of an SAE.
Discussion
This preliminary study of unilateral MRgFUS palli-
dotomy for the motor uctuations and L-dopa–induced
dyskinesia associated with PD demonstrated improve-
ments in both “on” and “off” medication ratings. As the
study’s primary clinical endpoint, total UDysRS assess-
ments were improved by 59% at 3 months following the
procedure. Similarly, the motor signs of PD, as assessed
from part III of the UPDRS contralateral to the lesion,
improved by 44% at 3 months and were maintained at 1
year. Safety is suggested by the mild and transient nature
of the AEs reported.
Stereotactic lesioning of the GPi had been shown in
multiple studies to result in signicant and long-lasting
improvement of motor signs and symptoms of PD, includ-
ing dose uctuations and L-dopa–induced dyskinesia.4–8
Although DBS is the current surgical standard of care for
PD, preferred over radiofrequency pallidotomy, it has risks
associated with all open surgical procedures of the brain,
particularly bleeding and infection.19,20
Previous studies involving patients with essential
tremor and tremor-predominant PD have established that
MRgFUS thalamotomy is an emerging alternative to DBS
for patients with a medically refractory tremor.22–25 This
study was designed to investigate if MRgFUS pallidotomy
could provide benets like radiofrequency pallidotomy
and pallidal DBS, while reproducing the high level of
safety and tolerance of MRgFUS of the thalamus seen in
patients with essential tremor.33
Our experience is also consistent with the previous lim-
ited reports of MRgFUS pallidotomy in PD. A 55-year-
old woman with PD was initially reported by Na et al. to
show a 62% reduction in baseline UDysRS score 3 months
after a unilateral MRgFUS-mediated pallidotomy and a
61.9% reduction in motor “off” scores with no AEs.29 In a
recently published study by Jung et al.,28 10 patients with
PD underwent unilateral MRgFUS pallidotomy. Of the 8
patients who successfully completed the procedure (in 2
patients thermal ablation could not be achieved, likely due
to poor transcranial acoustic transmission), there was an
improvement in total UDysRS by 52.7% and a 30.2% re-
duction in UPDRS “off” scores at 6 months.28 This is very
similar to the percentage reductions in the total UDysRS
and MDS-UPDRS part III in the “off” state in our study.
This magnitude of improvement in motor “off” state and
dyskinesia is also comparable to that seen in studies of
radiofrequency open stereotactic pallidotomy.4–8 This
amount of reduction in dyskinesias and motor “off” scores
persisted through the 12-month duration of the study and
is also clinically important, along with a meaningful re-
duction in functional interference by motor symptoms in
the majority of treated patients.30–32
The safety prole of our study of MRgFUS pallidot-
omy is also consistent with previous work investigating
its application for tremor. There were no SAEs (as de-
ned by the US FDA) in our 20 patients who underwent
the procedure. Of the 61 AEs reported, only 3 (5%) were
rated as severe, and all of these were transient (headache,
pain, nausea). Because the intent of MRgFUS is to create
a permanent brain ablation, possible neurological decits
due to damage to brain tissue adjacent to the target are
a clear concern. Neurological decits accounted for only
10 of the 61 reported AEs, 7 of which were considered
mild and none were rated as severe. Five of these decits
persisted for at least the duration of the study. With regard
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Eisenberg et al.
to neurological decits that had been previously associ-
ated with radiofrequency pallidotomy, only 1 patient had
a mild visual eld abnormality by confrontation that was
not detectable by later formal visual eld analysis. Anoth-
er patient noted memory difculties and showed decline
on one subtest of a neuropsychological battery, but im-
provement on another subtest. This experience is consis-
tent with an analysis of the safety of MRgFUS-mediated
thalamotomy for essential tremor, where the vast majority
of thalamotomy-related neurological AEs were mild and
rarely severe.33
As expected for this incisionless procedure, no intra-
cranial bleeding or infection occurred. The results of this
initial study compare very favorably to those of previous
studies of radiofrequency pallidotomy for PD, in which up
to several percent of patients showed reportable neurologi-
cal decits that were serious and persistent. Although the
total number of patients who have undergone MRgFUS
pallidotomy, including our study, is relatively small, the
current experience suggests an acceptable safety prole.
This early experience is also encouraging because applica-
tion of advancing imaging technology with improvements
in targeting has the potential to improve the safety and
efcacy of the procedure.34
Conclusions
The results of this initial study with regard to both ef-
cacy and safety support our ongoing approach of expanded
cli n ical investigation in the form of an ad e quately power e d,
blinded, controlled study of MRgFUS pallidotomy in the
treatment of patients with signicantly asymmetrical PD
and a uctuating motor response to medications, includ-
ing dyskinesia. Successful development of this technology
will provide patients with PD with a new, less-invasive
treatment option.
References
1. Alkhani A, Lozano AM. Pallidotomy for Parkinson disease:
a review of contemporary literature. J Neurosurg. 2001; 94(1):
43– 49.
2. Cif L, Hariz M. Seventy years with the globus pallidus: pal-
lidal surgery for movement disorders between 1947 and 2017.
Mov Disord. 2017; 32(7): 972–982.
3. Gross RE. What happened to posteroventral pallidotomy for
Parkinson’s disease and dystonia? Neurotherapeutics. 2008;
5(2): 281–293.
4. de Bie RM, de Haan RJ, Nijssen PC, et al. Unilateral palli-
dotomy in Parkinson’s disease: a randomised, single-blind,
multicentre trial. Lancet. 1999; 354(9191): 1665–1669.
5. Vitek JL, Bakay RA, Freeman A, et al. Randomized trial of
pallidotomy versus medical therapy for Parkinson’s disease.
Ann Neurol. 2003; 53(5): 558–569.
6. Eskandar EN, Shinobu LA, Penney JB Jr, et al. Stereotactic
pallidotomy performed without using microelectrode guid-
ance in patients with Parkinson’s disease: surgical technique
and 2-year results. J Neurosurg. 2000; 92(3): 375–383.
7. Kondziolka D, Bonaroti E, Baser S, et al. Outcomes after
stereotactically guided pallidotomy for advanced Parkinson’s
disease. J Neurosurg. 1999; 90(2): 197–202.
8. Shannon KM, Penn RD, Kroin JS, et al. Stereotactic palli-
dotomy for the treatment of Parkinson’s disease. Efcacy and
adverse effects at 6 months in 26 patients. Neurology. 1998;
50(2): 434–438.
9. Biousse V, Newman NJ, Carroll C, et al. Visual elds in pa-
tients with posterior GPi pallidotomy. Neurology. 1998; 50(1):
258 –265.
10. Higuchi Y, Iacono RP. Surgical complications in patients
with Parkinson’s disease after posteroventral pallidotomy.
Neurosurgery. 2003; 52(3): 558–571.
11. Olzak M, Laskowska I, Jelonek J, et al. Psychomotor and
executive functioning after unilateral posteroventral pallidot-
omy in patients with Parkinson’s disease. J Neurol Sci. 2006;
248(1-2): 97–103.
12. Palur RS, Berk C, Schulzer M, Honey CR. A metaanalysis
comparing the results of pallidotomy performed using micro-
electrode recording or macroelectrode stimulation. J Neuro-
surg. 2002; 96(6): 1058–1062.
13. Samuel M, Caputo E, Brooks DJ, et al. A study of medial
pallidotomy for Parkinson’s disease: clinical outcome, MRI
location and complications. Brain. 1998; 121(pt 1): 59–75.
14. Schmand B, de Bie RM, Koning-Haanstra M, et al. Unilateral
pallidotomy in PD: a controlled study of cognitive and behav-
ioral effects. The Netherlands Pallidotomy Study (NEPAS)
group. Neurology. 2000; 54(5): 1058–1064.
15. Blomstedt P, Hariz GM, Hariz MI. Pallidotomy versus pal-
lidal stimulation. Parkinsonism Relat Disord. 2006; 12(5):
296 –301.
16. Jiménez F, Velasco F, Carrillo-Ruiz JD, et al. Comparative
evaluation of the effects of unilateral lesion versus electrical
stimulation of the globus pallidus internus in advanced Par-
kinson’s disease. Stereotact Funct Neurosurg. 2006; 84(2-3):
64 –71.
17. Krack P, Martinez-Fernandez R, Del Alamo M, Obeso JA.
Current applications and limitations of surgical treatments
for movement disorders. Mov Disord. 2017; 32(1): 36–52.
18. Merello M, Nouzeilles MI, Kuzis G, et al. Unilateral radio-
frequency lesion versus electrostimulation of posteroventral
pallidum: a prospective randomized comparison. Mov Dis-
ord. 1999; 14(1): 50–56.
19. Patel DM, Walker HC, Brooks R, et al. Adverse events as-
sociated with deep brain stimulation for movement disorders:
analysis of 510 consecutive cases. Neurosurgery. 2015; 11(2)
(suppl 2): 190 –199.
20. Sillay KA, Larson PS, Starr PA. Deep brain stimulator hard-
ware-related infections: incidence and management in a large
series. Neurosurgery. 2008; 62(2): 360–367.
21. Kim MR, Yun JY, Jeon B, et al. Patients’ reluctance to un-
dergo deep brain stimulation for Parkinson’s disease. Parkin-
sonism Relat Disord. 2016; 23(9): 91–94.
22. Chang JW, Park CK, Lipsman N, et al. A prospective trial of
magnetic resonance-guided focused ultrasound thalamotomy
for essential tremor: results at the 2-year follow-up. Ann Neu-
rol. 2018; 83(1): 107–114.
23. Elias WJ, Lipsman N, Ondo WG, et al. A randomized trial of
focused ultrasound thalamotomy for essential tremor. N Engl
J Med. 2016; 375(8): 730–739.
24. Bond AE, Shah BB, Huss DS, et al. Safety and efcacy
of focused ultrasound thalamotomy for patients with
medication-refractory, tremor-dominant Parkinson disease:
a randomized clinical trial. JAMA Neurol. 2 0 1 7; 7 4 ( 1 2 ) : 1 4 1 2 –
1418.
25. Zaaroor M, Sinai A, Goldsher D, et al. Magnetic resonance-
guided focused ultrasound thalamotomy for tremor: a report
of 30 Parkinson’s disease and essential tremor cases. J Neu-
rosurg. 2018; 128(1): 202–210.
26. Magara A, Bühler R, Moser D, et al. First experience with
MR-guided focused ultrasound in the treatment of Parkin-
son’s disease. J Ther Ultrasound. 2014; 2(1): 11.
27. Martínez-Fernández R, Rodríguez-Rojas R, Del Álamo M,
et al. Focused ultrasound subthalamotomy in patients with
asymmetric Parkinson’s disease: a pilot study. Lancet Neurol.
2 0 1 8 ; 1 7 ( 1 ) : 5 4 – 6 3 .
Unauthenticated | Downloaded 03/27/23 12:20 PM UTC

Eisenberg et al.
J Neurosurg Volume 135 • September 2021798
28. Jung NY, Park CK, Kim M, et al. The efcacy and limits of
magnetic resonance-guided focused ultrasound pallidotomy
for Parkinson’s disease: a phase I clinical trial. J Neurosurg.
2 0 1 9 ; 1 3 0 ( 6 ) : 1 8 5 3 – 1 8 61 .
29. Na YC, Chang WS, Jung HH, et al. Unilateral magnetic reso-
nance-guided focused ultrasound pallidotomy for Parkinson
disease. Neurology. 2015; 85(6): 549–551.
30. Horváth K, Aschermann Z, Ács P, et al. Minimal clinically
important difference on the Motor Examination part of MDS-
UPDRS. Parkinsonism Relat Disord. 2 0 1 5 ; 2 1 ( 1 2 ) : 1 4 2 1 – 1 4 2 6 .
31. Horváth K, Aschermann Z, Kovács M, et al. Minimal clini-
cally important differences for the experiences of daily liv-
ing parts of Movement Disorder Society-sponsored Unied
Parkinson’s Disease Rating Scale. Mov Disord. 2017; 32(5):
789–793.
32. Mestre TA, Beaulieu-Boire I, Aquino CC, et al. What is a
clinically important change in the Unied Dyskinesia Rating
Scale in Parkinson’s disease? Parkinsonism Relat Disord.
2 0 1 5 ; 2 1 ( 1 1 ) : 1 3 4 9 – 1 3 5 4 .
33. Fishman PS, Elias WJ, Ghanouni P, et al. Neurological ad-
verse event prole of magnetic resonance imaging-guided
focused ultrasound thalamotomy for essential tremor. Mov
Disord. 2018; 33(5): 843–847.
34. Krishna V, Sammartino F, Agrawal P, et al. Prospective
tractography-based targeting for improved safety of focused
ultrasound thalamotomy. Neurosurgery. 2019; 84(1): 160–168.
Disclosures
Funding for the study presented was provided by InSightec Inc.,
the Focused Ultrasound Foundation, and the Michael J. Fox Foun-
dation for Parkinson’s Research. Dr. Elias reports being a consul-
tant for Second Sight.
Author Contributions
Conception and design: Fishman, Eisenberg, Elias. Acquisition
of data: all authors. Analysis and interpretation of data: Fishman,
Eisenberg, Krishna, Elias, Cosgrove, Gandhi. Drafting the article:
Fishman, Eisenberg. Critically revising the article: Fishman,
Eisenberg, Krishna, Elias, Cosgrove, Gandhi. Reviewed submitted
version of manuscript: Fishman, Eisenberg, Krishna, Elias, Cos-
grove. Approved the final version of the manuscript on behalf of
all authors: Fishman. Administrative/technical/material support:
Elias, Cosgrove, Gandhi, Aldrich. Study supervision: Eisenberg,
Krishna, Elias, Cosgrove, Aldrich.
Correspondence
Paul S. Fishman: University of Maryland School of Medicine,
Baltimore. pfishman@som.umaryland.edu.
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