MRI Guidance of Focused

Ultrasound Therapy of Uterine

Jonathan Hindley1 Fibroids: Early Results
Wladyslaw M. Gedroyc1
Lesley Regan1
Elizabeth Stewart2 OBJECTIVE. The purpose of this study was to explore our hypothesis that MRI-guided
Clare Tempany2 focused ultrasound therapy for the treatment of uterine fibroids will lead to a significant re-
Kullervo Hynnen2 duction in symptoms and improvement in quality of life. We describe focused ultrasound
Nathan Macdanold2 therapy applications and the method for monitoring the thermal energy deposited in the fi-
broids, including the MRI parameters required, in a prospective review of 108 treatments.
Yael Inbar3
MATERIALS AND METHODS. Patients presenting with symptomatic uterine fibroids
Yacov Itzchak3
who attained a minimal symptom severity score and who would otherwise have been offered
Jaron Rabinovici3 a hysterectomy were recruited. Thermal lesions were created within target fibroids using an
Kevin Kim4 MRI-guided focused ultrasound therapy system. The developing lesion was monitored using
Jean-François Geschwind4 real-time MR thermometry, which was used to assess treatment outcome in real time to
Gina Hesley5 change treatment parameters and achieve the desired outcome.
Brian Gostout5 Fibroid volume, fibroid symptoms, and quality-of-life scores were measured before treat-
Tillman Ehrenstein6 ment and 6 months after treatment. Adverse events were actively monitored and recorded.
Sylvia Hengst6 RESULTS. In this study, 79.3% of women who had been treated reported a significant improve-
Miri Sklair-Levy7 ment in their uterine fibroid symptoms on follow-up health-related quality-of-life questionnaires,
Asher Shushan7 which supports our hypothesis. The mean reduction in fibroid volume at 6 months was 13.5%, but
nonenhancing volume (mean, 51 cm3) remained within the treated fibroid at 6 months.
Ferenc Jolesz2
CONCLUSION. This early description of MRI-guided focused ultrasound therapy treat-
ment of fibroids includes follow-up data and shows that, although the volume reduction is
moderate, it correlates with treatment volume and the symptomatic response to this treatment
Received February 23, 2004; accepted after revision is encouraging.
May 15, 2004.
1Departments of Magnetic Resonance Imaging and
Academic Obstetrics and Gynaecology, Interventional MR
Unit, St Mary's Hospital London and Imperial College
School of Medicine, Praed St., London W2 1NY, England.
Address correspondence to W. Gedroyc
(w.gedroyc@imperial.ac.uk).
T he ability of ultrasound energy to
interact with biologic tissues has
been recognized for many years.
The earliest medical uses of ultrasound were
the direction of the ultrasound beam [3]. The
tissue in the path of the ultrasound beam but
away from the focus is warmed, but not to le-
thal temperatures, avoiding tissue damage ex-
2Departments of Obstetrics and Gynaecology and therapeutic rather than diagnostic, and the cept at the focus.
Reproductive Biology and Radiology, Brigham and Women’s ability of ultrasound energy to cause a rise in The possibility that focused ultrasound ther-
Hospital and Harvard Medical School, Boston, MA 02115.
3
tissue temperature was recognized as long apy might be developed as a result of control-
Department of Radiology and Obstetrics and
Gynaecology, Sheba Medical Centre, Tel-Hashomer 91120,
ago as 1927 [1]. ling these heating phenomena was introduced
Israel. Ultrasound energy propagates harmlessly by Lynn et al. [4] in the middle of the last cen-
4
Department of Radiology, Johns Hopkins School of through tissue with small amounts of energy tury. Their work was closely followed by the
Medicine, Baltimore, MD 21287. being absorbed; this energy is deposited as first descriptions of focused ultrasound therapy
5
Department of Radiology and Obstetrics and heat but is dissipated by the cooling effects of as a noninvasive surgical technique in the brain
Gynaecology, Mayo Clinic, Rochester, MN 55905. perfusion and conduction. If, however, the ul- [5]. These early uses of focused ultrasound ther-
6 trasound beam carries a high level of energy apy for Parkinson’s disease were quickly super-
Department of Radiology, Charité Medical Centre and
Humboldt University, Virchow Clinic Campus, Berlin and is brought to a tight focus, energy carried seded by drug therapies, and further
D-13353, Germany.
by the beam is rapidly converted into heat and development of this technology was delayed
7
Department of Radiology, Hadassah Medical Centre, a rise in temperature is observed [2]. If the until a resurgence in the 1990s [6]. In recent
Jerusalem 52621, Israel.
temperature at the target spot can be raised to years, focused ultrasound therapy has been used
AJR 2004;183:1713–1719
more than 55°C, protein denaturation occurs, in urology for the treatment of benign prostatic
0361–803X/04/1836–1713 resulting in cell death and the creation of a ci- hyperplasia [7, 8] and in the management of
© American Roentgen Ray Society gar-shaped lesion of coagulative necrosis in cancer of the prostate [9, 10]. There has been an

AJR:183, December 2004 1713


increase in interest in the use of focused ultra-
sound therapy in the central nervous system
[11], and reports of soft-tissue tumors of the
liver and kidney being treated with focused ul-
trasound therapy are encouraging [12].
The use of focused ultrasound therapy has
been hampered by the difficulty in precise
targeting of the ultrasound beam and in re-
ceiving feedback regarding the thermal dam-
age created. Ultrasound guidance has been
used to target the ultrasound energy, but its
thermal sensitivity is limited and therefore
real-time thermometry is problematic.
MRI guidance of focused ultrasound ther-
apy has been explored during the past decade
[13], and it has several attractive attributes. The
excellent soft-tissue resolution afforded by
MRI enables accurate planning of the tissue to
be targeted. MRI parameters have an intrinsic
sensitivity to temperature change and therefore
can be adapted to provide accurate, near real-
time thermometry, and thermal damage cre-
ated by focused ultrasound therapy can be as-
sessed immediately using MRI.
The shift in proton resonant frequency with
a rise in temperature can be detected using
phase imaging [14]. If sequential phase-shift
MR images obtained during an ultrasound
sonication are compared with an image ob-
tained immediately before that sonication, the
changes in those images can be calibrated to
create a real-time thermal map of the increas-
ing temperature at and close to the target [15].
The MRI-guided focused ultrasound therapy
system used in this study (ExAblate 2000, In-
Sightec) integrates fully with a 1.5-T MRI sys-
tem (Signa, GE Healthcare) to enable focused
ultrasound therapy to be planned directly with
MR images and to give real-time MR ther-
mometry feedback of each sonication. This
system, or its earlier prototypes [16], has been
used to create lesions in several different body
tissues [17–19].
MRI-guided focused ultrasound therapy
for fibroids has been shown to be a safe and
feasible treatment for uterine fibroids [20].
This article describes the details of MRI-
guided focused ultrasound therapy for fi-
broids and presents the early results of this
procedure in addition to posttreatment
changes in fibroid volumes.
Materials and Methods
Patients who presented to gynecology clinics in
participating hospitals with symptomatic fibroids
and who would otherwise have been offered conven-
tional surgical therapy were considered for MRI-
guided focused ultrasound therapy. All patients were
1714
Hindley et al.
more than 18 years old and had stated that they had
no future child-bearing plans. Patients who had
other pelvic or uncontrolled systemic disease were
excluded, as were postmenopausal women, women
who weighed more than 250 lb (113 kg) (because
this is above the tolerance for the MRI gantry), and
women who were unable to communicate with the
researchers during the treatment. Women who were
unsuitable for MRI, such as those with cardiac pace-
makers, were also ineligible for the study. All in-
cluded women had undergone cervical smears as
required according to local guidelines. All women
had negative pregnancy tests both at recruitment and
immediately before the treatment. Women who had
changed their use of oral contraceptive preparation
or of nonsteroidal preparations to control menstrual
loss in the preceding 3 months were ineligible for
the study. Women who had undergone previous ab-
dominal surgery were examined for scars, and if
these were extensive or obviously in the path of the
ultrasound beam, these patients were excluded from
the study. Previous experience has shown that such
scars have high ultrasound absorption as compared
with regular tissue and may lead to pain and even
thermal damage at the skin surface.
This multicenter phase III clinical trial study
was performed according to principles of good
clinical practice as defined by the Declaration of
Helsinki. The participating sites were situated in
Europe [2], the United States [3], and Israel [2].
All sites had local approval from their ethics com-
mittees or institutional review boards. All patients
gave fully informed consent.
Suitable subjects were asked to complete the first
eight questions of a Uterine Fibroid Symptoms and
Quality of Life Questionnaire [21]. Responses are
scored from 1 (not distressed) to 5 (distressed a great
deal) and provide a screening tool for fibroid symp-
toms with possible results from 8 to 40. A minimum
score of 21 points was required for inclusion in the
study. Women who scored more than 21 on the
screening questionnaire and who were enrolled in
the study went on to complete the full Uterine Fi-
broid Symptoms and Quality of Life Questionnaire
form consisting of 37 questions.
Fig. 1.—Schematic representation of patient lying on ExAblate 2000 (InSightec) focused ultrasound system ready
to be placed into MRI unit. Ultrasound transducer found in sealed water bath within MR table.
The anatomic suitability for MRI-guided fo-
cused ultrasound therapy was assessed using ei-
ther MRI or sonography. A clear pathway from the
anterior abdominal wall to the fibroid without
passing through the bladder or the bowel was re-
quired by the protocol. Fibroids greater than 10 cm
in diameter or women with uteri greater than a 24-
week pregnancy equivalent were excluded from
this early study.
In total, 109 patients were treated at seven sites.
Fifty-two patients were treated within the United
States, and 57 patients were treated in Europe and
Israel. The mean age was 44.8 years (range, 30–
58 years; SD ± 4.9). The proportion of black (Afri-
can American, African, or African Caribbean) pa-
tients was 11%, and the mean body mass index
was 25.8 (range, 18.6–3.9; SD ± 5.2).
Of the fibroids treated, 22% were submucosal,
57% were intramural, and 21% were subserosal.
Those fibroids that were intramural required disrup-
tion to the myometrium in conventional surgery.
Before the treatment, each patient was asked to
shave her anterior abdomen from the umbilicus to
the level of the upper margin of the symphysis pu-
bis. It has been noted in previous studies [20] that
the presence of hairs in the sonication pathway
was associated with the formation of small air
bubbles that absorb the ultrasound energy and po-
tentially cause heating at the skin surface and even
skin burns.
An additional pregnancy test was performed on
the day of treatment. All patients were counseled re-
garding the lack of safety data for pregnancy after
MRI-guided focused ultrasound therapy and, in par-
ticular, the possible theoretic risk of uterine rupture
suggested by the experience of women who became
pregnant after undergoing laparoscopic laser myoly-
sis for fibroids [22, 23]. A urinary catheter was in-
serted before the patients were positioned on the
ExAblate 2000 focused ultrasound therapy system.
The patients were placed in the prone position on the
system with the fibroid placed above the transducer
(Fig. 1). To ensure that an acoustic pathway was
maintained, the transducer was positioned on the
MRI table in a sealed tank of degassed water. The
AJR:183, December 2004
 Focused Ultrasound Therapy of Uterine Fibroids

Fig. 2.—T2-weighted image of 38-year-old woman with symptomatic fibroids ready for
MRI-guided focused ultrasound therapy. She is lying prone on gel pad, which is above
focused ultrasound therapy transducer. Sonication pathway is superimposed on image
and has been angled craniocaudally to avoid small bowel close to uterus. Spot where
irreversible thermal damage is expected is also superimposed onto this image. Figure is
screen capture from ExAblate 2000 system (InSightec) at time of treatment.
Fig. 3.—Phase-shift image taken 22.2 sec after onset of sonication in 38-year-old
woman with symptomatic fibroids. High-signal area is visible due to rise in tem-
perature and can be seen along sonication pathway. Signal is greatest within tar-
get spot and it is this area that has been heated sufficiently to cause irreversible
damage. Heating of anterior pathway will be dissipated by perfusion during cool-
ing period between sonications. Figure is screen capture from ExAblate 2000 sys-
tem (InSightec) during treatment.

acoustic pathway then passed from the transducer
through a thin membrane into a gel pad on which the
patient lay.
Once positioned, the patient is placed into the
MRI scanner, and the patient’s position and the
sonication pathway is checked using MR images
(TR/TE, 3,600/102; matrix, 256 × 224; echo-train
length, 16; field of view, 36 cm; number of excita-
tions, 2; slice thickness, 4 mm; slice spacing, 1
mm; scanning time, approximately 2 min 2 sec)
(Fig. 2). The patient’s pelvis is imaged using T2-
weighted fast spin-echo images in the coronal, ax-
ial, and sagittal planes. These images are then
transferred to the workstation of the focused ultra-
sound therapy system in which the volume to be
ablated is defined by the physician. The system
plots the individual sonications and shows the
pathway that each sonication will require. These
pathways are carefully checked to ensure that they
do not pass through any structures that ought to be
avoided—such as the small bowel—that can fall in
front of the uterus. The far beam also is checked,
because some energy deposition remains after the
beam has passed through the fibroid, and struc-
tures such as large neurovascular bundles should
be avoided. The transducer can be tilted in all di-
rections by up to ± 20° to find a suitable pathway.
Once correct positioning has been achieved, the
target volume defined, and the treatment planned,
verification sonications are performed. These soni-
cations are subtherapeutic at low power, typically
10–70 W for 10–20 sec at 1.0 MHz. This low-
power sonication is monitored by a thermal map
[14] created in the coronal plane and repeated with
a thermal map in the sagittal or axial plane to en-
sure that both the lateral and longitudinal targeting
are as planned. Any errors are corrected before re-
peating the verification at a therapeutic power.
Once the operators are satisfied that the targeting
is accurate, they proceed to the treatment cycle.
The treatment itself consists of consecutive
sonications producing thermal lesions within the
previously defined target area to produce a single
large area of ablated tissue. Each sonication is
monitored using phase subtraction fast gradient-
echo proton resonance frequency-shift-dependent
techniques [14].
Typical parameters for these scans were TR/RE,
27/13 msec; flip angle, 30º; bandwidth, 5.68 kHz;
matrix, 256 × 128; field of view, 28 cm2; and slice
thickness, 3/5 mm.
The focused ultrasound therapy system enslaves
the MRI system to ensure that these sequences are
timed and positioned to coincide with the deposition
of ultrasound energy. A baseline image is created
immediately before the sonication, and subsequent
images are created every few seconds during a sin-
gle heating and early cooling phase (Fig. 3). The im-
ages are compared and presented as a thermal map
either as simple subtraction images or colorized with
a threshold temperature. A graph of the temperature
rise over time also is created to enable actual temper-
atures to be assessed at any point (Fig. 4). The time
and temperature information for each voxel also is
used to calculate the thermal dose, and those voxels
with the dose above a threshold value of 240 equiv-
alent min at 438°C are indicated on the images [15].
Thus, for each sonication a complete picture of the
tissue effect is created. Although a typical power of
140 W for 20 sec and 1.0 MHz and fibroids with an
average depth of 7 cm will lead to a rise in tempera-
ture to about 60°C in a fibroid, this rise is extremely
variable. It is this extreme variation in response, both
between and within fibroids, that makes real-time
thermal mapping so vital to the balance of safety and
efficacy in MRI-guided focused ultrasound therapy
ablation of fibroids.
Most sonication parameters can be changed in
response to the thermal maps being created. The
power applied can be increased or decreased.
Clearly, greater power will lead to the generation
of a higher temperature. The aim is to reach a
threshold temperature without approaching higher
temperatures at which control of the thermal effect
may be compromised. The time for which the en-
ergy is applied can be changed. Higher power for a
shorter time may compensate for the cooling ef-
fect of perfusion in a highly vascular fibroid. The
cooling time after each sonication can be assessed
by extending the thermal map into the cooling pe-
riod. The default cooling period of 90 sec may be
altered if the thermal map suggests that a return to
baseline temperature is achieved in a shorter time
or indeed if it requires more time.
The spot size can be altered in both diameter
and length so that the target volume can be ablated

AJR:183, December 2004 1715

 Hindley et al.

Immediately after completion of the treatment,

an MRI gadolinium-based contrast agent (Omnis-
can [gadodiamide], Nycomed Amersham or equiva-
lent) was given and the effectiveness of the
treatment was assessed by measuring the nonper-
fused area that had been created in the target fibroid.
We used the following scanning parameters: T1-
weighted fast-spoiled (radiofrequency-spoiled) gra-
dient-echo, TR/TE, 200/1.2; flip angle, 75°; matrix,
256 × 128; zero interpolated to 5122; number of
excitations, 2; field of view, 36; slice thickness, 4
mm; slice spacing, 1 mm; scan time, approximately
52 sec for 17 slices (Fig. 5). The MR images were
sent to a central core laboratory where the fibroid
volume and the nonenhancing volume were mea-
sured using a standard method as described below.
The fibroid was identified on each slice, and the
Fig. 4.—Graph of temperature against sonication time. Green represents average temperature within target vol-
ume; red represents absolute temperature at specified point. This sonication has resulted in maximum temper- area of the fibroid on each image was estimated by
ature of 91.8°C. This is higher than is necessary for irreversible damage so this information can be used to drawing around that area on the workstation and us-
shorten sonication time or reduce acoustic power for subsequent sonications. Figure is screen capture from Ex- ing the workstation software to calculate the defined
Ablate 2000 system (InSightec) during treatment. area. The areas of fibroid from each slice then were
summated and multiplied by the sum of the slice
with as few sonications as possible while main- All patients remained conscious during the thickness and the interval between slices to calcu-
taining accuracy and control. treatment and were given IV analgesia and con- late the volume. This was repeated for the volume
The sonication frequency also can be altered. scious sedation as required. They remained in that did not enhance after contrast. This volume is
Increasing the transducer frequency will result in constant verbal communication with the opera- known to correspond to the thermal lesion [20].
more energy being absorbed in the near field thus tors and were asked to report any pain or dis- Before treatment, the patients were assessed for
decreasing the chance of heat buildup in structures comfort. The patients held an emergency stop symptoms and for the impact that the fibroids had
such as bone and nerves in the far field; similarly, button at all times, which enabled them to halt made on their quality of life using the Uterine Fi-
decreasing the transducer frequency will reduce further sonication. broid Symptoms and Quality of Life question-
the near-field absorption, limiting the chance of Once all the sonications in a target volume had naire. This is a disease-specific questionnaire that
skin-heating, decreasing aberration caused by the been completed, additional fibroid treatment could was developed to assess the efficacy of fibroid
beam passing through irregular structures such as be planned, up to a maximum treatment time of 3 therapies [21]. This questionnaire was used before
the muscles of the anterior abdominal wall, and in- hr or a maximum ablated volume of 100 cm3 per treatment and at 3 and 6 months after MRI-guided
creasing the depth at which treatment is possible. fibroid and a total of 150 cm3 per patient with mul- focused ultrasound therapy. The primary end-point
In our study, up to four fibroids were treated in tiple treated fibroids. This maximum treatment hypothesis for the study was defined as an im-
any one patient. A minimum margin of 1.5 cm from volume was a stipulation of the regulatory authori- provement in the Uterine Fibroid Symptoms and
the edge of the ablated area to the edge of the uterus ties and may have led to suboptimal treatment in Quality of Life Questionnaire of 10 points for at
(serosal or mucosal surfaces) was stipulated. patients with large or multiple fibroids. least 50% of patients.

Fig. 5.—41-year-old woman with symptomatic uterine fibroids.

A, T2-weighted sagittal image shows fibroid before treatment.
B, T1-weighted gadolinium-enhanced sagittal image with
fat saturation of same fibroid obtained immediately after
MRI-guided focused ultrasound therapy shows area of re-
duced enhancement corresponding to area of ablation.
A B

1716 AJR:183, December 2004

 Focused Ultrasound Therapy of Uterine Fibroids
Thorough clinical examinations of the patients
were performed immediately after treatment and 1
week, 1 month, 3 months, and 6 months later. A
structured interview was used to ensure that com-
mon or expected adverse events were identified
and recorded. Serious adverse events as defined by
the protocol (see Table 1) were reported to the lo-
cal ethics committee or institutional review board
and to the regulatory authority (the U.S. Food and
Drug Administration, the Medical Devices Agency
in the United Kingdom, and the National Helsinki
Committee in Israel). Adverse events were classi-
fied according to whether they were device re-
lated, disease related, or incidental.
Results
One hundred nine patients were treated at
seven sites. Fifty two patients were treated in
the United States, and 57 patients were
treated in Europe and Israel (age range, 30–
58 years; mean, 44.8 ± 4.9 [SD] years). The
proportion of black (African American, Afri-
can, or African Caribbean) patients was
11%, and the mean body-mass index was
25.8 (range, 18.6–43.9; mean, ± 5.2).
Of the fibroids treated, 22% were submu-
cosal, 57% were intramural, and 21% were
subserosal. Intramural fibroids definitively
require disruption of the myometrium in
conventional surgery.
The mean fibroid volume in patients in
whom only a single fibroid was treated (n =
60) was 346 cm3, ± 245 cm3. In patients with
multiple fibroids being treated (n = 32), the
mean fibroid volume was correspondingly
less at 294 cm3, ± 188 cm3. The region of
treatment as defined by the operators before
sonication was 39 cm3 (± 27 cm3) for single
fibroids and a similar 38 cm3 (± 24 cm3) for
multiple fibroid treatments. The actual vol-
ume that received a thermal dose as mea-
sured using MR thermometry was 36 cm3
(± 18 cm3)—around 10% of the fibroid vol-
ume, and 32 cm3 (± 23 cm3)—about 11% of
the fibroid volume, for single and multiple
treatments, respectively.
The posttreatment contrast-enhanced im-
ages showed that the volume of the fibroid
that was nonperfused was greater than the
thermal dose volume at 86 cm3 (± 82 cm3)
for patients with single fibroids and 85 cm3
(± 88 cm3) for those who had multiple fi-
broids treated; 25% and 29% of the fibroids
volume, respectively.
The mean time that the patients were in the
MR scanner was 202 min (range, 90–370 min;
± 56). This time is variable because much of
the time is taken with positioning the patient
correctly to align the sonication pathway opti-
AJR:183, December 2004
mally with the transducer. It was noted early in
the study that the likelihood of the patient
complaining about leg or buttock pain in-
creased if the sacrum was in the direct far field
of the sonication pathway close to the target
area. This was presumed to be related to ther-
mal nerve stimulation in the far field where a
nerve passes in close proximity to the sacrum
(3–5 mm) and patients were positioned to
maximize the distance between the thermal
spot and the pelvis in the far field. This usually
can be achieved by positioning the patient with
the fibroid farther back so the transducer can
be angled caudad (Fig. 2).
The pain and discomfort as reported by
patients before, during, and immediately af-
ter treatment were assessed on a 4-point
scale, with 0 = none, 1 = mild, 2 = moderate,
and 3 = severe. The pain and discomfort
scores are outlined in Table 1. Although 16%
of patients complained that the pain was se-
vere during the procedure, only 1% and 7%
stated that they were in severe or moderate
pain, respectively, when questioned immedi-
ately after the treatment.
Nine serious adverse events were re-
ported; of these, only one was thought defi-
nitely to be device related. Five of the
patients had continued heavy menses in the
weeks after the treatment, requiring blood
transfusions. These were thought to be re-
lated to the underlying cause (i.e., fibroids)
rather than to the treatment. Two of these pa-
tients withdrew from the study to undergo
definitive treatment in the form of hysterec-
tomy. One patient reported pain and bleeding
after the treatment. These symptoms were
consistent with the patient’s symptoms be-
fore the treatment and were thought to reflect
a treatment failure rather than a device-re-
TABLE 1
Pain and Overall Discomfort Before, During, and Immediately After
MRI-Guided Focused Ultrasound Therapy
Before
Variable
No. % No.
Pain
None 99 91
Mild 6 6
Moderate 2 2
Severe 2 2
Overall discomfort
None 79 72
Mild 21 19
Moderate 7 6
Severe 2 2
lated adverse event. This patient underwent
uterine artery embolization. An additional
patient was asked to remain in the hospital
overnight because of nausea after the treat-
ment. This was a treatment-related event and
represents the only early posttreatment
admission but probably was related to the
opioid analgesia used rather than the MRI-
guided focused ultrasound therapy itself.
This patient recovered overnight and was
discharged the next day.
Two patients reported serious adverse
events that were not thought to be related to
the treatment in any way. One had a preexist-
ing brain tumor that progressed during the
period of follow-up. The brain tumor was not
thought to be related to the treatment and, in-
deed, the patient had excellent symptom re-
lief. The other patient required admission
with a urinary tract infection some 14 weeks
after the treatment. She made a full recovery
with antibiotic therapy, and it was thought
that the temporal relationship between the
treatment and the event made causation ex-
ceedingly unlikely.
One patient complained of leg and buttock
pain immediately after the treatment. Exami-
nation of the MR images showed that the
sciatic nerve was in the far field of the soni-
cation pathway. Detailed MR neurography
and electromyography studies, however,
failed to show any intrinsic nerve damage.
The patient subsequently made a complete
recovery by the follow-up visit using only
conservative measures. The patient also had
excellent symptomatic relief from fibroid-re-
lated symptoms and had made a complete re-
covery by the final follow-up visit. This case
led to a change in operator practice, and 4 cm
is now considered the minimum distance be-
During After
% No. %
19 18 79 75
36 33 19 18
36 33 7 7
17 16 1 1
32 30 72 68
35 33 27 25
31 29 7 7
9 8 0 0
1717

tween the spot and any major nerve bundles
that are in close proximity to a bone surface.
The other reported adverse events were mi-
nor and transitory.
At 6-month follow-up, the mean fibroid vol-
ume was reduced by 13.5%, ± 32. Although
the change in fibroid volume is modest, the av-
erage relative treatment volume was approxi-
mately 0% and the average nonperfused
volume at the end of the treatment was approx-
imately 25%, which should have an impact on
the modest shrinkage. In addition, a mean non-
perfused volume of 51.2 cm3 (± 62.2 cm3) ex-
ists on contrast-enhanced MR images at 6-
month follow-up. This may represent future
shrinkage and certainly represents nonviable
fibroid tissue.
Clinical follow-up shows that 79.3% of
patients achieved a greater than 10-point re-
duction in the Uterine Fibroid Symptoms
and Quality of Life Questionnaire score (n =
82, p < 0.0001), thereby proving the primary
endpoint hypothesis to be correct. The mean
reduction in the symptom severity score on
Uterine Fibroid Symptoms and Quality of
Life Questionnaire was in fact 27.3 points
(p < 0.0.0001; range, 18.75– -81.25 points),
and although most of this improvement oc-
curs in the first 3 months after treatment
(24.1 points), improvement continues between
3 and 6 months. The Uterine Fibroid Symptoms
and Quality of Life Questionnaire can be bro-
ken down into symptoms caused by mass ef-
fect—where improvement is 32.8 points (63.9/
100–31.2/100)—or bleeding symptoms—in
which improvement is reported to be 32.8
points (60.1/100–25.3/100).
Discussion
Uterine fibroids are a significant cause of
personal, social, and financial problems for
many women of childbearing age [24]. The
fibrosis may be asymptomatic, but when
women seek help they usually complain of
bleeding problems, typically heavy and pain-
ful menses, pressure symptoms (most often
urinary frequency and nocturia), or problems
related to fertility and pregnancy [25]. Tra-
ditionally, and still most commonly, treat-
ment for fibroids has been surgical. In recent
years, a number of less-invasive alternatives
to open hysterectomy and myomectomy
have been developed. The most popular of
these has been hysteroscopic resection of fi-
broids and uterine artery embolization.
Thermoablative treatments for uterine fi-
broids initially were developed using laser en-
1718
Hindley et al.
ergy delivered via the laparoscopic approach
[26]. This resulted in significant reduction in
fibroid size and resolution of symptoms but
was associated with significant side effects
[27, 28]. Many of these side effects seem to
have been negated by using an MRI-guided
technique for laser ablation with MR ther-
mometry giving real-time feedback to control
the thermal lesion created [29]. Despite the
low incidence of adverse events, MRI-guided
laser ablation of fibroids appears to remain an
effective therapy for the treatment of symp-
tomatic uterine fibroids [30].
To our knowledge, we have presented the
first short-term follow-up study using MRI-
guided focused ultrasound therapy for uter-
ine fibroids. This article outlines the radiologic
parameters involved in this new treatment
technique, and we have discussed the radio-
logic appearances of the uterus immediately
after and 6 months after this treatment. Our
study shows that, despite only a small
change in leiomyomata volume, MRI-guided
focused ultrasound therapy results in a
marked symptomatic improvement in most
patients at 6-month follow-up. This improve-
ment is equally marked for pressure symp-
toms and menstrual bleeding symptoms.
There seemed to be greater improvement re-
ported in the Uterine Fibroid Symptoms and
Quality of Life Questionnaire by patients who
had a greater proportion of the fibroid treated.
The average improvement in the scores was
25.8 at 6 months in those patients in which the
nonperfused volume on contrast-enhanced MR
images obtained immediately after treatment
represented less than 30% of the fibroid vol-
ume compared with an improvement of 31.7 in
patients who had more than 30% of the fibroid
treated. The volume of the fibroid treated was
limited by safety margins imposed by the regu-
latory authorities. These restrictions now have
been lifted, and the challenge remains to in-
crease the proportion of the fibroid that is ther-
mally ablated while avoiding thermal damage
outside the fibroid (i.e., damage to the myo-
metrium, endometrium, or serosal surface). We
believe that the real-time thermal map, which is
integral to the performance of focused ultra-
sound therapy using the technique described,
will allow this challenge to be met.
Analysis of the contrast-enhanced images
at 6 months reveals that in many cases the
volume of the fibroid that remains nonen-
hancing is significant and therefore is not
perfused. The mean nonperfused volume on
the 6-month contrast-enhanced scans was
51.2 cm3 (± 62.2 cm3). This nonperfused
area may represent an area of burn that has
yet to resolve. If this is the case, it is reason-
able to expect further shrinkage beyond the
6-month follow-up reported here. This is the
case with MRI-guided laser ablation of fi-
broids—an analogous technique also result-
ing in thermal damage [30]. Confirmation of
this hypothesis will result when longer fol-
low-up is available. If the nonperfused vol-
ume is not an unresolved burn, it is likely to
be collagen deposits formed as a result of the
burn. If this is the case, it may be that the im-
provement in fibroid symptoms is not, in
fact, volume dependent but caused by the de-
struction of the leiomyoma cells and the
breakdown of local secretory pathways. The
mechanisms by which fibroid symptoms are
mediated are not yet fully explained.
The lesion produced is shown as the non-
enhancing volume in the immediate posttreat-
ment contrast-enhanced MR images and is
larger that the volume expected from thermal
damage alone. The mechanism by which this
occurs has not been elucidated. It may be that
the temperature required for lethal damage in
fibroid tissue is lower than the 55°C threshold
that we believed was required, but this seems
unlikely because the expansion in the lesion
occurs laterally as well as in the direction of
the sonication pathway. This expansion may
be a result of the passage of mediators of apo-
ptosis from the lethally damaged cells to their
neighbors [20], as previously shown in gene
transfection experiments on leiomyomas
[31]. Other mechanisms may be responsible.
These may include the thermal occlusion of
internal fibroid blood vessels leading to areas
of infarction, as has been shown in animal
models [32]. The striking absence of pain af-
ter the procedure, in stark contrast to uterine
artery embolization, suggests that pain is not
a major component in the tissue destruction
caused by MRI-guided focused ultrasound
therapy. Local edema produced as a result of
the thermal damage may cause a pressure rise
within the fibroid. Although fibroids are not
strictly encapsulated, they tend to have well-
demarcated edges effectively producing the
same effect as a capsule so that edema within
the fibroid would cause a rise in pressure that
may be sufficient to explain the local exten-
sion of the lethal volume. Another possibility
is that the delay between sonications (approx-
imately 60–90 sec) was not sufficient to avoid
thermal buildup in the ultrasound beam path
over the course of multiple sonications [33].
Because the MR thermometry only measured
temperature changes and a new baseline im-
AJR:183, December 2004
 Focused Ultrasound Therapy of Uterine Fibroids
age was acquired before each sonication, this
slow buildup of heat would not be detected
during the treatment. However, this effect
could not be the full explanation because
cases existed in which regions were nonen-
hancing that were distant from the targeted
zone and clearly unheated. Further studies
will be needed fully to explain this phenome-
non, which may of course have a multifacto-
rial explanation. It is clear that the expansion
of the lesion is confined in all cases to the
treated fibroid with no examples of damage
to the myometrium or endometrium beyond.
We believe that MRI-guided focused ultra-
sound therapy provides a potentially important
new noninvasive and effective treatment for
uterine fibroids, particularly in women who
wish to avoid invasive or painful therapies. In
particular, the total lack of invasiveness of
MRI-guided focused ultrasound therapy com-
pared with all other fibroid procedures and the
fact that the procedure is performed as an out-
patient procedure make it particularly attrac-
tive for patients.
We also believe that MRI-guided focused
ultrasound therapy for fibroids may prove to
be an important model for the spread of this
noninvasive, precise, controlled, tissue-de-
structive technology to other disorders in a
variety of organs.
References
1. ter Haar G. Wood and Loomis: the physical and
biological effects of high frequency sound waves
of great intensity. Phil Mag 1927;4:7–14
2. ter Haar G. Therapeutic ultrasound. Eur J Ultra-
sound 1999;9:3–9
3. Lele PP. Threshold and mechanisms of ultrasonic
damage to organized animal tissues. Proceedings of a
symposium on biological effects and characterization
of ultrasound sources (June 1–3). Rockville, MD:
Ultrasound in Medicine & Biology, 1977;224–239
4. Lynn JG, Zwemer RL, Chick AJ, Miller AE. A
new method for the generation and use of focused
ultrasound in experimental biology. J Gen Phys-
iol 1942;26:179–193
5. Fry WJ, Fry FJ. Fundamental neurological re-
search and human neurosurgery using intense ul-
AJR:183, December 2004
trasound. IRE Trans Med Electron 1960;ME-
7:166–181
6. Ballantine HT Jr, Bell E, Manlapaz J. Progress and
problems in the neurological application of focused
ultrasound. J Neurosurg 1960;17:858–876
7. Uchida T, Muramoto M, Kyunou H, Iwamura M,
Egawa S, Koshiba K. Clinical outcome of high-
intensity focused ultrasound for treating benign
prostatic hyperplasia: preliminary report. Urology
1998;52:66–71
8. Madersbacher S, Kratzik C, Susani M, Marberger
M. Tissue ablation in benign prostatic hyperplasia
with high intensity focused ultrasound. J Urol
1994;152:1956–1960
9. Madersbacher S, Pedevilla M, Vingers L, Susani
M, Marberger M. Effect of high intensity focused
ultrasound on human prostate cancer in vivo.
Cancer Res 1995;55:3346–3351
10. Gelet A, Chapelon JY, Bouvier R, et al. Treatment
of prostate cancer with transrectal focused ultra-
sound: early clinical experience. Eur Urol 1996;
29:174–183
11. McDannold N, Moss M, Killiany R, et al. MRI-
guided focused ultrasound surgery in the brain:
tests in a primate model. Magn Reson Med
2003;49:1188–1191
12. ter Haar GR, Rivens IH, Moskovic E, Huddart R,
Visioli A. Phase 1 clinical trial of the use of focused
ultrasound surgery for the treatment of soft tissue
tumours. In: Ryan TP, ed. Surgical appliances of
energy. Bellingham, WA: International Society for
Optical Engineering, 1998: 270–276
13. Cline HE, Schenck JF, Hynynen K, Watkins RD,
Souza SP, Jolesz FA. MR-guided focused ultrasound
surgery. J Comput Assist Tomogr 1992; 16:956–965
14. Ishihara Y, Calderon A, Watanabe H, Okamoto K,
Suzuki Y, Kuroda K. A precise and fast tem-
perature mapping using water proton chemical
shift. Magn Reson Med 1995;34:814–823
15. Chung A, Jolesz FA, Hynynen K. Thermal dosim-
etry of a focused ultrasound beam in vivo by
MRI. Med Phys 1999;26:2017–2026
16. Hynynen K, Freund W, Cline HE, et al. A clinical
noninvasive MRI monitored ultrasound surgery
method. RadioGraphics 1996;16:185–195
17. Hynynen K, Pomeroy O, Smith DN, et al. MR
imaging-guided focused ultrasound surgery of fi-
broadenomas in the breast: a feasibility study. Ra-
diology 2001;219:176–185
18. Gianfelice D, Khiat A, Amara M, Belblidia A, Bou-
langer Y. MR imaging guided focused US ablation of
breast cancer: histopathologic assessment of effec-
tiveness—initial experience. Radiology 2003;227:
849–855
19. Tempany CM, Stewart EA, McDannold N, Quade
BJ, Jolesz FA, Hynynen K. MR imaging guided
focused ultrasound surgery of uterine leiomyo-
mas: a feasibility study. Radiology 2003;226:
897–905
20. Stewart EA, Gedroyc WM, Tempany CM, et al.
Focused ultrasound treatment of uterine fibroid
tumors: safety and feasibility of a noninvasive
thermoablative technique. Am J Obstet Gynecol
2003;189:48–54
21. Spies JB, Coyne K, Guaou Guaou N, Boyle D,
Skyrnarz-Murphy K, Gonzalves SM. The UFS-
QOL, a new disease-specific symptom and health-
related quality of life questionnaire for leiomy-
omata. Obstet Gynecol 2002;99:290–300
22. Arcangeli S, Pasquarette M. Gravid uterine rup-
ture after myolysis. Obstet Gynecol 1997;89:857
23. Vilos GA, Daly LJ, Tse BM. Pregnancy outcome
after laparoscopic electromyolysis. J Am Assoc
Gynecol Laparosc 1998;5:289–292
24. Buttram VC Jr, Reiter RC. Uterine leiomyomata:
etiology, symptomatology, and management. Fer-
til Steril 1981;36:433–445
25. Stewart EA. Uterine fibroids: seminar. Lancet
2001;357:293–298
26. Goldfarb HA. Nd:YAG laser laparoscopic coagu-
lation of symptomatic myomas. J Reprod Med
1992;37:636–638
27. Donnez J, Squifflet J, Polet R, Nisolle M. Laparo-
scopic myolysis. Hum Reprod Update 2000;
6:609–613
28. Nisolle M, Smets M, Malvaux V, Anaf V, Donnez
J. Laparoscopic myolysis with the Nd: YAG laser.
J Gynecol Surg 1993;9:95–99
29. Law PA, Gedroyc WM, Regan L. Magnetic reso-
nance guided percutaneous laser ablation of uter-
ine fibroids. Lancet 1999;354:2049–2050
30. Hindley JT, Law PA, Hickey M, et al. Clinical out-
comes following percutaneous magnetic resonance
image guided laser ablation of symptomatic uterine
fibroids. Hum Reprod 2002;17:2737– 2741
31. Niu H, Simari RD, Zimmermann EM, Christ-
man GM. Nonviral, vector-mediated thymidine
kinase gene transfer and ganciclovir treatment
in leiomyoma cells. Obstet Gynecol 1998:91:
735–740
32. Hynynen K, Colucci V, Chung A, Jolesz F. Non-
invasive artery occlusion using MRI guided fo-
cused ultrasound. Ultrasound Med Biol 1996;22:
1071–1077
33. Damianou C, Hynynen K. Focal spacing and
near-field heating during pulsed high temperature
ultrasound therapy. Ultrasound Med Biol 1993;
19:777–787
1719