INTRODUCTION
Magnetic resonance imaging-guided focused ultrasound (MRgFUS) has gained considerable
attention in recent years as a promising, non-invasive therapeutic modality for various
medical conditions, including movements disorders, neuropathic pain, and neoplasm.[1 ] This innovative treatment offers the potential for precise tissue ablation with
minimal damage to surrounding structures, making it an appealing option for patients
who are unsuitable for or prefer to avoid invasive surgery.[2 ]
Essential tremor (ET) is the most common movement disorder. Individuals frequently
experience debilitating symptoms that substantially impair their quality of life.[3 ]
[4 ] Medications such as primidone and propranolol are first-line therapies, but a significant
number of ET patients eventually become unresponsive to pharmacological treatments.[5 ]
Recently, MRgFUS thalamotomy has emerged as an innovative treatment for patients with
medically refractory ET.[6 ] Following the publication of a landmark randomized controlled trial that demonstrated
the safety and efficacy of MRgFUS thalamotomy in ET, other centers have reported sustained
long-term benefits from the procedure.[7 ]
[8 ]
[9 ]
[10 ] Despite the rapidly rising number of indications, this technology is still not widely
available. Recently, the first medical unit offering MRgFUS treatments was established
in Portugal, constituting an expansion of the current evidence base into a novel clinical
and geographical context.
This retrospective observational study aims to present the results of the first five
patients with medically refractory ET who underwent MRgFUS treatment at this pioneering
medical unit in Portugal. We will discuss the clinical outcomes, safety profile, and
improvements in functionality and quality of life associated with the procedure for
these patients.
METHODS
Patients
We conducted a retrospective chart review for the first 5 patients who underwent unilateral
MRgFUS thalamotomy of the ventral intermediate (Vim) nucleus to treat medically refractory
ET at our FUS Medical Unit, using a 650-kHz system, Exablate Neuro 4000 Type 1.1 (INSIGHTEC
Ltd., Tirat Carmel, Israel).
A neurologist specializing in movement disorders confirmed the ET diagnosis according
to established criteria.[11 ] Refractory tremor was defined as disabling tremor persisting after at least two
adequate treatment regimens. A Vim thalamotomy was performed on the opposite side
of the patient's preferred hand.
All patients were eligible for the procedure, with no contraindications such as cognitive
decline, neurodegenerative diseases, brain tumors, vascular malformations, severe
unstable medical conditions, previous brain procedures, skull density ratio (SDR)
of < 0.35, or contraindications for magnetic resonance imaging (MRI). Informed consent
for the procedure was obtained as part of standard clinical care, in accordance with
the Helsinki declaration. The requirement for additional consent was waived due to
its nature as a retrospective study.
Clinical procedures
A comprehensive chart review was conducted to collect demographic data (age, gender),
disease characteristics (family history, duration, dominant hand), treatment parameters
(SDR, skull area, number of high intensity focused ultrasound elements activated,
sonication parameters including total number, mean and maximum temperature, and mean
and maximum energy delivered), and follow-up information (tremor scores, functional
status, quality of life, and adverse events).
Tremor severity was assessed using the clinical rating scale for tremor (CRST), which
ranges from 0 to 160 points, with higher scores indicating greater disability.[12 ] Additionally, the treated hand's score was calculated separately with a composite
tremor score (max score: 32; where higher scores indicate more severe tremor) derived
from CRST part A (resting, postural, and action/intention components of upper extremity
[UE] tremors) and part B (handwriting; drawing; A, B, and C; and pouring) in the hand
contralateral to the thalamotomy.
The functional status was assessed using the CRST part C (max score: 32), with higher
scores indicating more severe tremors. The score consists of 8 subscores, each evaluating
various activities, such as speaking, eating, drinking, personal hygiene, dressing,
writing, working, and social interactions.
Quality of life in ET patients was measured using the Quality of Life in Essential
Tremor Questionnaire (QUEST), with scores ranging from 0 to 120, and higher ones indicating
lower quality of life.[13 ] This is a patient self-report questionnaire designed to evaluate the impact of tremor
symptoms on five distinct aspects of quality of life: communication, work and finances,
hobbies and leisure activities, physical activities, and psychological wellbeing.
Adverse events were evaluated based on the Clavien-Dindo classification, which range
from 1 to 5, with higher scores indicating more severe events.[14 ]
These assessments were conducted at baseline, and at 1, 3, and 6 months, depending
on each patient's follow-up duration. The most recent evaluation was used to calculate
the tremor scores and QUEST outcomes.
Imaging procedure
Preplanning brain computed tomography (CT) and MRI exams were performed on patients
who were clinical candidates. The CT scan followed a special protocol with 1-mm slice
thickness reconstructions and specific post-processing to determine skull density
ratio (SDR), which is a limiting factor in successfully producing a thermal lesion.
Furthermore, MRI exam also followed a specific protocol with high resolution T2 sagittal
images, axial T2 fast spoiled gradient-echo (FSGRE) and fluid attenuated inversion
recovery (FLAIR) images, isotropic (volumetric) sequences, namely 3D T2 Cube, 3D T1
MP-RAGE and 3D fast gray matter acquisition T1 inversion recovery (FGATIR), besides
an axial diffusion-weighted imaging (DWI) with mesure of ADC map.
Patients with SDR > 0.35 and with no lesions that contraindicate the ablation procedure
detected either by CT or MRI (e.g. brain tumors, acute ischemic lesion, and arterial
or venous malformations) were considered confirmed candidates to the MRgFUS ablation
procedure.
After MRgFUS, a control MRI scan was performed 12 to 24 hours after the procedure
to evaluate the ablation lesion and its vasogenic oedema. The examination protocol
included a volumetric 3D sagittal T1 MPRAGE with reconstructions in coronal and axial
plans, axial T2 FSGRE and FLAIR with fat saturation (FS), as well as DWI (b50, b500,
b1000) with ADC map.
Surgical procedure
All procedures were performed in a SIGNA Architect AIR Edition (GE Medical Systems,
Milwaukee, WI, USA) 3-T MRI system, using an Exhalate Neuro 4000 Type 1.1 (INSIGHTEC,
Haifa, Israel). After head shaving, patients were placed in a stereotactic head frame
under local anesthesia. A membrane was carefully attached to the head as low as possible
to prevent air bubbles between it and the skin, coupled to an MRI-compatible ultrasound
transducer using degassed water. Vim nucleus localization was defined at the level
of the most posterior 1/4 of the anteromesial distance anterior to the posterior commissure
(PC), and 14 mm lateral to the midline or 11.5 mm lateral the wall of the third ventricle
in cases of ventriculomegaly. After real-time MRI targeting, acoustic energy was delivered
with slowly increasing intensity to reach temperatures sufficient for tissue ablation
(approximately 55–60° C).
Based on the tremor reduction, a submillimeter target modification was possible, and
done in cases in which the tremor was not sufficiently reduced as expected according
to the energy deliver with the first target verification sonication. After moving
the target, verification with low energy test sonications was performed, followed
by neurology assessment concerning tremor reduction and eventual adverse effects.
Only after good response (tremor reduction without adverse effects) did sonication
proceed to the treatment level, with higher energy delivery. Normally, two or three
treatments were enough to produce the desired tremor reduction, finalizing the ablation
itself. After the procedure, the transducer and head frame were removed. An MRI was
performed 12 to 24 h after the procedure. Patients were discharged 24 h after the
procedure.[6 ]
Statistical analysis
Continuous variables are presented as mean ± standard deviation (range), and categorical
variables as frequency (%). Tremor score comparisons were conducted using a paired
t-test. The threshold for statistical significance in group comparisons was set at
p < 0.05. Percentage of changes in tremor and quality of life were calculated by subtracting
pre- from posttreatment scores, then dividing the result by the pretreatment score,
and multiplying by 100. Statistical analyses were performed using the SPSS Statistics
for Windows, (IBM Corp., Armonk, NY, USA), version 25.0.
RESULTS
Demographics
A total of 5 cases were included in the study ([Table 1 ]). The mean patient age was 65.4 ± 20.5 (26–84) years, and 60% were male. All patients
had a positive family history. The mean duration of disease was 17.4 ± 5.6 (10–24)
years, and the dominant hand for all patients was the right. According to the patients'
personal preference, in 4 patients, the thalamotomy was performed on the left side,
and in the remaining one, it was on the right side. Regarding follow-up durations,
2 patients reached 6 months, 1 patient had 3 months, and 2 patients had reached 1
month at the time of the study ([Table 1 ]).
Table 1
Demographic, clinical characteristics and results
Patient
Age (years)
Gender
Family history
Disease duration (years)
Dominant hand
Laterality thalamotomy
Follow-up (months)
CRST total baseline
CRST total end follow-up
Improvement (%)
1
84
M
Yes
24
R
L
6
67
26
61
2
70
F
Yes
15
R
L
6
66
34
49
3
68
F
Yes
10
R
L
3
51
16
69
4
26
M
Yes
14
R
R
1
52
19
63
5
79
M
Yes
24
R
L
1
56
18
67
(65.4 ± 20.5)
(17.4 ± 5.6)
(58.4 ± 6.8)
(22.6 ± 6.6)
62 ± 7% (p < 0.05)
Abbreviations: F, female; M, male; R, right; L, left; CRST, Clinical Rating Scale
for Tremor.
Tremor scores, functionality, and quality of life
The MRgFUS thalamotomy led to significant improvements (reductions) in both the CRST
score and composite score for the treated hand. The mean total score decreased by
62 ± 7% (p < 0.05), going from 58.4 ± 6.8 at baseline to 22.6 ± 6.6 in the last evaluation ([Table 1 ]). Additionally, the mean composite score for the treated hand decreased by 73 ± 10%
(p < 0.05), moving from 18.2 ± 3.7 at baseline to 5.4 ± 2.5 in the last evaluation.
All patients experienced improvements in functionality and quality of life. The mean
CRST part C score dropped by 72 ± 9% (p < 0.05) from 17.8 ± 4.7 at baseline to 4.8 ± 1.6 in the last evaluation, while the
mean QUEST score declined by 52 ± 7% (p < 0.05) from 39.6 ± 6.9 at baseline to 19.2 ± 4.2 in the last evaluation.
Treatment parameters
The mean SDR was 0.60 ± 0.03 (0.56–0.64), the mean number of sonications performed
per treatment was 7.8 ± 1.6 (6–10), the mean highest acoustic energy used was 11,019.8 ± 2,498.5 J
(8,500–15,249), the mean number of high-temperature therapeutic sonications (> 55°
C) was 2.2 ± 0.4 (2–3), and the mean number of low-temperature therapeutic ones (50–54°
C) was 1.2 ± 0.4 (1–2), as shown in [Table 2 ].
Table 2
Treatment parameters
Patient
SDR
Sonications
per treatment (n)
Highest acoustic
energy used (J)
Low temperature
therapeutic sonications (50–54°C)
High temperature
therapeutic sonications (> 55°C)
1
0.64
8
9,372
1
2
2
0.58
10
12,628
2
3
3
0.56
6
8,500
1
2
4
0.64
9
9,350
1
2
5
0.58
6
15,249
1
2
0.60 ± 0.03
7.8 ± 1.6
11,019.8 ± 2,498.5
1.2 ± 0.4
2.2 ± 0.4
Abbreviations: SDR, skull density ratio; J, Joules.
Imaging results
In [Figure 1 ], the dark spot represents the submillimeter hemosiderin deposition as a result of
microhemorrhage in the center of the ablation lesion, which is expected in a successful
treatment, proving that the lesion is consolidated.
Figure 1 Intra MRgFUS (A ) axial T2 fast spoiled gradient-echo (FSGRE) image and (B ) detail acquired immediately after last sonication (patient still with the FUS helmet
equipment positioned), showing a millimetric ablation lesion in the left thalamus
on the Vim nucleus, with a very low signal intensity focus (dark spot) in the lesion
core.
In [Figure 2 ], the blooming artifact grossly overestimates the size of the microhemorrhage, which
is more realistically depicted on a DWI ([Figure 2D ]), as the central dark spot on the high signal lesion. For a successful ablation
([Figure 2 A, B, C ] and [D ]), it is expected to create a submillimeter microhemorrhage ([Figure 2C ]) on the core of the lesion, confirming it is a consolidated lesion. In [Figure 2D ], DWI B1000, the lesion itself appears with high signal by diffusion restriction,
corresponding to the cytotoxic oedema which represents necrosis. If we compare the
images in [Figures 2B ] FLAIR, and [2D ], it is easy to understand that most of the high signal seen on the FLAIR image does,
indeed, correspond to the vasogenic oedema (transient) and not to the cytotoxic one
(necrosis), as is latter shown on DWI image in [Figure 2D ].
Figure 2 The MR axial images acquired 24 h after HIFU treatment (A ) T1 weighted; (B ) FLAIR; (C ) T2*; and (D ) DWI (B1000) images, showing the millimetric ablation lesion on the left Vim (A and
D), the ablation lesion surrounded by vasogenic oedema (B) and the hemosiderin deposit
with its blooming artifact highlighted by the susceptibility-weighted T2* sequence
(C).
Adverse events
No severe adverse events were observed throughout the study period. All adverse events
during and following the procedure were mild (Clavien-Dindo classification, grade
1) and transient. At the time of the last evaluation, no patients reported any side
effects ([Table 3 ]).
Table 3
Adverse events
Patient
Intervention
1 month
3 months
6 months
1
Nausea (1)
None
None
None
2
Nausea (1)
Tingling in the hand (1)
None
None
3
Dizziness (1)
Unsteady gait (1)
None
4
Headache (1)
Dizziness (1)
None
5
Headache (1)
None
DISCUSSION
This study presents the results of the first five patients with medically refractory
ET treated at the inaugural Portuguese MRgFUS medical unit. All patients experienced
a significant improvement in tremor intensity, reaching a 73% reduction when considering
the treated hand. This improvement is reflected in the enhanced functionality and
quality of life for these patients. Our findings are consistent with the significant
tremor reduction reported by Elias et al.,[7 ] providing further evidence of the efficacy of MRgFUS thalamotomy, also observed
in the 5-year follow-up study by Cosgrove et al.[3 ]
Similar to the findings by Sinai et al.[9 ] and Lak et al.,[10 ] our study observed only mild and transient adverse events. No serious or persistent
adverse events, such as hematomas, occurred in any patients.
In our view, these results further substantiate the efficacy and safety of the MRgFUS
Vim thalamotomy for refractory ET.
The major limitations of this study include its small sample size, limited follow-up
duration, and the single-center design. Further research with a larger number of patients
is necessary to assess the long-term outcomes at our center and to identify potential
predictors of procedural success.
In conclusion, the initial results from Portugal's first MRgFUS medical unit, which
involved five patients with refractory ET, indicate promising outcomes. Patients demonstrated
improvements in their quality of life and experienced minimal adverse events. These
findings contribute to the growing body of literature supporting the efficacy and
safety of MRgFUS as a viable treatment option for patients with medication-resistant
ETs. Furthermore, studies have demonstrate its effectiveness and safety, with no associated
persistent adverse effects,which enables qualifying patients to have their second
side treated at least 9 months after their first side treated.[15 ] Long-term follow-up of these patients is crucial in assessing the durability of
MRgFUS treatment effects, identifying the potential late-onset side effects, and refining
our understanding of optimal treatment parameters and patient selection criteria.
It is likely that the indications for MRgFUS will continue to expand in the following
years, such as tremor-dominant Parkinson disease[16 ] and motor complications of Parkinson disease.[17 ]
In our experience, lack of awareness about MRgFUS and its indications among patients
and referencing physicians is still a significant problem, and it is possible that
many patients are not receiving the best possible treatment. Establishing Portugal's
first MRgFUS medical unit represents a significant advancement in providing state-of-the-art,
non-invasive therapeutic options to patients with ET, as well as and enriching the
burgeoning global discourse with critical empirical data on MRgFUS thalamotomy.
