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    Interventional procedure overview of MRI-guided focused ultrasound thalamotomy for treating moderate to severe tremor in Parkinson's

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    Evidence summary

    Population and studies description

    This interventional procedures overview is based on 261 people from 6 case series, 1 RCT (reported in 2 papers) and 1 systematic review. This is a rapid review of the literature, and a flow chart of the complete selection process is shown in figure 1. This overview presents 9 studies as the key evidence in table 2 and table 3, and lists 21 other relevant studies in table 5.

    One systematic review (Lin 2021) did a network metanalysis based on a Bayesian framework to compare the efficacy of DBS and MRgFUS in parkinsonian tremor. Twenty four studies were included in the analysis, comprising data from 784 people, 77 of whom had treatment with MRgFUS thalamotomy.

    One RCT, which was reported in 2 articles (Bond 2017 and Sperling 2018) assessed safety and efficacy at 12-month follow up of unilateral FUS thalamotomy for people with TDPD, accounting for placebo response. Assessments were double-blinded through the primary outcome and the placebo group was offered open-label treatment after unblinding.

    One prospective study (Zur 2020) of 56 people (17 with PD and 39 with ET) looked at tremor relief and structural integrity after MRgFUS thalamotomy in tremor disorders. People with ET or PD having thalamotomy were prospectively recruited between March 2016 and October 2018. Tremor and quality of life were assessed before, 1 month after, and 6 months after thalamotomy.

    A prospective study of 18 people with PD investigated cognitive outcomes after focused ultrasound thalamotomy for tremor (Saporito 2023).

    Three prospective studies (Yamatoto 2021, Sinai 2022 and Chua 2023) studied the long-term results of focused ultrasound thalamotomy in TDPD. In Sinai 2022, the primary aim of treatment was to relieve arm tremor. For people with other tremors such as leg, chin, and head tremor, the aim was to relieve those tremors as well.

    One retrospective study (Lak 2022) was a single centre study with 160 procedures of MRgFUS thalamotomy (10 procedures for people with PD, Lak 2022).

    Table 2 presents study details.

    Figure 1 Flow chart of study selection

    Table 2 Study details

    Study no.

    First author, date

    country

    Patients (male: female)

    Age

    Study design

    Inclusion criteria

    Intervention

    Follow up

    1

    Lin 2021

    N= 784 (77 for MRgFUS thalamus)

    NA

    Systematic review and network meta-analysis of 24 studies

    People with clinical diagnosis of PD

    MRgFUS

    Follow-up ranging from 1 month to 48 months

    2 and 3

    Bond 2017, US

    Sperling 2018, US

    N=27 (20 intervention and 7 placebo)

    (26:1)

    Median age = 67.8 years (IQR, 62.1-73.8 years)

    Randomised controlled trial

    People with tremor dominant Parkinson's disease

    Unilateral FUS thalamotomy

    12 months

    4

    Zur 2020

    Israel and US

    N=56 (17 PD and 39 ET)

    (13:4)

    Mean age (SD) for those with PD: 65 (8) years

    Prospective case series

    Individuals undergoing MRI-guided focused US thalamotomy with disabling tremor despite at least two full-dose therapeutic medication trials

    MRI-guided focused US thalamotomy

    6 months

    5

    Lak 2022

    N=160 (Laterality of Thalamotomy, Left, n = 128; Right, n = 32)

    (109:51)

    N=150 (medically refractory essential Tremor)

    N=10 (tremor predominant Parkinson's disease)

    Mean age (SD)= 75.0 (7.50) Years (range: 48 to 93)

    Case series

    People who underwent unilateral MRgFUS thalamotomy for medically refractory ET or tremor predominant Parkinson's disease from March 2016 to January 2021

    MRgFUS thalamotomy

    Mean= 14 months (range: 1 to 48 months)

    6

    Saporito 2023, Italy

    N=40 (22 ET and 18 PD)

    (38:2)

    Mean age (SD)= 67.7 (10.7)

    Prospective case series

    Adults who underwent unilateral MRgFUS thalamotomy

    MRgFUS thalamotomy

    2 years

    7

    Sinai 2022, Israel

    N=26

    (20:6)

    Median age = 60 years (range 46 to 79)

    Prospective case series

    People with tremor dominant Parkinson's disease

    MRgFUS VIM-thalamotomy

    Median follow-up= 36 months, range 12 to 60 months

    8

    Chua 2023, US

    N=48

    (38:10)

    Mean age (SD, range) = 73.27 (7.31, 56–90)

    Case series

    People with tremor dominant Parkinson's disease

    MRgFUS VIM-thalamotomy

    3 years

    9

    Yamatoto 2021 Japan

    N=11

    (5:6)

    Mean age= 71.6 years

    Prospective case series

    People with medication-refractory TDPD (TDPD was defined as tremor-dominant with tremor dominant/postural instability and gait difficulty ratio >1.15. This was calculated from the UPDRS in the "on" state)

    VIM thalamotomy with Transcranial MR-guided FUS

    1 year

    Table 3 Study outcomes

    First author, date

    Efficacy outcomes

    Safety outcomes

    Lin 2021

    UPDRS III-Tremor (medication-off):  

    Mean difference compared to baseline: 

    • MRgFUS (internal globus pallidus)=4.90 (95% CI 0.81 to 9,06) 

    • MRgFUS (ventral intermediate nucleus) =5.62 (95% CI 1.41 to 9.57) 

    • DBS (internal globus pallidus)=3.06 (95% CI 1.05 to 5.25) 

    • DBS (ventral intermediate nucleus)=6.64 (95% CI 4.49 to 8.93) 

    • DBS (combined subthalamic nucleus and caudal zona incerta) =6.92 (95% CI 1.72 to 12.09) 

    Pedunculopontine nucleus was the only DBS site that did not show a statistically significant change from baseline. 

     

    UPDRS III-Tremor (medication-on): 

    Mean difference compared to baseline: 

    • MRgFUS (internal globus pallidus)=3.54 (95% CI 1.54 to 5.74) 

    • MRgFUS (ventral intermediate nucleus) =2.54 (95% CI 1.11 to 4.18) 

    • DBS (internal globus pallidus)=1.64 (95% CI 0.06 to 3.32) 

    • DBS (combined pedunculopontine nucleus and caudal zona incerta)=2.95 (95% CI 0.31 to 5.80) 

    • DBS (caudal zona incerta)=3.34 (95% CI 1.66 to 4.78) 

     

    UPDRS III-Total (medication-off):  

    Mean difference compared to baseline: 

    • MRgFUS (internal globus pallidus)=13.46 (95% CI 2.46 to 25.10)  

    • MRgFUS (ventral intermediate nucleus) =18.62 (95% CI –2.09 to 38.79) 

    • DBS (internal globus pallidus)=15.24 (95% CI 5.79 to 24.82) 

    • DBS (ventral intermediate nucleus)=5.42 (95% CI –9.52 to 20.61) 

    • DBS (combined subthalamic nucleus and caudal zona incerta)=12.76 (95% CI –12.73 to 38.22) 

     

    UPDRS III-Total (medication-on): 

    Mean difference compared to baseline: 

    • MRgFUS (internal globus pallidus)=11.47 (95% CI 5.90 to 17.01) 

    • MRgFUS (ventral intermediate nucleus) =11.63 (95% CI 3.67 to 19.06) 

    • DBS (internal globus pallidus)=2.24 (95% CI  –2.34 to 6.60) 

    • DBS (combined pedunculopontine nucleus and caudal zona incerta)=11.65 (95% CI 0.73 to 22.39) 

    • DBS (caudal zona incerta)=7.62 (95% CI 0.42 to 14.71) 

     

    In the network meta-analysis, DBS and MRgFUS showed similar efficacy for tremor suppression (assessed using UPDRS) 

    GPi-MRIgFUS:

    Mild headache =10

    Back pain =4

    Dysarthria and grade III right motor hemiparesis =1 scalp hypoesthesia =1

    speech difficulties =7

    VIM-MRIgFUS:

    During sonications:

    headache =3

    dizziness =2

    vertigo =4

    lip paraesthesia =1

    Lasted from procedures:

    hypogeusia =1

    subjective unsteady feeling when walking =1 disturbance when walking tandem =1

    Thalamotomy Related:

    Finger paraesthesia:

    Transient =7

    Persistent =1

    Orofacial paraesthesia:

    Transient =1

    Persistent =4

    Ataxia:

    Transient =8

    Persistent =1

    Hemiparesis:

    Transient =2

    Persistent =2

    Dysmetria, transient =1

    Mild vocal change, persistent =1

    MRI or Ultrasonography Related, All Transient:

    Scalp numbness =1

    Headache =12

    Dizziness or vertigo =8

    Head pain or heat sensation =3

    Stomach pain or nausea or emesis =4

    Periorbital swelling =2

    Neck or back or shoulder pain =4

    Decline in mental status =1

    Pin site pain =1

    Anxiety =1

    Bond 2017 and Sperling 2018

    Median scores (IQR) for CRST, UPDRS, quality of life, neuropsychological and LEDD

    CRST:

    Tremor subscore (CRST A+B), treated hand (FUS group):

    Baseline = 17 (10.5 to 27.5)

    1 month = 4 (1.5 to 11.5)

    3 months = 4.5 (3.0 to 16.0)

    1 Year = 5.0 (2.0 to 14.0)

    Total CRST (FUS group):

    Baseline = 41.5 (28.0 to 65.0)

    1 month = 14.5 (7.0 to 43.5)

    3 months = 18.0 (8.0 to 52.0)

    1 Year = 18.0 (7.0 to 42.0)

    Tremor subscore (CRST A+B), treated hand (sham group):

    Baseline = 23 (14 to 27)

    1 month = 15 (12 to 17)

    3 months = 17 (12 to 21)

    Total CRST (sham group):

    Baseline = 48 (43 to 62)

    1 month = 39 (27 to 54)

    3 months = 37 (29 to 53)

    UPDRS:

    Total UPDRS (FUS group):

    Baseline = 37.5 (32.5 to 44.5)

    1 month = N/A

    3 months = 27.0 (11.5 to 41.0)

    1 Year = 19.5 (9.0 to 36.0)

    Total UPDRS (sham group):

    Baseline = 39 (25 to 53)

    1 month = N/A

    3 months = 24 (21 to 50)

    Quality of life:

    PDQ-39 (FUS group):

    Baseline = 21.2 (12.6 to 32.0)

    1 month = N/A

    3 months = 7.9 (4.8 to 23.5)

    1 Year = 7.5 (3.4 to 22.2)

    CRST disability (part C) (FUS group):

    Baseline = 13.0 (10.0 to 18.5)

    1 month = 2.0 (0.5 to 8.0)

    3 months = 3.5 (1.0 to 10.0)

    1 Year = 2.5 (0 to 11.0)

    PDQ-39 (sham group):

    Baseline = 25.0 (14.8 to 27.7)

    1 month = N/A

    3 months = 17.4 (1.8 to 20.6)

    CRST disability (part C) (sham group):

    Baseline = 17 (13 to 20)

    1 month = 16 (11 to 18)

    3 months = 16 (13 to 18)

    Neuropsychological:

    MoCA (FUS group):

    Baseline = 25.5 (23.0 to 28.0)

    1 month = N/A

    3 months = 25.5 (23.5 to 26.5)

    1 Year = 25.0 (24.0 to 26.0)

    BDI-II (FUS group):

    Baseline = 5.0 (2.5 to 9.0)

    1 month = N/A

    3 months = 6.0 (1.5 to 9.0)

    1 Year = 5.0 (3.0 to 8.0)

    MoCA (sham group):

    Baseline = 27.0 (23.0 to 28.0)

    1 month = N/A

    3 months = 26.0 (23.0 to 28.0)

    BDI-II (sham group):

    Baseline = 5.0 (4.0 to 8.0)

    1 month = N/A

    3 months = 8.0 (2.0 to 9.0)

    LEDD (mg):

    FUS group:

    Baseline = 751 (450 to 950)

    1 month = 573 (400 to 950)

    3 months = 500 (400 to 836)

    1 Year = 550 (400 to 800)

    Sham group:

    Baseline = 640 (550 to 1250)

    1 month = 640 (550 to 1250)

    3 months = 840 (550 to 1250)

    Results for FUS group at baseline, 1 month and 3 months n=20 and trial is blinded. At 1 year n=14 and trial is unblinded.

    Results for sham group at baseline, 1 month and 3 months n=7 and trial is blinded.

    Results from Sperling 2018

    Data are presented as median (IQR)

    Cognitive MoCA Test

    Baseline:

    Active=25.5 (23 to 27.5), Sham=27 (23 to 28), p=0.766

    3 months:

    Active=25.5 (23.3 to 26.8), Sham=26 (23 to 28), p=0.498

    Mood (High scores on all mood and behavioural measures indicate worse symptoms):

    BAI baseline:

    Active=6.5 (5 to 10), Sham=10 (5 to 14), p=0.4

    BAI 3 months:

    Active= 6 (3.3 to 11.8), Sham=12 (8 to 15), p=0.219

    BDI-II Baseline:

    Active=5 (2.5 to 9), Sham=5 (4 to 8), p=0.935

    BDI-II 3 months:

    Active=6 (1.25 to 9), Sham=8 (2 to 9), p=0.893

    Changes in quality of life after active treatment, PDQ-39 domains:

    Mobility:

    Baseline=17.5 (10 to 35), 3 months=10 (5 to 22.5), p=0.012, 12 months=15 (2.5 to 22.5), p=0.507, omnibus p value=0.093, MCID=9.13

    ADL:

    Baseline=37.5 (25 to 50), 3 months=20.83 (4.2 to 51), p<0.001, 12 months=12.5 (4.2 to 29.2), p<0.001, omnibus p value<0.001, MCID=12.12

    Emotion Wellness:

    Baseline=20.83 (8.3 to 29.2), 3 months=8.3 (0 to 24), p=0.035, 12 months=8.3 (0 to 16.7), p=0.023, omnibus p value=0.004, MCID= 9.89

    Stigma:

    Baseline=18.75 (12.5 to 43.8), 3 months= 2.5 (0 to 26.6), p=0.01, 12 months=6.25 (0 to 18.8), p=0.01, omnibus p value=0.005, MCID=15.51

    Social Support:

    Baseline=0 (0 to 8.33), 3 months=0 (0 to 0), p=0.301, 12 months=0 (0 to 0), p=0.496, omnibus p value=0.069, MCID=13.31

    Cognitive Impairment:

    Baseline=12.5 (6.3 to 37.5), 3 months=6.25 (0 to 20.3), p=0.005, 12 months=12.5 (6.3 to 31.3), p=0.197, omnibus p value=0.021, MCID=15.79

    Communication:

    Baseline=16.67 (0 to 26.7), 3 months=0 (0 to 27.1), p=0.381, 12 months=0 (0 to 16.7), p=0.048, omnibus p value=0.081, MCID=14.91

    Bodily Discomfort:

    Baseline=25 (8.3 to 33.3), 3 months= 6.67 (0 to 25), p=0.258, 12 months=16.67 (8.3 to 27.1), p=0.732, omnibus p value=0.064, MCID=17.13

    Total:

    Baseline=21.35 (12.9 to 28.6), 3 months=9.16 (3.9 to 31.9), p=0.003, 12 months=11.2 (4.23 to 23), p=0.018, omnibus p value=0.004, MCID=5.31

    Associations with quality of life:

    CRST A:

    3 months τb (Kendall tau-b)=0.266, p=0.06, change τb=0.12, p=0.4

    CRST B:

    3 months τb = 0.125, p=0.385, change τb=0.233, p=0.105

    CRST A&B:

    3 months τb=0.057, p=0.690, change τb=0.151, p=0.288

    UPDRS-III:

    3 months τb=0.374, p=0.008, change τb= −0.279, p=0.049

    UPDRS-II:

    3 months τb=0.609, p<0.001, change τb= −0.382, p=0.008

    Thalamotomy related adverse events n (%):

    Finger paraesthesia:

    Transient2 (33)

    Persistent 0 (0)

    Orofacial paraesthesia:

    Transient 2 (33)

    Persistent 0 (0)

    There were no reports of thalamotomy-related ataxia, hemiparesis or dysmetria.

    Transient adverse events resolved during the 1year study.

    Persistent adverse events were still present at 1 year.

    Zur 2020

    Tremor score for n=17 people with PD, mean (SD)

    Before ablation: 5.4 (1.6)

    1 month after ablation: 1.5 (2.1)

    6 months after ablation: 0.8 (2.2)

    QoL score for n=17 people with PD, mean (SD)

    Before ablation: 43.8 (20.9)

    1 month after ablation: 27.1 (20.4)

    6 months after ablation: 25 (24)

    No safety outcomes measured

    Lak 2022

    Mean Tremor Score at rest (measured using CRST Part A) for people with PD

    1 year follow up (n = 4) = 0.75

    2 year follow up (n = 2) = 1.00

    Loss of treatment benefit or recurrence

    1 year: n=9 lost more than 50% of their treatment benefit

    2 years: n=5 patients with recurrence

    Mean tremor scores at baseline in tremor predominant PD

    rest: 3.5 SD 0.52

    posture: 2.8 SD 0.78

    intention: 1.5 SD 1.18.

    Mean tremor scores after the procedure in tremor predominant PD

    1 day: 0.29 SD 0.48 (n=148)

    3 months: 0.50 SD 0.95 (n=110)

    1 year: 0.66 SD 1.08 (n=101)

    2 years: 0.87 SD 0.90 (n=49)

    3 years: 1.25 SD 0.57 (n=8)

    4 years: 1 SD 0.63 (n=6)

    Adverse events

    Motor weakness:

    • 1-day post-op= 14 (8.75%),

    • 3-months post-op= 6 (5.17%),

    • 1-year post-op= 3 (2.85%),

    • 2-years post-op= 1 (2.0%)

    Dysarthria:

    • 1-day post-op= 30 (18.75%),

    • 3-months post-op= 9 (7.75%),

    • 1-year post-op= 6 (5.71%),

    • 2-years post-op= 1 (2.0%)

    Sensory deficits (Paraesthesia/Numbness):

    • 1-day post-op= 40 (25.0%),

    • 3-months post-op= 28 (24.15%),

    • 1-year post-op= 17 (16.2%,

    • 2-years post-op= 5 (10.0%)

    Gait imbalance:

    • 1-day post-op= 91 (56.87%),

    • 3-months post-op= 30 (25.8%),

    • 1-year post-op= 15 (14.28%),

    • 2-years post-op= 9 (17.5%)

    Dysgeusia:

    • 1-day post-op= 1 (0.62%),

    • 3-months post-op= 9 (7.75%),

    • 1-year post-op= 3 (2.85%),

    • 2-years post-op= 2 (4.0%)

    Dysmetria:

    • 1-day post-op= 18 (11.25%),

    • 3-months post-op= 12 (10.34%),

    • 1-year post-op= 7 (6.66%),

    • 2-years post-op= 4 (8.0%)

    Headache:

    • 1-day post-op= 5 (3.12%)

    Others (hypotension/ light-headedness, somnolence, new onset LE tremor):

    • 1-day post-op= 4 (2.5%)

    Saporito 2023

    Neuropsychological tests

    Mini Mental State Examination:

    • Baseline 25.70 ± 3.78,

    • 6-month follow-up 27.31 ± 2.44 (p=0.072)

    Montreal Cognitive Assessment:

    • Baseline 22.56 ± 4.10,

    • 6-month follow-up 23.94 ± 3.65 (p=0.003)

    Frontal Assessment Battery:

    • Baseline 13.83 ± 3.31,

    • 6-month follow-up 14.33 ± 3.80 (p=0.189)

    Single letter-cued (phonemic) fluency test:

    • Baseline 26.04 ± 12.68,

    • 6-month follow-up 26.98 ± 13.67 (p=0.628)

    Single letter-cued (semantic) fluency test:

    • Baseline 9.04 ± 2.46,

    • 6-month follow-up 9.97 ± 3.27 (p=0.333)

    Rey Auditory Verbal Learning Test R.I:

    • Baseline 30.56 ± 8.36,

    • 6-month follow-up 32.94 ± 9.57 (p=0.093)

    Rey Auditory Verbal Learning Test R.D:

    • Baseline 4.73 ± 3.74,

    • 6-month follow-up 32.94 ± 9.57 (p=0.324)

    Raven's Progressive Matrices:

    • Baseline 28.23 ± 4.66,

    • 6-month follow-up 28.19 ± 4.09 (p=0.959)

    Hamilton Anxiety rating scale:

    • Baseline 5.50 ± 4.07,

    • 6-month follow-up 2.33 ± 1.94 (p=0.004)

    Beck Depression Inventory-II:

    • Baseline 2.78 ± 2.75,

    • 6-month follow-up 1.61 ± 1.94 (p=0.156)

    Parkinson's disease Questionnaire-8 (PDQ-8):

    • Baseline 5.61 ± 4.65,

    • 6-month follow-up 1.39 ± 2.33 (p=0.001)

    Recurrence

    N=1, at 12 months postoperatively

    Adverse events

    Dizziness: n=21.52%

    Scalp burning: n=16.40%

    Nausea: n=8.42%

    Headache: n=6.15%

    Vagal reaction: n=2.5%

    Thalamotomy-related complications

    Contralateral weakness: n=3, 7.5%

    Dysgeusia: n=1, 2.5%

    Gait instability: n=1, 2.5%

    Sinai 2022

    Median change of tremor and motor scores before and after FUS

    n=26 at baseline and 1 month, 22 at 6 months, 23 at 12 months, 15 at 24 and 36 months, 12 at 48 months and 7 at 60 months.

    UPDRS:

    Baseline (raw score), 22.5 (9 to 43)

    1 month, –10 (–34 to 6) p<0.0001

    6 months, –16 (–34 to 16) p<0.0001

    12 months, –18 (–31 to 47) p<0.0001

    24 months, –15 (–33 to –1) p<0.0001

    36 months, –16 (–29 to 0) p=0.0002

    48 months, –10 (–30 to –4) p=0.0005

    60 months, –19 (–31 to –5) p=0.016

    Hemi–UPDRS:

    Baseline (raw score), 15 (5 to 24)

    1 month, –9 (–19 to 4) p<0.0001

    6 months, –12 (–18 to 2) p<0.0001

    12 months, –12 (–20 to 6) p<0.0001

    24 months, –12 (–17 to 2) p<0.0001

    36 months, –10 (–17 to 2) p=0.0002

    48 months, –8 (–16 to –3) p=0.0005

    60 months, –8 (–17 to –4) p=0.016

    CRST:

    Baseline (raw score), 20 (9 to 70)

    1 month, –15 (–66 to -5) p<0.0001

    6 months, –17.5 (–64 to –5) p<0.0001

    12 months, –17 (–63 to –5) p<0.0001

    24 months, –20 (–69 to –6) p<0.0001

    36 months, –14 (–70 to 6) p=0.015

    48 months, –15 (–54 to 6) p=0.013

    60 months, –14 (–54 to 3) p=0.031

    Hemi- CRST:

    Baseline (raw score), 13 (5 to 28)

    1 month, –12 (–28 to –4) p<0.0001

    6 months, –13 (–28 to 2) p<0.0001

    12 months, –13 (–28 to 2) p<0.0001

    24 months, –14 (–28 to 1) p<0.0001

    36 months, –13 (–28 to 1) p=0.0002

    48 months, –14.5 (–28 to 0) p=0.0010

    60 months, –8 (–28 to 1) p=0.031

    PDQ39:

    Baseline (raw score), 32 (17 to 79)

    1 month, –18∗ (–42 to 27) p<0.0001

    6 months, –19 (–61 to 9) p<0.0001

    12 months, –15 (–66 to 11) p<0.0001

    24 months, –7 (–43 to 15) not significant

    36 months, –8 (–46 to 24) not significant

    48 months, –6 (–48 to 29) not significant

    60 months, –11 (–47 to 24) not significant

    Levodopa equivalent:

    Baseline (raw score), 300 (0 to 1050)

    1 month, 0 (–200 to 141) not significant

    6 months, 0 (–200 to 582) not significant

    12 months, 0 (–200 to 985) not significant

    24 months, 66 (–250 to 1676) not significant

    36 months, 199 (–250 to 1076) p=0.0049

    48 months, 122.5 (–250 to 1676) p=0.037

    60 months, 151 (0 to 1476) p=0.031

    Negative values indicate improvement on all scales.

    p values are based on Wilcoxon signed rank test of changes (follow-up – baseline). *N = 25 for this item.

    Note: there appear to be some discrepancies between the table and text of the paper regarding the labelling of outcomes.

    PD related outcomes

    Before FUS:

    Receiving levodopa: n=11

    Receiving symptomatic therapy but not levodopa: n=11

    Not receiving antiparkinsonian medication: n=4

    During follow-up:

    Started taking levodopa: n=6, 5 people for rigidity (6 months n=2, 12 months n=1, 24 months n=1, 60 months n=1) and 1 person for tremor (24 months) Motor fluctuations: n= 3

    At the last follow up:

    Not using levodopa: n=9

    Not taking any antiparkinsonian medication: n=3 people (12 months n=2, 36 months n=1)

    Not taking any antiparkinsonian medication: n=6 people (12 months n=1, 24 months n=1, 36 months n=1, 48 months n=3)

    Tremor suppression

    6 months, n = 22, p < 0.0001

    1 year, n = 23, p < 0.0001

    2 years, n = 15, p < 0.0001

    3 years, n = 15, p = 0.023

    4 years, n = 12, p = 0.012

    5 years, n = 7, p = 0.031

    Adverse events

    Week 1, mild level 1 events (resolved within 3 months:

    headache n=9,

    vertigo n=8,

    dizziness n=3,

    hand/scalp heat n=3,

    lip/tongue paraesthesia n=2

    hand paraesthesia n=1

    Adverse events after the procedure (resolved):

    objective unsteadiness on tandem gait (n=5, for 1–4 weeks),

    subjective unsteadiness of gait (n=1, for 7 days),

    arm ataxia (n=2, for 1–4 weeks),

    asthenia (n=2, for 1–4 weeks),

    mild right hemiparesis (for 3 months),

    hypogeusia (n=1, for 3 months) and

    scalp numbness (n=1, for one week).

    Chua 2023

    Total FTM score (SD, range):

    Baseline (n=49) = 6.31 (2.48, 2 to 13)

    1 day (n=49) = 0

    1 month (n=44) = 0.16 (0.52, 0 to 3)

    3 months (n=34) = 0.59 (1.24, 0 to 6)

    1 year (n=23) = 1.35 (2.41, 0 to 9)

    2 years (n=5) = 0.20 (0.40, 0 to 1)

    3 years (n=2) = 0.50 (0.50, 0 to 1)

    Adverse events:

    Motor weakness:

    1 day = 3 (6%)

    1 month = 9 (20%)

    3 months = 6 (18%)

    1 year = 3 (14%)

    2 years = 1 (20%)

    Upper extremity

    1 day = 1 (2%)

    Lower extremity:

    1 day = 3 (6%)

    1 month = 9 (20%)

    3 months = 6 (18%)

    1 year = 3 (14%)

    2 years = 1 (20%)

    Sensory deficit (paraesthesia/ numbness):

    1 day = 7 (14%)

    1 month = 12 (27%)

    3 months = 9 (26%)

    1 year = 3 (14%)

    Lips:

    1 day = 6 (12%)

    1 month = 6 (14%)

    3 months = 6 (18%)

    1 year = 2 (9%)

    Tongue:

    1 day = 1 (2%)

    1 month = 2 (5%)

    3 months = 1 (3%)

    Orofacial (lips and tongue):

    1 month = 3 (7%)

    3 months = 2 (6%)

    1 year = 1 (5%)

    Fingers:

    1 day = 2 (4%)

    1 month = 3 (7%)

    3 months = 1 (3%)

    Gait imbalance:

    1 day = 29 (59%)

    1 month = 28 (64%)

    3 months = 13 (38%)

    1 year = 6 (27%)

    2 years = 1 (20%)

    Dysarthria:

    1 day = 8 (16%)

    1 month = 6 (14%)

    3 months = 2 (6%)

    Dysgeusia:

    1 day = 3 (6%)

    1 month = 7 (16%)

    3 months = 2 (6%)

    1 year = 1 (5%)

    At 1 day (n=49), 1 month (n=44), 3 months (n=34), 1 year (n=22), 2 years (n=5) and 3 years (n=2)

    Yamatoto 2021

    Tremor

    UPDRS Part III score at baseline: Median (interquartile range) = 25 (18–34)

    UPDRS Part III score at 1 year: Median (interquartile range) = 9 (5–13)

    Median improvement in CRST scores (interquartile range)

    12 months postoperatively = 87.9% (70.5–100.0)

    Median improvement of functional disability in Part C on the CRST = 66.7% (15.5–85.1)

    Median improvement in total tremor scores from baseline to 12 months = 65.3% (55.7–87.7)

    Treated upper extremity:

    Resting tremor: 66.7% (50.0–100.0)

    Postural tremor: 100.0% (100.0–100.0)

    Action tremor: 100.0% (100.0–100.0)

    Levodopa equivalent dose in individual cases

    Of the 11 people treated, the levodopa equivalent dose remained the same or decreased in 6 and increased in 3 at 12 months, when compared to baseline. One person refused to take medications because of lack of efficacy and one other individual did not have a recorded dose at 12 months but their dose remained constant at baseline, 1 week, 1 month and 3 months.

    Recurrence 

    N=1, at 12 months postoperatively (maximum temperature was 49°C, and the lesion volume was 46.2 mm3, the lowest and smallest of all the patients)

    Adverse events related to thalamotomy

    Headache: During procedure=9

    Floating sensation: During procedure=3

    Gait disturbance: During procedure=1, 1 day=3, 1 months=1

    Exacerbation of bradykinesia: 1 day=3

    Dysesthesia: During procedure=1, 1 day=1, 1 month=1, 3 months=1, 12 months=1

    Hemiparesis: During procedure=1, 1 day=1

    Hypoesthesia: 1 day=1, 1 month=1, 3 months=1

    Ageusia: 1 day=1, 1 month=1

    Hypotonia: 1 day=1

    Bradypragia: 1 day=1

    Dysphagia: 1 day=1

    Dysarthria: 1 day=1, 1 month=1, 3 months=1

    Adverse events related tostereotactic frame

    Eyelid oedema: Eyelid oedema=2

    Procedure technique

    Of the 9 studies, 6 studies detailed the focused ultrasound procedure technique and devices used as being a Neuro ExAblate machine (NeuroAblate 4000, InSightec; Bond 2017, Sperling 2018, Yamatoto 2021, Sinai 2022, Chua 2023 and Saporito 2023). One study did MRI examinations on a 3.0-T system (Discovery MR750; GE Healthcare, Milwaukee, Wisconsin; Zur 2020). One study described the procedure technique but gave no details about specific devices (Lak 2022). Eight studies targeted the ventral intermediate nucleus of the thalamus (Bond 2017, Sperling 2018, Lin 2021, Yamatoto 2021, Sinai 2022, Lak 2022, Chua 2023 and Saporito 2023).

    Efficacy

    Quality of life

    In the RCT of 27 people comparing MRgFUS with a sham procedure, the quality-of-life rating, assessed by PDQ39 score improved to 7.5 (IQR, 3.4 to 22.2) at 1 year from 21.2 (IQR,12.6 to 32.0) at baseline, in the MRgFUS group. In the sham group the PDQ39 was 25.0 (IQR, 14.8 to 27.7) at baseline and 17.4 (IQR, 1.8 to 20.6) at 3 months. The CRST disability (part C) score improved to 2.5 (IQR, 0 to 11.0) at 1 year from 13.0 (IQR, 10.0 to 18.5) at baseline, in the MRgFUS group. In the sham group the CRST disability (part C) score was 17 (IQR, 13 to 20) at baseline and 16 (IQR, 13 to 18) at 1 year (Bond 2017).

    In the prospective study of 56 people (17 with PD) looking at tremor relief and structural integrity after MRI-guided focused US thalamotomy in tremor disorders, the quality of life increased after ablation (mean 43.82, SD 20.94 at baseline compared with 27.07, SD 20.37 at 1 month, p<0.001; Zur 2020).

    In the prospective study of 18 people with PD investigating cognitive outcomes after MRgFUS thalamotomy for tremor, there were statistically significant improvements in quality of life at 6-month follow up (PDQ-8: 5.61, SD 4.65 compared with 1.39, SD 2.33, p=0.001), and the overall cognitive status (MOCA 22.56, SD 4.10 compared with 23.94, SD 3.65, p=0.003; Saporito 2023).

    The prospective study of 26 people studied the long-term results of MRgFUS thalamotomy in TDPD. The quality-of-life rating, assessed by PDQ39 score, showed a statistically significant improvement after MRgFUS. The raw baseline score before treatment was 32 (range 17 to 79). At 1 month after treatment the change in median score was -18 (range -42 to 27, p<0.0001). At 6 months the change in median score was -19 (range -61 to 9, p<0.0001) and at a year it was ‑15 (range -66 to 11, p<0.0001). When compared with the baseline, the improvement in PDQ39 score was not statistically significant at the 24-month, 36‑month or 48-month follow up (Sinai 2022).

    Tremor

    In the RCT of 27 people comparing MRgFUS with a sham procedure, in the MRgFUS group, the tremor sub-score (CRST A+B) of the treated hand improved to 5.0 (2.0 to 14.0) at 1 year from 17 (10.5 to 27.5) at baseline. In the sham group, the tremor sub-score (CRST A+B) of the treated hand improved to 17 (12 to 21) at 3 months from 23 (14 to 27) at baseline. In the MRgFUS group, the total CRST score improved to 18.0 (7.0 to 42.0) at 1 year from 41.5 (28.0 to 65.0) at baseline. In the sham group, the total CRST score improved to 37 (29 to 53) at 3 months from 48 (43 to 62) at baseline. In the MRgFUS group, the total UPDRS score improved to 19.5 (9.0 to 36.0) at 1 year from 37.5 (32.5 to 44.5) at baseline. In the sham group, the total UPDRS score improved to 24 (21 to 50) at 3 months from 39 (25 to 53) at baseline (Bond 2017).

    In the prospective study of 56 people (17 with PD), tremor decreased in those with PD from 5.4 (SD 1.6) at baseline to 1.5 (SD 2.1) at the 1-month follow up (p<0.001; Zur 2020).

    In the prospective study of 11 people with PD, the median scores on the UPDRS part 3 were 25 (IQR 18 to 34) at baseline and 9 (IQR 5 to 13) at 12 months after surgery. During this procedure, tremor significantly improved for everyone. Also, from baseline to 12 months, the median improvement in total tremor scores on the CRST was 65.3% (IQR 55.7 to 87.7; Yamatoto 2021).

    In the retrospective study in a single centre with 160 procedures of MRgFUS thalamotomy (10 procedures for people with PD), the mean tremor component scores at baseline in tremor-predominant PD were 3.5 (SD 0.52; rest), 2.8 (SD 0.78; posture) and 1.5 (SD 1.18; intention). Intention tremor scores after the procedure were 0.29 (SD 0.48) at 1 day (n=148), 0.50 (SD 0.95) at 3 months (n=110), 0.66 (SD 1.08) at 1 year (n=101), 0.87 (SD 0.90) at 2 years (n=49), 1.25 (SD 0.57) at 3 years (n=8) and 1 (SD 0.63) at 4 years (n=6) (Lak 2022).

    In the prospective study of 26 people with PD, the median CRST score decreased by 15 points from baseline 1 month after treatment (p<0.0001). Tremor suppression continued during follow-up visits up to 5 years and remained statistically significant (6 months, n=22, p<0.0001; 1 year, n=23, p<0.0001; 2 years, n=15, p<0.0001; 3 years, n=15, p=0.023; 4 years, n=12, p=0.012; 5 years, n=7, p=0.031). Likewise, the median hemi-CRST dropped by 12 points (range ‑28 to -4, p<0.0001) after 1 month. Over time, the hemi-CRST score remained statistically significantly decreased. The median hemi-UPDRS score fell by 9 points at 1 month (range: -19 to 4 points; p<0.0001). Similar notable changes were also shown in part 3 of the total UPDRS. Over a period of up to 5 years, the median UPDRS part 3 and hemi-UPDRS remained statistically significantly decreased (Sinai 2022).

    In the retrospective study of 48 people, the FTM score was 6.31 (SD 2.48, range 2 to 13) at baseline, 0 at day 1 and 0.50 (SD 0.50, range 0 to 1) after 3 years (Chua 2023).

    In the systematic review of 77 people with PD, the network meta-analysis comparisons for UPDRS III-Tremor (medication-off) showed that the mean difference for MRgFUS (internal globus pallidus and ventral intermediate nucleus) compared with baseline was significant (4.90, 95% CI 0.81 to 9.06, and 5.62, 95% CI 1.41 to 9.57, respectively). For UPDRS III-Tremor (medication-on), the mean difference for MRgFUS (internal globus pallidus and ventral intermediate nucleus) compared with baseline was significant (3.54, 95% CI 1.54 to 5.74, and 2.54, 95% CI 1.11 to 4.18, respectively). The UPDRS III-Total (medication-off) showed that the mean difference for MRgFUS (internal globus pallidus and ventral intermediate nucleus) compared with baseline was significant (13.46, 95% CI 2.46 to 25.10, and 18.62, 95% CI –2.09 to 38.79, respectively). The UPDRS III-Total (medication-on) showed that the mean difference for MRgFUS (internal globus pallidus and ventral intermediate nucleus) compared with baseline was significant (11.47, 95% CI 5.90 to 17.01, and 11.63, 95% CI 3.67 to 19.06, respectively; Lin 2021).

    Use of antiparkinsonian medication

    In the RCT of 27 people comparing MRgFUS with a sham procedure, the LEDD (mg) was 550 (400 to 800) at 1 year and 751 (450 to 950) at baseline in the MRgFUS group. In the sham group the LEDD (mg) was 840 (550 to 1250) at 3 months and 640 (550 to 1250) at baseline (Bond 2017).

    In the prospective study of 11 people with PD, the levodopa equivalent dose remained the same or decreased in 6 people and increased in 3 people at 12 months, when compared with baseline. One person refused to take medications because of lack of efficacy and one other individual did not have a recorded dose at 12 months but their dose remained constant at baseline, 1 week, 1 month and 3 months (Yamatoto 2021).

    In the prospective study of 26 people with PD, before the procedure 11 people had levodopa, 11 people had symptomatic therapy but not levodopa, and 4 people did not have any antiparkinsonian medicine. Six people started taking levodopa during follow up, 5 people for rigidity (6 months n=2, 12 months n=1, 24 months n=1, 60 months n=1) and 1 person for tremor (24 months). Motor fluctuations occurred in 3 of these people. At the last follow up, 9 people were not using levodopa, and 3 people were not taking any antiparkinsonian medications and 6 people were not taking any other antiparkinsonian medications (Sinai 2022).

    Neuropsychological outcomes

    In the RCT of 27 people comparing MRgFUS with a sham procedure, in the MRgFUS group, the MOCA score was 25.0 (IQR 24.0 to 26.0) at 1 year and 25.5 (IQR 23.0 to 28.0) at baseline. In the sham group, the MOCA score was 27.0 (IQR 23.0 to 28.0) at 3 months and 26.0 (IQR 23.0 to 28.0) at baseline. In the MRgFUS group, the BDI-II score was 5.0 (IQR 3.0 to 8.0) at 1 year and 5.0 (IQR 2.5 to 9.0) at baseline. In the sham group, the BDI-II score was 8.0 (IQR 2.0 to 9.0) at 3 months and 5.0 (IQR 4.0 to 8.0) at baseline (Bond 2017).

    In the same RCT, the MoCA score change in the active group was 0 (IQR -1.5 to 2.5) and in the sham group was -1 (IQR -1 to 2; p=0.725). The change in BAI score, measuring mood, was -0.5 (IQR -4 to 2.8) in the active group and 3 (IQR ‑3 to 6) in the sham group (p=0.533). The change in BDI-II score, measuring mood, was 0 (IQR -3 to 2.0) in the active group and 1 (IQR -2 to 2) in the sham group (p=0.646; Sperling 2018).

    In the prospective study of 18 people with PD there was a statistically significant improvement in the overall cognitive status at 6-month follow up (MOCA 22.56, SD 4.10 compared with 23.94, SD 3.65, p=0.003). All the other cognitive and behavioural domains remained unchanged (Saporito 2023).

    Recurrence of tremor

    In the prospective study of 11 people with PD, 1 person had a tremor recurrence 12 months after surgery. The lesion volume in this person was 46.2 mm3, and the maximal temperature was 49°C. These were the lowest and smallest values among everyone in the study (Yamatoto 2021).

    In the retrospective study in a single centre with 160 procedures of MRgFUS thalamotomy (10 procedures for people with PD), 9 people had lost more than half of their treatment benefit at the 1-year follow up, and 5 more people experienced tremor recurrences at the 2-year follow up (Lak 2022).

    Safety

    Head discomfort or pain

    In the prospective study of 11 people with PD, 9 people experienced headache related to thalamotomy during the procedure (Yamatoto 2021).

    In the prospective study of 18 people with PD, 16% experienced scalp burning, 8% experienced nausea, 6% experienced headache and 3% experienced a vagal reaction (Saporito 2023).

    In the prospective study of 26 people with PD, 9 people experienced headache and 3 experienced hand or scalp heat during the first week, which was resolved within 3 months. One person experienced scalp numbness for 1 week after the procedure (Sinai 2022).

    In the systematic review of 77 people with PD, 3 people experienced headache during the sonications (MRgFUS targeting the VIM). During the MRI ultrasonography procedure, 1 person experienced scalp numbness, 12 people experienced headache and 3 people experienced head pain or heat sensation (all of these were transient and for MRgFUS targeting the VIM; Lin 2021).

    Vestibular symptoms (dizziness or vertigo)

    In the retrospective study of a single centre experience with 160 procedures of MRgFUS thalamotomy (10 procedures for people with PD), 1 day after surgery (n=160), 25% of people experienced sensory deficits. At the 3-month follow up (n=116), 24% of people experienced sensory deficits. At the 1-year follow up (n=105), 16% of people experienced sensory deficits. At the 2-year follow up (n=51), 10% of people experienced sensory deficits (Lak 2022).

    In the prospective study of 18 people with PD, 22% experienced dizziness (Saporito 2023).

    In the prospective study of 26 people with PD studying the long-term results of focused ultrasound thalamotomy in TDPD, 8 patients experienced vertigo and 3 experienced dizziness during the first week, which was resolved within 3 months (Sinai 2022).

    In the systematic review, 2 people experienced dizziness and 4 people experienced vertigo during sonication, 1 person experienced a subjective unsteady feeling when walking and 1 person experienced disturbance when walking tandem (from Schlesinger 2015 in the Lin 2021 review).

    During the MRI ultrasonography procedure, 8 people experienced dizziness or vertigo (all of these were transient and for MRgFUS targeting the VIM; Lin 2021).

    Paraesthesia or numbness

    In the RCT of 27 people comparing MRgFUS with a sham procedure, 33% of people (n=2) experienced transient finger paraesthesia (which was resolved within 1 year) and orofacial paraesthesia related to the thalamotomy (Bond 2017).

    In the prospective study of 26 people with PD, 2 patients experienced lip or tongue paraesthesia and 1 experienced hand paraesthesia during the first week, which was resolved within 3 months (Sinai 2022).

    In the systematic review of 77 people with PD, 1 person experienced lip paraesthesia during sonication (MRgFUS targeting the VIM). Seven people experienced transient finger paraesthesia and 1 person experienced persistent finger paraesthesia (MRgFUS targeting the VIM). One person experienced transient orofacial paraesthesia and 4 people experienced persistent orofacial paraesthesia (MRgFUS targeting the VIM; Lin 2021).

    Taste

    In the prospective study of 11 people with PD, 1 person experienced ageusia at 1 day and another 1 at 1 month (Yamatoto 2021).

    In the prospective study of 18 people with PD, thalamotomy-related complications were reported in 5 people with 1 person experiencing dysgeusia (n=1, 3%) with a gradual improvement in the 3 months after MRgFUS thalamotomy (Saporito 2023).

    In the prospective study of 26 people with PD, 1 person experienced hypogeusia for 3 months after the procedure (Sinai 2022).

    In the systematic review of 77 people with PD, 1 person experienced hypogeusia (MRgFUS targeting the VIM; Lin 2021).

    Gait disturbance

    In the prospective study of 11 people with PD, 1 person experienced gait disturbance related to thalamotomy during the procedure, 3 person experienced disturbance at 1 day, and 1 person experienced disturbance at 1 month (Yamatoto 2021).

    In the retrospective study of a single centre experience with 160 procedures of MRgFUS thalamotomy (10 procedures for people with PD), 1 day after surgery (n=160), the most common adverse event was gait imbalance (57%). At the 3‑month follow up (n=116), gait imbalance was seen in 26% of people. At the 1 year follow up (n=105), the second most common adverse event was gait imbalance (14%). At the 2-year follow up (n=51), the most common adverse event was gait imbalance (18%; Lak 2022).

    In the prospective study of 18 people with PD, thalamotomy-related complications were reported in 5 people, including contralateral weakness (n=3, 8%) and gait instability (n=1, 3%) with a gradual improvement in the 3 months after MRgFUS thalamotomy (Saporito 2023).

    In the prospective study of 26 people with PD, 5 people experienced objective unsteadiness on tandem gait for 1 to 4 weeks after the procedure and 1 experienced subjective unsteadiness of gait for 7 days after the procedure (Sinai 2022).

    In the retrospective study of 48 people, the most common adverse event at all follow-up time points was gait imbalance, with 59% (29/49) of people affected at day 1. This increased to 64% (28/44) by 1 month, then decreased over time (3 months 38% [13/34], 1 year 27% [6/22], 2 years 20% [1/5]; Chua 2023).

    In the systematic review of 77 people with PD, 1 person experienced hypogeusia, 1 person experienced a subjective unsteady feeling when walking and 1 person experienced disturbance when walking tandem, during sonication (MRgFUS targeting the VIM; Lin 2021).

    Hand ataxia

    In the prospective study of 11 people with PD, 3 people experienced exacerbation of bradykinesia at 1 day (Yamatoto 2021).

    In the prospective study of 26 people with PD, 2 people experienced arm ataxia for 1 to 4 weeks after the procedure, which did not persist (Sinai 2022).

    In the systematic review of 77 people with PD, 8 people experienced transient ataxia and 1 person experienced persistent ataxia (MRgFUS targeting the VIM; Lin 2021).

    Dysarthria

    In the prospective study of 11 people with PD, 1 person experienced dysarthria at 1 day, 1 month and 3 months (Yamatoto 2021).

    In the retrospective study of 160 procedures of MRgFUS thalamotomy (10 procedures for people with PD), 1 day after surgery (n=160), the third most common adverse event was dysarthria (19%). At the 1-year follow up (n=105), the fourth most common adverse event was dysarthria (6%; Lak 2022).

    In the retrospective study of 48 people, the least common adverse event was dysarthria (16% [8/49] at day 1, 14% [6/44] at 1 month, 6% [2/34] at 3 months; Chua 2023).

    Asthenia

    In the prospective study of 26 people with PD, 2 people experienced asthenia after the procedure for 1 to 4 weeks, which did not persist (Sinai 2022).

    Vocal change

    In the systematic review of 77 people with PD, 1 person experienced persistent mild vocal change (MRgFUS targeting the VIM; Lin 2021).

    Anecdotal and theoretical adverse events

    Expert advice was sought from consultants who have been nominated or ratified by their professional society or royal college. They were asked if they knew of any other adverse events for this procedure that they had heard about (anecdotal), which were not reported in the literature. They were also asked if they thought there were other adverse events that might possibly occur, even if they had never happened (theoretical).

    They listed the following theoretical adverse events:

    • sonications that are done too far laterally have a possibility of inducing limb weakness

    • sonications that are done too far inferiorly have a possibility of inducing chorea, which is usually reversible within 2 to 3 months.

    Five professional expert questionnaires for this procedure were submitted. Find full details of what the professional experts said about the procedure in the specialist advice questionnaires for this procedure.

    Validity and generalisability

    • Follow up ranged from 3 months to 60 months.

    • Studies were conducted in Israel, Japan, and the US.

    • There was no major variability in the procedure technique, and 5 of the 10 studies stated that the ExAblate Neuro device was used.

    • Some of the evidence included people with ET rather than PD, and safety outcomes have been included from both.

    • The manufacturer, Insightec, was involved in the funding and clinical research support in 6 of the 10 studies.

    • All studies concluded that MRgFUS ventral intermediate nucleus thalamotomy is a safe efficacious intervention in improving moderate to severe tremor in Parkinson's.