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    Interventional procedure overview of MRI-guided focused ultrasound subthalamotomy for treating Parkinson's

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    Evidence summary

    Population and studies description

    This interventional procedures overview is based on 95 patients from 1 RCT and 3 prospective studies. Of these 95 patients, there is an overlap of data on 33 patients. So, only 62 patients had the procedure. 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 4 studies as the key evidence in table 2 and table 3, and lists other 10 relevant studies in table 5.

    3 studies (1 RCT, 1 pilot study and 1 long-term prospective cohort study that included patients from both the pilot study [n=10] and the RCT [n=40]) assessed evidence for patients with advanced Parkison's. One small pilot study with 1‑year follow up assessed evidence for early-stage Parkinson's in younger patients. Table 2 presents study details.

    The long-term follow-up prospective cohort study included patients from the pilot study and an RCT, both funded by the device company. All patients were examined and assessed by the same team. 29% (13/45) of patients dropped out from initial studies, and this was mainly related to the covid pandemic.

    The small pilot study was in a group of patients with Parkinson's with highly asymmetric parkinsonism and short follow-up period. The target was slightly dorsolateral to the conventional localisation of the subthalamic nucleus (STN).

    In the small double blinded randomised sham-controlled trial, patients with advanced Parkinson's were randomised in a 2:1 ratio. Although assignment was concealed it was correctly guessed by patients and assessors. The procedure was offered to the sham group at the end of the study despite high complication rates. No interim analysis was done for adverse events. 12 patients from the control group crossed over and 11 completed 12 months of follow up. 2 patients in each group were lost to follow up at 12 months. No definitive inferences could be made for secondary outcomes because there was no plan for adjustment of the 95% confidence interval (CI). The trial was sponsored and monitored by the device company.

    Another small pilot study with short follow-up was done in patients with less advanced Parkinson's.

    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

    Martinez-Fernandez 2023

    Spain

    (NCT02912871, NCT03454425)

    N=32 (22:10)

    Parkinson's duration mean 6.8 (SD 2.8) years.

    Mean 56 (SD 10.1) years

    Prospective cohort study

    (this cohort includes long term follow-up of patients included in the pilot study [n=10] and an RCT [n=36]).

    13 of these patients were excluded from the 3-year follow-up.

    Patients with asymmetrical PD with suboptimal control of motor signs on the more affected side despite the use of dopaminergic medication, those that were not eligible or were reluctant to have intracranial surgery for DBS.

    Unilateral MRgFUS ablation of the STN in conjunction with medication

    36 months.

    7 patients were followed up for 5 years.

    2

    Martinez-Fernandez 2018

    Spain (NCT02912871)

    n=10

    (6:4) Parkinson's duration mean 6.3 (SD 2.4) years.

    59.5 (SD 10.1) years

    Prospective cohort study (pilot study)

    patients with markedly asymmetric parkinsonism that was medically uncontrolled, refused to undergo DBS, or not indicated because of mild parkinsonism on the less affected side or the absence of relevant motor complications, or both and those above 70 years.

    Unilateral MRgFUS ablation of the STN in conjunction with medication

    6 months

    3

    Martinez-Fernandez 2020

    Spain (NCT03454425)

    n=40 (26:14)

    Parkinson's duration mean 6.2 years.

    mean 57 years

    Randomised controlled, double blinded trial

    patients with highly asymmetric parkinsonism (asymmetry index, >1.5), refractory to medication, declined to undergo DBS (11 patients); had minor motor signs on the less affected side, no drug-related motor complications that would make the patient a candidate for DBS, or both (26 patients); or were poor candidates for intracranial surgery owing to advanced age or coexisting conditions (n=3).

    Unilateral MRgFUS ablation of the STN, n=27

    (16 in the left hemisphere and 11 in the right)

    sham procedure (of ultrasound), n=13

    (7 in the left hemisphere, and 6 in the right)

    medical therapy was used in both groups.

    12 months

    4

    Martinez-Fernandez 2024

    Spain (NCT04692116)

    n=12 (10:2)

    PD median time from diagnosis 3.0 (2.1–3.9) years)

    median 52 years

    prospective cohort study

    patients with PD of less than 5 years from diagnosis (early PD). Patients had asymmetrical parkinsonian motor features in the off-medication state with an asymmetry index higher than 1.5.

    Unilateral MRgFUS ablation of the STN,

    12 months (8 for right side, 4 left side)

    Table 3 Study outcomes

    First author, date

    Efficacy outcomes

    Safety outcomes

    Martinez-Fernandez 2023

    MDS-UPDRS motor part III, total score (on medication state), n=30

    Baseline mean 24.7 (SD 7.4)

    6 months 15.4 (SD 6.3)

    1 year 15.3 (SD 5.7)

    MDS-UPDRS motor part III, total score (off medication state), n=30

    Baseline mean 36.8 (SD 7.4)

    6 months 21.8 (SD 7.9)

    1 year 23.0 (SD 8.8)

    MDS-UPDRS III scores (for treated side of the body and as per locomotor condition)

    off medication state (primary outcome), n=32

    Baseline mean 19.0 (SD 3.2)

    4-6 months 7.7 (4.0)

    12 months 8.3 (4.2)

    24 months 8.5 (3.5)

    36 months 8.9 (3.3)

    Change in score baseline versus 36 months (10.1, 95% CI 8.7 to 11.6, p<0.001).

    Change in score 4-6 months versus 36 months (-1.2, 95% CI -2.5 to 0.2, p=0.089).

    on medication state, n=32

    Baseline mean 13.7 (SD 3.7)

    4-6 months 5.5 (3.4)

    12 months 5.5 (3.3)

    24 months 5.3 (2.6)

    36 months 5.8 (2.9)

    Change in score baseline versus 36 months (7.8, 95% CI 6.3 to 9.4, p<0.001).

    Change in score 4-6 months versus 36 months (-0.4, 95% CI -1.6 to 0.8, p=0.500).

    Tremor (off medication state)

    Baseline mean 5.2 (SD 2.3)

    4-6 months 1.2 (1.4)

    1 year 1.1 (1.6)

    24 months 1.6 (1.6)

    36 months 1.7 (1.8)

    Change in score baseline versus 36 months 3.5 (95% CI 2.9–4.2, p<0.001)

    Change in score 4-6 months versus 36 months −0.5 (95% CI −1.0 to 0.1, p=0.079).

    Tremor (on medication state)

    Baseline mean 3.7 (SD 1.9)

    4-6 months 0.9 (1.3)

    1 year 0.5 (1.0)

    24 months 1.0 (1.3)

    36 months 0.9 (1.2)

    Change in score baseline versus 36 months 2.8 (95% CI 2.1–3.5, p<0.001)

    Change in score 4-6 months versus 36 months 0.1 (95% CI −0.5 to 0.6, p=0.807).

    Bradykinesia (off medication state)

    Baseline mean 10.3 (SD 2.5)

    4-6 months 5.0 (2.8)

    1 year 5.4 (3.0)

    24 months 5.2 (2.5)

    36 months 5.5 (2.5)

    Change in score baseline versus 36 months 4.8 (95% CI 3.8 to 5.9, p<0.001)

    Change in score 4-6 months versus 36 months −0.5 (95% CI −1.4 to 0.4, p=0.311).

    Bradykinesia (on medication state)

    Baseline mean 7.3 (SD 2.4)

    4-6 months 3.6 (2.8)

    1 year 3.9 (2.6)

    24 months 3.2 (2.1)

    36 months 4.0 (2.2)

    Change in score baseline versus 36 months 3.3 (95% CI 2.3 to 4.3, p<0.001)

    Change in score 4-6 months versus 36 months −0.4 (95% CI −1.1 to 0.3, p=0.252).

    Rigidity (off medication state)

    Baseline mean 3.5 (SD 0.9)

    4-6 months 1.5 (1.3)

    1 year 1.7 (1.2)

    24 months 1.6 (1.1)

    36 months 1.7 (1.0)

    Change in score baseline versus 36 months 1.8 (95% CI 1.4 to 2.1, p<0.001)

    Change in score 4-6 months versus 36 months −0.3 (95% CI−0.6 to 0.1, p=0.174)

    Rigidity (on medication state)

    Baseline mean 2.8 (SD 1.1)

    4-6 months 0.9 (1.0)

    1 year 1.1 (1.2)

    24 months 1.0 (1.1)

    36 months 1.0 (0.8)

    Change in score baseline versus 36 months 1.8 (95% CI 1.4 to 2.2, p<0.001)

    Change in score 4-6 months versus 36 months −0.1 (95% CI −0.3 to 0.2, p=0.645)

    MDS-UPDRS III for the untreated side

    off-medication state

    Baseline mean 6.6 (SD 3.1)

    4-6 months 7.1 (3.2)

    1 year 7.5 (4.0)

    24 months 8.5 (3.2)

    36 months 10.1 (4.6)

    Change in score baseline versus 36 months −3.7 (95% CI −5.4 to −2.0, p<0.001)

    Change in score 4-6 months versus 36 months −3.4 (95% CI −4.9 to −0.9, p <0.001).

    on-medication state

    baseline mean 4.3 (SD 2.9)

    4-6 months 5.3 (2.9)

    1 year 5.5 (3.1)

    24 months 5.0 (2.5)

    36 months 6.6 (4.2)

    Change in score baseline versus 36 months −2.7 (95% CI −4.4 to −0.9, p=0.016)

    Change in score 4-6 months versus 36 months −1.7 (95% CI −3.3 to −0.1, p=0.041).

    MDS-UPDRS part IV, for levodopa-related motor complications

    total score

    Baseline mean 2.9 (SD 3.4)

    months 2.2 (3.0)

    1 year 2.0 (2.4)

    24 months 1.7 (1.8)

    36 months 2.6 (2.2)

    Change in score baseline versus 36 months

    (95% CI −1.2 to 1.3, p=0.642)

    Change in score 4-6 months versus 36 months −0.7 (95% CI −1.6 to 0.2, p=0.050).

    sub-scores

    Dyskinesia

    Baseline mean 0.3 (SD 0.8)

    4-6 months 0.5 (1.1)

    1 year 0.7 (1.0)

    24 months 0.6 (1.0)

    36 months 0.6 (0.9)

    Change in score baseline versus 36 months

    −0.3 (95% CI −0.7 to 0.1, p=0.123)

    Change in score 4-6 months versus 36 months −0.2 (95% CI −0.6 to 0.2, p=0.238).

    motor fluctuations

    baseline mean 2.0 (SD 2.2)

    4-6 months 1.4 (1.9)

    1 year 1.1 (1.6)

    24 months 1.0 (1.4)

    36 months 1.9 (1.7)

    Change in score baseline versus 36 months

    1. (95% CI −0.9 to 0.9, p=0.725)

    Change in score 4-6 months versus 36 months −0.6 (95% CI −1.4 to 0.2, p=0.068).

    Dystonia (off medication state)

    baseline mean 0.6 (SD 1.1)

    4-6 months 0.3 (0.5)

    1 year 0.3 (0.5)

    24 months 0.1 (0.3)

    36 months 0.2 (0.4)

    Change in score baseline versus 36 months

    0.4 (95% CI −0.01 to 0.8, p=0.062)

    Change in score 4-6 months versus 36 months 0.07 (95% CI −0.1 to 0.2, p=0.484).

    Functional disability/activities of daily living (assessed using the MDS-UPDRS II)

    baseline mean 10.0 (SD 5.4)

    4-6 months 6.8 (5.6)

    1 year 8.8 (5.3)

    24 months 9.6 (7.9)

    36 months 10.3 (6.1)

    Change in score baseline versus 36 months

    1.3 (95% CI −1.0 to 3.7, p=0.352)

    Change in score 4-6 months versus 36 months −2.5 (95% CI −4.1 to −0.7, p=0.011).

    Quality of life (assessed using PDQ39)

    baseline mean 17.7 (SD 11.2)

    4-6 months 11.3 (9.1)

    1 year 15.5 (9.4)

    24 months 16.1 (10.1)

    36 months 16.1 (9.7)

    Change in score baseline versus 36 months

    3.1 (95% CI−0.8 to 6.6, p=0.106)

    Change in score 4-6 months versus 36 months −5.2 (95% CI −8.1 to −2.0, p=0.004).

    Drug changes

    LEDD (milligrams)

    baseline mean 728.2 (SD 260.5)

    4-6 months 636.1 (319.9)

    1 year 683.4 (291.9)

    24 months 771.0 (332.3)

    36 months 835.4 (330.0)

    Change in score baseline versus 36 months

    107.3 (95% CI −5.4 to 220.1, p=0.061)

    Change in score 4-6 months versus 36 months 186.1 (−100.5 to 271.8, p<0.001).

    LDD (milligrams)

    baseline mean 453.9 (SD 229.9)

    4-6 months 390.6 (231.4)

    1 year 426.1 (231.82)

    24 months 431.1 (213.8)

    36 months 515.7 (220.8)

    Change in score baseline versus 36 months

    66.5 (95% CI −29.9 to 162.9, p=0.169)

    Change in score 4-6 months versus 36 months 116.5 (95% CI −49.2 to 183.8, p< 0.001).

    Patient satisfaction at 3 years (assessed using global impression of change questionnaire)

    satisfied with the treatment 89.7% (26/29)

    better global status 82.8% (24/29).

    Adverse events (graded as mild, moderate or severe)

    During the procedure 0

    Post procedure (at 4-6 months)

    Contralateral dyskinesias n=3 [9%]

    Contralateral levodopa-induced dyskinesias n=5 [16%]

    Clumsiness/weakness on treated side (moderate) n=1

    Facial asymmetry n=1

    Speech disturbance: dysarthria n=2 [6%], reduced verbal fluency n=1

    Gait disturbances: unsteady gait n=1

    Weight gain n=3 [9%]

    At 1 year (n=32)

    Contralateral levodopa-induced dyskinesias n=4 [12%]

    Clumsiness/weakness on treated side n=1

    Facial asymmetry n=1

    Speech disturbance: dysarthria n=1, reduced verbal fluency n=1

    Gait disturbances: unsteady gait n=1

    Weight gain n=3 [9%]

    at 24 months (n=20)

    Speech disturbance: mild dysarthria n=1, reduced verbal fluency n=1

    Contralateral levodopa-induced dyskinesias n=4 (20%)

    Clumsiness/weakness on treated side (moderate) n=1

    at 3 years (n=30)

    Speech disturbance: mild dysarthria n=1, reduced verbal fluency n=1

    Contralateral levodopa-induced dyskinesias n=8 (27%)

    Clumsiness on treated side n=1

    Weight gain n=2

    Parkinsonism on the nontreated side (needed either DBS or MRgFUS STN), n= 3

    Martinez-Fernandez 2018

    Spain

    NCT02912871

    Change in motor status (assessed with MDS-UPDRS III score), mean (SD)

    MDS–UPDRS III, treated side off-medication

    baseline mean 16.6 (SD 2.9)

    6 months 7.5 (3.9)

    change from baseline –9.1 (4.7); –53%

    MDS–UPDRS III, treated side on medication

    baseline 11.9 (3.1)

    6 months 5.8 (3.5)

    change from baseline –6.1 (4.1); –47%

    Tremor

    off medication state

    baseline 4.2 (2.1)

    6 months 1.2 (1.8)

    change from baseline –3.0 (1.8); –77%

    on medication state

    baseline 3.7 (1.9)

    6 months 0.9 (1.7)

    change from baseline –2.8 (1.9); –80%

    Bradykinesia

    off medication state

    baseline 9.4 (2.7)

    6 months 5.6 (2.9)

    change from baseline –3.9 (4.0); –37%

    on medication state

    baseline 6.5 (2.0)

    6 months 4.7 (2.1)

    change from baseline –1.9 (2.9); –23%

    Rigidity

    off medication state

    baseline 2.9 (0.7)

    6 months 0.8 (0.8)

    change from baseline –2.1 (1.0); –71%

    on medication state

    baseline 2.2 (1.2)

    6 months 5.8 (3.5)

    change from baseline –2.0 (1.4); –88%

    MDS–UPDRS III, untreated side, off-medication baseline 5.5 (2.5)

    6 months 6.2 (3.4)

    change from baseline 0.3 (1.7); 8%

    MDS–UPDRS III, untreated side, on-medication baseline 3.2 (3.1)

    6 months 4.3 (2.8)

    change from baseline 1.1 (2.8); 14%

    total MDS-UPDRS III score

    off medication state

    baseline 32.7 (5.4)

    6 months 21.2 (8.2),

    change from baseline –11.6 (6.9); –36%

    on medication state

    baseline 21.5 (6.3)

    6 months 14.5 (5.3),

    change from baseline –7 (8.1); –26%

    MDS–UPDRS IV scores

    baseline 4.2 (4.3)

    6 months 1.7 (2.2)

    change from baseline –2.4 (2.7); –45%

    UDRS scores

    baseline 10.1 (13.1)

    6 months 5.3 (7.5)

    change from baseline –4.7 (11.6); –32%

    MDS–UPDRS I

    baseline 5.9 (3.1)

    6 months 5.5 (4.9)

    change from baseline –0.4 (3.4); –18%

    MDS–UPDRS II

    baseline 7.9 (4.3)

    6 months 6.6 (7.1)

    change from baseline –1.3 (4.9); –32%

    LDD (mg)

    baseline 732.7 (346.4)

    6 months 564.4 (286.8)

    change from baseline –164.6 (131.9); –24%

    Quality of life

    PDQ-39SI score

    baseline 12.6 (8.8)

    6 months 10.4 (9.1)

    change from baseline–2.4 (8.2); –19%

    Treatment benefit (assessed with P-GIC and C-GIC)

    All patients except one had experienced a clinical improvement after 6 months according to the P-GIC. Neurologists found all patients very much improved as per GC-GIC scores.

    Adverse events

    During the procedure

    Transient warm cranial sensations (related to sonication), n=2

    Transient pin-site head pain (related to head frame), n=6

    Nausea (related to sonication), n=4

    Other events: back pain (n=2), anxiety (n=2), transient high blood pressure (n=5).

    6 months after the procedure

    Related to subthalamotomy

    Transient mild gait ataxia, n=6

    Facial palsy/asymmetry (n=1, resolved by follow-up).

    Post-discharge behavioural changes like impulsivity/disinhibition and abnormal cheerfulness (n=2, resolved within a month).

    Off-medication upper limb choeric dyskinesias (5 days after subthalamotomy, disappeared after 6 months), n=1

    Involuntary movements in treated arm/ on-medication upper limb dyskinesia (n=1, resolved after reduction in drug dose).

    Subjective speech disturbance (n=1).

    Other events: weight gain (n=2), fatigue (n=1), anxiety (n=1).

    Martinez Fernandez 2020

    RCT

    MDS-UPDRS-III scores (for the more affected side), change at 4 months

    off medication state (primary outcome)

    MRgFUS: baseline= mean 19.9 to 9.9; mean difference=9.8 (95% CI 8.6 to 11.1), 52.6%

    sham procedure: baseline=mean 18.7 to 17.1; mean difference= 1.7 (95% CI 0.0 to 3.5), 4.2%

    score difference between the groups

    8.1 points (95% CI 6.0 to 10.3, p<0.001)

    on-medication state

    MRgFUS subthalamotomy: baseline= mean 14.2 to 7.8, mean difference=6.4 (95% CI 5.2 to 7.6), 46.5%

    sham: baseline=mean 11.9 to 11.8, mean difference=0.1 (95% CI −0.3 to 0.6) 6.0%

    Score difference between the groups

    5.9 points (95% CI 3.8 to 8.0).

    MDS-UPDRS-III sub scores (at 4 months)

    off medication

    Rigidity

    MRgFUS: baseline= mean 3.5 to 1.6, mean difference=1.9 (95% CI 1.6 to 2.2), 60.0%

    Sham: baseline= mean 3.8 to 3.7, mean difference=0.1 (95% CI −0.3 to 0.6), 0.0%

    Score difference between the groups

    1.8 (95% CI 1.3 to 2.3)

    Bradykinesia

    MRgFUS: baseline= mean 10.8 to 6.8, mean difference=4.0 (95% CI 3.2 to 4.7), 33.3%

    Sham: baseline= mean 9.7 to 8.3, mean difference=1.4 (95% CI 0.3 to 2.4) 9.1%

    Score difference between the groups

    2.7 (95% CI 1.4 to 4.0)

    Tremor

    MRgFUS: baseline= mean 5.6 to 1.6, mean difference=4.0 (95% CI 3.3 to 4.6), 83.3%

    Sham: baseline= mean 5.2 to 4.9, mean difference=0.3 (95% CI −0.6 to 1.3), 0.0%

    Score difference between the groups

    3.6 (95% CI 2.5 to 4.8)

    on medication

    Rigidity

    MRgFUS: baseline= mean 2.6 to 1.3, mean difference=1.3 (95% CI 1.0 to 1.6), 50.0%

    Sham: baseline= mean 2.6 to 2.8, mean difference=−0.2 (95% CI −0.6 to 0.2), 0.0%

    Score difference between the groups

    1.5 (95% CI 1.1 to 2.0)

    Bradykinesia

    MRgFUS: baseline= mean 7.9 to 5.6, mean difference=2.3 (95% CI 1.5 to 3.1), 27.3%

    Sham: baseline= mean 6.4 to 5.6, mean difference=0.8 (95% CI −0.3 to 2.0), 12.7%

    Score difference between the groups

    1.5 (95% CI 0.1 to 2.9)

    Tremor

    MRgFUS: baseline= mean 3.8 to 1.1, mean difference=2.7 (95% CI 2.1 to 3.3), 92.9%

    Sham: baseline=mean 2.9 to 2.9, mean difference=0.0 (95% CI −0.8 to 0.9), 0.0%

    Score difference between the groups

    2.7 (95% CI 1.6 to 3.7)

    MDS-UPDRS II score (change at 4 months)

    MRgFUS: baseline= mean 11.3 to 7.2, mean difference=4.1 (95% CI 2.2 to 5.9), 42.9%

    Sham: baseline=mean 12.5 to 13.4, mean difference=−1.4 (95% CI −4.0 to 1.2), −11.8%

    Score difference between the groups

    5.5 (95% CI 2.2 to 8.7)

    MDS-UPDRS III total score (change at 4 months)

    Off-medication state

    MRgFUS: baseline=mean 39.9 to 24.7, mean difference=15.2 (95% CI 13.5 to 17.0), 34.2%

    Sham: baseline=mean 40.1 to 37.8, mean difference=2.3 (95% CI −0.2 to 4.8), 6.3%

    Score difference between the groups

    12.9 (95% CI 9.9 to 16.0)

    On-medication state

    MRgFUS: baseline=mean 26.9 to 18.5, mean difference=8.4 (95% CI 6.6 to 10.3), 33.9%

    Sham: baseline=mean 25.1 to 25.9, mean difference=−0.8 (95% CI −3.4 to 1.8), 0.0%

    Score difference between the groups

    9.2 (95% CI 6.0 to 12.4).

    MDS-UPDRS IV total score (change at 4 months)

    MRgFUS (n=17): baseline=mean 4.0 to 2.9, mean difference=1.1 (95% CI 0.0 to 2.1), 40.0%

    sham (n=9): baseline=mean 5.1 to 6.3, mean difference=−1.2 (95% CI −2.7 to 0.3), 0.0%

    Score difference between the groups

    2.3 (95% CI 0.5 to 4.1)

    Dyskinesia

    MRgFUS (n=4): baseline=mean 0.3 to 0.3, mean difference=0.0 (95% CI −0.4 to 0.3)

    sham (n=4): baseline=mean 1.1 to 1.5, mean difference=−0.4 (95% CI −0.9 to 0.2)

    Score difference between the groups

    0.3 (95% CI −0.3 to 1.0)

    Motor fluctuations

    MRgFUS (n=16): baseline=mean 3.0 to 2.1, mean difference=0.9 (95% CI 0.2 to 1.6), 26.8%

    sham (n=9): baseline=mean 3.5 to 4.1, mean difference=−0.6 (95% CI −1.6 to 0.4), 12.5%

    Score difference between the groups

    1.5 (95% CI 0.2 to 2.7)

    Dystonia, in the off-medication state

    MRgFUS 7(n=8): baseline=mean 0.7 to 0.5, mean difference=0.2 (95% CI −0.1 to 0.5), 75.0%

    sham (n=3): baseline=mean 0.5 to 0.7, mean difference= −0.2 (95% CI −0.6 to 0.2)

    Score difference between the groups

    0.4 (95% CI −0.1 to 1.0)

    PDQ-39 SI (change at 4 months)

    MRgFUS: baseline=mean 21.7 to 14.3, mean difference=7.4 (95% CI 4.1 to 10.6), 38.5%

    Sham: baseline=mean 23.9 to 22.3, mean difference=1.6 (95% CI −3.1 to 6.2), 29.0%

    Score difference between the groups

    5.8 (95% CI 0.1 to 11.4)

    LDD (milligrams) (change at 4 months)

    MRgFUS: baseline=mean 729.7 to 635.2, mean difference=−94.5 (95% CI −151.9 to −37.2), 7.5%

    Sham: baseline=mean 881.7 to 859.2, mean difference=22.5 (95% CI −60.2 to 106.4), 0.0%

    Score difference between the groups

    −117.0 (95% CI −218.0 to −16.0

    P-GIC at 4 months

    clinical improvement reported by 85% (23/27) in MRgFUS group and 15% (2/13) in sham group.

    Additional analysis

    MDS-UPDRS III score for the more affected side in the crossover subgroup (n=12)

    baseline 19.5±3.9

    4 months 11.6 (95% CI 8.4 to 14.8), 68.0%

    Adverse events

    MRgFUS Subthalamotomy

    total n=144 (mild 96, moderate 40, severe 8)

    sham procedure

    total n=31 (mild 13, moderate 16, severe 2).

    Intraprocedural adverse events

    Nausea, emesis, dizziness, head tilting, head discomfort, pin-site head pain, headache, back or neck pain, high blood pressure, fatigue, occurred in both groups but more frequently in the treatment group than in the control group; these events resolved after the procedure.

    Anxiety (in 6) and right inner ear pain (in 1) were reported in the treatment group.

    Other adverse events not related to the procedure

    Rib fracture (in 2), fall (in 2) and dysuria (in 1) were reported in the treatment group.

    MRgFUS subthalamotomy group

    Dyskinesia in off medication state 22% (6/27), mostly resolved within 4 months.

    Chorea, n=5; Ballism, n=1

    New onset dyskinesia in on medication state

    22% (6/27), persisted in 2 people at 12 months.

    Weakness 19% (5/27) persisted in 2 people at 12 months.

    Isolated facial asymmetry 11% (n=3), mostly resolved within 4 months.

    Speech difficulties 56% (15/27), mainly transient

    dysarthria n=7, (persisted in 1 person at 1-year follow- up)

    slurred speech n=8

    Gait disturbances 48% (13/27)

    unsteady gait n=10 (persisted in 1 person at 1 year follow-up),

    ataxia n=3

    other events: upper limb dysmetria in 2, impulsive binge eating in 1 (resolved after 2 months), weight gain in 2 and somnolence in 1 (resolved after 24 hours) were also reported.

    Perilesional oedema in all, resolved by 4 months.

    Martinez Fernandez 2024

    MDS-UPDRS III score for the treated side, median (range)

    off-medication state

    baseline 14.5 (12.7–17.2)

    12 months 4.0 (2.0–7.2), p= 0.002

    sub scores

    tremor

    baseline 2.0 (1.0–4.2)

    12 months 0.0 (0.0–0.0), p <0.001

    rigidity

    baseline 3.0 (2.0–4.0)

    12 months 1.0 (0.7–1.2) p<0.001

    bradykinesia

    baseline 9.0 (8.0–10.0)

    12 months 3.0 (1.7–5.0) p=0.002

    on medication state, median (range)

    baseline 9.5 (6.7–13.2)

    12 months 2.5 (1.0–4.2), p=0.001

    sub scores

    tremor

    baseline 1.5 (0.7–2.2)

    12 months 0.0 (0.0–0.0), p <0.001

    rigidity

    baseline 2.0 (1.0–3.2)

    12 months 0.0 (0.0–1.0) p<0.001

    bradykinesia

    baseline 6.0 (4.5–7.2)

    12 months 2.0 (1.0–3.0) p=0.008

    MDS-UPDRS III for the untreated side off-medication, median (range)

    baseline 4.5 (3.7–6.0)

    12 months 5.0 (2.0–6.5), p= 0.420

    MDS-UPDRS III for the untreated side on-medication, median (range)

    baseline 2.0 (1.0–2.2)

    12 months 3.0 (1.0–5.2), p= 0.131

    MDS-UPDRS III total off-medication

    median (range)

    baseline 26.5 (23.2–32.2)

    12 months 13.0 (8.7–18.0), p= 0.002

    MDS-UPDRS III total on-medication

    median (range)

    baseline 18.0 (12.7–19.5)

    12 months 8.0 (6.0–10.7), p= 0.016

    MDS-UPDRS IV,median (range)

    baseline 1.0 (0.0–3.0)

    12 months 1.0 (0.0–1.0), p= 0.408

    Dyskinesia

    baseline 0.0 (0.0–0.0)

    12 months 0.0 (0.0–0.0), p= 0.392

    Motor fluctuations

    baseline 0.5 (0.0–3.0)

    12 months 0.0 (0.0–0.2), p= 0.102

    Off-dystonia

    baseline 0.0 (0.0–0.0)

    12 months 0.5 (0.0–1.0), p= 0.275

    MDS-UPDRS I,median (range)

    baseline 4.0 (3.0–6.0)

    12 months 2.0 (1.0–3.5), p= 0.023

    MDS-UPDRS II,median (range)

    baseline 6.0 (2.0–7.2)

    12 months 3.0 (1.0–5.0), p= 0.022

    PDQ-39SI,median (range)

    baseline 11.6 (8.1–21.8)

    12 months 6.7 (3.5–10.6), p= 0.035

    LEDD (mg), median (range)

    baseline 560.0 (498.7– 668.7)

    527.5 (340.0– 606.2), p= 0.161

    LDD (mg), median (range)

    baseline 300.0 (237.5– 312.5)

    12 months 225.0 (200.0– 312.5), p=0.255.

    P-GIC at 12 months and patient satisfaction

    91.7% (11/12) reported a better global status compared with baseline (according to P-GIC questionnaire), while all patients reported being satisfied with the treatment.

    Adverse events (mainly mild and transient)

    Dyskinesia on treated side (off medication state)

    n=1, at 3 months

    New onset drug induced dyskinesia on treated side (3 in upper limb and 1 in lower limb) 33% (4/12) of these 1 persisted at 3 months.

    Isolated facial asymmetry 50% (6/12) (reported at different follow-up periods, of these 1 persisted at 12 months)

    Speech abnormalities (mild slur) 17% (2/12), 1 of which persisted at 12 months.

    Contralateral weakness n=1, resolved within 24 hours

    mild transient gait instability 42% (5/12), resolved within 2 weeks

    Pericranial hypoesthesia n=1, at 3 months

    Hiccups n=1 within 24 hours

    Foot dystonia 17% (2/12), resolved by 6 months

    Weight gain 58% (7/12), persisted at 12 months

    Cheerfulness n=1, resolved by 3 months.

    perilesional oedema in all, resolved by 6 months

    no cognitive worsening or behavioural changes were observed.

    Procedure technique

    A similar procedure technique and device was used in all studies.

    Efficacy

    Change in motor features

    In a prospective cohort study of 32 patients who had MRgFUS unilateral subthalamotomy for asymmetrical presentation of Parkinson's, change in motor status (assessed with part III of the MDS-UPDRS) for the treated side of the body (contralateral to the subthalamotomy), in the off-medication state (that is, after a minimum 12-hour overnight withdrawal of antiparkinsonian drugs) reported that the mean part III score (ranging from 0 to 44) was statistically significantly improved by 52% from baseline to 3 years (reduced from 19.0 to 8.9, 95% CI 8.7 to 11.6, p< 0.001). The scores did not change significantly from 4 to 6 months to 3 years (from 7.7 to 8.9, 95% CI −2.5 to 0.2, p=0.09). Individual improvement at 3 years was heterogeneous and ranged from 7.2% to 95.7%. The change in the MDS-UPDRS III score for the treated side in the on-medication state (assessed 45 to 60 minutes after the intake of usual medication) improved by 55% from baseline to 3 years (reduced from 13.7 to 5.8, 95% CI 6.3–9.4, p<0.001), and was maintained (from 5.5 at 4 to 6 months to 5.8 at 3 years, 95% CI −1.6 to 0.8, p=0.50).The MDS-UPDRS part III sub-scores for all specific motor features (tremor, dyskinesia and rigidity) for the treated side of the body in both off-medication and on-medication states were improved from baseline to 3 years (p<0.001 for all) and was maintained from 4 to 6 months to 3 years.

    The MDS-UPDRS III for the untreated side improved statistically significantly from baseline to 3 years in both the off-medication and on-medication states (increased from 6.6 to 10.1, 95% CI −5.4 to −2.0, p<0.001 and 4.3 to 6.6, 95% CI −4.4 to −0.9, p=0.016), respectively. The total MDS-UPDRS III score was significantly improved from baseline to 3 years in both the off-medication and on-medication states, from 36.8 to 27.4 (95% CI 6.0–11.5, p<0.001) and from 24.7 to 17.7 (95% CI 3.7–10.1, p<0.001), respectively. Scores were statistically significantly increased (worsened) at 3 years compared with 4 to 6 months in the off-medication state (from 21.8 to 27.4, 95% CI −8.6 to −2.7, p<0.001) but the increase was not significant for the on-medication state (from 15.4 to 17.7, 95% CI −5.1 to 0.4, p<0.093) (Martinez-Fernandez 2023).

    In a pilot study of 10 patients with asymmetric PD and medically-refractory motor features who had unilateral subthalamotomy with MRgFUS targeting the affected side of the body, the mean MDS–UPDRS III score in the treated side reduced by 53% from baseline to 6 months in the off-medication state (16.6 to 7.5) and by 47% in the on-medication state (11.9 to 5.8). All cardinal signs improved, notably tremor and rigidity. The scores in the untreated side did not change in either the off-medication or on-medication state. Total MDS–UPDRS part III score reduced by 26% in the on-medication state and by 36% in the off-medication state (Martinez-Fernandez 2018).

    A randomised, sham-controlled trial of 40 patients with refractory PD and asymmetric symptoms (in which 27 patients had unilateral MRgFUS subthalamotomy and 13 had a sham procedure) reported that patients in the MRgFUS group had improvement in contralateral MDS-UPDRS part III scores in the off-medication state compared with the sham group at 4‑month follow up. The mean MDS-UPDRS part III score for the more affected side decreased from 19.9 at baseline to 9.9 at 4-month follow up in the MRgFUS group (mean difference 9.8 points; 95% CI 8.6 to 11.1) and from 18.7 to 17.1 in the sham group (mean difference 1.7 points; 95% CI 0.0 to 3.5). The between-group difference was 8.1 points (95% CI 6.0 to 10.3; p<0.001). The sub-scores for all specific motor features (tremor, dyskinesia and rigidity) for the treated side of the body in the off-medication state improved from baseline to 4‑month follow up (by 83%, 33% and 60%). The MDS-UPDRS part III score for the more affected side in the on-medication state at 4‑month follow up decreased by 6.4 points (95% CI 5.2 to 7.6) in the MRgFUS group and by 0.1 points (95% CI 0.3 to 0.6) in the sham group (between-group difference was 5.9 points; 95% CI 3.8 to 8.0). Total MDS–UPDRS part III score in the off-medication state reduced by 34% (mean change 15.2; 95% CI 13.5 to 17.0) in MRgFUS group compared with 6% (mean change 2.3; 95% CI−0.2 to 4.8) in the sham group. The between-group difference was 12.9 (95% CI 9.9 to 16.0).

    The mean decrease in the score in the MRgFUS group at 12‑month follow up was 11.6 points from baseline (95% CI 9.9 to 13.3; 25 patients). Among patients in the unblinded crossover group (controls who had MRgFUS), the mean MDS-UPDRS part III score for the more affected side decreased from 19.5 at baseline to 8.1 (mean difference 11.6 points; 95% CI 8.4 to 14.8; 11 patients) at 4‑month follow up and to 9.7 at 12 months (mean difference 8.7 points; 95% CI 4.5 to 12.9; 8 patients) (Martinez-Fernandez 2020).

    Another pilot study of 12 patients who had MRgFUS subthalamotomy for early PD (<5 years from diagnosis) reported 68% mean improvement in MDS-UPDRS part III motor scores in the off-medication state at 12‑month follow up (from 14.5 to 4.0, p=0.002). Sub-scores for motor features improved significantly by 70% for rigidity, 64% for bradykinesia and 90% for tremor (p<0.001, p=0.002, and p<0.001 respectively). In the on-medication state, the treated side showed 69% improvement in part III motor scores (from 9.5 to 2.5, p=0.001) at 12‑month follow up. The total motor MDS-UPDRS part III score also improved significantly by 49% and 43% in both the off-medication states (from 26.5 to 13.0, p=0.002) and on-medication states (from 18.0 to 8.0, p=0.016) (Martinez-Fernandez 2024).

    Motor complications

    In the prospective cohort study of 32 patients, the total score for motor complications of treatment (MDS-UPDRS part IV) did not change from baseline to 3 years (2.9 to 2.6, 95% CI −1.2 to 1.3, p=0.64). The scores for main motor complications (dyskinesias, motor fluctuations and off-medication dystonia) were similar at baseline and at 3‑year follow up (Martinez-Fernandez 2023).

    In the pilot study of 10 patients, the total score for motor complications of treatment (MDS-UPDRS part IV) decreased by 45% from baseline to 6 months (4.2 to 1.7) (Martinez-Fernandez 2018).

    In the RCT, the total score for motor complications of treatment (MDS-UPDRS part IV) decreased by 40% in the MRgFUS group from 4.0 to mean 1.1 (95% CI 0.0 to 2.1) and in the sham group from 5.1 to −1.2 (95% CI −2.7 to 0.3). The between-group difference was 2.3 (95% CI 0.5 to 4.1). The score for dyskinesia and dystonia did not differ between the MRgFUS and sham groups at 4‑month follow up (between-group differences 0.3 points [95% CI −0.3 to 1.0] and 0.4 points [95% CI −0.1 to 1.0]). The between-group difference for motor fluctuations was 1.5 points (95% CI 0.2 to 2.7) (Martinez-Fernandez 2020).

    In the pilot study of 12 patients, the total score for motor complications of treatment (MDS-UPDRS part IV) did not change from baseline to 12‑month follow up (p=0.408). The scores of main motor complications (dyskinesias, motor fluctuations and off-medication dystonia) were similar at baseline and at 1‑year follow up (p=0.392, p=0.102, p=0.275) (Martinez-Fernandez 2024).

    Functional impairment in activities of daily living

    In the prospective cohort study of 32 patients, scores for functional impairment in activities of daily living (MDS-UPDRS part II) in the on-medication state did not show significant improvement from baseline to 3 years (from 10.0 to 10.3, 95% CI −1.0 to 3.7, p=0.352) (Martinez-Fernandez 2023).

    In the pilot study of 10 patients, scores for functional impairment in activities of daily living (MDS-UPDRS parts I and II) were slightly decreased at 6‑month follow up compared with baseline (MDS-UPDRS part I 5.9 to 5.5, MDS–UPDRS part II 7.9 to 6.6) (Martinez-Fernandez 2018).

    In the RCT, scores for functional activities of daily living (MDS-UPDRS part II) improved from baseline in the MRgFUS group (mean change 4.1, 95% CI 2.2 to 5.9) but not in the sham group (mean change -1.4, 95% CI −4.0 to 1.2) at 4‑month follow up. The between-group difference was 5.5 points (95% CI 2.2 to 8.7) (Martinez-Fernandez 2020).

    In the pilot study of 12 patients, non-motor and motor symptoms' impact on daily living activities (MDS-UPDRS parts I and II) improved significantly at 12‑month follow up (p=0.023, p=0.022, respectively) (Martinez-Fernandez 2020).

    Quality of life

    In the prospective cohort study of 32 patients, quality-of-life scores (PDQ-39SI) were comparable from baseline to 3-year follow up and were not statistically significantly different (from 17.7 to 16.1, 95% CI −0.8 to 6.6, p=0.10) (Martinez-Fernandez 2023).

    In the pilot study of 10 patients, quality-of-life scores (PDQ-39SI) reduced by 19% from baseline to 6‑month follow up (12.6 to 10.4) (Martinez-Fernandez 2018).

    In the RCT, quality-of-life scores (PDQ-39SI) improved from baseline in the MRgFUS group (mean change 7.4, 95% CI 4.1 to 10.6) at 4‑month follow up. The mean change in the sham group was 1.6 (95% CI −3.1 to 6.2). The between-group difference was 5.8 points (95% CI 0.1 to 11.4) (Martinez-Fernandez 2020).

    In the pilot study of 12 patients, quality-of-life scores (PDQ-39SI) improved significantly from baseline (11.6 to 6.7, p=0.035) at 12‑month follow up (Martinez-Fernandez 2024).

    Medication usage

    In the prospective cohort study of 32 patients, drug changes (assessed as LEDD and as levodopa daily dose) at 3-year follow up were comparable with those at baseline (LEDD from 728.2 to 835.4 mg, 95% CI −5.4 to 220.1, p=0.06; levodopa dose 453.9 to 515.7 mg, 95% CI −29.9 to 162.9; p=0.17) (Martinez-Fernandez 2023).

    In the pilot study of 10 patients, drug usage (LEDD) reduced by 24% after 6 months compared with baseline (from 732.7 to 564.4 mg) (Martinez-Fernandez 2018).

    In the RCT, drug usage (LEDD, mg) from baseline was statistically significantly reduced in the MRgFUS group (mean change -94.5, 95% CI −151.9 to −37.2) at 4‑month follow up. The mean change in the sham group was 22.5 (95% CI −60.2 to 106.4). The between-group difference was −117.0 points (95% CI −218.0 to −16.0) (Martinez-Fernandez 2020).

    In the pilot study of 12 patients, a non-significant reduction in anti-parkinsonian drug requirements of both LEDD and levodopa dosage was reported (Martinez-Fernandez 2024).

    Patient's or clinician's impression of change and patient satisfaction

    In the prospective cohort study of 32 patients, 83% (24/29) patients who completed the self-assessed P-GIC questionnaire 3 years after treatment (ranges from "very much improved" to "very much worsened") reported a better global status than before baseline. 90% (26/29) of patients reported overall satisfaction with the treatment (self-assessed with an adapted satisfaction scale) (Martinez-Fernandez 2023).

    In the RCT, clinical improvement (P-GIC) was reported by 85% (23/27) of patients in the MRgFUS group and 15% (2/13) of patients in the sham group (Martinez-Fernandez 2020).

    In the pilot study of 10 patients, all patients except one experienced clinical improvement after 6 months according to the P-GIC and neurologists found all patients very much improved as per C-GIC scores (Martinez-Fernandez 2018).

    In the pilot study of 12 patients, 92% (11/12) of them reported a better global status compared with baseline (P-GIC). All patients reported being satisfied with the treatment (Martinez-Fernandez 2024).

    Safety

    Complications

    In the prospective study of 32 patients with Parkinson's who had MRgFUS for subthalamotomy, adverse events were mostly mild including:

    • At 4 to 6 month follow up,

      • drug induced dyskinesias in 25% (8/32) of patients

      • speech impairment in 9% (3 patients)

      • weight gain in 9% (3 patients)

      • contralateral limb weakness, facial asymmetry and unsteady gait in 1 patient each.

    • At 6-month follow up,

      • off-medication dyskinesia in the treated arm (1 patient, almost resolved by 6 months)

      • on-medication dyskinesia in the treated arm (1 patient, resolved after levodopa dose reduction)

      • subjective speech disturbance (1 patient)

      • anxiety and fatigue (1 patient each) and weight gain (2 patients)

      • transient gait ataxia (related to subthalamotomy, in 6 patients)

      • transient pin-site head pain (related to the head frame, in 6 patients)

      • transient high blood pressure (during the procedure, in 5 patients)

      • transient facial asymmetry (in 1 patient)

      • moderate impulsivity (in 2 patients).

    • At 3‑year follow up,

      • reduced verbal fluency, mild dysarthria and clumsy hand in 1 patient each were reported (Martinez-Fernandez 2023).

    In the RCT, reported adverse events in the MRgFUS group included:

    • dyskinesia in the off-medication state in 22% (6/27) of patients, which was transient and mostly resolved within 6 months (of these 5 were chorea and 1 was ballism movement)

    • new-onset dyskinesia in the on-medication state in 22% (6/27) of patients, which persisted in 2 patients at 12 months

    • weakness on the treated side in 19% (5/27) of patients, which persisted in 2 patients at 12 months

    • isolated facial asymmetry or weakness in 11% (3/27) of patients, which mostly resolved within 4 months

    • speech difficulties in 56% (15/27) of patients, which were mainly transient. These include dysarthria in 7 patients (which persisted in 1 patient at 1‑year follow up) and slurred speech in 8 patients

    • gait disturbances in 48% (13/27) of patients. These included unsteady gait in 10 patients (which persisted in 1 patient at 1‑year follow up) and ataxia in 3 patients

    • other events included upper limb dysmetria in 2 patients, impulsive binge eating in 1 patient (which resolved after 2 months), weight gain in 2 patients and somnolence in 1 patient (that resolved after 24 hours)

    • perilesional oedema was reported by all patients in the treatment group but resolved by 4 months

    • intraprocedural adverse events occurred in both groups but more frequently in the treatment group. These included nausea, emesis, dizziness, head tilting, head discomfort, pin-site head pain, headache, back or neck pain, high blood pressure and fatigue. These events resolved after the procedure. Anxiety (in 6 patients) and right inner ear pain (in 1 patient) were only reported in the treatment group (Martinez-Fernandez 2020).

    In the pilot study of 12 patients who had STN-FUS for early PD (<5 years from diagnosis):

    • 17% (2/12) of patients developed foot dystonia that needed treatment with botulinum toxin

    • weight gain was reported in 58% (7/12) of patients and persisted after 12 months. Isolated facial asymmetry was reported in 50% (6/12) patients at different follow-up periods (1 persisted at 12-month follow up)

    • transient gait instability was reported in 42% (5/12) of patients and resolved within 2 weeks

    • new-onset drug induced dyskinesia on the treated side (3 in upper limb and 1 in lower limb) was reported in 33% (4/12) of patients, and persisted in 1 patient at 3 months. Dyskinesia on the treated side (off-medication state) was reported in 1 patient at 3 months

    • speech abnormalities (mild slur) was reported in 17% (2/12) of patients and persisted in 1 patient at 12 months

    • cheerfulness, hiccups and pericranial hypothesia were reported in 1 patient each (Martinez-Fernandez 2024).

    Anecdotal and theoretical adverse events

    NICE sought expert advice 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 no anecdotal adverse events.

    They listed the following theoretical adverse events:

    • stroke

    • sensory side effects

    • permanent side effects.

    Two 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

    MRI-guided focused ultrasound subthalamotomy is intended for unilateral treatment in Parkinson's:

    • there is limited evidence on MRgFUS for unilateral subthalamotomy with short-term follow up, predominantly for advanced Parkinson's. Patients were young with short duration of symptoms

    • there is a small RCT, comparing against sham. Although it was double blinded, all patients and assessors correctly guessed the group assignments

    • studies were mainly done in 1 centre in Spain. These studies were sponsored by the device company.

    Ongoing studies:

    • NCT03964272: A feasibility study on the safety and preliminary efficacy of bilateral subthalamotomy using the ExAblate transcranial system to treat the cardinal motor features of Parkinson's. Feasibility study (3 enrolled); primary outcome: mean change (from baseline to 6 months) in the motor MDS-UPDRS score, adverse events; Study location: Spain; study completion date: June 2023.

    • NCT02246374:ExAblate Transcranial MRgFUS of the Subthalamic Nucleus for Treatment of Parkinson's Disease: A randomised feasibility clinical trial of the management of the medically-refractory motor symptoms of advanced idiopathic Parkinson's with unilateral lesioning of the subthalamic nucleus using the ExAblate transcranial system. N=7, crossover assignment; exablate subthalamotomy compared with sham subthalamotomy; primary outcome: incidence and severity of adverse events, mean change in MDS-UPDRS Part III scores; study completion date December 2023; location US; study status active, not recruiting.