Prospective Long-term Follow-up of Focused Ultrasound Unilateral Subthalamotomy for Parkinson Disease

Abstract

Background and Objectives

Unilateral magnetic resonance–guided focused ultrasound subthalamotomy (FUS-STN) has been shown to improve the cardinal motor features of Parkinson disease (PD). Whether this effect is sustained is not known. This study aims to report the long-term outcome of patients with PD treated with unilateral FUS-STN.

Methods

We conducted a prospective open-label study of patients with asymmetrical PD who underwent unilateral FUS-STN. All patients were evaluated up to 36 months after treatment. The primary outcome was the difference from baseline to 36 months after FUS-STN in the score of the Movement Disorder Society–Unified Parkinson's Disease Rating Scale (MDS-UPDRS) motor part (III) for the treated hemibody in the off-medication state. The safety outcome included all adverse events occurring during follow-up. Secondary outcomes were the change in the MDS-UPDRS III score on-medication; subscores of rigidity, bradykinesia, tremor, and axial features; total MDS-UPDRS III; and the MDS-UPDRS part IV. Functional disability and quality of life were assessed using the MDS-UPDRS II and the PDQ39, respectively. Patient impression of change and satisfaction with the treatment were self-assessed. The Wilcoxon signed-rank test with subsequent Bonferroni's correction was used for data analysis.

Results

Thirty-two patients with PD were evaluated at 36 months after treatment. The mean (±SD) age at baseline was 56.0 ± 10.1 years, with a mean disease duration of 6.8 ± 2.8 years. The MDS-UPDRS III score for the treated hemibody off-medication was improved by 52.3% from baseline to 3 years (score reduction from 19.0 ± 3.2 to 8.9 ± 3.3, 95% CI 8.7 to 11.6, p < 0.001), and all specific motor features were improved from baseline. No disabling or delayed adverse events were reported. The total MDS-UPDRS III off-medication score was 22.9% lower at 3 years than before treatment (36.8 ± 7.4 vs 27.4 ± 6.2, 95% CI 6.0 to 11.5, p < 0.001). The MDS-UPDRS II, IV, and PDQ39 scores and levodopa dose were equivalent to those at baseline.

Discussion

The benefit of unilateral FUS-STN on PD motor features is sustained in the long term. FUS-STN contributes to better clinical control over several years of evolution. NCT02912871/03454425.

Classification of Evidence

This study provides Class IV evidence on the utility of focused ultrasound unilateral subthalamotomy in the treatment of people with Parkinson disease.

Transcranial magnetic resonance–guided focused ultrasound (FUS) is an incisionless neurofunctional technique that allows therapeutic deep brain thermoablation.¹ The technique is rapidly expanding worldwide for the treatment of movement disorders,² such as tremor with thalamotomy,^3-5 and the cardinal features of Parkinson disease (PD) with subthalamotomy,^6,7 and pallidotomy.⁸ One main concern is whether ultrasound ablation will provide sustained benefit in long-term evolution. Preliminary evidence indicates that the relief of essential tremor (ET) by FUS thalamotomy remains unchanged for at least 4 years without any delayed complications.^9,10 However, the long-term effect of ultrasound ablation on a progressive neurodegenerative disorder such as PD is not known. Here, we report a prospective evaluation of patients with PD treated with unilateral FUS-subthalamotomy (FUS-STN) for asymmetrical PD at 3 years after treatment. The primary objective of this study was to determine whether the benefit of FUS-STN over PD motor features was sustained in the long term and whether any delayed adverse events occurred.

Methods

Patients

This long-term follow-up cohort includes patients with PD who were enrolled at HM CINAC Hospital Puerta del Sur (Madrid, Spain) in a prospective open-label pilot study (10 patients)⁶ and a subsequent randomized controlled trial (36 patients)⁷ of unilateral FUS-STN for the treatment of PD motor features between April 2016 and May 2019. Patients were included if they had markedly asymmetrical parkinsonism with suboptimal control of motor signs on the more affected side despite the use of dopaminergic medication according to best medical treatment recommendations.¹¹ Patients were not eligible or were reluctant to have intracranial surgery for deep brain stimulation (DBS). The main exclusion criteria in these studies were meaningful axial motor manifestations, significant bilateral parkinsonism, severe levodopa-induced dyskinesia, significant cognitive impairment, and a skull density ratio (an index of skull penetration of the ultrasound beams) below 0.40. Complete inclusion/exclusion criteria of both studies are available in the initial reports.^6,7

Standard Protocol Approvals, Registrations, and Patient Consents

All patients signed informed consent before inclusion in the trials. Authorization has been obtained for disclosure of any recognizable persons in videos. The study protocols were approved by the Local Ethics Committee for Clinical Research and are publicly registered in clinicaltrials.gov (NCT02912871, NCT03454425). Long-term follow-up of the patients was an outcome contemplated in both protocols, although it was not specifically registered.

Focused Ultrasound Subthalamotomy

The procedure of unilateral FUS-STN has been described previously in detail.^6,7 Briefly, the subthalamic nucleus (STN) is targeted in the dorsolateral region (the motor area) and above, mediodorsally to affect the pallidothalamic tract.¹² The energy released and the location of the ultrasound focus were monitored in real time during the procedure by MRI thermometry and adjusted to reach ablative temperatures (i.e., higher than 54°C). The patient was regularly assessed during the procedure by the treating physicians to evaluate the clinical response. The procedure was considered finalized when sufficient clinical improvement had been attained and considering the total amount of energy delivered and the number of sonications above 54°C.

Study Design and Outcome Measures

This is a prospective open-label follow-up extension of a cohort of patients who received unilateral FUS-STN in 2 previous clinical trials.^6,7 Evaluation time points included baseline (i.e., pretreatment), 4–6 months (6 months for patients treated in the context of the pilot study and 4 months for patients treated in the randomized trial), 12, 24, and 36 months after treatment. Seven patients from the same cohort were also available for 5-year evaluation. All patients reported here were examined and scored by the same Movement Disorder team. The study provides Class IV evidence.

Two primary outcomes were established. The primary efficacy outcome was the difference from baseline to 3 years after FUS-STN in the Movement Disorder Society–Unified Parkinson's Disease Rating Scale (MDS-UPDRS) part III score for the treated side of the body (contralateral to the subthalamotomy), in the off-medication state (i.e., after a minimum 12-hour overnight withdrawal of parkinsonian drugs). The MDS-UPDRS III score for one side of the body ranges from 0 to 44. The persistence of initial benefit was assessed comparing the off-medication motor MDS-UPDRS at 4–6 months vs 3 years.⁹ The primary outcome of safety included all adverse events observed or reported during follow-up. Their severity was graded as follows: mild (not affecting daily routine activities), moderate (interferes with routine daily activities), or severe (inability to perform activities of daily living).¹³ In addition, a complete cognitive and behavioral assessment was performed between 24 and 36 months and compared with baseline values. To avoid any bias from patients not attending the long-term follow-up visit (i.e., dropouts) due to unsuccessful treatment, several measures were taken. First, characteristics at baseline and improvements in motor scores at 4–6 months of both groups were compared. Second, the primary outcome was conservatively reanalyzed adding to the sample those patients who were lost to follow-up (n = 13) and assuming that they had gone back to their MDS-UPDRS III baseline scores. Finally, adverse events at 4–6 months and at 12 months of the patients who dropped out throughout the follow-up were collected and compared with the group of patients who did not.

Most secondary outcomes were evaluated at the same time points as the primary outcomes (i.e., baseline, 4–6, 12, 24, and 36 months). They included the change in the MDS-UPDRS III score for the treated side in the on-medication state (assessed 45–60 minutes after the intake of usual medication); the MDS-UPDRS III subscores of rigidity, bradykinesia, and tremor for the treated side in both the off-medication and on-medication states; the total MDS-UPDRS III; the change in the MDS-UPDRS III for the untreated hemibody; axial MDS-UPDRS III motor scores; motor complications assessed through the MDS-UPDRS part IV; functional impairment in activities of daily living using the MDS-UPDRS part II questionnaire (assessed in the daily life in the on-medication state); quality of life evaluated through the 39-item PD Questionnaire Summary Index (PDQ-39SI); and the Patients' Global Impression of Change after treatment, a self-assessment scale that ranges from “very much improved” to “very much worsened.” Patients' overall satisfaction with the treatment was assessed with an adapted satisfaction scale (details in eMethods 1, links.lww.com/WNL/C589). Drug changes were assessed as levodopa equivalent daily dose (LEDD) according to accepted equivalences^14,15 and as levodopa daily dose. Brain MRI scans were also acquired in a few patients to observe lesion evolution in the long term.

Statistical Analysis

Clinical outcomes for continuous values are presented as mean ± SD. Comparisons between baseline and follow-up visits were ascertained using the Wilcoxon signed-rank test for nonparametric data. Bonferroni correction for multiple comparisons was applied. The statistical significance level was considered α = 0.05/n for Bonferroni-corrected comparisons, where n is the number of performed comparisons. Percent change from baseline was calculated as follows: (baseline scores minus posttreatment scores/baseline scores) × 100. To ascertain that the initial improvement after treatment was sustained in the long term (i.e., to prove the durability of the effect), the scores at the 4–6-month visit were compared with those at last follow-up. Differences between patients who reached last follow-up and the group of dropouts were analyzed using the Mann-Whitney U test for independent samples. In this case, a p value of less than 0.05 was considered to indicate statistical significance. Analyses were performed using statistics/data analysis software STATA (StataCorp LLC, version 16.1).

Data Availability

Anonymized data not published within this article will be made available by request from any qualified investigator.

Results

Thirty-two of 45 patients with PD previously treated with unilateral subthalamotomy in our center were available for long-term assessment. Thirteen patients did not reach the last follow-up visit for several reasons (Figure 1). Accordingly, the final cohort of this study consisted of 32 patients with PD who were evaluated at 3 years after treatment. Of note, baseline characteristics between the group of patients who dropped out and those who finished the long-term follow-up showed no significant differences, with the exception of disease duration and motor complications, which were higher in dropouts. Also, motor improvements at 4–6 months after FUS-STN were mostly equivalent between groups, although the missing patients showed lower reductions in the total MDS-UPDRS III on-medication (see details in eTable 1, links.lww.com/WNL/C589). For the 32 patients' cohort, the mean (±SD) age at baseline was 56.0 ± 10.1 years (range 35–74), with a mean disease duration of 6.8 ± 2.8 years. The mean MDS-UPDRS part III total scores at baseline were 36.8 ± 7.4 and 24.7 ± 7.4 in the off-medication and on-medication states, respectively. At baseline, the mean LEDD was 728.2 ± 260.5 mg, including a mean daily levodopa dose of 453.9 ± 229.9 mg. Baseline characteristics are detailed in Table 1. Through the 3-year follow-up, parkinsonism on the nontreated side of 3 patients worsened and was not adequately controlled with medication. Patients were offered contralateral STN-DBS or contralateral FUS-STN (the latter in the context of a bilateral staged FUS-STN clinical trial, NCT03964272). They chose to undergo FUS-STN and were treated at 36, 11, and 20 months after initial subthalamotomy. To avoid any bias, data from the latter 2 patients were only considered for the primary efficacy outcome.

Figure 1. Patient Inclusion Flowchart.

FUS-STN = focused ultrasound subthalamotomy; PD = Parkinson disease; RCT = randomized controlled trial; QT = chemotherapy.

Table 1.

Baseline Characteristics

Efficacy Outcomes

Off-Medication Evaluation

The difference in the MDS-UPDRS part III score for the treated side of the body off-medication (primary efficacy outcome) improved by 52.3% from baseline at 3 years (score reduction from 19.0 ± 3.2 to 8.9 ± 3.3, 95% CI, 8.7–11.6, p < 0.001; Table 2 and Figure 2A, Video 1, section 2). The patients' individual improvements ranged from 7.2% to 95.7% (Figure 2B). The initial benefit provided by FUS-STN was sustained throughout the follow-up. Thus, from the 4–6-month assessment to 3 years, the unilateral MDS-UPDRS III score on the treated side did not increase significantly (7.7 ± 4.0 to 8.9 ± 3.3, 95% CI −2.5 to 0.2, p = 0.09). All motor features on the treated side at 3 years remained improved as compared to baseline in the off-medication state. Hence, tremor, rigidity, and bradykinesia score reductions were 72.4%, 49.1%, and 45.0%, respectively. In the conservative reanalysis of the primary outcome adding those patients who were lost to follow-up and considering that they had gone back to their baseline unilateral MDS-UPDRS III score, 3 years after treatment, the score for the primary outcome still was significantly smaller (i.e., improved) than that at baseline (19.1 ± 3.4 to 11.9 ± 5.8, 95% CI 5.4 to 8.9 p < 0.001).

Table 2.

Clinical Effects of Unilateral Focused Ultrasound Subthalamotomy for Parkinson Disease

Figure 2. Efficacy Outcomes.

**p < 0.01; ***p < 0.001. At the 24-month time point, the analysis included 20 patients. Panel A shows the mean MDS-UPDRS part III (motor scores) for the more affected/treated hemibody in the off-medication state (primary outcome) at different time points (4–6 months, 12 months, 24 months, and 36 months). Initial significant improvement is sustained throughout follow-up for up to 3 years. Panel B shows the individual reductions (%) at 3 years in the MDS-UPDRS III score for the more affected/treated hemibody in the off-medication state. The motor MDS-UPDRS clinically significant change is classically established in the literature at 30% (dashed line); in this series, 29 of 32 patients had improvements that were considered clinically meaningful by that standard. Panels C and D show the mean MDS-UPDRS part III total score in the off- and on-medication states, respectively, at different time points (4–6, 12, 24, and 36 months). In both cases, patients at last follow-up remained improved from baseline. On-medication, the benefit achieved immediately after treatment was sustained in the long term. MDS-UPDRS = Movement Disorder Society–Unified Parkinson's Disease Rating Scale; ns = not significant.

On-Medication Evaluation

The MDS-UPDRS III score for the treated side in the on-medication state decreased by 55.2% from baseline to 3 years (13.7 ± 3.7 to 5.8 ± 2.9, 95% CI 6.3–9.4, p < 0.001), and durability was maintained (from 5.5 ± 3.4 at 4–6 months to 5.8 ± 2.9 at 3 years, 95% CI −1.6 to 0.8, p = 0.50). All specific motor subscores were also improved significantly at 3 years compared with baseline (Table 2).

Other Secondary Outcomes

The total MDS-UPDRS III score was improved from baseline to 3 years in both the off-medication and on-medication states, from 36.8 ± 7.4 to 27.4 ± 6.2 (95% CI 6.0–11.5, p < 0.001) and from 24.7 ± 7.4 to 17.7 ± 5.7 (95% CI 3.7–10.1, p < 0.001), respectively (Figure 2, C and D). There was a significant increase in the total MDS-UPDRS III scores from the first posttreatment visit at 4–6 months to 3 years for the off-medication (from 21.8 ± 7.9 to 27.4 ± 6.2, 95% CI −8.6 to −2.7, p < 0.001). The increase was not significant on-medication (from 15.4 ± 6.3 to 17.7 ± 5.7, 95% CI −5.1 to 0.4, p < 0.093). This increment in the total motor score was due mainly to the nontreated body side score, which increased significantly from baseline in both the off-medication and on-medication states (6.6 ± 3.1 to 10.1 ± 4.6, 95% CI −5.4 to −2.0, p < 0.001 and 4.3 ± 2.9 to 6.6 ± 4.2, 95% CI −4.4 to −0.9, p = 0.016, respectively, Table 2). Axial motor signs improved significantly in the short term (4–6 months) after treatment in the off-medication state. This improvement was sustained by 3 years (from 1.1 ± 0.3 at baseline to 0.9 ± 0.2, 95% CI 0.125 to 0.313, p = 0.008). See details in eTable 2, links.lww.com/WNL/C589. After 3 years, motor complications according to the MDS-UPDRS IV total score remained unmodified from baseline (2.9 ± 3.4 to 2.6 ± 2.2, 95% CI −1.2 to 1.3, p = 0.64). The scores of main motor complications (i.e., peak dose levodopa-induced dyskinesias, motor fluctuations, and off-medication dystonia) were equivalent at baseline and 3 years. MDS-UPDRS II scores (activities of daily living) followed a similar evolution (from 10.0 ± 5.4 to 10.3 ± 6.1, 95% CI −1.0 to 3.7, p = 0.352). Quality of life scores (PD39SI) remained lower than those at baseline, although the difference was no longer significant (PDQ-39SI from 17.7 ± 11.2 to 16.1 ± 9.7, 95% CI −0.8 to 6.6, p = 0.10). Finally, there was a trend for the LEDD to increase at 3 years as compared to baseline (from 728.2 ± 260.5 to 835.4 ± 330.0 mg, 95% CI −5.4 to 220.1, p = 0.06); however, the levodopa dose remained within the same range (453.9 ± 229.9 to 515.7 ± 220.8 mg, 95% CI −29.9 to 162.9; p = 0.17).

Notably, 24 of 29 (82.8%) patients who completed the Global Impression of Change Questionnaire reported a better global status at 3-year follow-up than before ultrasound subthalamotomy, and 26 of 29 (89.7%) patients reported being satisfied with the treatment (see details in eFigures 1 and 2, links.lww.com/WNL/C589, respectively).

Safety Outcomes

Adverse events at each time point are summarized in Table 3. Most of those that were present at 4–6 months were mild and did not interfere with the benefit induced by subthalamotomy. Main AE 4-6 months after treatment were dyskinesias in 8 patients (25%), contralateral limb weakness in 1 patient (3%), facial asymmetry in 1 (different) patient, speech impairment in 3 patients (9%), subjective unsteady gait in 1, and 3 cases of weight increase. These had progressively resolved or substantially improved as further time had passed. Thus, at 3 years, one patient still reported reduced verbal fluency that was not noticeable on the neurologic examination, another exhibited mild dysarthria, and one additional patient continued to show a clumsy hand without paresis. None of these adverse events were reported as disabling by the patients. A total of 8 of 30 patients (26.6%) at 3 years exhibited peak-dose levodopa-induced dyskinesia affecting one limb of the treated body side. Among them, all except one patient had reported dyskinesias within the first 4–6 months after treatment that, at that time, were resolved with levodopa dose adjustment. At the last follow-up, levodopa-induced dyskinesias were mild and nondisabling (MDS-UPDRS IV 4.1 + 4.2 scoring ≤2 in 6 of the 8 cases) and did not require any specific treatment. No significant differences between the baseline scores and the 3-year follow-up in the complete behavioral and cognitive examination were found (see specific scores in eTable 3, links.lww.com/WNL/C589). Brain MRI showed progressive reduction in lesion size without any delayed radiologic complication. Lesions were only identifiable as a focal hypointensity on susceptibility-weighted sequences years after treatment (see eFigures 3 and 4 for neuroimaging representative cases).

Table 3.

Adverse Events (AEs) Observed Throughout Follow-up

No significant differences in terms of FUS-STN–related adverse events at 4–6 months after treatment were found between patients evaluated at 36 months and those lost to follow-up, except for levodopa-induced dyskinesias that were more common in the former (16% vs 7%, respectively; see details in eTable 4, links.lww.com/WNL/C589).

Finally, a subgroup of 7 patients was followed up for 5 years. The results of this sample are presented in eResults 1 and eTable 5, links.lww.com/WNL/C589. In brief, the treated side was still improved from baseline in the off-medication state (49.6%, 16.2 ± 2.3 to 8.0 ± 2.8, 95% CI 4.7 to 11.7, Video 1, section 3). The total MDS-UPDRS III score, despite increasing, was still better than that at baseline in both off-medication (from 31.5 ± 5.1 to 28.0 ± 7.2, 95% CI −3.6 to 10.6) and on-medication (from 21.2 ± 6.1 to 16.7 ± 4.5, 95% CI −3.4 to 12.4) states. In one patient, levodopa peak-dose dyskinesias had become disabling.

Classification of Evidence

This study provides Class IV evidence on the long-term benefit of FUS unilateral subthalamotomy in the treatment of people diagnosed with PD.

Discussion

This study indicates that the motor benefit of unilateral FUS-STN in PD was sustained on the treated side of the body after several years. The effect was associated with a better overall motor status. It is noteworthy that side effects reported at 4–6 months remained mild and nondisabling over the long-term evolution, and no delayed adverse events were encountered. Among potential subthalamotomy-related side effects, dyskinesias deserve special attention. The occurrence of chorea-ballism after lesioning and aggravation of levodopa-induced dyskinesias have been the most feared complication when considering subthalamotomy in PD. There is certainly no doubt that blocking/lesioning the STN in the normal state is highly prodyskinetic, but experimental and clinical evidence indicates that, in the parkinsonian situation, the threshold to develop dyskinesias after subthalamic lesioning is higher than usual.¹⁶ Indeed, in our previous FUS-STN studies, dyskinesias on the treated body side were frequent but generally mild, and all had a positive evolution within the ensuing weeks or months without any specific treatment. In this long-term assessment, although LEDD returned to baseline levels, disabling levodopa-induced dyskinesias were not present. This fits well with previous results of radiofrequency-induced subthalamotomy.^17-20 The favorable outcome we have observed regarding dyskinesia may also be mediated by the intended extension of the lesion into the dorsomedial subthalamic area to affect the pallidothalamic tract, which has been shown to reduce the likelihood of hemichorea-ballism.^12,21

The duration and persistence of the clinical benefit achieved with functional neurosurgical therapies for movement disorders is a topic of major practical importance. Several series have shown the sustained benefit of radiofrequency-induced thalamotomy for essential and parkinsonian tremor^22,23 and pallidotomy and subthalamotomy in PD.^18,19,24 FUS and radiofrequency ablations are induced differently but essentially share the same therapeutic mechanism (i.e., heating-mediated elimination of brain targets where neuronal activity is abnormal), and the MRI features of lesions produced by either technique are comparable. Thus, an equivalent effect of both methods in the long term could be anticipated. Indeed, 2 open-label studies of FUS thalamotomy for ET have shown persistent tremor relief for up to 3–4 years.^9,10 Admittedly, ablation cannot be adjusted throughout disease evolution according to the patient's clinical needs, unlike DBS. Notably, STN-DBS reports for PD have shown that its long-term efficacy does not substantially rely on stimulation adaptability because typically stimulation parameters are not modified significantly beyond the first year after surgery.^25-27 This finding would suggest that once the optimal effect of the stimulation parameters and electrical field on the target is achieved, it remains stable. Consequently, we could anticipate that an adequately performed FUS ablation, even without the feature of adaptability, could emulate the therapeutic benefit normally achieved by DBS.

The number of patients available (N = 32) and time of follow-up assessment (3 years) were relatively limited. This is a natural consequence of the novelty of the approach and could be overcome in the future. The dropout rate from the initial sample of 45 treated patients was relatively high (29%). It was mainly caused by the restrictions related to the SARS-CoV-2 pandemic. Noteworthy, most baseline characteristics between the group of patients who dropped out and those who reached last follow-up were similar, except that dropouts had longer disease duration and a higher score for motor complications, which admittedly suggest greater disease severity. However, most motor improvements in the short term after treatment (including the primary outcome) and treatment-related adverse events showed no significant differences between groups. Also, an additional analysis including missing patients and conservatively assuming that they had worsened back to baseline scores showed that the improvement on the treated body side remained significant at last follow-up. Altogether, this reduces a selection bias having an impact on the long-term results. We also admit that the response (i.e., motor benefit) was variable. Individual improvement at 3 years was heterogeneous and ranged from 7.2% to 95.7%. This is probably related to specific individual factors governing the response, particularly the accuracy and precision of the lesion itself but also differences in disease progression. In the future, it may be possible to predict and select those candidates with the best chance of a good response.²⁸ It is also likely that greater clinical experience and technical developments will allow the FUS-STN procedure to be improved methodologically and lead to more homogenous results.²⁹

At last follow-up, most patients self-assessed their condition as better than before subthalamotomy and remained satisfied with the achieved benefit. By contrast, neither quality of life (PDQ-39SI) nor independence in activities of daily living (MDS-UPDRS II) showed significant improvement. These apparently contradictory findings could be partially explained by a floor effect caused by low baseline scores of the scales, a limitation that is not found in self-assessed qualitative questionnaires and, also, by the relatively small sample.

Our treated patients are typically asymmetrical. On the one hand, this could explain why the response to levodopa at baseline was only 30%, lower than the typical percentage improvement for patients who undergo bilateral STN-DBS.³⁰ Levodopa-refractory features (i.e., tremor) of the most affected side together with the floor effect for improvement on the least affected side most likely explain the relatively small magnitude of improvement achieved by levodopa. On the other hand, it limits the generalization of the results to the entire parkinsonian population. Of note, LEDD tended to increase throughout follow-up, and although not significantly, medication dosage was higher at last follow-up than at baseline. This could be explained mainly by disease progression leading to impairment on the nontreated side (about 50% on the unilateral motor score, details in Table 2). Of interest, though, only 3 of our 32 patients who had received unilateral FUS-STN required any other invasive neurosurgical treatment (i.e., contralateral staged FUS-STN) in the following years. Thus, according to our findings and previous radiofrequency ablation series, a unilateral approach in selected patients with PD, in conjunction with appropriate pharmacologic management, may be sufficient to maintain adequate clinical control of parkinsonism over a relatively long period.^18,19 Of course, the mid- and long-term evolution of a progressive neurodegenerative disorder such as PD inevitably poses challenges beyond the mere control of cardinal motor features. It is well established that the problems associated with long-term management of patients with PD treated with surgery are mostly related to the development of clinical features refractory to medication and stimulation/ablation such as nonmotor symptoms and freezing of gait.^26,27 On the other hand, functional interventions in the basal ganglia level may play a prominent role during the early, fundamentally motor-dominated stages of PD. In such circumstances, FUS might become a useful therapeutic tool to better control parkinsonism.

In conclusion, FUS-STN appears to provide sustained benefit in PD motor features years after treatment and does not raise safety concerns in the long-term evolution. Larger studies are needed to confirm these findings.

Video 1

The video shows the effect of the procedure and the evolution in a representative patient. A 68-year-old man with Parkinson disease diagnosed 6 years earlier. Pretreatment (section 1, baseline), parkinsonism in the off-medication state is predominant in the left hemibody, with rest and action tremor, as well as greater rigidity and bradykinesia. There was a net and sustained improvement of all motor features on the treated body side immediately after right subthalamotomy. The benefit in the same off-medication state is sustained after both 3 years (section 2) and 5 years (section 3, 73-year-old, 11 years of disease evolution), resulting in a marked reduction in asymmetry. No involuntary movements were present.Download Supplementary Video 1 ^{(49.7MB, mp4)} via http://dx.doi.org/10.1212/206771_Video_1

Glossary

DBS

deep brain stimulation

ET

essential tremor

FUS-STN

focused ultrasound subthalamotomy

LEDD

levodopa equivalent daily dose

MDS-UPDRS

Movement Disorder Society–Unified Parkinson's Disease Rating Scale

PD

Parkinson disease

PDQ-39SI

39-item Parkinson's Disease Questionnaire Summary Index

STN

subthalamic nucleus

Appendix. Authors

Study Funding

This study was supported by Fundación de investigación HM Hospitales. The initial short-term clinical trials (NCT02912871, NCT03454425) were supported by Insightec (Haifa, Israel), the Focused Ultrasound Foundation (Charlottesville, VA), and Fundación de investigación HM Hospitales and Fundación MAPFRE (Madrid, Spain).

Disclosure

R. Martínez-Fernández has received speaker honoraria from Insightec, Bial, Zambon, and Boston Scientific and reimbursement of travel expenses to attend scientific conferences from Insightec and Bial; E. Natera-Villalba was supported during 2021 by a fellowship from the Spanish Movement Disorders Group granted by Zambon; J.U. Máñez Miró has received speaker honoraria from Insightec, Bial, Zambon, UCB Pharma, Lundbeck, and Italfarmaco and reimbursement of travel expenses to attend scientific conferences from Insightec and Bial; R. Rodriguez-Rojas has received speaker honoraria from Insightec and Zambon; M. del Álamo has received speaker honoraria from Insightec and Boston Scientific and reimbursement of travel expenses to attend scientific conferences from Boston Scientific and Medtronic; J.A. Pineda-Pardo has received speaker honoraria from Insightec and reimbursement of travel expenses to attend scientific conferences from General Electric; C. Ammann is granted by Comunidad de Madrid (fellowship 2017-T2/BMD-5231); I. Obeso is granted by the AES-ISCIII-Miguel Servet (CP18/00038); D. Mata-Marín declares no conflicts of interest nor additional disclosures to report; F. Hernández-Fernández reports no disclosures relevant to the manuscript; C. Gasca-Salas has received speaker honoraria from Esteve and a grant from Asociación Madrileña de Neurología, funded by Bial; M. Matarazzo has received speaker honoraria from Teva Pharmaceutical Industries and Novartis and reimbursement of travel expenses to attend scientific conferences from Lundbeck and Cerevel Therapeutics; F. Alonso-Frech has received speaker honoraria from Boston SC, Zambon, Bial, and AbbVie and grants from the Michael J Fox Foundation and Lain Entralgo Agency; and J.A. Obeso has received honoraria for lecturing and reimbursement of travel expenses to attend scientific meetings by Insightec. Go to Neurology.org/N for full disclosures.