The Role of Focused Ultrasound in the Management of Movement Disorders: Insights after 5 Years of Experience.

Abstract

Movement Disorders Clinical PracticeVolume 8, Issue 5 p. 681-687 VIEWPOINTFree Access The Role of Focused Ultrasound in the Management of Movement Disorders: Insights after 5 Years of Experience Raúl Martínez-Fernández MD, PhD, Corresponding Author Raúl Martínez-Fernández MD, PhD rmartinez.hmcinac@hmhospitales.com orcid.org/0000-0002-0305-013X HM CINAC (Centro Integral de Neurociencias Abarca Campal), Hospital Universitario HM Puerta del Sur, HM Hospitales, Madrid, Spain Network Center for Biomedical Research on Neurodegenerative Diseases, Carlos III Institute, Madrid, Spain Correspondence to: Raúl Martínez-Fernández, Centro Integral en Neurociencias (CINAC), University Hospital HM Puerta del Sur, CEU-San Pablo University, Av. Carlos V 70, 28939 Móstoles, Spain; E-mail: rmartinez.hmcinac@hmhospitales.comSearch for more papers by this authorMichele Matarazzo MD, Michele Matarazzo MD orcid.org/0000-0002-2907-8667 HM CINAC (Centro Integral de Neurociencias Abarca Campal), Hospital Universitario HM Puerta del Sur, HM Hospitales, Madrid, Spain Network Center for Biomedical Research on Neurodegenerative Diseases, Carlos III Institute, Madrid, SpainSearch for more papers by this authorJorge U. Máñez-Miró MD, Jorge U. Máñez-Miró MD orcid.org/0000-0002-8995-8340 Search for more papers by this authorJose A. Obeso MD, PhD, Jose A. Obeso MD, PhD HM CINAC (Centro Integral de Neurociencias Abarca Campal), Hospital Universitario HM Puerta del Sur, HM Hospitales, Madrid, Spain Network Center for Biomedical Research on Neurodegenerative Diseases, Carlos III Institute, Madrid, SpainSearch for more papers by this author Raúl Martínez-Fernández MD, PhD, Corresponding Author Raúl Martínez-Fernández MD, PhD rmartinez.hmcinac@hmhospitales.com orcid.org/0000-0002-0305-013X HM CINAC (Centro Integral de Neurociencias Abarca Campal), Hospital Universitario HM Puerta del Sur, HM Hospitales, Madrid, Spain Network Center for Biomedical Research on Neurodegenerative Diseases, Carlos III Institute, Madrid, Spain Correspondence to: Raúl Martínez-Fernández, Centro Integral en Neurociencias (CINAC), University Hospital HM Puerta del Sur, CEU-San Pablo University, Av. Carlos V 70, 28939 Móstoles, Spain; E-mail: rmartinez.hmcinac@hmhospitales.comSearch for more papers by this authorMichele Matarazzo MD, Michele Matarazzo MD orcid.org/0000-0002-2907-8667 HM CINAC (Centro Integral de Neurociencias Abarca Campal), Hospital Universitario HM Puerta del Sur, HM Hospitales, Madrid, Spain Network Center for Biomedical Research on Neurodegenerative Diseases, Carlos III Institute, Madrid, SpainSearch for more papers by this authorJorge U. Máñez-Miró MD, Jorge U. Máñez-Miró MD orcid.org/0000-0002-8995-8340 Search for more papers by this authorJose A. Obeso MD, PhD, Jose A. Obeso MD, PhD HM CINAC (Centro Integral de Neurociencias Abarca Campal), Hospital Universitario HM Puerta del Sur, HM Hospitales, Madrid, Spain Network Center for Biomedical Research on Neurodegenerative Diseases, Carlos III Institute, Madrid, SpainSearch for more papers by this author First published: 12 April 2021 https://doi.org/10.1002/mdc3.13223Citations: 1AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Introduction Ablative neurofunctional approaches for the treatment of movement disorders date from the mid-twentieth century. The ablation of different targets, such as the globus pallidus, Forel's field or thalamus, seeking the most efficient one, were applied in several centers worldwide.1 In the mid-1990s, the development of the pathophysiological model of the basal ganglia allowed revitalization first of pallidotomy, and then deep brain stimulation (DBS)2-4 to treat tremor and Parkinson's disease (PD) motor complications. In the early 2000, after DBS started to spread worldwide, ablative procedures were relegated to a secondary role.1, 5 Recently, ablation has recovered interest with the introduction of MRI-guided focused ultrasound (FUS). The major innovation of this technique is the ability to produce thermoablation of deep brain structures without the need for skull opening, which eliminates the likelihood of surgery-related adverse events and broadens the array of potential candidates. Since the first case series of focused ultrasound thalamotomy for essential tremor (ET) were published in 2013,6, 7 more than 5000 treatments have been done worldwide. The field is expanding fast and the number of sites performing FUS procedures continues to rise. In this viewpoint, we aim to provide insights into the current evidence (see Fig. 1) as well as a perspective for the potential future applications of FUS ablation in movement disorders, considering our experience since 2015. FIG. 1Open in figure viewerPowerPoint Clinical milestones on the application of focused ultrasound for the treatment of tremor and Parkinson's disease. FUS = focused ultrasound; vim: Ventral intermediate nucleus of the thalamus; ET = essential tremor; PD = Parkinson's disease. Ultrasound for Essential Tremor In 2013, the first two open-label series of FUS unilateral ablation of the ventralis intermedius nucleus of the thalamus for the treatment of ET were published by North America groups.6, 7 They were followed by a randomized-controlled trial demonstrating the efficacy of FUS thalamotomy in terms of tremor control and improvement in disability and quality of life.8 More recently, data on safety in larger series,9 long-term (up to 4 years) benefit,10 and the application in very elderly patients11 has been added to that initial evidence. Furthermore, following previous experience with surgical procedures, FUS ablation of other brain targets, namely cerebello-thalamic tract (CTT), has also been investigated. Some case reports and CTT FUS series suggest positive results,12 but randomized trials are lacking. One of the main advantages of FUS is the favorable safety and tolerability profile. Thus, evidence from pivotal and post-pivotal studies (n = 186) shows that unilateral FUS thalamotomy for ET has a very low rate of severe adverse events (1%) with only 0.7% being permanent (accounting for balance impairment).9 Sensory disturbances are the most frequently reported complications (around 45% of patients) but are mild in severity in 91% of cases and mostly transient. Neither brain hemorrhages nor infection have been reported. In our experience, about 80% of patients are satisfied with the treatment, whereas unsatisfactory outcome mainly relates to relapse of tremor. Despite rate of relapse has not being formally worked out, in the randomized trial by Elias et al.8 13 of 56 (23%) patients presented, at 3 months, less than 30% of tremor improvement. This could be considered as a partial recurrence of tremor and is usually related to a small final lesion once the perilesional edema is resolved. This rate is usually reduced with increased team's experience.13 Notably, very severe tremors (4/4 as evaluated with the Clinical Rating Scale for tremor A) are more prone to relapse. Thus, patients with high-amplitude, severe tremor should be well aware of therapeutic limitations, and accordingly adjust expectations before treatment. Ultimately, given the low rate of procedure-related complications, retreatments can be considered. In terms of clinical practice several aspects are worth considering. Thus, FUS thalamotomy has a learning curve, like any other emerging technique, as suggested by a recent study showing worse results in the initial pivotal studies as compared to the post-pivotal trials.13 Increased team experience leads to: (1) Reduction of procedure duration, which is usually around 4 hours with the first treatments and may diminish to 2 with experience; (2) Increase in the team's skills in managing intraprocedural complications (including difficulties in achieving high-temperature effective sonications, lack of tremor improvement or the appearance of procedure-related complications, such as nausea); (3) Reduction in relapse rate, as treatments tend to become less conservative with longer experience; in this regard, the rate of tremor recurrence in ET patients for an unexperienced team could be rated around 20%, and usually decreases to 5% once the know-how is acquired, including more balanced patient selection; and (4) Reduction in the risk of permanent side effects, which are infrequent with experienced teams. In sum, currently, unilateral FUS thalamotomy is likely the best current therapeutic option for medically-refractory and disabling ET. Recently, our team, in collaboration with Baumann and collaborators from Zurich, has gained experience with staged bilateral thalamotomy, which in the literature is so far limited to one single case report.14 Results were also positive, and side-effects similar to the profile for unilateral thalamotomy. A controlled clinical trial is warranted. FUS therapy for ET has come to stay. Within the following years, several questions may be answered, such as the possibility of applying neuroimaging developments like tractography-based targeting15 to optimize the procedure and ensure clinical outcomes,16 or of performing bilateral ablations. The cohabitation standards of FUS thalamotomy and thalamic DBS remains to be defined. Parkinson's Disease Initial evidence of the benefit of FUS unilateral thalamotomy for PD also stemmed from a few open label studies,17, 18 followed by a randomized controlled trial.19 Thalamotomy for PD is an FDA-approved treatment, but in clinical practice parkinsonian tremor seems to be more refractory to thalamotomy than ET. Indeed, the mean improvements in tremor with FUS thalamotomy as compared to a sham procedure in the respective trials was superior for ET than for PD.8, 19 In this regard, it should be pointed out that the underlying mechanisms of parkinsonian tremor are not completely dilucidated and probably involve a more complex network than ET.20 Thus, the possibility of recurrence and a partial benefit should be taken into consideration and well-explained and accepted by patients and relatives. Indeed, we recommend adjusting patients' expectations before ultrasound treatment. Importantly, it is well-known that a thalamic impact improves parkinsonian tremor but has little-to-no effect on rigidity and bradykinesia.21 Experience with classical neurofunctional ablative approaches and DBS has shown that the subthalamic nucleus (STN) and the globus pallidus pars interna (GPi) are the best targets to control PD cardinal features, as well as motor complications22 and, therefore, those targets seem the most promising for FUS treatment also (Fig. 2). FIG. 2Open in figure viewerPowerPoint Brain MR T2-weighted (left) and susceptibility-weighted (right) axial sequences of representative patients who received ultrasound ablation in the thalamus (A), subthalamic nucleus (B) and globus pallidus pars interna (C). Brain MRI was acquired 24 hours after the procedure. Subthalamotomy The Data. One FUS unilateral subthalamotomy pilot study from our team23 suggested that subthalamic ultrasound ablation was feasible and resulted in a positive effect on PD motor features. Recently, the results of our randomized double-blind clinical trial in collaboration with Dr. J. Elias and colleagues from Virginia Medical Center (USA) studying unilateral subthalamotomy in 40 asymmetrical PD patients became available.24 We found significant motor improvement in the treated body side (ie, contralateral to the lesion hemisphere) with a median reduction in the Movement Disorder Society - Unified Parkinson's Disease Rating Scale (MDS-UPDRS) part III (for the treated hemibody) of 52.6% (Video 1). Side effects such as speech or gait disturbances after treatment were frequent but mostly mild and transient, and 5 patients developed contralateral motor weakness which recovered in all cases. Ballism was present in 2 of the 39 patients who received real treatment (either in the blinded phase or after crossover) with one case being monoballism and another hemiballism. Both improved progressively to a mild off-medication foot dyskinesia at 12 months. In addition, 5 patients developed off-medication chorea and in 8 (of 39) the levodopa-induced dyskinesia threshold decreased in the treated body side. They were mild-to-moderate in severity, improved after levodopa reduction (as with STN DBS-induced dyskinesias2) and subsided or were minimal after 12 months in all cases. This video cannot be streamed at this time, please download the video instead. VideoDownload Video (.mp4 47.2MB) Section 1: 47-year-old female with Parkinson's disease diagnosed 6 years earlier. In the off-medication state, she presented bilateral but markedly asymmetrical parkinsonism with greater impairment in the left hemibody, which also presents typical rest tremor. Right FUS subthalamotomy was performed resulting in immediate improvement but in the development of new-onset on-medication dyskinesia in the upper limb of the treated hemibody. Section 2: 18 months after treatment motor signs remained significantly improved in the left body side without showing any side effect. Mild rest tremor due to disease progression is visible in the right hand in the off-medication condition. Pallidotomy: The Data An open-trial in 10 patients treated with FUS unilateral pallidotomy in Korea25 described positive results, with 32.2% of improvement in the UPDRS III and 52.7% improvement in motor complications according to the Unified Dyskinesia Rating Scale score (UDysRS). In this study, 2 patients did not reach ablative temperature on the target and therefore, the ablation and the subsequent clinical outcome was suboptimal. It is known that in lateral targets ultrasound beam focusing is less effective, and hence, the higher laterality of the GPi as compared to the Vim or STN can reduce effective delivery of energy. In patients who present unfavorable skull metrics for ultrasound penetration, it can become a limitation of the approach. More recently, another open cases series including 20 patients has replicated these results, with 43% and 45.2% improvements at 12 months in the UDysRS and the motor MDS-UPDRS of the treated side, respectively.26 In this study, reported adverse events included visual field deficit (n = 1), dysarthria (n = 4), cognitive disturbance (n = 1), motor deficit (n = 2), and facial weakness (n = 1), being generally mild and transient. A randomized trial testing the efficacy of FUS-guided pallidotomy against levodopa-induced dyskinesia as primary endpoint has recently being finalized (NCT 03319485). Our limited experience (n = 6) is that pallidotomy, as shown by radiofrequency-induced lesions, is highly effective against the whole spectrum of Levodopa-induced dyskinesias (including peak dose chorea, diphasic dyskinesias and off-period dystonia, Video 2). This video cannot be streamed at this time, please download the video instead. VideoDownload Video (.mp4 58.1MB) Section 1: 52-year-old male with Parkinson's disease diagnosed 8 years earlier. At his baseline condition, the benefit of levodopa lasted only 2 hours, with the patient presenting severe and painful right hemicorporal off-dystonia after that interval. Section 2: 5 days after left FUS pallidotomy, off-dystonia had disappeared with the benefit of levodopa lasting longer than 5 hours. This effect remains stable 16 months after treatment (not shown). The pallidothalamic tract has been also targeted for PD in a single-center open series.12 This study described improvements in all parkinsonian motor features without significant permanent side effects. Certainly, these promising results deserve further exploration. Applications and Limitations of FUS in PD In conclusion, the STN appears to be the best target for treating parkinsonian motor features and reducing levodopa dosage (similarly to randomized STN-DBS trials despite levodopa reduction in our FUS subthalamotomy studies is lower due to the unilaterality of the approach27-29), whereas targeting the GPi would be more appropriate for patients with PD-related motor complications.28-30 Importantly, FUS ablation has only been attempted unilaterally and, therefore, this should be considered principally in patients who are markedly asymmetrical, those presenting surgical contraindications, or rejecting DBS.31 Anyhow, while the unilaterality of FUS ablation for PD could be considered a limitation, many patients remain little affected in one body side for several years. Of note, long-term experience with surgical radiofrequency lesions shows that eventual levodopa increases required by disease progression can be applied without significant complications (such as levodopa-induced dyskinesia) in the previously treated body side.32-34 Whether or not bilateral ultrasound ablation for PD (at any target) can be safely performed still needs to be tested. Studies with radiofrequency surgical ablations have generally produced highly concerning results, particularly when considering bilateral pallidotomy and thalamotomy.35, 36 Bilateral subthalamotomy was also carried out in a relatively small series of patients with reasonably positive results in terms of efficacy and safety.37-39 However, the approach is not identical with FUS and all this previous experience has to be taken with reservation. Indeed, ultrasound thermoablations are purely focal and thus less invasive than those performed with a surgical intervention, which could minimize adverse events. Finally, the possibility of implantation of one stimulation electrode in the hemisphere contralateral to a (radiofrequency) lesion has been successfully achieved in a few published cases.38 Other Movement Disorders There is scarce evidence on the application of FUS in other movement disorders. A few cases of successful treatment of non-ET tremors, such as fragile-X associated tremor/ataxia syndrome,40 multiple sclerosis-associated tremor41 or dystonic tremor42 have been reported. In addition, one case of musician's dystonia treated with ultrasound ventro-oral thalamotomy is also reported.43 Conceptually, any movement disorder improved by surgical ablation or DBS should benefit from FUS lesioning. Our clinical experience with tremor secondary to an underlying condition is positive overall and warrants further testing. However, in these patients the risk-to-benefit ratio must be balanced cautiously as long-lasting neurological complications in an already damaged brain are more prone to occur. FUS Ablation and Deep Brain stimulation-Complementary Rather than Competing Approaches FUS has revitalized therapeutic ablation in the DBS era. We believe that FUS will soon be accepted among the available options for treating movement disorders. A major advantage of FUS is the incisionless nature of this technique, which, along with the continuous improvement in neuroimaging and targeting, will allow optimizing of the procedure for a better benefit-to-risk ratio. Thus, in the near future, FUS will coexist with DBS as treatments that have demonstrated efficacy and will take advantage of technological development. Furthermore, progress in defining anatomo-functional regions of the basal ganglia (ie, STN, GPi) and cerebello-thalamic projections in part fueled by studies in patients with restricted focal lesions (by FUS) will also allow better results with DBS, for instance applying directional leads and adaptive stimulation. Importantly, there is a non-negligible number of patients who have contraindications for DBS that could be candidates for FUS (eg, elderly, reluctant to open brain surgery, etc) or who have required electrode removal and cannot be reimplanted. Currently advanced therapies such as DBS are usually considered when medications fail to provide a clinically meaningful benefit, and therefore usually at a more advanced stage. However, given that FUS is a less invasive therapy, and with relatively lower risk of serious and persistent adverse events compared with intracranial surgery, it could be considered at an earlier stage, even as an alternative to medication in selected cases. Importantly, the technique will continue to improve facilitating applicability. Notably, FUS does not preclude the possibility of performing DBS later on if needed. Finally, ablations are a one-time treatment with a much simpler follow-up management than DBS, which could be an advantage in medically underserved areas. In summary, we envisage that while some patients will be more suitable candidates for DBS, others could undergo ultrasound ablation, and the selection decision should be taken by a multidisciplinary team tailoring patient's needs and expectations on a case-by-case basis. Also, indications for each treatment will differ in a monosymptomatic condition such as ET and a multisystem progressive disease like PD. Conclusion FUS has opened a new therapeutic option for movement disorders as happened with levodopa for PD in the late 1960s and DBS in the 1990s. Hopefully, the evidence in the years to come will establish it as another standard therapy. Acknowledgments We thank Ms Ruth Breeze for language editing. Author Roles (1) Project: A. Conception; B. Organization; C. Execution.; (2) Manuscript: A. Writing of the first draft; B. Review and critique. RMF: 1A, 1B, 1C, 2A, 2B MM: 1A, 1B, 1C, 2A, 2B JUMM: 1B; 1C; 2B JAO: 1A, 1B, 1C, 2A, 2B Disclosures Ethical Compliance Statement The authors confirm that the approval of an institutional review board and informed patient consent were not required for this work. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines. The authors confirm that the approval of an institutional review board was not required for this work. Funding Sources and Conflict of Interest RMF, JAO have received honoraria for lecturing and payment of travel expenses to attend scientific meetings by Insightec. JMM receives grant support from Insightec. MM declares no conflicts of interest. Financial Disclosures for the Previous 12 months RMF reports honoraria for lecturing from Zambon, Boston Scientific and Abbvie. JMM reports honoraria for lecturing from Abbvie. MM reports grant support from Michael J. Fox Foundation and Parkinson Canada, and honoraria for lecturing from Teva and the International Parkinson and Movement Disorder Society. JAO reports honoraria for lecturing from Abbvie. References 1Hariz MI, Hariz GM. Therapeutic stimulation versus ablation. Handb Clin Neurol 2013; 116: 63– 71. https://doi.org/10.1016/B978-0-444-53497-2.00006-1. CrossrefPubMedGoogle Scholar 2Limousin P, Krack P, Pollak P, et al. Electrical stimulation of the subthalamic nucleus in advanced Parkinsonian's disease. N Engl J Med 1998; 339(16): 1105– 1111. https://doi.org/10.1056/NEJM199810153391603. CrossrefCASPubMedWeb of Science®Google Scholar 3Benabid AL, Pollak P, Louveau A, Henry S, De Rougemont J. Combined (thalamotomy and stimulation) stereotactic surgery of the vim thalamic nucleus for bilateral parkinson disease. Stereotact Funct Neurosurg 1987; 50(1–6): 344– 346. https://doi.org/10.1159/000100803. CrossrefCASGoogle Scholar 4Laitinen LV, Bergenheim AT, Hariz MI. Leksell's posteroventral pallidotomy in the treatment of Parkinson's disease. J Neurosurg 1992; 76(1): 53– 61. https://doi.org/10.3171/jns.1992.76.1.0053. CrossrefCASPubMedWeb of Science®Google Scholar 5Obeso JA, Olanow CW, Rodriguez-Oroz MC, Krack P, Kumar R, Lang AE. Deep-brain stimulation of the subthalamic nucleus or the pars interna of the globus pallidus in Parkinson's disease. N Engl J Med 2001; 345(13): 956– 963. https://doi.org/10.1056/NEJMoa000827. CrossrefCASPubMedWeb of Science®Google Scholar 6Elias WJ, Huss D, Voss T, et al. A pilot study of focused ultrasound thalamotomy for essential tremor. N Engl J Med 2013; 369(7): 640– 648. https://doi.org/10.1056/NEJMoa1300962. CrossrefCASPubMedWeb of Science®Google Scholar 7Lipsman N, Schwartz ML, Huang Y, et al. MR-guided focused ultrasound thalamotomy for essential tremor: A proof-of-concept study. Lancet Neurol 2013; 12(5): 462– 468. https://doi.org/10.1016/S1474-4422(13)70048-6. CrossrefPubMedWeb of Science®Google Scholar 8Elias WJ, Lipsman N, Ondo WG, et al. A randomized trial of focused ultrasound Thalamotomy for essential tremor. N Engl J Med 2016; 375(8): 730– 739. https://doi.org/10.1056/NEJMoa1600159. CrossrefPubMedWeb of Science®Google Scholar 9Fishman PS, Elias WJ, Ghanouni P, et al. Neurological adverse event profile of magnetic resonance imaging–guided focused ultrasound thalamotomy for essential tremor. Mov Disord 2018; 33(5): 843– 847. https://doi.org/10.1002/mds.27401. Wiley Online LibraryPubMedWeb of Science®Google Scholar 10Park YS, Jung NY, Na YC, Chang JW. Four-year follow-up results of magnetic resonance-guided focused ultrasound thalamotomy for essential tremor. Mov Disord 2019; 34(5): 727– 734. https://doi.org/10.1002/mds.27637. Wiley Online LibraryPubMedWeb of Science®Google Scholar 11Paff M, Boutet A, Boutet A, et al. Magnetic resonance-guided focused ultrasound Thalamotomy to treat essential tremor in nonagenarians. Stereotact Funct Neurosurg 2020; 98(3): 182– 186. https://doi.org/10.1159/000506817. CrossrefPubMedWeb of Science®Google Scholar 12Gallay MN, Moser D, Rossi F, et al. MRgFUS Pallidothalamic Tractotomy for chronic therapy-resistant Parkinson's disease in 51 consecutive patients: Single center experience. Front Surg 2020; 6(76): 1– 13. https://doi.org/10.3389/fsurg.2019.00076. Google Scholar 13Krishna V, Sammartino F, Cosgrove R, et al. Predictors of outcomes after focused ultrasoun thalamotomy. Neurosurgery 2020; 87(2): 229– 237. https://doi.org/10.1093/neuros/nyz417. CrossrefPubMedWeb of Science®Google Scholar 14Ito H, Yamamoto K, Fukutake S, Odo T, Yamaguchi T, Taira T. Magnetic resonance imaging-guided focused ultrasound bilateral thalamotomy for essential tremor: a case report. Neurol Clin Neurosci 2020; 8(6): 412– 414. https://doi.org/10.1111/ncn3.12438. Wiley Online LibraryWeb of Science®Google Scholar 15Shah BR, Lehman VT, Kaufmann TJ, et al. Advanced MRI techniques for transcranial high intensity focused ultrasound targeting. Brain 2020; 143(9): 2664– 2672. https://doi.org/10.1093/brain/awaa107. CrossrefPubMedWeb of Science®Google Scholar 16Martínez-Fernández R, Pineda-Pardo JA. Magnetic resonance-guided focused ultrasound for movement disorders: clinical and neuroimaging advances. Curr Opin Neurol 2020; 33(4): 488– 497. https://doi.org/10.1097/WCO.0000000000000840. CrossrefPubMedWeb of Science®Google Scholar 17Magara A, Bühler R, Moser D, Kowalski M, Pourtehrani P, Jeanmonod D. First experience with MR-guided focused ultrasound in the treatment of Parkinson's disease. J Ther Ultrasound 2014; 2(11): 1– 8. https://doi.org/10.1186/2050-5736-2-11. PubMedGoogle Scholar 18Schlesinger I, Eran A, Sinai A, et al. MRI guided focused ultrasound thalamotomy for moderate-to-severe tremor in Parkinson's disease. Parkinsons Dis 2015; 2015:219149. https://doi.org/10.1155/2015/219149. CrossrefPubMedWeb of Science®Google Scholar 19Bond AE, Shah BB, Huss DS, et al. Safety and efficacy of focused ultrasound thalamotomy for patients with medication-refractory, tremor-dominant Parkinson disease a randomized clinical trial. JAMA Neurol 2017; 74(12): 1412– 1418. https://doi.org/10.1001/jamaneurol.2017.3098. CrossrefPubMedWeb of Science®Google Scholar 20Helmich RC, Hallett M, Deuschl G, Toni I, Bloem BR. Cerebral causes and consequences of parkinsonian resting tremor: a tale of two circuits? Brain 2012; 135: 3206– 3226. CrossrefPubMedWeb of Science®Google Scholar 21Speelman JD, Schuurman R, de Bie RMA, Esselink RAJ, Bosch DA. Stereotactic neurosurgery for tremor. Mov Disord 2002; 17(Suppl 3): s84– s88. https://doi.org/10.1002/mds.10147. Wiley Online LibraryPubMedWeb of Science®Google Scholar 22Krack P, Martinez-Fernandez R, del Alamo M, Obeso JA. Current applications and limitations of surgical treatments for movement disorders. Mov Disord 2017; 32(1): 36– 52. https://doi.org/10.1002/mds.26890. Wiley Online LibraryPubMedWeb of Science®Google Scholar 23Martínez-Fernández R, Rodríguez-Rojas R, del Álamo M, et al. Focused ultrasound subthalamotomy in patients with asymmetric Parkinson's disease: a pilot study. Lancet Neurol 2018; 17(1): 54– 63. https://doi.org/10.1016/S1474-4422(17)30403-9. CrossrefPubMedWeb of Science®Google Scholar 24Martínez-Fernández R, Máñez-Miró JU, Rodríguez-Rojas R, et al. Randomized trial of focused ultrasound Subthalamotomy for Parkinson's disease. N Engl J Med 2020; 383(26): 2501– 2513. https://doi.org/10.1056/nejmoa2016311. CrossrefPubMedWeb of Science®Google Scholar 25Jung NY, Park CK, Kim M, Lee PH, Sohn YH, Chang JW. The efficacy and limits of magnetic resonance–guided focused ultrasound pallidotomy for Parkinson's disease: a phase I clinical trial. J Neurosurg 2019; 1306(6): 1853– 1861. https://doi.org/10.3171/2018.2.JNS172514. CrossrefWeb of Science®Google Scholar 26Eisenberg HM, Krishna V, Elias WJ, et al. MR-guided focused ultrasound pallidotomy for Parkinson's disease: safety and feasibility. J Neurosurg 2020; 1– 7. https://doi.org/10.3171/2020.6.jns192773. CrossrefGoogle Scholar 27Schuepbach WMM, Rau J, Knudsen K, et al. Neurostimulation for Parkinson's disease with early motor complications. N Engl J Med 2013; 368(7): 610– 622. https://doi.org/10.1056/NEJMoa1205158. CrossrefCASPubMedWeb of Science®Google Scholar 28Follett KA, Weaver FM, Stern M, et al. Pallidal versus subthalamic deep-brain stimulation for Parkinson's disease. N Engl J Med 2010; 362(22): 2077– 2091. https://doi.org/10.1056/nejmoa0907083. CrossrefCASPubMedWeb of Science®Google Scholar 29Odekerken VJJ, van Laar T, Staal MJ, et al. Subthalamic nucleus versus globus pallidus bilateral deep brain stimulation for advanced Parkinson's disease (NSTAPS study): a randomised controlled trial. Lancet Neurol 2013; 12(1): 37– 44. https://doi.org/10.1016/S1474-4422(12)70264-8. CrossrefPubMedWeb of Science®Google Scholar 30Lang AE, Lozano AM, Montgomery E, Duff J, Tasker R, Hutchinson W. Posteroventral medial pallidotomy in advanced Parkinson's disease. N Engl J Med 1997; 337(15): 1036– 1042. CrossrefCASPubMedWeb of Science®Google Scholar 31Moosa S, Martínez-Fernández R, Elias WJ, del Alamo M, Eisenberg HM, Fishman PS. The role of high-intensity focused ultrasound as a symptomatic treatment for Parkinson's disease. Mov Disord 2019; 34(9): 1243– 1251. https://doi.org/10.1002/mds.27779. Wiley Online LibraryPubMedWeb of Science®Google Scholar 32Ricardo Y, Pavon N, Alvarez L, et al. Long-term effect of unilateral subthalamotomy for Parkinson's disease. J Neurol Neurosurg Psychiatry 2019; 90(12): 1380– 1381. https://doi.org/10.1136/jnnp-2019-320523. PubMedWeb of Science®Google Scholar 33Alvarez L, Macias R, Pavón N, et al. Therapeutic efficacy of unilateral subthalamotomy in Parkinson's disease: Results in 89 patients followed for up to 36 months. J Neurol Neurosurg Psychiatry 2009; 80(9): 979– 985. https://doi.org/10.1136/jnnp.2008.154948. CrossrefCASPubMedWeb of Science®Google Scholar 34Patel NK, Heywood P, O'Sullivan K, McCarter R, Love S, Gill SS. Unilateral subthalamotomy in the treatment of Parkinson's disease. Brain 2003; 126(5): 1136– 1145. https://doi.org/10.1093/brain/awg111. CrossrefPubMedWeb of Science®Google Scholar 35Alomar S, King NKK, Tam J, Bari AA, Hamani C, Lozano AM. Speech and language adverse effects after thalamotomy and deep brain stimulation in patients with movement disorders: a meta-analysis. Mov Disord 2017; 32(1): 53– 63. https://doi.org/10.1002/mds.26924. Wiley Online LibraryPubMedWeb of Science®Google Scholar 36Merello M, Starkstein S, Nouzeilles MI, Kuzis G, Leiguarda R. Bilateral pallidotomy for treatment of Parkinson's disease induced corticobulbar syndrome and psychic akinesia avoidable by globus pallidus lesion combined with contralateral stimulation. J Neurol Neurosurg Psychiatry 2001; 71(5): 611– 614. https://doi.org/10.1136/jnnp.71.5.611. CrossrefCASPubMedWeb of Science®Google Scholar 37Alvarez L, Macias R, Lopez G, et al. Bilateral subthalamotomy in Parkinson's disease: Initial and long-term response. Brain 2005; 128(3): 570– 583. https://doi.org/10.1093/brain/awh397. CrossrefCASPubMedWeb of Science®Google Scholar 38Merello M, Tenca E, Lloret SP, et al. Prospective randomized 1-year follow-up comparison of bilateral subthalamotomy versus bilateral subthalamic stimulation and the combination of both in Parkinson's disease patients: a pilot study. Br J Neurosurg 2008; 22(3): 415– 422. https://doi.org/10.1080/02688690801971667. CrossrefCASPubMedWeb of Science®Google Scholar 39Tseng HM, Su PC, Liu HM, Liou HH, Yen RF. Bilateral subthalamotomy for advanced Parkinson disease. Surg Neurol 2007; 68(Suppl 1): S43– S50. https://doi.org/10.1016/j.surneu.2007.05.058. CrossrefPubMedWeb of Science®Google Scholar 40Cerquera C, Rumià J, Herrera JM, Moreno V, Bargalló N, Valldeoriola F. A single case report of MR-guided focused ultrasound thalamotomy for tremor in fragile X-associated tremor/ataxia. Parkinson Relat Disord 2016; 28: 159– 160. https://doi.org/10.1016/j.parkreldis.2016.04.002. CrossrefPubMedWeb of Science®Google Scholar 41Máñez-Miró JU, Martínez-Fernández R, del Alamo M, et al. Focused ultrasound thalamotomy for multiple sclerosis–associated tremor. Mult Scler J 2020; 26(7): 855– 858. https://doi.org/10.1177/1352458519861597. CrossrefPubMedWeb of Science®Google Scholar 42Fasano A, Llinas M, Munhoz RP, Hlasny E, Kucharczyk W, Lozano AM. MRI-guided focused ultrasound thalamotomy in non-ET tremor syndromes. Neurology 2017; 89(8): 771– 775. https://doi.org/10.1212/WNL.0000000000004268. CrossrefPubMedWeb of Science®Google Scholar 43Horisawa S, Yamaguchi T, Abe K, et al. A single case of MRI-guided focused ultrasound ventro-oral thalamotomy for musician's dystonia. J Neurosurg 2019; 131(2): 384– 386. https://doi.org/10.3171/2018.5.JNS173125. CrossrefWeb of Science®Google Scholar Citing Literature Volume8, Issue5July 2021Pages 681-687 FiguresReferencesRelatedInformation