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

Abstract

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. 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. 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). 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. 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). 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. 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 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 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. 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. We thank Ms Ruth Breeze for language editing. (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 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. 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. 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.

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