Focused Ultrasound Ablation of the Globus Pallidus Internus for Parkinson’s Disease.pdf
One of the challenges in the management of advanced Parkinson’s disease is the occurrence of motor fluctuations and dyskinesias in response to antiparkinsonian medications. The often unpredictable deterioration of motor function in the off-medication state and dyskinesias in the on-medication state can render patients disabled for many hours each day. Deep-brain stimulation of the subthalamic nucleus or the globus pallidus internus is an established treatment for patients with these complications.1However, not all patients are eligible for deepbrain stimulation owing to coexisting conditions, and some are unwilling to consider this treatment because it involves invasive placement of electrodes in the brain. It also requires frequent adjustment and expert monitoring of an implanted stimulator, which make it inaccessible for some patients. Ablative radiofrequency surgery, which has been used less frequently since the advent of deep-brain stimulation, is a more invasive and irreversible technique that does not allow for adjustments in response to changes in clinical features.
晚期帕金森病管理的挑战之一是对抗帕金森病药物引起的运动波动和运动障碍。 停药状态下运动功能的不可预测恶化和服药状态下的运动障碍通常会使患者每天数小时无法工作。 丘脑底核或苍白球内部的深部脑刺激是治疗这些并发症患者的既定治疗方法。 1然而，由于合并症，并非所有患者都适合进行深部脑刺激，有些人不愿考虑这种治疗，因为它涉及侵入性在大脑中放置电极。 它还需要对植入的刺激器进行频繁调整和专家监控，这使得一些患者无法接触到它。 消融性射频手术自深部脑刺激出现以来使用频率较低，是一种更具侵入性和不可逆的技术，不允许根据临床特征的变化进行调整。
Focused ultrasound ablation (FUSA), which involves noninvasive, externally applied sonication energy, allows for ablative surgery without the need for craniotomy and is a method for the creation of very focused brain lesions that is potentially safer than radiofrequency surgery. Focused ultrasound lesions of the thalamus have been shown to reduce symptoms of medically refractory essential tremor and tremor-dominant Parkinson’s disease,2 with sustained improvement for several years reported.3 A small randomized, controlled trial has shown improvement of motor function with unilateral FUSA of the subthalamic nucleus for markedly asymmetric Parkinson’s disease; adverse events, including speech and gait disturbances, unilateral weakness, and dyskinesia, were mostly mild and reversible but relatively frequent.4 Furthermore, open-label studies have indicated that unilateral FUSA targeting the globus pallidus internus for motor complications of Parkinson’s disease is associated with clinically meaningful reduction of dyskinesias as well as motor disability in the off-medication state.5-7
聚焦超声消融 (FUSA) 涉及非侵入性、外部应用的超声能量，允许进行消融手术而不需要开颅手术，并且是一种产生非常集中的脑损伤的方法，可能比射频手术更安全。 丘脑的聚焦超声损伤已被证明可以减轻医学上难治性特发性震颤和以震颤为主的帕金森氏病的症状，2 据报道持续改善了几年。3 一项小型随机对照试验表明运动功能有所改善具有明显不对称帕金森病的单侧丘脑底核 FUSA； 不良事件，包括言语和步态障碍、单侧无力和运动障碍，大多是轻微的和可逆的，但相对频繁。 4 此外，开放标签研究表明，针对帕金森病运动并发症的单侧 FUSA 靶向苍白球内侧与在停药状态下，具有临床意义的运动障碍和运动障碍减少 5-7
In this issue of the Journal, Krishna et al.8 report the results of a double-blind, randomized, controlled trial of unilateral FUSA of the globus pallidus internus for Parkinson’s disease with motor complications. A total of 94 patients were included, all of whom had at least mild motor fluctuations or dyskinesia; in contrast to a previous feasibility study,7 the trial did not require patients to have unilateral or markedly asymmetric symptoms. Despite these broad inclusion criteria, the trial showed a significant effect on the primary outcome: at 3 months, 45 of 65 patients (69%) who underwent FUSA (active treatment) were classified as having had a response, showing a reduction in motor impairment in the off-medication state or a reduction in dyskinesias in the on-medication state, as compared with 7 of 22 patients (32%) who underwent a sham procedure (control). In the active-treatment group, reductions were seen in motor impairment in the off-medication state in 29% of the patients, in dyskinesia in the on-medication state in 12%, and in both in 28%. Furthermore, open-label follow-up indicated that 12 months after the procedure, 30 of 39 patients in the active-treatment group who initially had had a response continued to benefit. At 3 months, adverse events in the active-treatment group included dysarthria, gait disturbance, loss of taste, visual disturbance, and facial weakness. These events were generally mild and reversible, but it is worth emphasizing that despite an incisionless procedure, FUSA of the globus pallidus internus is not risk-free. No explicit quality-of-life measure was included in the trial design, but the change from baseline to 3 months in the score on the Movement Disorders Society–Unified Parkinson’s Disease Rating Scale, part II (a measure of motor aspects of daily living and a secondary outcome), did not differ significantly between the two groups.
在本期期刊中，Krishna 等人 8 报告了一项双盲、随机、对照试验的结果，该试验采用单侧苍白球 FUSA 治疗帕金森病伴运动并发症。 总共包括 94 名患者，他们都至少有轻微的运动波动或运动障碍； 与之前的可行性研究 7 不同，该试验不要求患者出现单侧或明显不对称的症状。 尽管有这些广泛的纳入标准，但试验显示对主要结果有显着影响：在 3 个月时，接受 FUSA（积极治疗）的 65 名患者中有 45 名 (69%) 被归类为有反应，表明运动障碍有所减少与接受假手术（对照组）的 22 名患者中的 7 名 (32%) 相比，在停药状态下或在用药状态下运动障碍减少。 在积极治疗组中，29% 的患者在停药状态下的运动障碍有所减轻，12% 的患者在服药状态下的运动障碍有所减轻，28% 的患者两者都有。 此外，开放标签随访表明，在手术后 12 个月，最初有反应的积极治疗组的 39 名患者中有 30 名继续受益。 3 个月时，积极治疗组的不良事件包括构音障碍、步态障碍、味觉丧失、视觉障碍和面部无力。 这些事件通常是轻微且可逆的，但值得强调的是，尽管是无切口手术，但苍白球内部的 FUSA 并非没有风险。 试验设计中未包括明确的生活质量测量，但运动障碍协会-统一帕金森病评定量表，第二部分（衡量日常生活的运动方面和次要结果），两组之间没有显着差异。
Where does this trial place FUSA of the globus pallidus internus for treatment of Parkinson’s disease? The results confirm that it is effective in reducing motor complications of Parkinson’s disease, at least in the short term. However, the degree of improvement was less than suggested by previous open-label studies. Approximately one third of the patients in the FUSA group did not have a response at 3 months, and only one third of the FUSA group had both improved motor function and reduced dyskinesia. It is notable that a third of the patients in the control group were also classified as having had a response, a finding consistent with the high rate of placebo response in Parkinson’s disease trials. The reasons for the lower incidence of improvement in this trial than in previous studies may partly lie in the inclusion criteria. Patients in the current trial could have a predominance of motor impairment in the offmedication state with no or little dyskinesia in the on-medication state, as reflected in the low mean scores for dyskinesia at baseline, and there was no requirement for strong asymmetry of motor features for this unilateral procedure. The use of the percentage of patients with a response as the primary outcome measure, rather than the improvement in severity scores, was also perhaps more stringent than previous open-label studies. Nevertheless, the results suggest that not all patients derived a meaningful benefit from the intervention. The supplementary data provide preliminary information indicating that patients who were younger, had lower motor severity scores, or had higher dyskinesia scores were more likely to benefit, but the population most likely to benefit needs to be examined in further studies.
本次试验将苍白球 FUSA 置于何处治疗帕金森病？ 结果证实，它可有效减少帕金森病的运动并发症，至少在短期内如此。 然而，改善程度低于之前的开放标签研究所建议的程度。 FUSA 组中大约三分之一的患者在 3 个月时没有反应，只有三分之一的 FUSA 组患者的运动功能得到改善并减少了运动障碍。 值得注意的是，对照组中三分之一的患者也被归类为有反应，这一发现与帕金森病试验中安慰剂反应率高的结果一致。 与之前的研究相比，该试验的改善率较低的原因可能部分在于纳入标准。 本试验中的患者在停药状态下可能主要有运动障碍，而在服药状态下没有或很少有异动症，这反映在基线时异动症的平均得分较低，并且不需要强烈的运动障碍不对称这种单方面程序的特点。 使用有反应的患者百分比作为主要结果衡量标准，而不是严重程度评分的改善，也可能比以前的开放标签研究更严格。 然而，结果表明并非所有患者都从干预中获得有意义的益处。 补充数据提供的初步信息表明，年龄较小、运动严重程度评分较低或运动障碍评分较高的患者更有可能受益，但最有可能受益的人群需要在进一步研究中进行检查。
As with other surgical interventions in Parkinson’s disease, evaluation of benefit requires longer-term follow-up to establish the overall effect on patients’ functioning. The results of this trial are promising, but given the nonreversible nature of the intervention and the progressive nature of the disease, it will be important to establish whether improvements in motor complications are maintained over longer periods and whether treatment results in improved overall functioning and quality of life for patients.
与帕金森氏病的其他手术干预一样，效益评估需要长期随访以确定对患者功能的总体影响。 这项试验的结果是有希望的，但考虑到干预的不可逆性和疾病的进展性，重要的是要确定运动并发症的改善是否能持续更长的时间，以及治疗是否能改善患者的整体功能和生活质量。