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首页 » 帕金森病 » Lancet Neurol:恒流刺激延长帕金森病者无运动障碍时间

Lancet Neurol:恒流刺激延长帕金森病者无运动障碍时间

来源:爱唯医学网 2012-01-16 20:31

近日,佛罗里达大学运动障碍与神经修复中心的Michael S. Okun博士及其同事在Lancet Neurol杂志上发表文章"Subthalamic deep brain stimulation with a constant-current device in Parkinson's disease: an open-label randomised controlled trial"称,他们发现采用埋藏式恒流刺激器进行深部脑刺激治疗,可使帕金森病患者每天的“开”状态维持时间显著增加近3h。而深部脑刺激最常采用的是带有电压驱动装置的变流刺激器。

对照组患者在置入未启动的刺激器后短期内出现轻微改善,而在启动刺激器后3个月时获得了显著改善。这提示最大收益最可能来自刺激而非微损伤效应。

“由于深部脑刺激的作用范围应当保持稳定,而电压驱动装置易受脑组织阻抗变化的影响,因此恒流刺激器理论上优于变流刺激器。”为了验证这一点,研究者招募了101例帕金森病患者,置入恒流深部脑刺激装置后随机分组,对部分患者立即启动刺激装置,而对其余患者则延迟启动(3个月时再启动)。受试者基线时的平均年龄为60岁,平均病程为12年,在服药情况下平均每天有7 h处于高质量“开”状态。所有受试者均使用Libra恒流丘脑底核刺激器,分组治疗情况未对医生和患者设盲。主要终点为高质量“开”状态(即无明显运动障碍)时间的改变,次要终点包括帕金森病统一评定量表(UPDRS)评分、生活质量和睡眠质量、用药剂量和抑郁症状的改变。

两组患者均在3、6和12个月时接受评估。因此,立即启动组患者接受12个月的刺激治疗,而延迟启动组接受9个月的刺激治疗。结果显示,3个月时,两组患者均报告高质量“开”状态时间增加,但立即启动组改善程度明显更大,平均增加了4.27 h(从7 h增至11 h),而延迟启动组仅增加1.77 h(从7h增至9h)。

立即启动组的应答率(与基线相比至少增加2 h)为72%,而延迟启动组仅为38%,差异有显著性。立即启动组的UPDRS运动亚评分改善程度也显著优于延迟启动组。但两组3个月时的UPDRS心理活动、日常活动亚评分相似。两组患者的左旋多巴治疗副作用亚评分均显著降低,但立即启动组优于延迟启动组。两组患者的左旋多巴等效剂量呈同等水平下降,但立即启动组的治疗费用显著低于延迟启动组。

6个月时(延迟启动组已启动刺激治疗3个月),立即启动组的高质量“开”状态时间保持稳定,延迟启动组则增加至与立即启动组相似的水平。12个月时,两组患者的高质量“开”状态时间仍相似,左旋多巴等效剂量的下降程度也相似。两组患者在抑郁症状方面获得了相似程度的改善,研究者称近期一项研究显示,同样的深部脑刺激装置对难治性重症抑郁有效。

启动刺激装置3个月后,两组患者的语言流利性评分呈现相似程度的恶化,“提示手术置入丘脑底核刺激器可能诱发语言流利性缺陷,后者是最常见的深部脑刺激的认知副作用”。治疗3个月后,两组患者的语言流利性保持稳定但未再改善。

立即启动组有14例患者共发生20次不良事件,而延迟启动组有4例患者共发生7次不良事件。构音困难、疲乏、跌倒、术后疼痛和不适,以及水肿的发生率,立即启动组均更高。研究者称:“这一结果提示,虽然深部脑刺激可明显改善多种运动症状、‘开’状态时间和生活质量,但仍须警惕意料之外的副作用。”

德国维尔茨堡大学医院的Jens Volkmann博士在随刊述评中指出,这是第一项针对恒流深部脑刺激的研究,可能促使生产商研发更多、更好的深部脑刺激装置。“虽然这种新设备可能还算不上该领域的突破性进展,但是标志着20多年来深部脑刺激被一家生产商垄断的格局被打破,我们临床医生欢迎这种改变。”他强调,额叶执行功能受损这一深部脑刺激副作用仍未被解决,有待进一步研究。“该研究结果提示,这种认知损害是手术所致而不是由神经刺激引起,因此改进外科技术或许有助于解决这一问题。”(生物谷Bioon.com)

Subthalamic deep brain stimulation with a constant-current device in Parkinson's disease: an open-label randomised controlled trial.

Okun MS, Gallo BV, Mandybur G, Jagid J, Foote KD, Revilla FJ, Alterman R, Jankovic J, Simpson R, Junn F, Verhagen L, Arle JE, Ford B, Goodman RR, Stewart RM, Horn S, Baltuch GH, Kopell BH, Marshall F, Peichel D, Pahwa R, Lyons KE, Tröster AI, Vitek JL, Tagliati M; for the SJM DBS Study Group.

BACKGROUND:

The effects of constant-current deep brain stimulation (DBS) have not been studied in controlled trials in patients with Parkinson's disease. We aimed to assess the safety and efficacy of bilateral constant-current DBS of the subthalamic nucleus.

METHODS:

This prospective, randomised, multicentre controlled trial was done between Sept 26, 2005, and Aug 13, 2010, at 15 clinical sites specialising in movement disorders in the USA. Patients were eligible if they were aged 18-80 years, had Parkinson's disease for 5 years or more, and had either 6 h or more daily off time reported in a patient diary of moderate to severe dyskinesia during waking hours. The patients received bilateral implantation in the subthalamic nucleus of a constant-current DBS device. After implantation, computer-generated randomisation was done with a block size of four, and patients were randomly assigned to the stimulation or control group (stimulation:control ratio 3:1). The control group received implantation without activation for 3 months. No blinding occurred during this study, and both patients and investigators were aware of the treatment group. The primary outcome variable was the change in on time without bothersome dyskinesia (ie, good quality on time) at 3 months as recorded in patients' diaries. Patients were followed up for 1 year. This trial is registered with ClinicalTrials.gov, number NCT00552474.

FINDINGS:

Of 168 patients assessed for eligibility, 136 had implantation of the constant-current device and were randomly assigned to receive immediate (101 patients) or delayed (35 patients) stimulation. Both study groups reported a mean increase of good quality on time after 3 months, and the increase was greater in the stimulation group (4·27 h vs 1·77 h, difference 2·51 [95% CI 0·87-4·16]; p=0·003). Unified Parkinson's disease rating scale motor scores in the off-medication, on-stimulation condition improved by 39% from baseline (24·8 vs 40·8). Some serious adverse events occurred after DBS implantation, including infections in five (4%) of 136 patients and intracranial haemorrhage in four (3%) patients. Stimulation of the subthalamic nucleus was associated with dysarthria, fatigue, paraesthesias, and oedema, whereas gait problems, disequilibrium, dyskinesia, and falls were reported in both groups.

INTERPRETATION:

Constant-current DBS of the subthalamic nucleus produced significant improvements in good quality on time when compared with a control group without stimulation. Future trials should compare the effects of constant-current DBS with those of voltage-controlled stimulation.

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