深部脑刺激或有助于早期帕金森病治疗

法国和德国研究人员合作开展的一项随机试验显示，在药物治疗基础上加用下丘脑刺激，不仅可改善早期帕金森病患者的生活质量和轻度左旋多巴诱导的运动并发症，还可以减少后续的运动残疾。

主要作者W.M.M. Schüpbach博士和EARLYSTIM(对于早期帕金森病患者进行深部脑刺激的对照试验)研究组的同事指出，已知这种联合治疗对晚期帕金森病患者有益，而这一新发现提示“神经刺激可能作为较当前建议更早期患者的一种治疗选择” (N. Engl. J. Med. 2013;368:610-22 [doi:10.1056/NEJMoa1205158])。

研究者将127例有早期运动并发症的患者随机分配到最佳药物治疗组，同时将124例患者随机分配到上述治疗加下丘脑神经刺激组。神经刺激组患者接受双侧立体定位手术，置入电极(model 3389，美敦力公司)和一个脉冲发生器(Kinetra或Soletra，美敦力公司)。双侧半球的刺激相似，平均强度为2.8 V，平均刺激频率为142 Hz，平均脉冲持续时间为66微秒。刺激达到最大获益所需的时间大约为5个月。主要终点为100分帕金森病(自测)问卷(PDQ-39)汇总指数。基线时，两组各项指标无显著差异。两组患者的平均年龄均约为52岁，病程约7.5年，接受左旋多巴治疗约5年。患者发生左旋多巴诱导的运动并发症平均约18个月。作者认为，总之，研究受试者较以往神经刺激试验中的患者稍年轻，且病情较轻。

结果显示，2年时，神经刺激组报告PDQ-39汇总指数生活质量评分提高了7.8分；药物治疗组患者报告评分降低0.2分。2年时相对于基线的平均变化的组间差异为8.0分(P=0.002)。神经刺激组的运动残疾评分也更优，在无药物治疗情况下，70分统一帕金森疾病评定量表(UPDRS)第Ⅲ部分的组间差异为16.4分，神经刺激组更优(P<0.001)。使用适当的UPDRS部分评估发现，神经刺激组日常生活活动(P<0.001)和左旋多巴诱导的运动并发症(P<0.001)评定也中度优于药物治疗组。根据患者日记中的报告，接受神经刺激治疗组还报告有良好运动和无运动功能障碍的时间较长(P=0.01)。神经刺激组患者每日左旋多巴等效剂量减少了39%，而药物治疗组患者增加了大约21%。“因为仅接受药物治疗组的运动症状和生活质量保持相对稳定，故接受手术患者的改善可归因于神经刺激。”

神经刺激组有68例患者(55%)发生严重不良事件；共发生26起与手术或设备有关的严重事件，包括1起脑脓肿，但在治疗后痊愈。神经刺激组中重症抑郁症更多见。药物治疗组中有56例(44%)发生严重不良事件，多数为运动障碍和药物副作用的结果，如冲动控制障碍和幻觉。并且，该组患者因健康问题就诊的情况也更多见。神经刺激组的2例患者和药物治疗组的1例患者自杀；两组各有2例患者有自杀企图。

这项研究部分由美敦力公司资助，该公司为试验中使用的神经刺激设备的生产商。除1名研究者外，其他49名研究者披露与美敦力公司之间存在某种形式的利益关系，包括补助金、差旅费以及讲课、咨询、数据审查和教育材料开发费用。1位研究者为美敦力公司顾问委员会成员。首席研究者的部分薪酬是由该公司支付的。除美敦力公司之外，德国研究部和法国Clinique国家奥皮塔利耶研究项目也对这项研究给予了资助。

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By: M. ALEXANDER OTTO, Internal Medicine News Digital Network

The addition of subthalamic stimulation to medication therapy not only improved the quality of life of patients with early Parkinson’s disease and mild levodopa-induced motor complications but also reduced their subsequent motor disability in a randomized trial conducted in French and German centers.

The combination is already known to help advanced Parkinson’s patients. The new findings suggest that "neurostimulation may be a therapeutic option for patients at an earlier stage than current recommendations suggest," wrote lead author Dr. W.M.M. Schüpbach and coinvestigators in the EARLYSTIM (Controlled Trial of Deep-Brain Stimulation in Early Patients with Parkinson’s Disease) study group (N. Engl. J. Med. 2013;368:610-22 [doi:10.1056/NEJMoa1205158]).

The investigators randomized 127 patients with early motor complications to best-practices drug therapy and 124 to that plus subthalamic neurostimulation.

At the end of 2 years, the combination group reported a 7.8 point quality-of-life improvement on the 100-point Parkinson’s Disease [self-] Questionnaire (PDQ-39) summary index, the study’s primary outcome; medication-only patients reported a 0.2 point drop. The between-group difference in mean change from baseline to 2 years was 8.0 points (P = .002).

The neurostimulation group had better scores on motor disability, too, with a between-group difference on the 70-point Unified Parkinson’s Disease Rating Scale (UPDRS), Part III, of 16.4 points without medication in favor of neurostimulation (P less than .001). Neurostimulation was also modestly superior on activities of daily living (P less than .001) and levodopa-induced motor complications (P less than .001), both also assessed by their appropriate UPDRS sections. The group that received neurostimulation also reported longer times with good mobility and no dyskinesia, as reported in patient diaries (P = .01). Stimulation patients had a 39% reduction in their levodopa-equivalent daily dosages, while drug-only patients had an increase of about 21%.

"Because motor symptoms and quality of life" remained relatively constant in the drug-only group, "the improvement among patients who underwent surgical implantation can be attributed to neurostimulation," wrote the authors of the study, which was funded in part by Medtronic, the manufacturer of the neurostimulation equipment used in the trial.

There were no significant between-group differences at baseline. Patients in both groups were about 52 years old on average, sick for about 7.5 years, and on levodopa for about 5 years. They had levodopa-induced motor complications for an average of about 18 months. Overall, study subjects were a bit younger and less ill than in previous neurostimulation trials, according to the authors.

Sixty-eight patients (55%) in the combination group had serious adverse events; there were 26 serious problems related to the surgery or device, including a brain abscess, but they healed with treatment. Major depression was also more common in the neurostimulation group.

Serious adverse events were noted in 56 of the drug-only subjects (44%), most of which were the result of motor problems and medication side-effects such as impulse control and hallucinations. Those patients made more office visits for health problems, too.

Two patients in the neurostimulation group and one in the medication-only group committed suicide; two in each group made an attempt.

"We hypothesize that the decision to eventually undergo neurostimulation may select a specific subgroup of patients with a higher risk for suicidal behavior than the general population," the researchers wrote.

Neurostimulation patients had bilateral stereotactic surgery, with the implantation of electrodes (model 3389, Medtronic) and a pulse generator (Kinetra or Soletra, Medtronic). Stimulation was similar in both hemispheres, with a mean strength of 2.8 V, mean stimulation frequency of 142 Hz, and mean pulse duration of 66 microseconds. Stimulation took about 5 months to reach its maximum benefit.

All but 1 of the 50 investigators disclosed some form of financial relationship with Medtronic, including grants, travel funding, and speaker, consultant, data review, and educational-material development fees. One is a Medtronic board member. Part of the lead investigator’s institutional salary is paid by the company. In addition to Medtronic, the German Ministry of Research and the French Programme Hospitalier de Recherche Clinique National helped fund the study.

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Patients had less dementia than most with Parkinson's

"This is one of the most rigorously conducted trials of neurostimulation" of the subthalamic nucleus for Parkinson’s disease. "Medical treatment was provided systematically, in accordance with established evidence, and judged by an independent panel. Although true blinding is difficult in neurostimulation studies, reviewers who were unaware of the study assignments rated standardized videotaped assessments of motor function," Dr. Caroline M. Tanner wrote in an accompanying editorial (N. Engl. J. Med. 2013;368:675-6 [doi:10.1056/NEJMe1214913]).

"[But] the patients included in this study do not represent most patients with Parkinson’s disease. All the patients were 60 years of age or younger at the time of surgery, were in good general health, did not have dementia, and had a good response to a levodopa challenge. Very few patients with Parkinson’s disease meet these criteria," she noted.

Because of that, the results "argue in favor of using neurostimulation in carefully chosen young patients with a recent onset of motor fluctuations," she wrote, because it may provide for them many additional years of good functioning.

"Whether these results would be obtained in older patients with Parkinson’s disease or in less-experienced medical centers is not known," she wrote.

In addition, "suicide was increased in the neurostimulation group, even though mean scores in the assessment of depression improved in that group. Suicide has previously been associated with stimulation of the subthalamic nucleus but less so with other surgical targets used in the treatment of Parkinson’s disease. Since the risk of suicide appears to persist for years after surgery, careful and sustained monitoring should be a requirement," Dr. Tanner wrote.

"The surgical benefit appears to depend on the experience of a large, multidisciplinary team of experts. Most important, neurostimulation has a beneficial effect only on selected motor symptoms. The underlying progression of Parkinson’s disease and inevitable disability due to other disease features are not ameliorated," she added.

Dr. Tanner is the director of clinical research at the Parkinson’s Institute and Clinical Center in Sunnyvale, Calif. She said she has no personal commercial disclosures; her institution receives payments for her consultant work for Adamas and Impax pharmaceutical companies.