August 29, 2006 -- 一项大型流行病学研究指出，今日的肌萎缩性脊髓侧索硬化症(ALS)病患比20年前病程恶化减缓、存活较久。
Methodist神经研究中心的研究者发现，病患ALS发作后的平均存活，从1984年的平均3.22年增加为2004年的4.23年。
主要研究者Stanley Appel医师向Medscape表示，我们发现1991年前后病患病程有相当多的改变，而这和照护标准改变无关。
该研究登载于八月版的神经学档案(Archives of Neurology)期刊。
研究者将一整个ALS资料库分成两组— 历史组是指1984年1月1日到1999年1月1日间诊断者，当代组是指1999年一月2日到2004年11月1日间诊断者。
该研究测量的两个结果是存活和到达Appel ALS (AALSS)分数20分的时间，存活的定义是症状发作到任何原因导致之死亡的月数。
本研究共有1041位病患：647 (62.2%) 位属于历史组、394 (37.8%)位属于当代组。
除了延长存活之外，研究者发现当代组病患病程恶化较慢—到达AALSS分数20分的时间是10个月，历史组到达AALSS分数20分的时间是9个月。
【病患特征】
当代组病患较少有延髓的发作—延髓发作是
临床上典型预测不良预后的因子，此外， 该组有许多病患服用riluzole药物和接受非侵犯性呼吸 (NIV) 治疗。
另一方面，历史组病患较年轻，开始时之AALSS较低，较常接受经皮穿刺胃引流(PEG)治疗。
不过，忽略这两组病患之差异，多变项分析显示历年来的改变和症状发作部位、年纪、性别、延迟诊断和开始时AALDD等共存因子无关。
进一步来说，也和潜在的影响结果之治疗，如riluzole、NIV 和PEG无关。
Appel医师表示，我们很惊讶于当代组病患和相关变项无关的改变。
【因自然历史的改变？】
Appel医师指出，此结果提升了有关ALS自然史是否改变之疑问；他表示，我不希望任何人看了这篇报告后说ALS的自然史已绝对改变，不过的确提升了此一可能性。
不过，他补充，也有可能是目前广泛被各中心杰出运用的各种学问方法对此病之自然史产生冲击。
Appel医师表示，我们真的不了解这些因素对ALS自然史之影响，但事实上病患病患的确存活较久；此病是人类恶病症之一，当你日渐消瘦就可能罹患此病；不过，既然此病病程恶化减缓且存活较长，意指我们可以有绝佳机会帮助他们提升生活品质。
【研究意涵】
除了临床冲击之外，该研究也探索相关意涵；ALS双盲安慰剂控制研究通常必须承担巨大的花费，有许多药物等待评估但病患却很少，因此，Appel医师表示，他的团队支持的研究选择之一，是在采取任何双盲研究之前进行无疗效研究，当完成此一目标即可获得当代组之控制组病患资料库。
他指出，这些研究让我们以我们的当代组资料库作为安慰剂控制组，检测少数病患的潜在治疗方式，然后比较结果。
不过，他也补充，此研究的结果认为，使用当代病患组资料以确保类似研究的有效性是不可少的。
他表示，你可能会愚弄你自己，举例来说，我用10年前病患的资料比较治疗组的结果，结果将看似治疗组获得戏剧性的改善，因为并未纳入当代病患其他非关药物造成的改善因素。
ALS Patients Experience Slower Disease Progression, Are Living Longer
By Caroline Cassels
Medscape Medical News
August 29, 2006 — Patients with amyotrophic lateral sclerosis (ALS) have slower disease progression and are living longer today than they did 20 years ago, a large epidemiologic study suggests.
Researchers at Methodist Neurological Institute in Houston, Texas found that among contemporary patients, the average survival time from ALS symptom onset has increased from 3.22 years in 1984 to 4.23 years in 2004.
"We found that there was a considerable difference in the way patients were progressing before and after 1999 and that this effect was independent of improved standards of care," principal investigator Stanley Appel, MD, told Medscape.
The study is published in the August issue of Archives of Neurology.
The investigators stratified a large ALS database population into 2 groups — a historical group diagnosed between January 1, 1984 and January 1, 1999 and a contemporary group diagnosed between January 2, 1999 and November 1, 2004.
The study's 2 outcome measures were survival and time to 20-point progression in the Appel ALS score (AALSS). Survival was defined as the number of months from symptom onset to death from any cause.
A total of 1041 patients — 647 (62.2%) and 394 (37.8%) in the historical and contemporary groups, respectively — were included in the study.
In addition to longer survival, investigators found patients in the contemporary group progressed more slowly — 10 months to 20-point AALSS vs 9 months for the historical group.
Patient Characteristics
The contemporary group was characterized by a lower percentage of patients with bulbar onset — a clinical finding that typically predicts poorer prognosis. In addition, more patients in this group received the drug riluzole and underwent noninvasive ventilation (NIV) therapy.
On the other hand, patients in the historical group were younger, had lower AALSS at baseline, and underwent percutaneous gastrostomy (PEG) therapy more often.
However, regardless of the differences between the 2 patient groups, multivariate analysis revealed improvement in outcome over time was independent of confounding factors, including site of symptom onset, age, sex, diagnostic delay, and baseline AALSS.
Furthermore, patient outcomes were also independent of potentially outcome-modifying therapies, including riluzole use as well as NIV and PEG.
"We were very surprised to see that the improved outcomes in the contemporary patients were independent of all of these factors," said Dr. Appel.
Change in Natural History?
This result, said Dr. Appel, raises the question of whether the natural history of ALS is changing.
"I don't want anyone to look at this paper and interpret it as saying the natural history of ALS is absolutely changing, but it certainly raises the possibility," he said.
However, he added, it is also possible that the now-widespread multidisciplinary approach adopted by many centers of excellence is also having an impact on the history of the disease.
"We truly don't understand all of the factors that are contributing to the natural history of ALS, but the fact that patients are living longer is important for doctors to grasp. This is one of the worst diseases of humankind. You have a ringside seat as your body wastes away. However, the fact that these patients have slower disease progression and are living longer means we have a unique opportunity to help maximize their quality of life," said Dr. Appel.
Research Implications
In addition to clinical implications, the study also has research implications. Double-blind placebo-controlled studies in ALS usually entail enormous expense, and there are many drugs to evaluate and too few patients. As a result, said Dr. Appel, one of the research alternatives that his group supports is the use of futility studies before undertaking any double-blind studies, and to accomplish this goal a contemporary cohort of control "database" patients must be available.
"These studies allow us to test a potential therapy in a smaller number of patients using our contemporary database population as the placebo control group and then compare the outcomes," he said.
However, he added, the results of this study suggest that it is critical to use contemporary patient population data to ensure the validity of such research.
"You can fool yourself. If, for instance, I compared outcomes in a treatment group with outcome data in patients I saw 10 years ago, the results would look as though the treatment group is experiencing a dramatic improvement, because it doesn't take into account that contemporary patients may be improving independent of the drug," he said.
Arch Neurol. 2006;63:1139-1143.
作者：
Caroline Cassels 2007-6-20