An Overview of Amyotrophic Lateral Sclerosis

来自《JAMA》网络，这里是《JAMA临床综述》，为您带来医学、科学与临床实践中的创新对话与见解。

From the JAMA Network, this is JAMA Clinical Reviews, interviews and ideas about innovations in medicine, science, and clinical

实践。

practice.

欢迎全球的听众收听本期《JAMA临床综述》播客，感谢您的关注。

Welcome to listeners from around the world, and thank you for tuning in to this JAMA Clinical Review podcast.

我是您的主持人麦克德莫特，《JAMA》的副主编，今天很高兴邀请到拉维茨医生。

I am your host, McDermott, Deputy Editor of JAMA, and I'm here today with Doctor.

约翰·拉维茨。

John Ravits.

他是加州大学圣地亚哥健康中心的神经科医生，加州大学圣地亚哥医学院临床神经科学教授，同时也是该院ALS转化研究项目的负责人。

A neurologist at UC San Diego Health, professor of clinical neurosciences at UC San Diego School of Medicine, and head of ALS translational research at UC San Diego School of Medicine.

医生。

Doctor.

拉维茨医生是《JAMA》关于肌萎缩侧索硬化症综述文章的作者。

Ravits is author of a JAMA review on the topic of amyotrophic lateral sclerosis.

非常感谢您今天参与我们的节目，医生。

Thank you so much for joining us today, Doctor.

拉维茨医生。

Ravits.

谢谢您邀请我。

Thank you for inviting me.

我想先请您介绍一下，什么是肌萎缩侧索硬化症？这种病常见吗？

So I'd like to get started by having you tell us what is ALS and how common is it?

肌萎缩侧索硬化症是一种罕见的成人发病的神经退行性疾病，主要表现为进行性肌肉无力。

ALS is a rare adult onset neurodegenerative disease, which is characterized by progressive muscle weakness.

它涉及控制运动的运动神经元退化，因此最明显的症状就是无力。

It's a degeneration of the motor neurons controlling movement, and so the manifestation is weakness.

那通常最早出现的症状有哪些呢？

And what are the typical presenting symptoms?

比如，会是哪种类型的无力？

What type of weakness, for example?

所以关键特征就是肌肉无力。

So the key characteristic is weakness.

它实际上可能从身体任何部位的肌肉开始。

It can begin actually in any of the muscles of the body.

可能一开始是说话含糊不清，或者手臂、手部、腿部出现无力。

So it can start with problems with speech, slurred speech, problems of weakness in the arm or the hand, or in the leg.

通常它先出现在某个特定部位，然后逐渐扩散到附近的其他肌肉。

And it typically begins in just a very specific area, and then spreads to other muscle areas nearby.

那这种扩散一般会有多快？

And how quickly does that spreading happen?

发病很隐蔽，通常要三到六个月，患者才会意识到出了问题。

Well, the onset is insidious, so usually it's a matter of three to six months before patients even are aware that there's a pathologic problem.

很多时候，人们会误以为是缺乏运动或久坐不动造成的，就忽略了。

It's oftentimes attributed to disuse or lack of exercise or written off for other reasons.

所以三到六个月，有时候更久，患者才真正注意到不对劲。

So three to six months, sometimes longer, before patients become aware of the problem.

而且通常会在三到五年内逐渐加重。

And it typically progresses over about a three to five year period of time.

哪些人容易患上肌萎缩侧索硬化症？

Who is at risk for ALS?

典型的患者年龄、性别还有其他特征是什么？

What is the typical patient's age, sex, other characteristics?

平均发病年龄在55到65岁之间。

Well, the average age is between 55 and 65.

男性患者更多，大约占60%，女性占40%。

Males are predominant, about 60% male, 40% females.

有一种遗传型的，这个我们待会儿可以聊，发病年龄通常稍早一些，大概在55岁左右。

There is a genetic form of it, which we can talk about, and that's generally a little bit younger, about age 55 onset.

这种遗传型的话，男女比例就差不多了。

And then that would be equal, male and female.

对。

Yes.

你的综述会提到散发型和家族型肌萎缩侧索硬化吗？

Will your review discusses sporadic and familial ALS?

你能稍微讲讲这两种类型，它们和遗传有什么关系，为什么区分这两种形式很重要吗？

Can you talk a little bit about that and how that relates to genetics and why those two forms are important to distinguish?

当然可以。

Sure.

我们现在知道，大约百分之十五的ALS患者有遗传因素，通常是常染色体显性遗传，而剩下的百分之八十五属于散发型。

The genetics we realize now is about fifteen percent of the ALS population has a usually an autosomal dominant pattern of inheritance, and then about eighty five percent is sporadic.

家族型的研究推动了整个领域的发展，因为ALS最大的谜团就在于病因和分子机制。

The familial has led the research because once you have the mystery with ALS is what's causing it and what are the molecular mechanisms.

有了这些致病基因，研究人员就能建立更准确的模型，这大大推动了研究进展。

So with the genes, we now have handles to bring that into models, and it's opened up the research.

它对家庭管理也有重要意义，一旦发现某位家庭成员携带致病基因，所有直系亲属都需要关注风险。

It also has implications for family management because if a member's been identified with a genetic form, then it has implications for all the first degree relatives.

你会建议所有这些直系亲属都去做基因检测吗？

Do you recommend that all of those first degree relatives be tested?

这方面的做法其实一直在变。

Well, that's a changing practice.

以前因为没什么实际用途，所以不建议做检测。

It used to be that since it wasn't actionable, it was not encouraged.

但现在越来越多的患者会主动问，自己要不要做检测。

But more and more, I think patients are asking if they should be tested, if they want to be tested.

这最终成了个人的选择。

It becomes a personal decision.

我觉得越来越多患者的家人也开始关心自己的基因状况。

But I think more and more patients' families are interested in knowing their status.

对于遗传性病例，如果对一级亲属进行检测，有多大比例会呈阳性？

And for the familial form, what proportion of first degree relatives, if tested, would test positive?

大约是百分之五十。

Approximately fifty percent.

因为是显性遗传，如果是直系亲属，风险就是百分之五十。

If they're a direct relative, since it's a dominant inheritance, they would be a fifty percent risk.

我们对肌萎缩侧索硬化症的病理机制了解多少？

Do we know much about the pathophysiology of ALS?

你能稍微讲讲这方面的情况吗？

Can you talk about that a little bit?

在理解发病机制方面，最大的突破发生在2006年，当时发现了TDP-43这种蛋白质。

Well, biggest breakthrough in trying to understand the mechanisms came in 2,006 with the identification of a protein called TDP 43.

当时对它知之甚少，但它却打开了整个研究领域。

Very little was known about it at the time, but it's opened up the research field.

TDP是一种具有多种核内功能的蛋白质，主要存在于细胞核里，但会在核质之间来回穿梭。

The TDP is a protein that has a lot of nuclear function, so it's mainly a nuclear protein, but it shuttles back and forth.

在ALS患者中，神经病理学观察到细胞核内的TDP蛋白消失了，取而代之的是它在细胞质中聚集。

And in ALS, what we see in the neuropathology is that the nucleus is cleared, and the TDP protein is aggregated in the cytoplasm.

所以，现在研究的重点就是弄清楚为什么会发生这种情况。

So the research has really focused on why is that happening.

刚才你提到，ALS常见的首发症状可能是局部无力，或者突然出现的言语障碍，并且会逐渐加重。

A little bit ago, you mentioned that the typical presenting symptoms might be a focal weakness or a speech difficulty that's new and gradually progresses.

如果这样的病人去看全科医生，医生在体检时会注意哪些迹象来支持ALS的诊断？

If such a patient comes in to see, say, a primary care physician, what would they want to look for on physical exam that supports an ALS diagnosis?

好问题。

Great question.

ALS非常罕见，大多数出现无力症状的患者，其实都是由神经受压、肌肉问题或神经根病变引起的。

ALS is very rare, so most of the patients who have problems with weakness will have other problems related to pinched nerves, to muscle problems, nerve root problems.

但ALS患者的特点是兼具两种表现。

But what we see with the ALS patient is that it has mixed characteristics.

一方面会出现上运动神经元损伤的特征，同时也会看到下运动神经元损伤的表现。

It can have the characteristic of what we call upper motor neuron degeneration, and at the same time, we see characteristics of lower motor neuron degeneration.

上运动神经元损伤通常表现为动作迟缓、不协调、肌肉僵硬，反射亢进；而下运动神经元损伤则会导致肌肉萎缩、肌束颤动、肌肉抽搐、松弛无力，以及反射减弱或消失。

And they're each clinically recognized that upper motor neuron degeneration usually has slowed, incoordinated movements that are spastic, and there's hyperreflexia, whereas the lower motor neuron degeneration creates atrophy, fasciculations, muscle twitching, flaccidity, and a loss of reflex.

所以通常我们看到的是，这两种表现同时出现在同一个肢体上。

So typically, what we see is these two coexisting in the same limb.

真没想到。

Wow.

这挺有意思的。

That's interesting.

所以你可以说反射减弱或者反射亢进。

So you could either say hypo or hyperreflexia.

没错。

That's correct.

比如，一个人的手臂出现无力、萎缩、抽搐，同时反射却异常增强，这就说明上运动神经元正在退化。

An example would be somebody has weakness atrophy twitching fasciculations in the arm, that that arm has pathologic increase of reflexes, which indicates that there's upper motor neuron degeneration at the same time.

假设一位ALS患者首次就诊于全科医生，医生觉得需要做一些检查。

Let's say a patient with ALS comes in presenting for the first time to primary care, and the clinician feels they need to do some diagnostic testing.

你会建议做哪些检查？

What diagnostic testing would you recommend?

检查项目要看无力发生在哪个部位。

Well, the findings depend on where the weakness is occurring.

如果是说话或吞咽有问题，脑部核磁共振是最相关的检查。

So typically, if it's a problem of speech and swallowing, the MRI scanning of the brain would be the most relevant.

如果问题是出现在腿部，通常需要做脊柱影像检查，包括腰椎，甚至延伸到胸椎和颈椎。

If the problem is in the leg, usually spinal imaging, the lumbar spine, even up into the thoracic and cervical spine.

所以神经科医生会直接聚焦在相关的解剖区域。

So the neurologists typically focus right into the relevant anatomic area.

影像检查才是最关键的。

Imaging is really the most critical.

那在这些影像检查中，会发现哪些支持ALS诊断的迹象呢？

And what would one find supporting a diagnosis of ALS on those imaging studies?

影像结果通常是正常的。

The imaging is negative.

做影像检查主要是为了排除其他类似ALS的病因。

So the imaging is done to exclude other mimicking causes.

比如脊髓受压、中风、脑肿瘤这类可能引起类似症状的疾病。

An example would be a spinal cord compression, a stroke, a brain tumor, something like that that's creating the problem.

神经电生理检查，比如神经传导速度和肌电图，它们的作用是什么？

And what is the role of neuro diagnostic testing, like nerve conduction velocity and EMG?

我们通常就是在这里做出诊断的。

That's where we generally will make the diagnosis.

肌电图是一种检查。

EMG is a test.

它主要包含两部分：神经传导检测，以及用针头检查肌肉生理状态的肌电图部分。

It really consists of two major components, nerve conduction studies, and then the electromyography is the needle examination of the muscle physiology.

我们通常看到的是神经传导检测结果正常。

What we typically see is normal nerve conduction studies.

没有神经受压的情况。

There's no pinched nerve.

没有神经受压，但多个肌肉中出现了失神经和再神经化的迹象。

There's no nerve compression, but there is evidence of denervation and reinnervation in a number of muscles.

这表明支配这些肌肉的神经元正在持续受损。

And that indicates that there's an ongoing problem of the innervating neurons.

你的综述提到，这其实是一种排除性诊断。

Your review talks about this is rather a diagnosis of exclusion.

所以当一个人出现典型的症状和体征时，你做了这些检查，但它们大多并不特异，那还有哪些其他疾病需要排除，是你刚才没提到的？

So somebody has typical presenting signs and symptoms, and you do these other tests, and for the most part, you know, well, least they're not specific, what are other diseases in the differential diagnosis that should be excluded that you haven't mentioned?

通常来说，出现进行性肌无力的患者，先去看全科医生，之后往往会转诊给神经科医生。

Well, the typical path for a patient who's presenting with progressive weakness is from the primary care, oftentimes then referred to a neurologist.

神经科医生会做一系列检查，如果怀疑是渐冻症，通常还会进一步转给专门治疗渐冻症的专家。

And then the neurologist will do a number of tests, but then frequently will then, in turn, refer to an ALS specialist if they begin to suspect that it's ALS.

一些容易被误诊的情况，可能是其他神经退行性疾病。

Some of the mimicking problems can be other neurodegenerative diseases.

有些像帕金森病的病症，有时会被混淆。

There's Parkinson's like diseases that can sometimes be mistaken.

比如进行性核上性麻痹，或者多系统萎缩。

It's called progressive supranuclear palsy or multiple system atrophy.

还有一些罕见的退行性疾病。

There's a number of rare degenerative diseases.

如果是下运动神经元或神经肌肉方面的问题，也可能是肌肉本身的问题，比如多发性肌炎或包涵体肌病。

Sometimes for the lower motor neuron neuromuscular, it can be a muscle problem, polymyositis or inclusion body myopathy.

重症肌无力是一种影响神经肌肉接头的疾病，会导致无力和言语障碍等症状。

Myasthenia gravis, a disease of the neuromuscular junction, can cause weakness and speech problems, and so on.

所以，在排除了其他可能的疾病之后，就能做出诊断了。

So ultimately, after ruling out those other conditions, the diagnosis is made.

是这样吗？

Is that correct?

是的，诊断通常基于上下运动神经元同时受累、症状随时间进展，以及无力从一只手臂扩散到另一只手臂这些特征。

Yeah, the diagnosis is made usually on the duality of the coexistence of upper and lower motor neuron, the progression over time, and the spread from up the arm to the other arm, and so the spread of the weakness.

最终，肌萎缩侧索硬化症是一种临床诊断。

And ultimately, ALS is a clinical diagnosis.

一旦确诊，通常还会做基因检测，以排除遗传性病因。

Once the diagnosis is made, then frequently genetic testing is also done to exclude genetic causes.

但基因检测并不能确认诊断，它只是进一步明确患者的具体情况。

But the gene testing doesn't verify the diagnosis, it just further defines the specifics in the ALS patient.

通常的预后如何？

What is the typical prognosis?

总的来说，病情会持续恶化，大约三到五年内会致命。

Well, the prognosis overall is progressive and fatal in about three to five years.

但这对临床医生来说是个难题：一旦确诊，就要努力更精准地判断每个人的病情发展速度。

But that's one of the challenges that the clinicians have, is once the diagnosis is made, is trying to more individualize the progression.

有些患者病情进展非常缓慢，能持续五到十年甚至更久，也有些患者则进展得很快。

There are patients who have very insidious progression, five to ten years or longer, and then there are patients who can progress more rapidly.

有没有什么因素能预测病情是进展得慢还是快？

Are there factors that predict whether it will be a slower or faster progression?

目前还不太清楚。

Not well understood.

影响病情发展速度的因素，大部分还不得而知。

What is modifying the progression is, for the most part, not known.

我们知道，某些基因突变会导致病情迅速恶化，而其他突变则可能进展得比较缓慢。

We know that some of the genetic mutations are particularly rapid in that same gene, other mutations might be more slow.

所以，到底是什么在影响病情的进展速度，还不明确。

So, it's not clear what is modifying the progression rates.

我们来聊聊治疗吧。

Let's talk about treatment.

你的综述提到了三种获美国FDA批准用于渐冻症的药物。

Your review talks about three medications that are FDA approved for ALS.

你能详细说说这三种药吗？

Can you talk about those three medicines, please?

当然可以。

Yes, sure.

最老的一种药叫利鲁唑，是上世纪90年代被证实有效的。

The oldest medicine is a drug called Riluzole, which was proved in the 1990s.

它是一种谷氨酸抑制剂。

It's a glutamate inhibitor.

这药已经用了很久了。

It has been around a long time.

我们知道它的效果非常有限。

We know that its effects are very modest.

一般来说，它能延长患者两到四个月的寿命。

The general rule is it it adds two to four months of life.

更近的荟萃分析表明，实际的改善可能达到四到六个月。

More recent meta analyses have indicated that perhaps the magnitude of the improvement's better four to six months.

这些效果基本上是靠信任接受的。

The effects are basically just taken on faith.

没办法直接测量药物是否在起作用，也无法准确预测对某个具体患者会有什么效果。

There's no way to measure whether the drug is doing what it's supposed to do, and you can't really ascertain in any one individual what the effects are gonna be.

第二种药物是近五年内获批的，叫利鲁唑，是一种抗氧化剂。

The second drug that was approved more recently was within the last five years, a drug called daravone, which is an antioxidant.

研究表明，如果在功能尚好的早期阶段使用，它也能带来 modest 的益处，大约四到六个月。

And that has shown that if treated early in the high functioning patients, that it also has a modest benefit, perhaps four to six months.

这种药在美国获批了，在加拿大也能买到。

And that was approved in The United States, and it's available in Canada.

但欧洲人做过测试，认为它没什么效果，所以英国和欧盟都没批准它。

But the Europeans have tested it and didn't believe that it has any effect, and so it was not approved in The UK or the European Union.

最近获批的第三种药叫tofersen，这是一种全新的分子疗法，专门针对某种基因突变。

And the third drug that has more recently been approved is a drug called tofersen, which is a completely new approach to molecular mechanisms focused with a gene mutation.

这种药能降低SOD1基因的表达，而SOD1正是ALS最常见的遗传病因之一。

So this drug is a drug that reduces the expression of a gene called SOD one, which is one of the more common genetic causes.

它通过腰椎穿刺直接注入脊髓液，减少SOD1蛋白的产生，效果非常显著。

And so by it's given intrathecally, so by a lumbar puncture, and it reduces the production of the SOD1 protein, and that's proved to be very beneficial.

我们觉得，之前的一些研究可能低估了它的疗效。

Some of the testing, we think, has underestimated the benefits.

随着使用经验的积累，我们发现长期使用的好处越来越多，甚至有大约百分之二十五的患者出现了明显改善。

And so as the experience progresses, we're finding more and more benefit over long term, and we're even starting to see improvement in up to about twenty five percent of the patients.

由于这种药只对SOD1突变有效，这也是为什么建议直系亲属做基因检测——如果发现有风险，尽早干预效果会更好。

That's interestingly also now, since it's actionable for SOD1 mutation, that's one of the reasons for having genetic testing in first degree relatives because if they're at risk, then we're pretty confident that earlier intervention is going to be better.

你的综述还提到了一些改善ALS症状的干预措施，比如吞咽困难、构音障碍、呼吸功能下降和营养支持。

And then your review talks about interventions to improve ALS symptoms such as dysphasia, dysarthria, respiratory compromise, nutrition.

你能稍微展开讲讲这些方面吗？

Can you talk about that a little bit, please?

我们在ALS领域取得的一项重大进展，是加强了对患者的全方位支持。

One of the major advances that we've made in the ALS field has been in the support of patients.

自上世纪90年代以来，过去二三十年间，这种支持不断改进，主要是通过建立多学科协作的照护体系。因为ALS是种罕见病，每个患者的问题都不一样，比如说话、吞咽、呼吸、手臂功能或行动能力。

And this has been evolving and improving since the 1990s over the last, say, twenty, twenty five years in terms of organizing multidisciplinary care because it's such a rare disease, and the problems are so specific to each patient, whether it's speech or swallowing, respiratory, arm function, mobility.

我们现在组建了专门团队，主动提供多学科联合照护。

We've organized into teams that will deliver multidisciplinary care proactively.

我们大约每三个月见一次患者，全面评估他们的语言、吞咽、营养、呼吸、日常生活能力和行动状况。

So we see the patients approximately every three months, reassess all of these functions: speech, swallowing, nutrition, respirations, activities of daily living, and mobility.

然后根据他们的具体需求，提供相应的支持和帮助。

And we work with them to then support with whatever may be required.

那在沟通障碍方面，有没有一些新的治疗方法？

What about some of the novel therapies for difficulty with communication?

你能说说这方面的内容吗？

Can you talk about that?

有的。

Yes.

大约三分之二的患者在疾病发展过程中，无论早晚，都会出现说话和沟通方面的困难。

About two thirds of the patients will then progress at some point during the disease, either early or late, into problems with speech and communications.

对此我们有好几种应对方法。

And there's a number of things we can do.

其中一种是语音存档。

One of them is voice banking.

在患者说话还正常的时候，言语治疗师就会评估并录制他们的声音。

So early, when the patients have normal speech, the speech therapist will assess and bank their voice.

等以后需要的时候，可以通过电脑模拟，借助辅助设备来重现患者原本的声音。

And then with computer simulations later, if it's needed, then they can use augmentative communications such as computers and other assistive devices to then reproduce their voice.

那关于营养评估的时机呢？比如胃造瘘管，考虑到呼吸功能障碍这么普遍？

And then what about your review talks about the timing of nutritional evaluation, say for a G tube, given the respiratory compromise that is so common?

是的。

Yes.

我们在门诊中会密切监测两个关键指标。

We follow closely in the clinics two particular parameters.

我们监测所有这些指标，其中两个关键的是体重和呼吸功能。

We follow all of the functions, but one is their weight, and the other is their respiratory capacity.

通常我们会从100%开始，但这个数值可能提前或延后下降，不同患者的情况也不一样。

Typically, we'd start out at a 100%, but that can be affected earlier or later, and it's at different stages with different patients.

这不仅本身很重要，如果患者出现体重下降，我们就会在呼吸功能还能承受手术时，尽早考虑置入胃管。

But that's important not only in itself, but if they're having weight loss, we want to then intervene with G tubes when their respiratory capacity can handle the procedure.

所以现在趋势是更早地为患者置入胃管。

So the move has been more early intervention for G tube placement.

非常感谢您。

Thank you so much.

今天的讨论内容非常丰富。

This has been a really informative discussion.

我想问问，有没有什么我们今天没谈到，但您想补充的内容？

I'm wondering if there's anything that we didn't cover that you would like to add today?

我觉得这个领域一个令人振奋的方向是基础研究，我们正努力弄清这种疾病的内在机制，因为只有理解了这些，才可能找到根本性的治疗方法。

Well, I think one of the exciting things in the field has been in the research arena and really trying to understand the mechanisms underneath this disease with the belief that if we can identify those, we can really establish a fundamental treatment for the disease.

由于病情进展非常明显，而且患者通常愿意尝试新疗法，全球范围内围绕这一领域的临床试验和药物研发都非常活跃。

And because the progression is so observable and they're so oftentimes willing to take chances, clinical trials and drug development has been especially active in the field around the world.

我是玛丽·M。

I'm Mary M.

麦克德莫特，今天我与约翰·拉维茨医生进行了对话。

McDermott, and I've been speaking today with Doctor.

他刚刚在《JAMA》上发表了一篇关于肌萎缩侧索硬化的综述文章。

John Ravits about his JAMA review on the topic of ALS.

您可以在本集的简介中找到这篇文章的链接。

You can find a link to the article in this episode's description.

本集节目由丹尼尔·穆西西在《JAMA》网络团队制作。

This episode was produced by Daniel Mussisi at the JAMA Network.

如需收听本节目及其他《JAMA》网络播客，请访问 jammanetworkaudio.com，或在您常用的播客平台搜索“JAMA Network”。

To follow this and other JAMA Network podcasts, please visit us online at jammanetworkaudio.com or search for JAMA Network wherever you get your podcasts.

感谢收听。

Thanks for listening.

本内容由美国医学会拥有版权，所有权利保留，包括文本与数据挖掘、人工智能训练等类似用途。

This content is protected by copyright by the American Medical Association with all rights reserved, including those for text and data mining, AI training, and similar technologies.