Associate professor of medicine and neurology, and director, Duke ALS Clinic, Duke Health; and chief, Department of Neurology, Durham Veterans Affairs Medical Center.

Richard S. Bedlack, MD, PhD, MS

Jeremy, I have heard about a drug called arimoclomol. What can you tell us about that?

Arimoclomol has probably been around the ALS [amyotrophic lateral sclerosis] community for 15 years. It is a drug that was evaluated in preclinical models first and is a coinducer of a heat shock protein called Hsp70. Heat shock proteins are chaperones that help remove toxic elements from a cell. More research has been done on arimoclomol preclinically, and it clearly has a direct effect on lysosomal activity, and it enhances the ability of lysosomes and cells to clear protein aggregates. It was studied in a study of 100 patients. It was a 3-month study, and it was shown to be well tolerated and have good CNS [central nervous system] penetrance.

It was then studied in a group of patients with familial ALS with SOD1 mutations. Although that was a small study, there was a suggestion that it was positive in that group. It has then been studied in a variety of storage diseases including a disease called Niemann-Pick. A phase 3 study of Niemann-Pick was reported as positive, and the drug is being considered by the FDA for approval in that regard. In the context of a relatively large, relatively long placebo-controlled trial, arimoclomol is close to completion in ALS. I do not know the dates, but it is likely to be sometime this quarter or next when we will get the results, and we will find out whether it has a role.

 Thank you. Ammar, the next on our list of tongue twisting medications is masitinib.

Masitinib was part of a remarkably complex study design. It was a phase 2b/3 study. It transitioned seamlessly from phase 2 to 3. Masitinib itself is a tyrosine kinase inhibitor. It modulates mast cells and macrophages, and it and is thought to have neuroinhibitory, neuroprotective properties. The study randomized 394 people 1:1:1 of placebo with riluzole, masitinib at 3 mg/kg per day with riluzole, or masitinib 4.5 mg/kg per day with riluzole. In other words, everyone was given riluzole, and people were either given placebo or low-dose or high-dose masitinib. 

That was the basic dosing regimen, but that was superimposed on top of another stratification of patients. Patients were assessed for their ALS FRS [Functional Rating System] rate of decline and classified as normal progressors, which was defined as a rate of decline of 1.1 points or less per month, or fast progressors. They then ended up with people who were normal progressors on either of the 2 dose types or placebo. They then grouped normal progressors and fast progressors as the other group. It was not normal or fast; it was normal and fast as the comparator arm on the 3 different arms. It was an incredibly complex study design, which is part of the reason it has been difficult for the community to understand the results. 

The main result was that, for the people who were normal progressors and had a high dose, there was a significant difference in the rate of disease progression. There was an improvement in the rate of disease progression compared with the other arms, but the difficulty was that, even though these were prespecified by the study team as analyses, it was regarded as multiple testing and just trying every single thing in the hope that 1 would come out positive, which is not necessarily a fair interpretation of it. 

That is part of the difficulty is that this is a complex study design. The idea would be to go back and do the phase 3 study with a simpler study design and try with the normal progressors at a high dose and see what that shows. 

Jeremy, this past summer, in the New England Journal of Medicine, we saw the results of our first gene therapy trial in ALS. It was of a drug called tofersen. Can you tell us about that?

Tofersen is an antisense oligonucleotide, meaning it is a string of nucleic acids that was actually engineered to match a string of nucleotides that exist in the SOD1 gene. The purpose of this is that the antisense binds to the gene, inhibits production, and potentially even then provides a substrate for which the gene and the antisense together can be degraded. It was shown to reduce the amount of SOD1 protein successfully, whether mutant or normal, in experimental animals and in human subjects with ALS.

What was reported in the New England Journal of Medicine study was a seamless phase 1/2, phase 2 study where patients were initially given low doses of tofersen and then somewhat higher doses. The number of subjects at the higher dose was somewhat enriched so that they had a small number of patients there, but they potentially had enough to look at efficacy variables. They were now looking at patients with SOD1 who were rapidly progressive. Even over 3 months, you expect these patients to decline quite dramatically. 

The patients who were on the higher dose of tofersen, who were rapidly progressive, essentially progressed not at all for those 3 months. Even though it was a short study and even though it was a small number of people, that difference is apparently dramatic and suggests that this could be a dramatically effective treatment for patients with this form of ALS. An ongoing study is testing that same higher dose in a larger number of people to make sure that this is not a fortuitous finding.

One of the findings that also suggested this is potentially real is that a biomarker of axon degeneration on neurofilament light chain also was clearly reduced in patients taking tofersen. Neurofilament light chain is reliably increased in patients with ALS. Overall, this is quite encouraging.

 That sounds very exciting. Jinsy, how about ibudilast?

I will talk quickly about ibudilast, which is also referred to as MN-166, which is an investigational product. It is still in clinical trials. Ibudilast is an anti-inflammatory drug. It is a phosphodiesterase inhibitor, but it also inhibits the macrophage migration inhibitory factor. It is meant to be neuroprotective by helping to protect the motor neurons and prevent degeneration. It has already completed early phase clinical trials. It demonstrated a decent safety and tolerability, but the question now is its effectiveness. In the United States, and I believe there are sites in Canada as well, the clinical trial has launched and is actively recruiting for participants in a 12-month study. The randomization is 1:1 placebo or treatment. After that 12-month duration, the open-label extension will continue to be offered to the participants who complete that 12 months placebo-controlled study. The study is recruiting, and we are awaiting results.

This was a very exciting section. If I could look into a crystal ball and think about what the future in ALS might look like, there may come a day when we can pick off individual patients based on the specific cause of their disease. We could say there is 1 specific gene that we can go after and maybe stop the progression in that small percentage of patients. For everybody else, we may have a cocktail of medications that hit different downstream mechanisms, which is so-called rational polypharmacy. It is exciting to think about that. 

Let me ask 1 last question. I am going to ask this to each of you: If you could give 1 piece of advice to a community neurologist who is seeing a patient with ALS, what would it be? Jinsy?

I would ask for our community neurologists to know that ALS should not be said in the same sentence as “death sentence.” There is something that we can do for these patients, so they must try to identify these patients earlier and get them to an ALS center as quickly as possible.

Mine would be to think of ALS because, for the reasons everyone has discussed already, it can be difficult to think of. As Jinsy says, do not destroy hope. It is important to refer early and not destroy hope.

 I will sound like a broken record, but I completely agree that it is important not to destroy the person’s view of a life that is worth something and that ALS is best cared for in a multidisciplinary clinic. If there is 1 available in your area, please think about referral.

 I appreciate spending this time with the 3 of you. I do not know if I have ever gotten this much of your time before, but I have learned a lot from all of you today. To our audience, thank you for watching this NeurologyLive® Peer Exchange. If you enjoyed the content, please subscribe to our e-newsletters to receive upcoming Peer Exchanges and other great content right in your in-box.

Videos

Key opinion leaders review the study design and mechanisms of action for drugs in ongoing clinical trials and consider the future of amyotrophic lateral sclerosis (ALS). 

Ongoing Clinical Trials and the Future of ALS 

 I am smiling as I look at this next question on our agenda because I know we could easily spend hours on this. All of you are thought leaders and are passionate about clinical trials. I am going to ask you each to tell me 1 thing that excites you about the way we are doing ALS [amyotrophic lateral sclerosis] clinical trials now compared with 10 years ago. Ammar, I will start with you.

The most exciting thing is that we are working collaboratively with a specific aim that was not there many years ago, which is that we learn from every single trial. Regardless of whether the drug shows efficacy, we have learned something about ALS from that trial. Whether it is that biomarkers change and what the biomarker might be, or whether it is that gene variants affect prognosis, there is no trial that is giving us that information. 

That is important because patients and their families are giving huge amounts of time and effort into going into a trial. If the trial does not show a benefit at the end, then that is not respecting the time that they have given. If we are learning something, regardless of whether the drug itself works, even if it is a disappointing result, and we do not have a drug that works, then it at least means that we have learned something that we can take back to improve and do the next trial better because we have that extra information.

 I will be quick and say 2 things. One is that our expanding knowledge of the pathophysiology of ALS has led to a whole host of new targets that we can now assess whether we are influencing. As Ammar said, given that we can assess that, we can make a determination of whether that specific intervention has promise in ALS. I would then say that, not necessarily for phase 3 trials but for middle phase trials, the development of both fluid and other kinds of biomarkers gives us the potential to see drug- and disease-related activity based on your drug in a much shorter period of time with a smaller number of patients. We have the potential to speed up clinical development based on those 2 aspects. 

I do not have much more add except for the fact that what both Ammar and Jeremy pointed out lend lends itself to being innovative in the trial design itself. Using biomarkers to enrich the population that you would evaluate for a particular therapy because it is pertinent of the target might make us more successful in clinical trials by using clinical trial design to evaluate multiple drugs quickly. That is the basis behind what we call platform trials, which is an infrastructure that is set up both in Europe and also in the United States to evaluate drugs efficiently and quickly while being respectful of a participant’s time and altruism for their participation in the clinical trial.

Thinking innovatively about adaptive trial designs as well, we are at a time with ALS where all these components interplay with one another: collaborating, studying outcomes, studying biomarkers, and implementing them in trial design makes sure that we get to an answer more quickly. 

 I cannot help but answer this question myself as well. For me, it is patient engagement. In the past decade, we have seen patients transform from just subjects in our studies to partners. We now have a massive group of patients and families who are trained to understand research, and we are networking with them on a regular basis to get them more involved. 

They are helping us raise money. They are helping us change laws to get more studies. They are helping us ask more relevant questions. They are helping us with trial designs that are more attractive, where people are not going to drop out in such high numbers. They are helping us spread the word. They are helping sponsors craft a message about the results that the community understands. They are working with regulators like the FDA so they have a better understanding of what benefit-risk ratios look like from a patient’s perspective. That is my answer to that one. 

Let’s now shift our attention and talk a bit about some drugs in development. Jinsy, what can you tell us about AMX0035?

AMX0035 is an investigational product being evaluated in ALS. It recently completed a clinical trial. It is a combination of 2 compounds: sodium phenylbutyrate and tauroursodeoxycholic acid, also called tarso. Its mechanism of action targets a couple of different things, but it primarily targets ER [endoplasmic reticulum] stress and mitochondrial dysfunction. It hits on a couple of other things as well. There was a 6-month or 24-week study that was placebo controlled that evaluated the rate of decline of the ALS Functional Rating Scale, which is the main functional scale that we use to assess patients. People will typically lose about 1 point on this 48-point scale per month. 

In this trial, there was a slowing of the rate of decline in the treated population compared with the placebo arm. That difference was 0.24 point per month. It was statistically significant with a P value of .03. Essentially, all those numbers mean that, for a person living with ALS, time is a commodity. Essentially, there is an inherent progression of loss of function over time. This study, over the 6-month period, showed that AMX0035 was effectively able to slow down disease progression as measured by this Functional Rating Scale.

There was an open-label extension. How that was structured is this: After the placebo-controlled portion was completed, everybody was converted to the active treatment, which was AMX0035. When you looked at survival, it was published in the second publication; the initial results were in the New England Journal of Medicine, and the second publication of the survival data was in Muscle & Nerve. In that evaluation, they looked at patients who were initially started on AMX0035 and continued in the open-label extension compared with those who were on placebo initially and then converted later. 

There was a survival advantage of about 44%, which means that it is effective in line with some other approved medications like edaravone and riluzole.

A panel of experts provides insights into recent improvements in clinical trial design in amyotrophic lateral sclerosis (ALS) and discusses implications of recent clinical trial results. 

Advancements in Clinical Trial Design in ALS 

 Let’s delve into pharmacological management. We will talk about FDA-approved drugs as well as drugs in development. Ammar, riluzole, also known as Rilutek. What can you tell me about that 1?

 It is an interesting drug. It was found serendipitously, so the mode of action was thought to be related to the glutamatergic hypothesis of ALS [amyotrophic lateral sclerosis]. That is the idea that, for most neurons, when 1 neuron talks to the next neuron, it usually inhibits it. You cannot over-inhibit a neuron because it goes to 0, but some neurons excite the next neuron in the chain with glutamate, for example. It is possible to overexcite a neuron more than 100%. If that happens, then the neuron that is being hyperexcited is prone to death: to apoptosis or some similar process. That is called excitotoxicity.

Riluzole was designed because it is known to interfere with that glutamatergic transmission and modulate it to reduce it. That is why it was tried. It was trialed in the early 1990s. By 1994, it had been through a sufficient phase 3 trial that there was evidence that it provided benefit. But since then, other drugs that have a similar mode of action have not shown the same result. This suggests that the mode of action of riluzole is something different. It does not mean it definitely is, but it does make it seem more likely that it is something different, which is frustrating because if it had been the same, we would have hopefully been able to make a riluzole-plus that was better than the existing riluzole. Because it is an unknown mechanism of action, essentially, we do not know what to do to make an improved version.

 Is it always a pill, Ammar, or does it come in different forms?

 It is generally a 50-mg tablet, which is supposed to be prescribed twice a day. It is also available as a liquid, not just as tablets. If someone has a gastrostomy tube, then a liquid can be useful. In the United Kingdom, at least, the liquid can be difficult to obtain, so some people crush the tablet and add it to yogurt and put that down the tube. That is not how it is licensed to be used. Theoretically, the drug might stick to the plastic of the tube if it is not used in the correct way, but if there is no choice, then that is what people do.

When people come to me the first time, a common thing I hear is, “I heard about riluzole, but I was told it gives me only 2 extra months and it messes up my liver.” Is that accurate?

 I do not think that is accurate. Of course, there is a risk of the liver enzymes rising. It is known to do that in a portion of people. In my experience, I would say that probably about 10% of people will have that. In all the cases I have seen, stopping the drug or reducing the dose has reversed that change, and the liver enzymes have reverted to normal. In 1 case, in 27 years of prescribing it, I have seen the blood count drop. When we stopped the riluzole, it reversed. Those are known adverse effects, but they are unusual if the correct precautions and blood tests have been used. 

Addressing the 2-month survival aspect, the original clinical trial showed about a 2-month improvement in survival at 12 months. Remember, the original clinical trial was an 18-month trial, so it could not provide data beyond that. The interesting thing about it, to me, is that the technique used to come to that conclusion, the 2-month survival, was a Cox proportional-hazards regression analysis, which is a special type of survival analysis.

One of the assumptions of that type of analysis is that the change in risk is constant: It does not change during the course of the disease. In fact, it was a 38% improvement in survival that they showed, which translates to about 2 to 3 months. That 2- to 3-month improvement in survival is a percentage survival at 12 months, and you should theoretically see that improvement continued throughout the disease as an average change. Of course, we have the problem that Jeremy suggested at the beginning, which is that we do not know if everybody is a responder to the same amount or if there are some people who are bigger responders and other people who are less so, and the average is 2 months. That is probably the case. 

It is not just 2 months of survival. It is a 38% improvement across however long you would have lived. That is what the original trial says. That is different from 2 months, at 12 months, which is how people interpreted the original trial. Not all my colleagues would agree with that, but that is how I interpret that data. 

 I would say, even more strongly, that there are a host of studies that compared survival in different countries prior to the approval of riluzole and then again afterward. In the majority of those, there was some variability in the results, but the majority of those studies suggested an improvement in the life span of closer to a year. Those are not as well controlled, but they also may reflect the real world better to some extent. 

 If you were going to live 10 years, then a 38% improvement is 3 or 4 years. 

 That is a great way to look at it. Jeremy, edaravone, also known at Radicava in the United States, is another FDA-approved drug for people with ALS. What can you tell us about that?

Ammar suggested that riluzole was a serendipitous discovery. I believe that edaravone was as well. Edaravone is a drug that was developed in Japan many years ago to combat acute stroke. It is an intravenous [IV] drug and was given for 14 days as soon as the patient was admitted to the hospital with stroke. The data in Japan suggested that stroke severity was somewhat ameliorated. I do not know what the leap was to go from stroke to ALS, but there was a small academic study that looked at edaravone in ALS. 

The dose regimen was not conceived of in any particular thoughtful way. They picked the dose used for stroke, the 14 days of IV treatment, and they realized that it was probably impractical to give this to patients with ALS every day forever. They took a couple of weeks off, and they then started giving it 10 of every 28 days. It did not show a statistically significant benefit in the first trial, but it showed a trend toward some slowing of progression. The manufacturer of the drug then became more interested in it and supported a larger study, which was approximately 160 or so patients, of which 80 were given placebo and 80 were treated. It again showed some trends toward slower progression, but it was not statistically significant when the entire cohort was looked at. Subsequent post hoc analysis suggested that the earlier the patients were in their diagnosis and the more diffuse their disease was when they started treatment, the better they did. The actual amount of change in the ALS Functional Rating Scale [FRS], which was the primary outcome measure, was greater in these patients who were early onset and more rapidly disseminated early on. It was not statistically significant, but it appeared to be numerically different. If that treatment were reproduced in a bigger study, it would potentially be clinically important. 

A further study was conducted, and it was pretty small. It was about 136 patients, equally divided between treated and untreated patients, looking specifically for early onset patients who had disseminated ALS who also were progressing, at least at some criterion rates. Slow progressors were not allowed, so they took this subset that they saw the biggest change in and then did their study in those patients and found a statistically significant and clinically meaningful change in that, at the end of 6 months, the patients treated with the drug were about 33% slower in their rate of progression measured by the ALS FRS than the placebo patients. This is the study that led to FDA approval.

In the United States, there was not complete unanimity among ALS experts as to whether this was sufficient evidence to support approval. My view is that it was. It was a well-designed trial, and the effect was quite significant. Other secondary outcome measures went along in the same direction. The question was this: If the study was performed on only these patients with early onset—with rapidly progressive, disseminated ALS—is that the only group of patients that the drug works on? 

That kind of reasoning informed third-party payers’ ability or willingness to pay for a drug for ALS for a long time. My own opinion is that the investigators did a clinical trial trick that was wholly appropriate. They looked at patients that they thought, in a small, short trial, would be more likely to have a bigger effect than others, and that is whom they attended to. There was nothing, at least in my mind, about those patients that was etiologically different from the other patients. The previous study showed trend in every kind of patient with ALS toward the same beneficial effect, so my view is that the drug works. 

I encourage it for everybody. It has an attractive adverse-effect profile. It is difficult only because it requires IV access and either home- or infusion center–based therapy 10 of every 28 days.

Jinsy, you have had experience with both these drugs. Tell me about what your experience with riluzole and Radicava [edaravone] are like.

Since edaravone was approved in the United States, I proactively talk about the approved therapies at the start of the diagnosis as treatment option. We will often initiate riluzole first after a discussion of the risks and benefits, mainly because it is available in generic form, and it is available at all the pharmacies. It is easy to prescribe, and it is an oral tablet, so it is easy to take. In the United States, we have the liquid form, but it has some challenges to access because of cost. I believe there is a recently approved oral film of riluzole as well, but that is not easy to access. 

The tablet form is usually the formulation that we prescribe first. For edaravone, most patients are willing to try it and give it a shot to see how they feel. The first question I always get is, “Am I going to feel different?” This is difficult to answer because, based on the clinical trial data, we are intending it to slow down disease progression. I often have to make an analogy almost to their diabetic medications or their blood pressure medicines. They are not going to feel anything. It has an effect, but it will not be easy to tell. 

Most patients take it in our clinic at Columbia University Irving Medical Center, but that can be variable from clinic to clinic in the United States because of the payer situation and the because of physician attitude. Even people living with ALS might read the data and say, “What does that 2 to 3 months mean for me? Is that the last 2 to 3 months? If I have lost a lot of function, then I do not want to be around for that 2 to 3 months, so maybe I will not even start it.” It is difficult. In our clinic, we have 60% to 80% of patients who say, “Yes, go ahead right away.” From clinic to clinic, it can vary. It can be as low as 30% or 25% of the clinic population in the United States. That is driven a lot by physician attitude, about them thinking it is a modest medication. 

With edaravone, it is a lot newer. It has just a couple of years of experience for us. We present the data and present the risks and benefits, but the route of administration poses a challenge in our clinic. We are not able to provide the infusion at our center, so we often have to ask for prior authorization for the medication and for home nursing or an outpatient infusion center. It is a bit more complicated to access the medication, but I agree with Jeremy: For the people who have taken it, the medication itself does not pose any challenges. It is more the access to the medicine and the line management that are challenging. 

For the peripheral IV access, often we use PICC [peripherally inserted central catheter] lines, or we use a port catheter. For certain people and for several of our patients, we have had complications where either the line has a malfunction or there might be skin-integrity issues for PICC lines or infections. I have sometimes had a port-catheter-infusion site that does not heal properly, which I thought may be an ALS-specific thing because I have not had that happen in other disease populations. It is a lot of work. If anyone were to say no to it, it would be the people who might be just a little too healthy and say, “I do not want to have to do all that quite yet.” I have people who are working who do not want to maintain lines while they are doing their work, which may require physical activity. Oddly enough, living in New York, we have some people who want to go to warmer climates in the winter and swim. It is hard to manage a peripheral IV access and enjoy the beach and pool. Those are some of the challenges.

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Expert neurologists discuss clinical trial design and FDA approvals for current approaches to pharmacologic management of amyotrophic lateral sclerosis (ALS) and share personal experiences.  

Approaches to Pharmacologic Management of ALS 

Ammar, with many of my patients, after they see their primary care doctor for an annual checkup, they email me and they say, “My doctor wants to start this medicine” or “They want me to get this immunization. Should I do it? Is it going to affect my ALS [amyotrophic lateral sclerosis]?” Are there medications that patients with ALS should not take? Is it OK for them to get immunizations like the flu shot and maybe the COVID-19 vaccine?

There are some medicines that patients with ALS cannot access. For example, in Europe and in the United Kingdom, we cannot access dextromethorphan and quinidine. For pseudobulbar affect, we have to use antidepressants. In terms of medications that somebody should not take, it is largely around treatments that might interact with their existing medication, and I suppose treatments that could worsen existing symptoms, such as weakness. Those are usually obvious. The kinds of things that are going to worsen current symptoms are usually obvious.

In terms of immunization, it is important for somebody with ALS to stay up to date with their immunizations. The reason is that diaphragm weakness can occur early, so even if the person does not have symptoms, some studies have shown that up to 80% of people, right at diagnosis, have some diaphragmatic involvement even at that early stage. Of course, that makes it more difficult to clear chest infections. Most immunizations are against influenza or COVID-19, for example. They are meant to prevent respiratory infections. You are more likely to get a secondary bacterial pneumonia if you do not clear that. Immunization is important for that reason, particularly for somebody with a weak diaphragm.

Thank you. We have only briefly mentioned noninvasive ventilation [NIV]. Jeremy, tell us a bit more about noninvasive ventilation. How do we screen people for that? How do we decide when to start it? What do we start? What are the benefits?

 Noninvasive ventilation refers to a system that is interfaced with the patient using a mask or sometimes with a tube that they can sip on. In general, it most commonly refers to something called bilevel positive pressure ventilation, which means that there is air blowing out of the mask or the tube at all times, and it is triggered to the patient’s breaths. When a patient begins an inhalation, the pressure increases and allows them to fill their lungs to a greater degree than they could without it. When they stop their inhalation and begin to breathe out, the pressure declines, allowing them to breathe out more easily as well.

It mimics a ventilator for somebody who is intubated, in that the pressure increases, causing expansion of the diaphragm, and it then releases, causing a passive reduction in the volume of the lungs. It is effective for most patients with ALS who have good bulbar control. Patients who have difficulty controlling their lips or mouth or who are quite spastic in their face often have significantly more challenges in adapting to this. There are multiple studies that suggest that, when NIV is adopted at some point, it increases survival and increases quality of life, especially sleep. 

There are third-party payer guidelines that give you suggestions of when it is appropriate. In general, in the United States, it is a vital capacity less than 50% of predicted, or a negative inspiratory force less than 50% as well. These are number guidelines, but for me, I institute it when the patient history suggests that there is any kind of respiratory insufficiency that needs care. In particular, this is anybody who is having difficulty lying down to sleep, anybody who wakes up short of breath, anybody who wakes up with a headache, and anybody who feels short of breath during the day and feels like they have to stop what they are doing and just sit there.

There are standards that are more stringent than that, and they suggest that, at least in some cases, many people believe that any measurable respiratory deficit down to about 80% of normal forced vital capacity should mandate the institution of noninvasive ventilation. I have tried that in the past, but I have found that compliance is usually fairly poor. I have never been convinced that that in itself improves quality of life when it is instituted then. My thresholds may not be the same as they are for other people, but my decision is predominantly symptom-based. When somebody has a symptom that I think I can treat with that, and I have listened to them, then that is when I do it. I do not tend to do it prophylactically.

 Is that the same for you Ammar and for you Jinsy? Is it symptom-based?

 Ammar should comment because the criteria are a bit different than they are in the United States. For Jeremy and I, particularly for me, a patient has to come below half of their lung capacity, or 50% of their predicted value for forced vital capacity, to be eligible for the payer to pay for the noninvasive ventilator if we order it. I can sometimes get it if they are not that low, but if they are very symptomatic. Those symptoms can be morning time headaches, poor sleep quality, or daytime somnolence, feeling sleepy. I know that it is different in other regions. Ammar, maybe you can speak to the experience of trying to initiate it earlier and the criteria there. 

We use guidelines called the NICE [National Institute for Health and Care Excellence] guideline, which is an algorithmic process. It requires a lower threshold. If someone is symptomatic, you institute it earlier, and if they are not symptomatic, then you institute it later. Our vital capacity threshold is 70% generally, but also, if you cannot measure vital capacity, you can use oxygen saturation, or you can use sniff nasal inspiratory pressure within the guideline as well. It is a complicated algorithm, but it is what we use. It is really the same as it is for Jeremy and Jinsy: it is symptom-based, in fact.

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Key opinion leaders consider the importance of respiratory care in ALS by discussing immunization against respiratory illness as well as the use of non-invasive ventilation. 

Challenges of Respiratory Care in Patients with ALS

 Jinsy, in spite of our best efforts, many times our patients progress to where we have to have a difficult conversation about whether they want to have invasive ventilation through a tracheostomy vs a less aggressive approach where they would work with hospice. When do you initiate that conversation, and what does it look like?

 I have the desire to initiate that conversation, that discussion, and that thought process as early as possible. When someone comes in with a diagnosis of ALS [amyotrophic lateral sclerosis], I want to try to inform them of all the options through the journey, but it is overwhelming. I try to talk about it before a decision has to be made. I try to make sure that the family is involved in that discussion because I have often had situations where even a spouse or a child might think differently, or I am dealing with a very large family where half the members feel 1 way and half the members feel another way. Of course, being in New York City, I deal with a lot of different cultures that have different requirements about end-of-life decisions and about invasive ventilation. 

In New York, New Jersey, and some other states in the United States, it has been made a lot simpler because there has been a form developed that is basically a medical order for life-sustaining treatment. I am able to use this document as a guide. When people have not thought about it, it serves as a conversation starter to think about the things they need to do. It has made it a lot easier for me to introduce the topic. Previously, if people had to make decisions, they would have to get a lawyer and get a legally executed document of advanced directives, living wills, and health care proxies. This life-sustaining treatment form, as it exists in different versions in different states, helped not just guide the conversation but also allow it to be a decision between the health care team and the patient and their family.

More important, it is flexible. When they then come back, I review it. If they decided 1 thing last time but feel differently because the body has changed in some way or they have had a different thought, we can revise it. It has some flexibility and simplicity to it. We will often talk about it; the conversation usually starts for me when we start talking about noninvasive ventilation and feeding tubes. The conversation usually digresses over to that territory. 

We are often successful in getting decisions way before, but people sometimes do not want to talk about it. There are many reasons: It is not just because they are just in denial. There are sometimes cultural attitudes about having open discussions about it and having that be a negative influencer in what their destiny shall be. It has been interesting to learn the different backgrounds and cultures and trying to adjust ourselves and how we deliver our health care. I do not know how it is for you, Jeremy, or Ammar. 

 You are right. The desire to talk about it on your part does not always mesh with the desire of the patient to listen to it. I also think of this conversation as a Rorschach test for your own personality. I hope we get to clinical trials eventually, but 1 common point about clinical trials that Rick points out is that the likelihood of a patient getting into a clinical trial is incredibly dependent on the enthusiasm and commitment of the physician. To some extent, this discussion is a bit analogous in that it is hard to have this discussion without your own biases coming through.

I do my best to present the procedure and the life after having a tracheostomy and being chronically ventilated as objectively and unemotionally as I can. I find that, after I do that, I almost never have anybody who chooses to become chronically ventilated. I have accepted that that says something about me and my own attitudes toward life, but I do think that, to the best one can, one has to make the conversation about what their attitudes about life are and, as much as possible, a realistic expectation of what things will be like after the procedure. 

Yes, that it is a similar experience here in the United Kingdom. Although it is discussed, many people do not take up the option. The people who have taken up the option, are invariably positive about that, in my experience. Nowadays, that is probably even increasing because we have technology that did not exist some time ago. For example, Eyegaze technology is vastly superior compared with what it was 10, 15, or 20 years ago when you had to use a board and hope someone could see what you were looking at.

There are communication options available to people and beds that are more comfortable. All the technology has improved to make the experience better than it was, so that is probably why everybody I speak to is positive about it. Emotionally, it is quite a frightening thing for most people to consider because you will eventually be locked in on a ventilator. That is a frightening thought.

I have 1 small counterpoint: The experience is similar in the United States in that people who choose to become ventilated are happy with that decision. The data that I am aware of, though, suggests that it is incredibly stressful for the caregivers. The caregivers do not have anything close to the same view of it. We are taking care of the patient, but it is a family disease.

Panelists share approaches for building a dialogue on life sustaining care such as invasive ventilation and discuss the importance of social and cultural factors for patients and families.  

Building a Dialogue on Life Sustaining Care in ALS 

 Let’s talk a bit about symptom management in people with ALS [amyotrophic lateral sclerosis] now. All of us have what are called multidisciplinary clinics, where patients come, or by video, and are seen not only by a neurologist but also by a respiratory therapist, speech therapist, nutritionist, a physical therapist, an occupational therapist, a social worker, and sometimes some of the nurses.

Jinsy, these are incredibly resource-intensive clinics. They are difficult to put together with many hours for each patient of being evaluated. Why is this important to do?

I alluded to this a bit before: the multidisciplinary management of ALS is essential in trying to make sure we preserve quality of life, and it even impacts survival. Even in the era of telemedicine now, in the era of COVID-19, we at Columbia University Department of Neurology still do telemedicine visits as a multidisciplinary team. There are multiple providers and virtual rooms created where people with ALS and their caregivers can be sitting in, and we Zoom or video in and out of the visit. All the health care specialists will rotate through. The impact of that type of care and that type of attention to symptoms is underestimated.

Often, a person with ALS will come and ask me, “What kinds of medications or interventions will help me live longer?” It is often the simplest of things that I empathize, and that can make a massive difference in the way they live every day. That includes taking care of their psychological health and their emotional health. It is critical, and it is amazing: their perception of the disease is not related to their disability. Some people who have all limbs that are weak will be active and fundraising, and be very positive. Someone with just foot drop may be devastated by the loss of that function, so it is very individual. Taking care of psychological health is important.

Trying to talk about how to manage weight and keeping the weight stable is critical. We know that is important based on clinical trial studies. Also, trying to proactively intervene on respiratory symptoms. Historically, neurologists would often focus on the function but not look at early signs or early symptoms of respiratory insufficiency, so we should be intervening on those as early as possible. And then trying to be proactive about each of the symptoms that should come up. We should be trying to help with devices and durable medical equipment to help them be as efficient as possible at home to do the activities of daily living and prevent falls. All of those by themselves do not seem so special, but all of it together makes a big difference.

 Ammar, it certainly sounds like this approach makes sense. The disease is affecting so many different things so quickly in a lot of patients such that a team approach makes sense. Are there any data that people who come to these kinds of clinics do better in any medical way compared to people who do not?

Yes. There have been a few studies that have looked at that, and all of them show that people who come to a multidisciplinary clinic do better. Even measuring just survival, the effect is about the same as the effect of riluzole. The reasons for that are unclear, but they are probably related to the fact that, when you have a multidisciplinary team, you can suggest an intervention at the correct time. If you do not have a multidisciplinary team, the intervention that will improve the quality of life and probably quantity of life, is not necessarily suggested, or it may be delayed before it is implemented. So it is probably that type of expertise that will help. The quality of life is important as well as the quantity of life, and multidisciplinary teams have expertise that is not available elsewhere. For example, voice banking specialists are difficult to find outside a multidisciplinary team for ALS where they are needed, so it is important, and there is a lot of research suggesting that it is a good thing to do.

Thank you. Jeremy, among the many things that happen in the clinic, we screen for and manage lots of symptoms. Some people refer to this as palliative care. Do you have a palliative care expert in your clinic at Barrow Neurological Institute?

The word palliation has an unfortunate association in the United States. Palliative care and hospice care are often talked about in the same breath, but as you just mentioned in the way you framed the question, palliation means making something less severe. That is everything we do in the multidisciplinary clinic. If you take somebody who is having trouble walking and give them a foot brace, that is palliation. If you take somebody who is having respiratory difficulty, and you introduce noninvasive ventilation or a variety of things that help respiration, that is palliation. Palliation is most of medicine, so that is intrinsic to the whole purpose of taking care of patients with diseases you cannot cure.

On the extreme end, when you talk about palliative care and hospice together, then you are actively making decisions like, “I will do this because it will help somebody’s quality of life. But I will not do this even though it may extend their life because it will change their quality of life.” For me, the time for those discussions is really late. In many ways, the ability of a patient to think of themselves as being actively treated and trying to fight their disease is incredibly important to their quality of life. Unless I am forced by insurance regulations, or unless the patient tells me that they are not interested in therapies that might prolong their life or slow the course of the disease, I try to continue those until somebody tells me to stop. 

At the very end, we have a specific hospice group that is associated with our clinic, and they deal with the kind of palliation that is often what many people think about in terms of pain control, anxiety control, and control of air hunger. It is a much broader question, and we are doing palliation from the first time we see the patient.

I completely agree. We as neurologists all screen for modifiable symptoms that can be present the first time we see patients and all the way through the disease, not just at the end. Jeremy, as the person in your clinic who does that, what are some of the more common symptoms that you identify in your patients that are taking away their quality of life, and how do you manage those?

 I ran through some of them briefly. The symptoms on the bulbar side include difficulty with speech and difficulty with swallowing. In my experience, speech is not terribly well treated with speech therapy. Most of the conversations regarding speech revolve around alternatives to speech when speech is not available. We have a great speech therapist whose job it is to match the right kind of device or implement to the right person.

With respect to swallowing, we need to go through the kinds of things that are more difficult and less difficult and encourage people to change their diets as necessary. We should bring up the idea of a gastrostomy tube [G-Tube] and nonoral feedings relatively early because this is something that is quite a barrier in patients‘ minds. They think of this as sort of a near death event, but in fact, many patients’ quality of life is incredibly enhanced when they are no longer working like crazy to get enough calories and can either eat for pleasure or just get their nutrition from a G-tube. That is a critical thing. 

In terms of medically treatable symptoms…some of the things we just talked about, speech and swallowing, are actually medically tractable. The combination of dextromethorphan and quinidine has been shown to have a clear improvement on speech and swallowing activities, at least in some patients, so I use that. 

Many patients have difficulty handling secretions, and they drool like crazy. Anticholinergics are a good first step, but botulinum toxin can often be effective. For some people, their spasticity is incredibly useful because it helps them maintain an erect posture for transferring and even for walking, so if you reduce that, it makes them more symptomatic. Many patients have stiffness and spasms that can be treated either with an antispasticity drug, such as baclofen, or more recently, we use a drug called mexiletine, which is a drug that was not introduced for ALS, but it has been shown in a couple of studies to have a benefit on cramps. 

Jinsy mentioned emotional health a bunch of times. That is also incredibly critical. Finding the appropriate resources for counselling can be quite difficult, but convincing people that it is in their interest to take an antidepressant is something that we can do in the clinic. I certainly try to do that as much as I can. I am sure that I am missing many others, but I can stop and let the others speak up. 

Richard S. Bedlack, MD, PhD, MS: That is a great list. Ammar, anything to add?

Yes. It might be a cultural difference, but we at Motor Neuron Clinic, King’s College London use palliative care right at the first visit. We have palliative care integrated in the clinic. I completely agree with everything that you and Jeremy have said about the symptom control aspect of the neurologist. But the palliative care specialist in our multidisciplinary team is there not just because of their expertise in control of some symptoms, which is greater than mine, but also because they have a holistic approach and take in the whole family and the spiritual aspect of the patient that I do not bother with as a neurologist because I am not trained in it. I do not even see it; I cannot understand it. They are good at understanding the impact on the patient’s life in a way that I cannot. That is why we involve them early on. Otherwise, for every other aspect, Jeremy has gone through an exhaustive, comprehensive list there. It is the same.

I would have to agree. Palliative care in the United States is a tough thing to access. We do not have it readily available, so I do not have palliative care in the clinic at Columbia University Department of Neurology, but I have palliative care incorporated into the veterans’ clinic, which is a different payer system. The other thing that Jeremy highlighted was that palliative care is often tied with hospice care. Palliative care is very different, and it should be initiated as early as possible, especially in ALS.

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Expert neurologists discuss the importance of a multidisciplinary approach to the management of symptoms for palliative care in amyotrophic lateral sclerosis (ALS). 

Multidisciplinary Approach to Palliative Care in ALS  

 It is safe to say that we are all similar in terms of how we make a diagnosis and start the care of people with ALS [amyotrophic lateral sclerosis], but then COVID-19 hit a little over a year ago. Can you each tell me 1 thing that this did to challenge you in the ways that you make diagnoses and the ways you treat your patients? How did you find a way around it? Jeremy?

I would say that the 1 thing that has not changed much is the way I make diagnoses because our entire neurology practice quickly pivoted to seeing almost all of our patients by telemedicine, which does not make it impossible to do an examination. But to me, it makes it impossible to do an exam that would allow me to be confident about ALS. We have continued to encourage patients to come into the clinic at least once for a good exam. 

The things that need to have been done to make that diagnosis, we do in a similar manner. The differences are after that. Even with that visit, one of the mainstays of the return visit for patients with ALS is an assessment of the respiratory function. For a good chunk of this pandemic, the way we test respiratory function, which is with a spirometer by asking patients to take big breaths in and out through the spirometer, would mean potentially spewing droplets of what could be infectious particles throughout the room. This was felt to be, not unjustifiably, a risky procedure. 

The amount of these tests that we at Barrow Neurological Institute performed went way down, so we looked at different ways of getting that information, which we all would think is important. Some of the ways include giving people a small home spirometer, which costs about $100, and we encourage them to do it at home and send us the data. There are ways to estimate the vital capacity, which is the number that we use, either by asking patients to take a deep breath and count as far as they can, or just say “ah” as long as they can. Both of these have good correlations with vital capacity, so we jury-rigged that to some extent.

The biggest change in clinical care is simply that many patients do not come back, or they do not come back frequently after their initial visit and are seen by telemedicine. It has been, maybe not surprising, but it has been dramatic how much you can get done in that kind of a visit. Most of the interim care of the patient with ALS is formed by the discussion that you have with the patient. The ability to see the patient in their house, surrounded by their family, allows us to get a view of the ways that they can deal with the home environment, and that has been a significant plus. As patients then get more impaired, we used to feel increasingly bad about dragging people to the clinic when it took a whole day and knocked them out for 2 days after that. We can now see them in their home, and that has been a tremendous boon for many patients. My hope is certainly that we will not give up on that and that we will be able to do this at least in selected cases in the future. 

 I could add that it has been a similar experience for us at Columbia University Department of Neurology. New York City was hit hard with COVID-19, so we converted completely to telemedicine for clinical care. It posed challenges because I could not bring patients to the facility for a physical exam. Diagnosis was a major challenge, and this sometimes meant that people who had atypical presentations may have had some delay in their diagnosis during that period. 

For the most part, many had tests done already because we are a tertiary referral center. We are a specialist center, so we see a lot of patients who have already had many tests completed. As Jeremy said, you can do a lot on video in terms of assessing how a person speaks, moves, and you can look at things because observation is key. Often, if I was a bit unsure, I would start implementing some of the things that we do for ALS by explaining the risks and benefits of the treatment because the earlier you implement some of these things, including some of the pharmacological treatments, the more effect it may have on the disease progression. It was a complicated conversation when I was not entirely sure of the diagnosis. Some people took it and would try it, given that I would see them in the future to confirm, and we might or might not discontinue certain things. Simple things like nutrition, exercise, emotional health, and even trying riluzole early, was not too difficult.

 It is similar to Jinsy and Jeremy's experiences. We [at Motor Neuron Clinic, King’s College London] had a full lockdown, and we were not allowed to do face-to-face visits. That meant we had to convert to telemedicine. Most of our patients were able to handle video calls but not all of them. That made it difficult, so there were often technical difficulties at the other end, or there were poor internet connections, or it was somebody who did not quite understand how a video call might work.

Generally, it worked well. As both Jinsy and Jeremy have said, it is surprisingly informative. You can get a lot of information not only from the history, of course, which 90% of the diagnosis comes from, but you can get a lot of the examination findings. You can see fasciculation and wasting. You can see weakness. You can see the person’s gait. The key thing that you cannot to do is assess upper motor neuron findings easily. You can tell if a tongue is moving in a spastic way, and you can probably make some kind of test that would tell you if a hand tap or something like that might suggest spasticity. But it would be difficult, so there was that aspect. Of course, breaking the diagnosis by video is traumatic; it is difficult. 

The other things that were affected were the investigations. We are a tertiary referral center, so a lot of the tests have been done, but not always. If we wanted an MRI or EMG [electromyography], that was often delayed because staff were redeployed, or the service was not running. For other people who were more advanced who might have needed therapy, the therapist was able to do a video call, but that is not the same as seeing somebody face to face. If somebody needed a gastrostomy or noninvasive ventilation, that was difficult to implement but not impossible. We have COVID-19 safe sites where the person could go and then be fitted with a gastrostomy feeding tube or with noninvasive ventilation, but it was certainly challenging.


What will happen, as Jeremy and Jinsy have said, is that people will stick to telemedicine much more in the future because it is useful for somebody not to have to come up and be exhausted.

A panel of key opinion leaders provides insight into how COVID-19 has continued to impact the diagnosis and management of patients with amyotrophic lateral sclerosis (ALS). 

Diagnosis and Management of ALS During COVID-19 

This is the question that comes up a lot in my clinic, Jinsy: after we have the conversation about the diagnosis and talk a bit about the variability in prognosis, people want to know whether they should get genetic testing. What are your thoughts on that?

I have to say that I have been seeing patients with ALS [amyotrophic lateral sclerosis] for the past 15 years. In that time alone, my idea of offering genetic testing has changed dramatically, and for many reasons that Ammar talked about earlier, with the availability of gene therapy clinical trials. In the clinic, when we talk about ALS in a newly diagnosed person, we of course offer a review of the FDA approved treatments for ALS. We then talk about management of their symptoms, but we also talk about genetic testing right at the get-go, right at the start of the journey. The reasons are many, but one that was already highlighted in our discussion is that about 20% of people may not have a family history of ALS, but they might have some sort of gene that is associated with it, so it is important to do the genetic testing.

The second is that we have clinical trials for specific gene mutations, especially the SOD1 gene and the C9orf72 gene, that are in human clinical trials as we speak, and more are being developed in the pipeline. This also means that the availability of experimental therapies as they move through clinical development is changing our clinical practice. So not only is it about offering genetic testing to people who are diagnosed with ALS early, but it is also dealing with potential family members who are at risk of also carrying that gene mutation and implementing genetic counseling for the individual with ALS and for people at risk. It is no longer a practice where I just interact with 1 individual with ALS. Especially for people who tested positive for a gene, I am now involved with the patient plus their first-degree relatives or extended family who are also at risk. 

It becomes a bit more complex, and there are now many genes associated with ALS. There are many genes associated with ALS that are associated with other types of neurodegenerative diseases and even other psychiatric diseases. Genetics is very complex. Ammar can speak more about how complex it is and how many genes we know about, but it is something that we need to implement early in ALS management.

I would agree with everything Jinsy said, but I would also add that, in the United States, genetic testing is not uniformly available for free. There are many ALS centers with their own genetic academic interests and their own laboratories that can perform it, but if you ask insurance companies to pay for genetic testing, the response is quite variable. There are programs to provide at least limited genetic testing for free in the United States, but it is still a challenge for many patients in terms of affordability.

Do you offer genetic testing to all your patients? Which genes do you test them for?

We at Motor Neuron Clinic, King’s College London do not offer genetic testing for all our patients routinely, although it is something that we have discussed doing, and some centers are beginning to do it. The reason we do not is because, as Jeremy and Jinsy have said, there is a lot of work involved in deciding which genes to test in which person. It is a complicated thing to discuss, and we only have limited time. What we do is this: we bring people back to discuss those issues in a genetic counseling clinic, and then we offer the genetic testing. Not everybody wants to come back to that clinic, and some people do not want to hear about the genes that might be affected in them for their families. It becomes a complex issue quite quickly, quite easily, but we think about it for every single person. 

The people who we are allowed to offer it for are people who are 40 years old or younger and people with a family history, but what counts as a family history varies as well. For example, if you ask different neurologists, some people will count an uncle who is affected or a cousin or an aunt as being a positive family history. Other people will say that, no, it has to be a first-degree relative. Some people will count frontotemporal dementia in a relative as significant, and other people will not. There are a lot of things that determine whether the family history is counted as positive, and of course, the person may not have full knowledge of their family. We do not test everybody, although we should.

I was going to say this: you asked me which genes are tested. We have a set of genes that we can test, but we do them in order. The first 4 genes we test are SOD1, C9orf72, FUS, and TARDBP. The TARDBP gene codes for TDP-43 protein. We then have a panel of 38 further genes that will just be done as a panel. Because whole genome sequencing is now becoming much cheaper, we can get it done for about €150 on Black Friday and for €300 any of the time of the year, for example. I would say that is relatively cheap. It’s cheaper than a lot of the other panel tests. A lot of patients are beginning to get their whole genomes done, but you are then stuck with somebody who has a lot of genetic information and no easy way to mine it because the whole genome is a lot of data, and there is no easy way to be counseled about it. 

We have tried to tackle that. We have a service where you can upload your genome, and it will give you an automated report for ALS genes that you could then take to a genetic counselor. This kind of issue is going to become more and more prevalent as genetic testing becomes cheaper and because of the blocks that we have all mentioned to being tested in the clinical setting.

I would add that it is true that genetic testing is expensive here in the United States, but it is true that the whole genome sequencing is a little cheaper under a research basis. What was surprising for me in practice is that, when we offer the genetic testing, of course the person with ALS is always interested. There was an assumption that the family members may not be interested because we do not have anything that we can do right now. At Columbia University Department of Neurology, we call it the Families Project. It is a research project following asymptomatic carriers or asymptomatic relatives of people who have been diagnosed with gene-associated ALS. Those individuals surprisingly wanted a genetic counselor, so we have a genetic counselor incorporated into our clinic, which makes a big difference. Almost everyone asks for the test after a back-and-forth and discussion. When they are informed, they seem to want to do it, which was a bit surprising for me.

Richard S. Bedlack, MD, PhD, MS: Thank you for watching this NeurologyLive® Peer Exchange. If you enjoyed the content, please subscribe to our e-newsletters to receive upcoming Peer Exchanges and other great content right in your inbox. 

Experts in neurology give insight into recent advancements in genetic testing for amyotrophic lateral sclerosis (ALS) and discuss what factors to consider when offering it to patients. 

Genetic Testing for Patients with ALS  

 Back to you, Ammar. I hear about these different sets of diagnostic criteria called the El Escorial World Federation of Neurology Criteria and the Awaji Criteria for the Diagnosis of Amyotrophic Lateral Sclerosis [ALS], and I hear about these different staging systems. Can you explain those to us? How useful are those in practice?

You have to separate the 2 things, the diagnostic criteria and the staging systems, even though there is some relationship between them. The diagnostic criteria were initially designed for research purposes for clinical trial entry because the diagnosis needed to be an algorithmic process so you could say, “Yes, all of these people entering this clinical trial have ALS,” rather than using the “wisdom” of an ALS specialist, wisdom in inverted commas.

The El Escorial criteria were designed after a meeting in El Escorial, Spain, in 1993 or 1994, sometime like that. They divided the regions in the body into 4 parts: bulbar, cervical, thoracic, and lumbar. The rules were that you had to have lower motor neuron findings and upper motor neuron findings in the different body regions, and then by the combination of upper and lower motor neuron findings, you could classify people as to whether they had ALS. It was not a binary, “Yes, you have ALS,” or “No, you do not have ALS.” It was categorized into parts a bit like how multiple sclerosis was being categorized at the same time: suspected, possible, probable, and definite. That worked for clinical trials. It meant people could say, “We have taken everybody who has more than suspected ALS,” or “We have everybody who is in the definite and probable categories.”

But it led to a lot of confusion because they were called diagnostic criteria, but really, they were entry criteria for clinical trials. They had these words definite, probable, and possible ALS, even in somebody who the ALS specialist knew this person had ALS, but the person is being told that they have El Escorial-possible ALS. There is a lot of confusion around the nomenclature. It is probable that, if it had been called grade 1, 2, 3, and 4 ALS or something like that, it would have been a better choice. It is easy to make these comments in retrospect. Because of those difficulties and because one of the categories, which was suspected ALS, was pure lower motor neuron involvement, and because sometimes lower motor neuron findings can be difficult to find clinically but they are present electrophysiologically, the criteria were revised in Awaji, Japan. 

The Awaji criteria were designed to allow neurophysiological investigation to replace clinical examination as evidence for lower motor neuron involvement in a limb, so you could then change categories. It also allowed fasciculation, which was the key thing, in an unaffected limb. 

More recently at the Gold Coast in Australia, Jeremy nicely summarized all the findings from the meeting. We had a big meeting of many ALS specialists, and those criteria were simplified again, but we took on board the lessons of the last 25 years and understood that it is useful having a binary, “Yes, you have ALS,” or “No, you do not have ALS.” Now there are Gold Coast criteria that are designed around the El Escorial criteria, and they say that you have ALS if you have involvement in these body regions in a particular way. If people are interested, the paper is published. We can go through it. To summarize them briefly, the person must have progressive weakness without sensory involvement and with other causes excluded. The 3 body regions are used: bulbar, upper limbs, and lower limbs. You have to be involved of upper and lower motor neurons in 1 body region if that is what was affected, or lower motor neuron involvement in 2 body regions. That is the summary of the criteria for diagnosis.

As Jeremy said earlier, and as Jinsy has also said, an ALS specialist is the keyway of making the diagnosis rather than criteria, but they are useful for entry into research. In terms of clinical staging, staging is important in cancer because it can guide treatment if you are in an early stage or late stage of disease. It also allows you to measure whether treatment is improving because you will go back through the stages.

In ALS, there has not been a staging system for a long time. People tried various types, and they did not work, or they did not take hold. More recently, 2 staging systems have come into being. One is the King's ALS clinical staging system, which now widely uses the El Escorial regions of bulbar, upper limb, and lower limb. It counts the number of regions involved. If you have 1 region involved, you have stage 1. If you have 2 regions, then you are in stage 2, and if you have 3 regions, you are in stage 3. If you have the need for nutritional support or respiratory support, and those are defined within the staging system, then you are automatically in stage 4 regardless of the number of regions involved. 

Using that system seems to correlate quite well with the disease stage intuitively. If you asked any person dealing with ALS, it does not have to be a specialist, “Do you think this person is early disease, middle disease, or late disease? What number would you give their disease stage?” then it correlates quite well with that algorithm. 

There is also a functional staging system called the MiToS [Milano-Torino system], derived from the ALS functional rating scale, which asks questions in 12 different domains about function. There is an algorithm that uses those answers to stage people into 1 of 5 functional stages or the sixth stage, which is death.

 Are these things that you would think a primary care doctor, or a general neurologist should know about, or are they more for ALS experts, especially those who do trials?

They are not something that a primary care physician would need to know at all. Even many neurologists would not need to know them. It is for an ALS specialist or for entry into trials.

A panel of experts considers the usefulness of diagnostic criteria and disease staging systems for patients with amyotrophic lateral sclerosis (ALS) as entry criteria for clinical trials. 

Diagnostic Criteria and Staging Systems in ALS  

 Jeremy, back to you. When we have a patient with a diagnosis, what can they expect? How do they change over time?

 Most of us see patients in a tertiary care neurology practice, so we get patients who have probably heard the term ALS [amyotrophic lateral sclerosis] before and are often coming to us hoping that will tell them something different. The first thing they hear when they come to one of us and it is in fact ALS, is that the hopes they had for some more treatable disease is not the case. So an early job for an ALS specialist is to present reasonable expectations of what is going to happen.

One of the main things that I emphasize early on is that I do not know. I clearly expect that this is a disease that will get worse over time. By getting worse, I mean the weakness or stiffness or incoordination that they have in specific parts of their body will worsen, and that will spread to parts of the body that are currently doing pretty well. Those will start becoming affected as well.

What I do not know is what is going to change next and when that is going to happen. I make a major point to say that I do not know whether the changes that I expect to see are going to happen over the next 3 months, which is probably the next time I will see them, the next year, or the next 2 years. I do not know whether they will be walking in 6 months, in a year, or in 5 years. The rate of progression in ALS is incredibly variable.

We can get some sense of that, and I then use that to talk to them about getting the history of how long they have had symptoms before they have come to see me. That gives me some idea of how aggressive the disease is, but the pace is something that is incredibly erratic, and it is somewhat reassuring to patients because we are not telling them that the average lifespan is 2 1/2 years after diagnosis, and they can expect that to happen. What we need to be telling them is that not only are there things that we can do now, but that even without that, we do not know.

We prepare them as well. The things that cause tremendous morbidity in ALS are issues with breathing, so I go through that. I talk about the things that we can do if that becomes a problem to make that more manageable. For difficulty with swallowing, there are ways to make life sustainable and worthwhile even in the face of those kinds of problems. For difficulty with ambulation, walking, and difficulty with performing a lot of the activity of daily living that we take for granted, all of those things are things that, when we see people repeatedly, we go through them and do our best to help them deal with them in positive ways. Those are the things that ultimately get discussed.

 Thank you. Ammar, the first time you see someone, can you get any hints about how they are going to do? Can you tell if a person is likely to live just a year or live 20 years the first time you see them?

 I agree with Jeremy, that is a very variable condition. It is difficult to predict. We can get a feel for it if someone is showing aggressive disease or not aggressive disease so far, and that gives you some clues, but being more precise than that is difficult. The way I explain it to my patients is this: we can make mathematical models of survival, and we can even plug in the patient’s details, and it will then draw a nice probability curve of survival, but that is actually useless for an individual. It is good for groups of people.

The best way to understand it is with this example: I can make a mathematical model of how long the light bulbs will live in my house, and I could come back in 3 years and count the light bulbs and say, “Oh, 5 lightbulbs have blown, just as my model predicted.” It would be accurate for the light bulbs in my house, but if you ask me, “Will that light bulb be here in 3 years,” I cannot tell you. It is the same for individuals. Even though we can make a nice mathematical model that predicts survival on average, for an individual, it is useless. That is why we cannot tell people an accurate prognosis at all.

One more thing on a more hopeful note is that we now have 2 medications that alter disease progression, and 1 medication significantly alters significant symptoms in ALS. All these drugs work to some extent; they all have modest effects. A big question is this: do these individual drugs cause modest improvements or modest declines in rate of progression for everybody, or do they cause significant reductions in rate of progression in some people and much less significant in others? I do not think we have data to prove that one way or the other. My strong inclination is No. 2, that drugs work, when they work modestly, they work better in some people than others. That also adds both to the uncertainty and the potential optimism when you first discuss this with the patient, that you do have these agents that may significantly affect their life going forward.

 I want to drive both Ammar and Jeremy’s points at this particular time because there is still the perception by people outside of the ALS field that ALS is fatal, and is quickly fatal for everybody. The realizations that the disease is very individual, and it has a high degree of variability in prognosis are very real. 

As an example, on Monday, I was at the veteran’s hospital, and I saw a person who was diagnosed in 2017 and was told he had 6 months to live. He did not pursue any other medical care and got his affairs in order. Well, 2018 came, 2019 came, 2020 came, and now in 2021 his spouse attended a support group and found out that there is multidisciplinary care and that all these things including the treatments that Jeremy was talking about are available for him, and he finally came to the clinic. The thing is that this is still the perception. I want to drive home the fact that there is a lot of variability in prognosis, and 15% to 20% of people living with ALS can go well beyond that 5-year mark. There are a lot of things that we can do early in the disease that can impact disease progression and make people live longer and better.

Key opinion leaders ALS care comment on best practices when communicating with patients about the unpredictability of disease progression and prognosis. 