• ALS Crowd Radio Episodes
    • Jul 29, 2014

    ALS Crowd Episode 3: Dr. Michael Weiss on ALS among neurological disorders

Michael Weiss, M.D.: University of Washington
Director of the Neuromuscular Diseases Division
Professor of Neurology
Adjunct Professor of Rehabilitation Medicine

Interview date: Friday, August 1, 2014

Summary

Dr. Michael Weiss, MD of the University of Washington discusses ALS’ relationship to other neurological disorders and his current ALS medical trials.

 

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Full Transcript

Seth: Welcome to Episode 3 of ALS Crowd Radio. I’m your host, Seth Christensen, here with my co-host, Amy Christensen. We are excited today to have Dr. Michael Weiss of the University of Washington with us. I’ll have Amy introduce him.

Amy: Thank you.

Dr. Weiss, Director of the Neuromuscular Disease Division, is a University of Washington Professor of Neurology and Adjunct Professor in the Department of Rehabilitation Medicine. He sees patients at the University of Washington Medical Center. His clinical interests include the diagnosis and treatment of neuromuscular diseases including ALS and a vast number of other neuromuscular diseases.

Welcome to the show today, Dr. Weiss.

Dr. Weiss: Well, thank you so much, Seth and Amy.

Seth: It’s great to have you here today. Our listeners are excited to discuss ALS among other neurological disorders. I thought we will start off, Dr. Weiss, by asking you our typical loaded question. What is ALS?

Dr. Weiss: So ALS is a disorder that affects the nerves that arise in the brain and in the spinal cord that send signals to muscles. There are two populations of so-called motor neurons that seem to undergo this degeneration. And as a consequence over a period of time, the muscles begin to twitch and they shrink and then they become weak and the muscles can be any muscles in the arms and the legs, the muscles of breathing, and the muscles of speech and swallowing. Any of those areas can be affected and it’s variable in how those areas are affected usually and over time.

What we don’t know exactly is what triggers this disease. We have some ideas about that and that’s led to some therapy like Riluzole which is a glutamate-blocker. So we think that there’s a normal chemical in the nervous system called Glutamate that if there’s too much of it, it’s not cleared from the environment or the neurons by the supporting cells, the glial cells, and as a consequence, there’s damage to the motor neurons and over time, they die.

That discovery a number of years ago led to the initiation and development of Riluzole which remains the only FDA-approved treatment for the disease but unfortunately, doesn’t do nearly as much as we would like and it only slows the disease down somewhat.

So there are a lot of other areas of interest that are being explored as potential causes of ALS. Like so-called oxidative stress: whereby the byproduct of energy metabolism by these little energy factories and neurons and the motor neurons’ mitochondria cause damage to the neurons and cells because the byproducts of these oxygen-free radicals are not removed and they damage the motor neurons.

There are other ideas that we’re exploring like inflammation: activation of inflammatory cells in the brain and the spinal cord called microglia that they lead to a cascade of events that damage motor neurons. And then finally, I think another really interesting focus is about these proteins that deposit in, not where the nuclear material of the cells are, that is where the RNA originates but further out in the so-called cytoplasm, we can see these proteins deposit and there are different proteins but they all seem to be very typical of ALS but also of other degenerative diseases and that’s why ALS shares similarities shares with other degenerative diseases where this happens as well.

My area of focus recently has been on another potential cause of ALS which is something called hyperexcitability: there’s evidence that in ALS in very early stages, and looking at the animal models of ALS and tissue-culture models, that the neurons are over-excited, that they’re over-stimulated and the thought is that that could potentially lead to premature death of neurons. And so one thought would be “Could we rescue viable neurons by suppressing this excitation with medicines that do that?” So I’m doing a study using the drug mexiletine which is a sodium channel-blocker, sodium being important for exciting neurons and having them send electricity or action potentials down to their processes down to muscle.

And so mexiletine, we think, is suppressing that; we’re hoping it’s going to suppress that and that’s in clinical trial right now. We sure hope to have results of that study probably by the end of the year.

Seth: We love to hear about news, if that would be okay, we’d like to talk about that a little more later on.

Dr. Weiss: Sure.

Seth: One brief question. You mentioned two populations of motor neurons that are affected in ALS. Could you clarify what those are?

Dr. Weiss: Yes.

The two populations of motor neurons are motor neurons that arise in the cortex of the brain, the higher part of the brain, and then they send their projections or axons down to the spinal cord and then eventually they interface with spinal motor neurons, that’s the second population or they’re sometimes called anterior horn cells. And then those neurons send processes to the muscle and the muscle start to shrink and become weak as those neurons die because they require nutrients from those neurons via those axons, those projections, and that’s what leads to the wasting of the muscles. And when they’re damaged, that’s what leads to the twitching of the muscles, as well, and weakness, of course.

Seth: Now we have our heard our other guests mention upper and lower motor neurons. Are those synonyms or are those different?

Dr. Weiss: That’s another way that they’re categorized, cortical motor neurons or upper motor neurons. And so when they’re damaged, the typical manifestations are jumpy reflexes and stiffness or increased muscle tone, incoordination, and weakness, to some extent. But when the spinal motor neurons or the lower motor neurons, are damaged, that’s what leads to the wasting of the muscle and twitching as I mentioned. So that is another way to look them, upper and lower motor neurons.

Seth: Great. Thank you for that clarification.

Dr. Weiss: Sure, sure.

Seth: Now, you began to mention that ALS has some commonality with other neurological disorders. I would like us to talk a bit about those other distant or near cousins of ALS. What other diseases are in the same family?

Dr. Weiss: Well, I think that diseases that are similar are ones that have similar defining pathology, and so one of those diseases which also can co-exist with ALS is Frontotemporal Dementia. We all hear about Alzheimer’s Dementia, Frontotemporal Dementia is not uncommon but a less-common form of dementia and that is characterized so much by memory changes early on but rather behavioral changes where patient’s behavior seem to change or sometimes they become paranoid or obsessive-compulsive or they lose the ability to project into the future. They might seem like they’re depressed but they’re really just apathetic, it causes apathy. And sometimes it affects language so they have difficulty, not necessarily just slurring the words, but finding the words.

Recent studies have suggested as many as 10% of patients with ALS actually have Frontotemporal Dementia as well if you do some rigorous testing for it. Those are usually questionnaires that psychologists often administer. We do a bedside test called the ALS Cognitive Behavioral Screen, which is a sort of quicker screen that usually has to be corroborated with further testing to see if that’s indeed the case.

And then up to about probably another 40% of patients, or all-told, 50% of all ALS patients can have some more modest impairment of executive function like being able to project in the future plan, make decisions or behavioral changes or language problems. Not to the degree that they would meet well-defined criteria for Frontotemporal Dementia.So what’s common to both Frontotemporal Dementia and ALS or sporadic ALS at least, patients without SOD1 gene mutations, that form of familial ALS, is that there is a particular protein that seems to accumulate or aggregate outside the nucleus of neurons, both in Frontotemporal Dementia not in motor neurons but other neurons in the cortex but also in ALS patients and this is a protein called TAR DNA-binding protein 43,. And so that’s important regulatory protein for the nuclear machinery basically translating RNA into proteins and so that should usually be in the nucleus of these neurons. And every neuron normally, we have TDP-43 but for some reason but it seems to leave the nucleus and go into the cytoplasm and then it sort of clumps together. And that’s true of both Frontotemporal Dementia, not motor neurons but other neurons and in ALS. That’s what makes those diseases linked as well as the fact that ALS patients often have some element of Frontotemporal dysfunction that’s not Frontotemporal Dementia.

Seth: Great…we’ve heard from other guests of the interest in the connection between these two. What other diseases or disorders or syndromes are in the relative neighborhood of ALS?

Dr. Weiss: So other diseases that are on the spectrum of ALS–I tend to lump this together with classic Lou Gehrig’s disease because I just think it’s part of the same disorder. Diseases with patients with just pure lower motor neuron findings those are patients that have but it’s not as progressive muscular atrophy. Those patients don’t have the jumpy reflexes or the stiffness because they don’t have the upper motor neuron findings of classic Lou Gehrig’s disease patients but they do have the weakness and they do get breathing issues because it affects the muscles that help them breath like the diaphragm. They don’t usually get swelling problems either and it’s a disease that tends to progress in a manner that’s similar to ALS but at a slower rate.

And then other variants of ALS that I, again, think of as likely being on the same spectrum, for some they call Progressive Bulbar Palsy where patients just have speech and swallowing difficulties but over time, they usually develop the other features of ALS. And then there’s a disease that just involves the upper motor neurons and this disease, I think, there’s some controversy as to whether or not it really is on the same spectrum of ALS and this is called Primary Lateral Sclerosis and those patients have a very, very long course, decades. And while they can get breathing issues, they can certainly get swallowing issues, the progression is extremely slow. So the variants of ALS tend to be much less common than ALS itself. Certainly less that 5% or 10% for most of these disorders I mentioned.

Now other diseases that could look like ALS that are forms of motor neuron disease include a condition called Spinal Muscular Atrophy. That’s a disease that’s typically inherited and presents in most patients, in early life or childhood or in infancy, and it can be quite lethal when it presents very early in life. But occasionally in adults, there are patients that present or juveniles, we see that they present in a way that’s somewhat analogous to ALS. They just have lower motor neuron findings and they usually have fairly similar symptoms on both sides and it infects the muscles that are closer to the trunk and not so much further down. Sometimes, while not always, they have a genetic mutation that helps confirm the diagnosis. And then there’s another inherited late onset form of motor disease that we tend to see really just in men called Kennedy’s disease or X-Linked Spinal and Bulbar Muscular Atrophy. And that’s, again, a lot less common than classic Lou Gehrig’s disease. I think some recent literature suggests it’s probably a magnitude of maybe, I would say, certainly no more than maybe 1 in 5… So ALS are probably 4 to 5 per 100,000 new cases a year and Kennedy’s disease is more like 1 in 500,000 patients a year so a lot less common. Kennedy’s disease, we always want to identify if we can because it’s not a lethal disease, it’s very rarely lethal. It can run in families but because it’s X-Linked recessive, that means that the mother would be a carrier and then only typically men get it although there are rare reports of women getting mild forms of it. And it progresses in a manner that’s much slower than ALS but it typically involves speech and swallowing and it can involve the arms and leg muscles and it can involve the breathing and it just involves the lower motor neurons. It doesn’t involve upper motor neurons. So that’s a disease I always want to be sure about because it changes prognosis even if I don’t have a specific treatment for it.

I do want to call attention to one other disease that we always look for, that we want to be sure about even though it’s technically not a motor neuron disease and that’s a disease called Multifocal Motor Neuropathy. And so that’s a disease that is often mistaken for ALS. It’s a disease that affects not the neurons but rather the nerves and the nerves that are just in the arms and the legs, not in the brain. The nerves are extending from the spinal motor neurons. What happens in this disorder is patients can get weak and then over time, they can get some wasting or thinning of the muscle. Usually beginning in the arms, it doesn’t typically involve swallowing or breathing but it’s hard to find, it’s hard to identify sometimes. What happens is it causes injury to the coating around the nerve, the myelin, but those findings can be very hard indeed to spot and the only way to detect them is nerve conduction testing. But that’s a disease that maybe almost as common, according to some recent literature, as Lou Gehrig’s disease itself. So it’s one that we absolutely do not want to miss and I always consider that when I’m seeing a patient with the question of Lou Gehrig’s disease to be very sure I’m not missing that because it is potentially treatable. There was something called intravenous immunoglobulin therapy which is full human antibody which can reverse the weakness to some extent.

Seth: Now are disorders like Guillain-Barré, CIDP, and MS are considered related as well?

Dr. Weiss: They’re not related but sometimes — I don’t know about Guillain-Barré syndrome mimicking Lou Gehrig’s disease. I think that probably doesn’t happen too often because that’s a disease that is very formaden…It occurs very quickly over the course of a few weeks or patients start with no symptoms and they become quite weak. That’s not something that typically happens in Lou Gehrig’s disease.

Sometimes patients with Lou Gehrig’s disease have sort of precipitous additional weakness but over time, they continue to incur deficits that really gradually accumulate. In Guillain-Barré syndrome, they reach their weakest point typically within 2 to 4 weeks, certainly no more than 4 weeks. And they often have a sensory component where they have some changes in sensation and then the nerve test helps define that disease.

There is a chronic form of that disease called Chronic Inflammatory Demyelinating Polyneuropathy or Polyradiculoneuropathy which is a mouthful. It’s also known as CIDP and there are pure motor forms of CIDP and so those are rare; very, very rare, and those patients are defined by the nerve conduction study. Again, because even though they have weakness that’s progressing slowly in the manner analogous to ALS, they don’t have upper motor neuron signs and the nerve conduction testing shows again entry to the coating around the nerve, the myelin. That’s why that test is so important in trying to be very sure about the question of Lou Gehrig’s disease. In my opinion, as uncomfortable as it is, it’s indispensible because I don’t want to miss a treatable disorder.

Seth: Of course. And lastly the MS question, are they the same family?

Dr. Weiss: No. MS is a disease that I guess, commonly mimic Lou Gehrig’s disease but the difference is it presents usually with transient worsening multiple occasions. Occasionally, it will present with more of a slowly-progressive course but the symptoms are often incompatible or atypical for Lou Gehrig’s disease such as numbness or changes in vision. So those would make me think of a different disorder. And then the disease is virtually always detected by imaging, by doing an MRI of the brain usually; or if not the brain, the spinal cord. And I virtually always again will use neuroimaging, typically an MRI, in my evaluation, patients with Lou Gehrig’s disease, just to be sure about that possibility or anything else. Though I have to say, I think clinically-inexperienced ALS doctors are probably not going to mistake MS for Lou Gehrig’s disease; probably not because the symptoms are so different for the most part.

Seth: Thank you.

Amy: All right. We just want to tell our listeners to prepare any questions. We wanted to share the phone number that you need to call in at. The number is 516-590-0362. And if you have a question, please press the number 1 so we can know that you’ve called in.

Seth: Great. Thank you, Amy. Dr. Weiss, thank you for your answers so far.

Dr. Weiss: Sure.

Seth: So we are told that roughly 35,000 people in the US are living with the diagnosis of ALS at any given time. The disorders you mentioned are, in the most part, a smaller population. Do we have any idea of a comparative numbers for these other disorders?

Dr. Weiss: Yes. So the only disorder I think that would be more common than ALS is Multiple Sclerosis and I’m not sure I know off the top of my head what the incidence or the number of new cases or prevalence of multiple sclerosis is but I think it’s more substantial than ALS for sure. I can say this about this other more likely mimics given all these things that I think about more carefully because, as I said, I think MS is very unlikely to be mistaken for ALS most of the time. Diseases like Spinal Bulbar Muscular Atrophy or Kennedy’s disease, the incidence is probably 1 in 500,000 new cases a year so it’s a lot less common. Multifocal Motor Neuropathy with conduction block, this other really common mimic of ALS is very common. In fact, some recent literature suggests that it’s almost as common as ALS; it’s about 1 in 100,000. Whereas based on this very recent CDC epidemiologic study, which isn’t all that different from previous studies, they looked at the number of existing cases of ALS and they found there are 4 per 100,000 in United States so they didn’t list the incidence that is the new cases a year. So Multifocal Motor Neuropathy with conduction block is the most common mimic of ALS and that is the one that I absolutely don’t want to miss because, as I said, that is treatable. Motor CIDP or CIDP in general probably has an incidence that is not terribly different than ALS either but because most patients have sensory symptoms, they’re not going to be generally mistaken for ALs. But there is a pure motor form of CIDP that is so uncommon that I’ve only seen a few cases of it and we don’t know the incidence of that or the prevalence. That is how many new cases or how many current cases there are. My guess it’s very, very uncommon.

Seth: Thank you. Now, in researching these various disorders, are we learning more about ALS through cross-disease research?

Dr. Weiss: Well, I think we are with Frontotemporal Dementia, there’s no question about that. We’re finding this common connection that we didn’t know existed until very recently so we used to think that Lou Gehrig’s disease was a standalone disease; that it was very distinct from other degenerative diseases in that there’s only targeting of motor neurons and clearly that is not true for some patients. So it has gotten us thinking, “Are there other populations of nerve cells that could potentially be involved?” And so there is even some preliminary information that sometimes there is some minor component of sensory nerves that are involved. That hasn’t been well-corroborated but there definitely have been a few studies that suggest that. I think it’s always been hard to understand why just motor neurons are implicated in ALS so I think this is suggesting that maybe that it isn’t; clearly, it is not just motor neurons.

I’m not sure in terms of treatment if these are understanding of these diseases is going to push therapies along necessarily but I think that it really is helping us to define the pathology better, the sort of principle pathologic features of the disease that you’re hopeful will lead to treatment.

So one thought that I’ve had which I think there’s been somewhat conflicted evidence is that these proteins themselves, like TDP-43 in particular but other proteins like Ubiquitin which deposit in the cytoplasm on the neurons, that they actually in and of themselves, damage the neurons and that the reason why they’re there in the first place is because there’s a pyramid of a process by which they’re cleared from the cells. So we all have a breakdown of proteins in our nerve cells and other cells. So what do we do with these breakdown products is basically it’s sort of like when we finish our meal we have food that we have to get rid of, the next food part, whatever the end result of that meal is, how do we get rid of these proteins? Well, we do that by a process that’s called autophagy. And autophagy is basically — I use the analogy it’s like the garbage disposal cells. We get rid of constitutive proteins that we don’t need anymore; they’re byproducts of other processes within the cells. And so the question has been whether there’s impairment of autophagy in ALS. And there is some evidence for that but it’s somewhat conflicted. So another question then would be if we can be very sure about autophagy being impaired and therefore, that means that we can’t get rid of these proteins that are damaging to the cells, is there a way to fix the problem? Can we promote autophagy? Basically, can we throw some drano down the pipe and unclog it? So there are medications that can do that and these are medicines that are often used to suppress inflammation but primarily they’re in the family of anti-organ transplant rejection agents and one of them is Sirolimus, the other name for it is Rapamycin, and there’s other ones as well that do very much the same thing. And so that’s a question that I wonder about. If we could promote autophagy, could that at least arrest further damage of neurons? And that’s something that I haven’t put together in a trial but something I’ve thought about that maybe we should think about doing a specific trial to address that. There’ve been other studies using medicines that also promote autophagy. I believe Arimoclomol does have to some extent and lithium. And if lithium didn’t help but maybe another agent would. So I think that is an area of interest that I have that I think needs to explore it in terms of its therapeutic potential.

Seth: Excellent segue into your research. You mentioned areas of interest. Maybe now would be a good time to return to your work on hyperexcitability.

Dr. Weiss: Right, so a little bit more background about hyperexcitability in ALS. So this has become an area of interest and an area of focus for my therapeutic trials, in particular mexiletine, which is a study that I designed with some ideas that were put forth by Bob Brown who is previously at Massachusetts General Hospital, now University of Massachusetts. So he had done some initial studies thinking to show that there is evidence for hyperexcitability of motor neurons, in particular, in the mouse model, the most common use of mouse model for ALS, SOD1-mice. And then he showed that in particular, mexiletine slowed the rate of decline in these animals and improved survival significantly. Other studies have shown that in these animals, either before they’re even born, embryonic animals, if you take out their motor neurons and you measure the electrical current in the motor neurons using something called patch clamping, that there’s evidence that they’re over-excited, and then the reason for that appears that there’s too much sodium that’s being driven into the cells. So what mexiletine does is it blocks sodium current, to prevent sodium from getting into the cells. And so the big question is does that cause the damage? We don’t know that, but we do know that in these animal models for ALS, that they don’t develop signs of the disease until well after they’re born; usually a number of weeks after. There is also even some information in patients using a technique that induces movement in the limbs by sending magnetic waves down the motor neurons in the cortex all the way to the spinal cord then down the spinal motor neurons and their projections to the muscle. That the neurons are over-excited in ALS patients so these studies have been done in ALS patients because it takes much lower level of magnetic stimulus to generate a response. So that means that they’re very susceptible to the stimulus, that they’re over-excited.

Unfortunately, we can’t really do the same kind of experiments in humans that we can do in this mouse model and then there’s always this question as the model how reliable is it to humans, especially sporadic ALS. But nonetheless, there is this information that the hyperexcitability occurs and it occurs not only in the spinal motor neurons but in the cortex based on these kinds of experiments.

So that was what led to mexiletine and then there is another study that I’m not the principal investigator for but would like to be involved in it. It’s another NEALS study. It’s using a drug called Retigabine which is anti-epileptic. What Retigabine does is it also blocks current going in and out of neurons and it’s blocking specifically, potassium current, not sodium. This study, the idea for it came about because of the other experiments I mentioned, the other studies that I mentioned, but also based on experiments that were done at Harvard Medical School by Kevin Eggan whose a very prominent ALS neuroscientist there and others. Kevin has an interest in what are known as induced pluripotent stem cells or iPS cells. These are cells that are derived from other kinds of cells like skin cells, typically, and then they are reprogrammed to form other cells and in the case of what Kevin’s doing, motor neurons. So he actually took skin cells from patients with familial ALS with SOD1 mutations and then he reprogrammed them to make them into motor neuron cells and culture. And then he did very similar kind of experiments, what I mentioned earlier in the SOD1 mice where he had somebody help him probably, micro patch clamping. And again, he showed evidence for hyperexcitability that he could block with Retigabine. I think he looked at other medications but that was the one that he found was most helpful and that is an FDA-approved drug so it easier to do studies and potentially get the drug to patients if we already have a drug that’s on the market.

So that’s what led to this study that’s about to start, I don’t know when it’s going to start and we hope to be a part of it. It’s a NEALS-sponsored study but it’s addressing the exact same potential, so-called pathogenic mechanism for ALS, that is hyper-excitability leading to damage to the neurons, both the upper and lower motor neurons, and then questions can we arrest or slow the disease down by preventing that from continuing to happen with this medication.

Seth: Wonderful. And I am sure we’ll hear more about that as it becomes up and we will forward that through our website. On the study you are leading with mexcilitine…in that study, you mentioned that as well on the way, are you finished recruiting or how can we help?

Dr. Weiss: So we’re finished recruiting and we should have our last patient through the study that is get to their last visit by the middle of September. We hope to have some preliminary results to report at the Northeast ALS Consortium meeting in, I think it’s in late October. And then if not, then one of the other meetings like the Packard Center meeting which is an ALS meeting sponsored by Johns Hopkins University, or the American Academy of Neurology meeting which is usually in April. And so it’s a Phase 2 study which means it’s not a huge study and I don’t think there are any other studies that are Phase 3 right now for ALS but it’s 60-subject study, 10 centers, all NEAL sites, Northeast ALS Consortium sites. And so it’s going well, we haven’t had any major safety issues at all so we’ve learned that much that the drug is fairly safe. Now the question is can we show benefit in slowing the disease.

The other parameter that we’re measuring is because, unfortunately, a lot of clinical trial in ALS have not been successful in slowing the disease down, one other goal is even if it doesn’t do that, and we’re still optimistic that it will and we will need to probably do a bigger study to very much approve that, but the other goal is to see if it has an effect on muscle cramping. So muscle cramping, as I’m sure a lot of listeners are aware, is a very big problem in many ALS patients and there isn’t great medication for it. And the reason why the cramping occurs or we believe this is the reason, is because when the spinal motor neurons die and the nerve processes degenerate, then other neurons and their nerve processes can temporarily take their place. And then when they do take their place and they send little newly-formed branches to the muscle that’s lost its nerve supply, what happens is those branches, I guess, they’re not mature; they take a while to mature and sometimes they never do; they are again, over excited and that’s what leads to cramping. And so, again, the thought that is if we suppress that hyperexcitability, that could potentially benefit patients of cramping, as well. So that’s another part of the study, to see if it improves muscle cramping in our patients and we’re hopeful that that will be the case, as well.

Seth: Thank you. We’ll prepare for our last question and then invite listeners to call in, Amy.

Amy: Yes. The phone number for that is 516-590-0362. Please press number 1 if you have a question so we know.

Seth: Great. While our listeners dial in, I want to ask Dr. Weiss, what is the greatest opportunity in your mind for our listeners to get involved in ALS research?

Dr. Weiss: Well, it depends on how you mean. So obviously this is ALS research, we’re always looking for sources of funding. So if there are contributions, there are some very useful organizations. There are some organizations that I think could really use that money, Muscular Dystrophy Association. They have unfortunately had some financial issues which just made it real challenging for them to fund any clinical trials or any research recently. So they’re in great need of any support. There’s also an organization called the ALS Therapy Development Institute which is run by a very prominent neuroscientist, Steve Perrin. And his goal is doing what’s called translational research which is looking at this problem, not necessarily looking at the cause of ALS but trying to establish a potential treatment and then taking it usually with the help of Northeast ALS Consortium to the patient, or at least, into a critical trial, thus becoming a conduit for potential therapeutics. So I’m sure that’s another organization that would benefit from any contributions. And then probably the ALS Association as well but it doesn’t have to be financial contributions. There are always events that are important for raising money that I think having a presence would be of help. Like there are walkathons, the ALS Association has a walkathon coming up, I believe, I don’t remember the date. And obviously, patients can’t do it, with ALS, may not be able to walk but just having being present really, I think, it can show to the public the seriousness of this disease so that they become involved and potentially we can find another way to help finance some of these research projects that are under-financed because this is really still considered to be an orphan disease and that means that there isn’t a lot of funding coming from the NIH directed towards ALS research, unfortunately. Hopefully that will change but I don’t know when at this point.

Seth: Thank you. We here at ALS Crowd are huge fans of the MDA, ALS TDI, and the ALS Association. I’m grateful you mentioned them.

With that, we will prepare to go to the phone lines. We will take our first caller. Caller 1, you’re on the air with Dr. Michael Weiss.

Dr. Weiss: Hello.

Caller: Hi! I have a couple of questions. I want to go back to the MMN diagnosis. I am wondering, what is the testing for MMN? And I know it’s a lot of tests, there’s false positive, false negative, there’s no sure thing. Also along that line… IVIG treatment, how long do you normally give the treatment before you decide if it’s working or not or what’s the criteria to know if it’s working?

And then another question is why isn’t IVIG treatment being used for Lou Gehrig’s? Let me preempt that by saying I’ve been given IVIG treatment. I noticed a difference in how I felt; less fatigue, less fasciculation, more dexterity but oddly, my doctor said “No, it’s all in your head. No more.”

Dr. Weiss: So those are great questions and they do come up a lot.

So there had actually have been some small studies in just ALS patients alone with IVIG that have not clearly shown benefit. But if there’s any consideration of the diagnosis of the Multifocal Motor Neuropathy, I always give patients a treatment trial if their insurance will allow. That’s always a struggle.

So Multifocal Motor Neuropathy with conduction block is defined by the electrophysiology, the nerve conduction testing showing conduction block which is an area along the course of the nerve where we’re stimulating the nerve to the muscle where there is a block in the signal; the cause of loss of the coating or the myelin. Now there are patients for whom that is a challenge to see or maybe they don’t meet all the formal criteria that have been put forth by different organizations. But the thing that I always think about is they cannot have upper motor neuron signs so Multifocal Motor Neuropathy patients well should not have jumpy reflexes or increased muscle tone. That’s the case. I know they don’t have it.

There’s an antibody test for Multifocal Motor Neuropathy that is helpful but it’s not nearly as sensitive as we would like. It only has a sensitivity of about 40% and that is the antibody that’s something called GM1 which is a complex sugar that’s present on nerves. We used to think it was very sensitive but recent studies suggest it’s not. And occasionally, can even be weakly positive in ALS patients. If that test were to come back more than just weakly positive for sure, I think that’s the rationale for using IVIg but it’s really other things that… There’s a clinical features of Multifocal Motor Neuropathy that cannot have upper motor neuron signs. They shouldn’t have any trouble swallowing or chewing, and they don’t typically have breathing issues. Otherwise, sometimes it is hard to know for sure and sometimes I’ll just treat and ask what would I treat with, what should be my protocol? So the protocol I use is similar to what I use for CIDP patients which was pretty well-defined based on IVIg study done in CIDP called the ICE study.

And basically I do induction course or I’m giving patients a double dose, 2 grams per kilogram body weight is the dose I give them. And then every three weeks I give them 1 gram per kilogram body weight for three times. There isn’t any consensus on this but I’m measuring is I’m assessing individual muscle groups through using something called manual muscle testing…testing their muscles using a scale called the Medical Research Council scale which is what many neurologists use, MRC scale. And what I use as my criteria is the patients have to have an improvement of at least two muscles by at least one grade. This is just me so there’s no consensus for this, and then I measure their grip strength with a device called the dynamometer. And there are probably some other neurologists actually use dynamometry to measure other individual muscles. And so what I’m looking for is at least a 20% increase because I’m not looking for improvement of fatigue. Unfortunately, there’s really no way to measure that and I’m not looking for improvement of muscle twitching because muscle twitching or fasciculations in ALS vary all the time. They come and go, they don’t correlate well with the disease, and unfortunately, it’s not going to help me too much. But that’s just the way I do it. Now I don’t know what other neurologists use as their criteria but that’s just what I’ve always used. But when in doubt though, I always give patients a treatment trial.

I hoped I answered your question.

Caller: No, you did. My other question is you said on the nerve conduction test that you do see depletion of the myelin, and that’s seen with MMN because of nerve conduction blockage. I’m wondering if that is also true in ALS patients.

Dr. Weiss: No. no, so that is a distinguishing feature. So the myelin is not being damaged in ALS. So ALS — I’m sorry, what were you going to ask?

Caller: I was going to ask and that is only found with the use of a nerve conduction test?

Dr. Weiss: Yes, regrettably. Other than the clinical presentation of course which is somewhat challenging in distinguishing from motor neuron disease, ALS, it’s really the nerve conduction testing. What distinguishes MMN from ALS is the conduction block. That is actually required for a definitive diagnosis of MMN.

Caller: Sorry. I have one more question. What do you tell patients that you know… no one wants this diagnosis and you want to keep researching and finding things that can help you? But sometimes it’s so hard for a patient to find a doctor who’s proactive or will help them because it seems that they think, you know I should use the time I have left to do something great with your life or whatever. What advice do you give to your patient that really does want to keep searching out a way that they can improve this disease? They are living with this disease and hopefully finding that it’s not this disease.

Dr. Weiss: Well, I certainly try my best to be open-minded to what patients ask me about but my goal is also not to expose them to something that’s going to potentially decrease their survival. I don’t have this disease but I’ve talked to enough patients that say, “what do I have to lose?” Well, I guess it depends also on how fast the disease is progressing and in some patients, it doesn’t progress that quickly. And so the idea of subjecting them to an unconventional therapy that could potentially kill them is really for me, still somewhat unpalatable, and then that happens sometimes. But then there are other therapies where I tell patients I don’t know if this is going to help. There’s just no alert, no evidence one way or the other. I like there to be some kind of a rationale for doing it. Like it’s an antioxidant for instance and therefore it’s getting rid of oxygen-free radicals and so there are protocols that are being used by patients and I’m not going to go into detail but were that is the case, then I tell them “I don’t know. I don’t know if it’s helping. I don’t think there’s any harm to doing this, I’m not going to have a problem with you doing this if you want, and I’m okay with that.”

So it really depends on what they find out on what they research and what they ask me about, whether I’m okay or not. There is a very useful resource which obviously, if you were to read it, you may agree or not agree with the information. But there’s something known as ALS Untangled. I don’t know if you know about this. So ALS Untangled, I guess it’s a collaborative editorial. I don’t know how else to describe it. Basically, it’s an investigation of an alternative therapy for which there hasn’t been a real true clinical trial, nothing published on the National Library of Medicine website, and it’s run by Richard Bedlack who is the Director of the ALS Center at Duke University.

So what he does is he gets the opinion of all these ALS neurologists or I don’t know if it has to be a neurologist but usually neurologist, at ALS Centers, usually academic centers throughout United States, about alternative therapies and their utility or lack of utility, should they be even studied or is there really no good scientific rationale and are they potentially harmful? And of course, this is the opinion of himself and all of us who participate. But nonetheless, you might find that useful.

I don’t know the exact website but if you put in ALS Untangled, it will take you right to them and then there are multiple numbers of publications addressing specific topics. I think that Rick would be open to the idea of having some topics be patient-driven like you wanted to know, would he give you some information about it, I think that makes sense. If patients really want to know, then why don’t we see if we think it’s reasonable or not having or getting this consensus from ALS neurologists. There have been a number of these publications, they’re all open access. Yet they’re also published in a journal called ALS and other motor neuron. ALS, Frontotemporal Dementia, and other motor disorders is the name of the journal, which is the primary ALS journal.

Caller: Thank you. Thanks for giving your time. This has been a really great interview.

Dr. Weiss: I’m glad to hear it.

Seth: And thank you, caller, for pushing us and Dr. Weiss for keeping us abreast of the tough issues. We have time for one more caller. We’ll go to that caller now. You are on the air with Dr. Michael Weiss.

Dr. Weiss: Hello.

Amy: Go ahead with your question, caller.

Caller: Hello?

Seth: Yes, you are on.

Caller: Oh, yes. Hi! I have a question. Can you give us some perspective and help us understand about how many ALS specialists are worldwide that are maybe principal investigators doing active research?

Dr. Weiss: Well, I think the place to start is that there are a number of ALS centers through the United States that are either sponsored by the ALS Association or the MDA and they have specific expertise in ALS.

So the University of Washington, we’re an MDA-ALS center, and I believe there are something like 35 centers throughout the United States. Probably every center has a few ALS neurologists so if that gives you some perspective. And then the ALS Association, I imagine, has similar numbers, maybe more.

What I find is that in most big cities where there’s an MDA-ALS center, there’s probably equal numbers of ALS Association clinics. And all those groups of neurologists, probably most of them are doing clinical trials but they may not be the principal investigator, they may not be creating their own trial but they might be helping to implement it as a site.

So all the number of trials that are going on in the United States right now, most of them are being conducted through the Northeast ALS Consortium which is basically a group of physicians that are centered primarily at the Massachusetts General Hospital under the auspices of Dr. Merit Cudkowicz, I think she was on the program earlier. And what I can say is they basically run, I would say 2/3 of the ALS studies in the United States right now. And I believe there are probably about 12 or 13 studies going on right now and at least, 2/3 of them are sponsored by the Northeast ALS Consortium. My mexiletine study is sponsored by the Northeast ALS Consortium.

Then Europe, I don’t know what the infrastructures for doing studies. There are also basic scientists at a number of institutions have a real focus on ALS and they aren’t necessarily doing clinical trials. And there are groups at Johns Hopkins Hospital and University of Massachusetts and Massachusetts General Hospital and their place is along the West Coast like Bob Bellows group down at Peter Sinai and Bob Bowser down at the Barrow in Arizona. So those are among the focal points for ALS Neuroscience research. I don’t know if I can give you a specific number about how many doctors are involved in research. But it’s a fair number of neurologists so they have taken a very strong interest to understanding the disease and then trying to do trials. Do we want it to be more? Sure, we do. We want more doctors to be involved in this disease in trying to treat it. And I think the largest group of doctors probably at the Massachusetts General Hospital right now and they’re probably eight neurologists there have been doing trials or have an interest in ALS research.

I’m not sure I answered your question but I think that’s the closest —

Caller: Oh, no. you did. I just wanted to get some perspective.

And I have another question for you. With the mortality rate of ALS, it seems like… I know a lot of times the scientific research is very incremental. And I think in ALS, instead of base hits youwant really big swings in the plate. So in your opinion, what elements need to be in place for more aggressive or bigger risk-taking, I guess you would say, to really make a leap forward?

Dr. Weiss: Well, that’s a great question. So I think that we have to just start thinking outside the box more than we ever have and take new approaches that we haven’t taken before, but it’s also a question of study designs. So unfortunately, there have been a number of studies that have not shown benefit ultimately; maybe in smaller studies, they have. And then there was this very big study that was done a couple of years ago sponsored by Biogen, dexpramipexole study. And I believe that was the largest study, clinical trial, ever done in ALS, a multi-national study. I forgot the exact number of patients but there are probably over 80 centers; we were part of that study.

Unfortunately, it turned out that even after the fairly robust and surprising benefit from the smaller Phase 2 study which showed the drug was slowing decline and it was decreasing the rate of decline in regard to breathing parameters for FVC and changes in the ALS functional rating scales which is a very important questionnaire of activities of daily living that ALS patients. We have them fill it out in our clinic, a pretty straightforward questionnaire but very important parameter that we can quantify. But even though it showed improvement or slowing of the rated decline of those functions in the Phase 2 smaller study, Phase 3 study was negative, and it cost the drug company 75 million dollars. And I don’t think that they’re turning their back on ALS but the idea of doing another big trial like that that’s going to cost that much money who will not lead to, quite frankly, any additional revenue for the drug company is going to be unpalatable for some of these drug companies.

So then the question in my mind is should we looking at others kind of study designs that would really answer this question at least quicker? And there was a study that was done recently that tried to do that. It was the Tamoxifen/ Creatine study where there were two drugs that shown benefit mostly in pre-clinical animal models. And the idea being compared this two potential drugs and then we’re going to take whichever drug does better, assuming one does, to a bigger study. That way we’re sort of hedging our bets. And I think that that is a very unique way to look at clinical trial design that that might be a way to move things forward more quickly without wasting time on drugs that are just not going to work even though they should benefit in the ALS mice.

And so I think that that might continue to be a good approach to this. Unfortunately because it’s so much cheaper, if we have a positive Phase 2 trial, in my opinion, we have to replicate the Phase 2 trial before we do a big Phase 3. That way, we won’t scare off drug companies that are willing to invest a lot of money and then we sort of hedged our bets again by showing that we’ve corroborated the results on two different occasions. I guess it could even be done in parallel if that were possible except then you wouldn’t know if either study was going to be positive. So if there are short studies and one shows benefit, makes sense to me, just repeat the study see if it shows benefit again and then do a Phase3 if the drug company is willing to pay for it. So that’s kind of my thoughts about drug trials.

Caller: Another follow up to that. Are there any indications that there is maybe low-hanging fruit with some existing drugs that are maybe used for other diseases that might be applicable that you could pass in ALS? I think that would be a less expensive, more rapid type option.

Dr. Weiss: Absolutely! That’s what we’re all hoping to do, that’s why I picked mexiletine as the drug because it’s already FDA-approved. I didn’t mention this earlier, it’s a cardiac antiarrhythmic agent. Cardiologists don’t use it very much because it’s not very effective but it’s an older drug, so that’s one.

And then Retigabine is already the drug in the other trial I mentioned, going to start relatively soon, that’s another one that’s already FDA-approved for treating epilepsy. And then Tamoxifen/ Creatine, both of those drugs. Tamoxifen is anti-hormonal therapy for breast cancer and then Creatine is this over-the-counter supplement but Creatine did not work though. It doesn’t seem to be beneficial

So we are trying to do that because I think as clinical trials in ALS, we recognize how hard it is to start with a novel drug. Unfortunately though, if we could get a smart pharmacologist help us, I don’t think we can ignore that possibility that we need to come up with a new drug that is not out there. We kind of have to do both because we haven’t found the drug that’s already existing that clearly slows the disease down significantly. But you’re right. That’s easier to do those studies for sure if the drug’s already out there.

Caller: Well, it seems like they’re working on all angles so thank you, Dr. Weiss, so much for taking my call and for the show.

Dr. Weiss: You’re very welcome.

Seth: And thank you, caller, for those questions. We are now at the end of our call. Dr. Weiss, anything else that you would like to mention before we wrap up?

Dr. Weiss: Well, I’d just like to say for those patients out there, there are definitely a lot of neurologists out there who would like nothing more to see an end to this disease or some viable treatment. We’re on your side; we’re going to continue to be on your side. And I have no doubt we’re going to find a better way to treat this disease sometime in the near future. And so I don’t want you to give up hope because that’s one thing that I’m convinced there is somewhere down the road. I don’t know when but I’m sure that….

Seth: All right. When you figure that one please come back on this show.

Dr. Weiss: Seth, you’re going to be the first to know. You’ll be one of the first to know.

Seth: All right. Thank you for that. Thank you for not only time but your dedication to this community.

Dr. Weiss: I am happy to continue to help any way I can.

Seth: Excellent. For our listeners, a full transcript of this interview will be available within the week and posted to our website. Thank you to Dr. Michael Weiss and we look forward to solving this disease. Thank you.

Dr. Weiss: Thanks, everybody.

About Author

Seth Christensen

Seth is an ALS patient and founder of ALS Crowd, a division of the CrowdCare Foundation. As host of the ALS Crowd Radio show, he interviews top ALS researchers and focuses his efforts on the aggregation of big data to help researchers and patients find clues that will drive to a cure.

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