 Oh, actually, how do you go back? So I'm gonna ask Alexis to come up. I'm not gonna, there, there. Well, I'm just gonna leave the slide here because I don't want you guys to know the questions ahead of time. All right, thank you. Keep these mysterious for you. And we updated the wording slightly just based on some of the presentations that have been very relevant to this topic already. Oh, good. I'm just gonna struggle with that a little bit more. All right, so for the panel, the first question for you is, what has been your experience diagnosing patients with hereditary amyloidosis with polyneuropathy? And if anyone, yeah, please feel free to use your microphones as well. Okay, I'll start as the cardiologist. Well, I will tell you that it became most of diagnosis because I picked up cardiac amyloidosis and I routinely scream, especially if they're hereditary, I will send everybody for nerve conduction, EMG, and we have a combined, now over, it's been three years that I have my neuromuscular people join us for the clinic. Now, sometimes they can't make it or they can really only do three evaluations because their assessments take a long time. So we have created a neurology amyloid clinic, but it's still been a push for me to, because I want it to go the other way. When are they gonna make the diagnosis first? And the big issue I've had this over, the last five years is, they'll say, well, they have diabetes. So that's the most common thing because again, about 35% of my patients have diabetes. And so they'll say, well, I can't say that this is a neuropathy due to their amyloid or they have spinal. So I'm often in a battle one, especially when I'm trying to get approval for it, but there was a time when my neurologist could only prescribe the silencers. Now that's changed because now, anybody who's an amyloid provider can prescribe. But it was a big battle. And I think the issue is, they haven't made genetics part of their routine. They haven't made, my neurology haven't said that they've often just say, well, if there's diabetes, then we have a reason. And so I think I'll be interested to my neurologist about the patterns on EMG and nerve conduction and how to make sure we're not missing variant. And again, a lot of patients who have diabetes. Yeah, thank you. That was really good points. I think these days with the availability of genetic testing and the fact that it's also free for patients, I get to avoid the 20 minute long counseling session about trying to convince them to do genetic testing, which is something that I had to do back in the day before treatments became available and before genetic testing was so widely available. So I don't, there's really not much of an excuse to not do genetic testing early on in the game. And quite frankly, I don't understand the reluctance anyone in doing genetic testing. I think the point about diabetes is a good one. Dr. Dev and I have been communicating about one or two of his cases. So diabetes is a tough one because obviously it's so prevalent in the general population and about two thirds of diabetics will have a peripheral neuropathy. The thing to keep in mind also is sometimes the autonomic dysfunction can help you while diabetics can have orthostatic hypotension, it's uncommon, only 8% of diabetics will develop orthostatic hypotension, so it's a small number. So as I mentioned earlier, if you have a neuropathy with orthostatic hypotension, it is amyloid until you prove that it isn't through testing for light chain, AL, and then doing genetic testing. I do genetic testing in just about everyone that I see with a peripheral neuropathy and orthostatic hypotension for that purpose, and then you can look for other features. Additionally, the history of carpal tunnel is helpful. Almost everyone that I've ever seen who has a peripheral neuropathy had a history of carpal tunnel somewhere along the way, and importantly, it's bilateral, it's symmetric, and so that's also a very helpful feature. The issue of spinal stenosis is a tough one because many, or most of the patients, particularly if they've had the condition for a while or if they're older, I think at least that's my sense. Spinal stenosis is pretty common and that can be difficult to sort out from the peripheral neuropathy. What I would say to the neurologists who have reluctance to start treatment is that it's ridiculous. If you've ever, like some of us have, managed patients who have horrible neuropathy with, you know, who require two or three neuropathic pain medications, you're trying to help diarrhea that's developed. You're dealing with orthostatic hypotension and heart failure in that scenario. It's, you know, these cases stand out in our mind and why are we waiting until there's significant symptom accumulation prior to starting therapy? I'm not interested in, and I don't think we should be playing, making those decisions. We have a treatment that's effective. It stabilizes the condition and we should start treatment early, in my opinion. So, and then just one other thing is just the role of just being really sensitive to autonomic involvement in these cases. Again, sometimes patients may not recognize that they have autonomic impairment or they may attribute it to their cardiac condition. So at our institution, we do autonomic testing. I think Dr. Warner mentioned earlier, you can do postural vital sign measurements. They should be done, in my opinion, and you can pick up on orthostatic hypotension if that's present. That would most certainly be an indication for treatment, regardless as to whether an individual has a somatic peripheral neuropathy or not. Yes, thank you for actually inviting me as a neurologist, neuromuscular specialist in a group of cardiologists. So this is exciting that we're all coming together as a team. And I would like to borrow Dr. Goodman's sentence that said time is nerve. And so too is neurologists. Just like we have the door to needle time, I feel every step of seeing a patient with neuropathy right from the primary care physician up until just to have the suspicion and to increase the awareness about this, that is where it all begins and sometimes ends. So I think it's really important, just like these conferences that for us to kind of bring that to the fore for primary care physicians, that it is not just, and neurologists, I would also say our team is to bear that awareness as well, that when people come with neuropathy, it's the main thing in people's minds is I'm not diabetic. You've ruled that out. Or if I am diabetic, then it is diabetic neuropathy and the rest is all related to it. But dispelling the misinformation that neuropathy it is and it ends at that and there is no treatment for it. That's why we lose all of these patients. So I think just that's where we need to start. We need to know where we are losing our patients that we can really take. So door to needle time takes so long. And then just encouraging the fact that yes, there is a treatment even for amyloidosis. And that's how we, I think that's how we need to change the whole paradigm around amyloidosis, that it's not a basket case, it's not neuropathy, it's not treatable, just go on Amazon, find something. It's, we have moved neuropathy beyond that. It's not just neurology, the art of show and tell. Now we have more in our armamentarium. Yeah, and from the genetic counseling perspective, typically when I'm seeing patients with amyloid, the providers, the physicians have already ordered testing on the front end, which is great. And that means that I get to have that additional educational piece to talk to them about risk to family members, risk for different signs or symptoms, but they've most likely talked about the medication management treatment side of things, personal side of things with their doctors at that point. But we really start to get to focus on the family side of things. And then when they bring their family members in, and we might make a diagnosis of genetic risk for developing amyloid in the future, then they can get set up with the right, education to know what signs or symptoms to be looking for, potentially screening, if they're at an age where they might already be at risk for symptoms and get them set up with the right healthcare ahead of time, that's always great for those patients that want to know what their risks look like moving forward. And then for other patients where they might be referred, not for amyloid specifically, but they're referred for neuropathy or they're referred for cardiomyopathy, that TTR gene should be on any of those big panels. So when we're thinking about what's the differential for why someone has that feature or that feature, when that gene pops up, then we know, okay, this could be the potential cause and we should be thinking about sending over to amyloid clinic, which is a really great resource for those patients. Yeah, so from the pathology perspective, regardless of the patient has polyneuropathy or not, but the amyloid will essentially look the same. That said, certainly I think having a high index of suspicion is really important. So of course, if you're sending a nerve biopsy or a biopsy from anywhere else that you're looking for amyloid, put it on the requisition, right? Most of us, of course, are gonna have access to the medical record and should be looking at the medical record, but oftentimes, especially if you send your pathology out to maybe a tertiary center or a private group that services multiple hospitals, they might not have access to that medical information. So letting them know that that's what you're worried about, it seems like a small thing, but it can actually be really helpful. Another comment that I wanted to make, if you have a patient where you're considering a diagnosis of amyloid, it takes time obviously to get them to the point where you say needle time, getting to the point of getting additional tissue. Look back in their history. Maybe they've had biopsies recently for something else, a skin biopsy for a basal cell or polyps taken out from GI biopsies. You can actually ask your pathologist to go back and re-review those specimens to see if there might have been some hidden amyloid already there, and then you have your diagnosis. And as someone accurately mentioned earlier, that mass spec typing that we do is on formal and fixed paraffin embedded tissue. So anytime anyone has anything taken out for search path, whether it's a polyps, skin, lung, whatever it is, that's gonna be saved for years as formal and fixed tissue. So you can go back and potentially utilize that tissue to get to your diagnosis. All right, and so that's with the staining, right? Where the staining comes in after the biopsy looking for the specific, okay. And then just quick questions to follow up. So Dr. Goodman, I know you had mentioned when you start even considering that amyloidosis can be part of the driving reason for these symptoms, do you immediately order, you said you immediately order genetic testing. Is that covered by insurance companies? Is that extra costs for the, I mean, if the patients have that covered once you order genetic testing? Fortunately, genetic testing at this point is free to the patient, so it's wonderful. So there's just no reason not to order the genetic testing? I guess we could argue that point, but I would say no in the appropriate clinical scenario. So I think as neurologists, certainly, you know, it's particularly hereditary TTR, it's thought of as this very rare condition. And so some neurologists may have never seen it and certainly may not therefore think about it and think about ordering genetic testing, but I certainly wouldn't put cost at this point as a reason to not order the test personally. Absolutely. Just a follow-up question. So thank you to the industry partners here that are part of making these programs free right now. You know, my patients at the Providence VA certainly benefit from the El Nile and Mac program. And I know that there are several others out there. I guess the question for me is, is that that's sort of aligned right now between our patients and these companies, that may go away in the future. If that does happen, you know, what are the mechanisms that your institutions or other ways that we can get this testing in a cost-effective manner, assuming that those programs don't exist, let's say five years down the line, 10 years down the line? I can speak to that a little bit as, you know, someone who orders genetic testing as well. So, you know, some patients choose to go that sponsored testing route where they're open to, you know, having their de-identified information shared and participating in that program and having testing covered if they meet the eligibility criteria. Some patients choose not to do that. They'd rather go through their insurance or, you know, not be part of those sponsored programs. And typically when testing goes through insurance, you know, we're sending over notes, clinical documentation, that this is medically necessary testing. We hope that there's insurance coverage there and we don't get too much, you know, feedback from patients that they're having a hard time getting testing covered on that side of things. But with the testing labs, oftentimes they'll also offer insurance assistance in the sense of they'll provide patients with a benefit investigation ahead of time. So the lab will assist with checking with the patient's insurance to know what is this expected cost gonna look like for the patient. If it's gonna be over $100, for example, we'll reach out to the patient and let them know what that looks like. And there's typically an option to self-pay and usually that's about $250. So, you know, that's still not nothing, but that tends to be pretty reasonable for most patients. And if, you know, it's $250 to get that genetic testing and take that next step forward and that diagnosis and getting the right treatment plan for them, most people are typically okay with that. I'd like to start by thanking the panel for being here. This question is perhaps mostly for Sonya, but anyone can certainly answer. Dr. Govman and I were just chatting, you know, we send you patients, obviously, with a known diagnosis, but then ask you to help us facilitate the testing of potentially family members. And I was curious if you could share with us your experience about what concerns those family members may have about proceeding with the genetic tests and how you introduce the Gena Act or what additional pearls do you present to them? Perhaps some of the people here may or may not be familiar. Yeah, I really appreciate that question, Dr. Rosenthal. Thank you. So, one of the big things that we bring up with family members in talking about predictive or, you know, proactive genetic testing, there's a known familial mutation. They wanna know, did I inherit this and am I at risk? Sometimes they're concerned about how is this going to impact my life insurance eligibility? How is this going to impact my health insurance? Or maybe they don't even know that that's a concern that they should have. And so we certainly talk about it in case it is something that they have questions about or wanna look into more. But there's a federal law called the Genetic Information Non-Discrimination Act, and that protects most people from their health insurance and employers asking about or using genetic test results to discriminate against them. There are some limitations with that. Certain companies that have, you know, very small number of employees or people who are employed by the military or other federal institutions. So there are limitations to the protections there, but one of the biggest limitations is that other companies like Life Insurance, Long-Term Care Insurance, Disability Insurance Companies, they are at this time legally allowed to ask people questions about that and use that when they're deciding how much they're gonna charge someone for life insurance or if they're even eligible for their life insurance. So unfortunately we don't have really good data to know how many companies are actually asking these questions or what are they doing with that information if they are asking or are they looking for that when they ask for medical records to be released. So it's really hard for us to know what is the actual risk of that limitation of that law, but it is something that we want people to be aware of in case it's something that they're concerned about. So sometimes patients say, you know, I'm not really worried about that, I just want the information I wanna know how it, you know, it makes my risk look, what it makes the risk to my children look like, but other people, you know, that's something that they're worried about and they wanna go talk to Life Insurance Company ahead of time before they get that information or they wanna go look into it a little bit more, talk to a financial or legal consultant before they get that genetic diagnosis because once you know the information, you can't unknow the information. So we really spend time with patients in the predictive setting, you know, to talk with them about the possible implications of having that genetic information. Of course, not just from the financial and legal standpoint, we also talk about, you know, psychosocial implications and, you know, implications for family dynamics and things like that, but that genome law is, you know, a big thing that we wanna make sure people are aware of, because a lot of people are not familiar with it before they come into their genetic counseling visit. I forgot to mention, the first two people who have questions get prizes. So I think you had another question. So while you're doing that here, here, while you ask. So just to follow up on some of the sponsored testing, you know, one of the advantages, at least of the Onylem Act program is that you can also, thanks, you can also get genetic testing for other cardiomyopathies as well as neuropathies. And so when we talk about the $250 test, is that just for the TTR gene? Or is that include the whole panel of, you know, all the other cardiomyopathies and neuropathies? And the only reason I ask that is that it's become very useful that I didn't diagnose somebody with amyloid, but I definitely diagnosed them with something else. And so that's a really nice benefit to sort of give patients closure, even if they don't have amyloid. Yeah, and that's a really great question, which brings up sometimes people don't just have a TTR mutation. I've had patients where they come back with multiple genetic mutations on a cardiomyopathy panel, right? And so then we're talking about two different things that might both be impacting a person's heart disease risk or reason for their cardiomyopathy. But to answer your question directly, most of the time these panels, regardless of how small or large they are, if they're set up on the same sequencing platform, they're usually that $250 cost, yeah. So that's pretty standard across most labs. Not every lab is going to be like that, but generally that $250 self-pay price is what we look at these days. Okay, we have one more question. We have another question. All right, I need to look at that. I can tell, it's perfect. I'm going back to the precision part of it. You had mentioned all the ones about the orthostatic hypotension. So when you're talking about neuropathy plus orthostatic hypotension, it's amyloidosis and teleproven otherwise. What about normal EMG? So medium and larger, good, but the small fiber is diagnosed on biopsy. Would you consider small fiber with orthostatic hypotension as a reason to look for amyloidosis? Yeah, that's a great question. If somebody has orthostatic hypotension that's due to an autonomic neuropathy, those nerves that are responsible for orthostatic hypotension are small fiber nerves. They're the same nerves. Just one goes to the vasculature and helps clamp down on those vessels when you change position and the others come in from the skin and go into the nervous system. So in diagnosing a small fiber neuropathy, which again, amyloid, it characteristically involves small fiber nerves first and then as it gets worse, it will generally spread it to involve the large fiber nerves. So in diagnosing a small fiber neuropathy, it's clinical symptoms. So numbness, tingling, burning pain, typically in the feet, amyloid though. Sometimes it can be non-length dependent so it can involve the hands sometimes and not be carpal tunnel. It can sometimes be small fiber neuropathy in the hands. So use your history and then you look for findings on exam. So we'll do check pinprick and temperature and the other sensory modalities will be normal in a small fiber neuropathy. And then one of the other tools that we have, I think it may have been on one of these slides was skin punch biopsy. So skin punch biopsy can be performed. The advantage of that is you with that study, they count the number of epidermal nerve fibers, but they can also do congo red staining and look for amyloid on the skin punch biopsy. I don't have the sense that it's terribly sensitive for that. So in my opinion, I really question as to whether that should be utilized in determining whether somebody actually has a small fiber neuropathy due to amyloid. I would still do genetic testing if I was suspicious. And then one can also use autonomic testing to diagnose a small fiber neuropathy as well because again, it's the same population of nerve fibers. And I'm sorry if I was too long-winded with that question. All right, no more questions right now, right? Or do we have any more questions for the time? Okay, we'll move on to the next question, which is how do you decide when to think about hereditary amyloidosis and how does that impact your diagnostic workup? Again, this is coming from the cardiologist. So obviously the phenotype I'm dealing with is the heart failure patient that has, again, some of those red signs that we're talking about, the extra cardiac. Again, I'm always look at my own echo every time I'm seeing a patient, I review their images directly and their EKG. So that's a certain clue. And then, so I'm looking for TTR. So anybody that has TTR, I'm gonna do genetics on. So it's usually the algorithm for me as I suspect the cardiac involvement. I do the algorithm, and I, as I stated earlier, in my patient population, I'm usually doing the rule out light chain and the PYP at the same time. I have other biases that I didn't quite get into. Sometimes I have patients that have both light chain and TTR and I have a handful of those. And so anytime I get TTR, then I send the genetics and I use the sponsor genetics program. Most patients are amenable to, I just have to do my documentation and I've ended up becoming the genetic counselor for cardiology too. Does anyone have any questions based on that last question? Okay. And apparently we have more prizes. If you have questions, you get one of these. So just apply. All right. So the next, I feel like many of these have been somewhat answered already, which is always fun. So when the next question had been, what has been the role of genetic testing and genetic counseling in your practice? Which has been thoroughly answered, I believe. Would anyone like to weigh in any more on the question that has been somewhat answered? Just turn it off in the audience, how were they, were challenging the VA doing our best at our own institutions and carrying out that today, so very significant. I was, in addition to that, I was curious about access to genetic testing in rural areas. I'm not sure if it's available everywhere, right? And there was, I think Dr. Shug mentioned like primary care providers. I'm like, ooh, we don't have one, a panelist who's a primary care provider. Is anybody here who wants to weigh in or at least let us know your experience, barriers and facilitators to early diagnosis? I was just gonna say with the sponsored testing, which I sometimes have, I was just telling Nishant, I do a thing where I create the requisition and I still order it through my lab department and then they send that requisition so the patients, other than their date of birth and their medical record numbers all it's shared. However, we do remember the sponsored program and you have to answer clinical questions because that, and so I do have to share that their de-identified data will go. If I have had a couple who said I don't want it anywhere in my record back to the insurance issue, I do mention GINA, but they don't, so when you, I can order it through on the website and they mail a saliva kit. So it's almost, you can live anywhere as long as you get USPS, you can get a saliva kit delivered and they can mail it back. So for some people, they wanna just have it directly and then I do that sometimes when I'm doing family testing, they're non-vaterans and they agree for me to order it for them. So, and I'll put in the family member requisition number and I have to get their permission. That way they can do family testing and that I do all through US mail, directly from NVT. Yeah, and sometimes with the family testing too, the labs will partner with telemedicine companies. So places that have telehealth genetic counselors. So even if a relative maybe isn't in a location where there's a physical genetic counselor close to them, which is the case for many people, if they have internet access, they can have a telemedicine appointment, they can get the saliva kit shipped over, just like was said before. And then it becomes challenging of okay, if you're positive, where are you going to go get care, right? That becomes the next barrier, but if they want the information, there are resources for people to get that information. Sonia, this is a question for you. When we do this testing, there's a lot of variance of undetermined significance. How do you deal with that when you're counseling either patients or family members? Yeah, so those are tricky. I will say with the TTR gene, I see variance of uncertain significance or VUS is much less frequently than I see with other genes. Many of the variants that we typically get back are pretty well characterized. There are some that are even known to be pathogenic that we don't have too much data on when we're trying to think about characterizing possible phenotype, because there is some genotype-phenotype correlation that we can think about that's been documented in the literature. But with uncertain findings, it's hard because we have something that looks different than you would see typically in other people and we're not quite sure. Is it actually causing disease? Is it causing amyloid or is it completely harmless and just a normal variant? I would say if we have clinical evidence to say that the person has TTR amyloidosis and we've got a VUS that has a lot of evidence to say this is probably leaning pathogenic, we might be more suspicious of it and we just have to clearly document that this isn't a completely confirmed genetic diagnosis right now, but it is leaning that way, right? And then if it's patients who are pre-symptomatic or maybe they don't have a confirmed amyloid diagnosis right now, don't have that TTR positive biopsy or what have you, it makes things more challenging. But certainly having that conversation with patients and getting them to understand this is uncertain and there's uncertainty with genetics, there's uncertainty in all areas of medicine, but having the opportunity to sit down with them and say, we don't quite know what this means right now, certainly possible that in the future as more people are seen with this variant or more research is done with this variant, we can have changes in classification. That certainly happened before too where I've seen patients who have a VUS and then a couple years later, it's been upgraded to pathogenic and then we can say, okay, we've got that confirmed genetic diagnosis or they don't have that clinical diagnosis of amyloid and we just got a pathogenic variant and we still don't really know what's going on, why they're having the symptoms they say they're having if we don't have that clinical evidence of amyloid. It definitely gets tricky and it's all just being honest with the patient about what we do and don't know right now. Okay, thank you so much for, we have another question. It's, so my question is in case, it's a follow-up question for that, for the variants that you discussed. In case in the future, if you establish that there is a pathogenetic presentation of that variant, phenotypic presentation of that variant, do we have a data, do we have a system in place to contact those, the patients with those variants and get them into the system to get treated for it? Sure, great question. So most often what will happen is if the lab makes an upgrade or a downgrade, really if there's a change in classification of a variant, they have that patient's information in their system. So what they should be doing is notifying the ordering provider, hey, there's been a change to this test result, you need to let the patient know there's been a change in what we interpret this variant to be. So oftentimes if I'm the one who ordered the testing, I'm gonna get the notification I can reach out to the patient and that's great. It's challenging when the testing was maybe ordered at an outside institution and the patient doesn't talk with that provider anymore, right? Then it becomes a little bit more tricky because I'm not gonna get that notification. I might ask the patient, let's partner on this, reach out to me every couple of years. I can go in, you know, there's a variant database called ClinVar where different labs can update their interpretation of different variants. So we can check that regularly. We can call the lab again and say, hey, when was the last time you looked at this variant classification? Can you redo the interpretation? See if there's been any change? So we always tell patients to check in with us every couple of years just in case there's some miscommunication, some lack of communication with the lab updating us or, you know, something was ordered by an outside institution, et cetera. But in the majority of cases, the ordering provider's gonna get notified and they should hopefully take the responsibility of reaching out to the patient and updating them so that they can get looped in with the right providers if it is something like an upgrade to a pathogenic or if it's a downgrade to a benign, you know, that's reassuring too, right? We just crossed one thing off of the differential. Do we have any other questions right now? Okay, our next question is, we've heard about various types of biopsies to diagnose hereditary amylidosis from a skin punch to a fat pad, nerve biopsy, cardiac biopsy. What has been your experience with ordering a biopsy for hereditary amylidosis? I'll start as a cardiologist. So I tend to be the contact point, at least now I'm not the one that's carrying the specimens to pathology. We've upgraded a little bit. But I always send an email. I just, I'm a big communicator about making sure because I've had two specimens that dink it to Mayo Clinic and I keep emailing, where's my results? Where's my results? It should be back in 21 days, my mass spec. And I go like, oh, oh, so I've learned to, I just have to stay, you know, set reminders on my phone. So it's very important to communicate and the most important thing is my cardiac, my interventionalists to make sure that I have the right biotomes because we don't always have everything. It's not like we do biopsies all the time or I'm at a, you know, community VA. So it's always good to plan, make sure everybody knows that we're one of the specimen, make sure it gets to my intake histology that they know, that if they do the conga red and I don't trust them, I actually do ask for a send out even on that. And then to make sure that the specimen gets to Mayo Clinic, that I get documentation of that. I just had again another one where it took way too long for me to get the results but I just keep hounding the head of pathology and the lab manager. Unfortunately, you know, that's still been my model but it is really important what your people wanna know. In the early days, we used to put some in fresh tissue to send to UCLA for immunofixation but now we just do the formalin fix and it's just so much easier. Make sure we get enough specimens and make sure the lab knows and then I get documentation that Mayo Clinic's received it. For me personally, anytime I'm even a little bit worried about amyloid from a tissue standpoint, I'll order either a fat aspirate or I've been starting to order a minor salivary gland biopsy more for a couple of reasons but primarily because it was discussed last year at this conference that it might be more sensitive. Shout out, Dr. Dev. That's Dr. McPhail. Dr. McPhail. So yeah, fat aspirate or minor salivary gland biopsy. I'm not a huge fan of doing a seronal nerve biopsy just because I think the yield is questionable and then I think to myself, what am I gonna do with a negative result? It's probably not gonna change my thinking if it's abnormal, that's helpful. Skin punch biopsy, it's just not clear to me how sensitive that truly is for detecting amyloid so I think it's a good test to confirm the presence of neuropathy in somebody with amyloid and then one can start therapy if they're not already on it. But I question how sensitive it is and whether it should be, probably shouldn't be guiding our decisions regarding somebody not having amyloid if the test is negative. And then the other thing, perhaps Dr. Rosenthal could talk about it, she may have more experience than most in the room, just a reminder that the flexor retinaculum can be biopsied during carpal tunnel surgery, the ligamentum flavum can be biopsied during lumbar spinal stenosis, decompression, and that can identify amyloid in those cases. So I don't know if Julie has any comments on that, sorry to put you on the hot seat. Okay, thank you. I think that dovetails Dr. Goodman off of something Dr. Butt mentioned earlier. I can't tell you the number of times I've been able to make the diagnosis of amyloid by calling my friend Dr. Butt and her partners in the lab when a patient had a prior prostate biopsy you heard from Dr. Warner this morning, this is a disease of the evening, specifically TTR, but these tissues are saved. So you'd be really surprised to know that you can find a tissue diagnosis and you're seeing the clinic for a completely different organ. So it's not uncommon, I will ask or reach out to a patient, what kind of surgeries have you had, and call that outside hospital. And as Dr. Butt alluded to, there is a number of steps in terms of sources of error to prepare these samples for looking for amyloid. Generally does your tech have to feel comfortable with the proper staining of congal red, but then you need an expert pathologist to interpret. So I too have seen a lot of false negative reads in the community where you just ask for a second opinion. So I do like to make a non-tissue diagnosis. And then the other thing I learned from this conference last year actually was the mass spec component. I've always been an institution where that is called standard as you heard from Dr. Butt. But a lot of our labs in the community and respect around the country do not send for mass spec. So I really strongly encourage you to reach out to your lab and ask them to send it because that will help you decide what kind of amyloid, since there are more than 30 different types and treatment matters and type of treatment matters. So you do have to ask. In terms of staining for the carpal tunnel or ligamentum, I've gotten a little bit away from those because sometimes I've noticed, yes, it's there, but they don't have systemic disease. So I don't know what to do with that. And there was a nice retrospective study called the Danish. It was done by the Danes, but I think the trial was called CAPTIS, so somebody can correct me. But they basically did retrospective review all these carpal tunnels. And 10 years later, I looked to see if they had cardiac involvement. And it was a very low yield from a cardiac. So I think I'm changing my thought process a little bit where it's sort of like the risk factor when I'm screening for someone with coronary disease. So they have diabetes, obesity, smoking. So if I see a heart failure patient and they have carpal tunnel, then I would say that's a risk factor for amyloid. But I'm kind of changing my thought process over the last five years about the sort of proactive ligamentum and carpal tunnel where I was doing that pretty routinely like three years ago, but it was because of that CAPTIS trial. So I wanna push the panel to a maybe challenging case. So a diabetic patient with neuropathy with no motor impairment and no obvious autonomic dysfunction with known hereditary ATTR and has lumbar spinal stenosis, has carpal tunnel. So my colleagues in neurology have told me this patient has a stable EMG, non-progressive EMG and does not appear to have any small fiber involvement. By their estimation. But I have a case of a known hereditary ATTR, cardiomyopathy. How can I be sure this patient doesn't have sort of neuropathy due to hereditary ATTR? So I already know they have amyloidosis. So is there a biopsy? I'm looking at you, Dr. Butt. Is there a biopsy that can tell me about the status of the nerves? Because I don't wanna know about amyloid. I wanna know if it's affecting the nerves. Yeah, so a biopsy that has nerves in it will give you that answer. It may sound like a glib answer, but I mean, honestly, the only way to definitively say that it's the amyloid that's affecting the nerve, you would need to see the amyloid, like see it affecting the nerve. But you can see nerves in skin-punch biopsies. You can see them in any number of specimens. Usually don't see them in endomyocardial biopsies, but I think that would be the only definitive way. I mean, if you already know they have ATTR, then typing would give you TTR, right? So that wouldn't necessarily be helpful. So it would just be like actually visualizing the amyloid around the nerve, which would require a nerve biopsy or a tissue that you feel very confident would show you some nerves, like such as skin biopsy. Why would you do that? As neurologists, it's the clinical clues that lead us on. So as neurologists, personally, I don't like to chase the test. I like to treat or chase the patient. Are they complaining of those orthostatic symptoms? Are they complaining of the GI intolerance? So the symptoms and the science is what I would then base my surveillance on and just keep on asking them in the history and the follow-up visits. And not so much putting them under the knife, if you will. Looking for neuropathy, neurology, like I said, is the art of show and tell. It will present itself to you and then you chase it down. I'm not sure what lack of motor involvement means. You're waiting until motor involvement develops to treat. So I'm not sure I would agree with that approach. So my neurology consultants feel that it's a diabetic neuropathy. And so how can I be sure? I don't know. I mean, that's the way I need to see the status of the nurse. So, yeah. The problem is even a negative biopsy isn't gonna tell you that it's not amyloid. It helps you if it's positive, but... Well, so the patient has known cardiomyopathy and is on treatment. And what does that mean? Stabilize. Some neuropathy, but not progressive and not severe. So the other considerations for neuropathy, what you think in diabetes, what you think about and what I would think about in terms of, okay, how much is amyloid, how much is diabetes? So you may know, I mean, a diabetic peripheral neuropathy will be present with other organ damage in diabetes. So they will have a retinopathy, they will have nephropathy. A neuropathy generally will be more significant the longer that the patient has diabetes. So those would all sort of factor in. But I don't personally think there's a super great way of knowing this. You certainly could easily do a skin punch biopsy, look at nerves there and look, do congo red staining. And if you see amyloid, that would suggest that they have a small fiber neuropathy that's due to amyloid and not related to diabetes. If the serial nerve is abnormal, you could certainly go after that. It's a fairly easy thing to do. But again, it comes back to, okay, it's helpful if it's abnormal, but if it's not, it doesn't. So I personally don't know of any other way to tease that out. Sue, who's in the second row, asked last year, brought up a point where, which I think is a good one, could we have other biomarkers being abnormal and amyloid that are neurologic in nature? Like I think you mentioned neurofilament, if I'm not mistaken, last year. Which I think is a great idea. It would be nice if we had other biomarkers that we could point to and amyloid and not necessarily rely on our biopsy to tell us that amyloid is present in the nerve because it is often missed. Yeah, and one other thing too I wanted to add. Certainly we can see it around nerves, but I'll say in my experience and as well as my search in the database after you brought this up with me a week or two ago, it's not something that we diagnose very often. It's not a very common biopsy diagnosis. So I would worry about making that part of your algorithm to chase that, to prove that it's around nerves. It makes more sense to just follow the clinical of how the patient's presenting. If you know they have amyloids, it's proven amyloid and they have clinical signs of neuropathy. It makes sense just to follow that rather than trying to chase it from a biopsy because I think you might end up where you don't want to. My question is how will you change your treatment? Well, there's a different treatment, right, for cardiomyopathy and neuropathy. So it's a big question. So I kind of needed clear answer. Well, and I'm in an institution. I wanted to ask other people how many times are people on a stabilizer for their cardiomyopathy and on a silencer for their neuropathy? In my healthcare system, the VA currently, we can't be giving dual treatments or not approved by the criteria for use because there hasn't been a clinical trial showing patients with hereditary, cardiac, amyloid and neuropathy that having both together is better than one or the other. So the evidence isn't there yet, though I know I've had patients who are getting dual managed care and sometimes they get their silencer through one healthcare system and they're coming to me for the stabilizer. So I'm kind of curious from the panelists about how many are using combined treatment if they have a, if they're hereditary with both the cardiomyopathy and the polyneuropathy. I think we at Mayo have a number of patients on both. For me personally, I think the silencers seem to clearly prevent progression. And I'm not sure of the benefit of combined therapy as Dr. Rosenthal mentioned earlier. I think we definitely need data on that. But I think most of our patients who are on combined therapy, they've been on both for quite some time, a number of years and I don't think any of us dare take them off of either of their therapies. Just a quick question to go back to what Julie talked about with the carpal tunnel releases and the spinal stenosis decompressions. You know, I guess from my standpoint, you know, I understand that there wasn't cardiomyopathy later on in that particular study, but I just wonder how many of those people went on to have neuropathy or non-cardiac sort of manifestations. And I guess the more provocative question for me is, is that for meds that as we're talking about now, even in combination, don't seem to be affecting patients adversely. What's the downside, right? Why not, you know, I mean, besides money. So, but the idea is that I don't think we have data for that either, right? I don't, and if the goal here is to try to prevent disease in the way that we've been talking about it and to never have patients actually develop any of the bad things that we're talking about, we have to at some point either have the data or have the belief that we're gonna be able to prevent things by having patients on treatment. It's gonna be a tough thing and I agree that the cost-effectiveness stuff is gonna be hard to answer, but, you know, what if the first sign of disease is in, you know, the ligamentum flavium or in the carpal, you know, in the carpal tunnels are released, right? So, I think, for me at least, the jury's still out. I might say that, I agree with Julie in the sense that what I might wanna do is create criteria to say that we will only biopsy these types of patients and then just have the red flags or whatnot, whether it's cardiomyopathy or whether it's any of the other red flag signs that we talked about, but having something to say that at least some proportion of these people, we will systematically biopsy and we saw the Mayo Clinic data too that systematic screening in some form is going to help us diagnose more of these patients. That's just, my personal thought, I wanted to hear from the panel. I'll just say that I had noticed less of those specimens looking for amyloid, but when we do get them, I always look. I think for those of us that see a lot of amyloid, I think I diagnosed amyloid three times last week. I'm always looking for amyloid, right, regardless of the specimen I'm looking at. It's always in the back of my mind, could this be amyloid, could there be amyloid in the background? And I often get cases from colleagues who are in other specialties, like in the prostate. They're like, yeah, so they have prostate cancer, but then this vessel looks a little funny. Could that be amyloid? I'm like, oh, yeah, that's what that is. So you have to always be looking for it. Perhaps a history of bilateral carpal tunnel plus your smartwatch showing reduced heart rate variability. So perhaps in the future, our smartwatches will be algorithmic or pick up accelerometer data that one's golf game isn't quite as good or something like that in that in combination with carpal tunnel, I don't know. Do we have any other questions? All right, we're shifting towards questions about what has worked well from a health care system's perspective, in your perceptions, what has worked well from a system's perspective when evaluating patients with hereditary amyloidosis with polyneuropathy? I think what really works well is having a team that has the interest, for example, cardiologists with interest in or looking into amyloidosis or sending them to a cardiologist or neurologist that may not have an interest, you may get turfed in the wrong direction. So I think it's really great to have a team around this. I do whatever Dr. Rosenthal says. So clone Dr. Rosenthal. Any other suggestions in terms of like health systems, how to improve? Yeah, you're expert in this and can help us through this, right? But anytime there's a disorder that crosses specialties and is multi-systemic, it's challenging. And so it really challenges the health care system. And it creates a lot of operational challenges. And for those of us who may not have a lot of time to address those operational challenges, it's especially difficult. But I think it's important at the institutional level to communicate with, I guess, to use the lingo, the key stakeholders in the different areas, saying an appointment office, the administrators across specialties, and to figure out how to break down those barriers. The problem, at least it may own, I'm sure a lot of other places, a lot of these different areas are very siloed. And so there's no mutual accountability for health care systems failures and operational failures. And it's a huge problem in amyloid. And I think the interest is important. So it's critical to assemble a team that you trust or you just have somebody like Dr. Rosenthal. And then for those of us who have administrators, we need to get the administrators involved in working together across specialties. And then hopefully you have whatever version of the appointment office on the front end able to get those patients into the right areas. What's been important for us from a multidisciplinary clinic standpoint with our hematology team, nephrology, cardiology, neurology, and I'm sure I'm missing one. Pathology, GI is having pre-visit planning. So we're asking questions before the patient comes trying to predict who they might need to see, what testing we need to do. So we have nursing involved in that. So that's just been our challenges at an institutional level. Yeah, I think if you're feeling like you're the person that's in this room alone and nobody else is here from your institution, then you're gonna have to be the leader. And that's where I found myself 10 years ago, first partnering with my nuclear imaging people to get an investment from them and make sure that we got our imaging program reaching out to my neurology. And they keep turning over and they're doing a million things and they're running a million things and they are not just amyloid. And I pay my coordinator to try to coordinate programs. So I support out of my own funding to try to have somebody help me coordinate all this because I have no institutional support. So I have to try to keep reaching out and we send emails and reminders when we're having our combined neurology and cardiology, I use Teams all the time. We have Microsoft Teams, so I'm teamzing with my hematology and I just lost my hematologist who was the vested person. So now I've got two new hematologists that I'm trying to get engaged about each patient. I have a nephrologist that I know she's the one that'll pay attention. Most of the others I don't pay any attention. So I reach out to her through Teams about when it's very patient specific like this patient's got proteinuria, da, da, da, da, what do you think? Should we do a biopsy? So I find I identified my team members. We used to do monthly conferences, but everybody's so busy and it was really hard to maintain the multidisciplinary meeting. It was good in the beginning because I at least got my heart failure colleagues and my imaging person is great, my nuclear imaging and I have three team members on nuclear and they're very good about, I'll actually email them, I go, your report's kind of sucky, can you fix it? Can you drop the heart counter? Can you use one, zero, one, two, three, please and redo it or relook at the images? If I don't trust one reader, I call the other reader and say I need this reread, I don't trust the reading. And it just takes a lot of leadership but the key thing is identify your team members. If you're not like at Mayo Clinic where you have amazing people and RNs and nurse practitioners and schedulers so but have your key, identify your key clinicians who are gonna be vested on a patient care level. So it sounds like persistence, it sounds like having a provider champion and Dr. Butt, you had mentioned that you just always think amyloid and so whether it's through a monthly teams meeting or whether it's telling someone to reinterpret a test or reorder a test, is there anything else you can do to help other healthcare providers think amyloid? That to consider this as this driving symptoms. From the perspective of pathology, I mean if we see it we get to diagnose it so that's kind of the fun part we get to be the final say on it. But I will say just thinking back to training for pathology residents, amyloid is one of those many things that anytime somebody has a case they show it to the trainees because they're unlikely to have seen it before and the more times you see it the more likely you aren't actually recognizing the next time you find it. Like I said through the consult servants and things like that it's still very clear that it's often missed in the community for people who don't have the expertise in it but I think training is key. I think that's probably key from my perspective. So I would just add something to the system. So for any of you who are feeling like you're alone in this room and you don't have this excellent team I'm privileged to work with some of the members on this panel. I think the key is just asking you to ask the question could this be amyloid but then recognizing you should leverage the community to help you because if you're in a solo cardiology practice or nephrology practice or heme you might not have these other champions to help guide you through the diagnosis. So if you don't know who your champions are there's some really nice tools out there online. If you go to things like the amyloid support group website you'll find sort of where your centers of quote unquote excellence are even though that's not a formal Medicare designation. So you can kind of reach out to who your champions are in the community. In addition I believe it is through online. I think they are here. Someone can correct me but they actually have a website to kind of guide you where your providers are. So if you just type in your own zip code they can tell you who's caring and managing for amyloid patients. So if you're questioning this and you don't have an amyloid expert at your institution you might be able to find them in your neighborhood so to speak because it is quite complex as Dr. Dev highlighted and you're not expected to navigate these waters by yourself. I have a follow up question to something that had been presented earlier as well as something that Dr. Goodman had mentioned with the use of your own wearable as data right for whether or not you're exhibiting symptoms for amyloid, amyloidosis. Have any of you had any experience in your healthcare systems either using AI for electronic health records or using a patient using a wearable to kind of help with the early detection of amyloidosis? Or is that up and coming? Well I'm partnering currently with Dr. Dave and using the VA database so we call it the CDW and we've had what's called a heart failure dashboard that was initially pilot for GDMT to identify one of my colleagues was working on getting notifications to providers, hey this patient isn't on the right therapy but with Sandesh's leadership we've modified the dashboard and my colleague Nishant is also modifying this dashboard so it's real time interface with your database. Every time a patient gets an echo my database updates and it pulls for me the way they refined it. Right now we're just looking at at risk African-Americans and the dashboard comes up with the highest Davey's risk, pulls all the echo data so I have my relative wall thickness, my posterior septum and it gives me the last three echoes to look at so all of it's on the dashboard right away. I have the NT Pro, BNP, BNP, troponin levels, hospitalization, I have their medications, I have their upcoming visits so we've already started now notifying providers, I have a template saying this patient's been identified at high risk and linked them to our ordering menu so we're starting to try to leverage that right now to at least identify if we're working at risk black veterans. I could see at some point wearable biometrics having a role in this space, reduced heart rate variability and maybe it might be one on autonomic testing in amyloid patients whether it's hereditary or wild type almost all of them have reduced heart rate variability it's an early feature of the disease so I could see that playing some role now it's obviously not specific for amyloid but perhaps there could be other parameters on biometric data that one might see that we're not aware of at this point. Stride length plus something else, I don't know but I think definitely there's a future in that, I think the other thing that we in neurology need to do better at is with neurophysiology might there be ways of predicting in those carpal tunnel cases who's actually going to go on and develop hereditary amyloid. I don't think that was on our list of projects to do but I'm not sure if that's gonna happen but that would also be interesting. There might be some ways of predicting that so I do think there's some opportunities here. Just make a comment about the dashboard that we're working on and sort of a parallel effort to what Sundesh is doing. I think at the end of the day the reason we created the dashboard was is that as we've talked about a lot today putting together all of these disparate pieces of information is not really possible for a single clinician to do in a single time limited visit. All of us in this room are thinking amyloid, there are a lot of other people who are starting to think about it but the reality is that finding these things in real time is actually still very difficult even for those of us who are paying attention. So part of the dashboard that we're working on is to also put the information not only gather the information but also to just distill it down to a single, this patient is at risk of amyloid and has not been tested or this patient has been diagnosed with amyloid. So one of the big sort of things that we're trying to figure out is what is the denominator at any given institution or health system, right? I mean, I don't know, maybe somebody else in the room has already figured this out but what is the total population of people that we have to put through the algorithms that we just described today? I don't think anybody knows that in any large health system and so that's I think the first challenge is how big truly is the problem and then how do we get people to go through the algorithm in a way that makes sense. So that's kind of the point of what Sandesh and I are doing and hopefully, at least in the VA system we've got something that's working at least in Providence and hopefully soon in Nashville so there's more to come with that. Do we have any other questions right now? All right, this kind of piggybacks off of that last question as to what can we do better to improve the early diagnosis of hereditary amyloidosis. If there are any additional solutions then what was recommended by having teams and groups who were thinking of amyloidosis and champions and the use of wearables that could potentially be useful in detecting early symptoms. Can you think of anything else that you'd make for recommendation for enhancing the early diagnosis of hereditary amyloidosis? I feel a key vital sign that often gets missed with patients with lightheadedness or neuropathy is the checking of orthostatics and just very little, it's not, it's a big test but I've often seen that I think just getting those vitals, just getting the clinically when you suspect, then check and then you shall find. So I think we seek and you shall find kind of thing. I think that's just a one way small point that I would really like everyone to have a take home point if at all. It's simple, doable, cheap, yet not done many, many, many times. So it's very interesting, I make sure we do orthostatic but I'm kind of curious how you guys do in the clinic. I have my, the typical training is that you're supposed to do supine sitting, standing, wait three minutes and of course we also don't have an EKG on the person so it's very hard for us to really see what their heart rate response is and of course when I'm screening for POTS or other things and I really wish I hadn't monitored my nurses in the clinic, they do an okay job, they just do sitting, standing. I think they do wait three minutes but as I, when I have a symptomatic patient they don't wait three minutes to pass out. They don't wait three minutes to feel bad. So in the clinic I prefer to, when I have the patient come in I'll actually have them lay down and I'll chat with them and then I'll do supine to standing but I do it serially so with the automated cuff so I wanna see immediately what happens to blood pressure but the problem is the heart rate I don't, without an EKG sometimes I can use the pulse ox on the contral outer hand to see what their heart rate's doing because I wanna know what their autonomic response is so like I said I keep telling people I don't hand my stethoscope to the nurse to listen to the heart for me just while you're talking do your orthostatics and observe the patient. I think super important to do supine to do supine and just as a reminder you wanna have them supine for at least five minutes and then totally agree with checking an immediate standing I don't do setting I check an immediate standing blood pressure and that's hugely important because if you look at tilt table studies on these patients it's very common to have an initial drop in blood pressure they have early orthostatic hypotension and then they'll recover a bit and then if they stay up longer and then sometimes they'll start dropping back down again and with orthostatic hypotension so picking up on that early orthostatic hypotension is important and it provides you a clue that hey I should probably keep this patient up longer than just three minutes so to meet criteria for orthostatic hypotension you have to have patient up for three minutes and check it three minutes and then orthostatic hypotension should be sustained but remember that the orthostatic hypotension can get progressively worse as a person's upright so I think it's hugely important and there's a question you were really asking about is how to automate it that's one thing we don't have automated in our dashboard is orthostatics we can get a blood pressure but there's not a great way that that's documented so but I think it's going to be the automated risk stratifications can be critical just like we have clinical reminders I think in the future healthcare systems are going to want to have where their data is pulled and one of the things that we're having a challenge is getting the EKG voltage data imported there is a lot of data again Mayo Clinic great leaders on this and predicting other factors but if we can get just the wall thickness and peak voltage to other clues I think clinical reminders I think it's going to be something that AI can bring to clinicians to say this patient looks suspicious I think from a general health systems standpoint the other thing is is having your referral sources set up for those not in the same institution knowing who you're going to send a patient to like they shouldn't be waiting three, six or more months to get in with the clinic ideally so ideally you have those other specialties that are part of your team even if they're not in your institution hopefully those pipelines are set up so that there's always such delay in these patients care and if time is indeed nerve or myocardium whatever we're talking about I think it would be nice to see us cutting down on these times to getting a diagnosis or certainly times to getting a treatment started Thank you, those are all the questions that we have for this panel does anyone else have any other questions for the panel? We still have cups if you guys want to speak up I can give you one So I'm told bilateral carpal tunnel is a relatively common finding in diabetics so we get excited as cardiologists because we're thinking amylate but when I ask the neurologists they're like eh so tell me more about like what does carpal tunnel indicate for you and I know you mentioned looking for autonomic symptoms but how often do you see bilateral carpal tunnel? Bilateral carpal tunnel is common but the thing with amyloid is it's more symmetric so when you do your nerve conduction studies in EMG on an amyloid patient with carpal tunnel the sensory and motor studies will be involved to a similar degree now the patient may have worse symptoms on one hand but typically they'll be symptomatic bilaterally and remember to make a diagnosis of carpal tunnel a person has to have symptoms because it's a syndrome diabetics will often have median neuropathies at the wrist which is what carpal tunnel is but they may not have symptoms they often don't in fact so so I think the key just from what I've seen other people can weigh in is that it's more symmetric so normally you have a say a normal person coming off the street who doesn't have amyloid it's not uncommon to see bilateral carpal tunnel on an EMG but one side is typically much more involved than the other and but in carpal tunnel it doesn't look like that it's more symmetric at least that's my experience any other questions, parting remarks? seeing none I just wanna say thank you to our panelists for sharing your time and expertise