 Next we are going to bring up Dr. Brett Goodman from the Mayo Clinic. Brett Goodman, excuse me, from the Mayo Clinic will be talking about neurological presentations of ATTR. I promise to be a friendly neurologist. It's a privilege to be here part of the discussion today. My task is to focus on TTR and neurology. If I could break it down to maybe three take-home points. Really, I would have three take-home points. Number one would be this really does begin with carpal tunnel syndrome and we need to figure out how to identify patients with carpal tunnel who are going to have or have amyloid. Second, unfortunately we need to rely on neurophysiologic testing when evaluating and caring for these patients. I'll talk a bit more about that. And third, as has been mentioned earlier, we need to get treatment started as early as possible. Neurological improvement or at least stabilization that really relies on early diagnosis. And so those are my three main points today. With amyloid, particularly with TTR, this can do about anything to the peripheral nervous system and we've seen that, including carpal tunnel, radiculopathy, spinal stenosis, neuropathy, autonomic neuropathy. It truly can do about anything to the autonomic nervous system. Important to recognize it may be the first part of the body to be involved if you consider the median nerve running through the carpal tunnel to be a neurological symptom or sign, I would. Important to recognize that once there is significant neurological impairment, it may be difficult or impossible to reverse, to significantly reverse neurological impairment. So we need to get these folks diagnosed quickly, early, and get them on treatment. And then many of the patients need symptomatic treatment as well. The different forms of neurological impairment may provide clues to the different forms of amyloid, or perhaps even the different genetic subtype. So the different neurological manifestations, the most common that we see would be carpal tunnel, which you could consider orthopedic or neurological. Lumbar spinal stenosis, peripheral neuropathy, autonomic neuropathy. These are the most common things that we see. Our tools are the history, of course, our neurological examination. Most of these patients really do require neurophysiologic testing. They need nerve conduction studies and EMG to make these differentiations. And I'll talk a little bit about why here in a second. I would advocate for autonomic testing. We have a busy autonomic lab at Mayo. And I've cared for a number of these patients over the years. It can be very difficult to differentiate autonomic impairment in these patients from cardiac impairment. And sometimes, particularly if they're on antihypertensives, et cetera. So what's medication effect? What's cardiac? What's the result of an autonomic neuropathy? Autonomic testing can really help with that. We do skin punch biopsies. And many of these patients, and the role of that is to establish whether a small fiber neuropathy is present. But that skin can also be stained for amyloid. So that can be helpful, particularly in the pre-symptomatic or maybe minimally symptomatic patients in whom you're considering whether to start, let's say, silence or treatment on. Lumbar MRI, of course, is important in diagnosing lumbar spinal stenosis. But remember, after a couple of decades, nobody has a normal lumbar MRI. So that needs to be put together with the clinical story and then, of course, genetic testing. So as a neurologist, we consider these different forms of amyloid, as has been discussed. I would like to highlight, though, this study out of Mayo Clinic Rochester, some of the differences between what they called at the time, this was a number of years ago, familial amyloid versus AL amyloid. And you can see here in their retrospective study, peripheral neuropathy was much more common at presentation in the familial amyloid patients as opposed to AL amyloid patients. So important to recognize that. And then autonomic neuropathy, also much more common during the course of illness, familial amyloid, of course, this was largely pretreatment. So these definitely differences clinically between these two forms of amyloid just generally. So I find wild-type amyloid a challenge. Oftentimes, the patients are older. They may have a number of different medical comorbidities. Most of the patients, or really all of the patients that I see with wild-type amyloid on the neurological side of things have carpal tunnel and spinal stenosis. I can't think of a single patient over at least the last four or five years who hasn't had that history. So that's very typical. It can be very difficult to differentiate a neuropathy from spinal stenosis. I'll talk about that in a moment. And while it's not clearly established, I do think that these wild-type amyloid cases can develop a very mild neuropathy, although again, that can be very difficult to distinguish from lumbar spinal stenosis. If they develop an autonomic neuropathy, it's subclinical, meaning they don't have symptoms, but they may have some abnormalities on autonomic testing. Carpal tunnel syndrome, this is hugely important for us to recognize, and I think we spoke a little bit earlier about healthcare systems and how we might do a better job diagnosing earlier in someone's course. The important thing, I think, with carpal tunnel is this precedes the development of other things by sometimes many years. It can be five or ten years. So we really have to ask, all right, did you have carpal tunnel in time's pass? Did you have numbness tingling in your hands? Did you have surgery for carpal tunnel? It may not be concurrent with their current cardiac evaluation that a person is getting worked up for. So remember with carpal tunnel, it's numbness tingling in the hands, it may be pain, not everybody has pain, and it's often weakness. The helpful clue, possibly, is that it's bilateral, but it's also typically fairly symmetric. The problem is that carpal tunnel is so common and it's often bilateral. If we do an EMG on somebody who comes in with carpal tunnel in their right hand, their chance of having it in the left is upwards of 80%. So that bilaterality is helpful, but in amyloid it's often symmetric. The symptoms are often the same in both hands, but one of the things that we certainly need to be working on is perhaps what cardiology has done in looking at perhaps some AI techniques for identifying possible clues to carpal tunnel. What are the signatures for amyloid on EMG testing, for example? Lumbar spinal stenosis also extremely common, often precedes the development of other neurological issues, cardiac issues. Classically, this is back-and-leg pain that's present when upright, with ambulation. That gets better if somebody leans forward, but not all patients have that complaint. They may just complain of numbness in the legs or feet, which can make this very difficult to distinguish from neuropathy. So to make this diagnosis, we really need lumbar MRI and then an EMG to try to differentiate between neuropathy and spinal stenosis. The other thing that I look for clinically is asymmetry. Typically in the lower limbs, neuropathy related to amyloid is symmetric. So spinal stenosis is going to be any sensory symptoms related to spinal stenosis that are fixed, that are present all of the time, that aren't positional, are going to be asymmetric. They'll be worse on the right foot, worse on the left foot, worse comparing side to side in the legs. So those can be clues to differentiating between lumbar spinal stenosis and amyloid. So it is important to make that distinction. Is this multiple lumbosacral radiculopathy secondary to amyloid, or is this a peripheral neuropathy? So important to make that distinction. And the amyloid, what it does is it infiltrates the ligamentum flavum, so it results in narrowing of the spinal canal. I should have mentioned earlier with carpal tunnel, the amyloid infiltrates the flexor retinaculum within the carpal tunnel, and that's why people experience these issues. So peripheral neuropathy and amyloid. Now with amyloid putting carpal tunnel aside, amyloid involves the small fiber nerves first. So these are the nerves that send in pain and temperature information into the body. That's in distinction to the large fiber nerves which send in light touch, joint position sense, vibration. These are the nerves that help us out with balance. The small fiber nerves are the nerves that send in pain and temperature information. Small fiber nerves are involved first in amyloid. So if I'm seeing somebody with burning in the feet, they may actually have a normal EMG, they may have a small fiber neuropathy that's early due to amyloid. The only way I would diagnose that is with a skin punch biopsy. So important to recognize that somebody can have a normal EMG very early in the course because they have a small fiber neuropathy. So important to recognize that. Typically then if the amyloid progresses it will involve the large fiber nerves that will affect sensation more generally and then affect the nerves to the muscles and cause weakness in the legs. This is typically, it will start in the feet and then ascend. The general rule of thumb for neuropathy is that you expect the hands to be involved once the sensation gets to the knees. In amyloid it would be common to hear that history of carpal tunnel first and their hands may stay numb in spite of having carpal tunnel surgery five to ten years ago. So this is what you're looking for historically with a neuropathy with amyloid. Important to do an EMG again to distinguish electrically with EMG for us as neurologists to distinguish that from spinal stenosis can sometimes be difficult. And again remember the epidermal skin punch biopsy may play a very important role increasingly for us as we decide who to start treatment on. In my opinion it should be started on patients sooner rather than later. So I've mentioned difficult sometimes to distinguish between these different clinical syndromes. Autonomic neuropathy can be difficult to distinguish from cardiac related impairments. We're looking for a history of orthostatic intolerance so basically any symptom that's present when upright that gets better when somebody sits or lays down is a potential autonomic symptom. So typically that's postural lightheadedness. They may have syncope as a result of orthostatic hypotension or near syncope. They may have gastrointestinal disc motility. They may report heat intolerance. So important to do if not formal tilt table or autonomic testing postural vital signs. So I would have somebody supine for five minutes measure their heart rate and blood pressure then stand them up take immediate heart rate and blood pressure and then you test them at three minutes. So immediate and then at three minutes. Three minutes if they have a decrease in blood pressure without any significant change in heart rate then that's typically compatible with neurogenic orthostatic hypotension. Important to do that. Sometimes it can be difficult to differentiate between those who are on antihypertensive medications. Most of the time patients with orthostatic hypotension will have a drop in both systolic and diastolic blood pressure with standing so that can be helpful. But ideally these patients really I would encourage formal autonomic testing because sometimes quite often we will pick up things that you might not have necessarily expected based upon your history. And I would also say that these autonomic symptoms the orthostatic intolerance they don't correlate super well with what we find on autonomic testing. So I would advocate for autonomic testing particularly if you're wondering all right what systems are involved with this disorder. And then also of course think about GI motility testing and those who may have symptoms of abdominal bloating early satiety which is feeling like you fill up more quickly than you ought to when you're eating a meal. Many of these patients may develop a horrible diarrhea which may be due to amyloid infiltration of the GI system or small intestinal bacterial overgrowth or result from overflow from constipation. So this is a very significant problem if it develops it can be very difficult to treat. As a neurologist if I hear a history of peripheral neuropathy plus orthostatic hypotension and they don't have diabetes I'm doing genetic screening for TTR amyloid after doing serum immunofixation working up AL amyloid. So and then as a neurologist if I have somebody with an antecedent history of carpal tunnel syndrome and a neuropathy and I don't find some other cause of neuropathy I'm doing genetic screening for TTR amyloid the stakes are high we have to make this diagnosis and ideally we have to make this diagnosis early. So this was I just wanted to show this case we just had this come through one of our autonomic labs just a few weeks ago and I think it emphasizes what I'm suggesting which is the benefits or importance of early treatment. This is a 44 year old female she was diagnosed with TTR amyloid her dad had died after a liver transplant done for amyloid. She reported sensory symptoms and also postural lightheadedness which was present when standing still. She had actually quite an unremarkable neurological examination normal strength, normal reflexes just very mild sensory loss on her feet and her cardiac testing was unremarkable her EMG was kind of borderline abnormal her autonomic testing which I'll show in a second was abnormal. She was started on patissiran infusions due to the abnormal autonomic testing and the early signs of neuropathy this probably hopefully this comes across okay I included EMG in upper left which was only mildly abnormal heart stuff was unremarkable and here's her autonomic testing up top is sweating and so she had abnormal sweating up top those are the I don't know if I have a cursor here anyhow up top is abnormal sweating we put capsules on the skin Iontaferis acetylcholine and make people sweat at four sites forearm proximal leg, distal leg and foot this is one of the ways we diagnose an autonomic neuropathy and so she had abnormal sweating on the foot which would be suggestive of a peripheral neuropathy or an autonomic neuropathy in the middle is cardiovagal testing so we ask people to breathe at six breaths per minute and then measure how much heart rate variability they have we have normal values for that and that was reduced so these are very typical early signs of an autonomic neuropathy and then her tilt table is down below and you can see that she supine was 116 over 76 with heart rate of what is that, 51 and then so she drops her pressure a bit with tilt table testing so she was diagnosed with an autonomic neuropathy this in conjunction with her exam and the borderline abnormal EMG prompted the initiation of ptesiran and so we just recently got her autonomic redid or autonomic testing this is about a year and a half to two years ish and so her heart rate variability has improved, her sweating has improved and her tilt table study it ain't perfect but I would argue that it's better so I think an important demonstration of the peripheral nervous system can regenerate if you catch disease early enough and you treat it so I think it's super important and I think this really shows also the value of doing testing and allowing that to sort of factor into decision making in some of these cases so thank you very much, appreciate being here