 Hello everyone, my name is Saad Kuba from University of Arizona, Banner Tucson. I have the very nice task of introducing everyone. First we'll start off by introducing Dr. Brent Goodman. Dr. Brent Goodman is a board certified in neuromuscular medicine and neurology. He previously served as the practice chair, chair of neuromuscular neurology and director of the autonomic laboratories and autonomic program at Mayo Clinic. As an autonomic and neuromuscular neurology specialist, Dr. Goodman's clinical research efforts are focused on neurobiology, autonomic disorders and neuromuscular disorders. He's one of the country's top experts and has lectured nationally and internationally on various neuromuscular disorders, neurophysiology, autoimmune, neurology, shogren's disease and disorders of the autonomic nervous system, and he has won multiple awards for his research in patient care and research. Well, it's a privilege to be here, and thanks for inviting an urologist to what, amongst a bunch of cardiologists. So thanks. It's good to be here. I'm going to start with a case and end with a case. Title of this one is time is nerve, which I think we need to remember, right? We're in an awesome age of therapeutics, and I would advocate for starting them early and not letting patients develop like this one did. This was a 72-year-old man. I saw him a while ago, I think at least 14 years ago. He had been diagnosed with CIDP at a history of weakness and sensory loss, and for those unfamiliar with the term CIDP, it's chronic inflammatory, demyelinating, poly ridiculous neuropathy. It's an acquired, immune-mediated, demyelinating condition of nerves. So it's a chronic form of Gamberay syndrome if you're familiar with that. So initially presented with burning pains in his hands and his feet. He developed symptoms which ascended upwards, affected his arms. He developed marked gait unsteadiness and postural lightheadedness without syncope. I'm going to say it multiple times. This was CIDP do not develop orthostatic hypotension, red flag. So he had multiple evaluations prior to ours. A number of biopsies had been diagnosed with CIDP at a serial nerve biopsy which was reviewed at this large university in an adjacent state. There was no congo red staining, including review in our neuropathology lab. He was put on IVIG, put on rituximab symptoms continued to worsen. Maybe a family history of something, maybe MS, maybe something else. He had orthostatic hypotension on examination. Patients with CIDP do not develop orthostatic hypotension. Normal cranial nerves, he was weak in both upper and lower limbs, both distally and proximally, so horribly affected. He was actually in a wheelchair when he came. His reflexes were absent. Sensory examination. He had horrible sensory impairment, so he had a severe sensory ataxia. What that means is you lose your proprioception and you see a difficulty even standing. Even this gentleman, even when sitting on the bench, if he closed his eyes, he had a hard time staying seated upright. So horrible sensory ataxia. His laboratory studies were unremarkable. Here's his EMG. The zeroes are really bad, so he has zeroes everywhere, so no responses in his peripheral nerves. It doesn't look like CIDP. Here's his autonomic testing at horrible orthostatic hypotension, dropped systolic 80 points. Patients with CIDP do not develop orthostatic hypotension. This is his autonomic testing, which up top, the top tracing, shows a drop in blood pressure without any increase in heart rates in green, and so severe orthostatic hypotension. He had a fat aspirate, which was unremarkable. We reviewed his outside serial nerve biopsy. I did a second one. I wouldn't do a second serial nerve biopsy today, but this was 14 years ago or so. I ordered an echo. I was suspicious of amyloid when I saw him, and the echo was suspicious. We did an endomyocardial biopsy. He had amyloid on biopsy of the heart. We then did gene testing. These days, I would have done gene testing right after seeing him in the clinic. I wouldn't have ordered a serial nerve biopsy. His genetic testing showed transthyretin, interestingly. He came from a little area in Italy. At the time, this mutation had been reported in only one family in a nearby area in this little spot in Italy. Probably those family members that had supposedly been diagnosed with MS probably had amyloid. Take home points on this case. Tissue can be misleading, particularly serial nerve biopsy if it's negative. It's often negative in transthyretin amyloid. Remember that. Neuropathy plus orthostatic hypotension is amyloid until proven otherwise. Neuropathy plus orthostatic hypotension is amyloid until proven otherwise. CIDP, I think I've mentioned this a few times, CIDP does not cause orthostatic hypotension. If you read articles, they suggest that CIDP can be confused with amyloid. It really shouldn't. Historic dysfunction, that's significant. Doesn't happen in CIDP. So general considerations with respect to the nervous system. Nervous system involvement, it may be the first system to be involved. Obviously, we've talked a lot about the heart and we'll continue to do so. But remember that neurologically the peripheral nerves may be involved first. Or most patients, almost every patient I've ever seen with amyloid has a history of carpal tunnel. The carpal tunnel is bilateral. It's usually symmetric. Importantly, once there is significant neurological impairment, it's at least currently, even with the silencers, irreversible. So I would advocate strongly for early treatment in these patients. Many of the patients, if we don't catch them in time, they require symptomatic treatment. I think a question for us is whether particular mutations will look a certain way, phenotypically. Will they involve the autonomic nervous system? Will they involve the somatic peripheral nervous system, et cetera? I don't think we know that at this point. So what are the potential neurological manifestations? I personally consider carpal tunnel syndrome a neurological manifestation, but I also do EMG for a living. Lumbar spinal stenosis, we see that in many or most patients. Of course, the peripheral neuropathy and then autonomic neuropathy. So what are our tools? Of course, the history and the examination, nerve conduction studies, needle EMG, autonomic testing. We do autonomic testing. And on all our patients, suspected of having peripheral nerve or autonomic symptoms. One can consider doing epidermal nerve punch biopsy, looking for small fiber neuropathy. You can also do congo red staining on epidermal skin punch biopsy. Of course, lumbar MRI and genetic testing. I would advocate for genetic testing very early on. If I have an individual with a peripheral neuropathy and any significant amount of autonomic dysfunction, I almost always do genetic testing for transthyretin. So in neurology, we of course see a number of different types of amyloid. Probably the most common type that I'm seeing at this point is wild type, which can be associated with a mild, very, very, very mild peripheral neuropathy, some autonomic dysfunction. But usually, the autonomic dysfunction is subclinical and wild type amyloid, meaning we can see abnormalities on testing, but patients don't typically have symptoms. So ale amyloid, with respect to the nervous system, can look different than familial amyloid. And of course, it's more likely to have other systems involved. With transthyretin amyloid, again, we're looking for peripheral neuropathy, looking for autonomic dysfunction, and then you almost always hear that history of carpal tunnel, which often predates the history of significant autonomic dysfunction. With wild type amyloid, all of these patients have spine disease, and it's not just lumbar spinal stenosis. They often have cervical spinal stenosis too, so they get very complicated as they get older, and they're difficult to tease out neurologically. I'll talk a bit in a minute, I think, about how you tease out lumbar spinal stenosis type symptoms from peripheral neuropathy. It can be very tough, and it can be very tough in our EMG lab to sort that out. Patients with wild type, again, they don't typically, it would be unusual for a patient with wild type to develop orthostatic hypotension in my experience. So carpal tunnel and amyloid, as I mentioned earlier, often predates other amyloid manifestations, and this is an awesome thing in neurology to have something predate the development of more significant neurological issues like peripheral and autonomic neuropathies, but typically carpal tunnel and amyloid is symmetric. It's usually bilateral, of course, diagnosed by EMG. Patients with amyloid can also develop ulnar neuropathies as well. So with respect to lumbar spinal stenosis, so really the clue here clinically is patients will report sensory symptoms with lumbar spinal stenosis, but they'll be asymmetric. So that's your clue. So patients will say, yeah, I've got some back pain. It may be ridiculous. It may be present when they walk, pain down into the legs. They'll often have sensory symptoms, but the sensory symptoms will be asymmetric. So it'll be mostly in one foot, or they'll have it in a foot and a leg and not much in the other side, and that would be unusual for a peripheral neuropathy, so that's some clinical clues to help sort out, aside from EMG testing, which should be helpful in distinguishing peripheral neuropathy from lumbar spinal stenosis. But if somebody has amyloid and a significant peripheral neuropathy, it would be much more likely to be TTR than wild type amyloid if their neuropathy is due to amyloid. With respect to peripheral neuropathy and amyloid, amyloid affects small fiber nerves first, so the small fiber nerves are the nerves that send in information regarding pain and temperature. The small fiber nerves are also autonomic nerves. So these are the first nerves to be affected in amyloid, and so that's why patients will have oftentimes burning neuropathic type pain. That's due to involvement of those small fiber nerves, which happens first. So patients will otherwise present with sensory symptoms, and then as the neuropathy progresses, they can develop weakness and imbalance, and hopefully these days in the area of therapeutics, that's not going to happen. This is tough when you have patients with both neuropathy, lumbar spinal stenosis, and amyloid sorting out what's due to what. I think this is one of the huge challenges in amyloid patients. I mentioned earlier, you're really looking for asymmetries, and you use your MRI and your EMG additionally as tools to help distinguish what's what in these patients. With respect to autonomic neuropathy and amyloid, this can be tough to differentiate. What's autonomic from, say, symptoms being used to treat cardiac issues and then just cardiac involvement in and of itself, but you're looking for symptoms of orthostatic intolerance. So these are symptoms that are present when upright, they get better or resolve when you sit or lay down. It's orthostatic intolerance, also history of syncope or near syncope. The tricky thing also is many of these patients, particularly with transthyretin amyloid, they may have had autonomic symptoms for so long that they may not actually recognize them until we do autonomic testing on the patients. And then we say, hey, did you know that you dropped your blood pressure? And they say, yeah, actually, I've been thinking about it. I do have more lightheadedness than what I indicated when we first met. Enteric neuropathy, amyloid involvement of the gut is horrible. We shouldn't let it happen. It's impossible to treat and many of us who've cared for amyloid patients for a long time, particularly in the area prior to treatment. These patients haunt me because it's awful. The diarrhea is awful. And there's not a lot that you can do about it. So we should keep it from happening. Patients can present with heat intolerance. So they basically lose the ability to sweat due to loss of those small fiber nerves and so they'll complain of heat intolerance. GI dysmotility, they may complain of nausea. They have early satiety. So you ask them, do you feel like you fill up more quickly than you ought to when you're eating a meal? And that would suggest that they may have an impairment in small or in gastric emptying. They may have gastroparesis. Patients though may have an enteric neuropathy that affects the lower GI tract, including the small intestine, which is under-recognized in patients with autonomic neuropathy and that can also mimic gastroparesis but also be associated with bloating and diarrhea. So the importance of early treatment, this was an interesting case. This 44 year old female, she had a family history of TTR amyloid, her father had a liver transplant, died afterwards. And the patients came to us reporting peristegias in her calves and feet. She had postural lightheadedness when standing still. And really her neurological examination was quite unremarkable. You had to look pretty carefully to find any evidence on exam of a neuropathy. But she did have symptoms suggestive of a neuropathy. In addition to the orthostatic intolerance, suggesting autonomic involvement. So she probably saw Dr. Rosenthal. She had testing, EMG was just barely abnormal. Her autonomic testing, which I think I show in a second here, was abnormal. And yes, as a neurologist, we sometimes do treat patients. And so we initiated the patient on silencer treatment. And what I wanted to demonstrate, I'll just first show the studies. The EMG was minimally abnormal, cardiac testing, not all that unremarkable. And then here's her autonomic testing. So she doesn't sweat well in the foot. We put little capsules on the skin at four spots on the foot, distal leg, proximal leg and forearm. Iontaferis acetylcholine measures sweat output. And so the nerves going to the sweat gland and the distal in the foot are impaired. That'd be fairly typical of what we might see with an amyloid autonomic neuropathy. And then she had a cardio-vagal impairment as well. Which, so reduced heart rate variability with deep breathing. We have patients breathe at six breaths per minute and measure heart rate variability that was reduced. And then she had a postural drop in blood pressure, as you can see here. It wasn't horrible, but significant. And this is after treatment, so we were able to actually demonstrate that in this case of a mild autonomic neuropathy, that we can actually improve the autonomic system. So you can see her sweating went from 0.06 to 0.23. So sweating to the foot improved. Heart rate variability still abnormal, but better than it was. And you can see blood pressures were significantly better. She was actually fairly hypotensive at times. And so this was early treatment. Some people may not have treated this individual because the examination was not all that abnormal. The EMG was not all that abnormal. But she had significant autonomic involvement. The autonomic testing was abnormal. And I would advocate strongly for early treatment. Early treatment, even in the presence of neurological, peripheral nerve, autonomic dysfunction. We may see improvement in these cases. In conclusion, neurological complications, common. Maybe early. They can be very heterogeneous. They vary in severity. Multiple systems can be involved. Perforal somatic nerves, peripheral autonomic nerves, enteric nervous system, carpal tunnel, preceding the neurological involvement. Neurological testing is very helpful, particularly autonomic testing. Shout out to autonomic testing. And I would advocate strongly for early treatment. We shouldn't let patients get as far progressed as the first case that I presented. Thank you.