Chapters Transcript Video POTS (Postural Orthostatic Tachycardia Syndrome) — Diagnoses and Treatment Tae Chung, M.D., presents at the Johns Hopkins Department of PM&R’s Grand Rounds on August 20, 2019. Just wanna make sure. Um All right, everybody, sorry, we're a little more snug today. We got ousted out of our usual space. So um we will filter in more chairs if needed. Um Again, the uh today is August 20th 2019 and welcome to the Johns Hopkins um Department of Physical Medicine and Rehabilitation grand rounds. Um for those of you uh attending remotely, um and who would like to record your attendance and get CME credit the uh number to text and the phone number is on the screen right now. Um So take a few moments to do that if you have not already, if you uh for those who, well, you're not going to hear this, but if you arrive late, they usually people find me anyway. Um So today our keynote speaker is Doctor Tang. Uh he's a part of our Department of Physical Medicine and Rehabilitation here at Johns Hopkins. He is a neuromuscular medicine specialist. Um and he is a part of both our pots program, um which he's gonna talk about more today as well as uh the myositis um program here. Um I guess without further ado let you start your chat and, uh, hopefully we have no more technical Christian Center. All right. So, uh, for those who don't know me or not yet, uh, met me yet. My name is Tai Chong. Um, I'm a neuromuscular specialist and I run the pots program and, uh, I guess some of you probably heard about pots and I see some residents who work with me in my clinic, so they saw some pots patients. So today I'm gonna talk about many pots for sure. And I'm trying to kind of uh go through all the slides as fast as I can. I think I have a 1.5 hour, but I like to have at least probably 30 minutes or 15 to 30 minutes for kind of discussion. Um uh I like this to be a little more uh interactive. Uh If you have any burning questions, you can interrupt me in the me too. But now you can um wait until at the end to for the for, for the discussion. Uh Nothing to disclose. Uh These are the objectives. Now, if you go to, if you go to any lecture for parts, this is probably one of the most common slides you're gonna see. Uh blind men and elephant. Have you heard about this story before? This is like Hindu uh kind of ancient Hindu uh story where six blind men are touching the elephant, but these people are blind. So they don't know whether they are touching the elephants or something else. So they are touching different parts of elephant and, you know, there's some, some guys say, oh, it's a spare because there's um touching that, you know, the part of that, uh it's a snake, they're touching the nose, it's a wall, it's a rope, it's a fan. They're not seeing the big picture currently. Uh, parts uh like current status part is just like that. Um, you know, parts are, you probably heard about pots but you probably didn't learn in the medical school. Um And it's been, you know, there are not many uh specialists across the country in the world who sees pots and, you know, it's usually either neuromuscular doctor, neurologist or cardiologist, but sometimes it's allergist G I doctors and pediatrician, cardio cardiologist. And we are seeing uh from the different background. We are seeing kind of very different aspects of these pots. Uh We all agree that it's probably the same population but because we are, you know, neurologists or G I doctors, they are seeing from different angles. It's just like blind men touching different parts of the elephant. That's exactly what it is at this point. However, um I think the good news is if we are touching the elephant now, uh we're not ignoring the elephant in the room now. And another thing is, although we kind of like, you probably haven't heard a lot about pots yet. It's really common and I, I bet you've probably seen these patients in your clinic in the past. Uh I guess, I mean, I assume that most of you guys see patients in the clinic and imagine this patient, uh who's anxious kind of younger female comes into your room in your clinic. I complain of pretty much everything in the, in the world like they complain of a head, uh some kind of mild facial pain everywhere. It's pretty big. But if you ask them, uh, if you have like finger pain, they will probably say yes, they have a finger pain. If you have like foot pain or chest pain, they all have it. And you just ask them, they have pain everywhere. Uh, uh, but, you know, most commonly on the upper back, uh, and the neck kind of like cold hanger syndrome, that's probably most common. But of course, they have a lot of pain everywhere too. They have like severe G I symptoms, nausea, vomiting. Um, and, um, and also at the same time, they are chronically severely fatigued and completely. Um, and maybe depression and anxious. There are some psychological components there too. Well, but at the end of the day, I mean, you ask them like their pain level, maybe like three or four out of 10. Of course, they may say like 20 out of 10. Uh, but regardless they're completely disabled out of proportion. These are the people who used to go to like work and study and like type a student personality. But suddenly they just stop going to work, start going to school, they're just completely bedridden. So then uh you order the test uh because you learn the medical school, fatigue Throid function and all that kind of stuff that you know, you think is relevant and everything comes back as normal. So, um, well, first of all, have you seen these people before? Can you raise your hand? Anybody saw this patient in your clinic? So I guess uh pretty much everybody who you know, see any patient probably seen this patient at least once, right? So what's your diagnosis? Then if you see these people, you've already seen these people before? How did you label these people? What do you see them? Can you throw any uh I guess like most commonly fibromyalgia, it's a kind of default diagnosis to be honest, like personally, I'm not trying to cause any controversy or something. But uh personally, I don't know what fibromyalgia means. I don't think there's any solely biological basis for the diagnosis, but it's a good diagnosis if you don't have any, if you run out of all the things to say it's fibromyalgia, right? Uh It's combinations of pain and some anxiety and stuff like that. Well, and then at the end, like patient walks out of the room, you have your colleague and then they say like that, hey, this is a common jargon be used between doctors. They are probably crazy. It's conversion disorder. It's like psychological manifestation. I mean, physical manifestation of this, their uh psychological problem and so on. Well, I mean, you can easily blame their for their psychology and stuff like that. But I mean, at the end of the day, if you already all seen this patient, I just describe a little bit of that. But you're like, most of you are actually raising your hand saying that you've already seen the patient. So, and it's not just you guys or me, like if you like, I've been to some different uh places for this kind of lecture for cardiologists or, you know, uh primary doctors, they are all raising their hands. So it's possible that it's probably a clinical syndrome, right? Because if they're kind of characteristic, like these are, there are some characteristics that are, that are pretty common. So it could be called as some kind of cli syndrome, right? Um And in fact, it was actually, it has been called in the different names in the past and I'm just gonna go through really briefly about that. So there's a thing called neuro, have you heard about this term before? So it's actually still in the I CD 10 code. Uh So it's actually actual diagnosis. Uh literally, it's a nerve exhaustion, but I mean, it's been, it's a really popular term back in 19th century, but people don't use it anymore. Uh uh George Baird is the American neurologist back in 19th century who was uh he, he didn't create this term, but he was very popular uh and very famous for having this kind of clinic. And if you look at the description, it was actually a description describing in um it's actually New England Journal of Medicine, but I was called in different name. I forgot the name in Boston Surgical Medical Journal or something like that. So he published a case reports of neuro saying tenderness of scalp, sweating, hands, dryness, insomnia, and appropriate phobia, fatigue and anxiety. It just sounds like exactly the same publisher are talking about. He says it is at once the most frequent, most interesting and most neglected nervous diseases of modern times. I guess this is exactly the same too. It's also very neglected. He also call this as a disease of Fifth Avenue. He practiced in New York City. And at that time even probably now the Fifth Avenue is a really affluent part of the city and he sees all this patient, younger female from wealthy affluent family comes in and saying like, oh, I just can't do anything. So he call this as a disease of Fifth Avenue. He also thought that this is actually more common in industrialized world. So he also coined the term American nineties. So you see it in like, you know, kind of nice um you know, wealthy European countries in America at the time. So kind of American nineties, he couldn't have, he didn't know anything about that kind of sounds like also some psychological, social psycho, social, social factors there too. So was it, I mean, was it considered to be psychological at the time? Well, our famous uh Sigmund Freud actually didn't think so. He was actually very interested in neen. In fact, uh uh Sigmund Freud was actually neurologist, I mean, neuropathologist before he became psychologist. And uh at the time, he uh he is a neurologist. It's a kind of a modern version of selective rotation. So he was in Austria, but he went to the famous uh French hospital hospital where Jean Mary was practicing. And it's probably, you probably heard the story that he's a famous doctor, was a very famous neurologist. And um uh he was doing noses. Uh He used a lot of hypnotic techniques to put them in their sleep. And that time in the European countries in the 19th century, it was like, you know, booming in the economy. So uh there was a lot of like railroad construction um and a lot of people got injured and has an increasing number of insurance claims. And all this patient comes in with a para paralyzed arm and you as a doctor, your job is to figure out this is a real or actual nerve disease or nerve injury. And imagine 19th century, there's no MRI there's no x-ray, there's nothing. So you have to rely completely on your uh really good neurological exam. So uh the the, you know, Doctor Shark try to show that there's actually some something called conversion disorder. So psychological, physical man of psychological disturbance, he put them under hypnosis and completely get rid of the symptoms. These people, Dr Shark show that like under hypnosis, some patients they're paralyzed, but then now under hypnosis, they're walking around. So kind of proving that this is a psychological problem. However, Dr Freud was actually also very interested in neuro at the time. And he made clear distinction between hysteria and neuro saying that neuro is actually actual physiological neurological problem that they have a lot of G I problem headache. Whereas hysteria or anxiety, neurosis is more psychological in a sense that under the hypnosis, their symptoms can go away too. So it's, it's really not quite psychological and you know, um if he was interested in uh study more fortunately, unfortunately, he didn't do it. So he didn't really discover parts, but he, you know, literally founded um you know, the field of psychology afterwards. Um and moving on to early 20th centuries, another name uh is called Costa syndrome or also known as soldier's heart. And Da Costa uh was also American surgeon, I mean physician. And after uh American civil war, he found a lot of soldiers developed this anxiety palpitation, orea intolerance and severe fatigue. Kind of same population often developed after a battle of fever or diarrhea. So they kind of very similar to, uh Guillain Barre syndrome or something, which I think is kind of interesting observation at the time. Um However, he reported that there's a lot more men than women, which is slightly different from kind of population that we see. I guess that's probably because first he studied more in the soldier population. It's a little bit biased and also some of the symptoms of the anxiety and palpitation kind of sounds like PTSD too. And even in parts, there's some kind of talks about some relation between PTSD, some traumatic events uh between um uh parts as well. And you know, Stacey here, but doctor is here and there's some link between some pediatric kind of conclusion, mild conclusion to automate dysfunction and parts as well. So maybe there's a little bit of this uh connection there too now skip all the way to 20th century. Uh So that's actually modern day of a modern version of this, you know, whatever the syndrome we call it is gonna be part, it's coined by Doctor Philip Lowe at Mayo Clinic in 1993. Uh He still practices. Um So it's a relatively recent thing. So these people, the same publisher, we talked about like anxious female, like chronically disabled fatigue, intolerance and everything. He brought his patients to score two table tests. Are you familiar with this? So basically, it's a literally table that tilts up to 70 degree. Uh And these people, if you like, we actually now have a two table test in the green spring. So, if you want to actually try it yourself, you can, it's actually, if you don't have parts, it's one of the most boring tests you're ever gonna get, you just gonna lie in the table and tilts up for 70 degree for about 10, 15 minutes. That's all. And it's really boring and nothing to do. Um, and they're checking their vital signs. But for part patient, interestingly, if they put them um put, put those part patient on the two table test and just bring that up to 70 degree, most of them will have severe dramatic reproduction of their symptoms. They will feel, they feel they're gonna just die. They like a lot of them just peel and their heart rate goes. So by the definition is more than 30 B PM, increase within 10 minutes or 40 B PM, uh increase for pediatric patients uh or uh even though it's not, it's less than 30 B PM. If, if it is more than um at one point, if they develop heart rate more than 100 and 20 it's by definition uh posture tachycardia. Now, not only that, usually they have a dramatic reproduction of symptom, they, they just all go crazy, but often time they have to just stop the test right, right in the middle. Um And usually we will see their like baseline heart rate being like seventies and eighties and then just dramatically go up to 100 and 50 right away and they all like feel like they're gonna pass out, they don't usually pass out, they almost feel like they're gonna pass out. However, um So this is actually one of the first things, something that's suggestive of a physiological ideology of this or craziness, right? Um It's not a cardiac condition, you have to prove that their heart function is normal. Uh So it's kind of suggest that there's some kind of neural control problem in their circulation. So now we get to the point before that um a little bit of clarification and definition when I say posture tachycardia, uh this is a description of two table tails. So anything that meets the criteria for more than 30 B PM and everything is posture tachycardia. But when I say parts is a clinical syndrome, I'm talking about the old population that presents with the fatigue, anxiety palpitation G I problem and everything is a clinical syndrome, not necessarily posture tachycardia. And in fact, patient with pots is a clinical syndrome. Um on the two table test, they may show actually dropping blood pressure which is newly immediate hypertension. It can be even high tension like young, 20 or even 15 year old per patient, they can develop a shooting of blood pressure, uh which is another subtype called hyperergic type of pots. And it can be just normal response too. But usually they do have a reproduction of symptoms, but their vital sign response can be varied uh, various two. Now, when I said that it's a little bit controversial because, uh, it was still, uh, when I like, recently went to ni a workshop for pots and there's a bunch of doctors who really see pots patients. And this is actually probably like half of the room, half the people in the room will probably kind of agree with me in that part of the CS. They don't have to show the tachycardia, whereas some cardiologists have, they will probably say, well, you have to see tachycardia to call this as parts. Although even those cardiologists will probably agree that uh even if you don't see parts tachycardia, if you put them on a two table test the next time at some point, you definitely gonna see the tachycardia anyway. So they all agree that these are the same population. We just have a hard time labeling this population at this time. Some people may just call this a clinic fatigue syndrome like Dr Peter. But again, this is an ongoing process, but just for the sake of this talk, I'm just gonna talk about parts as a clinical syndrome. Um you know, calculating all this population, literally this um patient you are seeing all the time. Now, how do you explain all this stuff then? Right now, we kind of got to the point now we are talking about like maybe psychological, physiological. Now we are talking about, maybe there was a little bit of physiological stuff there too. Like two table test response is something that you can just fake. So how do you explain that? Um um Now before we go there, like let's just look at a little more detailed clinical features of parts. This is a very typical uh you know, presentation of parts uh usually starts in late teens and early twenties. I think media is probably 15 to, between 15 to 20 years old. Actually, just about half or a little bit more than half of these people will start their symptom, very sudden onset, uh within like, you know, they're just usually very normal, not only normal, actually, like I have kind of theory, but they're usually a really good student, like always a student, they are very active athletic and a kind of student and suddenly, uh they just can't just get out of, get out and get up and go to the school. Uh, it's pretty dramatic, it develops over like days and weeks and a lot of my patients actually can remember exact date, they just stop functioning. That's how dramatic uh they can be. And if you really ask them further, just about like 50 to 60% of patients will say, well, I actually have some kind of virus illness, some diarrhea or some kind of infection of, uh just about a couple of months before they present me this whole kind of craziness. Uh It's a severe, profound fatigue, that's actually the most debilitating symptoms. And with the static intolerance, whenever they get up, they get dizzy and lightheaded and that's very debilitating. Uh they also have a chronic muscle pain and headache, kind of muscle pain. There are different kinds of muscle pain but kind of muscle pain. I could let you guys know like what domes means, right? Delay and muscle soreness. Uh You probably experience that you go to gym, like I didn't go to the gym for a couple of weeks. So because I was sick and I have a lot of excuses. Uh If I go to the gym to catch up like five hours, I'm probably gonna have a lot of pain and this kind of pain is called these domes, right? Delay on most soreness, which is a physiological phenomenon. Everybody has it. Uh But these people, even without going to the gym, they just do some chores and things that they do all the time. They suddenly they just have all these domes like pain. They have like severe cramps everywhere. This kind of muscle pain that's debilitating. Oftentimes they have a severe nausea or vomiting or lack of appetite. Their digestant slows down, they just can't do it and they have like kind of ideas, alternating constipation and um diarrhea as well. And overall, like if you really ask them, um their course actually fluctuates quite a bit over time. So they start in like late teens and they are kind of debilitated, but then in the early twenties, somehow they got, they just kind of grew out, grow out of it. So they get, they go back to school, they kind of work back to the baseline normal, but they kind of function enough. But then like mid 20 or thirties, they, they have another flare and they just can't, they just drop out and they kind of fluctuates over lifespan. Um So how do you explain that physiologically? So kind of working hypothesis at this point? And a lot of what a lot of people think is probably is a fail to supply blood circulation. It's actually blood circulation problem. So for example, um for the muscle, like if you try to do like do like pain, uh imagine if you're trying to kind of work out and use your muscle and your blood can't really send circulation adequately, you're gonna have a lot of muscle pain for sure. It's kind of like lactic acid build up because there's no circulation. However, at the same time, if you do an EMG if you examine they are muscle and nerve their muscle and are fine, that's normal. That's the kind of the lattice that you're gonna do immediately, right? Their CK level is normal EMG is normal. So by default, you're gonna say it so crazy. But you know, you, you didn't look at the circulation, there's no good click or tools to look at the circulation. Uh There are a lot of oftentimes they complain lack of concentration and brain fog. Uh they, they say this is kind of foggy feeling, they really can't think right. And they have some kind of memory problem and also presumably there's a kind of lack of circulation there. And there's actually some evidence uh using the uh uh C Doppler when they have this brain fog, there's actually reduced circulation there too. Um Also, chronically, they do have a intolerance, chronic fatigue uh because they have a reduced preload because from the lower part of the body, uh they can all the blood circulation back to their heart. So of course, you have a pre reduced preload, you're gonna be very tired, right? So those explain some of the symptoms. But so I call this pump failure. They basically, what happens is the blood pump is not working and that pump is not really supporting the metabolic needs of each tissues to send all the uh with sending all the circulations. Uh So what happens is probably so imagine that this is blue diesels um in the picture. And basically, it's a uh you know what we call this dazzle motor innervation, basically, uh that fiber kind of wraps around arterial blood vessels. And whenever you need some blood, you know what happens, right? Uh kind of, you know, constrict or dilate blood vessel in a way that it kind of pumps blood to the target tissue and that specific fiber, the yellow stuff is actually comes from a sympathetic nervous system and that's actually what happens if you activate sympathetic nervous system, right? It's a vital flight reaction. So imagine some bad guys chasing after you. What happens, you get like anxious and everything but your muscle get tensed up and you have to run away. It's a flight direction, right? Fight or flight. So you need more blood pumping into the muscle. That's how that happens. So imagine that pump is not working the pot patient, it's somehow denervated. You're not pumping the blood. That's why you get, you get all these symptoms of so called pump failure. However, that's not the only thing that's happening in this population. They actually their bare receptor function is normal. And you guys all know what bar reflex uh bar receptor reflect is basically to simply speaking, this is basically a pressure gauge in your body because in your body, blood pressure maintenance is very critical for your survival, right? So body has all these mechanisms to maintain your blood pressure. So in AORTA, there's a couple of like chemo receptors and pressure receptors. So if you have like reduced pressure or preload, coming back from the lower part of your body, it activates this uh very reflex loop. And what what happens is that it directly connects to your brain. And then let's say if there's a drop in your blood pressure or reduce prec cardiac load. What happens is that through this uh reflex arc, your brain releases a activates your sympathetic nervous system very strongly, right? And then what happens is that it causes tachycardia, right? So it's a kind of natural response, compensatory uh response to kind of survive, right. So, if you have like reduced preload to your heart, what happens is that you have to beat fast to compensate for it, right. So that's actually why you get the tachycardia when you bleed or have some, you know, dehydration and stuff like that, right? So, in part patients, because there's a really reduced prec cardia load, they're, the receptor function is completely activated. It's kind of hyper activated. So they release a lot of um you know, sympathetic neurotransmitter such as like adrenaline. So they have a kind of adrenaline surge symptoms, uh that can be also debilitating too. So for example, so what happens is that not only they have this pump failure symptoms, muscle pain, intolerance, fatigue and Migra migraine. Now, now they're through the bar flex function, they actually increase their sympathetic nervous system and that causes a lot of symptoms too. So when they activate the sympathetic nervous system, well, of course, they, they, they cause tachycardia to, you know, compensate for this kind of a lack of circulation. But what also happens is that they get anxious and you know, if you're anxious, you're not gonna sleep. Uh it causes insomnia and uh it kind of, you know, on the fight flight reaction, on the sympathetic nervous system, you're not supposed to digest food. It kind of slows down your G I tract. So it kind of predispose nausea, vomiting and altered, um you know, kind of bacteria got bacterium predisposing cyber or irritable bowel syndrome. Uh and also often causes a lot of nausea, vomiting. And also you have a lot of hyper, meaning a lot of sweating at the same time. So basically, they experience a lot of adrenaline surge too at the same time. And that can be very debilitating and uncomfortable too. So, um what I usually do is just for the practical proposals. I actually kind of classify the symptoms in two categories and one of which is pump failure and the other is sympathetic overcompensation. And like I explained pump failure, symptoms are basically chronic fatigue, ea intolerance, dizziness, migraine and muscle pain and all that kind of stuff. Uh lack of circulation problem. And the other other thing is sympathetic over compensation, which is usually anxiety, nausea, vomiting, palpitation and sleep disturbance and all these other kind of stuff too. Now, if you think about it, these are actually kind of complete opposite end of the problem. It's this is actually basically sympathetic dysfunction, but in the one arm which is pump failure, I told you there's some suspicion that there's a sympathetic denervation going on, right. But at the same time, there's a sympathetic overcompensation. So uh, this is actually kind of paradoxical in a, in a sense that they have a lot of too much sympathetic symptoms. But at the same time, they suffer from lack of sympathetic function and that actually has a lot of implication in the treatment too because if you use some medication to treat sympathetic over conversation, that actually can worsen pump failure symptoms and vice versa too. And that's actually what makes this treatment kind of a little tricky. Now, uh before we go back to the uh treatment, uh ok, so just to summarize because as a new muscular doctor, my job is to usually try to neurological localize the problem. And now we said that, well, there's a probably peripheral sympathetic dysfunction, denervation, uh probably basal motor denervation that fails to regulate the circulation at the same time. Their central bar receptor reflex function is normal in intake. Not only that it's actually hyper activated. So we can probably localize to prepare for a sympathetic area. And uh with all the other reasons that I can tell you a little later, uh probably because if you look, if you imagine, like, you know, you probably will maybe closer to my medical school. So you probably remember the new anatomy. Do you know where the sympathetic nervous system is located? The answer is already in the slide, right? The segment is called uh sympathetic chain ganglia. So interestingly, our simple, there's actually a lot of evolutionary kind of reason for that. But our nervous system is clustered in the lumbar segment right next to uh the spinal cord and venture root. Uh It actually forms chains of these neuronal cell bodies. And this is actually the old sympathetic nervous system, axons coming out of and, and it's only in the segment. Whereas the parasympathetic system is all spread out everywhere. And the neuronal cell bodies in their tissues is kind of hard to find. But sympathetic nervous system is all clustered at the same place in the is a sympathy chain ganglia. But like I said, their very flex function is normal. That kind of suggests that their central nervous system is normal. So it's probably prefer nervous system problem, not the central nervous system problem, right? So what is the evidence? Do I have any evidence to say that? Not much? Uh just a little bit. OK. I'm not admitting that like nobody actually has. So I'm actually really honest. So when I come to see my patient, I say that, OK, if you see 10 po doctors in the country, you're gonna get 10 different versions of explanation. But at this point, nobody actually has a really solely good science to say that. Oh I'm right and everybody is wrong. This is actually all again, I'm one of the blind men here. OK. So it's a blind man and you're a muscular blind man. Um Some of the evidence is based on more like more clinical behavior so far and my experience, but some of the actually evidence suggests that this is probably the case. First of all, uh QR is uh called quantitative sumo axon reflex test. So just shortly simply this is actually pretty simple test. Um our sweat gland um uh is innovated by a sympathetic nervous system. And I'm gonna show you in the next picture, but basically, our sweat gland kind of looks like a little pocket and the pocket contains a lot of water which is sweat. And then when you activate your sympathy nervous system, it squeeze a pocket and produce the sweat. Ok. So simply, and this sympathy nervous system for the uh sweat gland, the neurotransmitter is actually zero cooling. So this test is pretty simple. You basically produce uh kind of, you know, release a zero cooling on the ski and stimulates the nerve and then produce the sweat. So, and then it measures the amount of production if you can see there's a time and amount on the Y axis. So you can actually check how much of sweating comes out per stimulation. The great thing about this test is that it actually has a normal standardized. So you can compare that with six match population and see how much you are far away from it and too much of it and so on. And in part patient, it's been well known since actually, you know, uh early 19 nineties. Actually, there's one of the first Doctor Phil Philip Lowe in New England Journal of Medicine publication showing that this patient actually have a flat response for QR meaning they don't produce, which is kind of a little weird because I told you that they have a lot of sweating. But then if you test that you don't have any sweat. Now, um it's paradoxical, right? And when the sympathetic innovation comes out again, like uh this comes directly from sympathetic chain ganglia, but from the same branch, it's not only the sweat, it, it uh it branches out to the blood vessels and it also innervates the blood vessels. So by showing the reduced innervation to sweat gland, we can kind of imagine that there's a reduced vessel, motor innervation as well. Now, just uh you know, like evaluating uh directly the s model innovation directly from. So it's kind of very technical. So there's no technique we can do, we're kind of trying to develop it at this point, but uh there's no really known standardized method of doing that. So uh that's actually relatively simple because you can, you know, just test that right away. Another piece of evidence that kind of as relate to that is a skin biopsy. Um You probably heard about this. We, we do, we do do this punchy skin biopsy, take a small piece of skin and we stain the nerve under the skin and we do see mainly a couple of things but mainly small fiber density and also sweat gland ation too. And Hopkins is actually one of the few skin labs that quantify the innovation, Skin sweat gland uh innovation. And the lower end uh the picture is that the black stuff is all this small fiber that's wrapping around uh the sweat glands. Actually, that's that uh that axons are basically a sympathy nervous system, right? And there's actually a method uh you know, doctor and this team just and everybody uh developed uh in the past to quantify this innovation. And I do have a preliminary data that's not been published yet. But we actually compare part patient and control. Although they kind of often time they reported as a normal and by normal, we define as more than lower 5th, 5th percentile uh from our own kind of value. But if they look at it, there is actually a significant difference between uh six metric uh population in terms of innovation, innovation of sweat gland. So taking this together, there's actually a functional deficit of sweat gland, innovation. And there's actually also pathological proof that there's a reduced innovation, which in turn suggests reduced s model innovation, right? So that's the evidence I have so far. The last piece of evidence I actually didn't do in the slide is that autopsy results. So the international I work with a lot, there's a big patient foundation, they actually started this autopsy study. And so far this is the end of one I didn't want to put it in the slide. But so far, what I heard from these people is that they actually, you know, autopsy, this person part patient who died from unrelated disease and she's only like 20 something years old and there's a tons of inflammation around the, uh you know, uh sympathetic and began to ganglia there too. So maybe that's a piece of evidence that's suggesting towards to this uh sympathetic denervation theory. Um, ok. So, so that's all the evidence. Um It's pretty short. So then what is the mechanism like? How? Ok. Well, if that's the case, like, why do they get it? Why do they have this problem? Also, there's a lot of uh theories surrounding? Ok. Well, could it be autoimmune problem? I think actually it's auto immune because first of all, uh, usually they have a lot of some infection before they on the symptoms. As in a lot of other autoimmune condition like Guillain Barre syndrome, we know that there's a vector, um, um, uh, you know, infection, uh followed by all the onset of the symptoms and, you know, and also their chose fluctuates and all that kind of stuff. Uh I, I kind of talk a little more about the auto immunity, but I feel like there's auto immunity there, there's a group of people who think it's all genetic and actually, in fact, a lot of my patients have a very extensive family history. A lot of people, when you ask them, their mom probably had it probably to a milder degree, their siblings have it. So there's actually strong family history there. So that kind of suggest probably some genetic presion or maybe it's a genetic condition, of course, always is with any disease. Always the answer is genetic presion and auto iun interaction with the gene and environment. That's always the answer, right? So you can't go wrong with that. Um So, and also another thing, actually IBIG probably helps. Um and I have a very small number of patients. Uh And as you probably know IBIG, especially at a higher dose, it's the immunomodulating therapy, it kind of pre uh pre precipitates all those bad oral antibodies. That's how kind of it people think it works. And uh with the IVIG, sometimes it can be dramatic. So you can get like complete wipe out of the symptoms of these parts. And I have some patients who just almost became normal with Ivig. So um just between you and me don't tell your patients about it, but because you're gonna get into trouble. Uh So another thing that I kind of want to mention that there's a lot of overlapping syndromes too. Um And when you see this patient as a past medical, these are the things that you commonly encounter. And not only these four I listed, there are so many other things that I probably don't, didn't think I was actually uh putting in, but I'm just gonna talk about two more, two things, mass activation syndrome and E DS. Uh and other things are a little bit kind of kind of minor uh mass activation syndrome. Have you heard about it by any chance? So, it's overlapping syndrome. So, if you actually, again, like, I actually, I went around and actually ask a lot of people now. So I, I actually did go to a lot of allergies at Hopkins. If you ask, you know, 10 allergies at Hopkins, well, probably seven or six or seven will probably say that's ob it's like fibromyalgia, like it doesn't exist. Some people believe there is such a thing there. Um And for those, like, but I'm not an analogy, I don't have any, like, real educated opinions about this, but this is actually a common phenomenon that I see all the time, the participation. So basically, it's basically some allergy. So if you see those people and you look at on their allergy, you see, like, probably, you know, 50 different allergens there, which doesn't make any sense. And if you really ask the allergies, true allergy, I mean, statistically speaking, the chance of having statistical chance of having any real allergies to more than three or four allergens are, it's almost like, you know, striking, getting like, you know, thunder, like three times in a row or something like that. It's just so it's very rare. So if you see anybody who's listing allergies more than five. That's just really not actual allergies. Right. But these people actually interestingly, uh, have kind of an allergy like syndrome. So they come with the, uh, they come with this kind of phenomenon where, you know, they're like, they're taking this medication for like, years and then suddenly they just break out all the, you know, rash and swelling everywhere, uh, just like, just like true allergies and then they stop it and then, you know, maybe years later they resume it, they're not gonna have any problem, same as a food. So it's not a true allergy in a sense that it's not specific to one allergy, but they have all these random allergy like symptoms like it can be asthma like swelling and rash everywhere. And the theory behind that is that uh you know what the mass cells are, right? So basically mass cells are the cells that's kind of, you know, residing in the different tissues and in the true allergic reaction when there's an allergen and antibody binds and that stimulates mass cells and mass cell has a lot of Granules there and Granules contain all the chemicals that causes all the allergy. Like these are the, you know, chemicals that causes the hives and you know, swelling and rashes and everything. So, mast cells are the cells that are kind of easy factor cells for allergic reactions. And there's a theory that these mast cells are unstable and without having true antibody antigen or allergic reaction, they can be stimulated and then burst open all these Granules. And that's the theory behind mass activation syndrome. And you know, it's common, you know, phenomenon that a lot of participation will complain. And you know, this is again, without any evidence. My own view is that there's actually um mass cells actually can be stimulated by cins like, you know, the sympathy in neurotransmitters. So I wonder if, because part patient have hyper activated sympathy nervous system, they release a lot of adrenaline. I wonder if that's stimulating mast cells and you know, causing these symptoms. So there's a lot of unknown things about this mass activation syndrome, but it's pretty common that you can encounter. Another thing that you will probably see is the syndrome. Uh and among the different types of E DS. Um and E DS type one and two there, the genotype and phenotypes are really well known. They have a really gene and biological mechanism that's found. But when you say Ed type three, another known is also known as the joint hypermobility syndrome or type three. It's basically diagnosed purely based on clinical phenotype being hypermobile joints. So if anybody has like fair skin and hypermobile joints without any other things, that's just by definition, the E DS type three, and there's no genes associated with no biomarkers associated with at this point. Uh But again, like if I see part patient, probably 70 80% of people, uh even without having a formal diagnosis, V DS, they are flexible in their joints. So they have like double jointed and everything. Actually, there's a criteria called Biden scale. So, you know, you have more than 90 degree in their uh pinky fingers and uh can touch their thumb to the forearm and all that kind of stuff. There's a score currently, like if they have a five out of nine score, it's definition E DS. But again, this is just a phenotype. Um um So, so because of that, uh some people think it's probably genetic, but I think it's more like genetic predisposition. I mean, uh like if you see 10 people with the uh ed type three, which probably suggest that their, their connective tissues are kind of loose. Um But like you can also imagine there's a analogy that I give to my patients that you can imagine like kind of water balloon and that's attached to the pump to me parts is a pump failure. So that's not squeezing the balloon effectively, right? But if you have this rubber, that's really stretchy, you are more predisposed to have this type of problem. So I don't think this is a, this is a causal relationship, but this is the kind of problem that they have. I mean, if they have this E DS kind of loose connective tissue, their symptoms are more exaggerated and more severe. Uh But these are two these two syndromes are most commonly encountered syndrome, overlapping syndrome with the parts that uh kind of mentioned that now uh briefly talk on the treatment strategy. So basically, so I treat them, people have a little bit different approaches. But again, at the end of the day, I'll probably say parts if you ask me about parties, it's a sympathetic denervation causing effective hypovolemia with a secondary sympathetic overcompensation. Is this simple enough? Anyway, so that's so that's part. So how do I treat them? Uh Just briefly speaking, I kind of try to treat differently for the pump failure, symptoms and sympathetic over compensation because again, these are completely two different things, opposite kind of uh direction for the pump failure. Basically, you're imagining this water balloon that's attached to the palm. So if you're not fixing the pump, what you're gonna do is filling the balloon with the water and expand the balloon. So as the balloon expands, it's going to build the pressure and we're gonna use that pressure as a pump. So that's, and in fact, uh I think one of the most uh when, when other doctors kind of treat pots, I mean, including myself too. Uh you know, pumping like actually the bottom expression works, but it's just not that easy. We're not rehydrating these people, they're not dehydrated, we're actually expanding the balloon. So, and these are human, not balloons. So it actually takes a lot of water to do that. I usually often times it's four liters of water and 5 g of sodium. Can you imagine how much it is? I mean, how much, how much water do you drink a day? I mean, this is like, I've tried it myself so I can tell you this is just crazy. It's a lot of water and even with this amount of water, you know, like we have a G I system, there's a kidney that's pumping out the water. So, you know, like it's, it's not maintaining quite for a long time. Like actually, even with the one gallon of water, there's a little tiny fraction of water that's stay inside of the balloon. So I sometimes I'm kind of liberal about this IV sailing infusion. I just come give IV infusion like 2 to 3 times a week. Even if I give one bag of Saline um over a couple of hours, the water, like only 20% stays effective uh in the uh uh effective volume and that volume stays only about 12 hours to 14 hours from, you know, if you look at the IC U book and stuff like that, it just pumps out right away, which is why you have to give them more frequent i vision. However, a lot of most people will probably say after just a bolus of sailing, I mean, they, these are the people who have been through like like Mayo Clinic or Harvard Hopkins, you just name it for 10 years and just one bolus of normal and they feel like pretty normal for just a few hours. So that's how, you know, dramatic can be just with the normal infusion. However, I'm not gonna put them on normal infusion three times a week forever for the rest of your life. So, so the next type of treatment is actually uh physical exercise and uh and to bridge that, I just keep Saline in vision and I use like me and flu to enhance their volume expansion. But the goal is actually physical exercise and how physical exercise works. Theoretically speaking. Now, I told you about the pump and pump failure, pumping the sympathetic nervous system. Now there's another palm, it's a skeletal muscle pump. So it's your leg, calf muscle, it's not just calf muscle, it like a lot of other muscles too, but these lower extreme muscles has no bell. I mean, there's a bell there. So if you, it, it kind of brings back uh blood back to your heart. Now, this scalar muscle pump is actually really powerful, much more powerful than you think. In fact, a normal person beats, you know, a normal cardiac output is just about a gallon of blood per minute. It pumps out about a gallon of blood per minute. Unresting if you start running and jogging around, it goes up to five gallons and some trained athlete can be even more than that. So, and that's mostly from scalar muscle pump. Right. So, imagine pot patient can do that level of, uh, you know, uh, cardiovascular exercise. They're getting like, probably four or five times more blood back to their heart. They feel much better. And I did a very few patients actually who actually follow through the exercise protocol and they, they are all saying it's kind of interesting. They, they usually say, uh, they had to do exercise to gain more energy. So if they do, if you guys do exercise, you exhaust your calories and everything, right, you get a little fatigue. But for participation, they get fatigue from the exercise. But the energy they get from the exercise is much greater than energy they lose from the exercise that they had to do exercise to maintain their function, which is kind of interesting. Um, but I told you they have exercise intolerance, they try to exercise, they can't pump the blood to the muscles. So they have a lot of set back and crash to before they get there, which is kind of what's tricky about the exercise program. And that's kind of my, you know, uh, the clinical program now. So that's kind of the key for kind of, I work with a lot of physical therapist and that's kind of the key like, how do, how, how can we increase their cardiovascular resistance, uh, without cutting a lot of crash? That's the main, no question that I have. And it's been kind of working Ok. Uh, but a lot of still patients have a hard time tolerating the exercise. Now, I didn't talk much about the over sympathetic, over, uh, activity symptoms. Now, this is kind of relatively easy because you can use a lot of sympathy lighting medications, which is pretty easy. However, you have to be cautious because for example, if you look at the pots and textbook will say, oh, you have to prescribe them better blockers, oftentimes better blockers, even at the low dose, it can worsen their fatigue or so called pump failure symptoms. They get the better blocker, they just just can't even get out of the bed. So you have to be really careful and they have to kind of, you know, carefully, you know, make sure what's main presenting debilitating symptoms are for now. Actually, Marinol has been my favorite drug. Uh You don't have, I mean, I, I guess the rehab population, you're familiar with the Marina, it's basically synthetic cannabinoids. My working hypothesis why Marino works is that it probably enhance some parasympathetic system. That kind of offset the sympathetic overdrive. That's kind of my, my own kind of view on why Marinol works. But regardless it works in magic, especially for those who have severe nausea, vomiting and lack of appetite. I have a patient who is on a G tube and like, you know, went to all the G A doctors at Hopkins. I tried all the known G I medication, uh in word, but Marano is the only only thing that keeps her from vomiting. Um So Marino can be really powerful. It can kind of work for generally other sympathetic symptoms for sleeping and a little bit of anxiety too. So Marinol works fine. Mestinon. Uh it basically works on, you know, this mein is basically medication developed for um my gravis its work, it works at the uh neosar junction, it's a Colin and methadone. Um because if you use me, they have a lot of choicy, they a lot of secret happening, they go to bathroom a lot. So people with the parts usually don't tolerate the side effects that well. So I don't, it's not my favorite medication, but when it works, it works the magic too. And that kind of suggest suggests that, you know, that gangling and problem is could be problem underlying peop parts too. Meditation and mindfulness. I'm actually increasingly aware that psychological intervention is critical, especially with the uh managing their sympathetic activation because I feel like this is the more central sympathetic activation. So uh you know, I work with a Zohar who is very interested in parts and she kind of, I mean, a lot of people actually use this called mindfulness technique, which I understand is some westernized version of meditation and it really works pretty well. I have a patient who swears that uh this mindfulness meditation is way better than or Marino or anything that she tried of course, just like exercise, they have a hard time actually following you through, but it can be really powerful. Uh The thing is that a lot of people, when I say psychology, psychologist, uh they will just run away because most time, often times, you know, same story, like people will say, oh, this is a psychological problem. They think this is kind of like they think that I think they are crazy. So, but if I if they understand this, uh like I understand that they are not crazy. Actually, they really want to see psychologists, they are very desperate for that. Um So kind of we were almost ended the slides. But so y pr as you can see, first of all, it's very debilitating condition. I have a lot of patients who are just completely bedridden. I mean, I see a lot of other neumos conditions on my even a s and even compared to these people, they are so much more debilitated. I mean, myocyte are stroke patient, they can still do certain things. Uh you know, part patient you think about it if you can get up and stand up, like what are the things you can do? There are not many things you can do without being able to stand up and tolerating, sitting up and doing stuff. So it's completely, a lot of my patients are just completely bedridden. Uh Multidiscipline approaches, right? Like you have to work at the PTS cardiologist and everything is by nature is apr and, and usually the main treatments really is the exercise and dietary lifestyle modification. So this is like what we do all the time. And most importantly, at this point, no specialist claim this is our, their disease, right? I mean, cardiologist, it's not a heart condition so they don't want to see them for some weird reason. I don't know, but neurologists just don't like it. So when they don't like it, we just have to take it, I guess. And so, you know, I think this is a good opportunity for a lot of female doctors and you know, because think about it, like, what are, what are our diseases like spinal Corry stroke probably is actually more neurology at this point. We're just kind of following as a PT or whatever. But um I'm sorry about that but, but like, you know, like it's diagnosed primarily by neurologists, right? Um But, you know, I feel like this is a new opportunity for a female doctor. I'm sorry about the stroke. I made a mistake. But uh but what I'm trying to say is that this is a new opportunity. And also to be honest, I mean, this is really make even financially makes a sense that people and doctors seeing patients. I mean, pediatricians, it takes too much time to see each patient, they really don't want to see them, these, these people. So that's actually why I we are getting a lot of support from other departments as well uh building of this parts program. And again, like I feel like this is a great opportunity in the future. I'm hoping that uh there are a lot more female doctors are taking care of this uh um part patient. So the summary is a very more probably more common than we thought. Uh Again, to me, it's a sympathetic dysfunction maybe in nature. Um You know, there is another discussion and also treatment requires a long term multitude approach, uh probably fit for female doctors. Now, back to the first slide, right? Blind um you know, uh the elephant. So I told you, ok, well, I think I'm a, I'm a very optimistic person. So a future I think it's bright now we are touching the elephant. However, what we're gonna do is we just need a lot of collaboration, right? So if you have a six blind men, we just have probably more blind men as a neurologist, more cardiologist, more whatever pediatrics or allergies, everything. So think about it. If you like 6000 blind men touching the elephant, now they will probably high chance of, you know, detecting this is the elephant, right? Instead of six people, that's how I see it. So we just need more people getting into the field. And I mean, actually it's probably more important than these people should be from different departments, different special different backgrounds. And I actually showed the same slide to cardiologists and they thought there are too many cardiologists, but regardless, um this is my end of the slide. So, um yeah, I think it really applies to the medicine is a sign of uncertainty and out of probability. So, any questions interesting, how do your patients tend to do after they come to your clinic and start receiving treatment? So, is there, is there some proportion of them that actually can maintain the volume expansion and tolerant well, or do you think? So? I, I don't know, I could be biased. I think they are doing better than when they first came in. Um Of course, they do have a lot of relapse and flares and that's probably because they are underlying petros being uh course fluctuating quite a bit. I recently asked the same question. So my clinic, I'm very aggressive about the volume expansion and, and also, uh I don't usually start exercise right away because they have a lot of crash. But at some point, if I'm sure that they are drinking a lot of water and getting all the volumes, then that's when I send them to physical therapy. And a recent same question, the PT they'll probably say most people actually just about like 70 to 80% of people will follow their exercise portal and they get actually better. Now, I never had parts myself and it feels like it's quote unquote, it's just crappy feeling every day. So even though like, like, so the benefit of actually following them, the PT is that we have some objective measures when they first came in, they can't even sit up and then now they're doing like walking around for a few blocks. So they, they may feel crap and they feel like they're not going anywhere. But if you actually look at them, look back, even those people who feel like they are flaring, not going anywhere, they actually have some kind of more measurable improvement in their pt. So, I mean, and also that work relates with the volume expansion, the more volume they get, the more activity they have and more functional uh function they get. So they, they do respond to, they actually really respond pretty well to the treatment that actually probably better than I initially imagined. And um the Democrats, does it still follow that um historic trend, mostly young women who are affluent or are you seeing a broader range? But I'm not sure about the social economic status of that. Like I, I'm not sure if they're affluent or not to be honest, but uh demographic wise, age and sex, 90% young female for sure. And that's same with other uh clinics that when I asked them and someone is predominantly Caucasian at this point, but I'm not sure uh if this is just kind of, you know, kind of biased or misrepresented or something like that. Um I think there are probably a lot more in other, you know, ethnic but it's just, I don't know, it's just, but it's the same in other clinics too. It could be possible, especially with the ed phenotype, their skin and flexible joints. Is it possible that Caucasians and more parts? That's kind of question at this point right there, of their mushrooms. So their muscles are actually completely normal a couple of things though. So, actually, one of the reasons that I, so the reason that I started my pots clinic is actually, I still have a clinic, right. And, and these people have a lot of muscle complaints and that's actually why they came to my clinic. And oftentimes they come, uh with some kind of like probably a single or a few episodes of repels which is normal. Uh, anybody, uh, who's doing a vigorous exercise without adequate drinking hydration, they can develop uh Reyes. Uh Of course, if you have like series of rely in your lifetime more than like five or 10, they could suggest some mitochondrial pathology or something. But like you can have a couple of, um, er, my and then, you know, they, they come to my clinic maybe just to work for any underlying mitochondrial problem or something like that. Uh I, I mean, often times even with those who develop a couple more rly, their mitochondrial function is normal, their muscle look normal emg muscle biopsy, all normal. However, I just wonder, you know, like with that lack of circulation, you know, uh they may, they may be prone to develop, rely, I'm not reply, prone to develop that. I'm not sure there's no study. Uh That kind of looked at the incidence of reply in this population when they exercise. I'm not sure about that. But uh but otherwise, uh physiologically, their muscles are completely normal. Do they complain? Um I, to be honest, I never really ask that. So I can't really tell, I can't really think of my bad. Um A couple of the demographic mechanisms are in place. So for example, why do you, why do you suspect? So again, nobody has any evidence at this point. It's just a speculation and theories and everything. So I'm gonna tell you a couple of kind of theories um that um that some people have actually raised before. So, like I said, uh this is probably just uh you know, again, effective hypovolemia, meaning without having actual vole, meaning their blood volumes are normal, but they're not regulating the blood volume right up and down against the gravity. Um because their nerve is not regulating it. Uh And uh but anatomically speaking, men and women, a woman has a lot of gynecological organs, they can pull the blood and they're more prone to uh kind of, you know, uh So the in female, especially with the uh like, you know, menstrual cycle when, when they lose blood and everything, they can actually uh kind of keep the keep a lot of blood volume in their gynecological organs. They can actually, you know, worsen their symptoms or predispose this kind of problem. I think that's actually most probably prevalent kind of theories behind why women have more of this kind of problem than men. But, but is there any hormonal problem specific? I'm not sure about that. Yeah, you mentioned that oftentimes this is the fifth or sixth different provider that a patient has seen. And it's not uncommon in psychology, but we also see patients who've seen all different specialists and they can't quite figure out what's wrong with them. Then they sent psychology. So are there things that we should be really listening for? Um And folks have not yet seen you or? Um yeah, actually that's a great question because I, I talked to a lot of psychologists and psychiatrists and when I say they have a pot, they're so excited because as a psychologist, psychiatrist, they, they feel like these are a little bit different population than their typical depression and anxiety patients. And this patient, I guess, um if they actually have a study intolerance or palpitation, um I think that's one of the most common symptoms. And also because uh you know, part is actually more common, statistically, there is probably a good chance that it could be actually part two. I think especially the palpitation intolerance are the ones that you can probably ask in addition to other things that you ask if they have a severe G I problem, that's more suggestive or kind of more physiological basis of the problem. They could be also, um, problem too. But again, I think, um, they look a little different in the sense that they're very debilitated. I mean, it's just very difficult again, like when I compare with other new muscular diseases, like a LS even, um, they are just completely, they just can't get out of the house. And, um, I think that's actually one of the things that I look at most but just symptomatically palpitation also study intolerance, fainting, passing out. Those are probably more telltale signs of pots for otherwise healthy person. Any other questions? All right. Well, you, you know how to, uh, reach me. Right. So, thank you very much for your call. Created by
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