This one-hour webinar features a comprehensive case-based discussion covering Graves鈥� Disease. The panel features a multidisciplinary team of experts from endocrine surgery, endocrinology, ophthalmology, and nuclear medicine. Learn about the old, effective and new treatments such as Tepazza from the specialists at Penn Medicine.听 Special topics include thyrotoxicosis, pregnancy, hyperthyroidism, medical, surgical and radioactive iodine therapy and evidence-based management strategies. 听Note that CME credit is no longer available.
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start. Good morning. I'm Rachel Carlson endocrine surgeon at the University of pennsylvania and this is a webinar from the endocrine disease team Grave's disease. Old effective and new treatments. Welcome to the C. M. E. Approved webinar sponsored by the endocrine disease team at the Abramson Cancer Center here at the University of Pennsylvania. Today we're going to focus on Graves disease which presents an opportunity for a lot of discussion regarding treatment options for hyperthyroidism including medication, radioactive iodine and surgery. In addition we will hope to raise awareness regarding novel treatments for thyroid eye disease. Um I will serve as a moderator for this session and I am also an insurgent and maybe jump in in that role as well. I'm joined by my four colleagues whose disciplines represent the multidisciplinary collaboration essential for care of this patient population. 1st Dr. Cesar Brazen Young from ophthalmology from endocrinology. We have dr Jessica Berman from nuclear medicine, doctor dan Prima and also from endocrine surgery. Dr Heather Wachtel, Good morning colleagues. Thanks for joining us today. Together our goal is to define and review the approach to a patient found to have hyperthyroidism and more specifically Grave's disease. We're going to provide an evidence based and patient centered approach will focus on the initial treatment and definitive treatment options as indicated by the course of disease. Will address issues related to hyperthyroidism and thyroid eye disease and the webinar will discuss and highlight points of care relevant to the management of these patients across their care team because our focus is on management decisions will be sharing three clinical vignettes and verbally providing other information as we go. Our vignettes will include a common patient, fire attack, psychosis and pregnancy. The objectives for o meet our speakers. There you go. Our objectives are to describe the diagnostic evaluation for a patient diagnosed with hyperthyroidism, review principles of medical, surgical and radioactive iodine therapy and discuss evidence based management strategies of graves hyperthyroidism. You can receive CMI for this webinar and about a week after the webinar you'll receive an email asking you to evaluate it and then your CMI credit should be um received. Their in the webinar is live and will be recorded um at any time you can submit a question by using the chat box. Please send to all Dr Susan Mandel, another colleague from endocrinology will be watching the chat box and we've also reserved 10 minutes for questions at the end of the session, the session is being recorded and the link will be provided for future listening. Here are our relevant financial relationships and again within a week of the meeting you'll receive an email for your CMI credit. So let's get started with our first case. We have the case of a 56 year old obese woman who presents to the emergency department with palpitations. She has a prior history of tobacco use and quit a year and a half ago. You can see her physical exam findings and vital signs noted here. It's important to note that she has a pulse of 120. Her b. m. I. is 23, she has no palpable thyroid abnormalities. She is found to be hyper reflexive in her upper extremities. Laboratory studies were ordered and a TSH was shown to be less than 0.1 with a free T 44.26, both abnormal as you can see from the provided reference ranges. So the emergency doctor um Jessica calls an endocrinology consult. Um and I'm hoping that you can take us through your initial evaluation when you see this patient with new onset hyperthyroidism. Sure, thank you everyone. Um So when I first get a consult um primarily the first thing I see are these labs of course. Um So when I get a consult for thyroid toxic oh sis. My first three thoughts at the top of my differential are gonna be Graves disease, A functioning adenoma or thyroid itis. And while of course the actual differential of thyroid type psychosis is much longer as you can see in table 12 on the right of your screen. Um those are the most common ideologies that we see clinically. And so that's where I start. And of course from clinical history you can get a lot of information that could clue you into the ideology but as far as differentiating between the possible ideologies. I rely first on really the physical exam. Um So looking at the physical exam is really helpful. So if somebody has an enlarged painful thyroid we might be more thinking along the lines of a sub acute thyroid itis. If they have a palpable nodule, of course it might lead you to think more along the lines of a functioning adenoma. And then as far as Grave's disease, sometimes they can have an enlarged probably a pain less thyroid. But of course as in this example the exam can be normal and so that brings me to the next part of the work up, which is really um really the most important for me when I see a patient with their attack psychosis are these Graves antibodies. So the first thing I order are the fire atropine receptor antibody, abbreviated trap and the thyroid stimulating immunoglobulin, abbreviated T. S. I. Um these are really the most efficient and cost effective way to make the diagnosis of Graves disease. Um And so that's really where I usually start. Um you can consider imaging um in the work of of these patients depending on what you find on exam. Of course, if you find a palpable nodule, that would definitely uh kind of clue me into getting some sort of imaging study. Um I do just want to mention one thing on the differential hair I have listed at the bottom is biotin um when somebody has a lab or kind of the lab pattern of fire a toxic oh sis um if somebody is on a high dose biotin supplement generally these are marketed as hair, skin nail vitamins. It can actually cause assay interference causing what looks like a hyper thyroid picture. Low TSH high free T. Four. So whenever you see these labs just be sure you check with the patient to make sure that they're not on biotin if they are um we have them stop the supplement for about three days and repeat their blood tests. So that's super helpful. You did mention the trap and T. S. I. Antibodies. And are those something that will be back immediately in the emergency department so that you can make an informed decision in that regard Or you gonna start some sort of treatment for the symptomatic patient before those returns. That's a really good question. So no of course these labs can take anywhere from like 3-7 days. In my experience they are send out lab um and so that would be you know at that point is really important to use your clinical history and physical exam findings to kind of clue you in. They have a family history. What was the you know the timing of onset. Do they have a trigger that you can identify that can kind of help you work through a differential um You know if your if your able in that setting specifically in the er doing a bedside ultrasound can help certainly um Graves disease on ultrasound is classically um really hyper vascular looks heterogeneous and so if you're kind of thinking along the lines of the Graves or functioning at a normal we can start treatment with medications which we'll talk about later versus the thyroid itis which generally is supportive care. That's a terrific segue. The treatment perfect. Um So once we make the diagnosis of Grave's disease which I generally most of the time make with those antibody tests um there are three parts to treatment medical, surgical and radioactive iodine for the vast majority of patients. We recommend starting with medical therapy of course unless they have some sort of contraindications or they're objecting to it but we will start with medical therapy which consists of um Guyana might or an anti thyroid drugs. Um My thumb is all PTU and car bazaar which is not available in the US but we generally use the missiles. First line therapy. It has its most potent, it has the longest half life. So it's dosed once daily and has a better side effect profile. Um We do use PTU which we'll talk about later in some specific situations. Um And the second part of medical therapy is beta blockade. So we use this not in every Graves patient but generally if they're symptomatic, they have cardiac disease if they're elderly. Um And especially if they're resting heart rate is above 90. We recommend starting it kind of while the meth um Azul is working to get the patient you thyroid Um I will draw your attention to one contra indication is in bronco spastic airway disease. We do use caution in these. So, um if they absolutely seem like they need one, it'll be kind of a multidisciplinary discussion in that sense. That's great. And I think those thresholds of looking at the heart rate, making an informed decision based on that regarding the beta blockers super helpful at night. I recall from more than 25 years ago that we're supposed to avoid a native blockers and those with the Bronco spastic airway disease. But I won't give away too much of my age anyway. So the patients sort of like stewing along. It's been a couple of years, you know, like a couple months a year or whatever. Um and they are interested in definitive treatment. There's a lot of debate and even differs across countries regarding um surgery versus radioactive iodine as preferred treatment for Graves disease. So, um Dr Wachtel, can you tell us a little bit about your considerations when the patients referred to to discuss surgery as a definitive treatment option of course. Um Well, glad to be here and happy to be able to chat about this. I think I want to first start off by reiterating what Jessica mentioned, which is that surgery is almost never the frontline treatment or the first line of therapy for patients with Grave's disease. And that's for two reasons. One because a fair number of them will actually achieve durable remission with medical therapy alone. And then the second reason is that we're we're often dealing with people in an acute setting when they are incompletely physiologically captured and adding a surgical stressor of a general anesthesia. And that setting will actually usually make things a little bit worse. So typically patients will have at least a trial of medical management and in an ideal world, there are going to be you thyroid or approaching you thyroid um prior to a surgery. And I always talk to patients about the fact that when we do a surgery for the Grave's disease, we must do a total thyroidectomy which commits them to lifelong thyroid hormone replacement therapy afterward. And that's just because if we leave any tissue insight you then those patients are actually set up for recurrence in the future because the antibodies never don't completely go away and that hypertrophic effect will persist and so the tissue will grow back inevitably over time. In terms of the situation where we would consider an early surgical therapy will often talk about this for patients who have failed medical management, have an acute contra indication to medical therapy and then for special situations. So patients who have a very large goiter potential airway compromise or patients who have a severe thyroid eye disease. And I know we have a fortunate to have an expert colleague on the line who's going to talk a little bit more like about thyroid eye disease as well as patients who are pregnant or desiring fertility in the near future. And those who are smokers. So these are all things that we discuss with patients up front. Um And we also I think it's important to engage the entirety of the multidisciplinary team so that everyone can weigh in in terms of finding the best treatment plan for each individual patient. So I really like the point that you brought up and I'm gonna bring it back to Jessica for a second um regarding uh you know, how long do you wait? So let's say somebody is nicely controlled on medication. How long do you wait before deciding that you should refer them for definitive treatment? And um are there any tests that you can do to make a diagnosis of remission? That's likely to be durable. Sure, that's a great question. So when we start medical therapy um we kind of have a discussion with patients. We generally keep them on medical therapy for somewhere between 12 to 18 months. Um because in that period of time is when uh if the patient is going to achieve a durable remission, they may do that and it takes some time. So we generally commit them Um to 12 to 18 months. Um at the end of that period will reevaluate generally with a trap. So the thyroid receptor antibody to determine what their likelihood of having a durable remission will be. So if at the end of that period there on with a missile and their travel is normal, they are likely to have some success coming off them with them is all um and not needing it anymore. Now if their trap is detectable, if it's elevated, that's really when we will push a little bit harder with the patient to decide on a definitive therapy because taking them off them at them as well as likely to be unsuccessful. They'll have recurrence and we'll have to put them back on. That's super helpful. So going back to surgery heather there are you know people hear about complications of an operation and it's scary. Can you comment a little bit about risk benefit profiles and how you talk about this with your patient. Of course. Well we have yet to invent a surgery that's actually entirely risk free. So everything comes with its own risk. And one of the discussions is always you know what type of risk that the patient is willing to tolerate. Overall thyroidectomy. For Graves disease is very, very safe and very well tolerated. And for a patient who goes into surgery stable without any acute medical issues can sometimes be done as an outpatient procedure. I always talk to patients about the potential major complications that we worry about which include recurrent torrential nerve injury leading to either temporary or permanent issues with their voice um or swallowing. And also hypo parathyroid ism or hypo calc mia which can be due to a combination of things. One many of these patients actually going into surgery are are actually a whole body depleted for calcium. And so they're set up for a low calcium after surgery. And then when we add on the I. A. Transgenic manipulation of the parathyroid glands. During the surgery, patients with Grave's disease are at higher risk of both prolonged and severe hypothyroidism and hipAA calc mia after surgery. So there sometimes is a role actually for repeating them prior to surgery and to to prevent this. Those are the major comorbidities or major complications of the surgery. The minor complications are typically self limited and will resolve in 1 to 2 weeks. So some sore throat, a little bit of stiff neck, um some irritation, some fatigue. And these will generally resolve very rapidly on their own. A very rare but worth discussing complication of surgery is a hematoma. So this is a bleed in the neck and this is an acute airway emergency. It is very uncommon and in skilled hands Maybe less than .5%. But this is one of the reasons that particularly for patients who have very large Reuters or um you know may have a need for anti coagulation or blood thinners that will often watch them overnight in the hospital. Yeah, I I always think it's funny one of my patients brought me this slide to ask about the realities of thyroid surgery. So I always think it's nice to think about what the patients are actually looking at before and after. They see us as clinicians to help mitigate some of their anxieties, you know, regarding these these experiences with surfing the web. So, um, I always like, I think an informed patient is probably the best patient. And of course surgery is not the only definitive treatment. So radioactive iodine, which is the most um, I think common treatment for definitive treatment for Grave's disease in the United States. This differs in europe. Um is another consideration. I think patients should hear about both treatments. Um, and I know the endocrinologist do a great job of this. Sometimes. I think it's also helpful just to get an opinion. One from a surgeon, one from somebody from nuclear medicine, learn a little bit more. So Doctor Prima, can you um tell me a little bit first about the radioactive iodine scan? What do you see? And more importantly, what does the report? Tell us about what you're looking at here? Yeah, So, and I was actually that slide before I need to borrow that and hang it in our clinic when makes radioactive iodine seem pretty benign. But um, so in in Graves disease typically not a subtle scan. So these are super overactive thyroid glands. Normally, nuclear medicine, we've got unclear medicine. You're looking for these little subtle things that only a nerd like me can find. But here it's just, all you see is the thyroid gland. It's a big land very often you can see the estimates typically should be just like a sliver of tissue that you can't really resolve on our scan. But you can see those nice big thick isthmus joining them. We often talk about a parameter lobe which is in the midline. You'll see some activity and that's actually remnant virus sites from when the thyroid developed at the back of the tongue and migrated down the thyroid glassell duct. Um And even those few virus sites get stimulated enough that they hypertrophy and you'll see them. Typically it looks pretty homogeneous. Um And the most important value we get is we do a measurement with these scans which you cannot do with Um the technician protected Tate scans. It does require radioactive iodine. But you measure a 24 hour uptake And that tells you what percent of that capsule you gave that ends up in the Thyroid Gland. And typically in graves disease, we're seeing like 60-80%. So imagine a patient is swallowing few picograms of iodine in this pill. And 24 hours later, 80% of that has been taken up. And organic fied in the thyroid gland. And so because of that's why we can treat with radioactive ID and have very little radiation exposure to the rest of the body. Just because that thyroid is so good at taking that iodine out of the bloodstream and organic firing it. So is there ever a time when you wouldn't see such high uptake in somebody with Grave's disease. And yet they still have the right that you have the right diagnosis, yep. So so the biggest thing is if the patients taking their anti thyroid medication up until the time of the treatment, so we want them off of it typically for five days prior to their scan. Um and that can certainly cause problems. We've we've had quite a few patients where they have some miscommunications or unclear instructions and that's the biggest cause of false positive um with things like thyroid cancer, we put patients on a low iodine diet and do a lot of other things to prevent suppression. But in Graves, it's really not necessary. I mean a patient can go straight from the sushi bar to nuclear medicine and that thyroid is just so hungry for iodine, it's not going to suppress. But we do definitely need them off their anti thyroid medicines. Um but knowing how severe and how 10uous their grades is is important in terms of when they should get back on their anti thyroid meds. Some some people, if patient gets treated, they don't put them back on interestingly, a lot of the time it is. And I'd be interested in Jessica's take on on when patients need to get back on their anti thyroid meds after their scam. So we're gonna Jessica come to in one second And another thing I have to follow up on you called? I don't know if you did it consciously or not, but you said a benign therapy. So it's radiation. I mean what what are the risk? Is there any evidence about a risk of you know, subsequent cancer as because of the exposure of the radioactive violin? Yeah. And and I just want to go back to the title of this webinar. It said old effective. And you and I wanted to make sure everyone realized that that's not mutually exclusive. So I think this is both old and effective. We know that radiation causes cancers. We know that from adam bomb survivors, we know that from patients getting external beam radiation, what we don't know is the minimum amount of radiation needed to cause a cancer. And we also know that cancers are very, very common. And so trying to find an incremental risk on top of something common is very difficult. Um The bottom line is there's been a lot of studies covering about half a million patients total that have looked at cancer risk. And in these meta analyses of all those studies, there's no detectable increased risk of malignancy. Um there were some signal that in two out of like the 11 studies that were looked at in the meta analysis, there was some correlation with cancer mortality. Um but it doesn't really make a lot of radio biologic sense that there could be no increased risk of incidents but increased risk of mortality. And so it's um it's still really up in the air. But in terms of overall I guess the reassuring thing is despite looking really, really hard, no one's seen a signal. So even if there is an increased risk, it's small enough that we can't really detect it on top of the overall lifetime risk of malignancy. And and as as Dr Wachtel said there no one's created a perfectly safe surgery. And that's generally true of anything. All these treatments. Um if you watch the news and hear all the side effects, they mentioned all the drug ads, you realize nothing is totally completely benign. But the safety profile is certainly they're in the risk of not treating these patients is higher than the risk of treating them. Thank you. So, you brought up a really interesting point as a surgeon. You know, literally the day after my patient you know, is treated, we stop all anti thyroid meds and in fact we start them on thyroid hormone replacement. Um Dr Berman, can you comment? How does that how does that translate to management after radioactive iodine? So generally um After radioactive iodine we wait at least like 3 4 days. And to have them restart them with them as well actually. Um engravings these specifically because we know that after radioactive iodine in some patients, they can actually become more thyroid toxic as the thyroid is being destroyed. So um as a precaution we put them back on them with them as all. And then check their labs, you know, 4 to 6 weeks after the treatment to kind of guide us if we're able to start tapering down there with them as well depending on um you know, if we see treatment effect and sometimes it doesn't it can take six plus weeks to actually see effects from the radioactive iodine. Um so in that time we do keep most grave patients back on their with him is all. And I and I should mention of course that we don't just abruptly stop their beta blockers because they do have some residual thyroid hormone in their systems. And so those get weaned off over time, usually by their endocrinologist. Um all all really interesting. The one thing that we haven't really talked a lot about yet is thyroid eye disease. So, I'm wondering dr percy no, if you would give us a little bit of an understanding of of thyroid eye disease and does every patient with Graves disease by definition of thyroid eye disease. And how do you know? And who should see an ophthalmologist? Thank you. Thank you for inviting me. So, thyroid eye disease is part of kind of the autoimmune millio that is everything we're discussing. And it turns out that an epidemiologic studies. It's about 30% of people who get diagnosed with grave's who ended developing the thyroid eye disease, thyroid eye disease is a unique autoimmune disease in the sense that it has one active phase. Typically That burns out over about an 18-month period. It does not have a waxing and waning forest, like many other Autoimmune conditions that we are used to thinking of, such as rheumatoid arthritis, etc. And so that active phase on average lasts about 18 months. And so people typically presents with something similar to what you see in the photograph here, red eyes that are bulging with eyes that look to open. Um and they're very red and very hot. You can see the inflammation from across the room and folks who are severe and that's what we call that active phase of the disease. We'll talk a little bit more about the path of physiology in a second, but then eventually that burns out into a quiescent inactive phase that can still be quite disfigured. Like what you see in the second photograph, there's no redness, there's no heat. But those eyes clearly are still bulging and are pointing in strange directions. So what you see in the graph is called Randall's curve. It's questionable how accurate this is, but it helps us to conceptualize and to explain this to the patient. Things are going to be hot. They're gonna be hot for a long time. You'll need a lot of supportive therapy while you're undergoing this inflammation. Eventually things will settle down and we may need to do surgery at that point now in recent years, we've had nice developments in terms of treatments for the active phase. We're going to talk a little bit more about that a little bit later. So we can actually go on to the next slide, please. And while we're transitioning, when does a patient like have to present with thyroid eye disease immediately at their first diagnosis? Or can it develop like down the road when they're on anti thyroid meds? Great questions. So it can actually come at any point. It can be before the thyroid state during or after. Um The vast majority of people present with both diseases within about one year of each other. And generally the thyroid state comes first. But there's no rule that says that that's the case. And often times we see people present to the ophthalmologist with what they consider to be ketosis. But in fact it's retraction of the other eyelid. And that's how this diagnosis is made because they're this thyroid state, maybe subclinical. And so um having a high suspicion for this is really important. Again, only about 30% of people end up manifesting it. But this is one of those inherent issues with epidemiology and a lot of subclinical people may never present. So it may be higher than that and we just don't know. Um the diagnosis is made clinically. So the trap and T. S. I. And all those things help us. But really the diagnosis of Graves disease. I'm sorry, the thyroid eye disease is made clinically. and the reason is because not everyone with thyroid eye disease who does have a thyroid state is in fact a Graves patient that's about 90% of the group, Another 5% can be high, both thyroid And then another 5% can be you thyroid altogether. And so it is truly a clinical diagnosis. And the most salient feature of it is retraction of the eyelids. Which is to say when you're looking at someone's face, you should not be able to see white on top of their iris, the colored part of their eye when there is white showing above. That's usually a telltale sign that something is going on. And usually that something is this thyroid disease. So really, really interesting. I um I wonder just along those lines. So should every patient be centrally ophthalmologist for an exam who does have um you know, a diagnosis of grades? I think it is a good idea. Yes, I think it is a good idea. I mean by and large healthy adults underutilized of atomic and optometric eye care. Um you know, we could all stand to have an exam to rule out all sorts of other common and asymptomatic conditions such as glaucoma and um you know, perhaps presbyopia, people who might need reading glasses before they realize and dealing with headaches and they don't know why. And so in general it's a good idea to have a once a year or once every other year checkup. Um but yes, in particular people who are at risk for this. So for among people who have Grave's disease, if they are a smoker, they have a seven times higher likelihood of developing the eye disease. And so this is one of those really convincing things for people to stop smoking because um once they have facial disfigurement, they tend to pay a lot more attention. But it's a good way to both prevent it and to mitigate it once the eye disease shows up. But even in the people who are not smokers, um, having a baseline evaluation of their eye health is really, really, actually very important. It's a great way to introduce them to that part of their chronic health care. And it's a great way for us to pick this up early, which makes it a lot more manageable, especially in the light of recent medical developments. So, um, you know, continuing along with kind of what you do early on, you know, the management of their and achieving a you thyroid state is by far the most important thing that needs to happen. So even though this is really a direct consequence of the autoimmune process, there is in direct correlation between their kind of sympathetic tone and their hormone level, as far as how severe the eye disease is. So the more they are you thyroid, the better off they will be in terms of their comfort. Um you want to get them to stop smoking because of what we just discussed. Um Generally their discomfort comes from a lot of dryness on the surface of the eye because the inflammation leads to under production of tears. And so something as simple as over the counter artificial tears can make people feel significantly better. Um selenium. It's questionable whether it makes a big difference, especially in north America, which is a selenium rich soil part of the world, but the supplementation that 100 micrograms twice a day tends not to have any really bad side effects and people feel like they're doing something And that matters, especially in thyroid eye disease, where you often have to just wait for stuff to happen. Um and then you know, there are the other kind of truly directed therapy. So for a long time, all we had was steroids and so that usually comes in a very high dose 500 mg metal bread for six weeks once a week. Um external beam radiation has fallen out of favor and more interestingly and recently as of 2020, the commercial availability of which has really radicalized how we treat this disease. So I'm really excited because I think this is the single most novel thing that we'll discuss on our webinar today and I want to note that it is coming up exactly at 7 30 perfectly timed. Tell us a little bit about the biology of thyroid eye disease and and this new treatment. So what we understand about the molecular underpinnings of this disease has been elucidated over the past roughly about 20 years by terry smith and Ray Douglas who are working out of U. C. L. A. And michigan. And what they realize is that there is um there's a peripheral blood cell line, the fibrosis sites that migrate to areas of tissue injury. And this is what they do under normal circumstances. Well it turns out that those cells in folks with thyroid eye disease behave rather differently. So because of the presence of these autoantibodies which are somewhat mysterious um they hone two areas that they are not supposed to. And this is not just the orbit. This is also the skin. When people have particular mix edema and and such. And what they have discovered through collecting and culturing these cells is that there is a particular signal cascade that involves memorization of the TSH receptor and the insulin like growth factor receptor. And when they come together on the surface of these fiber sites and these downward cascades are activated by these autoantibodies. It causes abnormal differentiation of these cells within the orbital space. So these cells travel to the orbit as if the orbit has suffered an injury which it has not. And within the orbit they further differentiate into abnormal melanocytes which infiltrate the extra ocular muscles and into abnormal sites which expand and harden the fat that is behind the eyes. So as a result because the eye is a bony socket that has nowhere to go out. And so you get prognosis and the very kind of dramatic stare appearance and the muscles themselves become fibrosis and hardened, which pulls the lid more open. So it's a double whammy your eyes further out and your eyes can't close and then the extra ocular muscles become hardened and so they end up pointing in different directions and they have double vision. In the worst case scenario, the hardening and expansion of these tissues is so severe that it clamps down on the optic nerve and thus causes a compressive neuropathy. And this is where this disease can become actually vision threatening the second way in which can become vision threatening is if the anterior disease is so severe that the eyes truly can't close, then the dryness of the cornea ends up scarring it and you end up having visual problems that way. And so the astute observation by dr smith and Dr Douglas is that you don't necessarily need to immuno suppressed in order to address this signal pathway because it is in fact a dime er of those two receptors, the TSH receptor and the insulin growth factor receptor. And so instead of targeting the TSH receptor they went after the insulin like growth factor receptor in order to prevent this cascade from happening and thus thus temper to math which was some shelves biologic that some company in Ireland had or something. They bought it and they built this up and so this has now the ability to those thyroid stimulating immunoglobulins don't have the ability to interact with that timer because the medicine is standing in between and thus all these downward cascades that happen from these abnormal fiberglass that used to be fiber sites cannot occur. And so for the first time there is a medicine that not only minimizes the progression of the disease but can actually reverse some of those fiber optic changes that we discussed in their phase two and phase three studies they had in people who are newly diagnosed. So this is a very carefully selected group of people to be fair. But they had an almost 90% success rate in reducing prognosis, reducing the tilapia and reducing clinical activity. Which is kind of the clinical sport that we used to say how hot people's orbits are. And so um it's nothing short of miraculous in terms of the treatment of this condition. Now, as far as its side effects they, compared to a lot of other biologics are actually rather mild but people do have to deal with some muscle spasms, it is affecting the insulin like growth factor receptor pathway. So they can be hyperglycemia, especially in people who are also diabetic and um there is reversible but nonetheless bothersome, sometimes tinnitus and mild hearing loss and also um mild alopecia and so you know these are things that are really important for patients to consider when they're going on such a drug. But I have not had a single patient stop the medicine yet permanently. I've had people take breaks because of side effects. They've all been very motivated to get back on it because of how positive the impact has been on their high disease. So is this a medication for life then or is there a point at which you're fully treated and you no longer would need it? Excellent question. So still to be determined um for life probably never. But the studies that were done were for eight infusions over a six-month period. And for those people who then became inactive, only about 15% of them actually reactivated thereafter. So the question is because of what we discussed earlier, the active phase of the disease last 18 months. So it's possible that you can treat and finish treatment and then keep going with your life and this inflammatory process is still smoldering in the background. And so there are indeed some patients who have benefited from a second, six month treatment or from an extension of the treatment that they initially started. The other question is, what do you do with people who have been diagnosed for more than six months? We're not new onset thyroid eye disease people. Well, it turns out that and this is only with small case series so far, there are larger studies that are ongoing, but it turns out it's effective in those people as well. So this speaks to the biology of scar tissue that it is living tissue and it constantly re deposits just like the rest of us. And so even in those individuals who are not in the active phase of the disease, remember this isn't an immuno compromising drug, it's dealing with the fibrosis itself in those individuals, they also tend to respond quite readily. And so, um, it's been on the market for two years and the post market studies are very actively happening right now. We are recruiting for them and providing data to, you know, the powers that be in order to really look at this in a more structured and scholarly way because right now a lot of what we depend on is anecdotal. But to try to answer your question more directly, I suspect that there's gonna be a subset of people who benefit for much longer therapy than just the six months. But the majority of people tend to actually get better and not recur that's really exciting. And of course this is like very new, very new information. You know, only been going on for two years. So we'll stay tuned and look forward to learning more as as you and the general community of ophthalmologists um learns more. We're now going to switch to the next phase of this case. It's called case too. It's actually the same woman. We're going to spend the next 15 minutes or so discussing the next two cases and then we'll leave a little time for additional questions at the end. So um unfortunately medication compliance is a challenge. And the our our young 56 year old woman winds up back in the E. D. Now she has bulging eyes. Um as you can see other symptoms of swelling, extreme fatigue, nausea, vomiting. Um and reports that she she was not compliant with her medication. So um she now has um you know jugular venous distention and lead lag. Uh You can see a picture not of this actual patient but of a patient who fits a similar profile. Um Dr Berman where do we go from here? Um So obviously um this patient looks a little bit different than the first patient or the same patient but that looks a little different than when she was first diagnosed. Um You know call your attention to hypotension tachycardia. She looks overtly thyroid toxic as far as all of the symptoms that you mentioned. And of course her labs um to an undetectable TSH and undetectable undetectable, high free T. Four. Um So this calls into question this uh you know kind of spectrum of disease like thyroid toxic cosas versus thyroid storm. And so thyroid storm is a really important uh diagnosis to talk about mostly because of its really high mortality rate. Um depending on the study anywhere between 10 to 30% mortality rate in these patients. So clinical suspicion for this condition should be really low and and starting treatment should be kind of um you should have a low threshold to do so to kind of mitigate some of that high mortality. So thyroid storm is actually a clinical diagnosis. There's no one objective criteria that, you know, their T. Four needs to be X. High. Their TSH needs to be this low. Um You know, it's it's generally defined as a systemic decompensation and a fire a toxic patient. So um You have to have the labs that show Tyra toxic, closest to what degree it differs. Every patient is different. Um someone might go into thyroid storm at a lower T. four than another patient. So um what we're looking for here is that pattern of labs plus a sign of some sort of systemic dysfunction. So there are a couple of scoring systems. Um One out of the japanese thyroid association and the one um you may have come into contact with in this country is the birch borzakovsky point scale and that's what um in the chart to the right. Um And so you can look at the criteria and they're basically looking at all a number of different systems and signs that there is decompensation and dysfunction and it can kind of help guide clinicians on um if the patient is likely to be in storm if they're an impending storm. Um And it can kind of help clue us into when we should be treating these patients as if they're in storm and and along that lines, what does treatment look like? So treatment is generally four parts. All parts are are important. Um First we use anti thyroid drugs just like we would when we treat their graves when they're not in Storm. Um This is one situation in which we do choose PTU over with them a soul if it's available and feasible. Um And the reason for that is that in addition to blocking new hormone synthesis, it also blocks T four to T three conversion. So you have less active thyroid hormone um kind of in circulation. PT is not available. We we use with him as all just as often. Um well not just as often, but we can use with him as all the next part are beta blockers. Um We generally use propranolol on this case. Um Again, because of high doses, the beta blocker can block this T four to T. Three conversion. I will note that patients and thyroid storm can develop heart failure. So of course if you're concerned clinically for that, these patients may need close monitoring because as we know, beta blocker could precipitate worsening of a heart failure exacerbation. The next is iodine. So we have legal solution or potassium aidan sk eye drops. Um And the reason we would use this is kind of taking advantage of the wolf takeoff effect where iodine load can actually stop new hormone synthesis and release. But something I will make take pause a note here is that this needs to be given at least one hour after the PTU or the mathematical is given because if you don't you can potentially worsen the condition and cause higher thyroid levels. And then lastly we used hydrocortisone, we use high dose steroids. Um Again, it's thought that these um reduced T four to T three conversion, which is primarily why we use them and then we block or protect against a relative adrenal insufficiency. So because Graves disease is the most common diagnosis when somebody has thyroid storm, it's an autoimmune condition. So they could be likely to have an autoimmune adrenal insufficiency we don't know about. Um and going into storm and someone with adrenal insufficiency is a is a recipe for adrenal crisis. So we kind of use it almost prophylactically in case that were to be the case. Um in the interest of time, I'm just going to note that sometimes we do get consulted as surgeons for thyroidectomy and these patients, if it's thought that they're going to get into too much trouble after they go home. Um and dr martell just very briefly, What do you what conditions do you need to accept this challenge. So this is always a challenge on multiple levels, on the medical level, on the critical care level and on the surgical level and essentially we have a conversation and it's really key that our critical care and endocrinology colleagues are involved. And if they can say that they have really maximized medical therapy and the patient is not responding or they have high concern for recidivism. We do consider that an indication for surgery as best as possible. We'd like the patient to be physiologically recaptured before we place that additional general anesthesia stressor on them. Um In particular Hema dynamic stability is of paramount importance. And so an s mobile infusion, an excellent anesthesia team who's poised, you know, and prepared to deal with rapid onset cardiac insufficiency. The main concern is that when we start to manipulate the thyroid inter operatively we can precipitate of how patient thyroid itis or even worse in thyroid storm. So we like to be prepared for that. Um So those are the main considerations. But sometimes it's really the only option. And in those cases we proceed after having a you know, intelligent conversation about it and fully informing the patient. Yeah. And I would just mention that sometimes um we have these patients transferred in from outside hospitals, even within our own system. So this is an operation that should be done in a center that has um you know, the capacity to deal for very sick patients in the operating room setting. I will say though it is really remarkable that how rapidly they actually write themselves and how much better they feel in a very, very short time. So it's it can be very gratifying as well, very gratifying. And I think that's a nice segue into this. I can read again slide as I like to call it um dr person you know we we heard a lot about your expertise as the medical side of ophthalmology. But of course ophthalmology is a medical and surgical specialty. So this patient you know, comes in uh let's say their smoldering medical problems being controlled um and they are having an acute eye problem. How does that differ? So um one of the issues that can precipitate urgent surgical intervention in thyroid eye disease is vision loss from the optic nerve compression. So the medical management that we have discussed often can lag to really give improvement in the compression at the orbital apex because the effect is not immediate. Obviously on infusion every three weeks. And the effect, yes, they start to see improvement. But you need something sometimes quite dramatic to happen in order to relieve the pressure on the optic nerve itself, allow blood flow to resume normally to that tissue and prevent Exxon loss. And so there are some instances in which we have to do urgent orbital decompression. This is one of them. So this patient was the sole driver in her household and was losing vision as you can see in her visual fields which are to the right basically where it's black, she can't see. And so in her left eye she had a hemi field defect on the right side. She started to have an enlargement of her blind spot. Um the right side was doing okay. So she was managing but this was progressing at a rapid clip. And so rather than depending on medical management which she already was on, we had to take her to the operating room in order to expand her orbital volume. And so in the first slide you see the CT scan before surgery and the second slide or the second picture. You see the CT scan after surgery. So we access this space by going through the content Eva so the innermost corner of the eye we displace the eye out of the way. And then with a small ultrasonic drill we basically take down the bones of the inner wall of the orbit as well as the floor to break them into the sinus cavities. So we use the space that's in the sinuses, it's like remodeling a house on HD Tv. We Bust down the wall and shrink one room in order to enlarge another. And so in the process we then decompressed the apex such that the blood flow is reestablished. And so as you can see two months afterwards the area that was darkened because the external loss was not yet permanent she was able to regain the majority of that and was able to both read and drive again which made her very happy. And so it's a dramatic intervention that we don't necessarily jump to. But in cases where there is acute loss it's appropriate. Well the open floor plan which is so popular today I am sure myself and many other people on the call would have a lot of questions about this. Probably a good topic for a subsequent webinar. Just to sort of focus on thyroid eye disease. In the interest of time. I'm gonna move us on to our third case. We're gonna really just stay very focused here on Um this lovely 36 year old woman who presents the emergency department at 12 weeks gestation. Um She you know has had significant nausea and vomiting and now comes in because she can't tolerate anything by mouth. Found to be hyper thyroid in the setting of pregnancy dr Berman. Where do we go from here? Yeah. So this is a common console that we end up seeing these labs where we have abnormal T. F. T. S. And a pregnant patient. So the question is um is this a new diagnosis of Graves disease or is it something called um just station all fire attacks ecosystem. And an interest of time. You can skip to the next slide. So we can kind of hone in on the crux of this case where um this is you know a common um kind of finding in the first late first trimester of pregnancy where because of the hm Ology between beta H. C. G. And T. S. H. Um patients the first trimester when their beta HCG levels are the highest. Can actually have stimulation of the TSH receptors by beta HCG. Um So it basically makes them look like they are fire attack psychosis. And they can actually develop mild fire attack psychosis from the stimulation of the TSH and thyroid hormone production by the beta HCG. It generally comes along with hyper and mrs graviton because the HCG does the same thing with nausea kind of augments nausea and vomiting and so on the left column here this picture of gestational thera toxic coast as we see nausea vomiting they can have fire a toxic symptoms are generally mild. Um But they won't have findings that are classic in Graves. They won't have the orbital apathy. They probably won't have a brulee or a greater on exam and their travel be negative. That's a key finding in these patients and how we differentiate definitively. Um And their ultrasound which in general if this is a patient you see in the er or something you can get or in clinic even um if you have bedside ultrasound you can really use that to differentiate the two as well. I will make a comment just about Grave's disease In pregnancy it requires a lot of monitoring. Um Some women will go into remission while they're pregnant and they don't need their anti thyroid medications. Um But some women will continue to need them. And generally the principle is P. T. U. Is used in the first trimester. Um Whether the patient has pre existing Graves or new diagnosis of Graves in the first trimester pt you just because um in studies it had fewer uh Terada genic effects. Um And that's when organogenesis is occurring. And so we use that when at that time and then they can switch to them as well in the second trimester. Um It is important to closely monitor these patients with a trap at least once a trimester because that has implications for um fetal monitoring and and the chance of fetal hyperthyroidism. And so that's important information to share with our, you know, M. F. M. Colleagues um so that they can be appropriately monitored during pregnancy. Yeah. I mean these are very real considerations and I think also women of childbearing age who may become pregnant I think. Um how do you how do you talk to the patient who's who has a history of Graves and is thinking about getting pregnant in terms of definitive treatment or can they stand medication? A really good and challenging question. Um Generally if we have if a patient comes our first diagnosis of Graves they're planning on having a child in the next few years, we generally will counsel them. That definitive therapy is probably the best option for them early on. Um We generally kind of think treating a hypo thyroid patient is a little safer and easier than treating a graves patient and pregnancy just because of these implications of uh within the NPT therapy during pregnancy there have been evidence of birth defects. And so if we don't have to have a patient on that, it's probably ideal. So if we have time in advance we probably counsel them to do some sort of definitive therapy in advance of trying to get pregnant and if they do up for radioactive iodine and they have to wait at least six months before they try to conceive. Um So this is terrific and we are now going to transition into our audience participation. We have a question from the audience that says I have a pregnant patient who I was able to discontinue with Emma's Ole, she's now in her third trimester. Her TSH is point oh 23 to 4.6. Should I start with a missile patients? Asymptomatic. So that that's a really interesting case actually. You know, I would be sure to check her trap to kind of see where that is. That's also like I said has implications for the baby. Um The other, you know that TSH is low. Um So I'd be interested to see what her trap is if she's you know been kind of stable prior to this point in pregnancy. Um and the free T four is normal. We do have different um TSH ranges in pregnancy, although 40.2 is a little bit low. So I check the trap to see to kind of confirm this as a recurrence. Um uh and then and then you may need to restart it if I think if that's positive. But now that you're in the she's in the third trimester. Hopefully the risks of that medication are diminished. Um and so about thyroid eye disease. Is it all right to refer a patient for radioactive iodine after successful treatment of thyroid eye disease with the petro to nap? Sorry, sorry, if I put through the name of that. Yes. But I think that the you know, there's been a lot of advances in terms of how we dose the and I don't know much about this. I'd have to defer to nuclear medicine about that. But how the dozing is done in the eighties versus now is different and therefore safer for as far as the kind of thyroid eye disease risk afterwards. But the pre imposed treatment with steroids is still something I would recommend because there is always that specter of the risk of reactivation of the disease. That's always their lifelong. And so to the degree that that can be mitigated, the person is not contraindicated against steroids. I was still pre imposed street with steroids for stranded protocols. And then that risk should be mitigated. It should be quite low. Yeah. And I would just add that. It used to be the sort of mantra was thyroid eye disease, No, radioactive iodine and I think it can be done safely. But the important thing is when I think about giving a patient steroids I think about a metro dose pack and that is not effective for patients with thyroid eye disease. They need doses of steroids that are enormous and prolonged and that really does need to be done under the supervision of an ophthalmologist. So I have a very low threshold to make sure my patients are seen and if they need steroids that they get the right regimen because a week or two is not sufficient. And this is a circumstance in which we often see patients actually for a surgical consult. So patients who have had a have known diagnosis of thyroid eye disease and are now looking for definitive therapy and I agree it's radioactive iodine is much safer than it used to be. I think. Um dr prima can talk to the protocol that we use that pen which is typically a lower ablation dose. Um however many patients aren't willing to take that risk, even though it's a very small and well controlled risk and usually very safe and well tolerated. And so this is sometimes a relative indications with thyroidectomy rather than radioactive iodine. Our next question is for you as well, we're down to the last few minutes. So I'm trying to get the questions in from the chat. But I'll let you finish your thought after I asked the question as well. I usually do not get thyroid uptake and scan for diagnosis. If patients are already on the team as a whole unless I have time before the final diagnosis. Do you recommend doing the scan after holding the thumb is all routinely? Yeah. And that's actually the question I was going to try to get out. So great minds. Um so typically no patients don't need a radioactive iodine scan to make the diagnosis of great. Um so if you've already made the diagnosis definitely don't stop their treatment just to get a scan and and re make the diagnosis. We typically do the scan if we're thinking about blading and we need to get that uptake measurement. And then also occasionally there are diagnostic dilemmas where it's unclear whether a patient may have sub acute thyroid itis um and things like that and and scans can be really helpful but that's definitely a minority of patients. So I would say. And and Jessica could answer more accurately than I can. How many patients she sees that I never see. Um But I'm guessing it's a bunch of them. Yeah. Um that's a nice segue. We have a question for you on can patient staying with them as a long term and then how long do you treat with Miss Emma's all to see if patient is responding before proceeding to secondary therapy. Um Yeah and I agree with you doctor prior to that we end up not scanning a bunch of people. If we have those antibodies. But there are certainly diagnostic dilemmas. We see those often as far as how long you can stand with them as well truly. You know it's up to the patient if they are kind of okay with accepting a risk of long term medication that has side effects. Close monitoring lab somewhere every 3 to 6 months. If that's a patient preference, they you can stay on with a mesotherapy lifelong um because of how cumbersome it is to monitor and and you know most patients don't want to stay on it. Um But there's really no absolute contraindications staying on it lifelong. I have a lot of older patients that are on very low doses that don't want to go through a surgery or the radioactive island and we just keep them on it. Um So it's a patient centered decision um in that sense. And then the second part of the question how long So generally um we will give them at least 12 to 18 months. You know for them to show signs that we can start tapering the medication and um that they may go into remission. So we give them 12 to 18 months. And then we have the discussion about definitive therapy Of course if the patient decides earlier that they want something definitive done, that's their prerogative and we'll do it earlier. But if the patient wants to see um if they're somebody that may go into remission, then we generally will give them up to 18 months before we have that discussion with them again. And and are those signs like stable or declining dose of anti thyroid meds and trap. Exactly. Exactly. So we let the lab's kind of guide us and tapering the medication where we can trap is helpful. Um like I I mentioned if the trap is still positive and we're trying to take them off the medication, they're likely to fail and riker. So we do monitor the trap, especially once we get down to the low doses and with them as all um to kind of help us know whether or not it's safe to take them off for a period of time. We will be running our thyroid nodule um and thyroid cancer webinar again in the fall and we will add in a little discussion about graves disease and thyroid nodules. Um at that time it is now the top of the hour and I really want to um thank our panelists and the whole audience for your participation and your engagement today. I learned a lot. I hope everybody uh found it interesting. You will be able to obtain your credits within a week after the meeting. You'll get an email with CMI from CMI with instructions. So please complete the evaluations as always interested in your feedback and suggestions. And if you have topics you'd like us to bring up on future webinars, please let us know, thanks everybody for your time and have a wonderful rest of your week.
