Thyroid eye disease (TED) can be an extremely distressing condition that affects both men and women, primarily in their formative years. Fortunately, our understanding of the disease process has increased dramatically of late, allowing for targeted treatments that have the potential to change the course of the disease. In this webinar, we will discuss the epidemiology of TED, the relevant pathophysiology, clinical manifestations and diagnosis, and state-of-the-art treatment.
Lecturer: Dr. Sathyadeepak (Deepak) Ramesh, WillsEye Hospital, Philadelphia, USA
DR RAMESH: Good morning, everyone. So thanks for taking the time to come and chat about thyroid eye disease. My name is Dr. Deepak Ramesh. I’m in private practice here in New Jersey, and I would like to thank the team at Orbis for inviting me to chat about one of my favorite topics, which is thyroid eye disease. The talk is gonna talk about kind of what we know about the underpinnings of thyroid eye disease. And then we’re gonna switch to the current state of the art, and then finally I’m going to talk about areas of improvement where I think we still have a lot to learn about diagnosis and management of the disease. So I do want to give my information for anyone who has questions after the talk. Please feel free to shoot me an email. If you think of something or if you have a difficult patient, and you want advice, I would love to share whatever experience I have, or the rest of the team at Wills that we have. We would love to help you out with that. So this is the broad outline of the talk. So let’s dive into the pathophysiology of thyroid eye disease. So there are many things that can make someone who has an underlying thyroid abnormality develop thyroid eye disease. So what are those? There are environmental factors, so things that patients come into contact with, or they ingest, genetic factors, and then of course, things that may be done to them by physicians. Those can put them at risk for thyroid eye disease. So let’s talk about why patients who have Graves’ disease get TED. We know that about 25% to 50% of patients who have underlying Graves’ disease — that is, autoimmune hyperthyroidism — do end up developing some form of thyroid eye disease. Whether it’s mild, moderate, or severe depends on things like age, sex, and race. But we do know that most of these patients have mostly a mild form of disease, where patients tend to improve or stabilize with very few patients having a chronic progressive severe disease. Now, this graph on the right is one of the classic epidemiologic studies of thyroid eye disease, done by Bartley and colleagues at the Mayo Clinic in the 1990s. They took 120 patients with thyroid eye disease and followed them from onset to quiescence of the disease. And they found that the incidence of thyroid eye disease is much higher in females, and it seems to follow this bimodal distribution, where there are patients in their 40s who have a high incidence of disease, and then patients who are in their late 60s who have a high incidence of disease. So there’s something about being in those particular age groups, and also about being female, that puts you at high risk for having thyroid eye disease. So if you see a patient who has Graves, they have palpitations, weight loss, they have system hyperthyroidism, and they happen to be female and in their 40s, you should have a higher suspicion that this patient may go on to develop eye symptoms or orbital symptoms. And I don’t want to gloss over the fact that this is a disease of women who are primarily in their late 30s and 40s. So in that age group, both men and women — but particularly women — are affected by this disease at a time where the appearance can really have a devastating psychosocial impact on their lives. So given that it’s a disease of the young, it affects women at a time where they may be trying to move forward in their careers, they may be trying to find a mate, all of these things that are important to understand in terms of the psychosocial impact that thyroid eye disease has on these patients, as much as all the medical manifestations. And for that reason, I like to take a look at patients’ old photos, to really try and make sure that I understand exactly what’s going on now. And to make sure that we have a full understanding of all the things that they may be affected by, even if they don’t express it. So Rundle’s curve. Rundle was a physician who published the classic curve for the activity of thyroid eye disease in the 1940s. And you can see on the top graph here that he only had five patients. So a lot of what we know is from these original five patients, where he followed their activity course over time. But this has been reinforced by later literature. And what we know is that the active phase of thyroid eye disease lasts about 18 months or so. And within that initial 18 months, patients have disease activity. Meaning they have inflammation, they may have disease progression, they have a changing physical exam, and they go through a curve where initially the disease worsens, and then it slowly improves, to a point where they reach quiescence. Now, as you note, the tail part of that curve — quiescent phase doesn’t mean that they reach their baseline. They reach a new baseline. And that baseline may be 50% better from how they were at their peak. It may be 80% better, or it may only be 10% better than how they were at their worst. So every patient has their own unique journey with thyroid eye disease. And our job is to figure out where they are in that journey, and support them. And then a small number of patients do tend to reactivate after they go through this Rundle’s curve. About 5% to 10%. And usually these patients tend to be older and they tend to be male. Reactivations can be caused by surgery, either orbital surgery or thyroid surgery, or prolonged bouts of uncontrolled thyroid hormone. So we talked about the epidemiology of thyroid eye disease. So let’s talk about heritability. So I told you that females are more likely to have disease. But males, if they have disease, are more likely to have more severe manifestations of disease. So there clearly is some heritable component to this. What this has to do with the sex and the exact pathophysiology is not exactly clear. But we do know that patients have this sex-based predilection for disease. Now, this Punnett square on the right shows us that: If you have the black circle, which is a patient who has thyroid eye disease, and you look at their family members, many patients — family members of TED patients, who are euthyroid, who don’t have any systemic Graves abnormality that has been diagnosed, often have early, early signs of thyroid eye disease, including particularly eyelid retraction. So the dark circles are patients who have full blown TED. The gray circles are asymptomatic patients who — the researchers just looked at them, and they found that they had eyelid retraction. So we know that there’s something genetically that predisposes Graves patients to actually develop TED. And we know from twin studies that Graves itself is partially heritable, when you compare monozygotic versus dizygotic twins. So we don’t know the exact genetic underpinnings of it, but there is a genetic predilection that can be passed on. It is heritable. Environmentally, what are things that can make a person who has Graves develop TED? Well, one thing absolutely is smoking. So we know smoking definitely increases the risk of having thyroid eye disease, and we know that that risk is correlated to the number of cigarettes smoked. So if you smoke more, your risk is higher. And if you stop smoking, your risk actually goes down. Such that current smokers are at much higher risk. If you’re a former smoker, meaning that you quit, your risk lowers. But your risk is still lowest of all if you have never smoked. And we think that this is because of the reactive oxygen species that are generated from the cigarette smoking. The gut microbiome may also play a role in this. So we know that there are certain bacteria. For example, this Yersinia, that express proteins that look like the TSH hormone receptor. And having that hormone receptor as an antigen in your gut can possibly predispose your immune system to recognize that TSH receptor and amping up that response, such that you’re more likely to develop TED. Now, this is not proven pathophysiology, but there’s a lot of research that suggests that this may be possible, and this may be one of the traits that’s passed on under the guise of heritability. So patients who are within a family tend to have similar gut microbiota, and they may have similar organisms that may predispose them to having TED. Other environmental factors include your diet. So we’ll talk about selenium later. But selenium is a co-factor for proteins that are used in the antiinflammatory response. And this famous paper in the New England Journal from 2011 shows that selenium actually reduces the progression of mild thyroid eye disease. So nowadays, with anyone who has thyroid eye disease, we tell them to take selenium supplementation. But what’s special about that selenium? Is it something that — the selenium is consumed? When you have an autoimmune disease? And supplementing it is necessary to replenish that depleted supply? Or is it that these patients actually are selenium deficient in their diets? We don’t exactly know the answer to that question. But we do know that different areas of the world have different amounts of these trace minerals, including selenium, in the soil. And a lack of selenium in the diet may actually predispose patients to having an inability to produce those antiinflammatory proteins necessary to handle this autoimmune thyroid eye disease. So in this paper from China in 2018, they looked at not only selenium, which is on the top left, but they also looked at other trace minerals, including cobalt and cesium. And these are other trace minerals that are also involved in the antiinflammatory pathways. And they were also found to be decreased in patients who have Graves’ disease and Graves orbitopathy. So cobalt and cesium have never been studied in a randomized trial, in a way that selenium was, but it’s quite possible that supplementation of cobalt and cesium can also aid in this disease. So we might want patients to take a multivitamin that covers as many of these vitamins and minerals as necessary. We don’t exactly know why, but we know these are necessary for the body to handle that autoimmune reaction. And vitamin D in particular is another vitamin that in multiple autoimmune diseases has been found to be deficient, and that is certainly also true with Graves’ disease. So again, there’s not clinical data for supplementing vitamin D in Graves eye patients, but first of all, there are many patients who have a natural vitamin D deficiency. And then secondly, it’s difficult to oversupplement someone with vitamin D. So the risk/benefit ratio really leans towards making sure patients have a balanced diet, full of these antiinflammatory materials, including the trace minerals and vitamins, and I think that it is beneficial for patients to be on vitamin D supplementation. So let’s get into the molecular biology of TED. So how does this happen? And the molecular biology really is the underpinnings of now the modern biologic treatments that we have. So Graves’ disease is where you have TSH receptors stimulating antibodies that attach to the TSH receptor, and have downstream effects. And that TSH receptor is not only found in the orbit. It is not only found in the thyroid. But it’s also found in the orbit and the orbital fibroblast, which is a mesenchymal stem cell that can differentiate into muscle cells, adipose tissue, or different kinds of cells that lead to the clinical effects that we’re seeing. And we know that not all patients who have thyroid eye disease have Graves. Some patients have Hashimoto’s, which is another thyroid autoimmune disease, where they have thyroid blocking antibodies, which still can stimulate this hormone and lead to very similar downstream effects. So these are some examples of these circulating antibodies. And we know that these thyroid-related proteins are expressed in the orbit. These are stains of orbital fibroblasts. And the different stains show that you do have thyroid-related antibody staining in the orbital fibroblast, and the higher the antibody level is, we have evidence that shows that the more likely that patients can have a more severe disease course. So there are other sites in the body that also have these thyroid antigens present. So the shins. Pretibial myxedema is another manifestation of systemic Graves’ disease. Where you have an extrathyroid site expressing these thyroid antigens. The antibodies bind and cause localized inflammation. So this is a similar process to thyroid eye disease, in that you have fibroblast activation and differentiation with inflammation and production of fat and growth of other tissues, because of the autoimmune disease. Now, the IGF1 receptor is very interesting, because now we have a new therapeutic for this, which we’ll discuss later. But the IGF receptor, as you can see here, is attached to that TSH receptor. They co-localize, meaning that if you have an antibody binding to this TSH receptor, it will also activate that IGF receptor. And the GF in IGF stands for growth factor. That activates different pathways that lead to adipose tissue growth, muscle growth, fibrous tissue growth, and that can often lead to a lot of the proptosis, strabismus, those clinical manifestations that we’ll discuss further. Now, these immunofluorescent stains show that in A, we have the TSH receptor. In B, we have the IGF-1 receptor, and in C, when we superimpose those stains, we see that the TSH receptor and the IGF receptor are in the same spots. So the red dots and the green dots really are in the same spots in those cells. So the two receptors are intimately attached, and they’re synergistic, but they have different downstream pathways that can lead to the clinical manifestations that we see. So the last part about the molecular biology that I’m going to discuss is the thyroid antigens themselves. So we know that different treatments… Can also have different effects on how patients develop thyroid eye disease. So, for example, we know that patients who have prolonged hypothyroidism or uncontrolled hyperthyroidism may be at a higher risk for thyroid eye disease. So antithyroid medicine is one way to treat these patients. Methimazole or propylthiouracil. But these medicines don’t reduce the level of circulating antibody. So you’re not necessarily reducing the risk of these patients getting thyroid eye disease. Radioactive iodine is uptaken by the sodium/iodine co-transporter, and it kills those cells, but it releases those antigens, so it can actually increase the risk of patients getting thyroid eye disease. And surgical thyroidectomy can lead to permanent hypothyroidism afterwards. And if that thyroid hormone is not replaced, then patients can have a higher risk for thyroid eye disease. So with all of these treatments, it’s important to make sure that they’re titrated for each patient. If you’re using oral medicine, you have to make sure that the patient has a low enough thyroid hormone level. If you’re doing radioactive iodine, you have to make sure that you co- or pretreat these patients with steroids, so that you don’t induce thyroid eye disease, and then with surgical thyroidectomy, you have to make sure that these patients don’t have a prolonged period of hypothyroidism after surgery that can also lead to thyroid eye disease. So these are some graphs. And you see here… On the bottom left, we see that patients who have radioactive iodine have a much higher serum level of thyroid antibodies. And at the top, we see that patients who have just radioiodine have a significant portion of patients who worsen, regarding eye disease, almost 25%. Whereas if you co-treat patients with prednisone along with the radioactive iodine, you can make sure that those patients don’t actually have a worsened thyroid eye disease manifestation. And then at the right, you see radioactive iodine versus surgery versus medical therapy. And you see that radioactive iodine gives people the highest risk of developing TED, and medical therapy gives people the lowest risk of developing TED. So if you have a patient in your office who has hyperthyroidism, they haven’t been diagnosed with TED yet, and the endocrinologist is asking you… Should I treat with radioactive iodine? If they have signs that are concerning, you probably want to tell them: You can co-treat with steroids, or you can choose medical or surgical therapy, but not solely radioactive iodine. Now, I see a couple of questions here. The first question is: Why does this IGF receptor have a predilection for ocular muscles in TED? And I actually don’t think that it does have a predilection for ocular muscles. I can’t tell you why the TSH receptor is in the orbital fibroblasts. But what I can tell you is that wherever the TSH receptor is, often there’s that IGF-1 receptor next to it. So because of that, that intermediary is present in the orbit, so not only do we get the manifestations of thyroid eye disease, but we can address the thyroid eye disease. Pretibial myxedema is in the shins. That also has the TSH and IGF-1 receptor. That’s how the formula response is mediated. There are cases where giving someone IGF-1 therapy not only improves the orbital disease, but also the pretibial myxedema. So it will work whether it’s the orbit or the shins. Now, the second question is regarding the elevated thyroid serum antithyroid antibody levels. So can a raised level be the earliest detected sign of someone who will have the disease in the future? That’s a tough question to answer, because by the time they see me or they see you, as an ophthalmologist or endocrinologist, they usually have some concern for eye disease already. What I can tell you is that there are a lot of patients who have normal thyroid hormone levels, but they have signs of eye disease, like eyelid retraction or proptosis. And you check their blood, and they do have elevated antibodies. So it’s possible to have elevated serum antibodies without having an elevated… Thyroid hormone level or palpitations, while still having orbital disease. So in that sense, yes, it can be an earlier sign. And regarding steroids before or during radioactive iodine, I usually give prednisone, 16 milligrams, starting one week to the radioactive iodine treatment, and then they continue. The radioactive iodine is usually given as one or two pills. So I continue until that second pill is taken, and then I taper over 4 to 6 weeks, depending on how the patient is doing. And you can follow that patient, and see if they develop a lot of inflammation, you can keep them on the dose for longer, but I do think it is helpful to give at least 40 to 60 milligrams of oral prednisone, if you’re doing radioactive iodine with someone who does not have thyroid eye disease yet. So in summary, you know, there’s a lot about thyroid eye disease that we don’t understand. But we do have a clue that there are some nutritional factors, some environmental factors, and some genetic factors that play a role in why Graves patients go on to develop eye disease. And antibody levels can help us in early diagnosis, and can also help in prognosis. So in the past, we used to just wait and watch. If someone has Graves’ disease, we would just wait and see, to see if they developed eye disease. Now we can check antibody levels to see if they’re high, and we can say — if they’re over 400 or 500, then maybe you’re at higher risk for having thyroid eye disease. In the future, we’d like to identify genetic heteromorphisms, vitamin deficiencies, and things that can really specifically give someone a risk for developing thyroid eye disease, and then possibly treat them prophylactically. So let’s talk about the clinical manifestation. There are four main clinical manifestations of thyroid eye disease. And the first is ocular surface disease. And then lid retraction, strabismus, and orbital signs and symptoms. And you can see here both from some of my research, as well as other published literature, eyelid retraction is the most common manifestation. Almost 90% or more of all TED patients present with lid retraction. Next is proptosis, followed by about 50% with strabismus or diplopia, and then compressive optic neuropathy is really quite rare, ranging between 5% to 10%, depending on the studies you look at. So ocular surface disease can be in two forms: Active or inactive. Active is when it’s in the inflammatory phase. This is SLK, the top picture here, with the rose bengal staining. These patients have inflammatory staining superiorly and sometimes diffusely across the cornea. So it’s important to check and see with either lissamine green or rose bengal if they have active ocular surface staining. Whereas this bottom patient — his thyroid eye disease is inactive. But he has exposure keratopathy. And he has inferior Ps that are present at the 2/3 junction, where the patient has lagophthalmos, or incomplete blink. So these two types of ocular surface disease are treated differently. So this is a snapshot of the tear film. And we see that patients with active thyroid eye disease have a lot of cytokines and inflammatory molecules that may be mediating this SLK response, compared to patients with inactive thyroid eye disease or controls. And from unpublished research, from the group at UCLA, we see that patients who have a higher CAS score, a clinical activity score, have a higher ocular surface disease inflammatory index. So the more disease activity they have, the more they feel ocular surface disease. So it is helpful to treat active patients with a topical steroid, which will give them relief, whereas with patients who reach quiescence, and they really have an exposure-based lagophthalmos-related corneal disease, those patients do better with artificial tears. So the top patient would do well with something like loteprednol or a short course of topical steroid. The bottom patient needs surgery or artificial tears. The next manifestation is eyelid related. More than 70% of patients have some form of eyelid retraction. And you can see that that can manifest as a superior scleral show. At the top right. As lagophthalmos on the bottom left. Or when the patient transitions from upgaze to downgaze, they have a decreased inability of the eyelid to relax. And all of that is related to inflammation in the levator palpebra superioris muscle. You can have myopathy, which can manifest with strabismus here, you can have elevated intraocular pressure in upgaze, as usually the inferior rectus is the first to enlarge. So in upgaze, that big fat inferior rectus can compress the eyeball and lead to an elevated intraocular pressure. And this is a photo — classic photo from Dr. Ralph Eagle, a patient with thyroid eye disease — you can see how large those muscles are in thyroid eye disease. Almost double the size or more. Orbital signs include proptosis, which you see at the top right, orbital congestion, which can be visible just as a vague chemosis, or conjunctival injection, and a patient feeling an ache behind the eye, or as optic neuropathy, when it gets quite severe. So the goal for you is to really watch out for subtle manifestations. So this is a young patient who has a little bit of eyelid asymmetry. And she actually had left upper eyelid retraction. And the way I knew this is I followed her over some time. And she ended up developing proptosis. So just because they have only one millimeter difference in the lids doesn’t mean necessarily that these patients are free and clear. They may go on to develop future disease. I find that the worm’s eye view is very quick and easy to identify proptosis. So on the frontal view, you can tell subtly that this patient has proptosis. But if you look at the worm’s eye, it’s much more apparent. So even if you don’t have a Hertel exophthalmometer in your clinic or you’re seeing somebody in a hospital or something, this is a really great way to identify quickly if someone has exophthalmos. And someone is asking if it’s reversible after controlling the hyperthyroid. Usually the exophthalmos slowly gets better, a little bit, without any treatment. Controlling the hormone itself doesn’t reduce the proptosis, but there are some other treatments that can, which I’ll discuss later. So let’s talk about medical therapy for thyroid eye disease. And there are a couple questions about steroids and thyroid eye disease. We’ll talk about that here. So first I mentioned vitamins. I won’t belabor the point, but I think vitamin D, selenium, and all trace minerals and vitamins are beneficial for these patients to reduce that antiinflammatory — to reduce the inflammatory response. And we know that especially in patients with mild disease, we can improve their quality of life and reduce disease progression by supplementing them with these vitamins and minerals. So a good multivitamin will cover a lot of these patients. And then topically, again, for patients in the active phase of the disease, a mild topical steroid, while paying attention to their IOP, is helpful. Whereas at the end of the disease course, when these patients are quiescent, vigorous lubrication with artificial tears is helpful. Injectable steroids are helpful for certain patients. Steroids in general provide symptomatic relief. They help improve soft tissue signs and symptoms of thyroid eye disease. But they’re not disease modifying. So they don’t shorten the course of Rundle’s curve. They don’t make that 18 month period of disease activity shorter. They also don’t reduce the peak. If someone is going to get optic neuropathy or strabismus, steroids really do little to change that. What they do is make patients feel better, because their eyes are less red. Or less swollen. And they have less ocular surface disease. Now, injectable steroids are quite helpful, and they’ve been proven to reduce the clinical activity score. Although once the steroid wears off, then the inflammation comes back. So steroids are really best timed when a patient is right at that peak of Rundle’s curve. You get them over that peak, feeling better with the steroid, and then the disease tends to regress on its own. And this patient had two sets of intraorbital steroids. And you see that the orbital inflammation really got much better, and then as they go over the slope of that curve, they can slowly start to regress on their own. The EUGOGO protocol for IV methylprednisolone is a good one. It can improve signs and symptoms, but it’s not disease modifying. So you see that when you compare oral to IV steroids, you actually get a better response with IV, compared to oral steroids. With a much significantly reduced side effect profile. So if I’m going to give someone steroids, I usually recommend once weekly IV steroids, rather than oral steroids, to answer one of the participants’ questions. And the reason for that is that: You can have a cumulative dose of 6 to 8 grams of steroids. Higher than that, you can have patients who have actually had liver failure and have died from fulminant liver failure, because of the cumulative dose. It’s really important to keep that cumulative dose in mind when you’re prescribing steroids. And also keep in mind that you really want to time the treatment such that you give it to them at their worst. So that once they come off the steroids, they don’t have a really severe rebound phenomenon in a situation where you can’t give them more steroids. The situation where I find steroids are really quite helpful is in patients who have optic neuropathy. So if someone presents with dysthyroid optic neuropathy, then if you give someone three days of a pulse dose of IV methylprednisolone, we have data that shows here that you can reduce the need for immediate surgery for optic neuropathy by about 25% to 40%. So the top graph are patients who had steroids for optic neuropathy. The bottom graph is patients who had immediate surgery for optic neuropathy. And on the whole, the patients who had steroids were able, like I said, about 40% to 50% of those steroid patients were able to avoid immediate orbital decompression for optic neuropathy. We could tide them over with the steroids until the disease quieted down, and then you can do a much safer surgery once the disease is quieter. And what’s the reason to avoid surgery in the active phase? Well, first of all, the surgery is technically more challenging, because the tissue is more inflamed, swollen, the surgery is bloodier, so it’s technically more challenging, but secondly, when you’re operating on someone in the active phase, it’s a moving target. So there’s a higher risk of having recurrent proptosis, or recurrent strabismus, or changing something, and then you’ve already used one of the tools that you were going to use already. So it’s better to always operate in the quiescent phase. And the dose of steroids for dysthyroid optic neuropathy — again, I like to admit someone, give them one gram of methylprednisolone a day for three days, and then at the end of the three days, if their optic neuropathy is better, I discharge them on an oral taper for about 6 weeks. Whereas if the optic neuropathy is not better, then I operate at the end of that three days. Before we go to orbital radiation, I’ll answer a couple more of these questions. Do I check serum selenium levels? I don’t. It’s very, again, uncommon for patients to have high serum selenium levels, especially if they have an autoimmune disease. So I just tell them to take an over-the-counter vitamin. Most of these have a sufficient amount of selenium and vitamin D, and I just have them bring the bottle in and make sure that they have those elements to take care of that. How long should we follow a patient with TED? And should we give oral steroid in the active phase? And why shouldn’t we do surgery in the active phase? As I mentioned, I prefer IV to oral steroids, because the side effect profile, particularly regarding fatal complications, is better. So you have less risk of fatal complications and a higher efficacy with IV steroids. And we don’t want to do surgery in active phase, because it’s a moving target, and the surgery is technically more challenging. There are some questions about the antibodies themselves. So what does it mean if a person has a raised level of antibodies, but a normal level of anti-TSHR? There are a lot of different antibodies that we can check now. There’s thyroid binding, thyroid blocking, thyroid inhibiting, thyroid stimulating. And the answer is… (audio drop) hypothyroid effects. But why do those two antibodies still cause orbitopathy? Well, I think it’s not necessarily related to thyroid hormone. It may be related more to that IGF receptor. So if a patient gets a thyroid blocking or a thyroid stimulating antibody, that co-localization with the IGF receptor can cause downstream effects, regardless of whether the antibody raises or lowers the systemic thyroid hormone levels. So that may be the reason for that. And yes, you can give topical or periocular steroids, or even intraorbital steroids, along with systemic steroids. There’s no contraindication, as long as you avoid that cumulative maximum dose of 6 to 6.5 grams total lifetime. Orbital radiation is something that’s controversial. There are some groups that really believe in it, and there are some groups that think it’s not helpful. The dose is 20 gray or 10 fractions, five days a week over two weeks, and the side effect profile is well tolerated. Because most patients who develop ocular problems from radiation have much less — have a much higher dose. So since this dose is much less, you usually don’t have those issues. Orbital radiation is synergistic with steroids. So patients who have radiation and IV methylprednisolone or even oral can have improvement in the soft tissue signs. There are some data that suggest that about 25% of patients who have double vision can have improvement with orbital radiation. There are also some studies that show that orbital radiation does not help double vision. So it’s murky data. But it is something that may possibly help double vision, and certainly has an effect on orbital inflammation and can even help with optic neuropathy in a patient who maybe is not a surgical candidate for maybe health reasons. And then let’s move on to biologics, which is really quite exciting. So there are a lot of different types of biologics. So there’s anti-TNF-alpha inhibitors, Humira, Remicade, Enbrel. There are anecdotal series that show some mild improvements here. Rituximab is interesting, because there were two trials, one American and one European, that came out at the same time. And one showed that rituximab had no effect and one showed that rituximab helped with thyroid eye disease. And there were differences in the populations between these two. So the criticism is that the group that didn’t improve maybe had thyroid eye disease for longer. Prior to getting the treatment. So maybe they were less active to begin with. So perhaps rituximab would have worked if they had given it to those patients earlier. That’s one criticism. Another criticism is that in the European group, the clinical activity score was measured out of ten instead of seven. And maybe that’s a little bit subjective, as far as whether you actually had improvement. So the summary is that there’s conflicting data as far as whether rituximab works or not. It may help disease. Tocilizumab is an anti-IL-6 drug. It does reduce the clinical activity score, it may reduce proptosis, but as the trial is ongoing, we don’t have final data for it. We’ll talk about teprotumumab, an IGF-1 inhibitor, which was just approved this year in the United States by the FDA for use. This is an exciting therapy, because this is actually the only therapy that is FDA approved for thyroid eye disease. And has been shown to improve not only inflammation, but also proptosis and double vision. And the exciting thing about this medicine is that teprotumumab is disease modifying. It shortens the course of the active phase of disease and the response is durable. Meaning that you give the patient treatment for 24 weeks, and if you recheck them, even up to 72 weeks we find that they have a sustained reduction in the proptosis. And the other factors that we measure. So this medicine stops activity, and it stops the disease progression. So it’s the only treatment that we have for that. Those who got teprotumumab had a reduction in proptosis by about 10 millimeters, and we found that more than half of patients who have teprotumumab have improvement in double vision, compared to just 20% to 30% of patients who got placebo. So this is from the latest New England Journal paper where we see reduction in size of the extraocular muscles after teprotumumab, and they also have clinical improvement in the proptosis and the double vision. This is an exciting medicine, because it gives us a new tool for double vision and proptosis treatment that’s not surgical. And I think those of us who are using it in the United States at least have had good early experiences with the drug, with a very favorable side effect profile. So in summary, medical treatment now is aimed at stopping progression. We want to target the molecular basis of these diseases, to ensure that we shorten that course of the active phase of disease. In the future, like with cancer therapy, we would like to have customized molecular therapy to halt progression of disease, before the onset of permanent complications like fibrosis. And then let’s finally swing on to surgical treatment. So orbital decompression is the mainstay of my treatment or rehabilitation after thyroid eye disease. And it helps with corneal exposure, optic neuropathy, and cosmesis. So the patient has less congestion, they have an improvement in their vision, they can have improvement in double vision, and they look better and they feel better. So I think orbital decompression is a fantastic surgery for most of these patients. And you can see that the exposure is reduced. On the worm’s eye view. And you can also see that orbital decompression improves congestion. So even though this patient doesn’t have profound proptosis, they have a tight orbit, a lot of resistance to retropulsion, redness, and chemosis. And decompression really improves that redness, it helps make the eyes much more quiet. They don’t feel their eyes. They don’t feel that ache behind their eyes. And I published this paper early last year, but actually… I prefer the deep lateral decompression. In this paper, I actually discuss not only removing that bone marrow behind the globe in the greater wing of the sphenoid, so here, I’m using a neurosurgical burr to drill out that greater wing of the sphenoid. But I actually take that all the way down to the level of the dura. And you can see here that I’m using an instrument, you can see a little window of dura behind you. And you can increase that dural exposure to as wide as you want. So here you see the dura of the temporal lobe kind of really opened up. So I’m connecting the orbit and the middle cranial fossa. And what we find is that in thyroid orbits, these orbits are under such high pressure that the orbital tissue actually pushes the brain back. So the orbit, instead of expanding to the sides, where you decompress into the sinuses, actually expands directly posteriorly into the cranial fossa, and that way you get the best axial reduction of proptosis. So I really want to make that clear. If you’re doing a medial or floor decompression, you’re decompressing the orbit to the side. So the eyeball tends to go to the side and you have a higher risk for double vision. Whereas if you decompress behind the eyeball into the deep lateral wall and even the cranial cavity, the eye will go straight back and you’ll have a much reduced risk for double vision. So I prefer this surgery for more than 90% of my orbital decompressions. Strabismus surgery I don’t do, but I have a good adult strabismus surgeon who really is magical, because these are challenging cases. I do like to wait after orbital decompression, because the global position change will affect the measurements. And a lot of patients may even have improvement of double vision, about 30% of patients have resolution of double vision, after a good deep lateral orbital decompression. And finally, with lid retraction surgery, what we’re doing is we are: Releasing those thickened levator muscle attachments, either in the upper lid or the lower lid, you know, one area of improvement here is contour. So you can see that these patients have improved lid retraction, and you can deal with this either through the conjunctiva, by removing the Mueller’s muscle, the levator aponeurosis, and you can see eyelid retraction repair on the upper left and bottom right, and both of those can improve scleral show. Of course, the contour is difficult to control when you’re doing retraction repair. And now of course we’re recognizing that there are a lot of cosmetic changes with thyroid eye disease. So patients have brow fat growth, they have lower eyelid fat growth, and they also have cheek fat growth. And we want to not only improve their medical symptoms, but we want to improve their cosmetic appearance at the same time. So this patient who had Graves’ disease had decompressions, but she also had fat removal, facelifts, cheek fat removal, and contouring of the fat in all of those areas, so that we really improve the overall aesthetic, because we want to make these patients feel like how they did before the onset of the thyroid eye disease. So there’s a lot that goes into that. I encourage you really to customize each surgery to the patient that you have. And in the future, we want to be able to treat patients like this. This is a really challenging patient who had decompression, had another decompression, had steroids, this was before the advent of teprotumumab. But this patient had progressive fibrosis. And fibrosis is the enemy. Fibrosis, once it occurs, is very, very, very difficult to reverse. And I think in the future, we are hoping that our current treatments can help prevent fibrosis. We would also like a treatment to help reverse fibrosis that has already occurred. Particularly in relation to the extraocular muscles. Because recalcitrant strabismus and double vision, I think, is the most challenging aspect of thyroid eye disease to treat. So we’re hoping that in the future, with our research, we can advance the field. So with that, I would like to thank all of you for listening me to speak about thyroid eye disease. I’ll go through the Q and A, and answer a few more questions. So first, what is the role of steroids in moderate inactive thyroid eye disease? If TED is inactive, I don’t think there is a role for steroids, because they don’t have soft tissue inflammation. Really, the treatment for inactive thyroid eye disease is surgery. So when do you do surgery for TED, and what is the criteria for surgery? Well, if the patient is bothered, then you should do surgery. If they’re inactive and they’re bothered by the proptosis, or they’re bothered by their corneal exposure, then do a decompression. That will improve their appearance, it will improve the proptosis, the congestion, and it will improve their ocular surface disease and their dryness. So as long as the patient is stable, and they have a complaint, you can address that specific complaint. You don’t have to do all types of surgeries on every patient. You can tailor it to what really bothers them. How do you manage upper lid retraction in a patient with normal TFTs but elevated antithyroid antibodies? If they have elevated antithyroid antibodies, even if they have normal hormone levels, if they have lid retraction, they have thyroid eye disease. So you manage them how you do every thyroid eye disease patient. You follow them in their activity phase every four to six weeks, make sure you reduce any risk factors such as radioactive iodine or uncontrolled hormone levels, and then at the end of the activity phase, you can decide to treat their eyelid retraction with surgery, or sometimes you can do it with Botox. Some questions about steroids. So after three days of IV methylpred for optic neuropathy, yes, you can go to the EUGOGO protocol, you can do a half protocol of 6 weeks instead of 12 weeks and see how the patient does. That’s something to reduce the orbital cumulative dose. Intraorbital steroid means — not intravitreal. It’s steroid into the peribulbar space. I inject sort of like a retrobulbar, but I don’t actually go into the space. I inject kind of into the midfloor of the orbit. Periocular. Yes. How do I taper systemic steroids? If you’re giving them EUGOGO steroids, you don’t really taper. You give them the 12 weeks and you stop. Tapering really depends on the patient’s signs and symptoms. You’re always balancing the risk of giving them high blood sugar or insomnia or weight gain with the improvement in their soft tissue signs and symptoms. So it’s really a personal decision. And I would encourage you to get people off oral steroids as fast as you can. And TED stands for thyroid eye disease. What causes mobility of extraocular muscles to be more affected than others? That’s a great question that we don’t necessarily know why the inferior rectus or the medial rectus is more affected. I wish I had an answer for you, for that. How many patients who present with limitation in EOMs do not present with strabismus? I think you mean how many patients who present with limitation in extraocular movement don’t have diploma? *diplopia. I think there are patients who have strabismus who don’t have diplopia, because the strabismus is comitant, they have poor vision but they don’t notice the diplopia, because it’s end gaze diplopia only. It’s highly variable among patients. Regarding teprotumumab, do you start all patients, even mild patients, on it? No, in the US you have to have a clinical activity score of more than 4 out of 7 to typically qualify for the treatment. But most patients have pretty significant inflammation initially. If you see them later on in their course, like 6 to 8 months into their course, most of the soft tissue signs and symptoms may have reduced. So if they just have eyelid retraction, then no, you don’t need to put someone on teprotumumab. But for moderate to severe disease, where you have proptosis and you have a little bit of strabismus, I think you can certainly treat those patients. Which orbital decompression is better for thyroid eye disease? When do you do it, and what is the effect of the ICP after the decompression? So I prefer bony decompression, because fat is attached to blood vessels and nerves and muscles. And I really don’t like the idea of removing a lot of fat. Because that gives you a higher risk for having hemorrhage or even complications of the vision. So I prefer bony decompression, because bone is inert, and I know exactly where I’m doing it. When to do orbitotomy and when to do orbital decompression? In the active phase, only when they have neuropathy. In the inactive phase, whenever the patient wants. If they have symptoms, I think it’s appropriate to do decompression, and I haven’t found any issues with the ICP, because — and I’ve been doing it this way for about three or four years now. I haven’t had patients with pulsatile proptosis or any of those conditions. It’s a small window of dura. About 7 centimeters. And the orbital tissue is under high tension, so it pushes into that cavity, rather than the intracranial tissues pushing forward. So I think it has been quite nice for these patients, because I’ve been able to avoid a medial decompression, which has that risk of double vision. So for low income countries, I think it’s hard to get patients to be on teprotumumab. Steroids are nice, intraorbital steroids are nice, and you can always watch and wait and treat with surgery. Surgery is good. You just have to wait until patients are stable. Side effect of teprotumumab… Hyperglycemia, muscle spasms, and some other milder things like a reversible hearing loss, reversible taste sensitivity. The serious side effects are in patients who have inflammatory bowel disease. Like ulcerative colitis or Crohn’s. So those are patients that you want to avoid. Let’s see. So TED is often bilateral, but typically asymmetric. So one eye is often more affected than the other. And what about immunosuppression such as MMF for TED? There are not that great data for immunosuppressants such as azathioprine, there are studies for methotrexate, but the improvements are weak. Typically I don’t find those helpful in patients with thyroid eye disease. Teprotumumab has not been studied in the pediatric cohort, so I can not give you any information on whether that is helpful for children. So tocilizumab — the picture I showed was from the company, in their paper. Like I said, I think it’s a good treatment. It does seem to have similar effects to teprotumumab, in that it improves proptosis and clinical activity score. I don’t know about double vision. It doesn’t seem to improve double vision like teprotumumab does. But we don’t have data from that clinical trial yet. Anecdotally, that drug has promise, and I hope it’s another option for patients with thyroid eye disease, but we don’t know because the trials aren’t complete yet. Do I follow sequence of treatment? If they present with strabismus only, how do we treat? Again, everything is tailored to the patient. If the patient has only strabismus, they’re not bothered by proptosis or lid retraction, do only strabismus surgery. You don’t have to do all four surgeries. Really customize everything to the patient. And those patients with double vision who are inactive — I think you can do strabismus surgery. It’s just challenging, and I’m glad for our strabismus colleagues who are much better at those surgeries than I am. Selenium in moderate eye disease… I don’t think it really changes moderate and severe eye disease that much. I don’t think it hurts them. So I still put them on it. But I think that’s fine. So with that, I think our time is up. And I again want to thank everyone for listening and asking questions, and hopefully everyone was able to learn something. And again, you have my email info. If you have any questions, feel free to email me later. I would love to chat with you about it. Have a good day!
November 19, 2020