During this live webinar, we will discuss how to diagnose and treat patients with thyroid eye disease (TED). We will discuss current treatment options including surgical and non-surgical approaches.
Lecturer: Dr. Andrew Harrison, Director, Oculoplastic and Orbital Surgery, University of Minnesota, USA
DR HARRISON: Good morning, Orbis friends. From Minneapolis, I’m Andy Harrison. I’m an oculoplastic surgeon at the University of Minnesota. And today I’m gonna talk to you about thyroid eye disease, one of my favorite topics. I do have some financial disclosures. Horizon Pharmaceuticals is the maker of Teprotumumab, and I’m on their board and have some equity in their company. The other two are unrelated to this presentation. So what are the things that scares the ophthalmologists? Patients presenting with optic neuropathy, patients presenting with acute proptosis, and patients with double vision. These are the things that scare all of us, including seasoned oculoplastic surgeons. So say this guy presents to your clinic Friday, 5:00 in the afternoon, with severe proptosis and angry-looking eyes. Or this patient comes in with a severe restrictive strabismus. I want you to take a deep cleansing breath. Because we’re gonna talk about ways to deal with these patients that should help you, so you don’t have that acute anxiety that we have often when we see these patients. Today I’m gonna talk about just an overview of thyroid eye disease. Some management strategies. Then I’m gonna talk about some research that we’ve done at the University of Minnesota, looking at the thyroid stimulating immunoglobulin. Then talk about new therapeutic options, as well as surgical options for treatment of patients with this disabling disease. So first, I’m gonna start with a query to the group out there, and see who’s out there today listening. So you can click on your screen, and we’ll see what the audience looks like. So just let me know if you’re an ophthalmologist. Oculoplastic surgeon. Pediatric ophthalmologist. Or resident or fellow in training. And this will stay up for about 30 seconds or so. And also, while this is up there, I just want to say: I am not by any means an expert in strabismus. I know there were some questions asked ahead of time about strabismus. That’s definitely not my interest here. But it looks like about half the people are ophthalmologists. About 8% of you are oculoplastic surgeons. 15% pediatric ophthalmologists or strabismologists, and a third are ophthalmology trainees. That’s fantastic. I should have something for everybody in this talk. I want to start with this case. This is a young woman who was a dermatologist, who presented to our clinic with proptosis of the right eye for several months’ duration. And she was quite upset about her appearance. I wanted to bring this up early. You can see she has proptotic right eye on the up the nose view. And some mild enlargement of the extraocular muscles on her CT scan. And six months later, she comes in, and she’s still a bit proptotic on the right side. Fairly stable. But she’s pregnant. And she wants to wait until her baby is born before she has any surgery or any other treatments. And here’s how she did. She did great. She said — her initial question is: What do you mean I have to wait until things are stable? And there she is, at the end, happy, with a nice cosmetic result. And functional result as well. But the point of this was that — and this was mild, obviously, in her case, and that was part of the point. Is that patients with thyroid eye disease experience this disfigurement, and it’s associated with severe emotional distress, and they have an increased risk for suicide, compared to the general population. And in some cases, their depression scores are equivalent to those with breast cancer. So I just wanted to make a picture, to make sure that you get these patients plugged in with psychological care as needed. Because it really is a disabling disease, both functionally and aesthetically. And it does have an impact on quality of life, including obviously vision impairment. They can’t perform the daily — activities of daily living, including reading, driving, working. It interferes with their social life. And as I said, has significant psychological consequences, and can lead to severe anxiety and depression and even suicide, unfortunately. So we need to be aware of this. Even as eyecare specialists. Just a little bit on terminology. The term Graves’ disease is really related to autoimmune thyrotoxicosis. And this is kind of the symptoms and the issues that we see with that diffuse goiter, systemic hypertension, palpitations, the proptosis, and then the other non-thyroid-related things that you can see. Pretibial dermopathy and thyroid acropachy, the changes in the joints, especially in the hands. As far as the eye is concerned, there are multiple terms. You can see them listed here. I’m gonna stick with thyroid eye disease. It’s easier for patients to understand, easier to say, and we can abbreviate it as TED. So this is an important slide. The immune system is really the bad actor here. It’s not the thyroid gland or the orbit. It’s the immune system affecting these two areas. And we know there’s really not much interplay between the two, although treatment of one can affect the other one, as we know, with radioactive iodine, which we’ll just touch on briefly. But the way I explain it to patients is: It’s two forest fires lit by the same match, which is the immune system. They burn at different rates. They might happen at different times. And what we see is these T-cells that produce autoantibodies that target the orbital fat and extraocular muscles, and the fibroblasts within the orbit are activated, and produce these inflammatory cytokines, as well as hyaluronic acid, and this leads to the changes that we see. Adipogenesis, and swelling and fibrosis of the muscles. This is a picture from an exenterated thyroid eye disease orbit. You can see the markedly enlarged extraocular muscles, and when you take a cross section, look at it under the microscope, you see this significant inflammatory response within the muscle fibers themselves. So this is the Rundle’s curve that shows the typical course of the patient with thyroid eye disease. They present, they develop this active inflammatory phase, and then this chronic fibrotic phase. The active inflammatory phase probably lasts on average one to three years. And I think that’s the hardest part of this disease, both for the doctors and patients to deal with. The patients during this active inflammatory phase. The demographics — thyroid eye disease is the most common cause of proptosis, both unilateral or bilateral. It has a female predominance, about 7 to 1. The mean age is in the 40s, although we see it in children all the way into older adults. So another polling question. A little test question here. What is the most common manifestation of thyroid eye disease? Proptosis, optic neuropathy, eyelid retraction, or strabismus? You can answer on your computer screen, and then we’ll get the results here. In 30 seconds or so. So 53% said eyelid retraction, which is the correct answer. Proptosis is also common, and we’ll talk about that. Optic neuropathy is in about 5% of patients, and we’ll touch on all of these here. So eyelid retraction is the most common clinical manifestation we’ve seen. And the reason for it is probably multifactorial. It’s not just that the eyes are bulging, pushing the lids open. It’s that there’s some sympathetic stimulation in the Muller muscle, inflammation and fibrosis in the levator, as well as proptosis. And it’s seen in 50% of patients who present to the clinic with thyroid eye disease. We define retraction as the margin reflex distance of 5 millimeters or more. Distance from the corneal light reflex to the upper lid margin. Lid lag. These patients develop lagophthalmos, obviously, and they have this characteristic lateral flare, which you can see in the upper picture there, how the lateral portion of the upper eyelid kind of becomes flattened out, if you will. Ptosis can occur in thyroid eye disease, but I always say there’s two things we worry about, myasthenia and thyroid. That’s ptosis and exotropia. So they can occur, but they’re uncommon. If you see them, you have to think about myasthenia gravis. 0.2% of patients with thyroid eye disease will have a coexistent myasthenia, and it’s that patients with one autoimmune disease can have a second or even third. Eyelid edema is present in a significant number of patients. It can be worse in the morning. And it can lead to permanent changes. And in this patient, you can see no only edema but the fatty hypertrophy around the orbit. Proptosis is present in approximately 60% of patients with thyroid eye disease. You can either measure it with the up the nose view, as I showed earlier, or with the exophthalmometer, as I’m showing in the picture on the right. So here the normal limits — the mean Hertel is about 17 in most adults. The upper limit is in the 22 range. And more than 2 millimeters of asymmetry is pathologic. In children, we did a study recently that showed the mean is about 15 millimeters. The upper limit of normal, 19. And asymmetry of less than 1 millimeter in most kids. Thyroid comes in multiple flavors. And one of the ways people have brought it down — and Bill Nunnery from Indiana was the one who first kind of talked about it in these terms — is this type I versus type II thyroid eye disease. The type I patient has predominantly fat hypertrophy, significant proptosis and lid retraction, with minimal if any extraocular muscle involvement, and a white, quiet eye. These are typically in younger female patients. The type II thyroid patient, as you see on the bottom, or thyroid eye disease patient, has more motility issues than fatty issues, and they present with these red hot orbits. Something else that I mentioned earlier is this brow fat pad expansion. And you can see in these patients on the right mild to severe fatty enlargement. But we do see this as a change within the fat around the orbits in these patients. Something that’s quite sensitive for thyroid eye disease is caruncular injection. You can see it in the patient on the top there. But they can have conjunctival injection. Obviously with inflammation, they develop chemosis, and they can also have these dilated veins over the extraocular muscle insertions. Patients with significant proptosis and lid retraction can develop exposure keratopathy, and this needs to be treated as well. And monitored. As far as strabismus, 50% of patients with thyroid eye disease will develop some strabismus during the course of their disease. And the way I remember it, the muscle involvement is I AM SLOW. Inferior, medial, superior, and lateral. Any or all muscles can be involved. We recently published a paper showing superior rectus only involvement. In patients with thyroid eye disease. But this can lead to orbital congestion. Also it’s important to know that patients after decompression, in studies, 5 to 30% of those patients can develop strabismus from the moving of the muscles into the sinuses, and the shift in the extraocular muscles. So imaging in thyroid eye disease — I know there are a lot of studies looking at MRIs. I’m still a big fan of CT. I use a non-contrast CT. Axial and coronal. And the reason I do that is for decompression. It’s nice to have the bony landmarks for planning your decompression surgery. And you can diagnose thyroid eye disease with a CT scan very easily. With the enlargement of the extraocular muscles. So a good time to do a CT scan — when do I do it? The diagnosis is in doubt. All patients presenting with unilateral proptosis. Compressive optic neuropathy. Looking for the compression at the apex. And also as I said for preoperative planning. I just wanted to show a quick case, showing the reason to get CT scans. So this is a patient who presented with Graves’ disease, with proptosis of the right eye, and we had her scheduled for an orbital decompression. You can see she has 5 millimeters of right eye proptosis. When we got a CT scan, it showed this large ethmoidal mucocele. So we sent her over to our colleagues in otolaryngology, who drained the mucocele, which helped to some extent with her proptosis. She then underwent floor and lateral wall decompression. This is before any eyelid work. But getting her eyes back to a normal state. So here was her presentation. After the mucocele was drained. And after the decompression. So the next question is: How do we decide what to do in these patients? So the European group, can the EUGOGO, has really done a lot of the seminal work in creating these scales, and looking at the various treatments, based on their clinical activity score and severity score. And I’ll talk about that briefly here. So the clinical activity score is this 7 point scale, seeing a patient — when you first see a patient. Each of these is given one point. Spontaneous retrobulbar pain, pain with eye movement, redness of the lids, redness of the conjunctiva, inflammation of the caruncle or plica, and chemosis. Each of those is given one point. If they have seven or more, it’s considered active thyroid eye disease. So then you have to decide: Do they have mild thyroid eye disease? Do they have moderate to severe disease? Or do they have sight-threatening disease, either due to optic neuropathy, or severe proptosis? And you can see these are very well defined. Basically you have these three options in these patients. And before we talk about treatment, I want to talk about the role of autoantibodies in thyroid eye disease. There’s three types of TSHR immunoglobulins. There’s the stimulating, the TSI, there’s blocking, and then there’s those that have neutral activity. And I just want to get a quick question out there. Because I know there is some controversy about using these immunoglobulin tests. But I want to know if people who treat patients with thyroid eye disease do test for antibodies in your patients. I’m gonna try to make a case for testing for them, and show a couple cases on where they can become helpful for the management. So a quick question. Do you test for them? Yes or no. And like I said, there’s a bunch of different tests. There’s a bunch of different assays. So 60% said yes. I use the TSI, or the thyroid stimulating immunoglobulin. And my feeling is that this is the match that lights the forest fire. So the TSI stimulates the TSH receptor, which leads to hyperthyroidism in the gland, and affects the orbital fibroblast in thyroid eye disease. So I’m gonna show a couple cases. This is a 67-year-old gentleman who was referred for eyelid evaluation. He said he came in actually for a ptosis/bleph consult. He felt like his eyelids were obstructing his vision, which he attributed to a recent 40 pound weight loss. He had a diagnosis of hyperthyroidism, untreated at this point, non-smoker. His eyes showed orbital discomfort at rest. No orbital pain with eye movements. He did have a brief episode of double vision on upgaze. But he felt his vision was okay. Here’s his exam. You can see his vision’s quite good. Color is intact. There was a question of an APD and red desat in the left eye. Pressures were normal and his extraocular motility appeared full. And here he is. External view showing no lid edema or discoloration. He does have bilateral upper lid retraction. No evidence of lagophthalmos. He has a little injection. And chemosis. And a little bit of caruncle inflammation. His exophthalmometry measurements… He did have active thyroid eye disease. He had pain, injection, chemosis, caruncle inflammation. We tested his TSI and it was 5.3, the normal being 1.3 in our assay. So our assessment was active moderate to severe thyroid eye disease. No optic neuropathy and no exposure at this point. And we’ll talk about his treatment in a little bit. Our second case is a 43-year-old, referred for a second opinion in thyroid eye disease. She was diagnosed with hyperthyroidism in 2010. About five or six years prior to us seeing her. She felt hyper and anxious. She was treated with an antithyroid drug for two years. She complained of left eye bulging over the last five years or so. No pain and no orbital double vision. Here’s her exam. Essentially unremarkable. Mildly elevated intraocular pressure in the left eye, but essentially a normal exam. Here’s her external photo. Showing no lid edema or discoloration. Some left lower lid retraction. Injection. And 5 millimeters of left eye proptosis. We can see that on the up the nose view. So her CAS score was 1/7. Her TSI test was normal, in the completely normal range. We looked at her old CT, which showed no mass on the left side, and extraocular muscle enlargement, consistent with thyroid eye disease. So in this patient, we felt she had inactive moderate to severe thyroid eye disease, with proptosis and lid retraction. No optic neuropathy. No significant exposure. And mildly increased intraocular pressure in the left eye. So just to show the two patients side by side, here’s our guy with active disease on the left. And inactive disease on the right. So how can we use these numbers, the TSI, to help complement our clinical assessment? We looked at three questions, at the University of Minnesota, looking at how TSI correlates with disease activity. How does TSI and CAS differ in patients with optic neuropathy? And what happens — what’s the difference in patients who present with higher or lower TSI testing? So here’s our first question. And you can see the TSI was correlated with the total CAS score, and a couple other things. The brow expansion score and the caruncle inflammation. So this has been previously reported. Back in 2000, Stu Sikes did a study showing antibodies associated with clinical activity. We knew this. But we wanted to make sure our assay was following along. It also showed some variability in the manifestation of disease activity, as measured by the CAS. And total CAS is clearly a useful measure of disease activity. The second question, which I think is quite interesting, was looking at TSI and CAS in patients with and without optic neuropathy. As we’ll discuss in just a minute, optic neuropathy is fairly rare in thyroid eye disease, thankfully. About 5% to 10% of patients will present with optic neuropathy, and here’s our patients that had optic neuropathy. So we had 6 of our 60 or so patients that we looked at over one year. And what you can see is: Patients with optic neuropathy have a high TSI and a lower CAS score. Patients without optic neuropathy had a lower TSI and a lower CAS score as well. So maybe these patients have a whole different disease process going on. We found that patients with an optic neuropathy may not have significant active disease, as this has been previously reported. But they do tend to have a higher TSI test. The absence of the TSI/CAS score suggests maybe a different pathophysiology in these patients. And most importantly, I think it’s important to carefully exclude optic neuropathy in a patient without very active disease, and with a high TSI score. Our third question was looking at patients with an elevated TSI, to see if they follow a different clinical course, in regard to the duration of their active inflammatory phase. And here’s the results of that. You can see patients who presented with the TSI greater than 1.3 had almost 500 days before they were stable for surgery, where the patients with the lower TSI had about 200 days. And what we think is the patients with the higher TSI do present with this prolonged course. As you can see on the bottom. So the Rundle’s curve is stretched out in these patients. And the final thing is that a normal TSI indicates the disease is inactive. So if it’s elevated, you know you’re in the inflammatory phase. And if it’s normal, you know you’re in this quiet chronic fibrotic phase. Which kind of makes sense. So our three conclusions were: TSI can be used as a biomarker of disease activity to aid in decision making and patient counseling. Optic neuropathy should be carefully excluded in patients with an elevated TSI, but without very active disease, and TSI may be used to predict time to surgical clearance. Meaning higher TSI patients may have a longer time to wait. So here’s our patient with inactive moderate to severe thyroid eye disease. So her TSI was less than 1. She has 5 millimeters of proptosis. And our recommendation in this patient was a medial and lateral wall and orbital fat decompression. So let’s talk about management during the active phase first. There’s been a multitude of studies that show that smoking makes this disease worse. And so I counsel all patients who present with thyroid eye disease to stop smoking. I think it’s imperative to improve both the course of their disease, as well as their overall health. That’s the first thing. And I’d say patients who present with severe thyroid eye disease, the majority of them are smokers. At least, in our clinic. Selenium has been studied as a treatment for mild disease. In Italy, in 2011, a study came out using 100 micrograms, twice a day, for six months. And this showed improved quality of life scores, less eye symptoms, less progression of disease, and minimal downside. Selenium is widely available, and quite inexpensive. The criticism of the study is that it was performed in a selenium deficient area, so maybe they were just supplementing people who didn’t have selenium, but I do recommend selenium for all of our patients that we see in the clinic with thyroid eye disease. Treatment of the anterior segment obviously… Lubrication, with proptosis, and lagophthalmos and eyelid retraction. Something else you can do, and Mike Kazim from New York wrote this up, is using this Glad Press and Seal, a food preservative plastic that you put over your food containers, and cutting a piece of this will hold the eye shut without having the problems of tape opening up or rubbing against the cornea. For eyelid edema, we’ll often prescribe hydrochlorothiazide, low dose, which obviously is an off-label use of that drug. And then have the patients raise the head of the bed or even sleep sitting up. And in acute management of strabismus, something — a little trick that we use is using gift wrap tape or scotch tape across the lens, to block the second image, or Fresnel prisms. So let’s talk about patients with moderate to severe disease. So they have a CAS score greater than 4. Active inflammatory signs. But no evidence of optic neuropathy. So here’s another question to the group. How do you treat these patients? Would you treat them with oral steroids? IV steroids? Some other immunosuppressives? Some of the new biologics? Or orbital radiation? And I’ll go over some of these treatment modalities. So it looks like 55% used oral steroids. 37%, IV. 5%, other immunosuppressives, and 2% use radiation. All right. Let’s talk about these. In many studies, it’s been shown that IV methylpred is superior to oral prednisone, both in terms of efficacy and side effects. And I’ll say this about oral prednisone. I certainly use it in some of my thyroid eye disease patients. The problem with oral prednisone is it’s very difficult to get the patients off of it. You can use it in short bursts. But the patients — everybody is happy on steroids. And it improves the inflammation, the double vision. The problem is I think it prolongs the disease process. So in our practice, we typically use IV steroids. And I’ll show you the different protocols that are available. So it’s really three main dosing regimens that people use. The Kahaly dosing regimen is 500 milligrams a week for six weeks of IV methylpred. And 250 a week for six weeks. So 4.5 grams total. There’s these several other versions of using steroids that have quite high total steroid dose, and I’ll tell you… Steroids aren’t without complication. In some of these studies, patients die because of liver failure, due to the high IV steroid dose. So my preference is for the Kahaly dose — it’s the shortest — not the shortest, but the smallest amount of overall steroid with, I think, the highest improvement rate. So in Kahaly’s study, there was a 70% to 80% improvement in patients with severe — with moderate to severe thyroid eye disease. So when do you treat with steroids? It’s really in the early active phase. That’s really when you want to hit these patients with the immunotherapy agents. If you hit them late in the chronic fibrotic phase, you’re not gonna see any changes at all. So here, let’s go back to our patient with active disease. So his CAS score, remember, was 4/7. He had elevated TSI. So here he is, after his first six weeks of IV steroids, and here is what he said. The pressure is off. It feels better. He has improved lid retraction. The proptosis has improved. His edema has improved. Chemosis is improved. And he still has a normal — generally normal eye exam, without optic neuropathy at this point. I did want to make a quick plug about radioactive iodine. For treatment of the Graves thyroid part of this disease. So patients with mild to moderate thyroid eye disease, these patients do need to be pretreated with oral prednisone. A half milligram per kilogram per day, starting one week before the treatment, and tapering over three months. If they have very mild disease, you can use a smaller dose of oral prednisone. And if there’s no TED, no Pred. So this is the one place that I will use oral steroids, is in patients who have active thyroid eye disease, who are going to have radioactive iodine to ablate their thyroid gland. So this is now orbital radiation for thyroid eye disease. Typically 1500 to 2000 centigrade per orbit. It’s been shown to be equally effective to prednisone in the early inflammatory phase. Takes 4 to 6 weeks for the effect to kick in. And of course, there is a risk with radiation retinopathy. Especially in diabetics. Orbital radiotherapy has been controversial since this Mayo Clinic study came out in 2001. They did a prospective randomized internally controlled double blind study, where they did 2,000 centigrade of one orbit, sham treatment to the other, and switched at 6 months. They then made multiple measurements at 3-month intervals, and what they found was no clinical or statistical difference, 6 months after treatment. They did show some decreased proptosis and muscle volume in the first treated orbit, at one year. The problem with this study, or multiple problems with this study, is they did not include patients with optic neuropathy, the duration of eye symptoms to study enrollment was 0.2 to 16 years, so they’re missing Rundle’s curve, essentially, in many of these patients. In 19 of the patients, the inflammation was less than 1.3 years. So those patients might have been within the active inflammatory. But that’s less than half of the patients that were treated. So when do we use radiation for thyroid eye disease? I use it in patients who have active disease. So a CAS score greater than 4. They respond to steroid, but recur when you taper the steroid. They have compressive optic neuropathy, and they’ve had decompression, and they continue to lose vision. Or if they’re unable to tolerate or refuse surgery. And I like to kind of have an arbitrary cutoff of 50 years of age for radiation. I don’t like radiating younger people, because of the risk of secondary malignancies in the irradiated field, although it’s low. And then some other relative contraindications are diabetics and patients who are younger. So what’s new that’s out there? This is kind of an exciting time for thyroid eye disease. People have tried rituximab. There’s multiple case reports with some improvement. Tocilizumab is an IL-6 receptor antibody. There are case reports out there showing some improvement in patients with thyroid eye disease. And Teprotumumab is an IGF-1 receptor antibody, that’s recently received FDA approval here in the US for treatment of thyroid eye disease. So I’m gonna talk about this anti-specific therapy to block insulin-like growth factor 1 receptor. Teprotumumab. So the insulin-like growth factor receptors are overexpressed on Graves’ disease fibroblasts. And antibodies to these receptors are elevated in patients with Graves’ disease. And you can see that in this study. And Ray Douglas and Terri Smith really have been doing this work for the last 20 years, looking at IGF-1 R, and you can see this overexpression in patients with Graves’ disease, versus the control patients. It’s also more frequent in Graves’ disease as opposed to other autoimmune diseases. And you can see that here in the far right, the overexpression in Graves, as opposed to rheumatoid arthritis and ulcerative colitis. This is really the key. And you can see the TSH-R in the green and the IGF-1R in red. On these orbital fibroblasts. And then the yellow is where they overlap. So this shows that these two are intimately involved on the cell of these fibroblasts. So here’s the proposed mechanism. The Graves’ disease IgG affects the Graves orbital fibroblasts. In these patients. And leads to cytokines, T-cell infiltration, inflammation, the proliferation of hyaluronan, which leads to tissue edema, adipogenesis, and the muscle changes that we see. So here it is pictorially. You can see this TSI or the Graves’ disease IgG. Attaching to the TSH receptor and the insulin growth factor 1 receptor. This stimulates this inflammatory cascade that leads to the development of hyaluronan, both in the orbit and within the muscle fibers of the extraocular muscles as well. So if we have a blocking antibody that can attach to this, and prevent the TSI from being able to attach, we can eliminate this inflammatory cascade. So here’s this emerging model of the insulin growth factor 1 receptor that’s overexpressed on these orbital fibroblasts. And then activation of these, as I showed in the last slide series, leads to inflammation and hyaluronan. And the other important point is that these — the insulin growth factor 1 receptor and the TSHR are co-localized on the fibroblast. Teprotumumab is this new medicine that’s a fully human monoclonal antibody inhibitor of IgF1R to block this signaling. And it blocks the autoantibodies from attacking the orbital cells and turns off the signaling at the disease source, the orbital fibroblasts, and this will reduce inflammation. And present excessive cell growth and hyaluronan buildup behind the eye. So here’s the time to treat. Kind of like we were talking about, both with steroids and radiation, you want to treat the patients in the active phase. This was first reported in the New England Journal of Medicine, in 2017. And here’s the way this is being given. It’s 8 infusions, given three weeks apart, and this is from the phase 3 study. And you can see the criteria. So they looked at patients with active thyroid eye disease, and the primary endpoint was an improvement in proptosis. At week 24. This is from the phase III study, and the results of this have recently been published in the New England Journal as well. You can see the randomization here. And again, the primary outcome of proptosis was significantly greater with Teprotumumab than with the placebo. And all the secondary endpoints were also met. And we’ll go through that here. So here’s a patient who was given placebo. You can see if you treat somebody with saline, with thyroid eye disease, they typically get worse over six months’ time. Versus somebody who was treated with the Teprotumumab. So this is 8 treatments, every 3 weeks, and the infusions are 60 to 90 minutes or so. I’m showing the up the nose view, showing marked improvement in proptosis. From the side view. Improvement in proptosis. Still has some lid retraction. So it’s not 100% improvement in the disease. But marked improvement. You can see in the patients — the clinical activity score improved significantly with Teprotumumab. At 24 weeks, the average was 4 point improvement. And 62% of patients with Teprotumumab had absent thyroid eye disease. Either a CAS score of zero or 1 at week 24. And here’s in the phase III study. Another patient treated with Teprotumumab. But you can see the average change in baseline proptosis is approximately 3 millimeters. So this is overall responders. So patients with a reduction in proptosis and improvement in their CAS score. And you can see 78% improvement… 78% of the patients treated with Teprotumumab, versus 7% of the placebo-treated patients. And this slide is really interesting. It shows that the more proptosis that the patient presents with, the more improvement that they got with the Teprotumumab. So patients with 23 millimeters proptosis or less got 2.6 millimeters of proptosis reduction. Whereas those with 23 or more got a mean reduction of 3.7 millimeters. This is also an interesting slide, that shows the effect of Teprotumumab on the orbit. This is an MRI scan of the orbit, showing inflammation and edema of the inferior rectus muscle on the left side, as well as inflammation within the orbital fat. With treatment, you can see on the right the inferior rectus muscle has come back to a normal size, and the inflammation within the orbital fat has essentially resolved. In patients… This is the diplopia response with Teprotumumab. You can see greater than 1 grade of improvement, with 70% of the patients, and complete resolution of diplopia in half of the treated patients. And this is the combination of phase II and phase III studies. I wanted to put this up there as well. Since I talked about quality of life at the beginning. You can see the improvement in the quality of life scores with the Teprotumumab-treated patients as well. The other question that people have is whether this is a durable effect, and you can see it’s approximately 53% maintained a response at 51 weeks, after the last infusion. And 67% maintained a response from their diplopia treatment at 51 weeks. So one year after. So you can see this drug is really gonna change the way we treat patients with thyroid eye disease. No drug is perfectly safe without any side effects. And Teprotumumab certainly has some as well. The most common is muscle spasms. In about 25% of patients. And these are described as cramps that can be massaged out usually at night. Nausea. Some alopecia. That was reversible. Usually just described as thinning of the hair. The other important point is hyperglycemia. The glucose needs to be monitored. And controlled in these patients. And there was some hearing changes as well, in 10% of the treated patients, that were reversible as well. All right. So that’s the news on Teprotumumab. I’m gonna move on and talk about patients presenting with optic neuropathy. And again, Teprotumumab was studied in active thyroid eye disease patients. So patients with optic neuropathy — again, it’s more common in smokers. 50% of the patients have what looks like a normal optic nerve. 25% swollen and 25% pale. Their vision can be okay in approximately 50%, with 20/40 or better vision. There’s two ways that this can occur. One is compression of the optic nerve by the enlarged extraocular muscles, which is the way we typically think about it. The big muscles squeeze at the apex and compress the nerve. But it can also be caused by stretch. This is much less common, but I’ve definitely seen patients with stretch optic neuropathy for massive proptosis. Optic neuropathy is a clinical diagnosis. And we look at visual acuity, color vision, the optic disc appearance, which is variable, as I said earlier, the visual field, and the relative afferent pupillary defect. Another polling question. How would you treat a patient with compressive optic neuropathy? Oral steroids? IV steroids? Orbital decompression? Or orbital radiation? Then there’s no right answer. Interesting. So 43% orbital decompression, 41% IV steroids. And that’s kind of the way I treat it as well. So this is what we do. I do high dose IV steroids, or oral prednisone. And then orbital decompression, within a week. So if I did IV steroids, I would do three days of 1 gram IV, ’til I could get them to the operating room to decompress them. Or oral prednisone, a milligram per kilogram per day. And then do an urgent medial wall decompression. So here’s a patient. She presented with a red eye. Her visual field showed a central scotoma on the right. And you can see she’s a great example of caruncle edema and erythema here, being quite sensitive for thyroid eye disease. So she’s a problem we need to worry about. Right? She’s got an optic neuropathy. Here’s her CT scan. You can see her enlarged extraocular muscles on the right orbit. And then something else that I wanted to point out — and this is something that came out in one of the EUGOGO papers — is this fat in this superior orbital fissure. So this is orbital fat that’s been squished out of the orbit into the superior orbital fissure, and this is a fairly sensitive sign for compressive optic neuropathy. That you can look for. So here she is after orbital decompression and strabismus surgery. Looking much better. So now we’ll talk about management of these patients during the fibrotic phase, or the quiescent phase of thyroid eye disease. So usually we wait for six months of stability. And decreased CAS to less than 4 in these patients. I also like to see the TSI at least coming down, if not totally normal. Some of these patients will never have a completely normal TSI. And this is the traditional teaching in thyroid eye disease. Is doing an orbital decompression, followed by strabismus repair, followed by eyelid repositioning, followed by the blepharoplasty or the so-called cosmetic clean-up. So again, first orbital decompression. And then this patient had an exotropia and had lateral rectus recession. So that’s kind of the way we do it. And then her lid surgery would be next. So orbital decompression can be done urgently. Obviously we talked about compressive optic neuropathy. Also in patients who are having corneal decompensation and ulceration due to massive proptosis, and we can do it later, due to disfiguring proptosis and preoperatively, for patients who have significant restriction. Those patients, once the muscles are released and recessed, the eyes are gonna come forward. So sometimes we’ll do a preoperative decompression for those patients as well. More commonly for the proptosis. Some of the risks of orbital decompression, obviously… Every surgery has its risks. Blindness, bleeding, numbness, diplopia, pupillary abnormalities, and scarring, although they’re quite rare, in my experience. So kind of the traditional oculoplastic options for decompression is a floor and medial wall approach, through a lateral canthal incision, and transconjunctival incision. And some of these patients you get a limited decompressive effect. Sometimes when the orbit is really tight, you can have a limited view of the medial orbital wall, which makes it difficult to decompress. And we try to leave that bony strut, which you can see marked here, between the medial wall and the floor, intact, to prevent postoperative strabismus, and the eye kind of falling into the maxillary and ethmoid sinus, or the medial rectus muscle, more likely, falling into the sinus. So some of the newer things — and these are pretty well established now — is doing transnasal endoscopic medial wall decompression. Balanced decompression, medial and lateral. Deep lateral wall and fatty decompression. So the endoscopic medial wall decompression is similar to functional sinus surgery. And it can be performed by ENT surgeons. There are some oculoplastic surgeons who perform it as well. The nice thing about medial wall being done through the sinus is you have this nice air-filled sinus, rather than a tight tissue-filled orbit, and so they can get quite far back into the sinus, to remove the medial wall. So this is just showing, again, the orbital versus the medial approach. The orbital versus the sinus approach. There’s these nice air filled sinuses that make it easier to get farther back, versus going transorbitally. Which you can definitely do. Both. So this is just showing an endoscopic medial wall decompression. You can see the fatty tissue on the right, herniating into the ethmoid sinus. So a balanced decompression is when you remove the medial and the lateral wall. This allows the muscle cone to shift posteriorly, rather than inferiorly, when you remove the floor. And it causes less problems with globe ptosis. And less diplopia. Theoretically. Here’s a patient who underwent a balanced decompression. You can see the lateral and the medial walls have been removed. And you can see in this slide very clearly the medial rectus muscle falling into the ethmoid sinus. Another approach that’s become quite popular recently is this deep lateral decompression, where you can remove a fair amount of bone from the lateral wall. You can also augment or advance the lateral rim. There’s less risk of diplopia, but there’s the risk of CSF leak as you’re drilling back towards the orbital fissure. Orbital fat decompression can also be performed. I use it as an adjunct to other procedures or alone as a standalone procedure in patients with milder amounts of proptosis. And you can remove a fair amount of fat from the superonasal quadrant and also from the inferotemporal quadrant, fairly safely. So which orbital bone do you remove in patients with proptosis? Here’s my standard approach. So normal Hertel, 15 to 20. If they’re less than 24, I’ll do a lateral decompression with fat or fat only decompression. If they’re in the moderate range, 24 to 26, a balanced decompression. And if they’re over 26, I’ll usually perform a 3-walled decompression. So typically I’ll do this with my ENT colleagues. And they perform the endoscopic medial wall decompression first, and then we do the lateral wall, through lateral canthal or upper blepharoplasty incision, and then a transconjunctival incision to remove the floor, and remove the periorbital widely, and remove the fat. So just a quick series of a lateral decompression. So a lateral canthal incision. Dissect down to the rim. This is using a drill to remove the lateral orbital wall, go all the way down to the superior orbital fissure, and get the bone between the superior and inferior orbital fissures with this approach. And then I remove some of the intracoronal fat. And it’s closed in a standard fashion. Some of the newer technology that’s out, that’s been really exciting to use, is both navigation and Sonopet. So intraoperative navigation has been used for the ENT and neurosurgery for many years. The problem was the getting access to this equipment, number one, and number two, the equipment tended to be in the way when you were performing orbital surgery. This is a navigation unit, created by Stryker Surgical, that I’ve been using for the last several years. And I like it, because it lays flat on the patient’s face and there’s kind of nothing in my way. This is what it looks like intraoperatively. The face mask has LED lights that are picked up by the tracker that sits above the patient’s head. And you can see while you’re operating you can touch within the orbit and see where you are on the patient’s scan that’s been placed into the unit. So what is the problem with drills? Why are we using this new technology? So drills — I do use drills a lot. But drills — they can be bulky. And in the deep orbit, sometimes they can compromise visualization. They can catch and tear soft tissue. And the heat and vibration can lead to damage of the orbital structures. So the Sonopet is not an anime creature. It’s this low frequency ultrasound that vibrates and cuts. So it’s very similar to a phaco handpiece. But instead of being tuned to the lens, it’s tuned to bone. This is what it looks like. And the handpiece looks very similar to a drill. There’s multiple different tips you can use. But it basically ultrasonically removes the bone, and has irrigation and aspiration at the same tip. And you can see I can use the navigation attached to the Sonopet tip here, and you can watch as you’re removing the bone. So this is a patient that had previous partial lateral wall decompression. This is an especially nice case to have the navigation. But you can see as we’re navigating where we are in the orbit, and it’s hooked up to the Sonopet, so that as I’m removing the bone, I can see actually what’s being removed. You can also do what I call the intraoperative Hertel, where you can see how much the eye has gone back, by placing this on the eyelid, and seeing how far back the eye has dropped. So just a couple cases. This is a two-wall orbital decompression, before and after. You can see the medial wall has been removed, as well as the lateral. Here’s another gentleman. Had a two-wall orbital decompression before and after. With no eyelid surgery. This is all just done with orbital decompression. With a three-wall decompression, we remove the floor, the lateral wall, and the medial wall. And you can get these dramatic results, where the eyes go back to a normal position. Another patient with three wall. Here she is, before, 27 and 25. And then afterwards. Her before and after. And just to show you what these patients look like, at two weeks, they still look pretty swollen and beat up. But they heal up quite nicely. Finally, we’ll talk about lid surgery. So lower lid retraction leads to the scleral show. And with inferior rectus recession, that tends to pull the eyelid down with it. The treatment is to release the lower lid retractors. Place a spacer graft, and suspend the lateral canthal tendon. I like hard palate graft for internal spacer. It’s nice. It’s the patient’s tissue. And heals nicely in the eyelid. You can also use the freeze-dried acellular dermal matrix grafts like Alloderm, or there are many others available now, and they’re sewn into the eyelid as a spacer. Between inferior edge of conjunctiva and retractors, and superiorly to the inferior edge of tarsus. So here’s another patient. Before and after. Here she is before any surgery. And then after her decompression. And strabismus surgery and after eyelid surgery. For upper lid retraction, I like the Mullerectomy approach, for 2 millimeters of retraction, just removing the Muller’s muscle. For more than that, I like full thickness blepharotomy procedure, where you release all the tissue from the upper eyelid tarsus. Here’s blepharoplasty and levator recession. A couple patients with upper and lower eyelid retraction repair. Finally, a patient who developed upper lid retraction after strabismus repair. You can see a right upper lid in that middle picture there. And then I wanted to end with this case. So this young woman presented with severe inferior rectus restriction. So she was taking selfies basically weekly. As her disease progressed. And you can see her in her wedding photo, what she looked like before. To how she was when she presented to us. So the first discussion is we have to wait. And this is probably the hardest discussion with these patients. She’s got marked proptosis. Severe restriction of the right eye. And a little bit on the left. And you can see her motility here. Her right eye is basically stuck in the infraducted position. So at 7 months, my strabismus colleague gave her some botulinum toxin to the right medial and inferior rectus with no response. At 10 months, she gave her 10 units with no response. So after one year of waiting, she was stable. So we went ahead and did lateral orbital decompression. And he did a right inferior medial and left superior rectus recession on an adjustable suture. And then we did upper and lower eyelid retraction repair. So here she is afterwards. The Bionic Woman. That kind of dates me to the ’70s. But we can rebuild her! We have the technology! So I think it’s key to have a customized approach in these patients. Where you tailor your treatment to the patient’s issues. The way we do that at the University of Minnesota, we have a thyroid eye disease center, with an oculoplastic surgeon, and their ophthalmologist and adult strabismus specialist. We see the patients every 4 to 6 months, as long as they’re not in a severe state, obviously. And do a CAS score. We do a TSI each time. We do orbital decompression as needed. We tend to use the oral steroid protocol for moderate to severe active disease, and once they’re stable, we rehabilitate them with surgery. So in summary — I know this has been a long talk. Thanks for hanging in there. Remember the CAS, to determine the activity. I think that’s really the key to decide how to treat these patients. TSI can help determine the course. I think we’ve shown that in our studies. IV steroids for moderate to severe disease. Teprotumumab is a new treatment option in the US which may change the way we’ll treat this disease forever, and the order of surgical restoration — orbital decompression, strabismus surgery, and eyelid surgery. And then need serologic and clinical evidence of thyroid eye disease, or perform imaging, to make sure that you’re not missing something. Remember, there’s multiple causes of proptosis, although thyroid is the most common. Radioactive iodine can worsen clinically active thyroid eye disease, so we use oral prednisone in those patients, and make sure you tell your patients to stop smoking. This is what our clinic looks like. These are all the doctors who work on thyroid patients in the University of Minnesota. Thank you. Now I’ll take some time for questions. I think there’s a few up here. So the first question is: What is your surgical approach to a patient with tight inferior rectus and medial rectus muscles and both ET of about 30 and right hypo of 15? This is a question for my strabismus colleagues. I’m not a strabismologist. But I can certainly hook you up with them. I’ll put my email. I’m happy to forward that. But my guess is they’d recommend… Medial rectus recession and inferior rectus recession in that patient, in one or both eyes. Have you started using Tepezza in your practice? So Tepezza is just coming on the market. We’re signing patients up for it. It’s not available yet in Minnesota. But yes, I am, and I am excited to start using this drug. Surgery for strabismus in TED is indicated when the disease is not in the active phase? What is the best clinical or radiological indicator in a patient for us to know that TED is not in the active phase and has entered the chronic phase. So the two things we use is clinical activity score less than 4, and seeing TSI come back to a normal level. So we like to see both those things. I think a lot of centers use just the clinical activity score or stable measurements. So for us, it’s stable measurements 6 months apart, before our strabismus doctors will perform strabismus repair. The next question. Does the radioactive iodine have any long-term side effects? That’s more of a question for the endocrinologist. Not on the eyes, as far as I know. So just from an orbital surgeon’s standpoint, no. But I would ask your endocrinologist that question. What’s your preferred treatment for patients with type one TED presenting with proptosis with lid retraction? So in those patients, again, type I is the fat dominant type with retraction, young women, with significant lid proptosis. I typically treat them with orbital decompression and depending on the amount of proptosis, I try to do as much fatty decompression in these patients, because I think that helps as much as the bony decompression. Because it’s a fat dominant disease process. So wait for stability and then perform the decompression. Next question is how about local triamcinolone injections or steroid injections for TED? That’s an excellent question. I used to do a lot of steroid injections for these patients. I’m a little worried about triamcinolone causing central retinal artery occlusion. So I’ve gotten away from triamcinolone or Kenalog, and I’ve gone to dexamethasone, which is not in a suspension. In the hopes that side effects would be less. I don’t know if it works as well. But I think that’s a reasonable alternative, rather than oral steroids, for helping patients along, especially in that active phase. If they’re kind of mild, moderate, active, I think local steroid injections — and the way I do it is inferotemporal quadrant with a short needle. So I don’t do a true retrobulbar. I usually do a peribulbar injection of 4 milligrams of dexamethasone in each orbit or in the involved orbit. Thanks for that question. I’m glad… I took that out of my talk a while ago. How about a patient — thyroid eye disease, glaucoma, uncontrolled with medication. If I want to do a trabeculectomy, should I give her steroid before a trabeculectomy? So there are a lot of studies on thyroid and glaucoma. And I think what we’ve seen is that if you do the orbital decompression, you can bring the intraocular pressures down. So if the patient is stable, I would recommend… If they do have proptosis, large muscle, et cetera, doing an orbital decompression and seeing how the glaucoma does. If it’s severe glaucoma, that’s totally uncontrolled, I think doing steroids to quiet the orbit down does make sense. It kind of depends where they are in the phase of the disease. Again, their CAS score and their complete exam. But yeah. I think you want to get the orbit quieted down a bit. Depending on where the glaucoma — how severe the glaucoma is. The next question: Is Tepezza superior to IV steroid? There’s never been a head to head trial, so it’s hard to answer that question. There are different medications. Teprotumumab is a disease modifying agent, whereas IV steroids is not. So nobody knows the answer to that yet. But my guess is there will be studies that look at that here in the near future. Great question. What will the approximate cost of a course of Teprotumumab be? I don’t know the exact cost of it. But the drug is quite expensive, as I understand. But it is a monoclonal antibody. It’s in that range. I’ve heard bantered about — and again, I don’t know the exact numbers. $150,000, $250,000 for the course of treatment. But don’t quote me on that. And I don’t know the exact number. Do you include mental health support in your team? Great question. We send patients to the psychology group at the University of Minnesota, if they need it. We do not have a mental health support person in our thyroid eye clinic. But that’s a great question. Thank you. Radiation therapy. So I have a slide that showed that — basically it’s for patients who recur off steroids. Again, in the moderate-severe active phase of the disease, patients who have compressive neuropathy, who have had maximal decompression, and patients who are unwilling or unable to undergo surgery. Those are kind of the big three. The next question is: What is the role of methotrexate in treating active disease? We don’t use methotrexate in thyroid eye disease. So I have no experience in using that medication. Is there a place for use of drugs to treat hyper or hypothyroidism? I’m skipping one. Sorry. Let me go back up. Have you experienced recurrence after decompression or corrective surgeries? Yes, definitely. So I would say the recurrence rate is around 5%, and it can happen months to years later. I’ve had patients who have recurred 10 to 20 years after their initial bout of thyroid eye disease. So you can definitely have recurrences. The next question is: Is there a place for use of drugs… Let me go back to that question, sorry. Antithyroid drugs? Yes. And a lot of our patients are on propylthiouracil or methimazole as the treatment for their disease. And again, I usually leave that to the endocrinologists. We do not treat the thyroid part of this disease. How many times can we repeat IV steroid course in active patients? That’s an excellent question. From my own experience, I think I’ve done it twice, where we’ve done it more than once. But I usually do it once. And if it doesn’t work, I assume it’s not gonna work a second time. But if they have a recurrence of the disease, I think it’s reasonable to repeat it. Again, it does add a significant steroid burden to the patient. So I’m a little hesitant to repeat that treatment course more than once. The next question: In thyroid optic neuropathy, if methylpred works, how long do you wait for orbital decompression? I usually still decompress them after a week. I don’t think the IV methylpred is gonna cure the optic neuropathy. I usually recommend those patients get orbital decompression. I don’t wait on optic neuropathy. I usually decompress those patients. I don’t let the steroids be the treatment. I have a patient with proptosis, lid retraction, restriction in upgaze, pain. What treatment do you recommend? So if she’s quiet, CAS score less than 4, I would recommend orbital decompression, followed by strabismus surgery, followed by lid retraction repair in that patient. The next question is: If local injections were used, how often can we repeat? We usually do it every six to eight weeks. To keep the disease quiet. This is local steroid injections into the orbit. So every 6 to 8 weeks. We had a patient with psychotic breaks related to megadoses of steroids. Had to admit to psych ward every time he came in with active disease. That’s definitely a risk of steroids, is the psychological changes. So patients need to be aware. I always tell them that steroids can make you anxious or depressed, and you need to let us know. But I’ve never had anybody that we had to admit to the psych ward. That’s pretty extreme. How do you manage the angry appearance of thyroid, especially the glabella and brows? That’s a good question. So you can do fat debulking in the area of the brows. The glabella is tough. You can try to use neurotoxins to try to settle it. And relax it. But it’s very difficult. I will say the patients with the Teprotumumab do have improvement in their fatty changes around the orbit, which is amazing. So maybe that’s gonna be the answer in the future. I don’t know. Has any patient experienced enophthalmos after decompression? I have seen patients from other institutions that did develop enophthalmos after decompression, and I treated it like an orbital fracture. I put in an orbital floor implant, in those patients. You suggested waiting before decompression and other surgical options. How long do we wait and when do we go in? Again, I wait for six months of stability. For decompression, we want to see their lid measurements, and their Hertel measurements stable for six months. CAS score less than 4 is what I usually do. And wait. So it’s a long time. These patients don’t want to wait. Especially the younger patients. As I talked about in the beginning. But you’ve got to wait a year or so, typically. What’s the dosage for peribulbar Dex? And how many times can we give? I use 4 milligrams per mil. So I give 4 milligrams into each orbit via peribulbar injection. And you can give it up to 3 or 4 times, is kind of what I’ve done, to get them through the year. So every couple months or so. So that is all the questions I have. Thanks, everybody, for listening! It’s been a pleasure. And I want to thank Lawrence and Orbis for allowing me to give this presentation. I hope everybody has a great weekend. Thank you!
February 14, 2020