KOL KNOCKOUT™: Endocrinology Edition – Challenging Cases of Thyroid Eye Disease

Introduction

Thyroid eye disease (TED) is a complex autoimmune condition characterized by inflammation and enlargement of the orbital and retroorbital muscle and connective and fat tissues of the eye.¹ Up to 50% of patients with Graves disease develop TED.^2,3 Given the strong link to thyroid dysfunction, most patients with TED will develop ocular disease while under the care of their endocrinologists. Therefore, in addition to managing thyroid dysfunction, endocrinologists are often tasked with recognizing and diagnosing TED. With overlapping clinical presentations to dry eye disease and ocular allergy, TED necessitates comprehensive clinical examinations, supported by laboratory tests and imaging, for accurate diagnosis.⁴ Additionally, TED is a lifelong disease with heterogenous presentation.

Effective management requires a symptoms-based approach that considers disease activity and severity as well as the patient’s quality of life.⁵ Because TED development and progression is independent from the thyroid’s immune and endocrine status, accurate and timely diagnosis is crucial for appropriate intervention and prevention of disease progression. Indeed, establishing robust referral and comanagement protocols is essential to facilitate patient access to specialized, collaborative TED care. This multidisciplinary approach integrates the collective expertise of various health care professionals to ensure comprehensive care and enhance the quality of life for patients with TED.

Captured from a series of three live-virtual “knockout rounds” chaired by Malini Gupta, MD, ECNU, FACE, the following case discussions between thyroid experts illustrate the importance of mastering TED diagnosis with clinical examinations and appropriate testing,⁶ devising individualized treatment plans, and establishing referral and comanagement protocols that ensure patient access to specialized and collaborative care.

ROUND 1

Case 1: A 56-Year-Old Nonsmoker With Graves Disease

Malini Gupta, MD, ECNU, FACE: Our faculty for this round includes Alireza Falahati, MD, FACE; Anupam Kotwal, MD, MSc, FACE, FRCP (Edin); and Rokshana R. Thanadar, MD. A 56-year-old woman with Graves disease presented with a thyroid stimulating immunoglobulin (TSI) about 60 times the normal value. The patient was a nonsmoker and had no history of radioactive iodine. Her history includes treatment with a solution of iodine and potassium iodide, methimazole, thyroidectomy for a large, compressive goiter, and injections for retinal bleeds. What do you see on a preliminary exam (Figure 1)?

Anupam Kotwal, MD, MSc, FACE, FRCP (Edin): She appears to have proptosis and eyelid retraction. We can see corneal exposure in the superior aspect. I can also see some periorbital edema.

Alireza Falahati, MD, FACE: I also notice that her right eye is deviated, which could be a potential cause of double vision.

Dr. Gupta: Yes, on examination, she did have right eye diplopia, redness of the eyelid, and dry eyes (Figure 1). She reported some headaches and pain behind her right eye but denied difficulty driving. What’s the diagnosis here?

Dr. Falahati: I would refer the patient to ophthalmology for a baseline evaluation, but it’s obvious she has TED. I would consider teprotumumab-trbw as a first-line therapy, depending on her insurance. Methylprednisolone could be an option as a bridging treatment, especially if required by her insurance. I would like to see an MRI of her eyes and then work with an ophthalmologist.

Figure 1. A 56-year-old woman with Graves disease. Image courtesy of Malini Gupta, MD, ECNU, FACE.

Dr. Kotwal: The TED appears to be bilateral even though one side is more pronounced. I agree that imaging can help to plan the management strategy. I would also measure visual acuity and measure proptosis with an exophthalmolmeter. Based on the patient’s symptoms, the disease is likely moderate to severe. An urgent assessment is crucial to initiate comanagement with an eye specialist to focus on diagnosis and treatment. I would also assess her quality of life, ie, how much do her symptoms bother her or affect her life? I agree with Dr. Falahati’s plan. It’s reasonable to consider teprotumumab depending on screening for glycemic issues, among other tests.

Rokshana R. Thanadar, MD, FACE, FEAA: TED is high on her differential diagnosis. Other diseases that may have similar presentations to TED must be ruled out. As far as treatment, I would let quality of life dictate the course. She can drive, but there may be more subtle things that she may have adapted to but are causing issues with her daily activities.

I would perform an objective assessment to determine if treatment shoud be conservative or aggressive. She may only need treatment to help with her symptoms, such as drops for dry eyes; however, I agree that referral to an ophthalmologist would be beneficial to understand if medical or surgical treatment may also be appropriate. Information gathering is important at this early stage of her journey.

Dr. Gupta: That’s a great point. As endocrinologists, our approach is very different. Dr. Thanadar, do you calculate a clinical activity score (CAS)?

Dr. Thanadar: In some aspects, I do. I ask about some of the clinical items that contribute to the CAS, but if a patient doesn’t present with those issues and their score is low (ie, <2), I may not proceed with all questions because it would be obvious that some of the more severe aspects of TED aren’t present.

Dr. Kotwal: I calculate CAS to assess inflammation, but it doesn’t capture patient quality of life. There is no weighting assigned to the clinical items, so worsening of one component over time doesn’t affect the score. There are some limitations to CAS. I think it’s helpful, but even patients with a low CAS may have severe symptoms like diplopia.

Dr. Falahati: I also use CAS but put more weight on additional clinical information and feedback from the ophthalmologist.

Dr. Gupta: According to her history, she saw an ophthalmologist in 2014. Why do you think they missed the TED?

Dr. Thanadar: There is a misconception that patients with Graves disease who have had a total thyroidectomy will no longer have issues with TED, so it may have been low on their differential. The older paradigm was that after a patient reached an inactive state of TED, the disease was no longer a consideration. Now, we know that Graves disease and TED are two separate diseases, and there can be recurrence and fluctuation of TED independent of the thyroid status.

Dr. Kotwal: Completely agree. It’s important to keep in mind that there are a percentage of euthyroid and hypothyroid patients who can develop TED.6 This is where antibody testing as well as clinical suspicion for TED can help make the diagnosis.

Dr. Falahati: I agree. If the ophthalmologist saw the patient in an emergent or urgent setting, their focus may have been on treating the retinal hemorrhage, not necessarily looking outside the eyeball. It can be missed in an acute setting.

Dr. Gupta: Both good points. In the end, I referred her to an oculoplastic surgeon who did not think she needed treatment. Do you agree with that assessment, Dr. Thanadar?

Dr. Thanadar: The oculoplastic surgeon may have been looking from the perspective of surgical rather than medical intervention. From that standpoint, there isn’t much benefit to treatment. That doesn’t mean that a medical treatment wouldn’t reduce the proptosis, which in turn, may help with corneal dryness and dry, itchy eyes. These patients suffer from this 24/7, so you can imagine what that does to quality of life. Even if a life-threatening issue isn’t present, a quality-of-life treatment may be helpful.

Dr. Falahati: Her profession certainly plays a role in the treatment choice. Does she frequently look at a screen? Does she feel uncomfortable with the asymmetric and bulging eye appearance? It may not be surgically indicated, but I think her quality of life needs to be considered.

Dr. Kotwal: I agree. She doesn’t have a lot of redness or edema, but given how much the symptoms affect her, I would consider the disease course, ie, has she been having flare-ups or has the disease been getting worse? It would be reasonable to consider nonsurgical treatment in this and similar scenarios.

ROUND 1

Case 2: A 73-Year-Old Smoker With Multiple Concomitant Conditions

Dr. Gupta: This case involves a 73-year-old woman was referred to me with a long history of Graves disease. She was treated with radioactive iodine in the 1970s, followed by orbital decompression surgery in 1980. She has a history of congestive heart failure, chronic obstructive pulmonary disease, type 2 diabetes, and hypertension. She is taking levothyroxine, was taking amlodipine and oxybutynin previously, and is not currently on steroids. Additionally, her mother had Graves disease and TED. Dr. Kotwal, what are some of the ophthalmic signs you see (Figure 2)?

Figure 2. A 73-year-old female with history of Graves disease, presenting with ocular complaints. Image courtesy of Malini Gupta, MD, ECNU, FACE.

Dr. Kotwal: There is definitely proptosis, periorbital edema, and conjunctival injection particularly on the lateral aspect of the left eye. There seems to be asymmetry of gaze as well, which could mean diplopia.

Dr. Gupta: The patient did report double vision. She stated that her eyes watered all the time and she felt pressure behind her eyes. She had disequilibrium when looking down, couldn’t drive, and had redness and swelling of the lids, especially in the morning. She stopped working as a teacher because she felt like her eyes scared the children. On presentation, she had a prominent stare and lid lagophthalmos. There was notable asymmetry. The left eye had more keratoconus than the right eye.

Dr. Falahati: She has had orbital decompression before, but I think she has a very advanced case of TED. Does she smoke? That could be a huge factor in making a definite clinical decision. 

Dr. Gupta: Yes, I’m glad you picked up on this. She was and still is a smoker, smoking 10 cigarettes a day. Her thyroid stimulating hormone (TSH) is 4.59, and she has some sensorineural hearing loss. What’s your diagnosis and plan, Dr. Thanadar?

Dr. Thanadar: I agree she likely has advanced TED given the number of symptoms and the effect on her daily life. For this patient, treatment may be difficult because she’s an active smoker, which can cause issues with therapeutic efficacy of different management options,7-9 and her history of type 2 diabetes and sensorineural hearing loss. I would refer her to ophthalmology to determine if medical treatment or potentially repeat surgery is warranted. It’s been a long time since she had surgery, and there may be technological improvements that may be beneficial. 

Dr. Kotwal: Additionally, I would want to make sure she is well controlled from a thyroid standpoint. Smoking cessation is critical to improve disease state. Conservative measures like lubricant eye drops may help. This is clearly active, chronic disease, and whether this is a flare-up or disease worsening over time, it is likely advanced but may not be sight-threatening at this time. I would be concerned about the hearing loss. It should be discussed in the context of treatment with either teprotumumab or intravenous steroids. While the diabetes is also a consideration for treatment, the fact that she is not on medication for it may mean it is very well controlled. 

Dr. Falahati: It is important to comanage this patient between an endocrinologist and ophthalmologist or oculoplastic surgeon. The patient must understand that she may already have lost hearing, but the last thing she wants is to lose her vision. As Dr. Kotwal said, the first thing she needs to do is stop smoking. The surgeons with whom I collaborate typically refuse to touch the eyes if the patient is smoking.

Dr. Thanadar: For patients, the recommendation for smoking cessation carries a lot of weight when it comes from their physician. As endocrinologists, we may not typically think about recommending this, but it would make a big difference to her overall health if she cut down from a half pack to a quarter pack, and eventually weans herself off. 

Dr. Gupta: In this case, I didn’t adjust the patient’s thyroid medicine because she was taking it with all of her other medicines, and there was heterophilic binding. No one had told her that for 40 years. I referred her to an oculoplastic surgeon for a comprehensive eye exam, and I suggested she wear a face mask when sleeping because she was unable to fully close her eyes.

Dr. Falahati: I agree with not adjusting the levothyroxine dose. In my experience of cases with severe TED, whether it is the patient’s perception or not, pushing for higher thyroid levels may result in increasing TED severity. A TSH of 4 or 4.5 is fine, you don’t want to overdose or underdose significantly. 

Dr. Kotwal: The nighttime measures are important. People may not realize their eyes stay open, which increases corneal exposure and can exacerbate dryness and redness, among other symptoms.

ROUND 2

Case 1: An 18-Year-Old Complaining of Rapid Heart Rate

Dr. Gupta: Our faculty for this round includes Round 1 winner Rokshana R. Thanadar, MD, FACE, FEAA; Kaniksha Desai MD, ECNU, FACE; and Melissa Garduno Young, MD, FACE, FACP, ECNU. This case involves an 18-year-old woman who presented to her pediatrician with extreme fatigue and complaints of a rapid heart rate. She wasn’t on any medications and did not smoke. She was referred to a cardiologist who ordered TSH; her TSH level was <0.0001. She was then referred to an endocrinologist who found that TSI was 20 times the upper limit of normal. The patient had a family history of celiac disease. Her grades had declined subtly during the past 2 years because she couldn’t concentrate and was tired all the time. Her heart rate, according to an app on her phone, had been between 120 to 130 beats per minute over the past 2 years. She did not have weight loss but had weight gain. On presentation, she had increased pain in her left eye (Figure 3).

Figure 3. A 18-year-old female presenting with rapid heart rate. Image courtesy of Malini Gupta, MD, ECNU, FACE.

Kaniksha Desai, MD, ECNU, FACE: She seems to have a little bit of deviation in her left eye, which is more obvious when she’s looking to the left.  She may have very mild chemosis, orbital edema, and lid swelling.

Dr. Gupta: I started the patient on methimazole 20 mg twice a day. Because I noted some left eye proptosis that was greater than the right, I referred the patient to an oculoplastic surgeon and started her on a short course of prednisone 10 mg for 5 days. Dr. Young, would you initiate prednisone before you send the patient to the oculoplastic surgeon? 

Melissa Young, MD, FACP, ECNU, FACE: We let the oculoplastic surgeon initiate it. I have a low threshold for referring patients to an ophthalmologist if I suspect they have TED. I usually defer to the eye specialist for the treatment plan.

Dr. Desai: I agree, I like to take a multidisciplinary approach from the beginning. I don’t mind prescribing a steroid, especially because some ophthalmology referrals take time. 

Dr. Thanadar: Depending on the patient’s feelings and symptoms, a short course of prednisone is relatively low risk and has the potential to improve inflammation. I don’t think it would delay care or interfere with the ophthalmologist’s treatment plan.

Dr. Gupta: A team approach to TED is extremely valuable, both from the ophthalmologists’ and endocrinologists’ perspectives. Both teams need to see patients as quickly as possible, even in cases of mild TED.

Figure 4. A 34-year-old male presenting with eye pain. Image courtesy of Malini Gupta, MD, ECNU, FACE.

ROUND 2

Case 2: A 34-Year-Old Smoker With Eye Pain

Dr. Gupta: This 34-year-old male presented to his primary care physician with eye pain on movement and grittiness, which had worsened over time. On examination, he mentioned experiencing watery eyes and a burning sensation (Figure 4). He smokes two cigarette packs a day, reports regular headaches, and has a family history of hypothyroidism and vitiligo. He recently took a night job where he doesn’t have to see many people. Dr. Young, what is the significance of vitiligo in the patient history?

Dr. Young: Vitiligo is an autoimmune disorder, as is hypothyroidism. The patient’s family history puts him at a higher risk for developing an autoimmune disorder, such as Graves disease.¹⁰ 

Dr. Gupta: Dr. Thanadar, is the patient at increased risk for TED?

Dr. Thanadar: The big red flag is that he smokes two packs a day. Hypothyroidism or vitiligo alone aren’t necessarily associated with TED, but these would still raise a red flag. We know that approximately 10% of patients with TED are hypothyroid.⁶ I’d also pay attention to the grittiness in his eyes and pain on movement because they could be indicative of disease progression to a more active disease state.

Dr. Desai: It appears he has bilateral proptosis (with his right being worse than his left). It’s best to measure this objectively because “normal” exophthalmometer measurements do differ between races, sexes, and ages.^11-13 He also has chemosis, inflammation of the caruncle, orbital edema, lower and possibly upper eyelid swelling, and eyelid retraction. He has a very classic stare for TED. 

Dr. Young: I think he also has thinning of his eyebrows.

Dr. Gupta: I agree. Dr. Thanadar, what labs would you order? 

Dr. Thanadar: In addition to TSH and free thyroxine (T4), I believe antibody testing, a baseline electrolyte panel, and a basic metabolic panel (BMP) would be helpful.

Dr. Gupta: Dr. Young, would you obtain any further testing for the heart or lungs? 

Dr. Young: It would depend on the cardiac physical exam. In addition to free T4 and BMP, I would order a comprehensive metabolic panel, including liver function tests. If possibly starting antithyroid drugs, I would order a complete blood count to have a baseline. 

Dr. Desai: I typically order an orbital MRI for patients with type 2 diabetes, and I would do the same here. He took a night job so people don’t notice his stare, so I would try to better understand how the disease is impacting his quality of life. 

Dr. Gupta: Dr. Thanadar, let’s say he has a lot of anxiety about seeing another provider and spending more time in a physician’s office. How do you decrease anxiety levels in someone who smokes two packs a day? 

Dr. Thanadar: Again, it’s important to have a multidisciplinary team with different areas expertise to help him with treatment, reinforce the message, and address other aspects of his life. I would explain that it’s not just about medications and treatments. Many times, there are lifestyle barriers that prevent patients from having a good quality of life, which is just as important as treating the symptoms of the disease.

The rise of telehealth has made consultations for patients like this a little easier. We can perform shared care visits, and they don’t necessarily have to go to one or multiple doctors. That gives patients the option to choose the connections they make and access different perspectives.

Dr. Gupta: How would you encourage him to stop smoking? 

Dr. Thanadar: Smoking is one of the hardest things to quit. Repeated counseling on smoking cessation is crucial. Patients do listen to physicians. I would get him in the frame of mind to say, “Yes, I can try,” and then set a goal date for when he would stop. This gives the patient time to get used to the idea of not smoking. Medications can help with the cravings, and behavioral psychologists and psychiatrists may offer a multidisciplinary approach. Even if the patient doesn’t completely stop, a decreased dependency might show him he can do it.

Dr. Gupta: In my practice, I actually have patients dump a week’s worth of cigarettes into a bowl so they can see how much they’re smoking and ask them to write on each cigarette the date with a marker of when they can have it. A pack has about 20 cigarettes. If he’s smoking 40 cigarettes, I challenge him to go down by two every week. This makes him feel like he’s getting somewhere and he’s not mindlessly smoking. I also have patients try journaling, writing down why they felt they needed a cigarette, to try to understand their behavior. In a patient like this, treatment won't be effective without also chipping away at his smoking.

Dr. Thanadar: One pack of cigarettes costs about $10. I often make them consider how much they are spending on cigarettes in a week/month/year and ask them what they could have bought with that money instead. Sometimes just putting the cost into perspective is enough to spark change. 

Dr. Gupta: It’s difficult for patients who are hyperthyroid and have a level of anxiety that drives them to smoke. This in turn makes their eyes worse and their anxiety worse; it becomes a terrible cycle.

The patient was diagnosed with Graves disease, started on methimazole and immediately experienced a rash. Dr. Young, what would you do next?

Dr. Young: If the rash was indeed attributable to methimazole, I would not advocate for I-131 treatment, as he has active TED. We know that radioactive iodine is associated with worsening of TED, more so than antithyroid drugs or surgery.^14-16 I would probably refer him to an endocrine surgeon for thyroidectomy.

Dr. Thanadar: How severe is the rash? If the patient’s body is completely covered, then surgery would be more appropriate than medical treatment. If it’s a minor rash, an antihistamine may help. 

Dr. Desai: Even though there’s likely to be immune cross-reactivity, he may benefit from treatment with propylthiouracil (PTU), particularly if the rash is not severe. We could consider PTU as a bridging therapy to surgery.

Dr. Gupta: The patient is skittish and doesn’t want to have surgery on his eye or thyroid gland. What other options does he have at this point? Would you use steroids in this case, Dr. Young? 

Dr. Young: Without surgical intervention as an option, I would give him corticosteroids as well as antithyroid drugs, especially if the rash was relatively mild. The corticosteroids would not only begin treating thyroid dysfunction but also the inflammation associated with TED. If the rash was severe, then he needs counseling to steer him toward surgery.

Dr. Gupta: Let me tell you what I did. I referred him to an oculoplastic surgeon. His primary care provider has already made an appointment with a head and neck surgeon to remove the thyroid, but we elected not to remove the thyroid and stay on methimazole. The rash went away after 1 week with the help of an antihistamine.

Figure 5. A 61-year-old female on thyroid replacement therapy. Image courtesy of Malini Gupta, MD, ECNU, FACE.

ROUND 2

Case 3: A 61-Year-Old on Thyroid Replacement Therapy

Dr. Gupta: This is a 61-year-old woman on thyroid replacement therapy for 20 years (Figure 5). She had decreased her dose multiple times and current TSH on no medications is 0.02. She did not smoke. Dr. Desai, what do you see on presentation? 

Dr. Desai: Bilateral chemosis, upper eyelid retraction, orbital swelling, lower eyelid swelling, and inflammation of the caruncle. It’s difficult to tell, but she may have worse proptosis in the right eye compared to the left eye. Her eyebrows also look thin. 

Dr. Young: There is certainly a disconjugate gaze and I think it’s her left eye that has the issue.

Dr. Gupta: Interestingly enough, her optometrist did not notice a difference in her vision or appearance, but I agree with you. The right eye had pain, watering, and lid swelling, which was worse especially in the morning. The left eye had occasional watering. The labs are positive for thyroid peroxidase (TPO) antibody but negative for TSI. Dr. Young, would you obtain an MRI in her case?

Dr. Young: I would. There likely is some issue with range of motion of the left eye, so I want to see the extraocular musculature. 

Dr. Thanadar: I may refer her to an ophthalmologist first to see if they felt that an MRI was needed for treatment with teprotumumab. It also depends on the ophthalmologist; some like to do their own imaging. 

Dr. Gupta: Dr. Desai, would you do anything for the right eye considering it is more painful than the left?

Dr. Desai: Due to the asymmetry of her disease, I would order an MRI to rule out a tumor or something else that might be causing the disease. It’s low on the differential, but you don’t want to miss it because pain is worse on one side. Interestingly, if she didn’t have a positive TSI, I would consider ordering a thyrotropin receptor antibody (TRAB). However, the positive TPO antibodies do support the idea that TED is a completely separate entity to Graves disease.

Dr. Gupta: Yes, this is a great case for that. As I see more and more of these cases, I feel better equipped to pick up on subtle changes in the eyes and identify TED by looking at the different components of the CAS. I also ask more questions with every autoimmune thyroid patient, which has helped identify TED in hypothyroid patients with no history of hyperthyroidism. Oculoplastics, ophthalmology, and optometry may not have picked that up because, in the past, they assumed it was a symptom of Graves disease.

Dr. Desai: TED is probably significantly underdiagnosed and I think it’s important to take the time to ask these questions.

Dr. Gupta: Absolutely. You have all done a great job at recognizing the pertinent signs from these images, but it can be very challenging. You really need to look at the eyes in different dimensions and assess patient symptoms in multiple gazes.

Dr. Thanadar: I think it’s just having the awareness to look for these things. At first glance, you may not see anything unusual or may second-guess yourself but, as Dr. Gupta noted, the more patients you see, the more you can pick up on subtle clinical features.

Dr. Gupta: In this case, I started the patient on 30 mg of methimazole in the morning. She did have 2 mm more proptosis on the right eye but there was no pain on eye movement. I sent her to an ophthalmologist to help with the dry eye. 

ROUND 3

Case 1: A 36-Year-Old Nonsmoker With Facial Swelling, Rapid Weight Loss, and Rapid Heart Rate

Dr. Gupta: Our faculty for the final round includes Sonalika Khachikian, MD; John Woody Sistrunk, MD; and Round 2 winner Kaniksha Desai, MD, FACE, ECNU. This case involves a 36-year-old woman presenting with swelling of her face and a tremor (Figure 6A). She had lost 20 pounds in 6 months and had a rapid heart rate, heat intolerance, hair loss, and some irritability. She had a family history of celiac disease and two C-section births. She wasn’t on any medications and did not smoke. Given this information, what would you ask this patient?

Figure 6. A 36-year-old female presenting with facial swelling and tremor. (A) Presentation at baseline. (B) Presentation after treatment with teprotumumab. Image courtesy of Malini Gupta, MD, ECNU, FACE.

Dr. Desai: Women in this age range are at a high risk for thyroid disease. I would ask if there’s a family history of other autoimmune conditions, including Hashimoto or Graves disease. I would do a physical exam to assess the swelling because it’s the most concerning symptom.

Dr. Gupta: She had puffiness around the eyes, pain on eye movement, watery and itchy eyes, but no change in vision. Dr. Sistrunk, anything to add?

John Woody Sistrunk, MD: I see bilateral periorbital edema, which is the first clue for TED. Whenever we treat patients with autoimmune thyroid disease and facial swelling, it’s crucial to make sure it’s not urticaria angioedema. In addition to puffiness around the eyes, there is some lid lag and scleral redness. The pain on movement is concerning to me, and I would ask about that. I’d also want to test visual acuity with a pocket card. Changes in vision can be subjective.

Sonalika Khachikian, MD: Oftentimes, swelling above the eyelids is called the rainbow sign. She looks like she has some ptosis and swelling of the lower eyelids. If you look closely at the light reflex, you’ll notice it’s asymmetric—which suggests double vision. I would ask if she smokes because we know that can exacerbate eye disease or autoimmune disease in general.^7-9 I’d also ask the patient when her symptoms started, ie, did they begin around the same time, did thyroid disease start first, does she have any seasonal allergies, does she have any other autoimmune conditions like Sjögren or lupus? The redness on her cheeks could be from a malar rash or it may have just been a hot day, but it’s important to be thorough.

Dr. Gupta: I ordered a CMP, CBC, TSH, free T4, free triiodothyronine (T3), TSI, and TPO antibodies. Would you order anything else?

Dr. Desai: Sometimes, a TRAb antibody can be positive when a TSI is negative, so I may order that as well. Further, if we’re focusing on the eyes and she has a lot of pain, a CT or an MRI of the patient’s orbital area may be helpful. I didn’t notice proptosis but a side view would help confirm.

Dr. Khachikian: I’ve had situations when I relied on the TSIs, and for whatever reason they’re negative, so I agree on ordering TRAbs. I would also consider an ultrasound of the neck. We were always taught during training that eye disease is pathognomonic for Graves disease, but if the patient hadn’t presented with classic symptoms or overt eye disease, you might think she had a Cushingoid facial appearance. The ultrasound can show increased blood flow, which would provide a good idea of what could be happening.

Dr. Sistrunk: I have also seen many patients with profound hypothyroidism, outside the context of TED, present with periorbital edema. Would you order a thyroglobulin antibody (TgAb) as well?

Dr. Khachikian: What would be your rationale for ordering TgAb in addition to the TSI and TPO?

Dr. Sistrunk: In Hashimoto thyroiditis, I obtain a TPO and TgAb. In Graves disease, I obtain a TSI and TRAb. In both Graves disease and Hashimoto thyroiditis, the discordance between the two antibodies can be profound at times. If you had a patient like this present with a suppressed TSH, and find that either one or both of the TSI or TRAb were positive, its Graves disease until proven otherwise.

Dr. Gupta: The results showed the patient had a very low TSH of 0.00 but elevated free T4 and T3. I started her on methimazole 20 mg twice a day and propanol as needed. She had dry mouth and high blood urea nitrogen to creatinine ratio, so I advised increased water intake. After 2 months, thyroid function improved, but her eyelid swelling did not. She was placed on a short course of steroids and referred to an oculoplastic surgeon. Dr. Khachikian, do you use steroids, either oral or intravenous?

Dr. Khachikian: It depends on what you want to achieve. A high dose of methylprednisone is most efficacious.¹⁷ However, I use steroids conservatively because most patients have compounding factors that may worsen with steroids. My experience is that patients may notice initial improvements because the inflammation subsides, but they relapse as soon as the steroids are withdrawn.

Dr. Gupta: The oculoplastic surgeon started her on eight infusions of teprotumumab, one every 3 weeks. After the 24-week course, she developed tinnitus that was not present before treatment. Audiology testing also revealed sensorineural hearing loss. She still had lagophthalmos after 24 weeks, but the proptosis and lid swelling improved (Figure 6B). Dr. Desai, how do you approach audiology testing in these cases?

Dr. Desai: Ideally, I like to do audiology testing before initiating teprotumumab and again halfway through, especially if there has been a change in hearing. At the time of reporting the first episode of tinnitus, I would have considered audiology screening. If she already had hearing loss prior to treatment, I might not have considered this medication. At 36 years old, I wouldn’t expect sensorineural hearing loss, but it’s important to do this testing because teprotumumab has been associated with hearing impairment.^18-23 While it is likely the tinnitus will have improved after treatment cessation, it is unclear whether the sensorineural hearing loss would have also improved or become a long-term issue.

Dr. Gupta: We have not discussed selenium yet. Dr. Sistrunk, when and how do you start selenium?

Dr. Sistrunk: For patients with eye disease, the first thing I discuss is ocular protection and not exacerbating any ocular surface disease, eg, wraparound sunglasses or eye protection while mowing the lawn. For patients with Graves disease, I discuss selenium on the first visit. I specifically reference the European trials, which found a 6-month course of twice daily oral selenium 100 μg decreased inflammatory symptoms, improved quality of life, and decreased the rate of progression from mild to moderate to severe TED.²⁴ You can get selenium 200 μg tablets at local stores, which is usually what I recommend.

ROUND 3

Case 2: A 57-Year-Old With a Bloody Eye

Dr. Gupta: A 57-year-old woman presents to her ophthalmologist with blood in her left eye (Figure 7A). She reports rubbing her eyes a lot from dryness. She smokes one pack per day and has a history of Graves disease. She was treated with radioactive iodine many years ago. The patient is currently on levothyroxine and has a family history of thyroid disease and lupus.

Dr. Khachikian: I am noticing bilateral proptosis, scleral show on the right eye, lid retraction, increased edema (rainbow sign) above both eyelids, lymphedema in the upper and lower lids, and inflammation of the left caruncle and plica.

Dr. Desai: Under the right eyelid, there is a bad bruise or under-skin hematoma, probably from eye rubbing, and a conjunctival hemorrhage on the left side.

Dr. Gupta: The ophthalmologist prescribed teprotumumab after baseline audiology testing. After 4 weeks, blood sugars increased from a baseline of 5.9 to 7.2 HbA1c, and she was sent back to endocrinology.^25-27 Dr. Desai, would you use metformin in this case?

Dr. Desai: If she’s only had one infusion, I don’t think the spike is enough to stop teprotumumab. I would first counsel lifestyle changes, but there’s no harm in initiating metformin. If her HbA1c decreases, it can be discontinued.

Dr. Khachikian: My approach would be to obtain a fructosamine level because it provides a better average for 2-week blood sugar readings. In itself, an HbA1c of 7.2 doesn’t seem too concerning as it suggests an average blood glucose of 150-170. If, however, the fructosamine level is checked and found to be grossly elevated, it may be a better gauge of glycemic control. As long as renal function is adequate and her baseline labs look good, I don’t think metformin is a terrible idea. I would recommend extended release tablets, starting with 500 mg twice a day and see how she tolerates it. Higher doses of 1,000 mg twice a day may be acceptable, but we run into the risk of gastrointestinal issues.

I would also consider a glucometer or, even better, a continuous glucose monitor (CGM), so the burden from the increased sugars isn’t adding to the burden of her eye disease. The CGM then would provide more current data, which gives me greater confidence in making changes.

This issue does divide endocrinologists and ophthalmologists. Having abnormal HbA1c values are not necessarily a contraindication to receiving or continuing teprotumumab, but more so an indication to pause and evaluate how we can get levels under control.

Dr. Desai: I would monitor the HbA1c carefully because she experienced quite a large increase after one treatment.

Dr. Khachikian: Teprotumumab seems to lead to insulin resistance, especially in patients with impaired fasting glucose;²⁸ however, interestingly, their glucose numbers decrease after the third and fourth doses. The vigilance is needed because there have been patients who have received teprotumumab and developed diabetic ketoacidosis.^29-32

Dr. Desai: The patient was probably predisposed because of her elevated HbA1c and her age.

Dr. Gupta: Those are great points. In addition to the metformin, she was started on a dipeptidyl peptidase-4 inhibitor. Luckily, she experienced improvement of her blood sugars during the course of the eight treatments. Her eye symptoms improved (Figure 7B), but she still needed ocular lubricants for dry eye. As a side note, other helpful adjuncts are ocular gel ointments, an eye mask at night, and no ceiling fan. At about 1 year, she maintained most of the improvement and remained on metformin.

Figure 7. A 57-year-old female presenting with bloody eye. (A) Presentation at baseline. (B) Presentation after treatment with teprotumumab. Image courtesy of Malini Gupta, MD, ECNU, FACE.

ROUND 3

Case 3: A 52-Year-Old With Iron Deficiency and Periorbital Swelling

Dr. Gupta: A 52-year-old woman with a history of iron deficiency from menorrhagia presented with periorbital swelling of her left eye. She was started on levothyroxine after labs drawn by her primary care physician showed hypothyroidism. When the patient lost weight in college, she was told she was hyperthyroid. She was on methimazole for 1 year. She is a nonsmoker and has a sister with hypothyroidism and vitiligo. The patient was recently divorced but not dating because she felt self-conscious about her eyes. On presentation, she had watery eyes, pain on eye movement, lid swelling, and headaches. Hertel measurements showed the left eye was 2 mm more proptotic than the right eye (Figure 8A).

Figure 8. A 52-year-old female with iron deficiency and periorbital swelling. (A) Presentation at baseline. (B) Presentation after treatment with teprotumumab. Image courtesy of Malini Gupta, MD, ECNU, FACE.

Dr. Khachikian: She also has lid lag/lid retraction in her left eye. She almost looks like she has like an opacification over the top left and bottom right corneas and some conjunctival injection. If you look at the light reflex, they’re asymmetric, which is suggestive of double vision.

Dr. Desai: She has sparse eyebrows from her hypothyroidism.

Dr. Sistrunk: The hyperpigmentation below the eyes bothers me. I would want to order a scan of the patient’s head to make certain we’re not missing something else, such as an infiltrative process, that could cause this type of appearance. We assume she had Graves disease, but since it has been 20 years, we should do her justice to make certain that we’re not missing something else.

Dr. Gupta: Do you start with a CT or an MRI?

Dr. Sistrunk: I think a CT would be sufficient, based on cost and easy access.

Dr. Khachikian: I agree, I would order a CT without contrast.

Dr. Gupta: Nothing on CT was concerning for a tumor, but it was consistent with signs of TED that is more unilateral. After her hearing studies came back normal, the patient was started on teprotumumab. Her period cycle was irregular during treatment, and she already had a baseline of iron deficiency from the heavy cycles. Dr. Desai, would you stop the teprotumumab or send the patient to obstetrics?

Dr. Desai: Because of her age, I wouldn’t necessarily stop teprotumumab just for the iron-deficiency anemia. I would refer to obstetrics to make sure she doesn’t have fibroids or other issues that might be causing excessive bleeding. I might do a workup to make sure she doesn’t have inflammatory bowel disease because the medication has been known to cause flare-ups. A colonoscopy would be considered if I wasn’t sure the anemia was directly related to the irregular menorrhagia.

Dr. Khachikian: I’d get a human chorionic gonadotropin level to make sure she is not pregnant. I would also test her estrogen level and consider getting luteinizing hormone and follicle-stimulating hormone levels to get a baseline. I’d ask if she were having frequent bowel movements or blood from her rectum. More frequently now, I have had patients that say they have a lack of menstrual cycles after their third or fourth dose, but it returns around 5 months after the full course of teprotumumab.

Dr. Desai: I would also check for celiac disease.

Dr. Gupta: I told the patient to take iron supplements and ordered a screening from obstetrics to check for fibroids, which she did have. Iron deficiency is common in thyroid disease and also exacerbated by fibroids.³³ A colonoscopy was also done to rule out any issues and make sure she didn’t have inflammatory bowel disease and/or cancer.

I find that most of my patients tolerate fortified iron water boiled in an iron skillet or simple nonconstipating vitamins for children. The proptosis of the left eye improved after treatment with teprotumumab (Figure 8B).

ROUND 3

Case 4: A 55-Year-Old With Multiple Sclerosis and Vision Complaints

Dr. Gupta: A 55-year-old woman with a recent diagnosis of multiple sclerosis (MS) presented with problems looking up, down, and to the sides. She had double vision, could no longer drive by herself, experienced heat intolerance, and had increased bowel movements. Dr. Desai, what do you see in this baseline photo (Figure 9A)?

Figure 9. A 55-year-old female with multiple sclerosis and vision complaints. (A) Presentation at baseline. (B) Presentation after treatment with teprotumumab. Image courtesy of Malini Gupta, MD, ECNU, FACE.

Dr. Desai: She has a prominent stare, and her right eye has more proptosis and lid retraction than her left. Comparatively, it almost looks like ptosis of the left eye. There is periorbital swelling of the lower eyelids and chemosis or conjunctival injection.

Dr Gupta: Her TSH was 0. She tested positive for TPO, TSI, and antinuclear antibody, and had a confirmed diagnosis of Graves disease. She was started on methimazole 20 mg twice daily.

Dr. Sistrunk: What were the manifestations that led to the diagnosis of MS? Are there any overlapping symptoms that could be attributed to TED only?

Dr. Gupta: Great question. As we know, MS can affect the eyes.³⁴ She had lid swelling, chemosis, and uneven bulging of the eyes. She also had eye dryness, spontaneous eye pain, restricted eye movements, and a CAS of 6 to 7. Dr. Khachikian, how often do you use the CAS?

Dr. Khachikian: I document it as part of my routine exam; however, now that new data on teprotumumab shows efficacy in both acute and chronic TED (ie, CAS ≤1),³⁵ and the FDA label has been updated accordingly, I document CAS more so for insurance purposes.

Dr. Gupta: What imaging would you order, given the concomitant MS diagnosis?

Dr. Khachikian: It may be better to obtain an MRI in this case because I want to see more clarity in the soft tissue and muscles.

Dr. Desai: I agree. If the patient were referred to oculoplastics and they were considering surgery, they might prefer a CT scan.

Dr. Sistrunk: I’m still worried about the diagnosis and making sure we have two different disease processes. If I felt an MRI could confirm other lesions in addition to the TED, I would order one.

Dr. Gupta: You can also see nerve impingement better on an MRI. The patient was referred to an oculoplastic surgeon and started on teprotumumab. She was placed on three medications for elevated blood pressure, which she had not experienced before treatment. She was referred to cardiology after seeing no improvement. She finished the 24-week course of teprotumumab and underwent orbital decompression. One year later, she maintained cosmetic improvement (Figure 9B) and her MS was stable. Her blood pressure remained erratic. Dr. Desai, have you seen patients with blood pressure that remains elevated?

Dr. Desai: Usually, the blood pressure improves after medication is stopped, but some symptoms can last a while. A year later, however, it’s unlikely to improve.

Dr. Khachikian: It almost looks like she has some swelling above her left eye this time.

Dr. Gupta: Interestingly enough, the orbital decompression was on the left side, not the right.

Dr. Desai: I assume her hyperthyroidism was treated and not the cause of her blood pressure issues?

Dr. Gupta: Correct. She was treated successfully on methimazole and remains on a 5-mg dose because of antibody elevation, but it’s lower than the baseline. I often find that if you remove the methimazole when the antibodies are elevated, a rebound will occur. The patient is happy with the cosmetic effect of teprotumumab and the orbital decompression. She is bothered by the elevated blood pressure. Would you do anything else, Dr. Desai?

Dr. Desai: Did she have a secondary workup for the hypertension? I would look at the three medications; it’s a very big jump. It could be a side effect, or maybe she has a predisposed condition that can be treated either surgically or with different medications to control her erratic blood pressure.

Dr. Gupta: Good answer. I think we must always do a workup of secondary hypertension when patients are on three or more medications without improvement. Her workup was negative for any secondary causes of hypertension, including pheochromocytoma and Cushing syndrome.

Thyroid disease is likely more prevalent than we think. I think we miss a lot of TED diagnoses because it is believed to be a symptom of Graves disease. It’s a separate disease from autoimmune thyroid disease, and the pathophysiology is different as well. I want to thank all of the panelists for their insightful comments and sharing their expertise in TED diagnosis and management.

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