SYMPTOMS OF TED
Thyroid Eye Disease (TED) is progressive, and early intervention has been shown to reduce disease impact1,2
Early signs and symptoms of TED may include1,2
Proptosis is caused by expansion of the orbital fat and muscles behind the eyes. The lacrimal glands are frequently involved and enlarged, causing bulging of the eye. Proptosis is one of the most common symptoms of TED.3
Diplopia is caused by swelling and inflammation of the extraocular muscles and typically restricts the movement of the eye, causing double vision. The most frequently involved muscle is the inferior rectus.4
Upper eyelid retraction develops from levator and Müller muscle inflammation and fibrosis or from levator muscle overaction caused by inferior rectus restriction. Symptomology overlaps between Graves’ disease and TED. Upper eyelid retraction is one of the most common symptoms of TED.3,4
Pressure and/or pain behind the eyes
TED causes an increase in the orbital soft tissue volume, which leads to a higher pressure within the inexpandable bone cavity.3
Photophobia, or light sensitivity, often occurs in TED patients when the upper eyelid retracts, resulting in corneal exposure. Evidence shows that up to 80% of patients develop upper eyelid retraction in early TED.1,5
Dry eyes and grittiness
Dry eyes and grittiness are frequently under-recognized signs of TED.6 In a long-term follow-up study in a single US county, 72% of patients with TED said dry eyes were their most frequent source of eye discomfort.7 These symptoms are often misdiagnosed as allergies or conjunctivitis.8
Redness, swelling, and excessive tearing
Erythema (redness) and edema (swelling) of the eyelids were the 2 most commonly reported signs in a pilot study of a tool designed to help non-eye specialists detect early TED.1 Corneal exposure due to eyelid retraction can lead to excessive reflex tearing.3,5
If you notice any changes or worsening symptoms it is important to consult with a TED Specialist quickly.3 Thyroid Eye Disease is a progressive, chronic, potentially vision-threatening autoimmune disease, and co-managing can change the course of TED3,9
TED SYMPTOMS ARE CAUSED BY THE STIMULATION OF ORBITAL FIBROBLASTS, WHICH CAUSES INFLAMMATION BEHIND THE EYE.4
Watch a video about TED’s unique mechanism of disease (MOD), its symptoms, and the importance of early diagnosis, featuring Dr Terry Smith, professor of ophthalmology and visual sciences and professor of internal medicine.
Hello. I'm Dr. Terry Smith
In thinking about Graves' disease of the thyroid, and thyroid eye disease, one is struck by not only the similar disease mechanisms underlying each, but also the divergence between the two diseases, and how the effective treatment of each is quite distinct. Remember, TED can present in patients with Graves' disease who are euthyroid, hyperthyroid, or hypothyroid, depending upon a number of factors, not least of importance is where in the disease temporality the patient might be at the time of presentation.
Because TED is separate, and distinct from Graves' disease, treating the hyperthyroidism, or hypothyroidism of Graves' disease does not address the pathophysiology or the symptomology of TED.
We've learned a lot about TED, its pathogenesis, and its natural course, over the last few decades. What we've learned is that the disease has, as its core, the interplay between multiple signaling pathways, receptors, and the molecular mechanisms involved in the activation of receptors.
Current research has shown that the IGF-1 receptor, when activated, may drive the pathophysiology of TED throughout the course of the disease. Patients with TED have increased receptor expression, and activation.
This cooperativity between the two receptors becoming activated results in the release of many pro-inflammatory cytokines, chemokines, and the subsequent infiltration of immune cells to the orbit. In addition, there is a coordinate overproduction of extracellular matrix molecules, including glycosaminoglycans, of which hyaluronan is the dominant specie. Fibroblast proliferation and terminal differentiation also result from activation of the receptor complex. In a patient with TED, auto-antibodies activate this receptor complex signaling, which stimulates orbital fibroblasts and the biosynthesis of a multitude of mediators of the disease.
We've also come to understand that the connective tissues in the orbits of patients with TED are unique. They are uniquely infiltrated with monocyte derived progenitor cells, known as fibrocytes. These fibrocytes are quite interesting cell types, because they're highly inflammatory. They express auto-antigens that may help us explain the localization of TED to the tissues around the eye.
So, what are the inflammatory effects of—of fibroblast activation? We need to remember that each of the components of pathophysiology of TED translates into the signs and symptoms of the disease, as we encounter in our clinical patients. Once activated, fibroblasts cause severe inflammation and over-expansion of tissue, muscle, and fat cells behind the eye. Inflammation and swelling and expansion of extraocular muscles, soft tissue, and fat in the context of a fixed bony orbit, can lead to clinical manifestations, including inflammation, a foreign body sensation, excessive tearing, dry eye, conjunctival or eyelid redness and swelling, orbital pain, chemosis, proptosis, and diplopia.
With regard to the importance of recognizing TED as early as possible, and when to begin instituting medical therapies, I can't stress enough the importance of recognizing the disease as early as possible. It just makes sense that since the disease, at its very core, has to do with remodeling of tissues, the earlier that the disease is recognized, and that potentially beneficial measures can be taken, the better.
TED is separate and distinct from Graves’ disease, and requires different treatment4,9-14
|THYROID EYE DISEASE (TED)||GRAVES’ DISEASE|
|THYROID EYE DISEASE (TED)|
Front and back of the eyes
Ocular myositis and expansion of orbital fat
TED is a heterogenous condition, meaning symptoms may vary from patient to patient.9
TED manifestations are often misdiagnosed as allergies or conjunctivitis. Misdiagnoses of TED symptoms can lead to significant delays in treatment. It’s important to ask your patients if they are experiencing any new or worsening symptoms of TED.3,8,15
- Mitchell AL, Goss L, Mathiopoulou L, et al. Diagnosis of Graves’ orbitopathy (DiaGO): results of a pilot study to assess the utility of an office tool for practicing endocrinologists. J Clin Endocrinol Metab. 2015;100(3):E458-E462. doi:10.1210/jc.2014-3146
- Bothun ED, Scheurer RA, Harrison AR, Lee MS. Update on thyroid eye disease and management. Clin Ophthalmol. 2009;3:543-551. doi:10.2147/opth.s5228
- Barrio-Barrio J, Sabater AL, Bonet-Farriol E, Velázquez-Villoria Á, Galofré JC. Graves’ ophthalmopathy: VISA versus EUGOGO classification, assessment, and management. J Ophthalmol. 2015;2015:249125. doi:10.1155/2015/249125
- Bahn RS. Graves’ ophthalmopathy. N Engl J Med. 2010;362(8):726-738. doi:10.2147/TCRM.S193018
- Dolman PJ. Grading severity and activity in thyroid eye disease. Ophthalmic Plast Reconstr Surg. 2018;34(4S Suppl 1):S34-S40. doi:10.1097/IOP.0000000000001150
- Bartley GB, Fatourechi V, Kadrmas EF, et al. Long-term follow-up of Graves ophthalmopathy in an incidence cohort. Ophthalmology. 1996;103(6):958-962. doi:10.1016/s0161-6420(96)30579-4
- Bartley GB. The epidemiologic characteristics and clinical course of ophthalmopathy associated with autoimmune thyroid disease in Olmsted County, Minnesota. Trans Am Ophthalmol Soc. 1994;92:477-588.
- Estcourt S, Hickey J, Perros P, Dayan C, Vaidya B. The patient experience of services for thyroid eye disease in the United Kingdom: results of a nationwide survey. Eur J Endocrinol. 2009;161(3):483-487. doi:10.1530/EJE-09-0383
- Wang Y, Patel A, Douglas RS. Thyroid eye disease: how a novel therapy may change the treatment paradigm. Ther Clin Risk Manag. 2019;15:1305-1318. doi:10.2147/TCRM.S193018
- Smith TJ, Hegedüs L. Graves’ disease. N Engl J Med. 2016;375 (16):1552-1565. doi:10.1056/NEJMra1510030
- Bruscolini A, Sacchetti M, La Cava M, et al. Quality of life and neuropsychiatric disorders in patients with Graves’ orbitopathy: current concepts. Autoimmun Rev. 2018;17(7):639-643. doi:10.1016/j.autrev.2017.12.012
- US Food and Drug Administration. FDA approves first treatment for thyroid eye disease. January 21, 2020. Accessed August 16, 2021. https://www.FDA.gov/news-events/press-announcements/fda-approves-first-treatment-thyroid-eye-disease
- Wiersinga WM. Graves’ disease: Can it be cured? Endocrinol Metab (Seoul). 2019;34(1):29-38. doi:10.3803/EnM.2019.34.1.29
- Graves’ disease. Mayo Clinic. Accessed August 23, 2021. https://www.mayoclinic.org/diseases-conditions/graves-disease/symptoms-causes/syc-20356240
- Konuk O, Anagnostis P. Diagnosis and differential diagnosis of Graves’ orbitopathy. In: Wiersinga WM, Kahaly GJ, eds. Graves’ orbitopathy: A Multidisciplinary Approach - Questions and Answers. 3rd ed. S Karger AG; 2017:74-92