As ophthalmologists, we are often the first to discover and diagnose signs and symptoms of systemic disease. Signs are often easily detectable, such as microaneurysms and dot-blot hemorrhages discovered on a retinal exam that are consistent with underlying diabetes mellitus. Other diseases, such as thyroid eye disease (TED), present in a less predictable fashion and are far less common; TED is estimated to affect 16 per 100,000 women, and 2.6 per 100,000 men. Therefore, a high level of suspicion is necessary to ensure we do not miss a potentially blinding diagnosis.

Here, I present advice on how to recognize and diagnose TED and a stepwise approach for the next steps to take once you have done so.

DIAGNOSIS

Recognition of TED is key

The typical presentation of a TED patient with eyelid retraction, proptosis and extra-ocular movement motility disturbances can be an easy diagnosis. The question then is whether we are doing an adequate job in recognizing this disease in its most subtle presentation. Are we underdiagnosing these patients and labeling them as dry eye patients and potentially delaying treatment that may lead to improvement in their quality of life?

Asking key questions during our patient interview (social history, history of present illness, day-to-day variability, family history of the disease) and performing a thorough physical exam will increase the chances of making the correct diagnosis.

TED commonly occurs in middle-age (45-65), affecting more females than males; however, men usually have more severe disease than women. It is also known that smoking can worsen the disease course.

Patient complaints

Having a high level of suspicion is important in the diagnosis of this disease. Common complaints include tearing, irritation and non-specific pressure behind or around the eyes. Patients also complain about feeling “puffy” or “swollen” around the eyes. This complaint of periorbital edema may not be obvious, especially in an older patient as the normal signs of aging include prolapsed orbital fat. I often ask patients to bring in pictures of what their “normal” is to have a benchmark for comparison. It is also important to have photo documentation for each visit to better compare their appearance at each exam.

Physical exam

Aside from our standard slit-lamp examination, assessing eyelid position, presence of retraction on upper and/or lower eyelids, fullness or swelling of the periorbital fat is important. In addition, measurements via hertel exophthalmometry to assess and quantify the level of proptosis is vital. A thorough motility exam noting any restriction should be performed along with confrontation visual fields. In patients with inferior rectus restriction, the IOP can often be elevated when measured in upgaze. It is appropriate to obtain a Humphrey visual field 30-2 to assess baseline optic nerve function.

TED can manifest itself prior to any thyroid dysfunction with normal lab values, also known as euthryoid eye disease. Thus, a lack of previous diagnosis of thyroid disease should not rule out TED.

Bloodwork

Once I have a suspicion for TED, I obtain appropriate blood work, including thyroid function tests, such as TSH, T3, T4, as well as TSI and TRAB levels. TSI and TRAB have been found to be elevated in the presence of TED and can be used as clinical markers to follow for disease activity.

Occasionally, one should consider obtaining a myasthenia gravis panel, as these two diseases can coexist in a small number of patients. In a patient with no prior medical history of thyroid disease, a full inflammatory panel should also be obtained, which usually includes ANA, pANCA, cANCA, ESR, CRP, IgG/IgG4, CBC with differential, ACE, LDH and BUN/Cr.

Imaging

Imaging exams are typically performed when the diagnosis is either not clear or to guide surgical treatment and assess the status of the nerve, muscles and periorbital tissues. Imaging may include CT or MRI of the orbits.

TED MANAGEMENT

Start by following closely

Once the diagnosis has been made, it is appropriate to follow the patients closely until stable. Establishing their clinical activity score, or CAS, is essential in assessing whether these patients will need treatment, which may include:

• Selenium supplementation
• Smoking cessation counseling
• Symptomatic relief with topical lubricants
• Systemic steroids
• Orbital radiation
• Targeted systemic biologics
• Surgical intervention

Involve the patient and others

Once the patient has been deemed to have active/inflammatory TED, treatment should be sought to prevent blinding/disfiguring disease.

Patient education is the top priority during the first few visits. Smoking cessation is strongly encouraged for every patient, and that should include second-hand smoke. Also, I will trend the patient’s blood markers TSI, TRAB as well as work hand-in-hand with the patient’s endocrinologist to assess any therapeutic plans, which may include radioactive iodine and thyroidectomy.

It is appropriate at this time to discuss possible treatments detailing what they entail, such as setting up infusions for medications.

Prescribe medication

Corticosteroids play a role in managing inflammation but do not affect diplopia nor proptosis. Orbital radiation has also been used in the past to treat sight-threatening TED, though with mixed results.

The FDA approved teprotumumab (Tepezza, Horizon Therapeutics) to directly target the IGFR-1 receptor, which is expressed primarily in the periorbital tissues of TED patients. Recent articles have also shown that this medication can also treat patients with chronic, long-standing TED. Attacking the primary target of the disease means potential disease-modification, therefore altering the course of the disease and possibly reducing the sequelae on the affected tissues.

There is a lot yet to be learned for this and other targeted therapies and their role in treating patients with chronic TED as well as patients who could be considered “mild to moderate” disease. In these cases, patients could avoid multiple reparative surgeries and all the associated downtime and economic burden related to surgery. However, it is still very hard to predict which patients will eventually end up with “end-of-spectrum” disease and which will only have mild symptoms that reverse once the disease has stabilized.

CONCLUSION

As physicians, we should be comfortable with diagnosing TED in its earliest presentation.

While saving sight should be our primary goal, we should be aware of its disfiguring changes to the patient that can alter not only their appearance but also suffer a significant cost to the patient, society and our healthcare system. The psychological impact of TED on patients is significant. Working closely to maintain the patient’s mental health should also be high on the priority list. This may include connecting the patient with support groups, a counselor or mental health professional.

The heterogeneous presentation of TED can make it challenging for the clinician to correctly diagnose and treat this disease. But, it is important to keep TED in our differential diagnoses, especially now, when we can potentially change the direction of the disease with targeted therapy. OM

Ana Carolina Victoria, MD, FACS, is an oculofacial plastic and reconstructive surgeon at Center for Excellence in Eye Care in Miami.

Disclosures: Dr. Victoria reports relationships with Candela Medical, Horizon Therapeutics and RVL Pharmaceuticals.