Graves disease (GD) is the most common autoimmune disorder with the main target of the immune system being the thyroid-stimulating hormone (TSH) receptor of the thyrocyte (1,2). In contrast to most autoimmune diseases that cause targeted tissue damage, the deleterious immunologic response in GD results in thyrocyte stimulation and over production of thyroid hormones (3). Thyroid eye disease (TED) is the most common extrathyroidal manifestation of GD (4,5). The extrathyroidal manifestations of GD occur from cross-reaction between activated lymphocytes and cells expressing the TSH and possibly other surface receptors (6). Although the pathogenesis of TED is not clearly understood, most researchers now agree that the orbital fibroblast is the primary point of attack of the immune reaction (7–11). TED may develop before or concomitantly with Graves hyperthyroidism, but in 60% of cases it follows (ranging from months to years) the diagnosis of systemic GD (12,13).
PREVALENCE AND NATURAL HISTORY OF THYROID EYE DISEASE
The occurrence of clinically evident TED in patients with GD varies greatly from 13% to 69% (14). In a nonintervention, prospective study from a single referral center, over an 8-year period, 346 patients were recruited to determine the prevalence and natural history of TED (15). At presentation, 73.7% of patients had no clinical evidence of TED, 20.2% had mild TED, 5.8% had moderate-to-severe TED, and 0.3% had dysthyroid optic neuropathy. Of the 194 patients who did not have TED on presentation, after 18 months, 87.1% continued to have no TED, 10.3% developed mild TED, and only 2.6% developed moderate-to-severe TED. Interestingly, of the 43 patients with mild TED on presentation, 58.1% improved spontaneously and only 2.4% progressed to moderate-to-severe TED.
Patients with TED present in 2 distinct phases conceptualized by Rundle curve (Fig. 1) (16,17). The active inflammatory phase is characterized by periorbital erythema and edema, conjunctival chemosis, orbital inflammation and congestion, associated with eyelid retraction, proptosis, and diplopia. The active inflammatory phase is frequently mild and self-limited and often requires only supportive intervention (e.g., artificial tears, sunglasses) (18). The inflammatory phase is typically followed after a variable period (between 6 and 24 months) by a quiet, minimally inflammatory chronic fibrotic phase associated with orbital fibrosis, glycosaminoglycan deposition, and enlarged extraocular muscles. The chronic fibrotic phase results in similar clinical findings (i.e., eyelid retraction, proptosis, and diplopia) to the active inflammatory phase (17).
Treatment of TED has relied on a shotgun approach of general inflammatory suppression with corticosteroids and orbital radiotherapy (ORT) during the active phase and surgical correction of the anatomic sequelae during the chronic phase. As with other autoimmune diseases, a more contemporary approach to TED focuses on targeted therapies directed at blocking the production or interfering with the activity of specific pro-inflammatory cytokines, manipulating the development, proliferation, and function of specific subtypes of B and T cells and inhibiting adipogenesis (19–21). In TED, such therapies will only be effective in the active inflammatory phase of the disease. Because of the broad clinical overlap of the active and fibrotic phases, it is important to identify, through improved classification schemes, where a patient is situated in the evolution of their disease.
CLASSIFICATION SCHEME AND CLINICAL ASSESSMENT OF THYROID EYE DISEASE
There has been great deal of discussion regarding the classification and assessment of TED for both clinical and research purposes (17,22–26). Given the emerging emphasis on a focused immunosuppression and immunomodulation approach to autoimmune diseases in general, and TED in particular, any such classification or assessment scheme must not only be reproducible but it must be able to accurately score the severity and activity of the inflammatory phase of the disease (27). In 1969, Werner devised the clever mnemonic NO SPECS (No signs and symptoms, Only signs, Soft tissue involvement, Proptosis, Extraocular muscle involvement, Corneal involvement, and Sight loss), which was the basis of the ophthalmology index for many decades (28–31). Although this classification has been used to document disease severity (its original intention was to summarize the overall [active and chronic] clinical manifestations of TED), it does not adequately identify patients in the active phase of disease (22). Since the development of NO SPECS, a number of other classification and assessment schemes have been developed including VISA (Vision, Inflammation, Strabismus, and Appearance) (32), CAS (Clinical Activity Score) (24,33), and the EUGOGO (European Group On Graves' Orbitopathy) system (34) (See Supplemental Digital Content, Table E1, https://links.lww.com/WNO/A100). These scoring systems assess inflammatory signs in an attempt to identify patients in the active phase who are most likely to respond to treatment.
TREATMENT OF ACTIVE THYROID EYE DISEASE
There is no consensus as to the best treatment strategy for TED. Management of active TED requires a comprehensive and multimodality approach in which the ophthalmologist and endocrinologist work as a team to develop a specific plan of care (34,35). As mentioned above, the decision to initiate treatment requires a careful analysis of the patient's ophthalmic status (severity) and determination of whether the patient is in the active or chronic phase of the disease (Fig. 1B). Specific questions to be addressed include:
- How active and severe is the TED?
- What TED risk factors can be modified or treated?
- What is the best management strategy for the Graves hyperthyroidism?
- What is the optimum treatment for the TED?
Modifiable Risk Factors for Development or Progression of Thyroid Eye Disease
There are many risk factors that can affect the development or progression of TED (Fig. 2) (36). Some of these, such as age, gender, ethnicity, genetics, and thyrotropin receptor antibody status, are not modifiable (37,38). Others, such as smoking and thyroid status, can be modified with a potential favorable impact on the course of the disease (4,38).
There is strong clinical evidence that cigarette smoking is associated with and adversely affects the development, progression, and management of TED (39). In a case–control study of 450 thyroid patients (with 400 controls), smoking cigarettes increased the risk of TED by 7-fold (40). Smoking has been associated with more severe and progressive TED (34), worsening of TED after radioactive iodine (RAI) treatment (41), and lessening the beneficial effects of immunosuppressive therapy (38,42).
As with the cessation of smoking, it is important to achieve and sustain a euthyroid state in patients with TED (38). Prummel et al (43) found that patients with hyperthyroidism or hypothyroidism had a greater eye severity score than euthyroid patients, which translated to an odds ratio of 2.8. It has also been shown that restoring euthyroidism can improve TED (44).
Treatment of Hyperthyroidism
There are 3 main treatment options for patients with Graves hyperthyroidism: antithyroid drugs, thyroidectomy, and RAI treatment (45). Each of these modalities has been studied in terms of the influence on the development and worsening of TED.
The thionamides (propylthiouracil, methimazole, and carbimazole) lower thyroid hormone production by inhibiting the iodination of thyroglobulin and ultimately the production of thyroxine (T4) and thriiodothryronine (T3) (46). Several studies have shown that antithyroid drugs do not adversely affect TED (34,47,48). Bartalena et al (49) studied the effect of methimazole on the development and progression of TED. Of the 148 patients treated with methimazole, 95% had no change in TED status, 3% improved, and only 3% worsened.
The effect of thyroidectomy on the course of TED remains unclear (34). Marcocci et al (50) performed a case–control study in which 30 patients with either no or mild TED treated with near total thyroidectomy were compared with 60 patients treated with methimazole. One patient (3.3%) in the thyroidectomy group had new or worsening TED compared with 2 patients (3.3%) in the methimazole group. The authors concluded that near-total thyroidectomy did not have an effect on TED. In a meta-analysis of 3 randomized clinical trials involving total thyroidectomy vs subtotal thyroidectomy (51), no difference was found between these 2 surgical procedures on the development or worsening of TED (52–54).
Radioactive Iodine Treatment
In 1967, Kriss et al (55) were the first to report the effect of RAI treatment on TED. Since then many retrospective reports have shown a negative effect of RAI treatment on TED (56,57). Approximately 15% of patients may experience new onset or worsening of TED after RAI treatment (See Supplemental Digital Content, Table E2, https://links.lww.com/WNO/A101) (34,49,58–62). Prophylactic treatment with oral prednisone during and for several weeks following RAI treatment may significantly reduce the risk of the development or progression of TED (49,59,63,64). Although the exact pathomechanism of TED development or worsening after RAI treatment is not precisely known, it has been suggested that there is a change in thyroid autoimmunity with the production of TSH receptor antibodies due to the release of thyroid antigens as the result of RAI-induced tissue damage (17,56).
All patients with TED should be counseled on risk modification, particularly smoking cessation. Although corticosteroids and ORT reduce the active inflammatory symptoms, there is no proven role for these modalities in reducing the risk of disease progression in patients with mild TED (65). Preservative free artificial tears and moisture chambers are very helpful for dry eyes and corneal exposure. Sunglasses can improve photosensitivity. Fresnel prisms (or monocular occlusion) can resolve double vision. Eyelid retraction can be temporarily treated with the injection of botulinum toxin into the levator superioris and Müller muscle complex (66–68).
The most common current treatment strategies for active moderate-to-severe TED involve corticosteroids and ORT.
Corticosteroids are the most often used therapy for TED. However, the precise dosage, duration, preparation, and route (intravenous [IV], oral [PO], or periocular) of administration remain a matter of opinion and debate (17,69,70). In most cases, corticosteroid use is reserved for patients with active moderate-to-severe TED and dysthyroid optic neuropathy (16,66,71). The response rate with PO corticosteroids is less than IV corticosteroids (60% vs 80%, respectively) (17,72,73). Pooled data have shown that patients who received IV corticosteroids compared with PO corticosteroids fared better in terms of double vision, ocular motility, and proptosis, with fewer side effects (72). To date, there have been only 4 randomized clinical trials that have compared the efficacy of PO corticosteroids with IV corticosteroids (See Supplemental Digital Content, Table E3, https://links.lww.com/WNO/A102) (74–78).
Based on a review of the literature, Zang et al (78) recommend a 12-week course of IV methylprednisolone (0.5 g as a single dose per week for 6 consecutive weeks followed by 0.25 g as single dose per week for 6 consecutive weeks, not to exceed a total of 8 g) for patients with active moderate-to-severe TED. EUGOGO performed a multi-center, randomized, double-blinded trial to access the efficacy and safety of 3 different cumulative doses (2.25, 4.98, and 7.47 g) of IV methylprednisolone over a 12-week period in patients with active moderate-to-severe TED. The 7.47 g group had the greatest positive short-term response in terms of CAS. This benefit did not persist at 24 weeks and was associated with a slightly higher rate of adverse events compared with the lower doses (79). Oral and IV corticosteroid treatment can be associated with significant hepatic, metabolic, cardiovascular, and cerebrovascular side effects and in some cases death. Patients must be monitored carefully with the benefits weighed against the risks (80).
Intravenous corticosteroids can be highly effective in reversing the visual loss due to dysthyroid optic neuropathy and should be instituted before considering alternative therapy, such as orbital decompression (16,66,81,82). The use of corticosteroids concurrently with ORT has been found to be more efficacious than ORT alone (see below) (17,72,73). Some patients can have worsening orbital inflammation during or after ORT, which can be suppressed with a short course of corticosteroids (83).
Selenium, through its effects from selenoproteins, plays an important role in cell development and proliferation, oxidative stress protection, and production of T3. Since selenium acts as a potent antioxidant, and oxygen free radicals contribute to the orbital inflammatory process, theoretically it could be of some therapeutic benefit in TED (84,85). In a randomized, double-blinded, placebo controlled trial of mild TED, the overall ophthalmic outcome was better in the selenium (100 μg twice daily) group compared with the placebo group (P = 0.01) (86). TED improved in 61% of the selenium group and 36% of the placebo group. TED worsened in 7% of the selenium group and 26% of the placebo group (selenium compared with placebo, P = 0.01). Although there were no adverse drug reactions in any patients taking selenium, concerns of selenium toxicity include the increased risk of diabetes mellitus, glaucoma, and neurotoxicity (87–89).
ORT can be effective in TED with an overall response rate of 60% (34,90). However, there remains much debate over the role of ORT in TED (91). The impediment to a general consensus of ORT in TED derives from the paucity of randomized clinical trials, nonstandardized clinical measures and outcomes, conflicting study results, and heterogeneity of study design and patient populations (See Supplemental Digital Content, Table E4, https://links.lww.com/WNO/A103). In general, ORT has been shown to improve ocular motility and possibly periocular soft tissue changes but not the degree of proptosis (92,93). ORT has not been shown to decrease the risk of disease worsening in patients with mild TED (94,95).
Three randomized controlled trials compared ORT with sham (94,96,97). Gorman et al (97) found no difference in the treatment effect between ORT and sham, but Mourits et al (96) found that ORT was superior to sham. Prummel et al (94) reported that ORT was efficacious in patients with mild TED but did not slow the progression of mild TED to more severe disease.
Five randomized controlled trials compared ORT with corticosteroids in various combinations (98–102). Bartalena et al (98) found that patients randomized to PO corticosteroids and ORT did better than patients randomized to PO corticosteroids alone. Marcocci et al (99) found that PO corticosteroids in combination with ORT was more efficacious than ORT alone. Prummel et al (100) compared ORT with PO corticosteroids and found no difference. Marcocci et al (101) found the addition of IV corticosteroids with ORT was better than PO corticosteroids with ORT. Finally, Ng et al (102) found that ORT in combination with IV corticosteroids was superior to IV corticosteroids alone. The effect of ORT on visual loss due to dysthyroid optic neuropathy has not been studied in a randomized controlled fashion (93). However, there are many reports that have shown dysthyroid optic neuropathy is responsive to either ORT alone or ORT in combination with corticosteroids (34,101,103,104).
The typical ORT protocol for TED is a total of 20 Gy (or 2,000 rads) per orbit fractionated in 10 days (2 Gy/d) over a 2-week period. However, the optimum fractionation, duration, and dosing of ORT remains unsettled, and lower doses seem to perform just as well as higher doses (105). Gerling et al (106) compared 2.4 Gy with 16 Gy of total ORT given over a 16-day period and found no statistical difference between the 2 groups based on 5 predefined outcome measures. In a pilot study, the clinical and radiological effects of low dose (1 Gy/wk) ORT for 10 weeks was explored (107). All 18 patients had improvement in most of the signs or symptoms of TED.
ORT is a relatively safe procedure but should not be recommended in patients with severe uncontrolled hypertension and diabetes mellitus (especially if there is pre-existing diabetic retinopathy) (92). The risk of radiation retinopathy has been estimated to be 1%–2% within the first decade of treatment (93). Cataract formation is also a potential complication of ORT, but in one long-term study, the risk of cataract development was not associated with ORT (108).
Surgical Treatment for Thyroid Eye Disease
In most cases, surgery (orbital decompression, eyelid recession, and strabismus surgery) is indicated for the rehabilitation of patients with stable, nonactive (fibrotic) TED. In active TED, orbital decompression is reserved for patients with severe orbital inflammation, severe proptosis resulting in corneal exposure, uncontrolled glaucoma from orbital congestion, and dysthyroid optic neuropathy (17). Some of the options that need to be considered when performing orbital decompression include (83,109–113):
- Number of orbital walls to be operated upon: 1, 2, or 3.
- Approach: coronal, external, endoscopic, or combined.
- Incision site: extended eyelid crease, transcaruncular, transconjunctival, etc.
- Type of decompression: boney decompression vs fat-only decompression.
- Orbital rim removal with refixation or preservation.
There are multiple retrospective studies that have documented the efficacy of orbital decompression in stabilizing or improving vision in patients with dysthyroid optic neuropathy (103,114–119). Soares-Welch et al (120) reviewed the results of 215 patients (344 eyes) with dysthyroid optic neuropathy that underwent transantral orbital decompression. Of the 205 eyes that had 20/40 or worse vision, 110 eyes (54%) improved by ≥3 Snellen lines and only 8 eyes (2%) lost ≥3 Snellen lines or more.
The timing of when to intervene with orbital decompression, before or after corticosteroid treatment, in patients with dysthyroid optic neuropathy remains unresolved. In the only randomized controlled study that compared IV methylprednisolone (1 g/d for 3 consecutive days, repeated after 1 week followed by a 4-month PO prednisone taper) with orbital decompression (3-wall coronal approach) in patients with dysthyroid optic neuropathy, 5 of 9 patients in the IV methylprednisolone group had improvement in vision compared with only 1 of 6 patients in the orbital decompression group. Interestingly, when the nonresponders in each group (88% of the orbital decompression group and 56% of the IV methylprednisolone group) switched therapy (in addition to receiving ORT in some cases), there was an improvement in vision in all but 2 patients. The authors concluded that IV methylprednisolone should be the first-line treatment for patients with dysthyroid optic neuropathy, and if that fails to improve vision, orbital decompression should be offered (81).
FUTURE TREATMENT OF THYROID EYE DISEASE
A variety of procedures, anti-inflammatory, immunosuppressive, and immunomodulating agents have been investigated in the treatment of TED, but few have been scrutinized in randomized controlled studies (See Supplemental Digital Content, Table E5, https://links.lww.com/WNO/A104) (86,121–176).
Despite our expanding knowledge of the underlying molecular and immunological mechanism of TED, the unpredictable behavior of the disease and confounding results of clinical studies complicate treatment paradigms. In addition, many published studies have provided a vast amount of data that are difficult to synthesize into specific universally accepted treatment recommendations. Organizations such as EUGOGO (http://www.eugogo.eu), International Thyroid Eye Disease Society (http://thyroideyedisease.org), and Neuro-Ophthalmology Research and Development Consortium (http://www.nordicclinicaltrials.com/nordic) are working diligently on both a national and an international level to develop a unifying clinically applicable system to reliably identify disease phase and accurately measure therapeutic outcomes (177). The efforts of these organizations will hopefully culminate in many global, multi-center, randomized controlled trials that will produce evidence-based data that can be uniformly integrated and analyzed to provide the necessary answers to many of the questions that still remain about the optimum management of TED. Until evidence-based guidelines are developed, we offer a treatment algorithm for patients with active TED (Fig. 3).
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