The effect of orbital radiation therapy on thyroid-associated orbitopathy complicated with dysthyroid optic neuropathy

Abstract

Thyroid-associated orbitopathy (TAO) is an inflammatory autoimmune disorder. The most serious complication of TAO is dysthyroid optic neuropathy (DON), which can lead to permanent vision loss because of volume expansion in the orbital apex. Orbital radiation therapy (ORT) is an anti-inflammatory treatment used in the treatment of active TAO. Clinical studies support radiotherapy as having a modest effect on DON, and early radiotherapy may protect against disease progression to DON. Current studies suggest that radiotherapy is generally safe. However, risks still exist in some cases. The possible effects of radiotherapy on TAO, especially complicated with DON, are reviewed. The effects of radiotherapy on DON are not completely known, and evidence from standardized, prospective, and multicenter clinical trials is still lacking.

Keywords

thyroid-associated orbitopathy / dysthyroid optic neuropathy / orbital radiation therapy

Introduction

Thyroid-associated orbitopathy (TAO) is an autoimmune inflammatory phenomenon that can lead to permanent vision loss. TAO is also known as thyroid eye disease or Graves’ ophthalmopathy [1] and is typically associated with hyperthyroidism (85%) due to Graves’ disease. However, the remaining 10% of the cases may also occur with hypothyroidism [2,3] or with euthyroidism. The incidence of TAO is 5.5 times [4] higher in women than in men, with an approximate prevalence of 0.25% [5]. Meanwhile, the ratio of females to males reverses to approximately 1:4 for severe TAO [6], and it is more severe in smokers [7]. Common clinical manifestations of TAO include eyelid retraction (90%) followed by exophthalmos (60%) and restrictive extraocular motility (40%) [8].

Although dysthyroid optic neuropathy (DON) occurs infrequently (5%) [9,10], it may be the most critical and severe complication of TAO, which was first described by Sattler and Behr in 1921 [11,12]. Unfortunately, most physicians believe that without prompt and appropriate therapy, 30% of patients with DON may suffer from loss of visual acuity, and this loss could become permanent despite subsequent aggressive treatments [13,14].

A prospective study by the European Group on Graves’ Orbitopathy analyzed a large case series of patients with DON and recently determined that loss of visual acuity, altered color perception, optic disc swelling, and the evidence of optic nerve compression at imaging were the most significant findings in DON diagnoses [15]. Severe proptosis and orbital inflammation are rare in DON [15] probably because proptosis can lead to orbital decompression, which has a beneficial effect on apical crowing and optic nerve stretching. Both computed tomography and magnetic resonance imaging can show extraocular muscle and soft tissue enlargement (Fig. 1). Positive results on visual-evoked potentials (VEPs) include increased latency and/or reduction of amplitude. VEPs have high diagnostic specificity, which is why some physicians suggest their additional use in the diagnosis and evaluation of DON [15–17].

The management of DON remains controversial. Treatment options include corticosteroids and decompression surgery. Orbital radiation therapy (ORT) can be considered as additional treatment in some patients [18,19]. Systemic high-dose steroid medication is the current first-line therapy; orbital decompression surgery is reserved for persistent defects; and ORT is rarely used. However, previous findings support the use of ORT in active DON as a surgery-delaying alternative. Evaluating the influence of ORT on TAO, especially with DON complication, is necessary.

Pathogenesis of DON

The enlargement of extraocular muscle and orbital fat is thought to be the cause of orbital congestion and hindrance of venous drainage [20]. Due to overcrowding in the orbit, episcleral venous pressure increases, which causes high intraocular pressure [20]. Orbital congestion also leads to extraocular movement limitation and optic nerve compression. The orbital septum limits orbital expansion as a tight barrier, thereby increasing orbital congestion. The disease becomes severe when the compression involves the orbital apex, where the bony orbit narrows. The extraocular muscle encircles the optic nerve becoming the annulus of Zinn [21]. The optic nerve and its vasculature are then compressed, including the ophthalmic veins, central retinal veins, central retinal arteries, and posterior ciliary arteries, which are the main areas of ocular perfusion [22]. The resulting severe orbital congestion can cause ischemic optic neuropathy, which leads to visual loss.

Biological effects of ORT

The biological effects of ORT in DON may be terminal fibroblast differentiation and lymphocyte apoptosis, which work together to alter the inflammatory cycle and cause the down-regulation of glycosaminoglycan and hyaluronan deposition [23]. ORT appears most efficacious when applied during the active phase of TAO, and its effects can be delayed for weeks to months [24].

Clinical studies of ORT

The use of radiation to treat TAO was first reported in 1913 [25]. However, the first irradiation procedure involved the thyroid glands of a patient with TAO. The radiation to orbital tissue was used after several attempts [26–28]. Since then, orbital radiation has been used as a medical therapy to improve the orbital signs of TAO.

Because TAO can be divided into three categories according to severity, namely, sight-threatening TAO (DON and/or corneal breakdown), moderate-to-severe TAO, and mild TAO [29], the influence of ORT on these three groups is worth discussing.

Sight-threatening TAO

Studies are mostly uncontrolled in terms of DON because of retrospective clinical case reports (Table 1) and lack of prospective randomized controlled trials. A retrospective review [30] of 59 patients with active TAO and treated with ORT was studied. Among the 59 patients, 11 of them were considered as DON patients who received retro-ORT of 20 Gy in 12 fractions over 2 weeks. After treatment, 10 of 11 (90.9%) experienced an improvement on their visual acuity (one Snellen line or more) during a mean follow-up of 6.5 months. Another study [31] reviewed 10 patients with DON. All patients received 20 Gy in 10 fractions with megavoltage irradiation to the orbits. Improvement on optic nerve function occurred in 8 of 10 (80%) patients. The average improvement in visual acuity was two Snellen lines. Of the two patients who did not show much improvement on visual acuity, one showed deterioration of visual acuity in one eye (20/25 to 20/40), actually had fluctuating visual acuities owing to corneal surface problems rather than optic neuropathy, and the other one improved early on but decreased back to the initial status at the last follow-up visit 6 months later and was the only patient to require surgical decompression. Optic neuropathy seems to be important to distinguish from corneal problems on a sight-threatening patient. ORT seems to be effective in reversing optic neuropathy in most cases, whereas medical corneal protection or an immediate surgery is a better solution for corneal problems [29]. However, oral prednisone was also administered in nine patients during the first week of ORT as they suffered relapse after tapering of corticosteroids. It is hard to tell whether the improvement was an effect of ORT or a combination of ORT and oral prednisone. In addition, Dr. Beckendorf reported his study [32] to evaluate the response of TAO to irradiation. Of the 24 patients presenting a loss of visual acuity initially due to neuropathy in this study, nine patients (37%) had a very satisfying response with improvement of visual acuity, 11 (46%) had partial response or stabilization (no deterioration), and 4 (17%) experienced a deterioration of visual acuity that required surgical decompression. In total, 83% of the patients with DON showed good response to ORT. In an early retrospective analysis in 1989 [33], 18 eyes (78%) visually improved, whereas 2 eyes (8.7%) worsened after ORT. In a Korean report [34], 28 of 29 (96.5%) DON patients avoided surgery in the ORT group and 10 of 16 (62.5%) in the corticosteroid group.

Moderate-to-severe TAO

In three randomized controlled trials (RCT) and a recent retrospective study for patients with moderate-to-severe TAO, ORT was compared with glucocorticoids as monotherapy or combination therapy; results showed that the combination of ORT and glucocorticoids was better than glucocorticoids alone [35–37]. ORT and oral prednisone appeared to be equally effective, but ORT presented better tolerability [38]. ORT was compared to sham radiotherapy in RCT with the primary outcomes of composite outcome score, which showed a risk ratio of success of 1.92 (95% confidence interval 1.27 to 2.91) in favor of ORT [39]. Moreover, early ORT for patients with moderate-to-severe TAO may also protect against disease progression to DON and restrictive myopathy according to Shams [40] and Yoon [41]. A significant drop (P<0.01) in mean intraocular pressure [42] and a reduction of deterioration in diplopia [41] after radiation therapy have been also found in recent studies.

Mild TAO

Only one study on ORT was reported in mild TAO [43]. In this double-blinded RCT, ORT was compared to sham radiotherapy, resulting in improvement in 23 of 44 (52%) irradiated patients versus 12 of 44 (27%) sham-irradiated patients at 12 months after treatment, showing a success in ORT with relative risk of 1.9 (95% confidence interval 1.1 to 3.4; P<0.02). They also indicated improvement in eye muscle motility, decrease in severity of diplopia, and less need for further treatment.

Contraindications and side effects of ORT

The contraindications of ORT include prior retinopathy, poorly controlled diabetes, inactive stage of TAO, and patients younger than 35 years of age due to a theoretical risk (0.7%) [44] of secondary ORT-induced malignancy [45]. No severe side effects have been reported in most of the reviewed studies, but the risk of conducting ORT still exists in some cases. Radiation retinopathy, as well as microvascular retinopathy [49], was diagnosed in these cases [46–48] after orbital irradiation according to the commonly used protocol in TAO. However, other confounding factors known to be associated with microvascular retinopathy were identified among these patients. Whether these factors were caused by ORT cannot be precisely ascertained. Secondary malignancy, such as meningioma [50] or pigmented basal cell carcinoma [51], is the most severe complication. Fortunately, long-term follow-up has not revealed a high incidence of radiation-induced secondary tumors [46,52].

The risk of exacerbation after ORT

Some authors indicated the risk of ORT on TAO exacerbation. ORT caused an acute worsening in a patient with stabilized DON [53] and caused DON in two patients with active, moderate TAO [54]. Therefore, close monitoring on optic nerve function is necessary if ORT is utilized for either mild or moderate TAO or DON. Surgical decompression was required in cases of exacerbation [53,54].

Conclusions

This report details the possible effects of radiotherapy in TAO, especially complicated with DON, by reviewing pathogenesis and clinical studies. ORT is effective by stopping the progression of disease through improving the comfort of patients, obtaining objective responses, and avoiding surgery in almost all cases, particularly when signs were mild to moderate. However, prospective RCTs in DON are lacking possibly because ORT may be useless for DON, which may lead to an acute worsening of visual acuity. As a result of our literature review, ORT seems to be effective in reversing optic neuropathy in most cases, however, not for all patients with DON. Thus, we proposed ORT in DON as an additional option to delay or avoid surgery. Current studies suggest that radiotherapy is generally safe, but severe risks still exist in some cases. We should emphasize the need for close monitoring of optic nerve function. The effectiveness of radiotherapy for DON remains uncertain. In the future, large-scale standardized, prospective, and multicenter clinical trials are needed to evaluate the effects and risks of radiotherapy for DON treatment.

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