Reduced Risk of Compressive Optic Neuropathy Using Orbital Radiotherapy in Patients With Active Thyroid Eye Disease

Accepted Manuscript Reduced risk of compressive optic neuropathy using orbital radiotherapy in patients with active thyroid eye disease Pari N. Shams, MRCP, FRCOphth Roy Ma, MD Tom Pickles, MD Jack Rootman, MD, FRCSC Peter J. Dolman, MD, FRCSC PII:

S0002-9394(14)00127-5

DOI:

10.1016/j.ajo.2014.02.044

Reference:

AJOPHT 8849

To appear in:

American Journal of Ophthalmology

Received Date: 9 December 2013 Revised Date:

19 February 2014

Accepted Date: 19 February 2014

Please cite this article as: Shams PN, Ma R, Pickles T, Rootman J, Dolman PJ, Reduced risk of compressive optic neuropathy using orbital radiotherapy in patients with active thyroid eye disease, American Journal of Ophthalmology (2014), doi: 10.1016/j.ajo.2014.02.044. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT 1 Title page Title: Reduced risk of compressive optic neuropathy using orbital radiotherapy in patients with active thyroid eye disease

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Authors: Pari N Shams, MRCP, FRCOphth,1 Roy Ma, MD,2 Tom Pickles, MD,2 Jack Rootman, MD, FRCSC,1 Peter J Dolman, MD, FRCSC1

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Institutional affiliations: 1 Department of Ophthalmology and Visual Sciences, Vancouver Hospital Eye Care Centre and University of British Columbia, Vancouver, Canada. 2

British Columbia Cancer Agency and University of British Columbia, Vancouver, Canada.

E-mail: [email protected]. Address for reprints: As above

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Correspondence: Peter J. Dolman, MD, FRSC, Clinical Professor, Department of Ophthalmology, University of British Columbia, 2550 Willow Street, Section I, Vancouver, British Columbia, Canada, V5Z 3N9.

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Short title: Reduced risk of optic neuropathy in thyroid eye disease

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Word count: Abstract 316 Text 3202

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Abstract Purpose: To compare the risk of developing compressive optic neuropathy in patients with active thyroid eye disease (TED) treated with corticosteroids with or without orbital radiotherapy.

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Design: Retrospective single center case control study.

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Methods: The clinical charts of 351 patients with active TED who received corticosteroids with or without orbital radiotherapy between 1999 and 2010 were reviewed. Patients with compressive optic neuropathy at the time of presentation were excluded. Group 1 received corticosteroids only and group 2 received corticosteroids as well as orbital radiotherapy. The primary outcome measure was the development of compressive optic neuropathy. Secondary outcome measures were changes in other parameters indicating the activity or severity of TED including soft tissue inflammation, diplopia, ocular motility restriction, and appearance.

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Results: There were 144 cases in Group 1 and 105 in group 2. Both groups were matched for age, gender and stability of thyroid function. The two groups differed only in the modality of treatment for active TED. The main indication for treatment in both groups was soft tissue inflammation. Corticosteroids were initiated an average of 2.6 months in group 1 and 2.5 months in group 2 following symptom onset. Group 2 received orbital radiotherapy on average 4.2 months following the initiation of corticosteroids therapy and 8% were intolerant to corticosteroids. At an average of 3.2 years follow-up, compressive optic neuropathy had developed in 17% (n=25) of group 1 and 0% of group 2 (p< 0.0001), on average 5.5 months following the initiation of corticosteroid therapy. Although both groups experienced a significant reduction in periocular inflammation, the radiotherapy treated group demonstrated a significantly greater improvement in ocular motility.

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Conclusion: The rate of compressive optic neuropathy was significantly lower and improvement in ocular motility greater in patients receiving orbital radiotherapy in addition to corticosteroids. Patients with active TED appear to have an effective and sustained response to orbital radiotherapy combined with corticosteroids which is protective against disease progression and the development of compressive optic neuropathy.

ACCEPTED MANUSCRIPT 2 Text: Introduction:

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Thyroid eye disease (TED) is an autoimmune disorder whose active (progressive) phase is characterized by inflammation and expansion of the orbital fat and extraocular muscles.1 Treatment of active TED is directed at quelling the immune reaction with the hope of minimizing proptosis, exposure keratopathy and in more severe cases progression to compressive optic neuropathy or extraocular motility impairment.2 Corticosteroids and adjunctive external beam orbital radiation are two immunomodulators commonly used in the treatment of progressive TED. The efficacy of corticosteroids is attributed to antiinflammatory and immunosuppressive properties. However, a significant number of patients (20–40%) respond poorly or partially to corticosteroids and recurrences are not infrequent on withdrawal and dose reduction.6 Furthermore their significant side effects can limit the dose and duration of effective therapy.

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External beam orbital radiotherapy has been used in the treatment of TED for almost a century. 7 It is presumed to work by inducing terminal differentiation in progenitor fibroblasts, suppressing the downstream consequences of fibroblast activation, and by reducing the secretion of pro-inflammatory cytokines from activated lymphocytes.8-11 8 12 Current high-energy linear accelerators provide targeted delivery of radiation to the retrobulbar orbital tissues.

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The degree of heterogeneity between published studies of orbital radiotherapy in TED makes it difficult to compare outcomes and perform meta-analyses.13 According to most studies, orbital radiotherapy is especially effective for soft tissue inflammatory changes and recent extraocular muscle involvement;14-18 however, its effect on progression of TED and in particular the risk of development of compressive optic neuropathy has not been sufficiently investigated.19 Currently the use of orbital radiotherapy is restricted to patients older than 35 years of age and without systemic vascular disease.

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Methods:

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In general, corticosteroids show effect within a day, but the benefit is short-lived. Orbital radiotherapy may not show benefit for several days to weeks, but its effects are longer lasting. Given this more sustained effect, our a priori hypothesis was that treatment with orbital radiotherapy in addition to corticosteroids was associated with a lower risk of compressive optic neuropathy compared with corticosteroid therapy alone.

All patients with active TED who received corticosteroids with or without orbital radiotherapy under the care of two clinicians (PJD or JR) were retrospectively identified from electronic databases at the Vancouver Hospital Eye Care Centre and the BC Cancer Agency between January 1999 and January 2010. The study protocol, to perform a retrospective chart review of all patients meeting the study criteria, was approved by the University of British Columbia Clinical Research Ethics Board and adhered to the tenets of the Declaration of Helsinki (study ID: H11-02430). The inclusion criteria were all patients with active TED who received corticosteroids with or without orbital radiotherapy and post-treatment follow-up of 12 months or longer. Group 1, the control group, received only corticosteroids. Group 2, in addition to concurrent or previous treatment with corticosteroids, received orbital radiotherapy. Exclusion criteria were compressive optic neuropathy at

ACCEPTED MANUSCRIPT 3 the time of initial presentation, treatment with orbital radiotherapy alone, a past history of optic neuropathy, previous orbital decompression surgery or incomplete clinical records.

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The following parameters were compared to evaluate how closely the two groups were matched: 1) demographics (age, gender); 2) history of diabetes, hypertension or smoking; 3) stability of thyroid function at the time of treatment; 4) indication(s) for treatment of TED; 5) pre and post treatment activity and severity of TED; 6) time from presentation of symptoms to receiving corticosteroids and orbital radiotherapy and 7) corticosteroids treatment regimen (oral/intravenous (IV)/both) . Differences in proportions and mean values for continuous, normally distributed data, were carried out using the chi square test or paired t-test and the Mann-Whitney rank sum test was used for non-parametric data. Statistical tests were performed using Sigmaplot® version 12.5 for Windows (Systat Software, Inc., San Jose, California, USA).

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The primary outcome measures were: 1) development of compressive optic neuropathy after presentation, based on reduced best corrected visual acuity of two lines or more AND reduced color vision of 2 plates or more on Harvey Rand Ritler test AND a relative afferent papillary defect in asymmetric cases with or without evidence of optic disc swelling and visual field defect and 2) time from initiation of corticosteroids treatment and/or orbital radiotherapy to development of compressive optic neuropathy.

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Secondary outcome measures were: 1) complications related to the effects of treatment and 2) change in other disease related end-points, using the VISA Classification system.19 The VISA classification measures four parameters of disease: 1) Vision documents the presence or absence of optic neuropathy (+1 = present, 0=absent); 2) Inflammation is graded from 0 to 8: orbital pain 0 to 2, chemosis 0 to 2, eyelid edema 0 to 2, conjunctival injection 0 to 1, eyelid injection 0 to 1; 3) Strabismus is graded in two parts from 0 to 3: S1- diplopia (0 = none, 1 = diplopia with gaze, 2 = intermittent diplopia and 3 = constant diplopia), S2- degree of ocular restriction is graded from 0 to 3 (measured using the pupillary light reflex 0 = >45°, 1 = 30-45°, 2 = 15-30°, 3 = < 15°);20 4) Appearance is graded 0 to 3 (1 for mild proptosis or lid retraction, 2 for moderate changes and 3 for severe exposure keratopathy or globe prolapse).

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The definition of active disease was based on the inflammatory score and subjective or objective findings of interval change in the four parameters of the VISA system. If the VISA score was less than 4/8, and there was no deterioration, the patient was managed conservatively with cool compresses, nocturnal head elevation, and non-steroidal anti-inflammatory drugs. In general, if the inflammatory grade was greater than 4 or if there was subjective or objective evidence of progression in inflammation or motility restriction, more aggressive therapy was offered, including oral or intravenous corticosteroids, orbital radiotherapy and in refractory cases immunosuppressives. Orbital decompression was performed only in the post-inflammatory phase except in cases of refractory compressive optic neuropathy. All patients with a VISA inflammatory score of greater than 4 were immediately given oral corticosteroids (prednisone 50mg for 2–3 days) to assess the response. If positive and depending on the severity of inflammation and rapidity of progression, the patient was offered IV corticosteroids (250– 500mg methylprednisolone weekly). If there was an improvement in the inflammatory score, this dose was reduced to the lowest maintenance dose. We offered orbital radiotherapy combined with

ACCEPTED MANUSCRIPT 4 corticosteroids (using similar doses as for inflammatory indications) as soon as the patient noticed diplopia or we detected ocular motility restriction.

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The main indications for offering orbital radiotherapy to patients were the development of restriction in ocular motility, high doses, poor response or intolerance to corticosteroids. In addition to these indications disease modulating agents were given when orbital radiotherapy was relatively contraindicated in patients less than 35 years of age or the presence of systemic vascular disease.

Results:

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A total of 351 clinical charts of patients with active TED were reviewed and 249 patients fulfilled the inclusion criteria. One hundred and two patients were excluded from the study (37 had compressive optic neuropathy at the time of initial presentation, 9 were treated with orbital radiotherapy only, 21 had less than 12 months total follow-up, and 35 had incomplete clinical records). Group 1 consisted of 144 patients who received corticosteroids only while group 2 consisted of 105 patients who in addition to corticosteroids treatment received orbital radiotherapy. The average length of follow up of both groups was 3.2 years +/- 2.2 (range 1.1- 11.8 years), 3 years in group 1 and 3.4 years in group 2. No patient had less than 1.1 years of follow up and all had complete clinical records. All orbital radiotherapy patients received a total 20 Gy in 10 fractions over 2 weeks, with 74% receiving a tapering course of oral corticosteroids for a three week period during and immediately following orbital radiotherapy to reduce acute exacerbation of inflammation from radiotherapy treatment.

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The average age at presentation was 53 years +/-12 (range 21-86 years) and 70% were female. There was no statistically significant difference in the demographics of age, gender, stability of thyroid function, smoking habit or medical co-morbidities between group 1 and group 2 (Table 1). Table 2 demonstrates the number of patients receiving IV and or oral corticosteroids in each group. A significantly greater proportion of group 1 received both IV and oral therapy (p< 0.002). In addition, a greater proportion of group 2 received IV steroids alone or oral steroids alone (p <0.001). However, the total proportion of cases treated with IV steroids in group 1 (100%) and group 2 (86.7%) was not significantly different (p= 0.49). Oral corticosteroids were used in 95% of group 1 and 61.9% of group 2 (p= 0.04).

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The indications for corticosteroid treatment were: 1) periocular soft tissue inflammation, 80% in group 1 (n=115) and 90% in group 2 (n=95), p= 0.57; 2) strabismus, 44% in group 1 (n=63) and 88% in group 2 (n=92),p= 0.001; 3) intolerance to corticosteroids, 0% in group 1 and 8.6% in group 2 (n=9), p= 0.002. The main indications for offering orbital radiotherapy to patients in group 2 were: 1) the development of significant restriction in ocular motility (87.6%); 2) total cumulative dose of corticosteroids reaching unsafe levels over 8 grams (17.5%); 3) intolerance to corticosteroids (8.6%); and 4) inadequate control of disease activity with corticosteroids (6.5%). Indications for offering other disease modulating agents were similar to orbital radiotherapy: 1) high total cumulative dose of corticosteroids (14%); 2) inadequate control of disease activity with corticosteroids, especially if ocular motility was not affected (4%); or 3) where orbital radiotherapy was relatively contraindicated in patients less than 35 years of age or in the presence of systemic vascular disease (3%). Corticosteroids were commenced an average of 2.6 months (group 1) and 2.5 months (group 2) after initial presentation (p= 0.98). Group two received orbital radiotherapy on average 4.2 months following

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the initiation of corticosteroids treatment or 7.4 months (range 2.8- 24 months) after initial presentation. One hundred percent of group 1 (n=144) and 86.7% of group 2 (n=91) received IV corticosteroids. The mean cumulative dose of IV corticosteroids received by group 1 was 4.3 grams (range 2-12 grams) and group 2 was 4.5 grams (range 2-9 grams). Due to side effects, 4% of group 1 and 8% of group 2 discontinued corticosteroids. A greater number of patients in group 1 (n=32) were treated with other disease modulating agents compared to group 2 (n=13) (p= 0.09), including cyclosporine and methotrexate (Table 2). In group 1 there was a significantly greater average cumulative dose of IV corticosteroids among those receiving disease modulating agents (5.2 grams) compared to those that did not (3.4 grams) (p= 0.02).

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After an average follow up of 3.2 years, compressive optic neuropathy developed in 17% of patients in group 1 (n=25) and 0% in group 2 (p< 0.001). Compressive optic neuropathy developed an average of 5.5 months following the initiation of corticosteroids treatment. All patients with compressive optic neuropathy were recorded as having reduced best corrected visual acuity of two lines or more AND reduced color vision of 2 plates or more on the Harvey Rand Ritler test AND a relative afferent papillary defect in asymmetric cases, with or without evidence of optic disc swelling (35%) and a visual field defect (performed in 55%). Nine patients were excluded from the study on the basis that they had received orbital radiotherapy only (without corticosteroids); none of these cases developed compressive optic neuropathy. Orbital radiotherapy was given to group 2 at an average of 6.7 months after presentation and compressive optic neuropathy developed in group 1 at an average of 8.1 months after presentation.

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All 25 patients with compressive optic neuropathy had received IV corticosteroids and 21 (84%) had also received oral steroids (Table 2). Twelve patients (48%) with compressive optic neuropathy were also receiving disease modulating agents and none were intolerant to corticosteroids. The mean cumulative dose of IV corticosteroids received by patients who developed compressive optic neuropathy was 6.5 grams (range 4-12 grams). This dose was significantly greater than that received by patients who did not develop compressive optic neuropathy (p<0.001). There were no diabetics among those who developed compressive optic neuropathy; there were six diabetics (4%) in group 1 as a whole and two (1.8%) in group 2 (p= 0.55). There were 26 patients (18%) with hypertension in group 1, and 17 patients (16.2%) in group 2. There were significantly more hypertensive patients (n=9 or 36%), among those who developed compressive optic neuropathy (p= 0.08), The average age of patients who developed compressive optic neuropathy was slightly greater compared with the rest of the cohort (56 versus 53 years) but this was not statistically significant (p=0.36) and fewer patients with compressive optic neuropathy had stable thyroid function at the time of presentation compared with the rest of the cohort (36% versus 46-50%) (p= 0.15). There was no significant difference in the need for subsequent orbital decompression surgery between group 1 (40%) and group 2 (29.5%), p=0.28 (Table 2). Of the 58 patient who underwent orbital decompression in group 1, urgent decompression (within 2-4 weeks of developing compressive optic neuropathy or vision threatening exposure keratopathy) was performed in 5 cases (8.6%). All 5 cases were among those who developed compressive optic neuropathy making the rate of urgent orbital decompression in this group 26.3% (5/19) (range 3 - 28 days). There were no cases of urgent decompression in group 2. All cases presenting with compressive optic neuropathy, which may have undergone urgent decompression, were excluded from the study. Strabismus surgery was performed in 46 cases in group 1 (31.9%) and 41 cases in group 2 (39%) (p= 0.5).

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No patients in group 2 developed orbital radiotherapy induced retinopathy, optic neuropathy or orbital malignancy up to the time of final follow-up. The proportion of patients in each group with side effects associated with a full course of corticosteroids treatment was similar; overall 56% of both groups reported side effects including hyperglycemia (15%), insulin resistance (10%), diabetes mellitus (2%), osteoporosis (8%), anxiety (6%), depression (3%), cataract (11%), hypertension (14%), dyspepsia (10%), colitis (1%), arrhythmia (0.3%) and amenorrhea (0.1%).

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Table 3 summarizes the disease activity and severity scores at presentation and 6 months following treatment. Both groups experienced a statistically significant reduction in periocular inflammation; however, this was not significantly different between the two groups (p= 0.19). Group two demonstrated a significantly greater improvement in diplopia (p= 0.003) and restriction in motility (p= 0.07) as compared with group 1. There was no significant change of appearance (proptosis/eyelid retraction) in either group (p=0.9).

Discussion

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Visual loss due to compressive optic neuropathy affects 5-8% of patients with TED.1 Despite its widespread use, the role of orbital radiotherapy in the prevention and management of compressive optic neuropathy in acute TED has not been sufficiently examined and is unknown.

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This study compared two groups of patients with active TED without a previous history of compressive optic neuropathy who differed only in the modality of treatment received. Group 1 were 144 patients treated with corticosteroids only and group 2 were 105 patients treated with orbital radiotherapy in addition to corticosteroids. There was no significant difference between the two groups with regards to age, gender or thyroid status. Where treatment was indicated for periocular soft tissue inflammation, the proportion of patients in the two groups were similar; however, there were significantly more patients with strabismus(diplopia and restriction) in group 2 compared with group 1 (p<0.001). After a mean follow-up period of 3.2 years, a significantly greater number of patients in group 1 had developed compressive optic neuropathy (17%) compared with group 2 (0%) (p<0.001).There was a higher rate of hypertension in those with compressive optic neuropathy (p< 0.04) but not diabetes. The rate of compressive optic neuropathy among all TED at this centre, excluding those presenting with compressive optic neuropathy, was 7.9%, in line with other published studies.

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Although the total number of cases treated with oral corticosteroids was greater in group 1, none of the patients who developed compressive optic neuropathy were on oral corticosteroids only; in fact, there were a greater number of cases in group 2 treated with oral corticosteroids only. Therefore it is unlikely that oral steroids have a detrimental effect on the development of compressive optic neuropathy. Additionally the total number of cases treated with IV corticosteroids was not significantly different in group 1 and group 2. Overall we do not feel the mode of steroid administration had a detrimental or protective effect on the development of compressive optic neuropathy. There were a greater proportion of patients on disease (non-steroidal) modulating agents in group 1, particularly in the group who developed compressive optic neuropathy; this may suggest that these patients were less responsive to corticosteroids or had more aggressive disease. The use of disease modulating agents in the two groups could be a confounding variable, detrimental to the development of compressive optic neuropathy.

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In this cohort, compressive optic neuropathy did not develop in patients who were treated with orbital radiotherapy. Although both groups experienced a similar and statistically significant reduction in periocular inflammation after 6 months of treatment initiation, the orbital radiotherapy treated group demonstrated a significantly greater improvement in diplopia and restriction in motility, supporting the idea that orbital radiotherapy provides a disease modulating response in TED that is both effective and sustained. These properties may protect against disease progression to restrictive myopathy and compressive optic neuropathy. While a high inflammatory score may be a good predictor of extraocular muscle involvement, reduction of inflammatory scores may not necessarily lessen the risk of developing other more disabling complications of TED.

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Corticosteroids are effective at suppressing acute inflammation but the response to corticosteroids is short-lived and may be poor or incomplete. Seventeen percent of patients in group 1 progressed to develop compressive optic neuropathy whilst undergoing treatment with corticosteroids. Corticosteroid treatment is also limited by side effects with 4% of patients in group 1 and 8% of group 2 discontinuing treatment due to intolerable side effects and more than half of patients in both groups reporting significant side effects whilst on treatment.

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Studies over the last decade have generated conflicting results and created controversy regarding the role of orbital radiotherapy in TED.14 15 17 18 Patients were included that may have had inactive TED at the time of the study, such that both orbital radiotherapy and corticosteroids were unlikely to influence the course of disease.21 Randomized, prospective studies have demonstrated that orbital radiotherapy combined with corticosteroids versus corticosteroids alone is more effective22 23 but these diseasereversing effects of orbital radiotherapy are modest at best.

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In this cohort of patients, there were no known adverse effects secondary to orbital radiotherapy. The vast majority of the literature reports that orbital radiotherapy is generally safe and well tolerated.24 We acknowledge the limitations of a retrospective study particularly with respect to selection of patients who in addition to corticosteroids also received orbital radiotherapy; however, there was no difference in age, gender, thyroid status, smoking habit, medial co-morbidities or disease activity between the two groups with active TED other than the treatment received. This data can be used to support further prospective studies to examine the effect of early orbital radiotherapy in progression of TED and its role as a disease modulating agent.

ACCEPTED MANUSCRIPT 8 Acknowledgments:

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1) FUNDING/SUPPORT: none 2) FINANCIAL DISCLOSURES: none 3) CONTRIBUTION OF AUTHORS: design and conduct of the study (PNS, RM, TP, JR, PJD); collection (PNS), management (PNS, PJD), analysis (PNS, PJD), and interpretation of the data (PNS, RM, TP, JR, PJD); and preparation (PNS, PJD), review (PNS, RM, TP, JR, PJD) of the manuscript. 4) OTHER ACKNOWLEDGMENTS- none

ACCEPTED MANUSCRIPT 9 References:

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1. Dolman PJ. Evaluating Graves' orbitopathy. Best Pract Res Clin Endocrinol Metab 2012;26(3):229-48. 2. Bartalena L, Tanda ML. Clinical practice. Graves' ophthalmopathy. N Engl J Med 2009;360(10):9941001. 3. Perros P, Crombie AL, Kendall-Taylor P. Natural history of thyroid associated ophthalmopathy. Clin Endocrinol (Oxf) 1995;42(1):45-50. 4. Bartalena L, Pinchera A, Marcocci C. Management of Graves' Ophthalmopathy: Reality and Perspectives. Endocr Rev 2000;21(2):168-199. 5. Trobe JD, Glaser JS, Laflamme P. Dysthyroid optic neuropathy. Clinical profile and rationale for management. Arch Ophthalmol 1978;96(7):1199-1209. 6. Juler FAI. Diseases of the orbit. Acute purulent keratitis in exophthalmic goitre treated by repeated tarsorrhaphy, resection of cervical sympathetic and x-rays; retention of vision in one eye. Trans Ophthalmol Soc UK 1913;33:58–62. 7. Kazim M, Garrity JA. Orbital radiation therapy for thyroid eye disease. J Neuroophthalmol 2012;32(2):172-6. 8. Dolman PJ, Rath S. Orbital radiotherapy for thyroid eye disease. Curr Opin Ophthalmol 2012;23(5):427-32. 9. Marcocci C, Bartalena L, Panicucci M, Marconcini C, Cartei F, Cavallacci G, et al. Orbital cobalt irradiation combined with retrobulbar or systemic corticosteroids for Graves' ophthalmopathy: a comparative study. Clin Endocrinol (Oxf) 1987;27(1):33-42. 10. Bartalena L, Marcocci C, Tanda ML, Rocchi R, Mazzi B, Barbesino G, et al. Orbital Radiotherapy for Graves' Ophthalmopathy. Thyroid 2002;12(3):245-250. 11. Alpert TE, Alpert SG, Bersani TA, Hahn SS, Bogart JA, Chung CT. Radiotherapy for moderate-to-severe Graves' ophthalmopathy: improved outcomes with early treatment. Cancer J 2003;9(6):472-5. 12. Bradley EA, Gower EW, Bradley DJ, Meyer DR, Cahill KV, Custer PL, et al. Orbital Radiation for Graves Ophthalmopathy: A Report by the American Academy of Ophthalmology. Ophthalmology 2008;115(2):398-409. 13. Rajendram R, Bunce C, Lee RW, Morley AM. Orbital radiotherapy for adult thyroid eye disease. Cochrane Database Syst Rev 2012;7:CD007114. 14. Gorman CA, Garrity JA, Fatourechi V, Bahn RS, Petersen IA, Stafford SL, et al. A prospective, randomized, double-blind, placebo-controlled study of orbital radiotherapy for Graves' ophthalmopathy. Ophthalmology 2001;108(9):1523-34. 15. Prummel MF, Mourits MP, Blank L, Berghout A, Koornneef L, Wiersinga WM. Randomized doubleblind trial of prednisone versus radiotherapy in Graves' ophthalmopathy. Lancet 1993;342(8877):949-54. 16. Kahaly GJ, Rosler HP, Pitz S, Hommel G. Low- versus high-dose radiotherapy for Graves' ophthalmopathy: a randomized, single blind trial. J Clin Endocrinol Metab 2000;85(1):102-8. 17. Mourits MP, van Kempen-Harteveld ML, Garcia MB, Koppeschaar HP, Tick L, Terwee CB. Radiotherapy for Graves' orbitopathy: randomised placebo-controlled study. Lancet 2000;355(9214):1505-9. 18. Prummel MF, Terwee CB, Gerding MN, Baldeschi L, Mourits MP, Blank L, et al. A randomized controlled trial of orbital radiotherapy versus sham irradiation in patients with mild Graves' ophthalmopathy. J Clin Endocrinol Metab 2004;89(1):15-20. 19. Dolman PJ, Rootman J. VISA Classification for Graves orbitopathy. Ophthal Plast Reconstr Surg 2006;22(5):319-24.

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20. Dolman PJ, Cahill K, Czyz CN, Douglas RS, Elner VM, Feldon S, et al. Reliability of estimating ductions in thyroid eye disease: an International Thyroid Eye Disease Society multicenter study. Ophthalmology 2012;119(2):382-9. 21. Marcocci C, Bartalena L, Bogazzi F, Bruno-Bossio G, Lepri A, Pinchera A. Orbital radiotherapy combined with high dose systemic glucocorticoids for Graves' ophthalmopathy is more effective than radiotherapy alone: results of a prospective randomized study. J Endocrinol Invest 1991;14(10):853-60. 22. Bartalena L, Marcocci C, Chiovato L, Laddaga M, Lepri G, Andreani D, et al. Orbital cobalt irradiation combined with systemic corticosteroids for Graves' ophthalmopathy: comparison with systemic corticosteroids alone. J Clin Endocrinol Metab 1983;56(6):1139-44. 23. Ng CM, Yuen HK, Choi KL, Chan MK, Yuen KT, Ng YW, et al. Combined orbital irradiation and systemic steroids compared with systemic steroids alone in the management of moderate-to-severe Graves' ophthalmopathy: a preliminary study. Hong Kong Med J 2005;11(5):322-30. 24. Wakelkamp IM, Tan H, Saeed P, Schlingemann RO, Verbraak FD, Blank LE, et al. Orbital irradiation for Graves' ophthalmopathy: Is it safe? A long-term follow-up study. Ophthalmology 2004;111(8):1557-62.

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Group 1 (corticosteroids only)

53 +/- 12 Range 24-86

53 +/- 11 Range 21-80

0.9

72% (96)

70.5% (74)

0.86

Stable thyroid function

45.8% (66)

49.5% (52)

0.82

Smoking habit At presentation In past

45.8% (66) 16% (23)

0.65 0.97

Number of patients Mean age at onset of presenting symptoms (years)

40% (42) 15.2% (16)

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Female gender

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P value

144

Group 2 (corticosteroids & radiotherapy ) 105

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Table 1. Demographics of patients with Thyroid Eye Disease

Diabetes

4% (6)

1.9% (2)

0.55

18% (26)

16.2% (17)

0.88

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Hypertension

-

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Table 2. Medical and surgical treatments used in the management of active Thyroid Eye Disease Group 2 (radiotherapy & corticosteroids )

P value

Compressive optic neuropathy group

144

105

-

25

144 (100%) 144 (100%) 7 (5%) 137 (95%) 0 137 (95%)

105 (100%) 91 (86.7%) 40 (38.1%) 65 (61.9%) 14 (13.3%) 51 (48.6%)

Average total cumulative dose of intravenous corticosteroids (grams)

4.3 (2-12)

4.5 (2-9)

0.3

6.5 (4-12) p<0.001

Disease modifying drugs (%)

32 (22%)

12 (11.4%)

0.09

12 (48%) p<0.001

Orbital Decompression (%)

58 (40%)

31 (29.5%)

0.28

19 (76%) p<0.001

Urgent orbital decompression

5 (8.6%)

0

0.009

5 (26.3%) p<0.001

9.6

10.1

0.9

41 (39%)

0.5

4.3 P= 0.07 11 (44%) P= 0.45

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Time from presentation to orbital decompression (months) Strabismus surgery (%)

46 (31.9%)

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0.93 0.49 <0.001 0.04 <0.001 0.002

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Corticosteroids Total (%) Intravenous (%) Intravenous alone (%) Oral (%) Oral alone (%) Intravenous and oral (%)

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Number of patients

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Group 1 (corticosteroids only)

25 (100%) 25 (100%) 4 (16%) 21 (84%) 0 21 (84%)

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Table 3. The activity and severity of Thyroid Eye Disease using the VISA classification system31 Group 2 (radiotherapy & corticosteroids)

(n=144)

(n=105)

Disease end points

Average scores At

6 months

Change in

At

6 months

Change in

presentation

post

score

presentation

post

score

0

0.17

+ 0.17 (17%)

0

p<0.001 2.6

0-8

-2.4 (-48%)

5.5

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5.0

0

0

<0.001

2.3

-3.2 (-64%)

0.19

P= 0.016

S1 (strabismus/

1.35

1.2

diplopia) 0-3

-0.15 (-11%)

2.3

P= 0.001 1.0

P= 0.75

S2 (strabismus/

1.5

1.2

restriction) 0-3 A (appearance)

-0.3 (-20%)

2.5

1.4

1.3

-0.1 (-7%)

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P= 0.82

1.9

-1.3 (-56%)

0.003

P= 0.001 1.3

P= 0.45

mild=1, moderate=2 severe=3

P value

treatment

SC

treatment V (vision /optic neuropathy) 1 =yes, 0=no I (inflammation)

RI PT

Group 1 (corticosteroids only)

-1.2 (-48%)

0.07

P= 0.007 1.8

-0.1 (-5.2%)

P= 0.9

0.9