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
RI PT
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
SC
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
M AN U
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.
TE D
Short title: Reduced risk of optic neuropathy in thyroid eye disease
AC C
EP
Word count: Abstract 316 Text 3202
ACCEPTED MANUSCRIPT
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.
RI PT
Design: Retrospective single center case control study.
SC
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.
TE D
M AN U
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.
AC C
EP
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:
SC
RI PT
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.
M AN U
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.
TE D
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.
AC C
Methods:
EP
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.
RI PT
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).
M AN U
SC
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.
EP
TE D
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).
AC C
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.
RI PT
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:
M AN U
SC
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.
EP
TE D
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
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
RI PT
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
SC
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
M AN U
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.
TE D
Short title: Reduced risk of optic neuropathy in thyroid eye disease
AC C
EP
Word count: Abstract 316 Text 3202
ACCEPTED MANUSCRIPT
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.
RI PT
Design: Retrospective single center case control study.
SC
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.
TE D
M AN U
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.
AC C
EP
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:
SC
RI PT
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.
M AN U
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.
TE D
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.
AC C
Methods:
EP
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.
RI PT
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).
M AN U
SC
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.
EP
TE D
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).
AC C
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.
RI PT
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:
M AN U
SC
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.
EP
TE D
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
