Ischemic vasculitis patients are more likely to have unilateral disease than the inflammatory type (79% vs. 35%, respectively; p = 0.006). They also tend to be older (p = 0.03) with more aggressive disease requiring immunomodulators, often with worse visual outcomes. One previously suggested reason for this split in age, prognosis, and treatment requirements is that the idiopathic orbital inflammation presentation represents the more benign, earlier stage of EGPA (granulomatosis), whereas the ischemic type represents the vasculitis stage, the final and most advanced form of EGPA. The younger age associated with the idiopathic orbital inflammation group corroborates this theory, as the granulomatous stage tends to precede the vasculitis stage of EGPA. However, this theory is challenged by one case which has features of both presentation types in the reverse order, where the vasculitis stage preceded the granulomatous stage. A 17-year-old boy developed retinal vasculitis, representing the systemic vasculitis phase, and then, 8 years later presented with sudden diplopia and unilateral exophthalmos, which is more typical of the granulomatous phase.24 Future cases of ophthalmic EGPA will continue to elucidate the optimal classification and management of this uncommon entity.
Diagnosis, per the American College of Rheumatology, requires the presence of 4 or more of 6 conditions: asthma, eosinophilia of greater than 10%, neuropathy, migratory or transient pulmonary opacities, abnormalities of the paranasal sinuses, and extravascular eosinophils on biopsy.6 In the authors’ literature review of ocular EGPA, asthma was reported in 95.6% of cases; eosinophilia of greater than 10% in 95.6% of cases; peripheral neuropathy in 60% of cases; pulmonary opacities in 51.1% of cases; paranasal sinus involvement in 64.4% of cases; and biopsy-proven extravascular eosinophilia in 73.3%. Figure 3 demonstrates the typical eosinophilic infiltration seen in inflammatory-type presentation. Of the 33 cases with tissue biopsies, 14 (42.4%) were conducted by an ophthalmologist, all performed in the idiopathic orbital inflammation group. The most popular locations were conjunctiva (n = 8), lacrimal gland (n = 4), and intraorbital masses (n = 3). Interestingly, only 35.6% of patients presented to the ophthalmologist with a known diagnosis of EGPA. In the majority of cases (64.5%), the ophthalmologist made the initial diagnosis either independently or together with a team of internists and/or rheumatologists, highlighting the importance of taking a thorough history and pertinent review of systems.
The differential diagnosis for EGPA in the orbit and eye includes hypereosinophilic syndrome, granulomatosis with polyangiitis (Wegener’s), microscopic polyangiitis, and parasitic infection. However, hypereosinophilic syndrome, unlike EGPA, typically does not have asthma, granulomas, or vasculitis. Likewise, although granulomatosis with polyangitis (Wegener’s), microscopic polyangitis, and EGPA are all ANCA-associated vasculitis, only EGPA is also associated with asthma and peripheral eosinophilia.
Further testing can be done to aid in diagnosis and management. Antineutrophil cytoplasmic antibody testing is routinely performed in cases of suspected systemic EGPA and yield positive results in 30% to 40% of cases.14 The most common subset of ANCA is myeloperoxidase with perinuclear staining pattern (myeloperoxidase-ANCA, aka P-ANCA) and proteinase 3. Of the 30 ocular cases which reported ANCA testing, the authors found similar rates of ANCA positivity (33.3%). Although Takanashi et al.2 reported that a positive ANCA test was associated with the ischemic presentation, review of the 45 ophthalmic EGPA patients showed no statistically significant difference in ANCA positivity between ischemic and inflammatory groups (p = 0.8). Of note, EGPA patients are the least likely of all the vasculitides to be ANCA-positive (whether or not there is ocular involvement), and, therefore, ANCA-positivity should not be used to make a definitive diagnosis.
However, ANCA may be used to monitor and manage patients. A positive ANCA is associated with peripheral neuropathy, renal involvement, and biopsy-proven vasculitis, whereas ANCA negativity is associated with heart disease, which can be fatal if untreated.54 With heart disease being the most common cause of death in patients of EGPA (50%), negative ANCA patients can be monitored even more closely for cardiac issues.55
Adjunct imaging has been used, largely in cases of the idiopathic orbital inflammatory type, to aid in diagnosis. Although CT or MRI can be used, MRI is preferred for improved visualization of the soft tissue, which is typically involved. Of the 19 ophthalmic EGPA patients who were imaged, 14 had positive findings, the majority of which were in the idiopathic orbital inflammatory group (n = 13). Seven cases used MRI to make the diagnosis; 6 used CT; and 1 used both. Overall, the most common findings were as follows, in order of prevalence: orbital mass or infiltration (n = 8, 57.1%); enhancement or enlargement of rectus muscles (n = 4, 28.6%); lacrimal gland involvement (n = 5, 35.7%); and enhancement along the optic nerve sheath (n = 2, 14.3). When broken down by imaging modality, the most common findings on CT scan were infiltration or expansion of the preseptal extraconal tissue (n = 5), enhancement of recti muscles or their attachments (n = 3), and enlarged lacrimal gland (n = 2); the most common findings on MRI were infiltration of orbital tissue (n = 3), enhancement of extraocular muscles (n = 3), lacrimal gland involvement (n = 2), and enhancement of optic nerve sheath (n = 2).
After diagnosis is made, a team approach with a rheumatologist and/or internist is crucial. Additional testing includes cardiac testing, renal function, and a thorough neurologic exam. Half of EGPA-related deaths were cardiac related,55 so cardiac workup with electrocardiogram and echocardiogram is crucial. A total of 11 of the 46 ophthalmic EGPA patients (24.4%) had cardiac involvement at the time of ocular presentation, compared with the general rate of cardiac involvement in EGPA, which has been reported as high as 62%.56
Primary therapy for EGPA is systemic glucocorticosteroids, starting with doses of prednisone 0.5 to 1.5 mg/kg/day for 6 to 12 weeks or until remission is attained, followed by a gradual taper. In cases of acute multiorgan disease, a higher dose of methylprednisolone 1 g/day for 3 days, followed by the above therapy, can be used. This is typically effective in idiopathic orbital inflammatory-type ophthalmic EGPA. Of the 21 reported cases, the majority was able to be treated with steroids alone (systemic or topical). A total of 17 of the 18 cases (94.4%) achieved complete regression of conjunctival lesions, myositis, edema, and/or proptosis. Topical steroids were effective in 1 case of isolated conjunctival nodules; in another, authors surgically excised the nodules after topical steroid drops failed.
In contrast, ischemic vasculitis-type ophthalmic presentations have a less dramatic response to steroids: of the 8 cases that used only systemic steroids and commented on visual outcomes, 5 showed no improvement in visual acuity (VA; anterior ischemic optic neuropathy [AION] n = 2; central retinal artery occlusion [CRAO] n = 3), and 3 showed minimal improvement in vision (AION n = 2; CRAO n = 1). Interestingly, all 3 of the patients with improvement were treated with intravenous steroids, whereas 2 of 5 cases without improvement were treated with oral steroids (the other 2 cases do not discuss the exact therapy; 1 case of AION without improvement used intravenous pulse steroids). This may indicate that ischemic vasculitis-type presentations benefit from more aggressive intravenous systemic steroid therapy. In addition, there are 2 reports of intravitreal triamcinolone acetonide use in addition to systemic steroids: Chen et al. used this to treat cystoid macular edema, with a temporary improvement in VA from 20/80 to 20/20. Unfortunately, the cystoid macular edema recurred within 6 months and resulted in a permanent decrease in vision.37 Partal et al.57 used intravitreal triamcinolone to treat retinal vasculitis with improvement from hand motion to 20/400 vision; however, this patient was also treated with the immunosuppressant cyclophosphamide.
In addition to steroids, there is literature suggesting that for patients scoring 1 or more on the commonly cited “5 factors score,” immunosuppressants are also recommended for 12 to 18 months.14,15 This score refers to age >65 years, cardiac involvement, renal insufficiency, gastrointestinal involvement, and lack of otorhinolaryngologic manifestations (presence is associated with better prognosis).13
Immunosuppressants for EGPA include cyclophosphamide, which is recommended to induce remission. Once obtained, this is switched to azathioprine to sustain remission and reduce the long-term toxicities of cyclophosphamide. Of the ophthalmic EGPA cases reported, 15 of 45 (33.3%) required immunosuppressants. One case of idiopathic orbital inflammation-type presentation (bilateral painless proptosis) was treated with cyclophosphamide alone, and there was no resolution of proptosis. Of the ischemic vasculitis types, 8 patients were treated with a combination of steroids and cyclophosphamide, with mixed results: 4 patients (ischemic optic neuropathy n = 1, combined branch retinal vein occlusion/CRAO n = 1, isolated CRAO n = 2) saw no improvement; 4 cases reported improvement in vision but did not report final VA (CRAO n = 2; proliferative retinopathy n = 1; amaurosis fugax n = 1).
Alternative immunosuppressants for EGPA include methotrexate and leflunomide,16 although the latter has not been used in reported cases of ophthalmic EGPA. Of the idiopathic orbital inflammation-type patients, 2 reported methotrexate use. In a case of conjunctival nodules, a combination of methotrexate (route of administration not stated) and oral prednisolone resulted in rapid resolution.19 In a case of marginal keratitis, oral prednisone and methotrexate (route not stated) were used, and although the active inflammation resolved quickly, residual scarring remained.30 There are no reported cases of ophthalmic ischemic vasculitis treated with methotrexate.
Lastly, certain presentations of the ischemic vasculitis-type EGPA have been treated with additional therapies. Anticoagulants were used in combination with systemic steroids to treat 3 cases of CRAO with minimal improvement in VA33,40,42 and 1 case of branch retinal artery occlusion with excellent improvement in VA (from 20/200 to 20/25).34
Management of the ocular manifestations of EGPA is driven by whether the presentation is classified as idiopathic orbital inflammatory or ischemic vasculitis type. Therapies should not be changed based on ANCA positivity, as this does not adequately reflect disease category or activity.17 As these treatments have well-known side effects, requiring constant monitoring and possible additional antibiotic prophylaxis, collaboration with rheumatology can prove vital.
Although ophthalmic EGPA is rare, ophthalmologists are in the unique position of being the first to diagnose EGPA from an ophthalmic manifestation. This is crucial as untreated EGPA has a 50% risk of death within 3 months of vasculitis onset. With treatment, survival improves this to 70% to 90% survival at 5 years. With half of EGPA-related deaths being cardiac related, cardiac workup is mandatory, and early diagnosis is the key.55 EGPA should remain on the differential for CRAO, idiopathic orbital inflammation, and other ophthalmic manifestations in the setting of steroid-dependent asthma, eosinophilia, or vasculitis.
It is equally important to note that based on the cases reviewed here, ophthalmic manifestations present an average of 6.02 years after the initial diagnosis of asthma, suggesting that all known EGPA patients may benefit from a baseline ophthalmic examination 5 years after the onset of symptoms. Known EGPA patients who are in or approaching the vasculitis phase should especially get a routine eye examination, as these patients who go on to develop ischemic ophthalmic manifestations almost universally present to the ophthalmologist with sudden-onset visual loss. Despite aggressive treatment, visual outcomes in these instances remain very poor. A fundoscopic examination may reveal evidence of retinal vasculitis that would prompt initiation of more aggressive systemic therapy in conjunction with the internist, rheumatologist, and/or cardiologist.
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