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Ophthalmic Eosinophilic Granulomatosis With Polyangiitis (Churg–Strauss Syndrome)

A Systematic Review of the Literature

Akella, Sruti S., M.D.*; Schlachter, Dianne M., M.D.†,‡; Black, Evan H., M.D.†,‡; Barmettler, Anne, M.D.*

Ophthalmic Plastic & Reconstructive Surgery: January/February 2019 - Volume 35 - Issue 1 - p 7–16
doi: 10.1097/IOP.0000000000001202
Major Reviews
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Purpose: To review and summarize the clinical features, presentations, diagnostic modalities, and management of ophthalmic manifestations of eosinophilic granulomatosis with polyangiitis (EGPA, formerly Churg–Strauss Syndrome).

Methods: A systematic PubMed search of all English articles on EGPA with ophthalmic involvement was performed. Emphasis was placed on English-language articles, but any article with an abstract translated into English was also included. Only those cases that satisfied the American Rheumatology criteria (1990) for diagnosis were included. Data examined included epidemiology, pathogenesis, presentations, diagnostic modalities, and management.

Results: There was a wide range in ophthalmic manifestations of EGPA. In order of most frequent presentation to least frequent, these include central retinal artery or vein occlusion, ischemic optic neuropathy, conjunctival nodules, orbital myositis, proptosis, dacryoadenitis, retinal vasculitis/infarcts/edema, cranial nerve palsy, and amaurosis. The 46 qualifying cases were divided into the categories of ischemic vasculitis versus idiopathic orbital inflammation due to prognostic significance. Ischemic vasculitis cases tended to be older patients (p = 0.03), unilateral (p = 0.006), require immunosuppressive therapy beyond steroids (p = 0.015), and were less likely to show improvement on therapy (p = 0.0003).

Conclusions: Prompt diagnosis of EGPA by the ophthalmologist can decrease patient morbidity and mortality. This requires knowledge of likely ophthalmic EGPA presentations, as well as recommended workups and treatment.

This study reviews all reported cases of eosinophilic granulomatosis with polyangiitis (EGPA, formerly Churg–Strauss syndrome) with ophthalmic manifestations and describes epidemiology, presentations, clinical features, and management.

*Department of Ophthalmology and Visual Sciences, Montefiore Medical Center, Bronx, New York, U.S.A.

William Beaumont Hospital, Royal Oak, Michigan, U.S.A.

Kresge Eye Institute, Wayne State University, Detroit, Michigan, U.S.A.

Accepted for publication June 27, 2018.

The authors have no financial or conflicts of interest to disclose.

Address correspondence and reprint requests to Anne Barmettler, M.D., Department of Ophthalmology and Visual Sciences, Montefiore Medical Center Bronx, NY 10467. E-mail: annebarmettler@gmail.com

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Eosinophilic granulomatosis with polyangiitis (EGPA), previously called Churg–Strauss syndrome or allergic granulomatosis and angiitis, is a systemic vasculitis of the medium and small blood vessels. The most commonly affected organs include the lungs, paranasal sinuses, skin, heart, and gastrointestinal tract. However, in 1956, Cury et al.1 became the first to describe ophthalmic involvement. More than 50 years later, Takanashi et al.2 categorized the rare ocular manifestations of EGPA into 2 groups, largely for prognostic reasons: idiopathic orbital inflammation-type and ischemic vasculitis-type. When the initial presentation of EGPA is involvement of the eye and orbit, the well-informed ophthalmologist is in a unique position to make the proper diagnosis and initiate treatment of this potentially fatal disease. This is essential as untreated EGPA patients have a 50% risk of death within 3 months of vasculitis onset, whereas the treated EGPA patient has a 70% to 90% survival at 5 years.2–5

As a systematic review of literature for ophthalmic manifestations of EGPA has not been published, the authors undertook a complete review of the English literature for ophthalmic EGPA. Of those cases meeting the American Rheumatology criteria for EGPA,6 there were a total of 46, including the authors’ experience, which were divided into the idiopathic orbital inflammatory-type and the ischemic vasculitis-type. The authors review these reports and identify important diagnostic and management updates to inform and prepare ophthalmologists, who may be in a unique position to recognize and treat this otherwise potentially fatal disease.

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EPIDEMIOLOGY

Eosinophilic granulomatosis with polyangiitis was first described in 1951 by Churg and Strauss as a rare disease characterized by disseminated necrotizing vasculitis with extravascular granulomas.7 Data on the epidemiology of EGPA are limited given its rarity but reflect a prevalence and annual incidence of 2 to 22 and 0.5 to 3.7 per million, respectively. EGPA occurs primarily during adulthood in a bimodal distribution, but the incidence peak of EGPA occurs slightly earlier than the other vasculitides, peaking at 30 to 40 or 55 to 64. No gender predominance or ethnic predisposition has been clearly identified.8 Rarely, childhood-onset (<18 years) EGPA has been described in fewer than 50 patients. In these adolescent patients, EGPA is more frequent in females, with a male-to-female ratio of 0.7.9

Of the 46 cases reviewed here, the age of patients with ocular manifestations ranged from 16 to 76, with an average and median age of 49.3 and 54 years, respectively. The male-to-female ratio was 1.42. Cases were divided into 2 groups: either ischemic vasculitis presentation or an “idiopathic orbital inflammation”-like presentation. There were 25 patients in the ischemic vasculitis group and 20 patients in the idiopathic orbital inflammation group; one additional case includes features of both group and is excluded from statistical analysis. Ischemic vasculitis patients tended to be older than the idiopathic orbital inflammation group with average ages of 54.3 versus 44.8 years, respectively (p = 0.03). There was no clear relationship between gender and type of ophthalmic EGPA. Ethnicity was not reported in the majority of articles.

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PATHOGENESIS

Although EGPA is still considered idiopathic, more is becoming known about the molecular cycle that drives the disease, starting with Th2 cells. Peripheral T-cell lines in EGPA patients are known from animal models to produce certain Th2-associated cytokines. This includes IL-4 and IL-13 with evidence of some upregulation of IL-5.8 These cytokines are strong promoters of eotaxin synthesis, which recruits the eosinophils that are a significant and defining part of EGPA’s clinical presentation.10 In EGPA, eosinophils are abundant in both the peripheral circulation and in EGPA lesions. They are believed to contribute to tissue damage in various ways (Fig. 1). First, activated tissue eosinophils secrete considerable amounts of eosinophil granule proteins (e.g., eosinophil basic protein, eosinophil-derived neurotoxin), which deposit in tissue and lead directly to organ damage and necrotizing granulomas. Eosinophils also secrete IL-25, which maintains the Th2-response described above.11 Second, eosinophils likely contribute to an overall hypercoagulable state. The exact mechanism of this remains unclear but may be related to initiation of the clotting cascade by tissue factor (released during degranulation), inhibition of vascular endothelial thrombomodulin by major basic protein, and activation of platelets.12 Finally, in vitro studies have also shown that eosinophils can directly injure nerve tissue by inducing neuronal retraction on contact13; however, it is widely thought that the mononeuritis multiplex seen in EGPA is likely due to nerve ischemia caused by eosinophilic infiltration of blood vessel walls.12

FIG. 1

FIG. 1

Antineutrophil cytoplasmic antibodies (ANCAs) are also an important component of the disease pathogenesis. In EGPA, these antibodies appear to be largely directed against myeloperoxidase. Clinical and animal models suggest that ANCAs activate neutrophils, resulting in the release of cytokines and proteins that ultimately damage tissue and endothelium. However, only 30% to 40% of EGPA patients are ANCA-positive.14 Some authors suggest that there may be 2 different subsets of EGPA (ANCA-positive and ANCA-negative), as each subset probably has a different pathogenesis and therefore a different clinical presentation.12–14 This is especially important for disease screening and management. Antineutrophil cytoplasmic antibody–positive patients are thought more likely to present with the classic small-vessel vasculitis clinical picture, which affects disease progression and outcomes. This vasculitis may be due to direct inflammatory infiltration and fibrinoid necrosis of the walls of the arteries, veins, and/or nerves by cytokines and eosinophils as described above. These vessels, inflamed by eosinophils that promote a local hypercoagulability, may then be susceptible to thrombosis and necrosis.12 ANCA-negative patients are thought to have generalized inflammation and are more likely to have heart and lung involvement.8

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CLINICAL PRESENTATION

Eosinophilic granulomatosis with polyangiitis is classically described as a disease that evolves throughout 3 stages (Fig. 2). The first stage is the prodromal asthmatic and allergic phase, which usually occurs in the second and third decades of life. The asthma is poorly controlled on inhaled steroids and typically requires systemic steroids.15 EGPA can sometimes manifest when those systemic steroids are reduced or stopped, and this happened in 8 (17.4%) of the ophthalmic EGPA patients.

FIG. 2

FIG. 2

The next eosinophilic phase includes peripheral eosinophilia and eosinophilic infiltration of multiple organs. This typically affects the lungs and the gastrointestinal tract, presenting as pulmonary opacities, asthma, or gastroenteritis.

The final phase is the life-threatening vasculitis phase, which involves the small- and medium-sized vessels. This phase occurs 8 to 10 years after the asthma phase and is often associated with extravascular granulomas (Fig. 2).15

Ocular involvement from EGPA is unusual and as the authors have described previously can fall into 1 of 2 categories: an “idiopathic orbital inflammatory”-like presentation or ischemic vasculitis. Review of the literature reveals 20 cases in the former group and 25 in the latter group (Tables 1 and 2). The idiopathic orbital inflammatory type typically presents an average of 6.9 years after the initial diagnosis of asthma, compared with 5.1 years for the ischemic vasculitis type (p = 0.05). Manifestations of the orbital inflammation type include conjunctival nodules (n = 8, 40%),16–22 orbital myositis (n = 5, 25%),2,19,22,23 orbital inflammatory syndrome (n = 4, 20%),24–26 dacryoadenitis (n = 2, 10%),2,27 and cranial nerve palsy (n = 2, 10%).28,29 These conditions frequently occur together. Rarely, marginal keratitis (n = 1),30 periscleritis (n = 1),2 and orbital apex syndrome (the authors’ case, n = 1) have also been described. The most common presenting symptoms, in order of prevalence, were redness (n = 6, 30%), periocular swelling (n = 5, 25%), diplopia (n = 4, 20%), foreign-body sensation (n = 1, 5%), and eyelid lesions (n = 1, 5%). In contrast, ischemic vasculitis presentations include retinal artery and vein occlusions (n = 12, 48%),31–42 ischemic optic neuropathy (n = 8, 32%),28,43–50 and retinal vasculitis or edema (n = 2, 8%).51,52 Interestingly, at least 6 patients28,32–34,49,53 with the ischemic vasculitis type reported episodes of transient amaurosis prior to permanent visual loss, perhaps suggesting that these patients may benefit from aggressive treatment of these transient episodes of visual loss before more serious sequelae develop. These patients presented most frequently to the ophthalmologist with acute-onset loss of vision (n = 22, 88%).

TABLE 1

TABLE 1

TABLE 2

TABLE 2

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.

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DIAGNOSIS

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.

FIG. 3

FIG. 3

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

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MANAGEMENT

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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