Continuing Education Activity

Sympathetic ophthalmia is a rare, devastating disease defined as bilateral uveitis following an eye injury. It may result in permanent bilateral vision loss in an otherwise healthy patient with no ocular morbidities. Initial symptoms and the timeline for the onset of symptoms after an injury are highly variable. Therefore sympathetic ophthalmia must be considered on the differential for any presentation of bilateral uveitis. Additionally, managing this disease may be highly challenging, requiring patients to be on several immunosuppressants. This activity reviews the evaluation and management of sympathetic ophthalmia and highlights the role of the interprofessional healthcare team in correctly identifying and managing patients with this condition.

Objectives:

• Outline the classic presentation and pathophysiology associated with sympathetic ophthalmia.
• Summarize the etiology and histopathology of sympathetic ophthalmia.
• Review the treatment modalities available for sympathetic ophthalmia.
• Explain the importance of early identification of sympathetic ophthalmia and differentiation from other pathologies.

Introduction

Sympathetic ophthalmia is a rare pathologic process characterized by bilateral uveitis following injury to one eye either from surgery or penetrating ocular trauma.[1] Though this is a rare process, it remains a serious disease that can cause blindness in both the injured eye (i.e., the inciting eye) and the contralateral eye (i.e., the sympathizing eye). The onset of symptoms typically occurs within one year of injury but can occur up to 66 years after the initial injury.[2] 

The exact pathogenesis of sympathetic ophthalmia is unclear. It is believed that there is a compromised immune-privileged status of the eye after a penetrating injury and exposure of previously sequestered uveoretinal antigens to the systemic immune system. The resulting inflammation in the eye can be devastating and cause permanent blindness. Therefore, early detection and intervention with immunosuppression are vital.

Etiology

First coined by William Mackenzie in 1840, sympathetic ophthalmia refers to bilateral ocular inflammation secondary to unilateral eye trauma or surgery.[3] Classically, sympathetic ophthalmia is defined as a bilateral diffuse granulomatous panuveitis that presents with mutton fat keratic precipitates. However, patient presentations of sympathetic ophthalmia may significantly vary in inflammation on presentation.

Per the Standardization of Uveitis Nomenclature (SUN) working group definition in 2021, the diagnosis criteria for sympathetic ophthalmia are as follows: (1) history of unilateral ocular trauma or surgery AND (2) ocular inflammation in both eyes or, if the inciting eye has no view, detectable inflammation in the sympathizing eye AND (3) either anterior uveitis with vitreous inflammation OR panuveitis with choroidal involvement.[1]

Penetrating ocular trauma and vitreoretinal surgeries have the highest risk of developing sympathetic ophthalmia.[4] However, cases of sympathetic ophthalmia have been reported with cataract surgery, glaucoma surgery, intravitreal injections, cyclodestructive procedures, choroidal melanoma radiation therapy, and pan-retinal photocoagulation.[5][6][7][8]

Epidemiology

A commonly cited general incidence of sympathetic ophthalmia is around 0.03 per 100,000 persons per year.[4] A retrospective analysis of sympathetic ophthalmia cases demonstrated around 62.7% of cases are secondary to accidental injury, and 34.5% are secondary to surgical trauma.[9] The incidence of patients developing sympathetic ophthalmia after traumatic eye injury was 0.19%.[10] The incidence of patients developing disease following vitreoretinal surgery was significantly lower, around 0.038%.[11]

Repeated inciting events, especially patients with repeated traumatic injuries, are at the greatest risk of developing sympathetic ophthalmia.[12]

The average age of presentation for sympathetic ophthalmia is usually between 40 and 45 years of age.[10][11][12] Several studies have also suggested a gender predilection, with males having sympathetic ophthalmia at higher rates than females.[13][14]

The timeline for the onset of inflammation after trauma or surgery can vary from weeks to decades after the inciting event, with the most significant risk period being within one year. 50% of patients have onset of symptoms within three months, and 90% of patients within one year.[15] Notably, a reported case of sympathetic ophthalmia began 66 years after the inciting traumatic injury.[2]

Pathophysiology

The precise pathophysiology of sympathetic ophthalmia is not clearly understood; however, most evidence points to an autoimmune inflammatory process secondary to ocular injury following trauma or surgery.[16] The eye is an immune-privileged space in the body where systemic immune responses to antigens are markedly reduced. This is achieved by the absence of intraocular lymphatics and by the presence of tight junctions in the retinal pigment epithelium (RPE), creating the blood-retina barrier.[17]

Disruption of this system in penetrating injuries results in exposure of previously sequestered ocular antigens to local conjunctival lymphatics resulting in activation of cell-mediated immunity, a type IV delayed hypersensitivity reaction.[18][19]

Though no singular culprit has been identified as the antigen responsible for sympathetic ophthalmia, several ocular antigens have been implicated, including arrestin (S-antigen), recoverin, rhodopsin, melanocyte-associated tyrosinase, interphotoreceptor retinoid-binding protein, and RPE-associated antigens. These have all been studied in animal models and shown to produce autoimmune uveitic reactions that mimic sympathetic ophthalmia.[19][20][21][22][23] 

Genetic predisposition to sympathetic ophthalmia is another emerging area of research, potentially enabling the identification of at-risk patient populations. Human leukocyte antigen (HLA)-DR4, HLA-A11, and HLA-B40 have been shown to be associated with sympathetic ophthalmia.[23]

More recent studies have shown the expression of HLA-DRB1*04 and HLA-DQA1*03 to be significantly associated with sympathetic ophthalmia across patient populations in both white and Japanese patients.[24][25]

Histopathology

The histopathology of sympathetic ophthalmia classically shows widespread bilateral uveal inflammation characterized by lymphocytes surrounding non-necrotizing granulomas composed of multinucleated giant cells and macrophages.[16][26] Notably, similar changes are found in both the inciting and the sympathizing eye.[16]

Immunohistochemical studies demonstrate lymphocytic granulomatous uveal inflammation where CD4+ T helper cells predominate during the early stages of the disease, followed by CD8+ T suppressor cells during later stages. More recent studies also unveiled B cells as potential contributors to the inflammatory process toward end-stage disease.[16][27][28] 

Tumor necrosis factor-alpha (TNF-alpha), an inflammatory cytokine, may play a role in mediating oxidative stress in the outer retina during sympathetic ophthalmia, resulting in photoreceptor apoptosis and vision loss.[29] Interleukin-23 and interleukin-17 may also target RPE cells in this disease. Classically, inflammation from sympathetic ophthalmia spares the choriocapillaris, though some recent studies have shown cases where the choriocapillaris can be involved.[28][30] 

Dalen-Fuchs nodules are RPE lesions characteristically associated with sympathetic ophthalmia, but they are only seen in 25 to 35% of cases and are not pathognomonic to the disease.[31] There are three different morphologies of these lesions:

1. Focal RPE hyperplasia and aggregation,
2. Classic Dalen-Fuchs nodules, described as lymphocytes and epithelioid cells that exist between RPE and Bruch's membrane, and
3. Nodules with disruption of the overlying RPE resulting in potential eruption into the subretinal space.[32]

Currently, there is no known correlation between the extent of histopathological findings and the final visual outcome in sympathetic ophthalmia.[28]

History and Physical

The timeline for the onset of sympathetic ophthalmia can range from days to years after the initial injury to the inciting eye; however, 90% of cases occur within one year.[15] Patients with sympathetic ophthalmia may have significant variability in their initial presentation. Unfortunately, patients may experience recurrent episodes despite resolution after the initial episode.

Upon seeing patients with bilateral uveitis, it is imperative to elicit an accurate history focusing on whether the patient has had a history of traumatic ocular injury or prior eye surgeries. Early-stage sympathetic ophthalmia may present with isolated mild anterior segment inflammation or isolated posterior segment inflammation. Detection during this early stage may lead to a better visual prognosis with prompt treatment.[14]

Patient symptoms may range from mild visual disturbances to significant vision loss. Other symptoms include pain, photophobia, epiphora, floaters, and redness.[10][33] Due to inflammation of the ciliary body affecting accommodation, near vision may be affected during the early stages of sympathetic ophthalmia. Most patients will have asymmetric bilateral uveitis displaying more significant inflammation in the inciting eye. 

Anterior segment findings may range from mild bilateral anterior segment inflammation to bilateral granulomatous inflammation with mutton-fat corneal precipitates. Posterior iris synechiae and peripheral anterior synechiae may be present. Iris thickening with or without iris nodules may also be seen. Intraocular pressure may be low in the setting of ciliary body shutdown or high secondary to trabeculitis or obstruction of the trabecular meshwork.[34]

Posterior segment exam findings may include mild to severe vitritis, Dalen-Fuch nodules (yellow-white lesions of the RPE), choroiditis, papillitis, and retinal vasculitis. Exudative retinal detachment may also be present, varying from small pockets of peripapillary exudative detachments to more extensive serous retinal detachments.[10][34] 

Chronic sympathetic ophthalmia may also cause subretinal fibrosis and choroidal neovascularization.[35] A classical late-stage finding of sympathetic ophthalmia is the "sunset glow fundus," where the retina has a red-orange appearance due to depigmentation of the inflamed choroid and RPE.[36]

Evaluation

The SUN working group criteria for sympathetic ophthalmia diagnosis is a patient with a history of unilateral ocular trauma or surgery with ocular inflammation in both eyes and either anterior uveitis with vitreous inflammation or panuveitis with choroidal involvement.[1] Though sympathetic ophthalmia remains a clinical diagnosis, multiple imaging modalities can assist ophthalmologists in confirming the diagnosis, tracking disease progression, and monitoring response to treatment.

B-scan Ultrasonography

B-scan ultrasonography may reveal diffuse choroidal thickening and serous retinal detachments. B-scan is particularly valuable in the case of dense vitritis, posterior synechiae, corneal opacity, or any other pathology that prevents a clear view of the retina.[35][37]

Fundus Autofluorescence (FAF)

FAF detects lipofuscin in the RPE, enabling visualization of RPE dysfunction and death. This simple, non-invasive test is useful in assessing sympathetic ophthalmia, showing the extent of damage caused by inflammation and helping identify potential sequelae like choroidal neovascularization.

In acute disease, a petaloid pattern of hyper-autofluorescence centered on the optic nerve may be present in areas of serous retinal detachments.[38] With the resolution of the subretinal fluid, FAF may display leopard spots with mixed areas of hyper- and hypo-autofluorescence.[39] 

FAF in chronic sympathetic ophthalmia has a varied presentation depending on the sequelae of the disease, as previously described. Decreased autofluorescence may be detected secondary to outer retinal damage, RPE loss, nummular scars, and peripapillary atrophy. Increased autofluorescence may be seen in cystic macular edema, subretinal fibrosis, and RPE proliferation.[40]

Optical Coherence Tomography (OCT)

Spectral-domain optical coherence tomography (SD-OCT) with or without enhanced depth imaging (EDI-OCT) and swept-source OCT (SS-OCT) are non-invasive imaging modalities that allow for high-resolution examination of the retina and choroid.

Sympathetic ophthalmia may initially present with serous retinal detachments that can be seen on swept-source OCT. These often contain hyperreflective septa, representing bacillary layer detachment splitting the photoreceptor layer at the inner segment myoid. Of note, this finding is also seen in Vogt-Kayanagi-Harada (VKH) disease and resolves rapidly with corticosteroid treatment.[41]

Dalen-Fuchs nodules, classically seen in 25 to 35% of patients with sympathetic ophthalmia, initially appear as round hyperreflective areas in the outer retina with occasional serous detachments of the overlying neurosensory retina. These lesions regress with therapy.[42] EDI-OCT and SS-OCT can also identify the presence of choroidal thickening, subretinal choroidal folds, and increased choroidal vascularity index. These findings typically resolve with treatment and can be useful in monitoring treatment response.[43][44]

Optical Coherence Tomography Angiography (OCTA)

OCTA is a non-invasive imaging modality designed to examine the chorioretinal vasculature without using intravenous dye. OCTA may demonstrate ischemia and reduced capillary density.[45] It can also be used to monitor ischemic areas as patients respond to therapy.[35][46] OCTA is also sensitive in detecting and differentiating choroidal neovascularization from inflammatory lesions, allowing more accurate tailoring of the patient's treatment plan.[47]

Fluorescein Angiography (FA)

FA is an excellent non-invasive imaging modality that can provide useful information both for the diagnosis and treatment monitoring of patients with sympathetic ophthalmia. In the acute phase of sympathetic ophthalmia, two patterns may be seen. The first is nearly identical to the pattern seen in VKH with initial diffuse pinpoint hyperfluorescent spots with late leakage with or without hyperfluorescence of the disc. Another less common variant is initial multiple hypofluorescent spots with late-phase pooling.[39] These spots may coalesce under serous retinal detachments in severe disease.[35][48] 

The second acute phase pattern resembles acute posterior multifocal placoid pigment epitheliopathy (APMPPE), demonstrating initial hypofluorescent foci that become hyperfluorescent in the late phase with staining of the lesions. Unlike APMPPE, the lesions in sympathetic ophthalmia are elevated and mottled in appearance.[49] The initial hypofluorescence may be secondary to obscuration from Dalen-Fuchs nodules or choroidal inflammation leading to focal obliteration of the choriocapillaris.[39]

Chronic sympathetic ophthalmia FA findings are more variable, depending on the inflammatory sequelae of the disease. Nummular scars from focal damage to the RPE and inner choroid present as window defects on FA.[14] Subretinal fibrosis may present with hyperfluorescent staining due to proliferated metaplastic RPE.[35][39][50] The presence of choroidal neovascularization may reveal leakage in the macula.[39]

Indocyanine Green Angiography (ICGA) 

ICGA can be used as an adjunct to FA, given its superior ability to assess the choroid and choroidal infiltrates. A common finding in sympathetic ophthalmia on ICGA is multiple hypocyanescent spots that correspond to hyperfluorescent spots on the FA. Histopathological studies of these lesions have confirmed that these spots are caused by cellular infiltrates of the choroid or due to blockage by overlying fluid.[51][52] These hypocyanescent spots are similar in all phases of sympathetic ophthalmia and tend to improve with adequate disease treatment.[39][52] The hypocyanescent spots may return in late-phase sympathetic ophthalmia, possibly due to choroidal atrophy.[53]

Treatment / Management

Surgical

Historically, it was thought that removal of the injured eye within 14 days of ocular trauma would protect the contralateral eye from the onset of sympathetic ophthalmia.[31][54] Once sympathetic ophthalmia occurs, enucleation would no longer portend any benefits to the sympathizing eye.[13] However, the practice of prophylactic enucleation lacked supporting scientific evidence and was based primarily on observation and clinical speculation.[55]

Sympathetic ophthalmia has been described to occur in the sympathizing eye despite removing the traumatic globe.[56] Removal of the inciting eye does not result in improved visual acuity of the sympathizing eye. In many individuals, the inciting eye may become the eye with the better overall vision.[54] Importantly, in most cases of ocular injury where the traumatic globe was not removed, patients do not develop sympathetic ophthalmia.[57]

The decision of when to remove and when to save a severely traumatized eye can be a difficult one. In a study of 660 traumatic globe injuries, over 98% of injuries could be successfully repaired surgically, and only 13% suffered no light perception (NLP) vision. Indication for primary removal of the globe only occurred in 1.7% due to the inability to repair the globe.[58] Additionally, patients with NLP vision after ocular trauma actually regains some vision in 16% of cases.[59]

Furthermore, the negative psychological impact of losing an eye cannot be understated and should be considered prior to enucleation or evisceration. Patients often experience body dysmorphia, depression, and increased anxiety from losing an eye.[60] There are also cosmetic benefits to saving an NLP phthisical eye since the eye often retains full movement, and the irregular anterior surface can better support an overlying ocular prosthesis.[55]

In cases where the ruptured globe is beyond repair, removal of the eye via evisceration or enucleation may be the only option. Significant debate exists as to which procedure is more appropriate. Critics of evisceration argue that evisceration poses a potential risk for disseminating unsuspected uveal malignancy and a theoretical risk of causing sympathetic ophthalmia due to remnant uveal tissues.[61] However, a more recent large retrospective study of patients showed no cases of sympathetic ophthalmia after evisceration.[33]

Evisceration is often favored since it is technically easier, and the preservation of the sclera can provide a barrier in preventing the orbital spread of infection. Evisceration may also provide a cosmetic and functional advantage for the patient.

Medical

Patients with sympathetic ophthalmia who receive prompt treatment with high-dose steroids and immunomodulatory agents have a better chance for good visual outcomes.[62] Upon diagnosis of sympathetic ophthalmia, it is recommended to initiate patients on high-dose intravenous corticosteroids at a dose of 1 to 2 mg/kg/day with adjunct topical cycloplegics and corticosteroids.[63] 

Improvements in retinal findings on OCT have been noted soon after the initiation of corticosteroids.[64] In very severe cases, intravenous pulse methylprednisolone can be considered at a dose of 1 gram/day for three days.[65] Patients should remain on steroids for a minimum of 3 months with a very slow taper if symptom improvement is noted.

Other immunosuppressive agents may be warranted if a patient experiences recurrence or worsened inflammation. Systemic corticosteroids may have significant complications, including uncontrolled diabetes, adrenal insufficiency, osteoporosis, and increased infection risk. Intravitreal steroids can be considered to avoid some of these systemic complications and enable a targeted high concentration of the drug at the site of the disease. Studies have shown intravitreal steroid therapy to effectively control uveitic macular edema.[66][67] Another study reported using intravitreal dexamethasone implants in place of systemic therapy; however, this is currently not standard of care.[68]

Immunomodulators can be considered in patients with contraindications to steroid use, significant or intolerable side effects, or uncontrolled disease despite steroid therapy. Up to 70% of patients with sympathetic ophthalmia need some form of immunomodulatory therapy.[18]

Most of these medications have significant systemic toxicities and require close monitoring; therefore, consultation with rheumatology or internal medicine specialists may be recommended for the co-management of these patients. Types of immunomodulators used for sympathetic ophthalmia management are as follows:

1. Cyclosporine is a calcineurin inhibitor that inhibits T-cell function. The recommended starting dose is 2.5 to 5 mg/kg/day. If improvement in a patient is noted for more than three months, a slow taper may be initiated, decreasing by 0.5 mg/kg/day every 1 to 2 months.[69] This medication can enable the control of even severe inflammation in sympathetic ophthalmia. While it is well tolerated in children and adolescents, increased side effects are noted with advanced age.[69] Potential side effects to watch for include hepatotoxicity, nephrotoxicity, gingival hyperplasia, and hypertension.
2. Azathioprine is an inhibitor of purine synthesis, affecting B and T-lymphocytes, and is effective in managing sympathetic ophthalmia.[70] The recommended dose is 1-3 mg/kg/day.[71] Close monitoring of complete blood count is warranted in these patients, given the risk of myelosuppression. Additional potential side effects include hepatotoxicity, pancreatitis, and increased risk for cancer.
3. Mycophenolate mofetil is an inhibitor of purine synthesis, potentially better tolerated than azathioprine, with fewer side effects.[71] It is usually dosed at 1-3 g/day and must be taken on an empty stomach.[35]
4. Alkylating agents like chlorambucil and cyclophosphamide have been shown to control inflammation in sympathetic ophthalmia.[72] However, these medications are associated with severe systemic side effects, including hemorrhagic cystitis, myelosuppression, secondary malignancies, and sterility. Therefore, patients should be monitored closely with internal medicine co-management.
5. Anti-TNF-alpha biologic agents such as infliximab and adalimumab are gaining traction as potential first-line corticosteroid-sparing agents since they target the specific inflammatory cytokine involved in the pathogenesis of sympathetic ophthalmia. Adalimumab offers the convenience of a subcutaneous injection every two weeks, which can significantly improve a patient's quality of life receiving care.[35] Importantly, before initiating therapy, patients should receive testing for tuberculosis, given the concern for disease reactivation.

Differential Diagnosis

Vogt-Koyanagi-Harada (VKH) syndrome is a well-delineated bilateral panuveitis that may mimic the presentation of sympathetic ophthalmia both on the clinical exam and on various imaging modalities. However, unlike sympathetic ophthalmia, VKH is not associated with prior ocular trauma or surgery and tends to follow a more set evolutional disease progression.[73]

Classification criteria for early-stage VKH include evidence of either exudative retinal detachment or panuveitis with at least two neurologic signs (headache, tinnitus, dysacusis, meningismus, or cerebrospinal fluid pleocytosis) and no history of prior ocular trauma or ocular surgery.[73]

Classification for late-stage VKH includes evidence of early-stage VKH and either presence of a sunset glow fundus or uveitis with cutaneous findings of vitiligo, poliosis, or alopecia.[73] Of note, systemic neurologic symptoms and cutaneous findings can also be present in patients with sympathetic ophthalmia but with significantly lower frequency.[74]

VKH demonstrates a higher prevalence in certain groups, including Asians, Hispanics, and Middle Easterners, and it tends to affect women with a higher frequency.[75] Sympathetic ophthalmia does not have a geographic predilection and tends to occur more in men than women.

Patients with bilateral uveitis must also undergo a full systemic workup to rule out masquerading diseases such as lymphoma, tuberculosis, syphilis, and sarcoidosis.[65][76][77] Lymphoma workup should include a thorough neurologic evaluation, and if suspicion is high, a vitreous sample should be obtained for cytologic analysis and flow cytometry. Tuberculosis, syphilis, and sarcoidosis usually present with systemic signs and symptoms, which should be elicited when obtaining a history. Bacterial, viral, and fungal endophthalmitis may also be on the differential but typically do not involve both eyes. If there is suspicion of endophthalmitis, a vitreous sample should be obtained for further testing.

Prognosis

Early initiation of immunomodulatory therapy is key for improving visual outcomes in patients with sympathetic ophthalmia. Studies show initiation of treatment within 15 days of symptom onset allowed over 85% of sympathizing eyes to achieve visual acuity of 20/40 or better and over 20% of inciting eyes to reach at least 20/80.[63] However, patients will need lifelong follow-up to avoid vision-threatening complications, given the relapsing nature of this disease.[48]

Complications

The most common complications seen with sympathetic ophthalmia are cataract development and ocular hypertension leading to glaucoma.[13] Cataract development can result from recurrent or persistent intraocular inflammation as well as from long-term corticosteroid therapy. Cataract extraction for patients with sympathetic ophthalmia is safe with meticulous surgical planning and careful preoperative and postoperative management of intraocular inflammation.[78] 

However, final visual acuity depends on the extent of the patient’s posterior segment disease. Ocular hypertension can occur in the setting of acute inflammation causing trabeculitis or in the chronic setting secondary to extensive peripheral anterior synechiae formation or pupillary block secondary to posterior synechiae.[79]

Chronic serous retinal detachments can lead to subretinal fibrosis, which can severely compromise vision if the macula is involved. Compromised choroid and RPE can lead to choroidal neovascularization (CNV), which may require anti-vascular endothelial growth factor (VEGF) intravitreal injections.[80] Bevacizumab, ranibizumab, or aflibercept are equally appropriate for treating CNV in patients with sympathetic ophthalmia.[34] Other potential side effects of chronic disease include choroidal atrophy and phthisis.[35]

Deterrence and Patient Education

Sympathetic ophthalmia is a severe bilateral uveitis that can result in permanent vision loss if appropriate therapy is not initiated immediately. Patients who have suffered any traumatic ocular injury should be counseled on the potential risk of this condition, especially within the first year of injury. Patients should contact their ophthalmologist or go to the nearest emergency room if they experience pain, redness, or vision loss in either eye.

Providers of higher-risk intraocular surgery, such as vitreoretinal surgeons, should also consider discussing the risks of sympathetic ophthalmia with their patients. Given that the inflammation in sympathetic ophthalmia may be chronic and relapsing, patients should also be educated on recognizing signs and symptoms of recurrence, including worsening vision, photophobia, eye pain, redness, and irritation.

Enhancing Healthcare Team Outcomes

Sympathetic ophthalmia is a clinical diagnosis requiring a carefully detailed history and physical exam to parse out the diagnosis from potential masqueraders. Ophthalmologists are almost always involved in caring for patients presenting with sudden onset eye pain or vision loss. Still, they may not be the first healthcare provider to evaluate the patient. Nurses, optometrists, and emergency medicine clinicians need a baseline understanding of this disease and know when to refer for subspecialty care. The patient will also require an interprofessional team that includes internal medicine clinicians and pharmacists to co-manage their disease, given the need for long-term steroid use or immunomodulator therapy. [Level 3]