Sympathetic Ophthalmia

Etiology

First coined by William Mackenzie in 1840, sympathetic ophthalmia refers to bilateral ocular inflammation secondary to unilateral eye trauma or surgery.[10] Classically, sympathetic ophthalmia is defined as a bilateral diffuse granulomatous panuveitis that presents with mutton fat keratitic precipitates. However, patient presentations of sympathetic ophthalmia may significantly vary in inflammation on presentation. Per the Standardization of Uveitis Nomenclature 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 cause the highest risk of developing sympathetic ophthalmia.[11] 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.[12][13][14][15]

Triggering Events

• Trauma 
• Surgical intervention
• Other ocular pathologies [16][17]

Trauma

• Open globe injury
• Closed globe injury
• Chemical injury
• Thermal injury [18]

Surgical Intervention 

• Gunderson flap
• Cataract surgery 
• Penetrating keratoplasty 
• Glaucoma surgery
• Para plana vitrectomy
• Diode cyclophotocoagulation
• Scleral buckle
• Intravitreal injections
• Enucleation
• Evisceration
• Treatment of choroidal melanoma with proton bean
• Iridectomy
• Iridenclesis
• Iris incarceration in wound
• Paracentesis
• Phakic intraocular lens implantation [19][20][21][22][23][24]

Ocular Pathologies

• Fungal keratitis
• Bacterial keratitis
• Acanthamoeba keratitis

Epidemiology

A commonly cited general incidence of sympathetic ophthalmia is around 0.03 per 100,000 persons per year.[11] 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.[25] The incidence of patients developing sympathetic ophthalmia after traumatic eye injury was 0.19%. The incidence of patients developing disease following vitreoretinal surgery was significantly lower, around 0.038%. Repeated inciting events, especially patients with repeated traumatic injuries, are at the greatest risk of developing sympathetic ophthalmia.

The average age of presentation for sympathetic ophthalmia is usually between 40 and 45.[26][27][28] Several studies have also suggested a gender preference, with men having sympathetic ophthalmia at higher rates than women.[29][30] 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 1 year. 50% of patients have onset of symptoms within 3 months, and 90% of patients within 1 year.[31] Notably, a reported case of sympathetic ophthalmia began 66 years after the inciting traumatic injury.[2]

Gomi and colleagues have indicated that sympathetic ophthalmia accounts for approximately 0.3% of all uveitis presentations. Further research posits that the incidence could range between 0.2% and 1% following penetrating ocular injuries and around 0.01% after intraocular surgical procedures. Liddy and Stuart observed that sympathetic ophthalmia manifested in 0.2% of non-surgically inflicted ocular injuries, distinguishing that 0.19% resulted from penetrating trauma and a mere 0.007% post intraocular surgery. Holland’s findings denote that sympathetic ophthalmia occurs in 0.5% of ocular trauma cases. Gass and colleagues noted a prevalence of 0.01% after standard pars plana vitrectomy, which escalated to 0.06% when the vitrectomy was associated with penetrating trauma.[32]

A higher preference exists for post-traumatic sympathetic ophthalmia in men, with incidence rates being 1.8-fold greater in comparison to women—likely linked to greater exposure to occupational risks and a predominance of outdoor activities. Conversely, the incidence rate of post-surgical sympathetic ophthalmia is analogous between the sexes, with recent trends indicating a rise in cases. Castiblanco and team found that post-surgical events contribute to 44% of sympathetic ophthalmia cases, with 21% arising after pars plana vitrectomy. A recurrent theme in these occurrences is the presence of a penetrating injury that leads to complex wound-healing challenges, often compounded by the entrapment of ocular structures such as the iris, ciliary body, or choroid.[33]

Pathophysiology

The Mechanism of Pathology

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.[34] 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 tight junctions in the retinal pigment epithelium, creating the blood-retina barrier.[35] Disruption of this system in penetrating injuries results in exposure of previously sequestered ocular antigens to local conjunctival lymphatics, activating cell-mediated immunity and a type IV delayed hypersensitivity reaction.[36]

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 retinal pigment epithelium associated antigens. These have been studied in animal models and shown to produce autoimmune uveitic reactions that mimic sympathetic ophthalmia.[37][38][39][40] Genetic predisposition to sympathetic ophthalmia is another emerging area of research, enabling the identification of at-risk patient populations. Human leukocyte antigen (HLA)-DR4, HLA-A11, and HLA-B40 are associated with sympathetic ophthalmia.[41]

More recent studies have demonstrated that the expression of HLA-DRB1*04 and HLA-DQA1*03 is significantly associated with sympathetic ophthalmia across white and Japanese patients.[42][43] Accidental penetrating injuries and iatrogenic surgical trauma are the primary precursors in 60% to 70% and 30% of sympathetic ophthalmia cases, respectively. Historically considered exacerbated by infectious agents, current understanding confirms that the condition predominantly arises without intraocular infection. Research conducted by Marak and subsequent studies by Wong et al have elucidated that patients exhibit lymphocytes that react to specific uveal-retinal antigens. These findings underscore the pivotal role of genetic predispositions in the etiopathogenesis of sympathetic ophthalmia. Notably, associations have been identified with specific HLA haplotypes, namely HLA-A11, HLA-B40, HLA-DR4/DRw53, and HLA-DR4/DQw3. Moreover, a notable correlation has been established between HLA-DRB14 and HLA-DQB104 alleles and the susceptibility to sympathetic ophthalmia.[44]

The pathophysiological mechanism underlying sympathetic ophthalmia is hypothesized to initiate with an iatrogenic or traumatic event that triggers the afferent arm of an autoimmune response, possibly due to the unveiling of hidden ocular antigens to the immune system or a disruption in immune tolerance to these antigens.[45] Despite the absence of a traditional lymphatic system in the eye, antigen-presenting cells, predominantly macrophages or dendritic cells, process the ocular antigen and present the peptides to autoreactive CD4+ T cells, specifically Th1 cells via HLA class II molecules within the lymph nodes or spleen. The interaction of the antigen peptide with the T cell receptor results in Th1 cell activation and proliferation. These autoreactive cells traverse to the ocular tissues, where a confluence of altered endothelial integrity, a shift in cytokine profiles, and the activation of several effector pathways culminate in damage to the sympathizing eye.[46]

Immunological Cascade

A widespread granulomatous inflammation within the uveal tract defines the immunopathological profile of sympathetic ophthalmia. This reaction comprises an aggregation of lymphocytes, plasma cells, and clusters of epithelioid histiocytes. Notably, pigmentation is often identified within these epithelioid cells and giant cells. A distinctive characteristic is that the inflammation does not extend to involve the choriocapillaris or the retina in histopathological specimens.[4] The choroid remains the primary focus of inflammatory activity, while retinal involvement is typically minimal. Clinically, Dalen–Fuchs nodules present as yellow-white lesions within the peripheral retina, which can progress toward the optic disc and potentially affect the posterior pole. The frequency of Dalen-Fuchs nodules in cases of sympathetic ophthalmia ranges from 25% to 35%. However, this incidence rises to 41.5% when a single peripheral nodule is considered indicative of the disease.[3] These nodules exhibit various morphologies: some display focal hyperplasia of the retinal pigment epithelium, while others show intact retinal pigment epithelium overlying lymphocytes and epithelioid cells. In more advanced stages, the degeneration and disorganization of the nodules can occur, leading to the subretinal discharge of the nodular contents.[47]

Initially, the physical mass of nodules results in an apparent elevation of the overlying retinal structures, which, over time, gives way to atrophic changes. These nodules consist of nodular accumulations of pigmented epithelioid cells between the retinal pigment epithelium and Bruch membrane. Under microscopic examination, these cells reveal a distinctive ultrastructure featuring prominent organelles consistent with an active metabolic state. Autofluorescence studies reveal these cells as innumerable yellowish-orange specks corresponding to lipofuscin, reinforcing the theory that transformed cells constitute the primary cellular component of Dalen-Fuchs nodules.[48] When the retina typically remains unscathed, mononuclear cellular aggregates around blood vessels and over Dalen-Fuchs nodules have been observed in enucleated specimens. The sclera may also be implicated along emissary veins, and inflammatory exudates have been noted to extend to the optic nerve and meninges. Atypical histopathological features have been documented, such as phaco anaphylactic reactions to the disrupted lens material characterized by zonal granulomatous inflammation.[49]

Immunohistochemical analyses have identified a predominance of T lymphocyte infiltration within the uveal tract, with B lymphocyte presence in more protracted cases or those managed with corticosteroids. The early stages of the disease are characterized by a Th1 response, marked by an abundance of CD4+ T cells and the secretion of proinflammatory cytokines. In contrast, CD8+ T cells are more common in chronic presentations of sympathetic ophthalmia.[50] Emerging research implicates TNF-α-induced oxidative stress within the outer retina as a potential early event precipitating photoreceptor apoptosis and subsequent vision impairment in sympathetic ophthalmia. Conversely, protective molecular markers, such as α-A-crystallin, have been detected in the outer retinal layers. The increased expression of Fas and FasL in afflicted eyes hints at apoptosis playing a regulatory role in mitigating ocular inflammation.[51] Interleukin-23 or interleukin-17 signaling has been implicated in autoinflammatory and autoimmune uveitis pathogenesis akin to sympathetic ophthalmia, influencing cell function and exacerbating intraocular inflammation. Targeting this pathway may represent a novel therapeutic approach. Additionally, altered expression of specific microRNAs has been associated with increased proinflammatory cytokine activity, particularly TNF-α, and NF-κB, underscoring their importance in the pathogenesis.[52]

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.[53] Notably, similar changes are found in the inciting and the sympathizing eye. 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.[34][54]  TNF-α, an inflammatory cytokine, may mediate oxidative stress in the outer retina during sympathetic ophthalmia, resulting in photoreceptor apoptosis and vision loss.[55] Interleukin-23 and interleukin-17 may also target retinal pigment epithelial cells in this disease. Classically, inflammation from sympathetic ophthalmia spares the choriocapillaris, though some recent studies have documented cases where the choriocapillaris can be involved.[56][57] 

Dalen-Fuchs nodules are lesions of the retinal pigment epithelium characteristically associated with sympathetic ophthalmia. Still, they are only seen in 25% to 35% of cases and are not pathognomonic to the disease.[58] Dalen–Fuchs nodules are present in an estimated 30% of patients. These microscopic structures comprise lymphocytes, histiocytes, and altered retinal pigment epithelial cells beneath the Bruch membrane. Morphological diversity in these nodules occurs. Descriptions outline 3 distinct types of lesions: the first involves localized proliferation and clustering of retinal pigment epithelial cells, the second is the traditional Dalen–Fuchs nodule, where a continuous layer caps epithelioid cells and lymphocytes, and the third is characterized by degenerative changes, leading to disorganized nodules and potential dispersion into the subretinal region.[3] Three different morphologies of these lesions follow:

• Focal retinal pigment epithelial hyperplasia and aggregation
• Classic Dalen-Fuchs nodules, described as lymphocytes and epithelioid cells that exist between retinal pigment epithelial and Bruch membrane
• Nodules with disruption of the overlying retinal pigment epithelial resulting in potential eruption into the subretinal space [59]

No known correlation exists between the extent of histopathological findings and the final visual outcome in sympathetic ophthalmia.[56] Sympathetic ophthalmia is a comprehensive inflammatory eye disease that manifests as panuveitis. Upon histological examination, the disease exhibits a pervasive thickening throughout the uveal tract, including the choroid, ciliary body, and iris. Notably, the inflammatory alterations are comparable in both the triggering and the affected eye. Though the proportions vary, the inflammatory response predominantly comprises lymphocytes, epithelioid cells, and multinucleated giant cells. Traditionally, the condition is understood to spare the choriocapillaris; however, research by Rathinam et al uncovered instances of lymphocytic infiltration within the choriocapillaris in select regions, alongside focal necrosis in cases where sympathetic ophthalmia is concurrent with endophthalmitis.[60]

Immunopathologically, the condition is marked by an initial surge of CD4+ helper or inducer T cells, with a subsequent rise in CD8+ suppressor or cytotoxic T cells, illustrating an active and changing T cell-mediated immune response during the progression. Additionally, B cells within the uveal infiltrate have been observed, contrasting with the previously believed T cell dominance and suggesting the potential role of B cell-mediated activation of autoreactive T cells as the disease progresses. Evidence suggests genetic factors may contribute to the susceptibility to sympathetic ophthalmia, particularly alleles in the human leukocyte antigen system, such as HLA-A11, Cw, DRB104, DQB104, DR4, as well as the related DQw3 and DRw53.[61]

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 1 year.[31] 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, an accurate history focuses 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.[30]

Symptoms may range from mild visual disturbances to significant vision loss. Other symptoms include pain, photophobia, epiphora, floaters, and redness.[26][62] Due to inflammation of the ciliary body affecting accommodation, near vision may be affected during the early stages of sympathetic ophthalmia. Most patients 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 is seen. Intraocular pressure is low in the setting of ciliary body shutdown or high secondary to trabeculitis or obstruction of the trabecular meshwork.

Examination of the posterior segment in cases of sympathetic ophthalmia commonly reveals a spectrum of inflammatory manifestations, including vitreous haze and opacities, inflammation of the optic nerve head, inflammation of the retinal blood vessels, serous retinal separation, and inflammation of the vascular layer beneath the retina. The initial indicators often involve subtle inflammation in the front of the eye, minimal cells behind the lens, and optic disc redness. The severity of the inflammatory response can range from minor, with several small, isolated serous detachments near the optic nerve and macula, to extensive serous retinal separation. These presentations may include discreet yellowish-white spots at the choroidal level in the early stages, commonly identified as Dalen–Fuchs nodules. They are typically observed around the eye’s equator and peripheral regions.[63]

Over time, these nodules are prone to degenerative changes, leading to thinning and atrophy. The pattern and magnitude of the fluid accumulation beneath the retina are quite variable, sometimes presenting as localized detachments in the region adjacent to the optic disc across the central retinal area or as a more extensive detachment scenario. Though indicative of the underlying inflammatory process, these nodules are often a marker of disease progression and the body’s response to the condition. Posterior segment exam findings may include mild to severe vitritis, Dalen-Fuch nodules (yellow-white lesions of the retinal pigment epithelium), choroiditis, papillitis, and retinal vasculitis. Exudative retinal detachment may vary from small pockets of peripapillary exudative detachments to more extensive serous retinal detachments.[3][26] 

Chronic sympathetic ophthalmia may also cause subretinal fibrosis and choroidal neovascularization.[4] A 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 retinal pigment epithelium.[64] The “sunset glow” fundus, a hallmark characteristic often observed in the advanced stages of sympathetic ophthalmia, emerges due to pigmentary depletion within the choroidal layer and alterations in the retinal pigment epithelium. Recurrent inflammation in the front part of the eye, accompanied by this “sunset glow” appearance, is a notable clinical manifestation of sympathetic ophthalmia. The range of post-inflammatory sequelae varies widely and is influenced by the intensity of the inflammation and the timeliness and effectiveness of the treatment. Complications such as secondary glaucoma and cataract formation are frequently encountered, either as direct consequences of the disease or as adverse effects of corticosteroid therapy. Additionally, atrophy of the retina and optic nerve can develop as a sequel to persistent retinal separation, subretinal scarring, and attendant atrophic changes in the choroid. Although less common, the development of choroidal neovascularization and phthisis bulbi are serious complications that typically indicate a history of delayed diagnosis or suboptimal management.[65]

Evaluation

Essential for diagnosing sympathetic ophthalmia are the characteristic findings of bilateral uveitis following an event of trauma or surgical intervention to 1 eye. This condition presents with inflammation across multiple eye segments involving the anterior chamber, vitreous body, and choroid. While the diagnosis primarily rests on clinical grounds, a suite of imaging techniques is pivotal for confirming and tracking treatment efficacy and disease course. These supplemental diagnostic measures are instrumental for clinicians in comprehensively managing sympathetic ophthalmia. 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.[4][66] Enhanced-depth imaging optical coherence tomography (EDI-OCT) is the preferred method for assessing choroidal thickness. Research indicates that individuals with sympathetic ophthalmia often exhibit widespread choroidal swelling and a mild serous retina detachment, particularly in the macular region.

Fundus Autofluorescence

The imaging detects lipofuscin in the retinal pigment epithelium, enabling visualization of dysfunction and death. This simple, noninvasive 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.[67] With the resolution of the subretinal fluid, fundus autofluorescence (FAF) may display leopard spots with mixed areas of hyper- and hypo-autofluorescence.[68] 

Fundus autofluorescence 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, retinal pigment epithelial loss, nummular scars, and peripapillary atrophy. Increased autofluorescence may be seen in cystic macular edema, subretinal fibrosis, and proliferation.[69] During active phases of the disease, enhanced autofluorescence imaging reveals intensified signals that align with areas where the neurosensory retina has detached. As the disease resolves, leading to alterations in the retinal pigment epithelium, the autofluorescence patterns evolve, displaying a speckled increase in autofluorescence that resembles leopard spotting. Autofluorescence imaging is useful to assess the condition, where increased autofluorescence signifies a metabolically active epithelium, and decreased signals indicate loss. Nevertheless, since sympathetic ophthalmia primarily affects the choroidal stroma, imaging does not facilitate diagnosing or managing the condition.[70]

Optical Coherence Tomography

The introduction of enhanced depth imaging OCT (EDI-OCT) and swept-source OCT technologies has revolutionized the visualization of retinal and choroidal structures, producing high-definition images spectral-domain optical coherence tomography (SD-OCT) with or without enhanced depth imaging (EDI-OCT) and swept-source OCT (SS-OCT) are noninvasive imaging modalities that allow for high-resolution examination of the retina and choroid.[71] Sympathetic ophthalmia may initially present with serous retinal detachments seen on swept-source OCT. The detachments contain hyperreflective septa, representing bacillary layer detachment splitting the photoreceptor layer at the inner segment myoid. Of note is that this finding is also seen in Vogt-Kayanagi-Harada (VKH) disease and resolves rapidly with corticosteroid treatment.[72] 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.[73] 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, though useful in monitoring treatment response.[74][75] 

Research conducted by Gupta and colleagues noted the repair of these OCT-detected abnormalities, including the continuity of the retinal pigment epithelium–Bruch membrane complex and inner segment and outer segment of photoreceptor cells junction, following timely treatment in the acute phase of the disease. Furthermore, acute-phase alterations in the choroid are not limited to the outer retina but include extensive choroidal thickening, observable folds, and a loss of normal choroidal structure. Such choroidal thickening is a significant OCT-based biomarker for tracking disease progression. The choroidal vascularity index (CVI), a novel OCT biomarker, has been introduced to monitor disease activity in cases of sympathetic ophthalmia. Notably, the CVI is considered a reliable metric, remaining constant and less susceptible to alteration by physiological variables.

Optical Coherence Tomography Angiography

This noninvasive imaging modality is designed to examine the chorioretinal vasculature without intravenous dye. Optical coherence tomography angiography (OCTA) may demonstrate ischemia and reduced capillary density.[76] OCTA can also monitor ischemic areas as patients respond to therapy.[4][77] OCTA is also sensitive in detecting and differentiating choroidal neovascularization from inflammatory lesions to tailor the patient’s treatment plan.[78] OCTA has been pivotal in identifying small regions of compromised choriocapillaris perfusion, suggesting areas of ischemia within the choriocapillaris. These areas appear as flow voids on OCTA images, which typically diminish and resolve with appropriate treatment. OCTA has also enhanced the visualization of choroidal neovascular membranes, providing clearer images than other imaging modalities.[79] In contrast to fluorescein angiography and indocyanine green angiography (ICGA), which yield 2-dimensional images, OCTA generates 3-dimensional visualizations based on volumetric data; this provides a more detailed analysis of the choriocapillaris and ischemic conditions, which often present as flow voids on OCTA and are analogous to the hypocyanescent lesions seen on indocyanine green angiography in inflammatory choroidal diseases such as Vogt-Koyanagi-Harada and sympathetic ophthalmia.[80] 

Despite the advantages as a noninvasive imaging technique, especially for conditions affecting the choriocapillaris, OCTA has limitations in adequately capturing medium and large choroidal vessel details. Additionally, signal loss and artifacts can complicate the interpretation of flow voids, necessitating careful differentiation and occasionally leaving the utility of OCTA somewhat ambiguous. The primary basis for diagnosis remains the patient’s history of ocular trauma and the presentation of clinical features. Multimodal imaging continues to be essential for tracking the disease’s progression, identifying recurrences, and evaluating therapeutic responses. Advanced OCT technologies have facilitated the noninvasive assessment of retinochoroidal microstructural and microvascular alterations in diseases like sympathetic ophthalmia and Vogt-Koyanagi-Harada. OCTA, in particular, is an increasingly favored instrument in diagnosing and managing choroidal disorders, attesting to its utility in ophthalmic practice.[81]

Fluorescein Angiography

This excellent noninvasive imaging modality provides useful information for the diagnosis and treatment monitoring of patients with sympathetic ophthalmia. In the acute phase of sympathetic ophthalmia, 2 patterns are seen. The first is nearly identical to the pattern seen in Vogt-Koyanagi-Harada 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. These spots may coalesce under serous retinal detachments in severe disease.[82] The second acute phase pattern resembles acute posterior multifocal placoid pigment epitheliopathy (APMPPE), demonstrating initial hypofluorescent foci that are hyperfluorescent in the late phase with staining of the lesions. Unlike APMPPE, the lesions in sympathetic ophthalmia are elevated and mottled in appearance.[83] The initial hypofluorescence may be secondary to obscuration from Dalen-Fuchs nodules or choroidal inflammation leading to focal obliteration of the choriocapillaris. Chronic sympathetic ophthalmia findings are more variable, depending on the inflammatory sequelae of the disease. Nummular scars occur from focal damage to the retinal pigment epithelium and inner choroid and present as window defects.[30] Subretinal fibrosis may present with hyperfluorescent staining due to proliferated metaplastic retinal pigment epithelium.[4][84] The presence of choroidal neovascularization may reveal leakage in the macula.

Indocyanine Green Angiography 

Indocyanine green angiography (ICGA) is instrumental in examining the choroidal vasculature, significantly enhancing our understanding of the pathogenesis of diseases like sympathetic ophthalmia, which primarily affects the choroid. ICGA is used as an adjunct to fluorescein angiography, given the superior ability to assess the choroid and choroidal infiltrates. A common finding in sympathetic ophthalmia on ICGA is multiple hypocyanescent spots corresponding to the hyperfluorescent spots. Histopathological studies of these lesions have confirmed the spots are caused by cellular infiltrates of the choroid or due to blockage by overlying fluid.[85] These hypocyanescent spots are similar in all phases of sympathetic ophthalmia and tend to improve with adequate treatment.[68][86] The hypocyanescent spots may return in late-phase sympathetic ophthalmia, possibly due to choroidal atrophy.[87] Bernasconi and colleagues have further explored these observations, noting that the presentation may indicate scarred lesions. In contrast, the diminishment signals active inflammatory lesions. Importantly, these hypocyanescent lesions typically resolve with corticosteroid treatment, a change that correlates closely with clinical improvement in patients. This dynamic reflects the critical role of ICGA in guiding the diagnosis and monitoring the treatment response, providing a clearer picture of the choroidal involvement and the effectiveness of therapeutic interventions.

Treatment / Management

Surgical

Historically, removal of the injured eye within 14 days of ocular trauma protects the contralateral eye from the onset of sympathetic ophthalmia.[58] When sympathetic ophthalmia occurs, enucleation no longer benefits the sympathizing eye.[29] However, the practice of prophylactic enucleation lacks supporting scientific evidence and is based primarily on observation and clinical speculation.[88] Sympathetic ophthalmia occurs in the sympathizing eye despite removing the traumatic globe.[89] Removing the inciting eye does not improve the sympathetic eye’s visual acuity. In many patients, the inciting eye may have better overall vision.[90] Importantly, in most cases of ocular injury where the traumatic globe was not removed, patients do not develop sympathetic ophthalmia.[91] The decision of when to remove and when to save a severely traumatized eye is difficult. In a study of 660 traumatic globe injuries, over 98% of injuries were successfully repaired surgically, and only 13% resulted in no light perception vision. Indication for primary removal of the globe only occurred in 1.7% due to the inability to repair the globe.[92] Additionally, patients with no light perception vision after ocular trauma regain some vision in 16% of cases.[93] Furthermore, the negative psychological impact of losing an eye cannot be understated and should be considered before enucleation or evisceration. Patients often experience body dysmorphia, depression, and increased anxiety from losing an eye.[94] Cosmetic benefits include saving the phthisical eye since the eye often retains full movement, and the irregular anterior surface better supports an overlying ocular prosthesis.[88](B2)

In cases where the ruptured globe is beyond repair, removal of the eye via evisceration or enucleation is 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.[95] However, a more recent large retrospective study of patients showed no cases of sympathetic ophthalmia after evisceration.[62] Evisceration is favored since this is technically easier, and preserving the sclera can provide a barrier to prevent the orbital spread of infection. Evisceration may also provide a cosmetic and functional advantage for the patient.

Medical

Patients with sympathetic ophthalmia who undergo prompt treatment with high-dose steroids and immunomodulatory agents have a better chance for positive visual outcomes.[96] The initial treatment for sympathetic ophthalmia typically involves administering high-dose systemic corticosteroids, with the specific regimen tailored according to the clinical presentation, disease severity, and initial visual acuity. In 1995, the National Eye Institute highlighted the efficacy of such high-dose systemic anti-inflammatory therapy, recommending corticosteroids at dosages ranging from 0.5 to 2 mg/kg/day of prednisolone to preserve vision. Upon diagnosis of sympathetic ophthalmia, initiating patients on high-dose intravenous corticosteroids at a dose of 1 to 2 mg/kg/day with adjunct topical cycloplegics and corticosteroids is recommended.[97] Improvements in retinal findings have been noted soon after the initiation of corticosteroids.[98] In very severe cases, intravenous pulse methylprednisolone can be considered at a dose of 1 gram/day for 3 days.[7] Patients should remain on steroids for a minimum of 3 months with a very slow taper if improvement is noted.(B2)

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 that intravitreal steroid therapy controls uveitic macular edema effectively.[99][100] The results of another study suggested the use of intravitreal dexamethasone implants in place of systemic therapy; however, this is currently not the standard of care.[101] For severe cases characterized by iris nodules, pronounced granulomatous panuveitis, and serous retinal detachments, intravenous corticosteroid therapy is usually preferred. High-dose intravenous pulse therapy, often using methylprednisolone at 1 g/day for 3 days, quickly reduces significant pathological changes like vitritis, multifocal retinal detachments, and inflammation in the anterior chamber. Depending on the patient’s response, this intravenous treatment might extend for 5 to 7 days.(B3)

However, the aggressive form of treatment has potential risks, including rapid changes in blood pressure and blood glucose levels, along with serious side effects such as the possible reactivation of pulmonary tuberculosis. As such, these initial intensive treatments should be carefully managed, weighing the risks against the benefits. Following the control of the acute inflammatory phase, the regimen usually transitions to a lower dose of systemic corticosteroids, starting at 1 mg/kg/day of prednisolone, gradually tapered over 2 to 3 months. This duration allows for an adequate assessment of the treatment’s effectiveness. Should further surgical interventions become necessary, increasing the corticosteroid dosage may be required to manage inflammation effectively.[102] 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 immunomodulatory therapy.[36] Immunosuppressive therapies are often prescribed for patients with sympathetic ophthalmia to minimize the dependence on prolonged systemic corticosteroid treatment. Typically, a regimen combining corticosteroids with immunosuppressive agents is started early in the treatment process, allowing sufficient time for the immunosuppressives to take effect. Additionally, alternative immunosuppressive drugs are introduced if a patient shows intolerance to a specific medication.[103](B2)

A variety of agents are available for the management of sympathetic ophthalmia. Commonly utilized medications include mycophenolate mofetil, azathioprine, cyclosporine, and cyclophosphamide. Cyclophosphamide is generally reserved for cases resistant to other treatments due to the potential for severe systemic side effects. 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 cases. Types of immunomodulators include:

• 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 3 months, a slow taper may be initiated, decreasing by 0.5 mg/kg/day every 1 to 2 months. This medication can enable the control of severe inflammation in sympathetic ophthalmia. Though well tolerated in children and adolescents, increased side effects are noted with advanced age. Potential side effects include hepatotoxicity, nephrotoxicity, gingival hyperplasia, and hypertension.
• Azathioprine is an inhibitor of purine synthesis that affects B and T lymphocytes and effectively manages sympathetic ophthalmia. The recommended dose is 1 to 3 mg/kg/day. Given the risk of myelosuppression, close monitoring of complete blood count is warranted in these patients. Additional potential side effects include hepatotoxicity, pancreatitis, and increased risk for cancer.
• Mycophenolate mofetil is an inhibitor of purine synthesis, better tolerated than azathioprine, and has fewer side effects. The medication is usually dosed at 1 to 3 g/day and must be taken on an empty stomach.
• Alkylating agents like chlorambucil and cyclophosphamide control inflammation in sympathetic ophthalmia. 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.
• Anti-TNF-α 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 2 weeks, which can significantly improve a patient’s quality of life. Importantly, before initiating therapy, patients should undergo testing for tuberculosis, given the concern for disease reactivation.[4][104][105][106]
(B2)

Differential Diagnosis

Vogt-Koyanagi-Harada syndrome is a well-delineated bilateral panuveitis that may mimic the presentation of sympathetic ophthalmia both on the clinical exam and in various imaging modalities. However, unlike sympathetic ophthalmia, the syndrome is not associated with prior ocular trauma or surgery and tends to follow a more set evolutional disease progression. Classification criteria for the early stage of the syndrome include evidence of either exudative retinal detachment or panuveitis with at least 2 neurologic signs (headache, tinnitus, dysacusis, meningismus, or cerebrospinal fluid pleocytosis) and no history of prior ocular trauma or ocular surgery. Classification for late-stage includes evidence of early-stage syndrome and either the presence of a sunset glow fundus or uveitis with cutaneous findings of vitiligo, poliosis, or alopecia.[107] Of note, systemic neurologic symptoms and cutaneous findings are present in patients with sympathetic ophthalmia but with significantly lower frequency.[108]

Vogt-Koyanagi-Harada syndrome demonstrates a higher prevalence in certain groups, including the Asian, Hispanic, and Middle Eastern populations, and affects women with a higher frequency.[109] Sympathetic ophthalmia has no geographic predilection and occurs 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.[7][110][111] Lymphoma workup should include a thorough neurologic evaluation and 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 the suspicion of endophthalmitis persists, a vitreous sample should be obtained for further testing. The list of differential diagnoses includes:

• Vogt-Koyanagi-Harada disease: This is a panuveitis that includes serous retinal detachments and may present with systemic symptoms such as vitiligo, alopecia, and hearing loss.
• Sarcoidosis: A systemic granulomatous disease can present with granulomatous uveitis mimicking sympathetic ophthalmia and may involve other organ systems.
• Intraocular lymphoma: This malignancy can cause uveitis and retinal detachment, requiring a biopsy for a definitive diagnosis.
• Infectious uveitis: This includes tuberculosis, syphilis, and viral infections such as HSV and cytomegalovirus (CMV), which can cause panuveitis.
• Behçet disease: A systemic vasculitis that can cause panuveitis, oral and genital ulcers, and skin lesions.
• Uveitis associated with juvenile idiopathic arthritis: Juvenile idiopathic arthritis can be associated with chronic uveitis, especially in younger patients.
• Posterior scleritis: The condition may cause painful inflammation with similar fundus changes to sympathetic ophthalmia.
• Ocular toxoplasmosis: This is infectious uveitis that can lead to retinal necrosis and choroiditis, sometimes similar to sympathetic ophthalmia.
• Endophthalmitis: Acute inflammation of the intraocular cavities, usually due to infection that can mimic the panuveitis seen in sympathetic ophthalmia.
• Posterior uveitis of other causes: Idiopathic or drug-induced causes.
• Masquerade syndromes: Conditions that mimic intraocular inflammation but are not due to true uveitis, such as retinoblastoma in children or melanoma in adults.
• Multifocal choroiditis with panuveitis presents multiple choroidal lesions and inflammation resembling sympathetic ophthalmia.[112][113][114][115][116][117]

When assessing a patient, a comprehensive clinical examination, detailed patient history, and relevant ancillary tests are crucial for differentiating from these other conditions. An accurate diagnosis is vital for providing the correct treatment and improving the prognosis.

Treatment Planning

Sympathetic ophthalmia does not have a universally accepted staging system like some other diseases, largely due to its rarity. However, the clinical presentation of the disease can be described in terms of the severity and the extent of ocular involvement. A potential approach to staging could consider the following factors:

Onset of Symptoms

• Acute: The sudden appearance of symptoms following trauma or surgery to the fellow eye, typically within days to months.
• Delayed: Symptoms manifesting months to years after the inciting event.[3][118]

Clinical Features

• Mild: Mild uveitis with slight discomfort, minimal visual impairment, and few inflammatory signs
• Moderate: More pronounced uveitis with moderate pain and visual impairment, keratitic precipitates, and vitreous haze
• Severe: Intense inflammation with significant pain, photophobia, severe vision loss, and the presence of exudative retinal detachments or choroidal neovascularization [119]

Anatomical Involvement

• Anterior uveitis: Inflammation primarily in the iris and ciliary body
• Intermediate uveitis: Inflammation centered in the vitreous
• Posterior uveitis: Inflammation affecting the retina and choroid
• Panuveitis: Involvement of all segments of the uvea [120]

 The Extent of Systemic Immune Response

• Localized: Inflammation confined to the eyes with no systemic immune reaction
• Systemic: Evidence of a more generalized autoimmune response potentially affecting other organs [121]

Complications

• Stage I: No complications, inflammation controlled with medication
• Stage II: Development of complications such as cataracts or glaucoma, controllable with treatment
• Stage III: Complications such as chronic cystoid macular edema, optic atrophy, or subretinal neovascular membranes leading to irreversible vision loss [122]

Response to Treatment

• Responsive: The disease responds to initial therapy without recurrence
• Refractory: Disease not adequately controlled with standard therapy, requiring more aggressive treatment or resulting in chronic condition [123]

This staging is not officially recognized and is more for descriptive purposes, as clinicians often tailor treatment to the individual patient’s condition rather than a specific stage. Due to the variability of the disease, a multidisciplinary approach is often required for management, and staging may be more complex than in other diseases with well-defined classification systems.[124]

Toxicity and Adverse Effect Management

Managing the toxicity and adverse effects of treatment for sympathetic ophthalmia is an important aspect of patient care. Treatment regimens, particularly those involving long-term corticosteroid use and immunosuppressive agents, can lead to various side effects. Here are general strategies for managing such complications:

Corticosteroid-Induced Side Effects

• Osteoporosis prevention: Calcium, vitamin D supplements, and bone density monitoring
• Hyperglycemia control: Blood sugar level monitoring and collaborating with a primary care physician for diabetes management
• Increased infection risk: Educate patients on signs of infection; possibly prescribe prophylactic antibiotics for specific situations
• Cataract and glaucoma: Regular eye examinations, pressure monitoring, and surgeries as needed

Immunosuppressive Drug Monitoring

• Liver and kidney function: Regular blood tests to monitor liver enzymes and kidney function due to the potential hepatotoxicity and nephrotoxicity of medications like methotrexate and cyclosporine
• Blood dyscrasias: Complete blood counts to monitor for anemia, leukopenia, and thrombocytopenia
• Infection surveillance: Patients on immunosuppressive therapy are more susceptible to opportunistic infections 

Biologic Agents

• Injection site reactions: Local care and possibly adjusting the administration technique
• Risk of reactivation of tuberculosis: Screening for tuberculosis before starting therapy with biologic agents, particularly TNF-α inhibitors
• Demyelinating disorders: Neurological assessment for any new-onset neurological symptoms

General Health Maintenance

• Nutritional support: A balanced diet may help manage weight and maintain overall health.
• Physical activity: Encourage weight-bearing exercises to maintain bone density and muscle strength.
• Psychosocial support: Access to mental health professionals to address any psychological effects of chronic illness and vision loss is important.

Patient Education

• Medication adherence: Stress the importance of not abruptly stopping medications to avoid acute rebound effects.
• Adverse effect awareness: Educate patients about potential adverse effects and when to seek medical help.

Treating clinicians must tailor management plans based on the specific medications used and the patient’s overall health profile. Regular and comprehensive monitoring for side effects can mitigate the risks associated with treating sympathetic ophthalmia.[125][126][127][128][129]

Staging

Sympathetic ophthalmia does not have a universally accepted staging system like some other diseases, largely due to its rarity. However, the clinical presentation of the disease can be described in terms of the severity and the extent of ocular involvement. A potential approach to staging could consider the following factors:

Onset of Symptoms

• Acute: The sudden appearance of symptoms following trauma or surgery to the fellow eye, typically within days to months.
• Delayed: Symptoms manifesting months to years after the inciting event [3][118]

Clinical Features

• Mild: Mild uveitis with slight discomfort, minimal visual impairment, and few inflammatory signs
• Moderate: More pronounced uveitis with moderate pain and visual impairment, keratitic precipitates, and vitreous haze.
• Severe: Intense inflammation with significant pain, photophobia, severe vision loss, and the presence of exudative retinal detachments or choroidal neovascularization.[119]

Anatomical Involvement

• Anterior uveitis: Inflammation primarily in the iris and ciliary body
• Intermediate uveitis: Inflammation centered in the vitreous
• Posterior uveitis: Inflammation affecting the retina and choroid
• Panuveitis: Involvement of all segments of the uvea [120]

 The Extent of Systemic Immune Response

• Localized: Inflammation confined to the eyes with no systemic immune reaction
• Systemic: Evidence of a more generalized autoimmune response potentially affecting other organs [121]

Complications

• Stage I: No complications, inflammation controlled with medication
• Stage II: Development of complications such as cataracts or glaucoma, controllable with treatment
• Stage III: Complications such as chronic cystoid macular edema, optic atrophy, or subretinal neovascular membranes leading to irreversible vision loss [122]

Response to Treatment

• Responsive: The disease responds to initial therapy without recurrence
• Refractory: Disease not adequately controlled with standard therapy, requiring more aggressive treatment or resulting in chronic condition [123]

This staging is not officially recognized and is more for descriptive purposes, as clinicians often tailor treatment to the individual patient’s condition rather than a specific stage. Due to the variability of the disease, a multidisciplinary approach is often required for management, and staging may be more complex than in other diseases with well-defined classification systems.[124]

Prognosis

Early initiation of immunomodulatory therapy is key for improving visual outcomes in patients with sympathetic ophthalmia. Studies show that the initiation of treatment within 15 days of symptom onset caused 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. However, given the relapsing nature of this disease, patients need lifelong follow-up to avoid vision-threatening complications.[82][97] The prognosis of sympathetic ophthalmia varies significantly and largely depends on how quickly and effectively the inflammation is controlled. Here are several factors that can impact the prognosis:

• Timing of treatment: Early diagnosis and prompt treatment initiation are crucial for a better prognosis. Delayed treatment can lead to irreversible ocular damage.
• Severity of inflammation: The severity of inflammation at the time of presentation is a key determinant. More severe inflammation is associated with a poorer prognosis.
• Response to treatment: A positive response to steroids and immunosuppressive therapy can help preserve vision and improve the long-term prognosis.
• Complications: The development of complications such as cataracts, glaucoma, or subretinal neovascularization can worsen the prognosis. Management of these complications is an essential part of improving the overall outcome.
• Recurrence: Recurrent episodes of inflammation can lead to cumulative damage to the eye, resulting in a poorer visual prognosis.
• Systemic disease: If sympathetic ophthalmia is associated with systemic autoimmune disorders, managing the overall systemic condition is also necessary for a better prognosis.
• Adherence to treatment plan: Patient adherence to a long-term treatment plan, including systemic medications with potential side effects, is crucial for maintaining disease control and improving outcomes.[62][129][130][131][132][133][134]

Despite these considerations, modern immunosuppressive treatments have improved the prognosis of sympathetic ophthalmia compared to the pre-steroid era. However, due to the potential for chronicity and recurrence, some patients may experience a decline in visual function over time. Current research and newer therapies continue to facilitate improvements in the management and prognosis. Regular follow-up with an ophthalmologist and, when appropriate, a rheumatologist or immunologist is essential.

Complications

The most common complications seen with sympathetic ophthalmia are cataract development and ocular hypertension, leading to glaucoma.[29] Cataract development can result from recurrent or persistent intraocular inflammation and 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.[135] However, final visual acuity depends on the extent of the patient’s posterior segment disease. Ocular hypertension can occur in acute inflammation causing trabeculitis or in the chronic setting secondary to extensive peripheral anterior synechiae formation or pupillary block secondary to posterior synechiae.[136]

Chronic serous retinal detachments can lead to subretinal fibrosis, severely compromising vision if the macula is involved. Compromised choroid and retinal pigment epithelium can lead to choroidal neovascularization, which may require anti-vascular endothelial growth factor intravitreal injections.[137] Bevacizumab, ranibizumab, or aflibercept are equally appropriate for treating choroidal neovascularization in patients with sympathetic ophthalmia.[3] Other potential side effects of chronic disease include choroidal atrophy and phthisis.[4] Sympathetic ophthalmia can lead to several severe ocular complications, some threatening vision. The complications are often a result of the underlying inflammatory process or the side effects of the intensive treatments required to control the disease. Common complications include the following:

• Glaucoma: Increased intraocular pressure can lead to glaucoma either due to the disease or as a side effect of steroid therapy.
• Macular edema: Inflammation can cause fluid accumulation in the retina, particularly in the macula, leading to cystoid macular edema, impairing central vision.
• Choroidal neovascularization: Abnormal blood vessel growth under the retina, stimulated by chronic inflammation, can cause bleeding and scarring, threatening vision.
• Optic atrophy: Prolonged inflammation can damage the optic nerve, leading to optic atrophy and permanent vision loss.
• Band keratopathy: Deposition of calcium in the cornea can occur as a chronic response to inflammation.
• Epiretinal membrane formation: Scar tissue may form on the retina’s surface, distorting vision.
• Scleral and corneal thinning: Chronic inflammation can lead to the thinning of the sclera and cornea, potentially leading to structural weaknesses.
• Uveitic glaucoma: A specific type of glaucoma that arises due to uveitis can be difficult to manage because the eye is already compromised.
• Phthisis bulbi: In severe, end-stage cases, the eye is atrophic, shrunken, and non-functional.[138][139][140]