Long-term clinical outcomes of patients with sympathetic ophthalmia

Sympathetic ophthalmia (SO) is an inflammatory disease characterized by bilateral granulomatous uveitis [1], occurring after a penetrating ocular injury (0.19%) [2] or intraocular surgery (0.01%) [3]. An autoimmune response is believed to arise when uveal antigens are exposed to Langerhans cells, which are present in the conjunctiva [4]. The traumatized or operated eye is considered the exciting eye, and the fellow contralateral eye is the sympathizing one [5].

The theory was first suggested by Hippocrates [6], but it was not until 1840 that Mackenzie coined the term Sympathetic Ophthalmia [7]. It is a rare disease, with an estimated yearly incidence rate after open globe injury of 33 per 100,000 persons (95% CI 19.61–56.64) [2].

The onset time varies; patients can present with decreased vision, pain, or floaters in the sympathizing eye between 5 days [8] and 66 years [9] following the incident. Most cases (90%) arise within the first year of injury/surgery [10]. The clinical signs can also vary, and they may include mutton-fat keratic precipitates, exudative retinal detachment (ERD), and Dalen-Fuchs (DF) nodules [3] which are the characteristic pathological finding of SO [11]. Optical coherence tomography (OCT) can be used to indicate the presence of DF nodules, monitor macular edema, and follow the disease’s progression [1].

We aim to present the long-term clinical outcomes of seven patients with sympathetic ophthalmia evaluated between 2002 and 2022.

This report provides information on seven patients with SO, including their characteristics and long-term clinical outcomes. It aligns with previous studies, indicating that ocular trauma is the primary risk factor for SO, accounting for 75–80% of all SO cases [13]. In our review, 6 out of 7 patients (86%) experienced ocular trauma as the main trigger. While intraocular surgeries are not a common cause of SO, they have become a prevalent risk factor. Kilmartin et al. [14] reported that the risk of SO after pars plana vitrectomy and external retinal detachment repair was 1 in 1152 retinal surgical procedures. Additionally, as observed in our study, the majority of patients with SO were males, which is due to the fact that ocular injuries are more prevalent among males. According to Park et al., [15] ocular injuries caused by major trauma are more common in men, with an incidence rate of 81.7%. Moreover, most SO cases mentioned in the literature report symptoms occurring within one year after the incident, as observed in our study [10, 16]

Even though there is no consensus on SO treatment, it is widely recognized by experts that recognizing and treating the condition promptly is crucial. The key to controlling inflammation and maintaining good visual outcomes is initiating immunosuppressive treatment using systemic steroids [17]. However, steroid therapy has risks, including cataract formation, diabetes mellitus, hypertension, adrenal insufficiency, and osteoporosis [18]. Jonas et al. [19] reported on a patient with SO who developed severe Cushing’s disease after long-term treatment with systemic steroids, including steroid-induced diabetes mellitus, arterial hypertension, and obesity. To improve the prognosis, a combination of steroids, antimetabolites [20], or biologic immune modulators [21] is now commonly used at the onset of the disease. In our study, all patients received systemic steroids at presentation, and in six cases (86%), MTX, Azathioprine, mycophenolate mofetil, and TNF-α inhibitors were added to control inflammation.

Several studies have discussed and debated the option of preventive enucleation of the exciting eye. The prevailing theory suggests that enucleation within 2 weeks of the initial trauma can prevent SO [22]. However, controversy still exists on whether enucleation is still beneficial once SO symptoms have begun. According to Lubin et al., [5] enucleation within 2 weeks of symptom onset can improve visual outcomes in the sympathizing eye.

In our small study, no correlation was seen between the visual outcome and the time of enucleation or evisceration. Patient #2 had enucleation within 2 weeks of the onset of symptoms and preserved initial BCVA, whereas patient #5 underwent evisceration within 2 days of symptom onset and experienced a decrease in initial BCVA. However, our findings suggest that it was unclear whether enucleation or evisceration improves the visual outcome of SO, as we have limited data. Nowadays, ophthalmologists are less likely to recommend enucleation as a precaution, as SO is rare, and the affected eye may eventually recover. We observed this in Case 4, who maintained the same BCVA in her exciting eye 7 years after the initial assessment. Therefore, enucleation should only be considered in cases with no potential for vision improvement.

Patients with SO can experience future exacerbations in the sympathizing eye [18]. Previous studies have shown that treatment cessation may have implications for this. Patel et al. [4] found that 25% of their patients relapsed after stopping treatment, with a mean post-cessation period of 131 months. No association was found between exacerbation and age, gender, white blood cell count nadir, or duration of treatment. Gupta et al. and Makley et al. reported that a significant number of patients experienced recurrences or flares of their condition after every attempt to stop steroid treatment [16, 23]. In our study, five patients had a relapsing nature. Three of them (pt#2, 4, and 6) experienced a flare-up after stopping or reducing steroid treatment, and two (pt#5 and 7) experienced flare-ups while on maintenance treatment with systemic steroids. Hence, it is difficult to determine the connection between relapse and stopping treatment. Nevertheless, long-term immunosuppressive therapy is recommended for visual preservation [24].

Nearly half of the patients with SO reportedly have a BCVA of 20/40 or less in their sympathizing eye [17]. In our study, the final BCVA in the sympathizing eye was 20/40 or more in 4 cases (57%). We found a link between the patient’s health status, age, co-morbidities, and secondary complications to their visual outcome. Patients 1–3 were young, healthy, and had a favorable long-term visual condition (Tables 1, 2). Case 4 was 34 years old with Turner syndrome but no health issues at the time of the disease and maintained initial BCVA in BE. On the other hand, cases 5–7 had co-morbidities (DM/HTN/Hyperlipidemia) that may have negatively influenced their visual outcome.

One theory is that controlling blood glucose levels is challenging for diabetic patients on steroid treatment, leading to noncompliance and uncontrolled uveitis or its reactivation. Another hypothesis is that chronic hyperglycemia increases the production of pro-inflammatory cytokines [25], potentially intensifying and worsening inflammatory conditions such as in SO. For instance, studies have suggested that diabetes can worsen outcomes in patients with systemic lupus erythematosus (SLE), causing an increased risk of cardiovascular disease, renal damage, and other complications [26]. More recent data suggested that individuals with diabetes and multiple sclerosis (MS) may experience a more aggressive disease course due to intensified oxidative stress [27]. However, this hypothesis has not been explored in previous publications, and due to the limited number of cases, we cannot confirm or deny its validity. As a result, further research is necessary to investigate this topic.

Complications in patients with SO may include glaucoma, cataract formation, choroidal atrophy, maculopathy, ERD, macular edema, and phthisis bulbi [21]. The frequency of these complications varies among different studies. According to Galor et al., [28] 47% of patients experienced complications at presentation, with 40% developing new complications each year. Makley et al. [16] reported that 70% of cases had sequelae, with cataract formation (47%), secondary glaucoma (43%), ERD (25%), and severe choroidal atrophy (25%) being the most common. In our review, 4 cases (57%) showed complications at presentation, with ERD in the sympathizing eye in 2 cases (29%) and phthisis bulbi in the exciting eye in 4 cases (57%). Cases 1, 2, and 3, only had choroidal atrophic lesions, while Case 4 had additional complications of pigmentary changes in the macula. Cases 5–7 had more severe complications such as posterior synechiae, maculopathy, cataracts, and rubeosis. These results reinforce the hypothesis that pre-existing conditions such as diabetes can worsen inflammation control, resulting in more complications and a less positive visual outcome. This suggests that a patient’s age and overall health can have a direct impact. However, further studies are needed as our review was limited to a small number of patients.

Our study is unique as we have followed up the patients for a mean of 6.8 years between 2002 and 2022, which is longer than most other studies. While Galor et al. and Gupta et al. have reported on long-term outcomes, their follow-up durations were shorter than ours [23, 28]. Makley et al. [16] reported a mean follow-up of 10.6 years. Our extended follow-up is particularly important as SO is an ongoing process with recurrent exacerbations and complications. Therefore, it was crucial to record the clinical outcomes over several years in our review.

Insights into the follow-up periods of patients with SO have been provided in previous articles [16, 23, 28]. However, there seems to be a lack of direct mention concerning the duration after discontinuing treatment and the timeframe during which patients remained without a relapse. Our report calculates a mean (± SD) follow-up period of 28 ± 22.8 months in four patients (pt#1–4) after a drug-free remission period. This information is particularly valuable as it raises an important question about whether patients can successfully discontinue therapy. By further researching the duration of follow-up periods after discontinuing treatment, healthcare professionals can make more informed decisions about the management of SO.

Sympathetic Ophthalmia is a severe sight-threatening condition that follows an ocular trauma or intraocular surgery. The disease responds well to prompt diagnosis and treatment, and recurrences are expected. Since this disease is rare, it is difficult to study, but more research is needed to understand how different treatments and their duration affect the condition. In this study, younger, healthier individuals had better visual outcomes, while older patients with co-morbidities had poorer outcomes. To prevent a relapse, long-term therapy is important, and some cases may require additional use of biological or immunomodulatory agents.