Sympathetic ophthalmia (SO) is a rare autoimmune disease that causes bilateral granulomatous panuveitis following perforating ocular trauma or intraocular surgery in one eye. Trauma or surgery exposes uveal tissue to the immune system, triggering an autoimmune reaction against melanin proteins.
The injured or operated eye is called the exciting eye, and the contralateral eye is called the sympathizing eye. This concept has been known since the time of Hippocrates, with the earliest literature dating back to the 1500s. The modern concept was established by Mackenzie in the 1840s. 8)
| Cause | Incidence | Notes |
|---|---|---|
| After penetrating ocular trauma | 0.2–0.5%4) | More common in males (proportional to trauma) |
| After surgery involving perforation of the eyeball wall | 0.01–0.05%4) | More common after multiple surgeries |
| After vitreoretinal surgery | 0.01–0.06%7) | UK/Ireland prospective survey |
There is no racial difference, and it occurs in various age groups. A prospective surveillance in the UK and Ireland by Kilmartin et al. (2000) confirmed that it is an extremely rare disease with an annual incidence of 0.03 per million population.7)
The interval from injury to onset is most commonly 2 weeks to several months. A retrospective study of 32 cases by Chan et al. (1995) reported a range of 5 days to 66 years, indicating the possibility of onset after a long period.5) In recent years, due to improvements in surgical instruments and techniques resulting in smaller incisions, postoperative cases have been decreasing.9)
Virtually any intraocular surgery can be a cause. It is particularly common after multiple surgeries such as retinal detachment repair and vitrectomy. Cyclodestructive procedures are reported to have a slightly higher incidence. With recent small-incision vitrectomy (25–27G), the incidence is extremely low. 9)
In the early stage, headache, hearing loss, tinnitus, and bilateral visual loss and metamorphopsia appear. Decreased near vision is often an early symptom.
Extraocular symptoms include meningeal irritation (headache, nausea, nuchal rigidity), inner ear symptoms (sensorineural hearing loss, tinnitus, vertigo), and skin symptoms (vitiligo, alopecia, poliosis). These may present the same extraocular findings as Vogt-Koyanagi-Harada disease.
Acute Phase Findings
Anterior segment: Mutton-fat keratic precipitates, anterior chamber inflammation (cells, flare), posterior synechiae, Koeppe/Busacca nodules.
Posterior segment: Optic disc hyperemia and swelling, serous retinal detachment, choroidal thickening, vitreous opacities.
Dalen-Fuchs nodules: Yellowish-white nodules between the retinal pigment epithelium and Bruch’s membrane (a pathological feature shared with Vogt-Koyanagi-Harada disease).
Recovery and Chronic Phase Findings
Sunset glow fundus: Fundus changes due to depigmentation of the choroidal melanin.
Multiple peripheral patchy atrophic lesions: Occur frequently during the convalescent stage.
Secondary cataract and secondary glaucoma: Caused by chronic inflammation and steroid use.
Intraocular pressure may be elevated due to inflammatory glaucoma or decreased due to ciliary body dysfunction. Large cohort studies report that visual acuity of 20/200 or worse occurs in approximately 30–40% of patients at the final visit. 4)
The pathology is the same as Harada disease, but the triggering event differs. Harada disease has no preceding ocular trauma and has a higher rate of systemic findings (cerebrospinal fluid pleocytosis, skin symptoms). In Harada disease, posterior findings precede anterior inflammation. In sympathetic ophthalmia, trauma or surgical scars in the exciting eye are key to diagnosis.
The pathology of sympathetic ophthalmia is considered identical to that of Vogt-Koyanagi-Harada (VKH) disease. Ocular trauma or surgery exposing the uvea triggers recognition of uveal tissue by the systemic immune system, leading to a T-cell-mediated autoimmune disease against self-melanin proteins.
Main risk factors:
Immune checkpoint inhibitor (ICI)-related sympathetic ophthalmia: Cases of recurrence after pembrolizumab administration have been reported. Particular caution is needed in patients with a history of ocular trauma and malignant tumors. 2)
Diagnosis is made comprehensively based on a history of penetrating ocular trauma or intraocular surgery, ocular findings, imaging findings, and extraocular symptoms. Even if the trauma history is unclear, scar traces on the eyeball during examination can provide diagnostic clues.
| Differential Disease | Differences from Sympathetic Ophthalmia |
|---|---|
| Harada Disease (VKH) | No history of trauma. High rate of systemic findings (CSF, skin). 3) |
| Sarcoidosis | Pulmonary lesions, elevated ACE. Bilateral hilar lymphadenopathy. |
| Tuberculous Uveitis | Infectious (QFT/T-SPOT positive). Systemic tuberculosis findings. |
| Syphilitic uveitis | Differentiate by serological tests (RPR, TPHA). |
| Posterior scleritis | Severe eye pain. T sign present. |
Exclusion of infectious uveitis (tuberculosis, syphilis) is essential before starting immunosuppressive therapy. 3)
There is a classic report that removal of the exciting eye within two weeks of injury prevents chronic uveitis in the sympathizing eye and leads to a good prognosis. 5) However, with advances in modern immunosuppressive therapy, cases that do not require removal are increasing. 8) Removal after onset is not thought to improve inflammation in the sympathizing eye. The decision to remove should be made on a case-by-case basis.
Sympathetic ophthalmia shares the same pathology as Harada disease, and treatment follows the VKH protocol. 3) Once infection is ruled out, immunomodulatory therapy should be started promptly.
| Treatment Stage | Drug/Dosage | Notes |
|---|---|---|
| Pulse therapy (first-line) | Methylprednisolone 1 g/day × 3 days IV | Rapid inflammation control |
| High-dose therapy (continued) | Prednisolone 1–2 mg/kg/day orally | Taper after several months of continuation |
| Tapering phase | 60 mg/day → reduce by 10 mg every 4 days → 40 mg/4 weeks → 20 mg/4 weeks → 10 mg/4 weeks → 5 mg/4 weeks | Discontinue over 6 months or more |
High-dose steroids rapidly resolve serous retinal detachment, and a study by Galor et al. (2009) reported that final visual acuity of 20/40 or better was achieved in approximately 50% of cases. 4) Oral steroids should be tapered slowly and discontinued over at least 6 months even without recurrence.
In cases with repeated recurrence during steroid tapering, immunosuppressive drugs are used in combination.
Biologic agents (refractory cases):
There is debate regarding enucleation of the exciting eye. Classic reports suggest that enucleation within 2 weeks of onset may help prevent chronicity in the sympathizing eye. 5) However, with advances in modern immunosuppressive therapy, many cases do not require enucleation. 8, 9) Conditions to consider enucleation:
Recent meta-analyses have not provided consistent evidence for the effect of enucleation after onset, and a neutral judgment is required. 8, 9)
With modern treatment, enucleation is not always necessary. The exciting eye may retain some vision and can sometimes be preserved with appropriate steroid therapy. Enucleation is considered only under specific conditions: when the exciting eye has very poor vision with no hope of recovery and the sympathizing eye has severe inflammation. It is important to discuss with your doctor and make a careful decision.
The pathogenesis of sympathetic ophthalmia overlaps with that of Vogt-Koyanagi-Harada disease in many aspects. The eye is an immune-privileged organ, and antigens within the uvea are normally not easily recognized by the systemic immune system. 1) Perforating trauma or intraocular surgery disrupts this immune privilege, exposing intraocular antigens such as melanin proteins to the immune system.
Immune response:
Histopathological features:
When immune checkpoint inhibitors (ICIs) are used, it has been suggested that a history of exposure to intraocular antigens may trigger unintended reactivation of T cells. 2)
In the VKH subanalysis of the FAST Uveitis Trial (double-blind RCT) by Acharya et al. (2024), MTX showed equal or greater efficacy compared to MMF in improving acute chorioretinal findings (serous retinal detachment, choroidal thickening). 10) Since sympathetic ophthalmia shares the same pathophysiology as VKH, the findings of this trial may be applicable to the selection of immunosuppressive drugs for sympathetic ophthalmia.
OCT-A, which enables quantitative assessment of choriocapillaris blood flow, is being studied as a biomarker to detect potential disease activity after clinical inflammation has subsided. 8) Longitudinal monitoring of choroidal thickness using EDI-OCT is also expected as a predictor of recurrence.
With the widespread use of 27G and 25G vitrectomy, the postoperative incidence has significantly decreased compared to conventional open incision surgery. In a review by Patel et al. (2022), improvements in modern surgical techniques are considered the main reason for the reduced incidence. 9) On the other hand, post-traumatic incidence remains difficult to reduce without trauma prevention, and caution is still required.
Experience with biologics such as adalimumab and infliximab has been accumulating in refractory cases of VKH and sympathetic ophthalmia. 6) However, evidence is mainly from case reports and small series, and drug selection should be individualized based on inflammation severity, recurrence, and systemic comorbidities.
Recurrence of sympathetic ophthalmia after pembrolizumab administration has been reported, posing a new clinical challenge in the era of cancer immunotherapy. 2) Enhanced ophthalmic monitoring is recommended when initiating ICI in patients with a history of ocular trauma.
