Occlusive Retinal Vasculitis Following Intravitreal Drug Delivery

Intravitreal (IVT) drug delivery now surpasses cataract surgery as the most commonly performed ophthalmic procedure worldwide. In 2020, nearly 23 million IVT injections were given globally,¹ with more than six million done in the United States alone.² While the overwhelming majority of IVT injections involves dosing of vascular endothelial growth factor (VEGF) inhibitors to treat neovascular age-related macular degeneration (AMD), diabetic macular edema (DME), and retinal vein occlusion (RVO), IVT injections are also used to administer antibiotics to either prevent or treat intraocular infection, to deliver corticosteroids to treat inflammatory disease, and occasionally to give other therapeutic agents, such as methotrexate to treat primary vitreoretinal lymphoma.

When performed properly,^3,4 IVT injections are both well tolerated and safe.^5–8 Still, serious complications can occur, including moderate to severe noninfectious uveitis,⁹ bacterial endophthalmitis,⁶ and, rarely, viral retinitis.¹⁰ While post-injection inflammation or infection may be accompanied by varying degrees of retinal vascular leakage, sight-threatening retinal vascular occlusion is generally uncommon. Rare instances of severe, vision-compromising occlusive retinal vasculitis have been described, however, following both intentional and inadvertent intraocular delivery of several agents. These include the aminoglycosides amikacin and gentamycin^11–18 vancomycin^19–23 - which has recently been associated with a rare form of hemorrhagic occlusive retinal vasculitis (HORV); and brolucizumab (Beovu®, Novartis International AG) – the most recently approved anti-VEGF agent, now associated with multiple cases of occlusive retinal vascular disease.^24–26 Although other anti-VEGF agents have not been described to cause occlusive retinal vasculitis,²⁷ Iyer et al. ²⁸ recently reported worsening of initial brolucizumab-induced retinal vascular occlusion following continued treatment with ranibizumab. Given the time delay from initiation of therapy to onset, both brolucizumab²⁸ and vancomycin-associated occlusive retinal vasculitis are believed to be immune-mediated rather than a toxic effect of the drug - although direct evidence establishing an immune mechanism has yet to be provided. Isolated reports of retinal vascular occlusion following inadvertent injection of mitomycin C during anterior segment surgery, ^29–31 a direct toxic effect, and after intentional IVT injection of cefuroxime³² and rituximab³³ have also been described. In this issue of Ocular Immunology & Inflammation (OII), an original article describes a favorable outcome in a patient with HORV following intraocular delivery of vancomycin,³⁴ while one case report³⁵ and two letters to the editor^36,37 discuss the appearance of occlusive retinal vasculitis in the setting of bacterial endophthalmitis, thus highlighting the importance of considering infections in patients who develop such findings in similar settings.

Sodhi et al. ³⁵ retrospectively studied a 68-year-old woman who developed HORV two weeks following intracameral injection of vancomycin for endophthalmitis prophylaxis following the completion of uncomplicated cataract surgery. Once necrotizing herpetic retinitis and post-operative bacterial endophthalmitis were excluded by Polymerase Chain Reaction (PCR) and Gram stain/culture, respectively, the patient was treated with high-dose systemic, periocular, and topical corticosteroids with recovery of best-corrected visual acuity (BCVA) to 20/25. Secondary neovascularization of the iris (NVI) developed and was managed with maintenance intravitreal bevacizumab injections. The authors suggested that their approach generally supported recommendations of the American Society of Cataract and Refractive Surgery (ASCRS) and American Society of Retina Specialists (ASRS) joint HORV Task Force,¹⁹ which included directed testing to exclude both viral retinitis and bacterial endophthalmitis and aggressive local and systemic corticosteroids. While the joint Task Force also recommended early anti-VEGF injections and panretinal photocoagulation to areas of retinal ischemia to minimize the risk of NVI and neovascular glaucoma, both of which are common following HORV, and most patients do poorly even when all recommendations of the Task Force are followed, selected subjects have done well when treated with aggressive corticosteroids without these additional measures.^19,38 Shared clinical characteristics identified by the HORV Task Force included a rapid but delayed onset (mean 8 days; range 1 day to three weeks), often painless, mild anterior chamber and vitreous inflammation, and retinal non-perfusion - typically peripheral and with a predilection for venules producing associated areas of intraretinal hemorrhaging. While early reports postulated that HORV might be an antibody-immune-complex-mediated Type III Delayed Hypersensitivity reaction similar to leukocysoclastic vasculitis or Henoch-Schönlein purpura seen rarely with systemic vancomycin, a more recent clinical-histopathological analysis performed on an enucleated blind, painful eye following HORV failed to identify immune complexes, inflammatory cells, or evidence of leukocytoclastic vasculitis in the neurosensory retina.³⁹ However, histopathological analysis did show marked, chronic, non-granulomatous choroiditis with a necrotic, hemorrhagic vasculopathy in the overlying retina. Immunophenotyping of the choroidal infiltrate showed mostly T-cells, consistent with a drug-mediated Type IV hypersensitivity reaction of the type seen with Stevens Johnson Syndrome or toxic epidermal necrolysis of the skin. A direct drug toxicity would seem improbable given what is typically a delayed onset in HORV.

Greenberg et al. ³⁶ described a case of a 69-year-old woman suspected to have HORV following uncomplicated cataract surgery when she developed decreased vision associated with diffuse intraretinal hemorrhages and retinal vasculitis. There were, however, features atypical for HORV, including aching pain, increased intraocular pressure to 35 mmHg, conjunctival chemosis, corneal edema, and moderately anterior chamber and vitreous inflammation. The ultimate diagnosis of bacterial endophthalmitis was confirmed when anterior chamber and vitreous cultures both grew Staphylococcus epidermidis. Aggressive treatment with intravitreal dexamethasone and antibiotics, including vancomycin, clindamycin, and fluoroquinolones, leads to clinical improvement with a vision at last follow-up of 20/30. The authors emphasized the importance of considering both bacterial endophthalmitis and necrotizing viral retinitis when evaluating patients with features of HORV, particularly in the early post-operative period.^40,41 A similar presentation has been described in cases of bacterial endophthalmitis following IVT injection.^27,42,43

Chen et al.³⁴ retrospectively studied 40 eyes of 40 patients who developed exogenous bacterial endophthalmitis with retinal vasculitis and posterior pole pre-retinal exudates seen over a 10-year period at a tertiary referral center in Taiwan. Preceding events included cataract surgery (n = 30; 75.0%), trauma (n = 5; 12.5%), trabeculectomy (n = 2; 5.0%), and one each (2.5%) for penetrating keratoplasty, pars plana vitrectomy (PPV) and iridoplasty. Vision at presentation was hand motion in 25 eyes (62.5%), light perception in 12 eyes (30.0%), and no light perception in 3 eyes (7.5%). All involved eyes had hypopyon formation and 13 (32.5%) had elevated intraocular pressure (IOP). Pars plana vitrectomy was performed on all patients, either within eight hours of presentation or after 12 to 24 hours of a poor response to vitreous aspiration followed by intravitreal injection of antibiotics. During PPV, eyes were characterized as having either focal or diffuse vasculitis (two quadrants or less vs more than two quadrants), whereas pre-retinal exudates were described either as sparse/discrete or condensed over the posterior pole. Retinal vascular occlusion was noted in some subjects. Patients were injected with dexamethasone, vancomycin, and either ceftazidime or amikacin at the end of the procedure. All eyes had a positive culture, including a 34 (81.0%) that were Gram positive and 8 (19.0%) Gram Negative. The most common isolates included coagulase-negative Staphylococcus (CoNS; n = 16; 38.1%), Enterococcus (n = 8; 19.0%), and Streptococcus sps (n = 6; 14.3%). Follow-up ranged from five to 45 months (mean 12.5 months; median 16.0 months), with BCVA at last visit 20/40 or better in 14 (35.0%), between 20/50 and 20/200 in nine (22.5%), and worse than 20/200 in 17 (42.5%). Uncorrected, univariate analysis identified increased patient age, poor presenting vision, elevated IOP at presentation, non-CoNS microbial isolates, diffuse retinal vasculitis, retinal detachment, use of silicone oil tamponade and visualization of condensed or posterior pole pre-retinal exudates during PPV as predictors of poorer visual outcome. Using multivariate linear regression analysis, only increased IOP at presentation and the presence of posterior pole pre-retinal exudates at PPV retained statistical significance. The authors concluded that these two factors, in particular, may portend worse visual outcomes.

Tabuenca Del Barrio et al.³⁷ described a 13-year-old boy who developed pain and hand motion vision in his right eye associated hypopyon formation, dense vitritis, and retinal vasculitis associated with retinal exudates and intraretinal hemorrhages. The patient was treated initially for positive necrotizing herpetic retinitis with valacyclovir, 2 g three times daily, and ultimately underwent PPV, culture from which grew Haemophilus influenzae. The eye progressed to retinal detachment, requiring repeat PPV and silicone oil tamponade, but vision remained limited to hand motion at last follow-up. A source for the presumed endogenous endophthalmitis was never identified. The case emphasized the importance of considering both viral retinitis and bacterial enophthalmitis in eyes with acute-onset, severe, unilateral panuveitis, and again showed that retinal vasculitis may be a prominent feature in some eyes with bacterial endophthalmitis.

Together, these and related studies call attention to the selected therapeutic agents capable of causing a rare, vision-threatening occlusive retinal vasculitis following either intentional or inadvertent intraocular delivery, including the aminoglycosides amikacin and gentamicin, vancomycin, brolucizumab, mitomycin-C, cefuroxime, and rituximab. They also highlight the importance of considering bacterial endophthalmitis and necrotizing viral retinitis in eyes that develop retinal vasculitis following surgery, IVT injection, or trauma. Although drug-induced retinal vasculitis is often both occlusive and visually devastating, selected cases can do well with prompt diagnosis and management, as demonstrated in the case report of vancomycin-associated HORV in this month’s issue of OII. In contrast, retinal vasculitis that occurs in the setting of endogenous uveitis is most often non-occlusive, mild to moderate in severity, and readily reversible with treatment.⁴⁴

Declaration of interest

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.

Financial conflicts

ETC, RSM, and AJW have no relevant financial conflicts. MZ is a consultant to AbbVie, Alimera, Santen and Gilead.

Acknowledgments

The authors received no financial support for this editorial.