Hemorrhagic Occlusive Retinal Vasculitis (HORV) is a unique retinal vasculitis that occurs after intraocular vancomycin administration during cataract surgery. It was formally reported and named by Witkin et al. in 2015.
Retinal vasculitis is an inflammatory disease that threatens visual function, where perivascular inflammation leads to vascular occlusion. 1) HORV is distinguished among these as a subtype with a clear trigger: intraocular vancomycin.
The main epidemiological features of HORV are as follows.
HORV is an extremely rare complication, reported only in cases where intraocular vancomycin was used. It does not occur without vancomycin. Currently, routine use of vancomycin for endophthalmitis prophylaxis is strongly discouraged. 2)
HORV often shows no abnormalities on the first postoperative day with undilated examination; characteristic fundus changes appear several days later.
Fundus Findings
Sectoral intraretinal hemorrhages: Appear in areas of nonperfusion along small veins. The peripheral retina is affected in all cases.
Venous sheathing: Reflects accumulation of inflammatory cells around peripheral small veins.
Anterior chamber and vitreous inflammation: Mild to moderate. No hypopyon and almost no corneal edema.
No venous changes: No venous dilation or tortuosity. An important distinguishing feature from CRVO.
Imaging Findings
FA (Fluorescein Angiography): Sectoral vasculitis and vascular occlusion corresponding to hemorrhages. Marked late hyperfluorescence due to vascular leakage. 1)
OCT: Hyperreflectivity and thickening of the inner retina. In advanced cases, inner retinal thinning secondary to macular ischemia is seen in both eyes. Rarely CME (cystoid macular edema). 1)
In severe cases, macular ischemia is added, leading to irreversible visual impairment. 1) 56% of patients rapidly progress to neovascular glaucoma. 3)
Suspect HORV if sudden painless vision loss occurs within a few days to 2 weeks after surgery. Important clues include a normal fundus on postoperative day 1, and absence of pain or hypopyon (differentiating from endophthalmitis). See also “Diagnosis and Examination Methods” section.
The main cause of HORV is intraocular vancomycin administration during cataract surgery. The route of administration is predominantly intracameral bolus. 3)
Diseases causing retinal vasculitis are broad, including those secondary to infections, tumors, systemic inflammatory diseases, and rarely idiopathic cases. 1) HORV is distinct from these, being a specific drug-induced type.
Other triggers besides vancomycin include reports of occlusive retinal vasculitis after intravitreal injection of brolucizumab (anti-VEGF drug). 1)
A comparison of alternative antibiotics is shown below. Selection based on endophthalmitis prophylaxis efficacy and HORV risk is important. 3)
| Antibiotic | OR for endophthalmitis prophylaxis | HORV risk |
|---|---|---|
| Vancomycin | 0.09 | Yes (not recommended) |
| Cefuroxime | 0.29–0.30 | No |
| Moxifloxacin | 0.26–0.29 | No |
It has only been reported in cases where intraocular vancomycin was used. It does not occur without its use. The risk is particularly high in patients with a history of penicillin allergy or when HORV has occurred in the fellow eye of the same patient.
Diagnosis is based on the diagnostic criteria established by the ASRS/ASCRS Task Force. HORV is diagnosed when the following conditions are met.
Important diseases for differential diagnosis are listed below.1)
| Disease | Difference from HORV |
|---|---|
| Endophthalmitis | Hypopyon present, severe pain |
| Viral retinitis | Necrotic changes, virus positive |
| CRVO | Venous dilation and tortuosity present |
| Intraocular lymphoma | Vitreous opacity predominant, systemic workup needed |
HORV is characterized by no pain, mild posterior uveitis, no hypopyon, and a normal fundus on postoperative day 1. Endophthalmitis presents with pain, hypopyon, and marked vitreous opacity. Misdiagnosing HORV as endophthalmitis and administering additional vancomycin leads to severe worsening.
Treatment for HORV is centered on suppressing inflammation, managing neovascularization, and treating macular edema.
Steroid Therapy
Systemic steroids: Oral prednisone is used as first-line treatment to achieve early suppression of inflammation.
Local steroids: Sub-Tenon injection of triamcinolone 40 mg followed by transition to oral steroids has also been reported. 1)
Anti-VEGF and PRP
Intravitreal anti-VEGF injection: Performed early to manage neovascularization and macular edema.
Panretinal photocoagulation (PRP): Essential for prevention and treatment of neovascular glaucoma. Performed early if there are extensive non-perfusion areas.
Wang P et al. (2021) reported a 76-year-old male (visual acuity 2/200, vitreous hemorrhage, NVD) who received sub-Tenon triamcinolone 40 mg injection followed by oral prednisone. After 3 months, visual acuity improved to 20/300, with regression of optic disc neovascularization and resolution of vitreous hemorrhage. 1)
Visual prognosis is generally poor. Complete recovery is rare if macular ischemia is irreversible. 56% of patients progress to neovascular glaucoma. 3) Early combination of steroids, anti-VEGF agents, and PRP may lead to some improvement, but functional visual recovery depends on the extent and severity of the lesion.
The pathogenesis of HORV has not been fully elucidated, but a type IV hypersensitivity reaction (delayed-type hypersensitivity) is presumed to be the main mechanism.
Histological examination of enucleated eyes has reported the following:
In ICI-associated occlusive retinal vasculitis, pathological features include disruption of the blood-retinal barrier, CD4+ T cell-mediated lymphoplasmacytic infiltration, and upregulation of vascular endothelial adhesion molecules. 4) This shares aspects with the T cell-dominant inflammatory process in HORV, potentially contributing to understanding the universal mechanisms of vasculitis.
The ultimate cause of visual impairment is macular ischemia due to inflammation and thrombus formation, leading to irreversible inner retinal damage. 1)
The HORV registry established by the American Society of Retina Specialists (ASRS) and the American Society of Cataract and Refractive Surgery (ASCRS) is advancing case accumulation and epidemiological analysis. 2) Through this database, the overall picture of HORV incidence, risk factors, and prognosis is becoming clearer.
Investigations into alternative drugs that maintain endophthalmitis prophylaxis efficacy while avoiding HORV risk are ongoing. Although the odds ratios for cefuroxime and moxifloxacin (0.26–0.30) are higher than that for vancomycin (0.09), they are being reevaluated as safe profiles that do not cause HORV. 3)
Occlusive retinal vasculitis has also been reported after intravitreal injection of the anti-VEGF agent brolucizumab, suggesting that similar pathology may be induced by drugs other than vancomycin. 1) Elucidation of the mechanism and preventive measures remains a challenge.
Research on retinal immune-related adverse events due to immune checkpoint inhibitors has detailed the CD4+ T cell-dominant vasculitis mechanism. 4) Comparative studies with HORV are expected to lead to a unified understanding of drug-induced retinal vasculitis pathophysiology and the exploration of novel therapeutic targets.
