Delayed-Onset Glaucoma Following Intravitreal Bevacizumab in a Preterm Infant with Retinopathy of Prematurity: A Case Report

Dear Editor,

Intravitreal injections of anti–vascular endothelial growth factor (anti-VEGF) agents are widely used in the management of retinopathy of prematurity (ROP). Although these injections often cause a transient intraocular pressure (IOP) elevation, the pressure usually returns to baseline within minutes [1,2]. Sustained IOP elevation after anti-VEGF therapy has been documented in adults [2,3], but there have been no reports of glaucoma requiring surgical intervention following intravitreal anti-VEGF treatment for ROP. Herein, we present a case of delayed-onset elevated IOP and subsequent glaucoma in a preterm infant after off-label intravitreal bevacizumab (IVB) therapy for ROP. Written informed consent for publication of the research details and clinical images was obtained from the patient’s parent.

A premature infant, born at 24 weeks’ gestation with a birth weight of 590 g, had a medical history of patent ductus arteriosus that required oxygen therapy and surgical ligation. Ophthalmic screening at 30 weeks’ postmenstrual age revealed stage 1 to 2 ROP with plus disease in zone I of both eyes and grade 2 tunica vasculosa lentis; both corneas were clear. IVB (0.625 mg) was administered in each eye. Eighteen days after injection, both ROP and plus disease had improved. By 3 weeks after injection, plus disease had resolved; however, mild corneal edema and increased optic nerve head (ONH) cupping were noted in both eyes, despite normal IOP measurements (10/10 mmHg; iCare IC200 tonometer, iCare). One week later (4 weeks after injection), IOP rose to 25/28 mmHg. The right eye showed moderate corneal edema and the left eye exhibited severe corneal edema and opacity (Fig. 1A, 1B). ONH cupping was more pronounced in the left eye. Maximum tolerated medical therapy, including dorzolamide/timolol and latanoprost, was initiated to lower IOP, and the patient was referred to a glaucoma specialist. Combined trabeculotomy and trabeculectomy were performed on both eyes. Intraoperative gonioscopy revealed high iris insertion bilaterally. Postoperatively, corneal clarity and IOP improved. At 4 months after surgery, ROP with plus disease recurred, necessitating repeat IVB injections in both eyes, as laser treatment was not feasible due to corneal haziness. At 6 months, examination under anesthesia revealed clear corneal status in the right eye and Haab striae in the left eye (Fig. 1C, 1D). Cycloplegic refraction showed myopia of −10.5 diopters (D) in the right eye and −6.0 D in the left eye, and spectacles were prescribed. Fundus examination indicated no recurrence of ROP in the left eye, but the right eye demonstrated active retinal neovascularization in zone II, which was treated successfully with laser photocoagulation. By 2 years, IOP normalized to under 15 mmHg in both eyes with no further ROP recurrence.

Fig. 1

Anterior segment photographs under a microscope. (A) Moderate corneal edema in the right eye. (B) Severe corneal edema in the left eye 3 weeks after intravitreal bevacizumab injection for retinopathy of prematurity. (C) Clear cornea in the right eye. (D) Haab striae in the left eye 6 months after trabeculectomy and trabeculotomy.

IOP elevation is a known short-term effect of intravitreal anti-VEGF injections, usually returning to normal levels within minutes [2]. However, sustained IOP elevation has been reported in adults, leading to secondary glaucoma and potential optic nerve damage [1,3]. The exact mechanisms are unknown, but hypotheses include microscopic drug particles accumulating in the trabecular meshwork, leading to inflammation and fibrosis or direct toxic effects on trabecular meshwork cells [3]. Glaucoma can develop in ROP patients due to immature anterior chamber development, ROP itself, or its treatment. Premature patients are susceptible to angle-closure glaucoma due to incomplete trabecular meshwork development and other anterior segment abnormalities [4]. Other mechanisms include neovascular glaucoma, ciliolenticular block glaucoma, and arrested angle development [5].

It remains uncertain whether the changes observed in this case were directly induced by IVB treatment or represented the natural course of congenital glaucoma. Given that the intraoperative gonioscopic findings suggested developmental anomalies, IVB-induced IOP fluctuations may have exacerbated an underlying predisposition.

Notably, the temporal association between IVB administration and clinical findings, such as corneal edema and ONH cupping 3 weeks after injection, suggests a potential contributory role. However, the elasticity of the infant’s sclera and cornea could have initially masked actual IOP elevations. These findings might represent either IVB-induced changes exacerbating a predisposition or the natural progression of congenital glaucoma in an immature anterior chamber.

Early recognition of subtle signs, such as mild corneal edema and ONH cupping, is essential as they may indicate pathological IOP elevations not detected by standard measurements due to the elasticity of the infant’s sclera. Clinicians should closely monitor for glaucoma after IVB treatment in ROP, with prompt intervention to prevent irreversible optic nerve damage. Further evidence is needed to clarify the mechanisms of delayed-onset IOP elevation following IVB in infants with ROP.