Vascular endothelial growth factor (VEGF) plays an important role in the development of retinopathy of prematurity (ROP). Recently it has been shown that serum VEGF levels are elevated in cases of threshold and stage III ROP. It is thought that VEGF is responsible for an increase in vascular permeability, the suppression of genetically programmed endothelial cell apoptosis, and the promotion of neovascularization in ROP.
With the recognition of VEGF's role, interest has grown in the use of anti-VEGF agents to treat ROP. Reports in the literature have shown the efficacy of primary use of anti- VEGF agents without laser for severe ROP.1,2
We performed a study to evaluate the efficacy and safety of intravitreal injection of bevacizumab without laser as primary therapy in patients with moderate to severe ROP.3
Included in the study were patients with moderate to severe ROP (stage III, threshold, or plus disease in zones I and II). We obtained written consent from the parents, including disclosure of the off-label use of the drug, its unknown safety and efficacy for this indication, and its unknown effects in children.
All patients received a single dose of intravitreal bevacizumab 0.625 mg through a 30-gauge needle after anterior chamber paracentesis under topical anesthesia. The procedure was performed in the operating room with standard aseptic precautions.
Follow-up examinations were performed at postoperative day 1, weekly for 1 month, then monthly for 1 year. Careful systemic and ocular monitoring were performed along with neonatal and pediatric neurological examinations. Outcome measures at 1 year post-injection included progression of ROP and any adverse events including findings on electroretinogram (ERG) or visual evoked potential (VEP).
RESULTS AT 1 YEAR
Of 63 eyes enrolled in the study, 27 have completed
1-year follow-up. Mean birth weight in these infants was
1033 g, mean gestational age at birth was 29.2 weeks, and
mean age at the time of injection was 1.6 months.
All eyes showed complete resolution of severe neovascular plus disease. This was particularly noted in the form of decreases in venous dilatation, arterial tortuosity, and/or dilatation of the pupil. In eyes that had extraretinal fibrovascular proliferation, this became involuted and appeared as a separated, whitish wisp floating in the vitreous. No patient developed any ocular or systemic complications. In all cases, the ERG and VEP were normal at 1 year
A case example can illustrate the typical results in these cases. One infant had severe plus disease (Figure 1) and a small pupil with rubeosis iridis (Figure 2) at presentation. On the third day after intravitreal injection of bevacizumab, the rubeosis is gone (Figure 3), the fibrovascularization has completely disappeared, and the progression of the retinal vasculature can be seen beyond the neovascular tissue into peripheral avascular retina (Figures 4 and 5). No laser therapy was applied. ERG and VEP are normal at 1 year.
DISCUSSION
Based on our results to date, we believe that injection of
an anti-VEGF agent immediately halts neovascularization in
eyes with moderate to severe ROP. It is particularly useful in
progressive or unresponsive rush disease. This approach to
therapy is also advantageous in eyes with rigid pupils or
hazy media, or in sick babies in whom laser would be difficult
to administer. It allows continued anterior growth of the vasculature into previously avascular retina in these
developing eyes.
Pharmacologic treatment with an anti-VEGF agent might also avoid complications that can be seen with laser such as the onset of visual field loss, myopia, amblyopia, cataract, or anterior segment ischemia. Most important, because of the pathogenesis of severe ROP disease, repeat injections are less likely to be needed.
After 1 year follow-up in these 27 eyes, we believe intravitreal injection of bevacizumab is an extremely safe and effective modality of therapy for moderate to severe ROP. It is particularly advantageous in eyes with progressive or unresponsive disease, rush or plus disease, and patients with small, rigid pupils. Primary therapy alone is effective in many cases. Regarding the long-term safety concerns of apoptosis and photoreceptor degeneration, ERG and VEP findings are normal at 1 year.
However, further studies are necessary to determine the best choice of drug, as well as optimal dose and timing, the need for repeat treatments, and the possibility of ocular or systemic complications.
Alay S. Banker, MD, is in private practice at Banker's Retina Clinic and Laser Centre, Ahmedabad, India. Dr. Banker states that he has no financial interest in the products or companies mentioned in this article. He may be reached at +91 79 26569457; or via e-mail at alay.banker@gmail.com.
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