We thank Sangtam & colleagues1 for the interest in our case report on the utilization of intravitreal becacizumab (Avastin) for anterior segment ischemia following ablative laser for aggressive posterior retinopathy of prematurity (ROP).
Eyes of neonates with active ROP and significant ischemia can manifest two forms of prominent iris vessels, either engorgement of the preexisting tunica vasculosa lentis (TVL) or the formation of iris neovascularization (rubeosis or NVI). In some severe cases both conditions can coexist. We have used fluorescein angiography in a series of neonates with recalcitrant ROP to further evaluate these iris vessels. They were distinguishable, in that the TVL was a web of distinct vessels anterior and posterior to the lens, whereas NVI was a finer lacy or fibrillar network that usually concentrated at the pupillary margin. Both types of vessels manifested heavy fluorescien leakage in the late frames.
It has been our experience that many eyes with aggressive ROP and unmitigated vascular endothelial growth factor (VEGF) activity will have both an engorged prominent TVL as well as NVI by 36 weeks post-conception when most lasers are performed. These vessels may wane in response to ablative therapy or become more active in eyes with persistent ischemia. Iris neovascularization in particular may not be well recognized until it becomes florid, but can manifest and be detected early in ischemic ROP. In fact, we have witnessed it developing in conjunction with retinal neovascularization within a matter of a few days in particularly devastating forms of ROP. We believe this is different from other retinal vasculopathies of adults in which rubeosis is a sign of chronic ischemia "and takes months to develop. In our patient rubeosis was likely to have been present at threshold, diminished in response to ablation and then returned in a more aggressive presentation one week later in the setting of anterior segment ischemia."
The reports by Lambert et al.2 and Kaiser et al.3 were instrumental in recognizing the distinct clinical entity of anterior segment ischemia. The authors did not suggest that eyes were monitored closely for NVI at close intervals, they only suggest that it was clinically present as part of a syndrome that included hypotony and cataract that was apparent at approximately one month post laser. Thanks to their early descriptions and newer imaging technology, we can now follow patients with severe disease more closely and detect potential complications of laser earlier.
Furthermore, we would like to caution readers that ROP has great phenotypic variations that probably relate to geographic, genetic and nutritional factors. As we have previously described,4 ROP in India typically differs from that seen in the United States. The former is more likely to present in an older child with less plus disease and more arterio-venous malformations. ROP in India may be more related to oxygen toxicity than ROP seen in the United States. It is likely that the onset and evolution of NVI in ROP is also different in these distinct populations.
Although we cannot prove the therapeutic effectiveness of bevacizumab in a single case report, the authors were impressed by the prompt reversal of disease progression in response to the intravitreal injection. The eye involved was much worse than the fellow eye, with evolution of hypotony and NVI leading to anterior membranes; based on our experience and literature reports, phthisis was imminent. The dramatic recovery suggests that the bevacizumab injection had a positive influence. We do not suggest that prolonged topical steroids and cycloplegics would not have helped the eye to gradually turn around, as occurred in the fellow eye, but we believed this to be unlikely. The experience mimics that observed in refractory ROP eyes with vascularly active retinal detachments that were treated with intravitreal triamcinolone prior to vitrectomy which we have previously described.5 Since the description of this report, one of us (KAT) has had an experience with a second neonatal eye with anterior segment ischemia that also showed improvement after intravitreal bevacizumab, but ultimately also required vitrectomy and lensectomy and oil injection to reverse the hypotony and proliferation.
We do emphasize and reiterate the concept that care should be taken in using suppressors of VEGF in precious babies with immature organs. Findings of studies for age-related macular degeneration, diabetic vascular disease and vascular occlusion cannot be generalized to neonates with ongoing retinal development; we cannot predict how VEGF blockade will affect these eyes. We do concur that carefully monitored clinical studies will provide information that is most meaningful to our patients.
1. Shah PK, Narendran V, Tawansy KA, Raghuram A, Narendran K. Intravitreal bevacizumab (Avastin) for post laser anterior segment ischemia in aggressive posterior retinopathy of prematurity Indian J Ophthalmol. 2007;55:75–6
2. Lambert SR, Capone A Jr, Cingle KA, Drack AV. Cataract and phthsis bulbi after laser photoablation for threshold retinopathy of prematurity Am J Ophthalmol. 2000;129:585–91
3. Kaiser RS, Trese MT. Iris atrophy, cataracts and hypotony following peripheral ablation for threshold retinopathy of prematurity Arch Ophthalmol. 2001;119:615–7
4. Pons ME, Shah P, Lee H, Narendran V, Tawansy KA. Comparison of Threshold ROP in Southern India and Southern California Invest Ophthalmol Vis Sci. 2005;46:E–Abstract 4103
5. Tawansy KA, Lakhanpal RR, deJuan E Jr. Intravitreal triamcinolone for severe ROP refractory to laser ablation: one year results Invest Ophthalmol Vis Sci. 2005;46:E–Abstract 3493