The Penumbra Obscura Stimulates Iris Neovascularisation after Isolated Central Retinal Artery Occlusion

Dear Editor, Jung et al. [1] are to be congratulated on definitively demonstrating what could only be surmised in the past— that intraocular angiogenesis after central retinal artery occlusion (CRAO) occurs in that small proportion of cases wherein retinal reperfusion fails to materialize [2,3]. However, your contributors appear to be unsure as to the mechanism whereby neovascularisation of the iris (NVI) arises after “CRAO alone.” While they reject Hayreh’s [4] assertion that “chronically hypoxic retina ... is totally missing” after what is otherwise called “isolated CRAO” (and implicating ocular ischemia in NVI development due, for example, to carotid arterial stenosis), the crucial link between isolated CRAO and NVI was not elucidated. In reality, there is a perfectly straightforward explanation for NVI after isolated CRAO that entirely resonates with Jung et al.’s findings. A recent review of the electrophysiological data from legacy experiments in primates has shown that a transparent mid-peripheral hypoxic tissue compartment–the “penumbra obscura”–evolves within the inner retina after CRAO (Fig. 1) and surrounds the opacified anoxic infarct in the posterior pole [3]. The penumbra obscura is marginally oxygenated by the choroid and is analogous to the ischemic penumbra that surrounds the infarct core in cerebral stroke. After cerebral arterial occlusion, however, penumbra-to-umbra conversion takes place within approximately 6 hours of ischemia onset, with incorporation of most if not all of the penumbral cortex into the infarct. By contrast, the hypoxic swathe in the retina endures and secretes pro-angiogenic molecules such as vascular endothelial growth factor (VEGF). Furthermore, neovascularisation within the eye is not self-limiting in nature, in contrast to angiogenesis elsewhere, because the (iris) neovascular response is remote from the (retinal) hypoxic source [5]. In other words, the penumbra obscura does not become revascularized as part of the angiogenic process. Although the link between CRAO and NVI is readily apparent, final proof of concept is still lacking (e.g., by demonstration of VEGF secretion from the penumbra obscura in eyes enucleated for rubeotic glaucoma secondary to CRAO). In the meantime, all eyes with complete CRAO and diffuse opacification in the posterior pole should be considered to be “at risk” of intraocular angiogenesis. However, the majority of eyes with CRAO will undergo spontaneous or therapeutic CRA recanalization and inner retinal reperfusion, resulting in hypoxia-to-normoxia conversion within the penumbra obscura and cessation of VEGF secretion. As Jung et al. [1] point out, therefore, documentation of retinal reperfusion by fluorescein angiography (or other means) dictates that close follow-up of the patient for signs of NVI is no longer necessary. Theoretically, the volume of the penumbra obscura (and the risk of rubeosis iridis) will also be reduced if there is associated posterior ciliary arterial occlusion (e.g., due to cranial arteritis) since penumbral (hypo-)oxygenation by the choroid will be compromised. This may help to explain Jung et al.’s [1] observation of eyes with failed CRA recanalization but no NVI. Korean J Ophthalmol 2017;31(2):177-179 https://doi.org/10.3341/kjo.2017.31.2.177