The Importance of the Cortical Vitreous in Retinal Disease

Whereas many ophthalmologists consider themselves to be vitreous surgeons, a title more appropriately reflecting the key task of vitrectomy surgery is cortical vitreous surgeons . It is the cortical vitreous membrane, also called the posterior hyaloid surface, that causes retinal pathologic features most often requiring surgical intervention. More specifically, it is vitreous liquefaction and the ensuing posterior vitreous detachment (PVD), in which the cortical vitreous pulls on and then away from the retinal surface, that causes retinal tear, RD, vitreomacular traction syndrome, epiretinal membrane, and macular hole (MH). Interestingly, all of these retinal conditions have a peak age of incidence after 50 years, matching the peak age of incidence of posterior vitreous separation. Thus, these common retinal disorders are all likely to have liquefaction of the vitreous gel as the underlying cause. In fact, Sebag in 2004 has proposed that gel liquefaction in excess of the degree of vitreoretinal dehiscence defines anomalous PVD and that anomalous PVD is the unifying concept in vitreoretinal disease.

The cortical vitreous also plays a key role in the pathogenesis of proliferative diabetic retinopathy (PDR) and diabetic vitreous hemorrhage. Neovascularization of the disc or elsewhere occurs in the presence of an attached cortical vitreous. In the process of PVD, the cortical vitreous membrane elevates the abnormal vessels. The resultant traction may lead to vitreous hemorrhage. Elevated vessels do not grow after PVD. Consequently, some researchers have proposed intentional PVD as a way of preventing PDR in high-risk eyes with severe preproliferative diabetic retinopathy (DR). Is this because the new vessels require the scaffold supplied by the cortical vitreous, or does PVD prevent PDR by some other mechanism? Recent advances in our understanding of the vitreous gel suggest that other mechanisms may be involved.

The Importance of the Gel Vitreous in Nuclear Sclerotic Cataract

Vitrectomy surgery offers compelling evidence that an intact vitreous gel protects against nuclear sclerotic cataract. The statistics are impressive: in patients older than 50 years, nuclear sclerotic cataract requiring cataract surgery develops in up to 95% within 2 years after vitrectomy in one study. For eyes in patients younger than 50 years, the percentage is less than 10%. This difference may be explained by the fact that the younger crystalline lens is more resistant to nuclear cataract or that the younger gel structure just behind the lens not removed by vitrectomy retains a protective function. In a corroborating study, eyes undergoing retinal surgery for epiretinal membrane in which none of the vitreous gel was removed experienced no increase in nuclear sclerotic cataract compared with the fellow, unoperated eye after 5 years of follow-up.

New evidence has emerged that the extent of vitreous degeneration correlates with the development of nuclear sclerotic cataract. In a study of 171 cadaver eyes, Harocopos and associates found that vitreous liquefaction was associated linearly with nuclear sclerotic cataract. This association was independent of age between 50 and 70 years. Through our own observations as ophthalmologists, we all recognize that ocular conditions such as Stickler syndrome include both premature vitreous degeneration and premature nuclear sclerotic cataract. Recently, axial myopia, a condition associated with early onset vitreous liquefaction, has been associated with earlier onset and more dense nuclear sclerotic cataract formation than emmetropic control eyes. Although numerous studies have correlated age-related nuclear sclerotic cataract with various factors such as smoking, diet, and socioeconomic status, one clinical observation given little attention remains constant: eyes with nuclear sclerotic cataract also demonstrate vitreous degeneration. Thus, an intact gel structure may protect against nuclear sclerotic cataract.

The Importance of the Gel Vitreous in Nuclear Sclerotic Cataract

Vitrectomy surgery offers compelling evidence that an intact vitreous gel protects against nuclear sclerotic cataract. The statistics are impressive: in patients older than 50 years, nuclear sclerotic cataract requiring cataract surgery develops in up to 95% within 2 years after vitrectomy in one study. For eyes in patients younger than 50 years, the percentage is less than 10%. This difference may be explained by the fact that the younger crystalline lens is more resistant to nuclear cataract or that the younger gel structure just behind the lens not removed by vitrectomy retains a protective function. In a corroborating study, eyes undergoing retinal surgery for epiretinal membrane in which none of the vitreous gel was removed experienced no increase in nuclear sclerotic cataract compared with the fellow, unoperated eye after 5 years of follow-up.

New evidence has emerged that the extent of vitreous degeneration correlates with the development of nuclear sclerotic cataract. In a study of 171 cadaver eyes, Harocopos and associates found that vitreous liquefaction was associated linearly with nuclear sclerotic cataract. This association was independent of age between 50 and 70 years. Through our own observations as ophthalmologists, we all recognize that ocular conditions such as Stickler syndrome include both premature vitreous degeneration and premature nuclear sclerotic cataract. Recently, axial myopia, a condition associated with early onset vitreous liquefaction, has been associated with earlier onset and more dense nuclear sclerotic cataract formation than emmetropic control eyes. Although numerous studies have correlated age-related nuclear sclerotic cataract with various factors such as smoking, diet, and socioeconomic status, one clinical observation given little attention remains constant: eyes with nuclear sclerotic cataract also demonstrate vitreous degeneration. Thus, an intact gel structure may protect against nuclear sclerotic cataract.

The Importance of the Gel Vitreous in Open-Angle Glaucoma

Vitrectomy surgery also offers highly suggestive evidence that an intact vitreous gel protects against open-angle glaucoma (OAG). When the gel is removed surgically, a substantial percentage of eyes show evidence of OAG if followed up long-term. Chang was the first to demonstrate an increased risk of OAG after vitrectomy surgery. He estimated the risk to be 15% to 20% of eyes with long-term follow-up, suggesting “that up to 30,000 new cases of glaucoma may develop annually in the United States after vitrectomy.” Chang’s observations since have been confirmed. With a mean follow-up of just 4 years, OAG developed in 8 (7.9%) of 101 eyes after vitrectomy surgery. With longer follow-up, that percentage is likely to increase. Interestingly, both studies also found the presence of the crystalline lens to be protective.

Primary open-angle glaucoma (POAG) is associated with conditions that include premature vitreous liquefaction, the absence of a crystalline lens, or both. For example, age is an important independent risk factor for POAG and the extent of vitreous liquefaction increases with age. Although the association of vitreous liquefaction with glaucoma has never been explored formally, it merits further attention. Myopia is a risk factor for glaucoma, although not a strong one. There is a higher incidence of vitreous liquefaction and even PVD in myopia. Other clinical examples are abundant. Aphakia is associated with POAG particularly refractory to treatment. The absence of a crystalline lens and the surgically induced vitreous liquefaction likely are contributing factors. Vitreous loss during cataract surgery in glaucoma patients adversely affects long-term control of IOP. Finally, in children, glaucoma often develops after surgery for congenital cataract, suggesting that the presence of the crystalline lens is protective. Thus, an intact gel vitreous (and crystalline lens) may have some function that protects against POAG.

A New Function of the Gel Vitreous: Consumption and Distribution of Molecular Oxygen

The concentration of ascorbate in human vitreous is remarkably high. In eyes with an intact vitreous gel, the mean concentration of ascorbate is approximately 2 mM. Blood levels are only 50 to 60 μM, a 33- to 40-fold difference. The high level of ascorbate in the vitreous is maintained by a sodium-dependent ascorbate transporter (SLC23A2) in the pigmented layer of the ciliary epithelium. The physiologic purpose of so much ascorbate in human vitreous has received past experimental investigation and speculation, but largely has remained unexplained. Recently, Shui and associates found that vitreous metabolizes molecular oxygen in an ascorbate-dependent manner, thereby regulating intraocular oxygen tension. The vitreous gel, by virtue of its large size and central location within the eye, allows the vascularized retina to be highly oxygenated while protecting tissues that are more sensitive to oxidative stress, such as the lens and trabecular meshwork. Molecular oxygen diffusing into the vitreous from the retinal vasculature is likely to be consumed by ascorbate before it reaches the lens and anterior segment.

Importantly, Shui and associates also found that gel vitreous has a higher concentration of ascorbate and consumes oxygen at a faster rate than liquid vitreous (ie, vitreous gel that has undergone age-related liquefaction or surgical removal). Thus, the gel state of the vitreous is critical. Transvitreal movement of small molecules such as oxygen depends on several mechanisms, including diffusion, hydrostatic pressure, osmotic pressure, convection, and active transport by surrounding tissues. Barton and associates recently showed that the diffusion of small molecules through the vitreous gel occurs at the same rate as through a liquid. The critical difference between oxygen movement in a gel and liquid lies in convection currents or flow within the eye. When the vitreous is mostly in the gel state, oxygen diffusing into the gel from retinal vessels is elevated only near the retinal tissue, as shown by oxygen microelectrode studies in experimental animals. However, when the vitreous liquefies, oxygen from the retinal vessels can be carried away from the retina and distributed throughout the eye by fluid currents generated by movement of the eyes or head. The more that oxygen mixes with the vitreous fluid, the more opportunity it will have to react with ascorbate. Both ascorbate and oxygen are consumed in this reaction. If the active transport of ascorbate into the eye is constant, the net effect of increased mixing with oxygen would be to lower the concentration of ascorbate in the vitreous fluid, slowing the consumption of oxygen and permitting more molecular oxygen to reach the lens. If the crystalline lens is replaced by an intraocular lens, more oxygen also may reach the trabecular meshwork.

This oxygen hypothesis is consistent with the observation that vitreous ascorbate concentration was lower and oxygen tension higher in eyes with vitreous liquefaction or eyes that had undergone vitrectomy. In addition, it is consistent with other recent work in which the presence of the crystalline lens was protective for the long-term risk of postvitrectomy OAG.

This new understanding of vitreous function links vitreous liquefaction to disease processes in which excessive oxygen causes oxidative stress and tissue damage. Nuclear sclerotic cataract is the result of oxidation of proteins within the lens nucleus. There is growing evidence that oxidative stress may damage the cells of the trabecular meshwork as well as induce apoptotic neuronal cell death, two important mechanisms of OAG. An interesting corollary of this oxygen hypothesis is that vitreous liquefaction or surgical removal and the subsequent elevation in intraocular molecular oxygen may benefit ischemic retinal disease.