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Clinical Update: Retina
A New View of the Vitreous in Ocular Health and Disease
The vitreous gel doesn’t get much respect. In fact, many surgeons consider it more of a nuisance than a vital component of ocular health. But these attitudes are beginning to change, as a relatively small number of researchers work to define the vitreous gel’s role in protecting against several sight-robbing conditions.
“The vitreous gel is the orphan organelle of the eye,” said Nancy M. Holekamp, MD, director of retina services at the Pepose Vision Institute and clinical professor of ophthalmology and visual sciences at Washington University, both in St. Louis. “If you apply for a research grant from the National Institutes of Health, you find study sections on ocular immunology, retina, glaucoma, cataract and anterior segment eye disease—but nothing on the vitreous. So it really has been understudied and overlooked.”
Hard to see, easy to ignore. Michael T. Trese, MD, chief of pediatric and adult vitreoretinal surgery at Oakland University’s William Beaumont School of Medicine in Royal Oak, Mich., agreed. “Physicians have commonly perceived the vitreous as an empty space and not really thought too much about it in terms of retinal disease, in part because it is very difficult to examine either clinically or with an imaging system.”
This dearth of research may be surprising in light of recent insights into the role the vitreous gel plays in nuclear sclerotic cataract, primary open-angle glaucoma, diabetic retinopathy, retinal vein occlusion and age-related macular degeneration.1 Dr. Holekamp noted that the late Belgian-American surgeon Charles L. Schepens, MD, of Harvard Medical School—considered to be the father of modern retinal surgery— tried to engage his students and colleagues in discussions of potential downsides of removing the vitreous gel. “But no one wanted to talk about it,” she said. “Everyone was going full steam ahead because they now had this new surgery that had led to remarkable advances in treating retinal diseases—and until recently, no one had gone back and asked that initial question: ‘What’s the downside?’”
Oxygen consumption by the vitreous. The downside, it turns out, may be significant. Removing the vitreous gel inhibits the eye’s ability to consume and regulate oxygen, according to experiments by Ying-Bo Shui, MD, PhD, and David C. Beebe, PhD, both researchers in the department of ophthalmology and visual sciences at Washington University and colleagues of Dr. Holekamp’s.
Based on these findings, and with informed consent and institutional review board approval in hand, Dr. Holekamp removed 0.3 cc of undiluted vitreous from a patient’s eye. “We put the vitreous in a glass capillary, placed an oxygen probe inside and made it airtight; then we watched as the vitreous gel consumed oxygen,” she said. “That was the first time anyone had demonstrated that vitreous gel has this biochemical property.” Repeating the experiment on vitreous gel from 66 additional patients produced similar results.2 “We now know that this function of the vitreous has huge implications for ocular health.”
Dr. Holekamp and colleagues went on to show that oxygen was consumed by reaction with the high levels of ascorbic acid (vitamin C) in human vitreous.2 In subjects with previous vitrectomy or advanced vitreous liquefaction, ascorbate levels and oxygen consumption were markedly decreased. Previous studies by Dr. Holekamp and colleagues had shown that the oxygen levels in the human vitreous are normally very low (approximately 1 percent), suggesting that these hypoxic conditions are a normal aspect of ocular physiology. Together, loss of the vitreous gel and reduced oxygen consumption exposes the posterior of the lens to increased molecular oxygen.
Among the possible implications is that the vitreous gel has a protective effect in several ocular disease processes involving oxidative damage, including nuclear sclerotic cataracts and open-angle glaucoma.
New Insight Into Cataract Formation
The concept that advancing age causes cataracts is only part of the story. A more complete explanation involves the vitreous, as well. In younger people, oxygen from the retina diffuses into the vitreous gel, where much of the oxygen is consumed. But with aging and an increasingly liquefied gel, oxygen reaches and oxidizes the lens, causing it to discolor, opacify and harden. “So the real causes of age-related nuclear cataracts include vitreous liquefaction, as well as age,” Dr. Holekamp said.
She points to evidence that as many as 95 percent of patients older than 50 years who undergo vitrectomy develop nuclear sclerotic cataracts requiring cataract surgery within two years of vitreous removal.1 Among patients younger than 50, however, the two-year incidence of vitrectomy-related cataracts is less than 10 percent. This age-related difference may be attributable to a younger crystalline lens that is more resistant to cataract formation or to a protective effect of the younger gel structure retained behind the lens—or to a combination of both, she said.
Vitrectomy and POAG
Carla J. Siegfried, MD, professor of ophthalmology and visual sciences at Washington University, has explored the link between vitrectomy and late development of open-angle glaucoma. She traces her interest in the topic to the 2006 Jackson Memorial Lecture given by Stanley Chang, MD, professor and chairman of ophthalmology at Columbia University in New York. Dr. Chang had observed that his patients who underwent vitrectomy and subsequent cataract extraction appeared to be at higher risk of developing primary open-angle glaucoma, and he hypothesized that both cataract and glaucoma development after vitrectomy could be due to oxidative damage.
In his retrospective study, Dr. Chang followed the course of 65 patients (68 eyes) who had undergone vitrectomy (mean time since surgery, 56.9 months; range, 7 to 192 months).3 The patients were classified into three groups: suspected glaucoma, glaucoma that developed after vitrectomy, and preexisting glaucoma. Among glaucoma suspects, the mean IOP was significantly higher in the eye that had undergone vitrectomy than in the fellow eye. In patients with new-onset glaucoma, 23 of 34 eyes (67.6 percent) developed glaucoma only in the eye that had undergone vitrectomy, and the time to development of the condition was longer in phakic eyes than in nonphakic eyes (a mean of 45.95 months versus 18.39 months, respectively). Moreover, the study participants who had preexisting glaucoma required more antiglaucoma medications to control intraocular pressure in the eye treated with vitrectomy than in the eye that did not undergo the surgery.
Koreen and colleagues conducted a subsequent case-control study to estimate the incidence of and risk factors for the development of late-onset open-angle glaucoma following vitrectomy. 4 In their analysis of 285 eyes (274 patients), the researchers found that 11.6 percent of patients developed glaucoma after vitrectomy. In a subgroup analysis, however, the risk was 1.4 percent in phakic eyes compared with 15 percent in nonphakic eyes (p = 0.001), revealing that lens extraction is an important risk factor for the development of late-onset open-angle glaucoma after vitrectomy.
Oxygen distribution in the eye may be crucial. Building on Dr. Chang’s work, Dr. Siegfried and her coworkers explored oxygen distribution within the eye and its effects on the development of glaucoma after vitrectomy. Dr. Chang’s observations “struck a chord with us,” said Dr. Siegfried.
In response, she and her colleagues recorded oxygen distribution with a fiberoptic probe in patients undergoing surgery for cataract, glaucoma or retinal disease.5 They measured oxygen partial pressure (pO2) beneath the central cornea, in the mid-anterior chamber and in the anterior chamber angle. For pseudophakic patients or those who were scheduled for cataract extraction, pO2 also was measured in the posterior chamber and near the lens.
The researchers found that eyes that had undergone vitrectomy had significantly increased pO2 in the posterior chamber. Prior cataract surgery was also associated with significantly elevated pO2 in the posterior chamber and in front of the intraocular lens. Eyes that had undergone both vitrectomy and cataract surgery showed increased pO2 in the posterior chamber and anterior to the IOL, as expected, and pO2 doubled in the anterior chamber angle. These observations led them to propose that long-term exposure to increased molecular oxygen damaged the cells of the trabecular meshwork, leading to increased outflow resistance and glaucoma.
Implications for Practice
Intravitreal drug distribution. Dr. Trese points out that a growing understanding of the vitreous gel raises some interesting questions about commonly performed procedures. “We inject various drugs into the vitreous cavity, and we try to judge their effects based on the results of randomized, prospective, controlled clinical trials,” he said. “But, in a way, the data set we have is a little incomplete because even though there may be a question in the examination forms about ‘Is the vitreous attached or detached?’ it may be very hard to tell clinically.
“We have some very simplistic clinical signs that we use, such as ‘Is a Weiss ring present?’” he continued. “If there is, we assume that the vitreous is separated from the retina. But that may not be the case in totality, or it may be that some of the vitreous is left along the retinal surface. The question then becomes, ‘Does that affect the drug’s ability to penetrate the retina or the subretinal space?’ And does this alter the period of time that the drug will remain in the eye, with the vitreous acting as a reservoir for drug delivery?’” Dr. Trese added that ophthalmologists’ increasing reliance on intravitreal injections to treat vitreoretinal diseases makes understanding the relationship between the vitreous and the retina even more critical.
Enzymatic drugs on the horizon. He noted that, in the not-too-distant future, some vitreoretinal diseases will likely be treated enzymatically, an approach also known as pharmacologic vitreolysis. “Then our thinking can be expanded because you avoid the risk and expense of vitrectomy. I think—and hope—that this will stimulate imaging-technology companies to find ways to image more of the vitreous and will get more people thinking about the biochemical effects of the vitreous in the vitreous cavity—particularly at the vitreoretinal juncture.”
Dr. Siegfried added that any therapeutic approach that creates a posterior vitreous detachment may also expose the lens to higher oxygen and lead to more nuclear sclerotic cataract, indicating the need to find novel ways to protect the lens from oxygen exposure.
Possible relevance to diabetic retinopathy treatment. Diabetic retinopathy is likely to be at the top of the list for enzymatic treatment. “This is something that clinicians have been very aware of for decades, and yet the manipulation of the vitreous in diabetes has generally been reserved for tractional retinal detachment or for bleeding into the vitreous, and not so much for earlier disease,” Dr. Trese noted. “This is despite the fact that a substantial amount of evidence indicates that changes in the retina occur after a very short period of time in diabetic retinopathy. By the time these changes become visible clinically, a long pattern of change in the retina has already occurred.
“With a disease like diabetic retinopathy, manipulating the vitreous might be a mode of management that could be preventive. A lot of work needs to be done to prove that, but it’s a really exciting new area.”