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February 2012

 
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Myopia Doubles the Risk of OAG

Reports dating as far back as 1925 have identified myopia as a possible risk factor for open-angle glaucoma (OAG).1 Now researchers from the Netherlands have assigned a number to that risk.

In a meta-analysis of 11 cross-sectional, population-based studies, they found that individuals with myopia have an approximately doubled risk of developing OAG compared to those without myopia.2

“We conducted the study to clarify the relationship between myopia and OAG,” said lead author Michael W. Marcus, PhD, an epidemiologist with the department of ophthalmology at University Medical Center Groningen. “Myopia and OAG are two important public health problems, but there is conflicting evidence in the literature about their relationship.”

The Dutch researchers found a strong correlation. “We were surprised to see that, in contrast to what has been reported in the literature, there was no large difference between the association of low and high myopia and OAG,” Dr. Marcus said.

Seven of the 11 studies reported risk estimates for both low and high myopia, yielding a pooled odds ratio of 1.77 for low myopia and 2.46 for high myopia. In other words, individuals with high myopia are about 21/2 times more likely to develop OAG than are individuals without high myopia. And low myopes are 13/4 times more likely to develop glaucoma than are those without low myopia.

The 11 studies were culled from a literature search that yielded more than a thousand articles. Many of the studies, such as those on animals or children and those about medications, proved useless for this analysis, Dr. Marcus said. “We included only studies with the same design to reduce methodological flaws in our analyses.” A population-based design is likely to minimize the possibility of selection bias, he said.

The final analysis included more than 48,000 individuals from Asia, North America, Australia, Europe and Barbados. The global reach of the data allowed the authors to generalize their findings to all or most ethnic groups, Dr. Marcus said.

The authors acknowledged that published studies and meta-analyses are subject to publication bias because journals are more likely to publish studies with significant findings than those that yield insignificant results. The authors found no such bias in this study.

The findings still don’t explain why myopia puts individuals at risk for glaucoma. The authors speculate that the answer may be related to myopic eyes’ longer axial lengths and deeper vitreous chambers; such eyes may be more prone to deformation of the lamina cribrosa, a proclivity that may contribute to a glaucomatous optic disc change. But more research needs to be done in order to better understand the pathophysiology underlying the association between the two conditions, they say.

The authors suggest that ophthalmologists take this study’s findings into account when screening patients and making treatment decisions. “Ophthalmologists already incorporate myopia as a risk factor in individualized risk management of OAG,” Dr. Marcus said, “but they should not limit this to high, or even severe, myopia only.”

—Miriam Karmel   

1 Knapp A. Trans Am Ophthalmol Soc. 1925;23:61-70.
2 Marcus MW et al. Ophthalmology. 2011;118(10):1989-1994.

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Retina Report 

Immune Response Derails siRNA Development

Nature loves surprises. So, once again, scientists are pondering an unexpected consequence of throwing a monkey wrench into the genetic machinery of cells.

The latest surprise came from studies of specially designed, double-stranded pieces of RNA called short-interfering RNAs (siRNAs). An international research team led by University of Kentucky ophthalmologist Jayakrishna Ambati, MD, conducted the studies and expected to learn more about a previously described1-3 indirect process in which siRNAs suppress angiogenesis within retinal cells from the outside. siRNAs bind to toll-like receptor 3 (TLR3) on cell surfaces, and the researchers expected to detect that binding process and resulting suppression of angiogenesis.

Instead, they found that the activated TLR3 receptors marshaled an intense immune attack against the siRNA-laden cells—killing them all.

This activation of an innate immune response by siRNA was reported last fall by Dr. Ambati’s group.4 Dr. Ambati is professor and vice chairman of ophthalmology and visual sciences and professor of physiology at the university.

In a series of experiments in mice and in cultured human retinal pigment epithelial (RPE) cells, the group showed that the immune response was independent of the specific gene-silencing structure of a siRNA. Instead, the response occurred only when the siRNAs were exactly 21 nucleotides long. Shorter fragments did not activate the TLR3 receptors, perhaps because a 21-nucleotide chain is the minimum length required to span the receptor and lock onto it, the researchers suggest.

Unfortunately, 21 nucleotides is the standard length of the siRNAs that have been tested as therapies, Dr. Ambati said. He speculates that the immune response his group discovered might explain some of the dead ends encountered in clinical trials of drugs based on RNA interference (RNAi).

“To date, siRNA trials in people with macular degeneration have all been discontinued without any explanation,” Dr. Ambati said. “There’s every reason to expect that the mechanism we found might be involved in the trials’ apparently negative results.”

By 2010, large pharmaceutical companies were retreating after pouring mountains of cash into RNAi efforts. Novartis ended its partnership with industry leader Alnylam (Cambridge, Mass.). Pfizer and Roche abandoned their entire RNAi programs. Several clinical trials were terminated without the release of any data.

Dr. Ambati said the lack of information about what happened in these trials signifies a larger issue for basic researchers and clinicians who study blinding diseases. “In general, when trials are discontinued, the folks who run them very rarely discuss why that has been done,” he said. “In the field of biomedicine in general, there is a growing desire to see data from failed trials so that we can understand why those drugs didn’t work.”

—Linda Roach   

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1 Kleinman ME et al. Nature. 2008;452(7187):591-597.
2 Gu L et al. Exp Eye Res. 2010;91(3):433-439.
3 Ashikari M et al. Invest Ophthalmol Vis Sci. 2010;51(7):3820-3824.
4 Kleinman ME et al. Mol Ther. Oct 11, 2011. [Epub ahead of print]

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Trends in Practice 

Toric IOLs Preferred Over Relaxing Incisions

To implant or to incise, that is the question. Or, at least, it was one question asked about the management of astigmatism during cataract surgery in a recent Academy survey of comprehensive ophthalmologists.

Among those who responded to the survey, more than half prefer or perform only toric intraocular lens (IOL) implants, which can currently correct between approximately 1 D and 4 D of astigmatism at the corneal plane. About 15 percent of respondents perform only peripheral corneal relaxing incisions (PCRIs), whereas a quarter do so only for lesser amounts of corneal astigmatism and use toric IOLs for higher amounts.

Douglas D. Koch, MD, professor of ophthalmology at Baylor College of Medicine in Houston, has had excellent results with PCRIs. “But our use of them has decreased with the advent of toric IOLs,” he said. “We have found that the lenses offer greater predictability for astigmatism of 1.5 D and up, eliminating the surgeon-related variable of the manual cut made with a diamond knife.” And with toric IOLs, patients don’t experience the side effects that can occur with relaxing incisions, including surface irritation or dryness or neurotrophic keratopathy. In addition, the risk of PCRI-related problems rises along with increasing incision length and depth, he said.

Moreover, enhancements, if needed, are often easier to perform with toric IOLs than with PCRIs. Small relaxing incisions usually can be added with a toric IOL, especially if the patient is undercorrected, said Dr. Koch; whereas with PCRI, adding another relaxing incision or extending an existing one can be more challenging and may require long incisions. With either approach, LASIK or PRK is a good option for enhancement, he said.

Will the growing popularity of femtosecond lasers as scalpels change the use of PCRIs? Dr. Koch says that femtosecond lasers will lead to an increase in use of PCRIs because lasers offer several advantages over the diamond knife: 1) much greater surgical precision, 2) the opportunity to titrate the correction by selectively opening incisions postoperatively and 3) the ability to correct lower amounts of astigmatism with incisions that do not penetrate the ocular surface. “These advantages should increase accuracy and decrease complications.”

—Annie Stuart   

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Dr. Koch is a consultant to Alcon, AMO and OptiMedica.

CLINICAL PREFERENCES. To better understand current practices on a number of topics, the Academy surveyed comprehensive ophthalmologists about how they would handle various clinical situations. Each month, EyeNet will feature one question—this month about toric lenses versus relaxing incisions—and ask an expert to provide perspective on the responses.

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Cataract Prevention 

Low Vitamin C Linked to Cataract Formation

In a recent study, a strong association between vitamin C deficiency and cataract formation has been documented among adults in India’s lower- and middle- income population.1

The study involved more than 5,500 men and women 60 years of age or older. Researchers measured plasma vitamin C in all participants, along with other antioxidants such as alpha- tocopherol and beta-carotene. The investigation controlled for lifestyle influences, such as alcohol consumption and tobacco use, nutritional status, blood pressure, midday sun exposure and body mass index. The dramatic inverse relationship between vitamin C depletion and the presence of all types of cataracts was seen in groups from both northern and southern parts of the country. Gender made no difference.

Low levels of vitamin C didn’t seem to impact overall health in observable ways, and the precise mechanism through which depletion might affect cataract etiology remains elusive, said Ravilla Ravindran, MSDO, lead author of the investigation and chairman of Aravind Eye Care System in Madurai, India. He noted that it is not yet established whether lack of vitamin C is a cause, a contributing factor or a trigger for an underlying process that predisposes individuals to developing cataracts.

It is time to determine whether a vitamin C–enriched diet might protect against cataract in a population similar to his study group, said Dr. Ravindran. “We are looking at conducting a prevention study; it is under discussion.”

—Anne Scheck   

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1 Ravindran RD et al. Ophthalmology. 2011;118(10):1958-1965.
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Dr. Ravindran and his coauthors have no financial interest in the subject of this study.

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Cornea Update 

Steroid Benefits Limited in Corneal Ulcers

Does adding topical steroids improve visual acuity in patients with bacterial corneal ulcers?

According to results from the first large, prospective, randomized trial on this question,1 the answer is no, with one potential exception: In a subset of patients—those who had more severe ulcers at baseline—treatment with steroids was beneficial, with these patients gaining an additional average of 1.7 lines. Principal investigator Thomas M. Lietman, MD, professor of ophthalmology at the University of California, San Francisco, said, “These patients tended to have the worst ulcers and a visual acuity of 20/400 before treatment.”

Researchers in the Steroids for Corneal Ulcers Trial (SCUT) enrolled 500 patients at three sites. The majority (485) were treated at the Aravind Eye Hospitals in India; the remaining 15 were evaluated in the United States. Overall, agricultural workers accounted for the largest percentage of study participants, and vegetative matter was the primary source of injury. Baseline visual acuity was similar between Indian and U.S. participants.

The patients were randomized to one of two treatment groups: 1) 0.5 percent topical moxifloxacin plus topical placebo or 2) 0.5 percent topical moxifloxacin plus 1 percent topical prednisolone. The primary outcome measure was best spectacle-corrected visual acuity (BSCVA) at three months.

At the three-month mark, BSCVA was similar between the two groups, as was infiltrate or scar size and time to re-epithelialization, the researchers report. Adverse events did not differ between the treatment groups, Dr. Lietman said, with seven perforations observed in the placebo group, versus eight in the steroid group.

With regard to specific organisms, steroids were associated with significantly worse outcomes in those with Nocardia species, said Dr. Lietman. In contrast, steroid treatment produced a “very modest effect” (a 0.4-line gain) among patients with Pseudomonas, he said. Dr. Lietman and his fellow researchers, including Muthiah Srinivasan, MD, the principal investigator in India, plan to conduct subgroup analyses to explore the treatment effect by organism, he added.

—Jean Shaw   

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1 Srinivasan M et al. Arch Ophthalmol. Oct. 10, 2011. [Epub ahead of print]
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Dr. Lietman reports no related financial interests.

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