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November/December 2005

News in Review
A Look at Today’s Ideas and Trends
By Linda Roach, Contributing Writer
Edited by Brian A. Francis, MD

• Beware RLE in Highly Myopic Patients
• Leber’s Patients May See the Light in New Trial
• Microarray Screens for Many Disease Genes
• Executive VP Honored

Beware RLE in Highly Myopic Patients

Although middle-aged—or younger—patients with high myopia might be eager to undergo refractive lens exchange, ophthalmic surgeons should weigh their risk of postoperative retinal detachments, a small chorus of voices is beginning to warn.

At the Academy’s 2005 Annual Meeting, it was common for presenters to speak enthusiastically about visual results in patients in their 40s and 50s who had one of the new presbyopia-correcting IOLs implanted bilaterally. But some tempered the enthusiasm with a reminder: The risk of retinal detachment after clear lens exchange increases, perhaps as much as seven or eight times, in high myopes compared with the general cataract population.

Emanuel S. Rosen, MD, reported on his meta-analysis of studies since 1994 looking at detachment rates after routine cataract surgery or refractive lens exchange in myopic eyes. He found rates as high as 8.1 percent, which echoed the findings of the only prospective study of refractive lens exchange in eyes more than –12 D.1 That compares to a retinal detachment risk of 1.2 percent in the general cataract population, according to Dr. Rosen’s estimates. Dr. Rosen is visiting professor of vision sciences, University of Manchester, England.

Retinal Detachment
Caption: Risk of retinal detachment is high in myopes who undergo refractive lens exchange could be as high as 8.1 percent, according to one meta-analysis.

“I’m concerned that some surgeons might be moving too quickly to do refractive lens exchange in highly myopic patients,” noted Deepinder K. Dhaliwal, MD, associate professor of ophthalmology at the University of Pittsburgh. “And if so, then in a few years we’ll see these patients developing retinal detachments that they might not otherwise have suffered.”

The various studies Dr. Rosen reviewed show that male gender, younger age and higher degrees of myopia all raised the risk of retinal detachment. These last two factors are widely attributed to retinal traction as the younger, healthy vitreous moves forward to compensate for volumetric changes caused by lens extraction. These changes would be larger in high myopes because of their longer axial length, he said. Assuming no intraoperative mishaps, the riskiest refractive lens exchange surgeries would be in male myopes under 45 years of age and with an axial length greater than 25 millimeters, said Dr. Rosen.

Stephen S. Lane, MD, clinical professor of ophthalmology at the University of Minnesota, said he wouldn’t want to replace a clear lens with an IOL unless the myopic patient’s refractive error was 6 D or less. Hyperopes represent the best possible patients for refractive lens exchange because of their short eyes, he said. “There are going to be the more aggressive physicians who will be willing to do a lens exchange for high myopes,” Dr. Lane said. “Others are going to say, ‘I just don’t think it’s the best treatment option at this time.’”

For nonmyopic eyes, the retinal detachment risk appears to be vanishingly small. Kevin Lee Waltz, MD, an Indianapolis eye surgeon, reported zero retinal detachments in a group of 460 emmetropic and hyperopic eyes with refractive lens exchange, during a mean follow-up of 39 months.2

Nonetheless, all patients undergoing lens exchange need to be warned that they might be trading refractive correction for an increased risk of retinal detachment, Drs. Lane and Rosen said. “All patients, especially myopes, should be followed more closely. They should be made aware of the signs and symptoms of a retinal tear,” Dr. Lane said.

1 Colin, J. et al. Ophthalmology 1999;106(12):2281–2284.
2 “Absence of Retinal Detachment After Refractive Lens Exchange in an Emmetropic and Hyperopic Population,” presented at Refractive Surgery Subspecialty Day, Oct. 15, Chicago.

Retina Update

Leber’s Patients May See the Light in New Trial

A mystery molecule that is crucial for restoring light sensitivity to bleached photopigment has been discovered—hiding in plain sight.

“It is a protein that all of us had known about for years,” said Gabriel H. Travis, MD, professor of ophthalmology and biological chemistry at the University of California, Los Angeles, and lead researcher on the project.

The protein Rpe65 is the most abundant found in normal retinal pigment epithelium, which is the site of visual chromophore regeneration, Dr. Travis said. Biochemists long have known that regeneration depends on an unidentified enzyme, which converts esters of vitamin A (all-trans-retinyl palmitate) to 11-cis-retinol, the precursor of the visual chromophore in rhodopsin.

But, several years ago, Rpe65 was mistakenly ruled out as this long-sought isomerase in the visual cycle. Problems with biochemical assay techniques had masked its presence, he said.

In a series of experiments reported in Cell,1 the UCLA team designed a better assay of isomerase enzyme activity. This allowed them to perform an unbiased screen of bovine RPE and pinpoint the isomerase gene and its protein.

After the researchers recovered from their surprise at the isomerase’s identity, they realized that their “treasure” also would be golden to clinicians.

That’s because a lack of Rpe65 is a known cause of the blinding disease Leber’s congenital amaurosis, in which a child’s photoreceptors appear healthy but don’t function. The group’s discovery neatly explains why: Without Rpe65, photoreceptor cells lack regenerated visual pigment, and hence cannot detect light.

An NEI clinical trial of gene therapy on Leber’s patients is ready to start. A normal copy of the RPE65 gene contained within a harmless virus will be injected into the eyes of these patients.

“But some clinicians have expressed concern about the idea of giving patients a gene for a protein whose function isn’t known,” Dr. Travis said. “I was at a meeting a couple of years ago where a scientist stood up and said, ‘You biochemists have got to figure out what Rpe65 is doing. We are on the verge of treating Leber patients by gene therapy and we have no idea what the normal Rpe65 protein does!’”

Now, they know.

1 Minghao, J. et al. Cell 2005;122: 449–459.

Eye on Research

Microarray Screens for Many Disease Genes

Thanks to genetic science, ophthalmologists know that at least 18 faulty genes can cause autosomal recessive retinitis pigmentosa. The information’s clinical usefulness so far, though, has lain mainly in being able to tell members of affected families which of them have genes for their family’s variant of recessive retinitis pigmentosa.

So clinicians must use fundus findings, visual field testing and electroretinograms to try to answer newly diagnosed patients’ most urgently asked question: Will my disease progress quickly, slowly or not at all?

A first step toward being able to give gene-specific answers was announced this fall by scientists at the University of Michigan’s Kellogg Eye Center. They designed a DNA sequencing microarray that, with a single test, can find mutations at 11 known retinitis pigmentosa autosomal recessive-gene loci. The gene-testing chip is the first technology, in any disease, that uses a single platform to screen simultaneously for mutations in multiple disease genes.

Ultimately, the relative ease of microarray-based screening could make it possible to correlate different retinitis pigmentosa disease courses with the gene mutations, said Kellogg scientist Radha Ayyagari, PhD. (A second microarray chip is planned for the remaining known retinitis pigmentosa genes.)

“We see many different phenotypes with RP,” Dr. Ayyagari said. “One of the goals of this chip is to study the phenotype-genotype associations, so we can tell a patient, ‘These are the mutations you have, and this is the prognosis for this combination of mutations.’” Dr. Ayyagari was a senior author on the paper reporting the genetic microarray.1

In addition, this approach can detect not just the presence of the 11 known mutations in the 11 retinitis pigmentosa genes tiled on the chip but also any undiscovered mutations in these RP-genes, Dr. Ayyagari added.

“By screening multiple genes on a single platform we will also identify if there are mutations in different genes contributing to the phenotype. That is the strength of this approach,” she said. “This is the kind of information we hope to generate eventually.”

In the future, knowing the genes involved in recessive cases of retinitis pigmentosa also might help guide treatments, said John R. Heckenlively, MD, a specialist in inherited eye disease who also participated in the study.

“Perhaps one patient will benefit from dramatically limiting exposure to sun or high-energy artificial light, and another will use certain vitamins or supplements to stop progression of the disease,” Dr. Heckenlively said. “Obtaining a molecular diagnosis is going to be very important in helping to guide gene-based treatments for patients in the coming years.”

1 Mandal, M. N. et al. Invest Ophthalmol Vis Sci 2005;46: 3355–3362.


Around the Academy

Executive VP Honored

In early November the AMA presented Academy Executive Vice President H. Dunbar Hoskins Jr., MD, with its 2005 Medical Executive Achievement Award. AMA President J. Edward Hill, MD, said, “Under Dr. Hoskins’ leadership, the American Academy of Ophthalmology membership has grown to an impressive 94 percent of ophthalmologists within the United States,” and 7,500 internationally. Dr. Hill also recognized Dr. Hoskins’ achievements during his 12-year tenure in addressing members’ educational, practice management and advocacy needs. He praised Dr. Hoskin’s role in launching the Academy’s Leadership Development Program, and in founding Medem, an online patient-physician communication network.

In turn, Dr. Hoskins said, the Academy is “blessed with an extraordinary staff and physician leaders and volunteers,” and thanked them for their contributions to the organization.