American Academy of Ophthalmology Web Site: www.aao.org
News in Review
A Look at Today's Ideas and Trends
Righting Retinal Development in ROP
Omega-3 and omega-6 polyunsaturated fatty acids (PUFAs) are so crucial to newborn babies’ neural and vascular development that these nutrients have been added to baby formula in Europe since 1992 and in the United States since 2002.
But what about infants born prematurely? Their total parenteral nutrition usually contains little, if any, of the essential omega-3 fatty acids. That is despite the fact that, more than a decade ago, some experts in lipid nutrition began suggesting that PUFAs are necessary for normal brain and retinal development.
This hypothesis gained new life this summer when a multinational group of researchers published a study in Nature Medicine showing that supplementing the diet of young mice with omega-3 fatty acids docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) can prevent pathologic angiogenesis in hypoxic retinas.1
If the findings are confirmed in a planned clinical study, this relatively simple nutritional change for preemies might be a way to promote normal retinal development, said study senior author Lois E. H. Smith, MD, PhD, associate professor of ophthalmology at Harvard University and Children’s Hospital Boston. The supplementation should mimic what occurs naturally in utero, she said.
“In the third trimester of pregnancy there’s a massive transfer of omega fatty acids from the mother to the fetus,” Dr. Smith said. “A premature infant loses access to these fatty acids, which it needs for rapid growth of the brain, retina and blood vessels at this stage in development. But the current total parenteral nutrition formulation contains only omega-6 fatty acids, and minimal or no omega-3 fatty acids.”
The most abundant PUFAs in the retina are DHA, an omega-3 fatty acid, and arachidonic acid (ARA), in the omega-6 category. They are located primarily in neural and vascular cell membrane phospholipids. DHA accounts for more than 50 percent of the fatty acids in the photoreceptors and nearly as much in the pre- and postsynaptic membranes. A second omega-3, EPA, is a precursor to DHA and is found in the retinal vascular endothelium.
In their series of mouse experiments, the researchers showed that a higher retinal content of the omega-3 fatty acids, obtained from food, protected young mice from neovascularization after hypoxia. A lower ratio of omega-6 to omega-3 also had a protective effect.
However, the mechanism did not involve rescuing ischemic vessels. Instead, the additional DHA and EPA worked by promoting new growth of healthy replacement vessels, the researchers report. They also reduced the activity of an inflammatory cytokine, tumor necrosis factor-alpha.
“The omega-3-PUFA suppressive effect on retinopathy in the mouse eye is comparable in magnitude to that of treatment with a vascular endothelial growth factor (VEGF) inhibitor, and it is likely to be additive to anti-VEGF therapy,” write the researchers.
The new study’s findings were welcomed by, but hardly surprising to, Michael A. Crawford, PhD, director of the Institute of Brain Chemistry and Human Nutrition, London Metropolitan University. Since the early 1990s, Dr. Crawford has called repeatedly for feeding premature babies more PUFAs than even full-term infants require.
“If you study the blood levels of the preterm infant at birth, you find that there is a huge loss of ARA and DHA,” Dr. Crawford explained. “I think this is really the thing that is underpinning all the membrane disorders we’re seeing in premature babies.”
Custom Contact Lenses for Cone-Shaped Eyes
Surgery, typically corneal transplantation, is the only treatment option for patients with advanced keratoconus who are no longer able to tolerate hard contact lenses.
Now researchers at the University of Rochester are developing a soft contact lens that has the potential to restore normal vision to patients with abnormal corneas. With funding from the NEI and Bausch & Lomb, Geunyoung Yoon, PhD, and colleagues developed a method for customizing soft contact lenses using wavefront technology and a precision lathe for sculpting the front surface of the lens. The results on three eyes are reported in Optics Letters.1
Dr. Yoon, whose degree is in laser physics and optics, was inspired to seek a noninvasive solution for keratoconus patients after observing how profoundly the disease impairs vision. “Without corrective lenses they can’t lead a normal life. That was the main motivation for me,” said Dr. Yoon, who is assistant professor of ophthalmology and biomedical engineering, the Center for Visual Science, and the Institute of Optics, both in Rochester, N.Y.
The tailor-made contact lenses with customized front profiles are designed to neutralize the detrimental effects of the irregular surface profiles of keratoconic eyes and thus correct for specific aberrations. Three trial lenses, each with a different base curve (8.2, 8.4 and 8.6 mm) were tested on each eye. The most stable of the three was selected for design of the individual lenses. Stability is an important quality because it is essential to compensate for shifting of the lenses induced by normal blinking. Greater stability guarantees the lens will return to its original design position for optimal correction.
Corrections with the customized lenses resulted in an average improvement of 2.1 lines in visual acuity, or from 20/48 to 20/29 for a 6-mm pupil, over the use of the conventional spherical and astigmatic corrections alone. Dr. Yoon hopes to bring the concept to a company for commercial development. “I think 10 or 15 eyes would be a good number to demonstrate feasibility,” he said.
Still, the lenses are not for everybody. They are contraindicated in anyone with a damaged cornea, dry eye symptoms or other physiological problems that preclude lens wear. But, he assured, “as long as they can wear conventional soft lenses, they can wear these lenses.”
1 Opt Lett 2007;32(8):1000–1002.
Bevacizumab Beneficial in Radiation Retinopathy
Even when radioactive plaque therapy for a choroidal melanoma eradicates an ocular tumor, radiation damage to previously healthy retinal tissue often causes a slow retinopathy that, when located in the macula, leads to blindness within a few years.
Enter bevacizumab (Avastin). Intravitreal injections of the drug can stabilize, and in some cases improve, the visual acuity of patients with radiation maculopathy, according to a study published in the Archives of Ophthalmology.1
Lead author Paul T. Finger, MD, an ocular melanoma specialist and clinical professor of ophthalmology at New York Eye & Ear Infirmary, sees this preliminary study as important because currently the only treatment for radiation retinopathy is a destructive one, laser photocoagulation. It also isn’t completely effective; fewer than half of the ocular melanoma patients who undergo brachytherapy can see 20/200 or better in the treated eye after five years.
“There’s really no treatment for radiation maculopathy. If you laser the macula, the patient loses vision,” Dr. Finger said.
He explained that he was intrigued by reports that bevacizumab was being used to block ischemia-induced molecules of vascular endothelial growth factor from promoting other types of retinal degeneration. He wondered: Would bevacizumab do the same thing for retinas damaged by radiation?
The study reports on six patients who had developed maculopathy an average of 41.5 months after plaque radiotherapy for ocular melanoma. Intravitreal injections of bevacizumab (1.25 mg in 0.05 ml), spaced six to eight weeks apart, consistently produced a resolution of the patients’ macular edema. In addition, the size and distribution of retinal hemorrhages decreased, microaneurysms closed and vascular permeability decreased. BCVA improved in two patients (20/320 to 20/100, and 20/32 to 20/20) and stabilized in the others (20/20 for two of the patients, 20/25 and 20/80). Four also reported a subjective decrease in metamorphopsia.
Dr. Finger said he has treated another dozen patients since the study, and has found that they follow a common pattern. Patients with less advanced disease reach normal, functional BCVA after treatment, but those with advanced disease—though they do have measurable improvement—stabilize at a poor acuity.
Needles: Thin = Better
Syringes with thinner needles might be more comfortable for patients who face multiple ocular injections of antiangiogenic drugs to treat their retinal diseases, according to a Mayo Clinic study.1
The small proof-of-principle study compared injection performance and patient comfort between a standard 30-gauge needle and a thinner 31-gauge needle (Becton-Dickinson Ultra-Fine II), the size commonly used by diabetics to inject insulin.
Respectively, the needles measure 0.31 mm and 0.26 mm in diameter, compared with 0.41 mm for a 27-gauge needle. However, the 31-gauge needle has 40 percent less flow resistance than either of the other needles, thanks to its design with a thinner wall and a larger lumen, the researchers note.
The four patients judged the 31-gauge injections as more comfortable than 30-gauge. The researchers saw no increase in reflux with the thinner needle.
“Because of increasing use of recurrent intraocular injections in patients with retinal diseases, use of 31-gauge needles over the present 27- and 30-gauge needles may allow patients to have less discomfort and a higher acceptance of these recurrent injections,” the authors conclude.
Eye Screenings at Age 40
The Academy now recommends that adults with no signs or risk factors for eye disease get a baseline eye disease screening at age 40—the time when early signs of disease and changes in vision may start to occur. Based on the initial exam, an ophthalmologist will prescribe the necessary intervals for follow-ups. For individuals at any age with symptoms of, or who are at risk for, eye disease, such as those with a family history of eye disease, diabetes or high blood pressure, the Academy recommends they see their ophthalmologist to determine how frequently their eyes should be examined.
“Much like regular mammograms and diabetes screenings, eye disease screenings will help identify signs of disease at an early stage, when many treatments can have the greatest impact,” said H. Dunbar Hoskins, Jr., MD, executive vice president of the Academy.
Nanotech Meets Glaucoma
The high-tech field of nanotechnology is knocking at ophthalmology’s door in the form of a specially treated nanoparticle that researchers say can latch onto molecules of a glaucoma drug without compromising its functionality.
In a paper published last summer in the Journal of Physical Chemistry C,1 University of Central Florida scientists reported that they had attached molecules of a carbonic anhydrase II inhibitor to cerium oxide nanoparticles. In vitro tests showed the sulfonamide drug retained its functionality in a dose-dependent manner.
The idea of using nanocarriers to improve bioavailability of medication is under investigation for conditions ranging from cardiovascular disease to cancer. And many dozens of studies in recent years have been launched to find materials suitable for ophthalmic use.
So far, researchers have found that nanoparticles’ small size (usually less than 100 nm) allows them to diffuse through tissues quickly, which might allow drug- carrying nanoparticles to improve efficacy by raising the penetration rate beyond the usual 1 to 3 percent.
The Florida research group reported earlier in the year that extremely small (2 to 5 nm) unmodified cerium oxide nanoparticles have a second, independent characteristic that might prove useful in the eye: Their surface chemical properties appear to protect cells from oxidative injury. They do this apparently by scavenging free radicals in a self-renewing, autocatalytic process, according to the group’s working hypothesis.2
Amid the excitement over nanotechnology, however, a few voices of caution are beginning to emerge. Two scientists at the National Institute of Occupational Safety and Health warned last December that nanotechnology is a “major concern” because nanoparticles smaller than 100 nm could damage the health of those who breathe or ingest them.3
“Inhaled [nanoparticles] may evade phagocytosis, cross cell membranes, and redistribute to other sites of the body, causing systemic health effects,” they write. “Therefore, the unbridled growth and use of nanotechnology in medical and human health evaluations opens society to the possibility that [nanoparticles] could become the ‘asbestos’ of the 21st century.”
2 Das, M. et al. Biomaterials 2007;28(10):1918–1925.
3 Gwinn, M. R. and V. Vallyathan. Environ Health Perspect 2006;114(12):1818–1825.