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News in Review
A Look at Today's Ideas and Trends
CXL for Refractory Acanthamoeba
Studies in the field of transfusion medicine have found that bacteria, viruses and parasites in blood products are often a poor match for vitamin B2 and ultraviolet A Light. The combination, known in ophthalmology as collagen cross-linking (CXL), has also proved useful in treating keratoconus, post-LASIK keratectasia and certain melting disorders.
Now researchers have demonstrated its effectiveness against Acanthamoeba keratitis (AK) with three medically refractory cases—contact lens wearers who were first treated with multidrug regimens for at least 30 days.1 After they didn’t respond to that approach, they received CXL treatment, involving topical 0.1 percent B2 solution applied to the ocular surface plus 30 minutes of UVA irradiation targeted to the corneal ulcer.
Within the first 48 hours of CXL, pain and inflammation increased to an extreme level, said study coauthor Ashley Behrens, MD, executive medical director at The King Khaled Eye Specialist Hospital in Riyadh, Saudi Arabia, and KKESH/Wilmer Eye Institute professor of international ophthalmology. “We think that destruction of the Acanthamoeba cysts released toxins and caused a significant reaction,” Dr. Behrens said. (He compared it to the Jarisch-Herxheimer reaction, which commonly follows the treatment of syphilis.)
But within three days of CXL, the AK patients experienced a rapid reduction in symptoms and decrease in ulcer size. After reaching a plateau in the healing process about one to three weeks later, they underwent a second treatment, which mostly resolved any remaining inflammation and eradicated all signs of infection. All epithelial defects closed within two months of the first treatment.
Dr. Behrens speculated that treating patients even earlier might avert the severe initial inflammatory reaction as well as minimize other damage to the eye. In this study, two of the three patients required penetrating keratoplasty due to development of central corneal scars. Strikingly, a check of these corneal buttons revealed no signs of Acanthamoeba cysts, although cells resembling necrotic tissue and degenerated keratocytes were present.
“By contrast, we have seen patients who are clinically stable for one or two years following other types of treatment, yet Acanthamoeba shows up in their keratoplasty samples,” he said. In fact, 30 percent of grafts like these become reinfected. 1
Researchers theorize that this combination therapy works in one or more ways: The oxidative process during CXL may deplete the natural source of nutrition to microorganisms, thus acting as a cysticidal agent. In addition, activated flavins and free radical insult to DNA or RNA may cause genome damage. Given this wide mechanism of action, the therapy has the potential to become a wide-spectrum treatment against a variety of organisms, said Dr. Behrens.
UV light exposure is another possible, but less plausible, mechanism of action, said Dr. Behrens. Based on previous studies, the power of the UV light is unlikely to be strong enough to create a major antimicrobial effect. Dr. Behrens and his colleagues are conducting more studies to learn the ideal parameters as well as the prospects for using other sources of light such as blue-light lasers, which might shorten exposure time and create more efficient treatment.
“One of the major advantages of this treatment, however, is you can localize it,” said Dr. Behrens. This is important, given that potential damage to healthy cells is a remaining area of concern.
Dr. Behrens has no financial interests in the products described in this article.
1 Khan, Y. A. et al. Ophthalmology 2011;118(2):324–331.
Lipid Metabolites and Neovascular Disease
The protective effects of omega-3 polyunsaturated fatty acids (PUFAs) on the retina appear to derive from specific metabolites, while metabolites of omega-6 fatty acids promote neovascularization, according to a review of lipid-based mediators and the pathogenesis and treatment of neovascular eye disease.1
Both omega-3 and -6 PUFAs are essential fatty acids obtained from the diet. However, while omega-3 fatty acids appear to be associated with a reduced risk of AMD, omega-6 PUFAs appear to be associated with an increased risk.
“It may be that, if you’re trying to prevent retinopathy—including retinopathy of prematurity, diabetic retinopathy and neovascular AMD—you are in fact talking about lipid metabolism and metabolic lipid by-products that can prevent disease,” said article coauthor Lois E. H. Smith, MD, PhD, professor of ophthalmology at both Harvard and Children’s Hospital in Boston.
The retina has the highest omega-3 PUFA concentration of all tissues (20 percent), and these lipids are vital to normal retinal structure and function.
The differing effects of the omega-3 and -6 metabolites would explain why omega-3 PUFAs are associated with a lower risk of AMD, Dr. Smith said. It also would explain why greater consumption of certain fish, high in omega-3 lipids, has been associated with lower AMD risk. She noted that, in a recent report, women who ate fish once a week had a 40 percent lower risk of developing any AMD over the course of 10 years than those who did not.2
If the outlines of this complex story hold up to scrutiny in human studies, the personal and societal implications would be big, Dr. Smith said. “This has profound implications for health care in general,” Dr. Smith said. “If we could supplement Americans’ diets with omega-3 fatty acids at a cost of less than $10 a month, and decrease the amount of AMD by 40 percent, this would very substantially reduce health care costs and improve health.”
Conversely, new drugs could be developed to block pathological metabolites of omega-6 fatty acids from promoting retinal neovascularization in patients with AMD and diabetic retinopathy, she said. But that clinical scenario is likely to be far off, Dr. Smith cautioned.
The multinational group of researchers is now taking a retrospective look at the correlation between omega- 3 levels and ROP in 50 premature Swedish infants.
1 Stahl, A. et al. Br J Ophthalmol Published online March 18, 2011.
2 Christen, W. G. et al. Arch Ophthalmol Published online March 14, 2011.
Bevacizumab for NVG Pain
In a recent study, a single injection of bevacizumab offered quick pain relief in eyes with neovascular glaucoma (NVG). Moreover, the anti-VEGF drug reduced surgical bleeding, allowing for safer IOP-lowering surgical intervention.1
Researchers at Moorfields Eye Hospital in London enrolled 50 patients (52 eyes) with NVG, which occurs when fibrovascular tissue proliferates within the anterior chamber angle. Forty-two patients (44 eyes) completed the six-month follow-up period.
The Moorfields researchers delivered 1.25 mg of intravitreal bevacizumab via the pars plana. Four eyes required repeat injection for persistent iris neovascularization. At week one, the subjective pain score, on a scale of zero to nine, fell to one, from a median score of three before treatment. At one month, the score fell to zero, and it remained there through the sixth month.
Thirty-one eyes required IOP-lowering drainage tube surgery within the first two months after bevacizumab injection. Two eyes developed hyphema during the tube surgery, which resolved within seven days. “We believe bevacizumab makes surgery safer by making it easier to complete and allows for better postoperative outcomes as tubes are not occluded by clotted blood,” said study coauthor Alexander Spratt, MRCOphth, ophthalmology registrar at Moorfields.
Previous studies have attributed pain relief in NVG to a reduction in IOP, but in this study, at one week, pain relief was accompanied by only modest pressure reduction. The authors speculate the pain relief may be associated with regression of iris neovascularization and reduced vascular permeability of inflammatory mediators into the eye.
The ideal dose and protocol is unknown. And while Dr. Spratt cautioned, “Bevacizumab does not replace panretinal photocoagulation,” the researchers conclude that it is a useful adjunct in managing NVG.
1 Kotecha, A. et al. Arch Ophthalmol 2011;120(2):145–150.
Oxidative Stress Involved in Hallmark of Fuchs
Oxidative stress, or damage due to reactive oxygen species—molecules that have been associated with aging—is involved in endothelial cell death, the hallmark of Fuchs endothelial corneal dystrophy (FECD), according to researchers at the Schepens Eye Research Institute in Boston.1
Ula V. Jurkunas, MD, and her Schepens colleagues compared normal corneal endothelial cells from cadavers with corresponding specimens obtained from patients who underwent corneal transplant surgery for the treatment of FECD. “We found that there are many changes in the corneal endothelial cells of FECD patients that are related to chronic oxidative stress,” said Dr. Jurkunas, who is coauthor of the paper and assistant professor of ophthalmology at Harvard.
As the endothelial cells of the cornea gradually die, guttae (protein deposits) accumulate in between the cells, causing the cornea to swell and become opaque. Patients in the advanced stages of FECD often require corneal transplantation, which has led to the search for alternative solutions. “While we are still seeking the ideal treatment target, our findings open up a huge area for investigation. If we can find the specific molecules to block the effects of the reactive oxygen species, we can eventually prevent the loss of these cells in early cases of FECD before a transplant is required,” Dr. Jurkunas said.
Until the precise antioxidant( s) is/are identified that will counteract or repair the damage caused by oxidative stress, Dr. Jurkunas said that ophthalmologists should advise patients—particularly those who are in the early stages of FECD or who have a family history of the disorder—to “wear UV-protective sunglasses, take multivitamins in a dose recommended by a primary care physician and eat as many green leafy vegetables as possible.” And smokers should be counseled to quit.
1 Jurkunas, U. V. et al. Am J Pathol 2010;177(5):2278–2289.
EyeNet thanks Susan B. Bressler, MD, and Christopher Rapuano, MD, for their help with this issue’s News in Review.