Article Date: 6/1/2010

JOURNAL CLUB

JOURNAL CLUB

RECENT NOTEWORTHY STUDIES TO STIMULATE DISCUSSION AND DEBATE

ANDREW E. MATHIS, PhD, MEDICAL EDITOR

CNV without AMD. While choroidal neovascularization is the most obvious complication of exudative age-related macular degeneration, CNV can also be a complication of other ocular disorders. Given the success in using anti-VEGF agents in treating CNV due to AMD, it is not surprising that retinal physicians are testing anti-VEGF agents to treat CNV in other conditions. The May 2010 edition of Retina includes three articles reporting data from such trials.

One study looked at macular function changes evaluated with microperimetry following treatment with bevacizumab for subfoveal CNV in high myopia. Physicians in Rome examined 15 eyes of patients treated with one intravitreal injection of 1.25 mg bevacizumab; patients were retreated if leakage recurred or was persistent on fluorescein angiogram or if intraretinal fluid was visible on OCT. The study authors found that mean macular sensitivity increased by 2.62 dB at the 12-month follow-up and mean number of measurement points within the central absolute scotoma decreased by 6.2. Mean visual acuity improved from 20/66 at baseline to 20/38.

Another study looked at the use of either bevacizumab or ranibizumab in CNV associated with pseudoxanthoma elasticum (PXE), a genetic connective-tissue disorder that causes dimpling of Bruch's membrane, leading to angioid streaks. New York-based physicians injected nine eyes an average of 8.4 times over a mean follow-up period of 28.6 months; then they measured visual acuity and found that it had either stabilized or improved in all nine eyes. OCT demonstrated an average decrease in central retinal thickness of 207 μm.

The third study tested bevacizumab in seven eyes of seven Japanese patients with idiopathic choroidal neovascularization. These patients received a mean number of 2.7 injections at one-year follow-up. Mean central retinal thickness decreased from 332 ±83 μm to 261 ±66 μm, and mean logMAR visual acuity improved from 0.31 ±0.29 to 0.15 ±0.38, although the greatest improvements were in patients whose visual acuity at baseline was at least 20/40 or better.

The results of these three studies all indicate that anti-VEGF agents may promise better outcomes for patients with these disorders. While patients with myopic CNV and PXE are currently receiving photodynamic therapy and/or laser treatment, patients with idiopathic CNV are generally being treated with triamcinolone acetonide, but none of these treatments are optimal.

Single-session vs multiple-session laser. Ophthalmologists in Birmingham, UK, and Santa Clara, CA, have collaborated in conducting the first pros pective, randomized clinical trial to validate the potential efficacy of nonconventional panretinal photocoagulation treatments on safety profile, disease activity and visual outcomes in proliferative diabetic retinopathy. They report their findings in the May 2010 issue of Archives of Ophthalmology.

Forty eyes of 24 patients with PDR were treated with PRP given as 1,500 burns of 400 μm spot size, administered either in a single session (20 msec per burn) or in three sessions (100 msec per burn). Visual acuity and central retinal thickness were measured at baseline, four weeks and 12 weeks.

The study authors found a statistically significant increase in central retinal thickness with multisession panretinal photocoagulation, with no corresponding significant increase in the single-session cohort. Visual acuity gains were larger in the single-session group at four weeks (two letters vs one letter) and at 12 weeks (four letters over baseline), although these results were not statistically significant.

Mean treatment time for single-session PRP was 5.04 minutes, compared to 59.3 minutes for multisession treatment. There were no adverse events in either group. The authors report that single-session PRP is a safe and rapid alternative to multisession PRP, and they believe a single session of treatment may improve patient compliance.

"I've got you under my skin." With apologies to Frank Sinatra, we note that a Dutch study published in the May 2010 British Journal of Ophthalmology reports that skin autofluorescence, which is a nonin vasive marker for advanced glycation endproducts, increase in patients with neovascular age-related macular degeneration.

Seventy-three patients with AMD were compared with 31 healthy patients serving as a control group. All subjects had the skin of their forearms measured for autofluorescence.

Compared to the control group, AMD patients had increased skin autofluorescence (2.57±0.68 vs 2.23±0.63 arbitrary units × 10−2). Furthermore, exclusion from both groups of patients with cardiovascular disease or of patients who smoked did not change the statistically significant difference in skin autofluorescence.

The authors of the study believe that measurement of skin autofluorescence can be useful as an adjunct in diagnosing and treating age-related macular degeneration because of the putative role that oxidative stress may play in the disease. As advanced glycation endproducts tend to accumulate in the eye in the presence of oxidative stress, the buildup of these compounds in the skin might indicate buildup elsewhere in the body.

Nutrition and retinal dystrophies. A pair of recent studies review the effects of certain supplements on retinal dystrophies. The first, published in the April 2010 Archives of Ophthalmology, examined the use of lutein in patients with retinitis pigmentosa. Two hundred twenty-five patients in Massachusetts and Iowa were given 12 mg of lutein per day or a control. Also, 15,000 IU per day of vitamin A was given to both the study group and the control.

Outcomes were measured using the Humphrey Field Analyzer. For the HFA 60-4 program, a decrease in mean rate of sensitivity loss was observed that was statistically significant. The authors concluded that lutein supplementation slowed loss of midperipheral visual field on average.

The second trial, conducted in Israel, studied oral 9-cis-beta-carotene given to seven patients with fundus albipunctatus, another genetically linked retinal dystrophy. All seven patients showed improvements in peripheral visual field, with a highly significant improvement in rod recovery rates as measured by electroretinogram.

The study authors concluded that oral 9-cis-betacarotene supplementation had actually led to reversal of dystrophy. They urge that the supplement be tested in other dystrophies, including retinitis pigmentosa.

Gene news. Three articles published recently deal with important genetic issues that impact retinal disease. The article likely to have the largest effect, from the May 25 issue of the Publication of the National Academy of Sciences, deals with new genes identified in the development of agerelated macular degeneration.

A team of geneticists from the University of Michigan executed a genome-wide association scan for AMD, looking at 2,157 patients with the disease and 1,150 controls. Five loci were identified as being susceptible to AMD. In the next step of the study, findings from Michigan were compared to results from a study done at Tufts University/Massachusetts General Hospital; 30 markers were identified in this comparison.

Combining these methods, a susceptibility locus near the TIMP3 gene was found — a gene previously identified with HDL blood cholesterol levels. The authors believe identification of this marker can lead to uncovering cellular pathways that can be targeted with new therapies.

The second gene study, on Stargardt disease, appeared in the April 2010 American Journal of Ophthalmology. It is a single case study of a couple undergoing in vitro fertilization. The husband in the couple is affected with Stargardt disease, and before transfer of embryos back to the mother following fertilization, polymerase chain reaction and restriction enzyme analysis were carried out to find mutation of the ABCA4 gene associated with Stargardt disease. Both affected embryos and carriers were identified.

As more genetic determinants of retinal disease are identified through continuing genetic research, it will become more common that retinal diseases are detected at the embryonic stage when couples undergo IVF. The third study originated in Hong Kong and looks at Best vitelliform dystrophy in 26 patients, along with 100 healthy subjects. Results are reported in the May 2010 Retina. Volunteers were screened BEST1 gene mutations and underwent complete ophthalmological exam.

Six new mutations were identified, and an earlier identification of a mutation was confirmed. The Hong Kong team suggests that the occurrence of such a large number of mutations may indicate a significant interethnic difference in how these mutations are expressed, given that the volunteers in this study were all Chinese, whereas other studies tend to have much smaller percentages of Asian subjects.

Since the Human Genome Project completed in 2003 mapping the over 20,000 genes of human DNA, the number of genes implicating in disease processes has skyrocketed. These three studies offer just a peek at the potential that genetic research may provide into possible therapies, which may revolutionize the way retinal disease is treated. While a genetic solution to AMD may be many years off, the PNAS study, in particular, offers great potential in both the prevention and treatment of this disease.

OCT in diabetic macular edema. A meta-analysis from the Wills Eye Institute in Philadelphia, appearing in the May 2010 issue of Current Opinion in Ophthalmology, sings the praises of optical coherence tomography in the diagnosis and treatment of diabetic macular edema. Darrell E. Baskin, MD, of the Wills Retina Service, writes, "Arguably, OCT is the single most important diagnostic and prognostic tool in the management of DME."

Dr. Baskin's study is useful, among other reasons, for its classification of references into those he deems "of special interest" and those "of outstanding interest." These sources are marked with single and double asterisks, respectively, both within the text of the article, as well as in the list of references at the article's close.

Baskin also summarizes OCT terminology for the reader and reviews data from the Diabetic Retinopathy Clinical Research Network. RP



Retinal Physician, Issue: June 2010