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Triple Tx for CME
In the first evaluation of a triple-therapy regimen to treat chronic cystoid macular edema, eyes treated with the topical NSAID nepafenac showed sustained improvements in retinal thickness and visual acuity.1
The 16-week study was designed to evaluate the effectiveness of the addition of a topical NSAID to the combination of intravitreal injections of triamcinolone (Kenalog) and bevacizumab (Avastin). Four different NSAIDs were compared.
“Chronic CME is difficult to treat. We’ve been struggling with it for years,” said lead author Keith A. Warren, MD, head of Warren Retina Associates in Overland Park, Kan. “With the advent of the newer NSAIDs, the questions for me became: Would an NSAID augment a corticosteroid-antiangiogenic combination, and was there a difference in the NSAIDs’ efficacy?”
All of the 39 patients who completed the trial had chronic pseudophakic CME of at least six months’ duration. At baseline, their mean visual acuity was nearly 20/80, mean retinal thickness was 557.2 µm and mean IOP was 16 mmHg.
The patients were randomly assigned to receive placebo eyedrops or one of four topical NSAIDs: diclofenac (Voltaren), ketorolac (Acular), nepafenac (Nevanec) or bromfenac (Xibrom). In addition, all were treated with 4 mg of intravitreal triamcinolone and 1.25 mg of intravitreal bevacizumab at the beginning of the trial, and the bevacizumab injection was repeated after the first month. “The rationale for limiting the Avastin injections to the initial phase of the study was to isolate the effect of the NSAIDs,” explained Dr. Warren, clinical professor of ophthalmology at the University of Kansas, Kansas City.
At the four- and eight-week evaluations, patients in all five groups showed similar reductions in retinal thickness. However, by the end of the 16-week trial, this benefit was greatest in those treated with nepafenac or bromfenac.
Nepafenac was the only NSAID to produce sustained improvements in visual acuity. Early on in the study, all treatment groups experienced modest gains in visual acuity, but by week 16, all but those in the nepafenac group had lost most of that gain. The mean visual acuity for those in the nepafenac group had improved by an average of 19 percent.
Seven of the 39 patients experienced a rise in IOP during the study and were treated with IOP-lowering medications. Because this occurred across all groups, the researchers note that it was likely the result of the intravitreal injections of corticosteroids or bevacizumab rather than the NSAIDs.
The authors note that a larger sample size, double-masking and a multicenter design are needed to confirm the results.
1 Warren, K. A. et al. Retina
OCT Uncovers Fraud
Attributing authenticity to centuries-old paintings has posed a challenge to conservators for years, but Polish researchers have found a new way to identify forgeries with the use of optical coherence tomography.1 In the past, examination techniques have been limited and have not always been reliable owing to the inherently invasive and random nature of sample extraction.
OCT enables conservators to look at various points on a canvas. “Scanning an entire painting is unnecessary,” said Piotr Targowski, PhD, associate professor of physics at Nicolaus Copernicus University, Toru, Poland, who explained, “We survey up to 100 areas in real time via a computer screen. If we encounter an area of interest, the data is saved for additional analysis. The images are cross-sectional and relatively easy to interpret—a trained conservator can perform an analysis without the assistance of a physicist.”
Dr. Targowski and his colleagues have been promoting OCT as a noninvasive method for revealing what lies beneath the layers of a canvas since 2003, and the technique is slowly gaining popularity. Their current research demonstrated the effectiveness of OCT by detecting alterations in two paintings. “The idea is not to replace present techniques but add to the existing set,” said Dr. Targowski.
1 Targowski, P. et al. Acc Chem Res.
E-published Dec. 31, 2009.
Spectroscopy May Have Diagnostic Potential
With early glaucoma detection a Holy Grail of ophthalmology, Raman spectroscopy researchers are optimistic the quest may no longer be quite so elusive.
Already showing promise in cancer diagnosis, Raman spectroscopy is a technique that can provide highly detailed chemical information about cell samples by measuring the wavelength and intensity of scattered Raman photons representing the energy of molecular vibrations. Different molecules produce unique “fingerprints” because they interact with light differently, said Chenxu Yu, PhD, lead researcher and assistant professor of agricultural and biosystems engineering at Iowa State University in Ames.
Described at the National Meeting of the American Chemical Society,1 Dr. Yu’s method involves shining infrared laser light onto retinal ganglion cells collected from dogs. The cells scatter the light and produce a spectrum from all the molecules. “This reveals a general landscape of the chemical composition of the cells,” said Dr. Yu, who was drawn to this research after being identified as a glaucoma suspect.
An increase in IOP triggers signal transduction pathways that turn on and off expression of certain genes, he said. This translates into changes in levels of proteins and other molecules. Comparing spectra in healthy dogs with spectra in dogs with end-stage hereditary glaucoma and those with acute elevation of IOP, the researchers were able to detect glaucoma with nearly 90 percent accuracy.
“Although the total amount of proteins in healthy and glaucomatous eyes appear to be quite similar,” said Dr. Yu, “the composition of the proteins is changing.” And, early-stage and late-stage glaucoma spectra are very similar, meaning the technique not only detects chemical changes, but also provides spectroscopic markers that are specific to glaucoma.
As they work to develop an in vivo model, said Dr. Yu, one goal is to lower laser power without compromising spectroscopic sensitivity. In humans, Dr. Yu’s team predicts a 30-minute test that would involve a few minutes of testing interrupted by periods of rest—a process that could diagnose not only glaucoma years earlier than currently possible, but eventually other diseases as well.
1 Wang, Q. et al. Exploring Raman spectroscopy as a nondestructive diagnosis tool for glaucoma. Presented at the American Chemical Society Meeting, March 24, 2010, San Francisco.
Dr. Yu reports no financial interests related to this story.
Topical Timolol for Capillary Hemangioma
After a team of French doctors reported that the beta-blocker propranolol successfully treated capillary hemangioma in 11 infants,1 ophthalmologists were impressed by its efficacy, said Suqin Guo, MD.
She said that treatment of these infants is critical since their incidence of amblyopia is high. If not treated promptly, the periocular hemangioma may lead to blindness.
But systemic use of propranolol has severe side effects, including bradycardia, hypotension and bronchospasm. This led Dr. Guo to wonder: If a systemic, beta-blocker works, why not try topical timolol, which is in the same class as propranolol?
“I used timolol hoping not only to achieve a good effect, but to reduce systemic adverse effects and the need for close monitoring of those babies,” said Dr. Guo, assistant professor of ophthalmology at New Jersey Medical School.
Dr. Guo’s first timolol patient was a four-month-old girl with a large capillary hemangioma on her left eyelid, covering her pupil. The child’s mother was instructed to apply two drops/twice daily of timolol maleate, 0.5 percent to the tumor surface. By five weeks, the hemangioma was dramatically reduced and the visual axis cleared. At four months no local or systemic adverse effects existed.2 Dr. Guo said she and her colleagues have since treated more infants with superficial hemangioma with good results.
Why a beta-blocker can treat hemangioma is unclear, but hypotheses include vasoconstriction, decreased expression of VEGF and apoptosis of capillary endothelial cells.
A larger study is under way at Dr. Guo’s institution.
1 Léauté-Labrèze, C. et al. N Engl J Med
2 Guo, S. and N. Ni. Arch Ophthalmol
New Night Blindness Details
Just over a decade ago, researchers learned that the type 2 form of X-linked, incomplete stationary night blindness (CSNB2) occurs because of genetic defects in certain voltage-gated calcium channels in the retina (type: Cav1.4).1,2 Subsequent investigators suspected that the channels’ lack of a distal carboxy tail was switching off their normal inactivation mechanism, whereby elevated intracellular calcium inhibits Ca2+ transport through the channels.3,4
Now, Johns Hopkins University neuroscientists have found that the distal carboxy tail functions more like a fine-tunable rheostat, rather than as an on-off switch, for this inactivation mechanism.5 This discovery was made by a team led by David Yue, MD, PhD, professor of biomedical engineering and director of the Calcium Signals Lab at Hopkins.
The researchers used a fluorescent sensor molecule to track the activity in living cells of calmodulin (CaM), a protein that attaches to calcium channels, and senses and binds Ca2+ ions in the course of orchestrating channel activation. The sensor revealed a three-part system of highly sensitive calcium-transport feedback loops involving the Cav1.4 channel, Ca2+ and CaM.
In normal rod photoreceptors, the channel’s distal carboxy tail section modulates the system by “retuning” how sensitive the calcium channels are to CaM, the researchers found. This retuning of CaM sensitivity in turn finely adjusts how sensitive the channels are to intracellular Ca2+.
In CSNB2 mutations with this channel defect, the dysregulation of calcium ion transport produces night blindness by somehow preventing the rod photoreceptors from sending neurotransmitter signals to adjacent bipolar cells in the retina, Dr. Yue said.
“In talking to my colleagues, I’m finding that they’re excited that we can think about understanding a disease from the clinical perspective, right down to the actual molecular mechanism, and that because we’re understanding the precise molecular deficit, there’s a hope for one day devising a rational therapy,” he said.
1 Bech-Hansen, N. T. et al. Hum Genet
2 Strom, T. M. et al. Nat Genet
3 Singh, A. et al. Nat Neurosci
4 Wahl-Schott, C. et al. Proc Natl Acad Sci USA
5 Liu, X. et al. Nature
EyeNet thanks Susan B. Bressler, MD, for her help with this issue’s News in Review.