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Passages: Charles D. Kelman, MD, 1930-2004

Diabetic Macular Edema: Oxygen Helps

LASIK Is Possibly Linked to Macular Hole

High-Resetting an Owl's Sights

In the Pipeline

Passages
Charles D. Kelman, MD, 1930–2004
Academy Laureate and member Charles D. Kelman, MD, best known for inventing phacoemulsification, died of cancer on June 2. He was 74.

“Dr. Kelman was one of the world’s greatest medical pioneers, as well as a true Renaissance man,” said Academy president Allan D. Jensen, MD. “He will be missed not only by those of us in ophthalmology, but also by the entire medical community.”

Last year, the Academy honored Dr. Kelman as an inaugural recipient of the Laureate Recognition Award in Anaheim for his distinguished career and contributions to ophthalmology including phacoemulsification, cryoextraction of cataracts and freezing for retinal detachment repair. The Laureate Award is bestowed on outstanding ophthalmologists whose significant scientific contribution to the field has shaped the way modern ophthalmology is practiced.

For a full biography, please visit www.aao.org/laureate, click “Related Links” and then “List of Past Awardees.”

Diabetic Macular Edema
Oxygen Helps
Reducing hypoxia in the inner retina might help focal laser photocoagulation shut off the molecular signals that underlie diabetic macular edema, a pilot study of oxygen supplementation in DME patients suggests.

The pilot study, reported last spring in Investigative Ophthalmology & Visual Science,¹ originally was intended only to validate a working hypothesis, said study coauthor Peter A. Campochiaro, MD, professor of ophthalmology and euroscience at Johns Hopkins University. Researchers wanted to see if they could show a role for hypoxia in development and maintenance of DME—but they also found an apparent treatment effect.

The reduction of edema in the five patients (nine eyes) was significant enough to spark further study in a randomized, controlled, crossover trial that Dr. Campochiaro’s group has begun.

The pilot study found that:

  • Four eyes exhibited decreases in foveal thickness of more than 90 micrometers after three months of continuous oxygen supplementation. That was nearly double the decrease seen in studies of two separate drugs against DME. (See “In the Pipeline: Update on Drugs for DME” below) The decreases were smaller in other eyes, in which the baseline DME was less severe.
  • Excess foveal thickness in the patients fell a mean of 43.5 percent, excess central foveal thickness by 42.1 percent and excess total macular volume by 54 percent. 
      (The term “excess” was defined relative to the group’s unpublished study of normal foveal thickness in diabetics without retinopathy: 179 µm overall, 158 µm for the central fovea and 6.47 cubic-millimeters for total macular volume.)
  • In the three eyes with the mildest DME, the absolute decline in macular thickness was small but represented a large proportion of the excess fluid. One eye had only a 0.3 cubic-mm decrease, but that was 100 percent of the excess macular volume—in essence, a complete resolution of the DME.
  • When oxygen supplementation ended, DME returned in the eyes that had been most severely affected at baseline. But four of the nine eyes remained stable.

The results suggest that there is a “vicious cycle” of feedback underlying DME, the researchers said. The cycle would begin with hypoxia, followed by the release of vascular endothelial growth factor (VEGF) and other growth factors that cause leaky blood vessels. Then, as fluid accumulates, there is increasing distance between oxygen-supplying choroid and the inner retina, making it physically harder for oxygen to reach the inner retina.

“It suggests there’s a feedback loop, that once the retina gets thickened to a certain degree it adds to the hypoxia,” Dr. Campochiaro said. “And then it can be difficult to treat successfully with the laser.”

Indeed, this additionally might explain the therapeutic effect of laser treatment, since it cuts down on hypoxia by killing photoreceptors.

“It stands to reason that the ischemia caused by diabetic changes to the retinal vasculature causes release of vasoactive factors including VEGF,” said Peter K. Kaiser, MD, associate staff at the Cleveland Clinic. “By reversing this process with supplemental oxygen, the release of those factors is reduced and subsequent macular edema improved.”

But Dr. Kaiser said oxygen supplementation for all DME patients would be impractical, cumbersome and possibly a fire hazard.

Dr. Campochiaro noted that, because photoreceptors use the most oxygen at night, it might be possible to avoid these problems by giving DME patients extra oxygen only during the nighttime hours.

Meanwhile, the simplicity and wide availability of oxygen supplementation might be expected to cause a demand for the treatment- a phenomenon with which Dr. Campochiaro already has experience.

"There was one patient who heard about the study and came to see us. But he lived in North Dakota so he couldn't be in the trial," Dr. Campochiaro said. "He was so persistent about wanting the treatment, though, that we agreed to have his physician at home monitor his oxygen treatment. And we get happy e-mails from this patient quite a bit."
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1 Nguyen, Q.D. et al. Invest Ophthalmol Vis 2004;45(2):617-624.

Retina Report
LASIK Is Possibly Linked to Macular Hole
When Amr L. Dessouki, MD, started observing that some of his patients with macular holes had recently undergone LASIK, he wondered if there was a connection. So the private practitioner from Campbell, Calif., started asking around and found that other retinal specialists were observing a similar pattern. Their discussions led to a small, retrospective study of 27 patients who had developed unilateral full-thickness macular hole after undergoing LASIK for refractive correction.

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Caption: One suggestion: Let patients
know that LASIK does not prevent ocular
problems such as macular hole.


The seven doctors who pooled their cases thought a link between LASIK and macular holes might exist. But Dr. Dessouki said, “Right now we cannot conclude that there is a relationship . . . I don’t think LASIK causes macular hole.”

A more likely explanation, he said, is that the eyes in the study were highly myopic, therefore at increased risk for retinal problems.

“Maybe myopia is the cause [of the macular holes],” said Clement K. Chan, MD, a coauthor of the study, which was presented at the 2004 annual meeting of the Association for Research in Vision and Ophthalmology. But it’s equally possible, he noted, that LASIK is a contributing factor. “We have to be careful not to rule out any possible contribution,” he said, adding that it might be easy to overlook a potential connection because the incidence is so low (0.03 percent).

Dr. Chan, who practices in Palm Springs, Calif., and is associate clinical professor of ophthalmology at Loma Linda University, theorizes that LASIK may stress the vitreous base and have some influence on the vitreoretinal relationship. He added that without a prospective study, there is no way to prove cause and effect.

In the meantime, Dr. Dessouki advises doctors to warn patients that LASIK does not prevent retinal problems. He said that people are under the impression that once they get rid of their glasses their vision problems will dissappear.

- Miriam Karmel

Comparative Ophthalmology
Resetting an Owl's Sights
Surgeons at the University of Wisconsin’s School of Veterinary Medicine won’t win a popularity contest among small woodland rodents. In May, the veterinary ophthalmologists performed two-hour, bilateral cataract surgery using a specially made IOL on the eyes of a great horned owl so the raptor could return to preying on field mice and other small creatures. The owl, named Minerva, was found emaciated and starving to death last winter in eastern Wisconsin.

The nature of the owl’s eye and the need for anesthesia meant the surgery took far longer than a human cataract procedure. “The eye of a great horned owl is bigger than a human eye, and the human lens is much smaller,” said veterinary ophthalmologist Christopher J. Murphy, DVM, PhD, and the anterior chamber is deeper than in humans.

“The phaco tip reach was an issue and keeping the globe inflated was an issue,” said second-year resident Renee T. Carter, DVM, who assisted Dr. Murphy. Unlike in human eyes, the owl iris has striated muscle, needing a curariform agent to dilate the pupil. The surgery itself involved a clear corneal incision and phaco emulsification.

The only complication, said Dr. Murphy, was an easily remedied prolapsed iris through the clear corneal incision. “It is the first bird, to our knowledge, to be released with IOLs,” he said. He noted there is no evidence that owl cataracts are inherited, thus minimizing concern that a genetic defect can be passed on.

The bird, fitted with a radiotransmitter for tracking, is doing fine, said Susan Theys, a wildlife rehabilitator.

- Harvey Black

In the Pipeline
Update on Drugs for DME

What’s new with molecular-based therapies for retinal disease? A year or two ago, the answer would have involved AMD. Today, one of the hottest areas of interest is diabetic macular edema. This is good news for the 500,000 Americans who already suffer from DME as well as the 75,000 who, according to the American Diabetes Association, are diagnosed with this long-term complication of diabetes every year.

Indeed, results are beginning to trickle out for DME trials of medications that ophthalmologists previously have looked at mostly in connection with AMD. Among the results this year:
  • EyeTech Pharmaceuticals reported positive visual and anatomical outcomes in its initial Phase 2 study of Macugen (pegaptanib sodium) for DME. At a dose of 0.3 milligrams, the same as with AMD, 34 percent of the DME patients gained 2 or more lines of vision (P = 0.003) at the 36-week time point, compared with 10 percent in the sham-injection group; 59 percent gained 1 or more lines, compared with 34 percent for controls (P = 0.01); and 27 percent lost vision, compared with 51 percent in the controls (P = 0.02). Retinal thickness decreased a mean of 50.79 micrometers with the Macugen group, compared with 12.68 µm in controls. EyeTech and partner Pfizer expect to seek approval of Macugen for wet AMD this year.
  • A Johns Hopkins University group reported on oral administration of Novartis’ kinase inhibitor PKC412 in patients with DME.1 A third of the patients given 150 mg per day of PKC412 had a 20 percent decrease in total retinal volume after three months of treatment compared with zero declines among controls. The mean decrease in thickness was 58 µm. However, the drug will need to be delivered locally because of liver toxicity and other side effects with systemic dosing, said study coauthor Peter A. Campochiaro, MD.
  • Inspire Pharmaceuticals began a Phase 2 clinical trial with INS37217 (denufosol tetrasodium), a P2Y2 receptor agonist that also is in preclinical testing against DME. The current 160-patient study is testing up to three intravitreal injections of the drug as a first-line treatment for rhegmatogenous retinal detachment. The manufacturer hopes the drug’s P2Y2 activity will stimulate removal of the subretinal fluid.

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1 Campochiaro, P. A. et al. Invest Ophthalmol Vis Sci 2004; 45(3):922–931.

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