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News in Review

Possible Heart–Eye Connection in AMD

Oxidative Stress and Vision

The Eye Keeps Body in Sync

Know How Patients Perceive Informed Consent

Possible Heart–Eye Connection in AMD
The search for biomarkers to predict the course of AMD took a new turn last winter when researchers showed a link between AMD and blood levels of C-reactive protein (CRP), an indicator of systemic inflammation that has been shown to be predictive of both heart and peripheral vascular disease.1 “The rationale for designing this study was the link between risk factors for cardiovascular disease and risk factors for AMD, like smoking and diet,” said Johanna M. Seddon, MD, ScM, principal investigator. “This is the first report of an association between CRP levels and AMD.”

For the moment, the association won’t affect how clinicians follow their patients with AMD, said study coauthor Michael L. Klein, MD, professor of ophthalmology at Oregon Health & Science University. But it points to the potential for inflammation control as a preventive therapy in early AMD, he said.

“We know from experimental evidence that there’s an inflammatory component of AMD, and this shows that you can demonstrate that clinically just by doing a blood test,” he said. “But that doesn’t mean that patients worried about AMD should go out and have the test. I think the major implications are for the future, in terms of possible ways to intervene before AMD progresses to the advanced stages.”

In the study, researchers evaluated CRP levels in stored blood samples from a subset of 930 Massachusetts and Oregon patients who were part of the Age-Related Eye Disease Study (AREDS). The tests showed that high CRP levels were twice as likely in people with intermediate and advanced stages of AMD compared to those participants without the disease.

This association held up even when the analysis took into account other potential risk factors for AMD, including smoking and obesity, said Dr. Seddon, ophthalmic surgeon and director of epidemiology at Massachusetts Eye and Ear Infirmary.

“Smoking increases inflammation in the body, but here we found that even if you didn’t smoke that the highest levels of CRP were a risk factor for AMD. Why is that? We’re not really sure,” Dr. Seddon said. “A combination of fat consumption, obesity, lack of exercise and decreased antioxidant levels still could be driving the whole system, but there may be other factors as well.”

Those lifestyle-related risk factors for AMD—which also are associated with cardiovascular diseases —have been teased out of the AREDS data and other studies over the last decade.

CRP’s elevation in AMD patients suggests that the vascular dysfunction in AMD and cardiovascular disease share a common pathogenesis, Dr. Seddon said. That would imply the need to investigate whether using anti-inflammatory drugs, including statins, might slow progression of AMD in patients.

Before testing statins or other medications, researchers would have to show an association between CRP levels and AMD progression. Dr. Seddon and her MEEI colleagues are looking for this in the same prospective study of AMD progression on which they reported last year,2 as well as in the AREDS subjects. She expects results this spring.
1 Seddon, J. M. et al. JAMA 2004; 291:704–710.
2 Arch Ophthalmol 2003;121:1728–1737 and 785–792.

Research Report
Oxidative Stress and Vision
A strain of mouse with a too-big heart has led to evidence of a novel pathway to various retinal degenerations: a gene defect that impairs mitochondria and reduces endogenous antioxidants.

The hypothesis gives ophthalmic researchers an entirely new etiology to plumb for clues on how to block retinal disease at the molecular level. It also suggests another physiologic reason for why the antioxidants used in the Age-Related Eye Disease Study helped protect the fellow eyes of people with AMD, and how retinopathy of prematurity is triggered by oxygen.

“This gene and perhaps other members of its class seem to be critical responders to oxygen content, whether those contents are low or high,” said Joseph A. Garcia, MD, PhD, assistant professor of internal medicine at the University of Texas Southwestern Medical Center, Dallas.

“Alterations in oxygen content come from a number of pathologic causes. Nevertheless, this may be a common pathway to the damage that those various conditions cause.”

Dr. Garcia’s group bioengineered “knockout” mice to lack a key gene for producing a protein, hypoxia-inducible factor-2alpha. Although HIF-2alpha already was known to be involved in the cell’s response to oxidative stress, the specific effects in vivo had not been characterized.

The knockout mice have multiple-organ pathology that includes an enlarged heart and liver, skeletal myopathy and deficient bone marrow, according to the paper Dr. Garcia’s group published in the December Nature Genetics.1 However, ophthalmic serendipity entered the picture when the experimenters also noted peculiar movement patterns, he said.

“We initially noticed that the knockout mice, unlike their wild-type littermates, preferred to roam around the periphery. They did not cross to the middle of the enclosure,” Dr. Garcia said. “That was a clue—in retrospect—that they had impaired vision and were relying more on touch for their orientation.”

Overall, the knockout mice’s symptoms resembled those of children with mitochondrial disorders. “When we realized we had disparate organs involved, and when we also realized that oxidative stress could explain a lot of the pathology, then we started looking for other pathological findings associated with oxidative stress and mitochondrial diseases, including retinopathy,” he said.

Although their optic nerves appear normal, the knockout mice’s retinas resembled those of juvenile wild-type mice raised in high-oxygen environments, Dr. Garcia said. They showed marked retinal thinning and some dysmorphic features. “In some respects, their retinopathy also resembles findings observed in AMD and other retinal disorders seen in adults,” he said.

Testing showed the mice also had enhanced levels of reactive oxygen species and reduced expression of genes that produce antioxidant enzymes. The researchers concluded this combination was in part responsible for the varied organ damage. Confirmation came when prenatal or postnatal treatment of the mice with a superoxide dismutase antioxidant prevented some of the symptoms.

1 Garcia, J. A. et al. Nat Genet 2003;35(4):331–340.

Sleep and the Eye
The Eye Keeps Body in Sync
Even blind eyes seem to have an important function in the body, a Washington University study of the retinal role in circadian rhythms has demonstrated.

Published in the February Ophthalmology, the study compared sleep patterns of children who had optic nerve–caused blindness with those of blind and sighted children with functioning optic nerves.1 The goal was to show clinically that a small subset of ganglion cells—discovered in the retina just a few years ago—sends signals to the brain to regulate the body’s sleep-wake patterns.

The study found that blindness in general caused these patients to have more erratic sleep-wake cycles, said Iggy Provencio, PhD, assistant professor of anatomy, physiology and genetics at the Uniformed Services University, Bethesda, Md., who has been a leader in the field of characterizing the retinal basis for circadian rhythms. “Then within that group of the blind, the subgroup of optic-nerve blindness had the most dramatic effects. The results came out exactly as I would have expected, and that surprises me, because science doesn’t always work like that,” he said.

Dr. Provencio and others reported in 2001 and 2002 on finding a dendritic network in the retina of nonrod, noncone photoreceptors containing the photopigment melanopsin.2 These retinal ganglion cells have a peak sensitivity to 484 nanometer wavelength light and connect to the suprachiasmatic nucleus (SCN), the area of the brain that regulates the mammalian body clock.

Since then, other studies have shown that, although these specialized photoreceptors represent 80 percent of the ganglion cells that project to the SCN, the other 20 percent are from rod and cone cells whose role in diurnal rhythms has not yet been characterized, Dr. Provencio said.

This latter finding could account for the gradation in sleep problems that was seen in this recent study, he said.

From a clinical perspective, this confirms what he and other circadian researchers have been suggesting: Even a blind eye can serve an important physiological function, and so shouldn’t be enucleated unnecessarily.

“The liver, the heart and other organs all have their own circadian rhythms, but they’re considered slave oscillators to the main system regulated by the eye and the SCN,” Dr. Provencio said. “So if both eyes are removed, it’s likely that all of your physiological systems would come out of sync with each other.”

1 Wee, R. and R. Van Gelder. Ophthalmology 2004;111:297–302.
2 Provencio, I. et al. Nature 2002; 415(6871):493.

Additional citations are as follows:
Berson, D. M. et al. Science 2002;295(5557):1070–1073.
Brainard, G. C. et al. J Neurosci 2001;21(16):6405–6412.
Gooley, J. J. et al. Nat Neurosci 2001;4(12):1165
Hannibal, J. et al. J Neurosci 2002;22(1):RC191(1–7)
Hattar, S. et al. Science 2002;295(557):1065–1070.

The Law and You
Know How Patients Perceive Informed Consent
Why do cataract patients who were told about potential complications later claim they didn’t know anything could go wrong? It might be that informed consent happens too late, a group of Austrian researchers suggests.

Writing in the Archives of Ophthalmology, the group used a psychology term—cognitive dissonance—to explain that with surgery imminent, the patients may unconsciously suppress information that doesn’t support their already-made decision.1 “If patients in court claim that they have not heard about a certain consequence, they are not necessarily lying, since cognitive dissonance causes selective perception and cognitive information processing,” the researchers write.

According to research by ophthalmologist Marvin F. Kraushar, MD, and colleagues at the University of Medicine and Dentistry of New Jersey, lack of informed consent is alleged in 90 percent of the cataract surgeries that result in malpractice lawsuits.

In the Austrian study, 70 patients were asked a series of 15 questions to gauge their estimation of the surgical risks both before and after being given informed consent the day before surgery. Seventy-six percent thought they faced no risks at all. However, after being warned, all 70 patients said their decision to have surgery either was not influenced by informed consent or was confirmed by it. (Some of the patients interpreted the extensive warnings as confirmation of the surgeon’s competence.) “People tend to prefer and to give excessive weight to information that is in favor of their existing decision when the alternatives are presented sequentially and allow a selection,” the researchers explain.

The study supports the clinical observation that “once a patient has decided to have a procedure, there’s very little that will deter them,” said Richard L. Abbott, MD, the Academy’s secretary for Quality of Care and Knowledge Base Development. It also suggests a need to give informed consent earlier, he said. “I think the informed consent needs to be done ideally at least a week before, so there’s an opportunity to think about the pros and cons, ask questions and discuss the options with family members,” he said.

“I’m not sure in cataract surgery it would make that much difference whether the informed consent was a day before or a week before,” Dr. Abbott said. However, he added, “With more types of IOLs available, informed consent might become more of an issue. But in LASIK surgery where it is truly elective, there the informed consent tends to be more important in avoiding legal problems later.”

1 Kiss, C. et al. Arch Ophthalmol 2004;122(1):94–98.

News compiled by Linda Roach.

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