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June 2012

 
News in Review
A Look at Today's Ideas and Trends
 
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Space Travel Changes Astronauts’ Eyes

The mission “to boldly go where no man has gone before” appears to have physiological consequences beyond bone mineral loss and muscle atrophy. Astronauts also experience visual changes and intraorbital and intracranial abnormalities similar to those caused by idiopathic intracranial hypertension, which causes swelling at the juncture between the optic nerve and eyeball.1

Although astronauts have reported blurred vision in the past, most cases resolved once they returned to Earth, said researcher Larry A. Kramer, MD, professor of diagnostic and interventional imaging at the University of Texas Medical School at Houston. But more severe changes, such as papilledema and irreversible choroidal folds, started showing up after longer cumulative time in space. “This really began to escalate everyone’s level of awareness,” said Dr. Kramer. It also prompted his recent retrospective analysis of astronauts.

Study results. Using thin-section, 3-D, T2-weighted magnetic resonance images (MRI) taken with a 3-T unit, researchers at the University of Texas studied the brains and eyes of 27 astronauts who had been exposed to zero gravity (microgravity) for an average of 108 days. The astronauts had traveled on space shuttle missions or the International Space Station, a research facility that’s been orbiting Earth since 1998. 

More than 30 days of cumulative exposure to zero gravity was associated with expansion of cerebrospinal fluid space surrounding the optic nerve in 33 percent of those studied, flattening of the posterior eyeball in 22 percent, bulging of the optic nerve in 15 percent, and changes in the pituitary and its connection to the brain in 11 percent. Although less pronounced, changes even showed up in some astronauts who traveled for fewer than 30 days. However, Dr. Kramer said the 3-D technique used in the study likely created a bias overall toward larger optic nerve sheath diameter measurements than previously reported using thicker 2-D slices.

Eight astronauts had a follow-up MRI after a second excursion into space for an average duration of 39 days. The most dramatic result from this group, said Dr. Kramer, was illuminated by before-and-after images in one astronaut showing the development of flattening of the posterior globe. “This was the first time we were able to document a dramatic change in the eye we could temporally ascribe to space flight,” said Dr. Kramer, acknowledging the study’s limitations—its retrospective nature and lack of a control group. 

Gravity of microgravity. What is the common denominator among affected astronauts? The researchers theorize that microgravity is to blame, as it allows upward shifts in internal fluids that, on Earth, would be kept lower in the body due to the pull of normal gravity; among the effects are facial congestion and disappearing wrinkles. Of greater concern, however, is that “when blood redistributes from the lower extremities toward the brain,” said Dr. Kramer, “venous or cerebrospinal fluid outflow may be impeded; and, due to the skull’s rigidity, the retained fluid would increase intracranial pressure. This increased pressure, even if mild, would be a more serious problem in an environment where it is raised 24 hours a day.” 

Because fluid around the brain is in communication with the fluid around the optic nerve, said Dr. Kramer, pressure is raised in both areas simultaneously. However, the spaces in the skull and orbit are not identical. Lacking a surrounding rigid bone structure, the optic nerve sheath is able to elongate to some degree, folding upon itself and kinking. As it expands, he said, it also presses on the posterior aspect of the globe, causing flattening. Another theory for flattening had been hypotony, he said, but previous research has not supported this mechanism.

In order to learn more, NASA is now performing regular MRI scans and other ocular imaging before and after each flight, as well as conducting various tests.

—Annie Stuart

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1 Kramer LA et al. Radiology. doi:10.1148/radiol.12111986. Published March 13, 2012.
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Dr. Kramer reports no related financial interests.
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Dr. Kramer and colleagues published a related report: Mader TH et al. Ophthalmology. 2011;118(10):2058-2069.

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Retina Report

Missing Enzyme Contributes to Dry AMD

A multinational research team has delineated the molecular pathway by which lack of an RNA-cleaving enzyme in the retinal pigment epithelium (RPE) leads to the dry form of age-related macular degeneration (AMD).

The researchers found that the RPE cells die because of a molecular chain reaction that hijacks the cells’ innate immune system. The inflammatory process is not due to an infiltration of immune cells, they write in the journal Cell.1 Rather, RPE cell death and geographic atrophy (GA) are the final outcomes of this “dysregulated homeostatic anti-inflammatory mechanism” within the RPE cell. 

Previously, members of the group linked GA to low levels of an RNase, DICER1, in RPE cells.2 The deficit causes a toxic overabundance of a noncoding RNA molecule, Alu RNA. 

In the current study, the scientists wanted to understand the mechanism by which the excess Alu RNA harms the RPE, said study leader Jayakrishna Ambati, MD, professor and vice chairman of ophthalmology and visual sciences, and professor of physiology at the University of Kentucky, in Lexington. 

The researchers determined that the extra Alu RNA activates a specific group of inflammatory proteins, called the NLRP3 inflammasome. The activated inflammasome floods cells with interleukin 18, and this cytokine in turn activates the cell-killing molecule MyD88, they found. (Eventually, the lack of RPE support endangers the adjacent photoreceptors, too.)

NLRP3 is known to be active in many diseases, including atherosclerosis, type 2 diabetes, and Alz-heimer disease. 

The researchers’ hunt for the mechanism of Alu RNA toxicity moved, step-by-step, from one upregulated protein or activated gene in the chain to the next, first in knockout mice and then in human eyes with dry AMD. 

Human confirmation was possible because Dr. Ambati’s lab maintains a molecular library of dry AMD, assembled from dozens of autopsy eyes, he said.

“Our approach is to go from bedside to bench to bedside again,” Dr. Ambati said. “That’s why we collect these very precious samples of geographic atrophy eyes. We try to see whether the pathways we found in human cells and in mice are present in the GA eyes.”

—Linda Roach

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1 Tarallo V et al. Cell. 2012 April 26. [Epub ahead of print]
2 Kaneko H et al. Nature. 2011;17;471(7338):325-330.
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Dr. Ambati cofounded iVeena and is a member of the scientific advisory board of Biomolecular Therapeutics, both of which are evaluating drugs to treat dry AMD. He is named as an inventor on patent applications filed by the University of Kentucky.

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Trends in Practice

Imaging for Keratoconus

When it comes to ruling out keratoconus before refractive surgery, comprehensive ophthalmologists choose from a variety of screening methods, sometimes selecting more than one. In a survey conducted by the Academy, about two-thirds of respondents reported using Placido disk topographic imaging of the anterior cornea; almost half use Scheimpflug imaging, and another half choose slit-scanning imaging of the anterior and posterior cornea; and more than one-tenth use corneal optical coherence tomography (OCT).

Placido disk—the initial gold standard—and Scheimpflug, which is a newer version of slit scanning, are indispensable in ruling out keratoconus, said Ronald Krueger, MD, medical director of refractive surgery at the Cleveland Clinic. The survey results, he said, are surprising; he thought that more clinicians would be using Placido disk imaging as their first-line screening tool. 

Using Placido technology alone, however, may be problematic for two reasons. 

First, it evaluates only the anterior corneal surface. Dr. Krueger noted that there was debate at the Academy’s Annual Meeting Subspecialty Day: Some ophthalmologists say there is not yet proof that evaluating the posterior surface is essential to rule out keratoconus, while a larger number recommend doing so. 

Second, accurate Placido imaging requires an adequate tear film. “If the tear film breaks up on the surface, it can give an artifactual area of steepening or flattening on the Placido that makes the whole thing look suspicious,” Dr. Krueger said. Thus, if the tear film is spotty on the Placido image, it is essential to generate a more uniform ocular surface and reevaluate with the Placido or Scheimpflug.

With the ability to capture multiple slit images from side to side, Scheim-pflug (used in Oculus Pentacam and Galilei Dual devices) works fine as a single choice and is growing in popularity, he said. Although standard slit scanning has some potential limitations, it is adequate, he said. 

Dr. Krueger reserves corneal OCT for cases where he needs to evaluate thickness profiles.       

—Annie Stuart

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Dr. Krueger is a consultant for Alcon, Clarity, LensAR, and Presbia.

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CLINICAL PREFERENCES. To better understand current practices on a number of topics, the Academy surveyed comprehensive ophthalmologists about how they would handle various clinical situations. Each month, EyeNet will feature one question—this month about screening for keratoconus—and ask an expert to provide perspective on the responses.

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Cornea Report

Pollution & Conjunctivitis

Air pollution irritates the eye. Although this makes intuitive sense, few studies have been published on the topic. Now a team of researchers reports that pollutants increased demand in Taiwan for outpatient care for nonspecific conjunctivitis.1

The team, which includes an ophthalmologist, a biochemist, and an environmental engineer, measured the impact of air pollution on ocular health by coupling national health insurance data for outpatient visits between 2007 and 2009 with daily ambient air quality data tracked by the Taiwan Environmental Protection Administration. 

Unlike other conditions affected by air pollution—asthma, for example—the effect on the eye from exposure to pollutants is immediate. 

The researchers found that ozone (O3) and nitrogen dioxide (NO2) produced the strongest effects. Large-diameter particulate matter (PM) had an adverse effect, although fine PM did not. 

The authors report that conjunctivitis accountsfor more than 40 percent of ophthalmologic outpatient visits annually in Taiwan.

The study’s conclusion did not surprise Susan M. MacDonald, MD, who noted that the term “urban eye allergy syndrome” is already part of the medical lexicon. “Poor air quality can exacerbate allergic conjunctivitis and dry eye,” said the director of comprehensive ophthalmology, Lahey Clinic Medical Center in Burlington, Mass.

But Dr. MacDonald said that it is easy to overlook air quality when evaluating patients. She called the study “a good reminder that air quality does affect our patients’ eyes and should be considered when we are evaluating patients with ocular irritation.”

—Miriam Karmel

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1 Chang C et al. Invest Ophthalmol Vis Sci. 2012;53(1):429-433.
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Dr. MacDonald is a consultant to Alcon. 

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