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June 2005

Clinical Update: Retina
New Screening Tests for AMD
By Marianne Doran, Contributing Writer

Over the next 15 years, the number of people in the United States with AMD is expected to increase more than 70 percent—from 1.75 million today to nearly 3 million in 2020. Millions more will be at risk. Without a simple, reliable way to screen for the first signs of AMD, early detection and treatment will remain a problem.

Many experts agree that to cast the widest net, a new screening test is needed—one that can be performed by a primary care physician or optometrist, who would then refer the patient to an ophthalmologist for treatment. Specificity is paramount, but a technique that is also quick, easy to use and portable would extend screening to larger numbers of people and presumably help reduce the toll of severe vision loss.

Investigators have taken various approaches to the screening challenge, including frequency-doubling perimetry and psychophysical tests such as noise field perimetry and multifocal electroretinography. Each of these techniques has its limitations, and the search continues.

Scanning Laser Entoptic Perimetry
A recent entry is scanning laser entoptic perimetry, an experimental technique that stimulates the retina to look for visual disturbances. William R. Freeman, MD, professor of ophthalmology and director of the Jacobs Retina Center at the University of California, San Diego, and his colleagues developed the scanning laser device with Microvision Inc. It is an outgrowth of the company’s military technology, which includes a helmet-mounted scanning laser that can superimpose maps and other real-time data onto the retina of a pilot or of a soldier on the ground.

How it works. The ophthalmic system involves a virtual retinal display (VRD), a laptop computer to generate the stimulus and another computer through which the operator controls delivery of the signal. A splitter device allows the operator to see the same image as the one being delivered to the patient through the VRD, and the operator is also able to see the patient’s macula.

The VRD, which has a 1-millimeter aperture, delivers a monochromatic image by means of a scanning laser beam projected onto the retina. Each pixel in the image is randomly assigned to an “off” or “on” value—black for off and deep red (635 nanometers) for on. This creates the effect of random particle motion and is designed to circumvent the Troxler phenomenon. The patient sees areas of visual disturbance as gray or motionless and uses a digital pen and a touch-sensitive pad to outline the areas of visual deficit.

For testing, the patient sits in front of the VRD and places forehead and chin against an adapted slit-lamp headrest to minimize head movement. With one eye patched, the patient looks through the tiny aperture at a specified fixation point. If fixation wanders, the stimulus disappears and the patient sees only a black field.

Why a virtual retinal display? In early screening of cytomegalovirus retinitis patients for peripheral visual dysfunction, Dr. Freeman’s group used entoptic perimetry with a computer monitor or television to display the stimulus. But a flat screen limited the area of the retina that could be examined and posed other problems, as well. The development of the VRD provided a solution.¹

“We use the scanning laser technology because it can be incorporated into a very small machine, it can scan large areas of the retina and you can present a very bright object or a dim object,” Dr. Freeman said. “And the refraction is not important because the scanning laser has a very good depth of field. It’s always in focus.”

Study results. Dr. Freeman’s group recently conducted a prospective study using scanning laser entoptic perimetry to screen for AMD.2 The study involved 91 patients with diagnosed AMD (171 eyes) and 24 controls without AMD (43 eyes). The patients had a dilated exam with indirect ophthalmoscopy and slit-lamp biomicroscopy, followed by fundus photography to document areas of retinal disease.

The investigators stratified the eyes into eight categories by disease stage: 1) mild drusen, 2) moderate drusen (many soft drusen), 3) mild geographic atrophy, 4) moderate to advanced geographic atrophy, 5) pigment epithelial detachment, 6) untreated CNV, 7) inactive previously treated CNV and 8) untreated but regressed CNV. More than half the eyes were classified as having the two mildest forms of AMD.

The researchers calculated sensitivities for each of the eight disease stages and a combined sensitivity for the three categories representing the earliest stages. They reported that the overall sensitivity of scanning laser entoptic perimetry was 82 percent, and the specificity was 100 percent. Sensitivity in the three earliest stages was greater than 70 percent and rose to more than 90 percent for moderate to late-stage disease.

Clinical convenience. The screening test usually takes less than one minute per eye to perform, and the system is portable, making it easy to use in outpatient clinics or nursing homes. Before the scanning laser testing, each person is given a brief tutorial (usually no longer than two minutes). The tutorial includes a demonstration of the stimulus and fixation point and instruction in how to use the digital pen to outline any areas of visual disturbance.

“It is easy for patients to understand,” Dr. Freeman said, adding that the test is very intuitive. With the random particle movement in the peripheral vision, he noted, the patient says, “Ah, over there in that corner, I don’t see them” and then draws the area on the touch pad.

Alfredo A. Sadun, MD, PhD, said one advantage of scanning laser entoptic perimetry is that you have the potential to know where the subject is looking.

“One of the problems with any visual field system is fixation. The subject obviously has to keep his eye precisely aligned in one direction while you are mapping what he can and cannot see,” said Dr. Sadun, chairman of vision research and professor of ophthalmology and neurosurgery at the University of Southern California. “The more precise the mapping system, the more problematic [a loss of fixation] becomes because the tiniest break in fixation will change the map.” He said because the system projects the image into the eye, the operator can see the macula and the landmarks of the eye and can compensate if any eye movement occurs.

Automated Amsler Grid Test
Dr. Sadun and Wolfgang Fink, PhD, a visiting associate in physics at the California Institute of Technology, have developed another type of computerized system for assessing visual fields. Their 3-D computer-automated threshold Amsler grid test involves looking at a computer’s touch screen.3

How it works. The subject focuses on a central fixation marker and then traces breaks in the grid lines with a finger. The computer converts the tracings into coordinates.

“The lines are presented with less and less contrast, the person sees more breaks and, after four or five minutes, that is re-created into a three-dimensional image,” Dr. Sadun explained. The 3-D depiction of scotomata provides information on their location, extent, slope, depth and shape. The test is simple to set up and requires only a touch-sensitive computer monitor and the testing software. The researchers are using the system mainly to detect abnormalities of the optic nerve, but they also have used it to assess AMD.

Removing the guesswork. Michael F. Marmor, MD, professor of ophthalmology at Stanford University, commented that the value of techniques like these is that you can quantify and localize the degree of functional damage, rather than try to guess the degree of visual change from a photograph. “That can be extremely important when you want to know whether the use of a drug or a vitamin or a transplant is actually interrupting the aging process.”

Dr. Sadun also emphasized the importance of developing sensitive and quantitative ways of assessing treatments for AMD, especially since the treatment advances thus far are small steps, not giant strides. “It’s too easy for the patient and even the doctor to be fooled into thinking there has been an improvement or a delay in the progression of AMD,” he said. “But these relatively small improvements are easily lost to the placebo effect. And in order not to be led astray by overinflated impressions of which treatments work, we need to stay with psychophysical science of this kind.”

1 Plummer, D. J. et al. Arch Ophthalmol 2000;118:1205–1210.
2 Freeman, W. R. et al. Arch Ophthalmol 2004;122:1647–1651.
3 Fink, W. and A. A. Sadun. J Biomed Opt 2004;9:149–153.

Dr. Marmor has no related financial interests. Dr. Freeman has a proprietary interest in scanning laser entoptic perimetry. Dr. Sadun has a proprietary interest in the 3-D computer-automated threshold Amsler grid test.