In many cases the progression of eye disease can be slowed, even halted, by early detection. Most of the instruments and techniques used to detect eye disease were developed years, even decades, ago—which is in stark contrast to the ongoing cutting-edge advances in treatments we hear about in the news nearly every day.

In this article we describe two significant advances in early detection of eye disease: one for glaucoma and one for diabetic retinopathy. Each holds out hope of significantly earlier diagnosis, and each was prompted by a reassessment of scientific research and technology choices from decades ago.

Early Detection of Glaucoma

According to the BrightFocus Foundation, over 3 million Americans currently live with glaucoma, 2.7 million of whom are over 40 years of age. It's the leading cause of blindness among Hispanic and African Americans, the latter of whom are 15 times more likely than non-Hispanic Caucasians to go blind due to this progressive disease.

There is currently no cure for glaucoma. Early detection is critical. If diagnosed early enough, vision loss can be limited with medications, surgery, or both.

Regular testing by an eye specialist is essential. During the exam a puff of air may be directed at the eye to determine intraocular pressure, which is to say the pressure of the vitreous fluid that fills the eye and holds its shape. Normal pressure is between 10-21 mm Hg (millimeters of mercury). The average pressure reading is approximately 16. Above 21 mm Hg is considered high, which has historically been linked to the onset of glaucoma.

A standard eye exam will also include an ophthalmoscopy. After eye drops have been used to dilate the pupil, the doctor uses a slit lamp to examine the shape and color of the optic nerve to spot any signs of damage. If the intraocular pressure exceeds the normal range, or if the optic nerve appears abnormal, a visual field test may be ordered to detect any vision loss. For this procedure the patient looks into an eyepiece and indicates if and when he or she detects a pinpoint light that is directed toward various retinal areas to make sure they are functional.

Unfortunately, by the time most people display the nerve damage associated with glaucoma, the disease has already robbed them of some of their vision. And glaucoma can be a stealth disease. "One of the misconceptions most people have about glaucoma is that it's caused by high intraocular pressure which damages the optic nerve," observes Michael Kalloniatis, OD, PhD., Professor of Optometry and Vision Science at the University of New South Wales, and Director of the Centre for Eye Health, an initiative between the university and Guide Dogs NSW/ACT. "When I was in optometry school the rule of thumb was that if your intraocular pressure was greater than 21 mm you had glaucoma, if it was lower, you didn't."

According to Kalloniatis, nearly half of people with glaucoma have normal intraocular pressure, including his own mom, who has what doctors now call Normal Tension Glaucoma. "The current thinking is that it's not the high pressure that causes the damage, it's the differential between the intraocular pressure and the blood pressure in the retinal vessels."

This is why a thorough eye exam usually also includes a visual check of the retinal nerves, and, if called for, an optical coherence tomography, which offers an even closer look at potential nerve damage. And if something looks wrong there, the doctor may perform a visual field test.

In a visual field test, the patient gazes into an eye piece and reports when he or she perceives flashes of light that are directed to various locations on the retina. "Sometimes, however, there will be detectable nerve damage, only the visual field test will appear normal," says Kalloniatis. "In those cases most doctors will take a wait-and-see approach.

To Kalloniatis this didn't make sense. "If there are structural changes, we should really expect to see functional changes as well," he says, and Kalloniatis began to wonder if perhaps the visual field test itself might be part of the problem.

"The generally accepted thinking is that glaucoma vision loss begins with the peripheral vision, and then progresses toward the center,  " notes Kalloniatis. "We theorized that this may not be the case, and that the reason some people might show loss of nerve function but still pass the visual field test is because of the limitations of the test itself."

Back when visual field studies were first being developed, there was one standard with varying specifications for the size of light that would be used to trigger the retinal response. Two of these specifications are called Goldmann II and Goldmann III, named after the developer, Dr. Hans Goldmann. Goldmann III uses a light that is the size of approximately one half of a degree of the retinal surface. Goldmann II uses a light that is the size of a third of the area covered by Goldmann III, and is "far more sensitive," says Kalloniatis.

To picture why this is so, imagine the dot of light cast by the Goldmann III standard as a very basic computer screen consisting of 16 pixels. If four of those pixels are not working, the image will still be largely visible. For Goldmann II, shrink that computer screen down to four pixels. Now, those four defective pixels block the image completely. The damage is easily detected.

Kalloniatis and his colleagues began including the more sensitive Goldmann II test in their patient screening at the Center for Eye Health. They discovered that many of the people with detectable nerve damage who had passed a standard visual field test also passed a more sensitive, Goldmann II test?at least at their vision's mid-periphery, which is where conventional wisdom says glaucoma damage begins. They did, however, detect abnormalities closer to the optic nerve—within 15 degrees of the patients' central vision. Additionally, they discovered that these early warning signs were most pronounced in those with normal tension glaucoma, which is far less likely to be diagnosed and treated before serious nerve damage has occurred.

"According to our models of how the disease progresses, this central damage could be occurring years before it shows up on a standard retinal exam or visual field test," predicts Kalloniatis.

So why do standard visual field tests still use the larger Goldmann III specification when Goldmann II is so much more sensitive? "Back when the testing machines were first being developed, the engineers decided that Goldmann III was as small as they could go and still project a light that was strong enough to be perceived," observes Kalloniatis. "The technology has advanced, but now we have decades of published research based on the Goldmann III specification, which makes it the gold standard for research. Also, who is going to invest the millions of dollars to get regulatory approval for a change of resolution when as of today, most experts aren't even aware the change could help with early diagnosis?"

Glaucoma isn't the only eye disease where the reliance on old technologies and ways of thinking may be hampering early diagnosis.

Early Detection of Diabetic Retinopathy

In the US there are an estimated 30 million individuals with diabetes. Nearly one quarter of these people also develop diabetic retinopathy.

As with glaucoma, early diagnosis is essential for those with diabetic retinopathy. The longer an individual has diabetes, the more likely it is that he or she will develop diabetic retinopathy. Unfortunately, according to Rithwick Rajagopal, MD, PhD, Assistant Professor, Ophthalmology and Visual Sciences at Washington University, "Although the standard is that a newly diagnosed diabetic should schedule an eye exam within six months, even among those with excellent access to health care only between 40 and 50 percent actually make an appointment, and among those with limited health care access, this number drops to just 20 percent."

More emphasis on awareness and early medical intervention can make a significant difference. So could more effective screening. Currently, the diagnosis of diabetic retinopathy is only made after a specialist detects changes in the delicate blood vessels that nourish the retina. But according to Rajagopal, "By that time there has already been significant damage."

Rajagopal and his colleagues suspected there might be ways to detect the disease earlier. "Going back to the scientific literature, we found studies conducted in the 60s where diabetic mice were given a vision test called electroretinography that revealed measurable vision loss with no perceivable vessel damage," he relates. Rajagopal suspected there must be another functional defect causing the vision loss. He hypothesized the loss was neural in nature, but he was unable to test his hypothesis because most of the past and current animal-based diabetes research is performed using mice that have been injected with pancreas destroying compounds. "These substances are neurotoxic, so any retinal nerve research using these mice would be flawed from the start," notes Rajagopal.

It was time to build a better mouse.

Rajagopal and his colleagues began overfeeding test mice with a high-fat, high-calorie diet, leading to obesity, high fasting glucose levels and other insulin-related issues. At six months Rajagopal already began seeing retinal nerve damaged as measured by the same electroretinography tests, which track the time it takes the retina to respond to a flash of light and the strength of that response.

"The earliest changes we noted were in the lengths of time between the flash and the response," says Rajagopal. "The test mice responded upwards of 10 percent slower than the control mice. It was another six months before the same mice began displaying the retina vessel damage that has traditionally been thought to cause the retinopathy. "Extrapolating these results to the average human life span, our research indicates we could spot vision damage decades earlier than is currently feasible," Rajagopal predicts. "This could also lead to new neural based therapies once further research reveals what, if any, causal relationship there is between the vessel damage and the nerve damage that precedes it.

Looking Forward

Rajagopal's mice will cost much more than standard lab mice, and, as with the visual field test standards, there are decades of research and professional reputations that are based on the old model. It is not ours to say whether these two developments represent genuine medical advances. After all, there is always the chance the studies were flawed, or unrepeatable. Hopefully, the medical community will not dismiss these potential advances out of hand, but will give them the scientific inquiry and analysis they seemingly deserve.

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Bill Holton
Article Topic
Vision Research