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RECENT data from prevalence studies is not only challenging long held assumptions about the risk factors for glaucoma but is also changing the very definition of the disease, Harry Quigley MD told the 4th International Glaucoma Symposium.

The studies have provided a much firmer scientific basis for gauging patients’ risk of developing glaucoma. The new insights are also leading to the development of more accurate means of diagnosing the disease, he said.

Dr Quigley noted that what makes identifying the risk factors for glaucoma so important is that while the disease is second only to cataract as a cause of blindness worldwide, it is diagnosed in only 50% of cases in developed countries and in an even lower proportion in the developing world.

The latest estimates are that glaucoma affects about 50 million people worldwide. Of those, eight million have been blinded by their disease. That is despite the fact that, in the case of open-angle glaucoma, early treatment can prevent progression of the disease in over half of patients and bilateral blindness in 90%.

One of the greatest changes in thinking the studies have brought about is the de-coupling of IOP from the aetiology of glaucoma. While the new data does show that an elevated IOP is the most important risk factor for glaucoma and that this does accelerate the progression of the disease, it is not the root cause of the degeneration of the optic nerve head which results in vision loss.

"Those of you who treat glaucoma have locked the idea of IOP and glaucoma together and we have learned from prevalence surveys that this is wrong," Dr Quigley said.
Several studies have shown that although glaucoma patients as a group have a higher IOP than do unaffected individuals, there is considerable amount of overlap between the two groups, he pointed out.

For example, in a survey of Spanish-speaking Americans in Arizona, Dr Quigley and his associates found that the average IOP among those without glaucoma was 15mmHg and that of those with glaucoma was 18mmHg. Only one in four with the disease had an IOP greater than 21mmHg.

"Only a minority of glaucoma patients have very high pressures and many have normal pressures. That challenges the idea that normal tension glaucoma is different or distinct. We should therefore stop using the terms low or normal tension glaucoma."
A better basis for defining and diagnosing glaucoma is to look for both structural and functional evidence of glaucomatous optic neuropathy, he said. Population studies have been useful in that regard, as they have determined more precisely what changes to expect in an optic disc affected by glaucoma.

To illustrate the principle, Dr Quigley cited a study of which he was a co-author (Foster et al, BJO 2002;86:238-242). The researchers found that in 98.5% of a given population the cup-to-disc ratio was greater than 0:7.

"On that basis, in order to be defined as glaucoma a patient would have to have that cup-to disc ratio and at the same time a visual field defect in that eye on the Humphrey perimeter such as an abnormal hemi field test or an abnormal pattern standard deviation," Dr Quigley explained.

Two things that prevalence studies have shown are not the clear-cut risk factors for glaucoma that they were once thought to be are high blood pressure and diabetes.
The new data indicates that high blood pressure is only a risk factor for open angle glaucoma among very old people. In the rest of the population the risk for glaucoma is worse among those with low blood pressure.

"The relationship between blood pressure and eye pressure is more complex than we thought in the past. It’s going to require more study and there are more issues to resolve in terms of whether we want to optimise blood pressure rather than simply lower it."

As regards diabetes, Dr Quigley pointed out that while conventional wisdom has been that diabetes is a risk factor for open angle glaucoma, nearly every prevalence survey has indicated that it is not. What makes that finding particularly surprising is that diabetics on average have higher IOPs than non-diabetics.

"Since eye pressure and age are the highest risk factors, that should mean that diabetics should have more open angle glaucoma. Therefore, it may be that diabetics who don’t yet have bad retinopathy are still releasing growth factors and cytokines into their retina that may be protective against ganglion cell death," he commented.
Prevalence studies and clinical studies such as OHTS have also identified new risk factors for glaucoma, including a large optic disc size and thin corneas. Both factors may be related to the biomechanical stresses exerted on the optic disc, although the contribution of thin corneas may be partly due to the calibration errors they cause in IOP measurements.

Most studies still indicate that myopia is a risk factor, although that may be due to large optic disc sizes of such individuals.
One good piece of news to emerge from prevalence studies is that among patients in developed countries only about 3% of open angle glaucoma patients get worse every year and have a worsening of field.

That means that over the average 15 year period such patients live with the disease and about 45% will have a progression of their disease. The rate of blindness from open angle glaucoma is also fairly low at 4% to 8%.

"That means you can tell your average open angle glaucoma patient that they have a 50/50 chance that they will never get worse if treated in time and a 90% chance that that they will reach the end of their life without being bilaterally blind."
However, prevalence studies suggest that the prospects are much bleaker for patients with angle closure glaucoma, who account for approximately one third of glaucoma patients worldwide. Current estimates from China indicate that 25% of those with angle closure glaucoma develop blindness in their lifetime.

Prevalence studies also continue to shed new light on the role hereditary factors may play in the pathogenesis of glaucoma. They indicate that the impact of glaucoma will vary in different populations according to their racial composition.

For example, the studies show that among people of European descent aged over 40 there is ten times more open angle than there is angle closure glaucoma. Among Chinese persons of a similar age, the rate of angle closure glaucoma is five times that of European individuals, although both groups have similar rates of open angle glaucoma.
Meanwhile, among those of African descent the prevalence of closed angle is about the same as that of those of European descent, but open angle glaucoma is four times as common.

"There is an excess burden of angle closure glaucoma in China and an excess burden of open angle glaucoma among African-derived populations, so that has to be taken into account in our future plans," Dr Quigley noted.

Among Spanish-speaking Americans, age has a strongly modifying effect on the incidence of open angle glaucoma. Among younger individuals the incidence is similar to that of people of European descent, but among the older Spanish-speaking population the incidence is similar to that of African Americans.
The largest group with an excess burden of glaucoma actually comprises half of the world’s population - and that is women. Prevalence studies have shown that women have three times more angle closure glaucoma than men.

"Since angle closure is a more malignant disease, women worldwide are at substantially greater risk for all three of the major causes of blindness. Women get more cataracts, more angle closure glaucoma and they also get more trachoma. Therefore, in applying health measures in the world we should give women special attention," Dr Quigley said.

Harry Quigley MD
The Johns Hopkins Hospital, Baltimore, US
Email: hquigley@jhmi.edu

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