Today, intraocular pressure remains the primary risk factor for the development of glaucoma, and the only parameter that we can treat to avoid progression of the disease. Nevertheless, the data from many studies makes it clear that IOP is not the only factor involved. All of the large-scale, long-term glaucoma studies, for example (i.e., the Early Manifest Glaucoma Trial, Advanced Glaucoma Intervention Study, Ocular Hypertension Treatment Study, Collaborative Initial Glaucoma Treatment Study and Collaborative Normal Tension Glaucoma Study) have found some progression in many subjects regardless of the amount of IOP reduction. Furthermore, some untreated control-group patients with elevated IOPs in those studies did not progress.

Although the American Academy of Ophthalmology recognizes that glaucoma is a multifactorial disease, research into other contributing causes has been limited. However, several studies have now shown clear connections between blood pressure/perfusion levels in the eye and glaucomatous damage (the intuitive explanation being that reduced perfusion may be starving the optic nerve of oxygen and nutrients, leading to damage). For example:

Perfusion pressure inside the globe depends on the difference between blood pressure and IOP. Technically, perfusion pressure is the difference between arterial blood pressure and venous blood pressure. In the eye, however, venous pressure is very similar to IOP. So, we can get a close approximation of ocular perfusion pressure by substituting IOP for venous pressure in that equation: Ocular perfusion pressure equals arterial blood pressure minus IOP.

The possibility of blood pressure being a factor in the genesis of glaucoma has one upside: Blood pressure is easy to measure. It can even be measured throughout the day and night automatically. Unfortunately, measuring ocular perfusion is much more difficult, for two reasons. First, even though several instruments have been developed to evaluate ocular blood flow—i.e., color Doppler imaging and scanning laser ophthalmoscopy—these instruments are expensive and rely on the ability and experience of the examiner to generate reproducible results. Second, we don't know which vascular bed is most important in terms of the pathogenesis of glaucoma. Should we monitor retrobulbar circulation? Choroidal circulation? Retinal circulation? We simply don't know.

 

There's no doubt that blood flow inside the eye can be reduced by elevated IOP. Several studies have shown an improvement in blood flow after IOP reduction, which makes sense intuitively.^9,10 Given that relationship, blood flow reduction could certainly be secondary to IOP elevation.

However, there's some indication that the blood flow component can be primary. For example, consider disc hemorrhages. These are a classic vascular manifestation of a change in perfusion of the tissue. If optic perfusion pressure reduction were secondary to high IOP, you'd expect to find more disc hemorrhages in patients with primary open-angle glaucoma and high IOPs. However, disc hemorrhages are found more frequently in patients with normal tension glaucoma, who have lower, closer to normal IOPs. That suggests that the vascular change could be primary in some cases.

The other reason to suspect perfusion changes can precede development of glaucoma is that, especially in patients with normal-tension glaucoma, we often find vascular concerns that extend far beyond the eye. Such patients may have Raynaud phenomenon or areas of cortical atrophy in the brain, suggesting a systemic vascular problem that may be contributing to the development of glaucoma.

The beauty of the concept of perfusion pressure is that it enables us to quantify the association between IOP and blood pressure. It helps explain, for example, why individuals with a very high IOP have a lower perfusion pressure, and why some patients who have a normal IOP still end up with a lower perfusion pressure (because the blood pressure is low). Overall, it may help to explain why we can have such different patterns between patients in terms of IOP and optic nerve damage.

 

Working with colleagues at a hospital in Mexico, we recently conducted a study comparing the 24-hour profile of IOP, blood pressure and perfusion pressure in glaucoma patients and a control group of healthy patients. We went out of our way to find subjects for both groups who did not have systemic hypertension and were not taking anti-hypertensive medication—not an easy group to assemble! We wanted to exclude the influence of vasoactive drugs, as well as the influence of changes in the vascular bed that hypertension can lead to over time.

We found some very interesting differences between the two groups. Most notably, they had different patterns of perfusion pressure—especially diastolic perfusion pressure—at night. It's well-known that IOP tends to increase when we are in a horizontal position at night, probably because of an increase in episcleral venous pressure. We also know that diastolic blood pressure and perfusion pressure behave differently in normals than in glaucoma patients. What our study found is that early in the morning glaucoma patients have a higher diastolic blood pressure than normals. In fact, their overall mean diastolic blood pressure was higher than normals' pressure. But at night, it became significantly lower than normals'. That indicates a greater fluctuation of diastolic blood pressure.

Interestingly, this echoes data previously found in two studies, although the comparison in those studies was between patients who were progressing and those who were not.^1,8,11 This doesn't prove that the greater fluctuation caused the glaucoma, but it certainly suggests that the connection between them is significant and worthy of further investigation.

Unfortunately, data regarding 24-hour fluctuation in blood pressure or perfusion pressure is limited. None of the major long-term glaucoma-related clinical trials looked at IOP, blood pressure or perfusion fluctuation. (Some of those studies calculated the IOP variation between office visits and referred to that as fluctuation, but this is entirely different from pressure fluctuation over a 24-hour period.)

 

Although our findings are interesting, we also need to take a look at what happens to patients who take systemic anti-hypertension medications. How does this affect the drop in diastolic perfusion pressure at night? An obvious possibility is that these medications reduce nighttime diastolic perfusion pressure even further. The issue is complicated by the fact that there are multiple systemic anti-hypertension medications on the market, and they may not have identical effects.

One interesting finding regarding systemic medications for hypertension came out of a study that drew data from the Thessaloniki Eye Study in Greece.¹² In the population they studied they found that cup area and cup-to-disc ratio were increased in previously hypertensive subjects who now had normal diastolic blood pressure as a result of treatment, compared to patients with high diastolic blood pressure who weren't treated, as well as compared to patients with normal diastolic blood pressure. In other words, there appears to be a correlation between reducing diastolic blood pressure to normal levels with medication, and an increased cup area and cup-to-disc ratio. This means there could be an association between blood pressure and ocular structure—and treatment for hypertension could be having effects far beyond the reduction in blood pressure.

 

The negative impact of systemic hypotension is easy to understand: Lower blood pressure translates to lower perfusion pressure and decreased blood flow to ocular tissues. However, some studies have found an association between glaucoma and systemic hypertension (which, in theory, should produce increased ocular perfusion).^13-15

There are three possible explanations for these findings. The first possibility is that systemic hypertension may be causing long-term changes in the vascular bed—changes that impair normal optic nerve autoregulation, especially in the arteries. Autoregulation allows an organ to maintain adequate blood flow despite factors that would otherwise interfere with perfusion pressure, such as increased blood pressure or increased IOP. Normally, the optic nerve has the ability to autoregulate. However, this ability may be impaired in some patients with glaucoma, and that impairment could allow a change in blood perfusion at IOP levels that would not lead to change in a patient with normal, functioning autoregulation.

The second possible explanation is that measurements of glaucoma patients tend to show higher systolic and diastolic blood pressure compared to normals if you take just one measurement per day, which could account for some of these findings. In other words, these findings may not be accounting for the increased 24-hour fluctuation that we found in our study.

The third possible explanation is that many of these patients could be taking medications for hypertension. This could be causing changes in diastolic perfusion pressure, especially at night, which may be associated with glaucoma.

 

Given the likelihood of a connection between blood perfusion pressure and glaucoma, when I'm in the clinic I stay alert for cases in which I suspect a patient being treated for hypertension may be progressing in spite of normal in-office IOP measurements. In those cases, I ask for an opinion from the patient's cardiologist about how much blood pressure reduction the patient needs. I may also have the patient undergo 24-hour blood pressure monitoring. In some instances I've found significant nocturnal pressure dips in patients taking systemic anti-hypertensive medications. In that situation, I talk to the cardiologist or doctor in charge and try to modify the treatment to avoid those blood pressure drops at night.

Clearly, perfusion pressure is not the only factor relating to glaucoma risk. But the more we investigate it, the more obvious it becomes that a connection exists. I've been investigating vascular risk factors for a long time, and I believe they need to be investigated in much greater detail. It would be extremely helpful to have large-scale, long-term clinical data regarding IOP and blood pressure fluctuation over the course of 24 hours; that would enable us to evaluate the true importance of those factors in terms of the risk of progression.