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71st Annual Meeting & Exhibition of the Canadian Ophthalmological Society

Whistler, British Columbia / June 11-14, 2008

Although it has been known for many years that blood pressure (BP) and perfusion pressure are related, there has been a recent increase in interest in their implications for glaucoma. As reported by Dr. Paul Lee, Glaucoma Service, Duke University Eye Center, Durham, North Carolina, a published study demonstrated that patients with lower ocular perfusion pressure present with worse visual fields (Choi et al. Invest Ophthalmol Vis Sci 2006;47(3):831-6). Dr. Lee also pointed out that since cardiologists have made very low BP a goal of therapy, it has become more common for patients with normal intraocular pressures (IOPs) to experience progression of visual field loss, particularly with diastolic pressures <60 mm Hg. It has also long been known that nighttime dosing of hypotensive therapy can cause loss of vision due to decreased nocturnal ocular perfusion pressure.

Nocturnal Ocular Perfusion: Double Jeopardy

Treatment of nighttime pressures may be the most important priority in the management of glaucoma, according to Dr. David Yan, staff ophthalmologist, Mount Sinai Hospital, and Assistant Professor of Ophthalmology, University of Toronto, Ontario. “The performance of a medication at night may actually be more important than the performance of the medication during the day, if indeed the story pans out that what is happening at night is actually when most of the damage is occurring.”

He cited the Baltimore Eye Study, in which researchers showed that the prevalence of primary open-angle glaucoma (POAG) increases sharply at low diastolic ocular perfusion pressure (DOPP) (Tielsch et al. Am J Epidemiol 1991;134(10):1102-10). This finding has been confirmed by several major landmark longitudinal studies. DOPP is the difference two opposing forces: diastolic BP (DBP), which Dr. Yan likened to the pressure of water held back by a hydroelectric dam; and IOP, which he compared to the low water downstream of the dam. DOPP can therefore be increased by either increasing DBP or lowering IOP, he explained.

Some individuals undergo a large decrease in DBP at night (known as “dippers”). Dr. Yan referred to data from a study that indicated dippers are significantly more likely to suffer progression of visual field loss than non-dippers (Graham SL, Drance SM. Surv Ophthalmol 1999;43(suppl 1):S10-S16). Of 48 patients with progressing visual field loss, 34 were dippers, while only nine of 22 patients with stable visual fields were dippers (P=0.01). Importantly, daytime and mean 24-hour BP measurements were not correlated with progression. Numerous other studies have shown nocturnal hypotension to be associated with increased incidence of glaucoma, increased severity of disease at diagnosis and increased risk of progression. Dr. Yan told delegates that patients with normal-tension glaucoma (NTG) have larger than normal nocturnal dips, and NTG patients with progression have larger dips than those who are stable. He recommended that ophthalmologists have their patients undergo 24-hour BP monitoring to measure nocturnal changes in DBP.

On the other side of the DOPP equation is nocturnal IOP. Dr. Yan explained that because of lying in a recumbent position at night, nocturnal IOP has been shown to be higher than measured in the office in the daytime (Mosaed et al. Am J Ophthalmol 2005;139(2):320-4). As a result of what he termed this “double whammy,” patients who appear to be well controlled are actually experiencing significant DOPP drops at night, leading to disease progression. Treatment for low nocturnal perfusion is problematic, said Dr. Yan. Suggestions have included increasing sodium load at bedtime, e.g. by drinking V8, sleeping in a semi-recumbent position, and reducing antihypertensive medication, particularly diuretics, which were identified as a strong risk factor for progression to glaucoma in the European Glaucoma Prevention Study (Miglior et al. Ophthalmology 2005;112(3):366-75). Choice of medications may be important, as some are more effective at night than others, remarked Dr. Yan, citing studies that included one that showed latanaprost and dorzolamide were more effective than alpha agonists and beta blockers at lowering nocturnal IOP, while having no effect on BP (Quaranta et al. Invest Ophthalmol Vis Sci 2006;47(7):2917-23).

Blood Flow More Important Than IOP

In making an argument for the importance of blood flow, Dr. Mark Lesk, Associate Professor of Ophthalmology, Université de Montréal, Quebec, cited the Barbados Eye Studies, which found a 50% increase in risk of OAG for every 10 mm Hg decrease in OPP (Leske et al. Ophthalmology 2006;113(1):29-35). Findings from the Early Manifest Glaucoma Trial study indicated that 100% of patients who had IOP >21 mm Hg and a history of cardiovascular disease progressed . “Cardiovascular disease seems to be really, really important,” Dr. Lesk stressed. A prospective study found an association between progression and reduced blood flow in the ophthalmic and other arteries (Martínez A, Sánchez M. Acta Ophthalmol Scand 2005; 83(6):716-22). He cited several other studies that demonstrated that IOP had no effect at all in some patients. “Where IOP is important in glaucoma, some of its effect is via ocular blood flow, ” Dr. Lesk noted.

Progression in Normal-tension Glaucoma and Blood Flow

Dr. Cindy Hutnik, Associate Professor, Departments of Ophthalmology and Pathology, University of Western Ontario, London, has been collaborating with Dr. Stephen Drance, Professor Emeritus of Ophthalmology, University of British Columbia, Vancouver, regarding patients with apparently normal IOP who nevertheless suffer progressive visual field loss. These are often younger people in the range of 40 to 60 years old, she observed.

Although some researchers suspect an autoimmune component to normal-tension glaucoma, Dr. Hutnik believes that blood flow within the eye may be the culprit. She offered, “Maybe the nerve is becoming damaged because it is relatively deprived of oxygen because it is not getting the blood to it. Like all things in clinical medicine, trying to actually correlate a parameter with an outcome is very difficult, so a lot of people have [dismissed] the blood flow idea, but I think it is being reborn.”

Dr. Hutnik believes that carbonic anhydrase inhibitors (CAIs) have potential in addressing the blood flow issue, as indicated by many basic science and preclinical studies. Quaranta’s work was particularly important, she added. “They followed eye pressure and BP, systolic and diastolic pressure, over 24 hours. They found that the alpha agonists and the beta blockers, which have an effect on BP, have a negative effect, but the medicines that do not affect BP have a positive effect, so [the results] clearly showed that dorzolamide did have a beneficial effect, it lowered the eye pressure but did not lower the BP, so the eye was being perfused,” she explained.

The blood flow concept is a credible one, Dr. Hutnik confirmed. “If you have a patient who is getting worse, certainly using [dorzolamide/timolol] is an option, because it will not hurt anything and there is some evidence it may help. Mark Lesk has taken patients with glaucoma and shown that when you give them dorzolamide, it increases blood flow to the eye.” A research group in Toronto is directly measuring carbon dioxide levels, she remarked, because CAIs release carbon dioxide, which dilates the blood vessels. “So there is, I think, a lot of circumstantial evidence to support this story,” she indicated.

It is important to keep in mind that the eye is not independent of blood flow in the rest of the body, stressed Dr. Hutnik. For example, hypoxia resulting from lowered nocturnal diastolic BP could be responsible for nerve damage in the eye.

Twenty-four-Hour Therapy

There is good evidence supporting the effectiveness of dorzolamide/timolol over 24 hours, commented Dr. Hutnik. “There has been a real push in ophthalmology to use these prostaglandin drugs which are once-a-day drugs. You dose them at night, but if you look carefully at the research, if you dose them at 8:00 pm, at around 10:00 pm, they start wearing off before they kick in again; their peak effect is in the morning, but they tend to wear off at night. The thing about dorzolamide/timolol is it is a twice-a-day drug: you dose it in the morning, you dose it at night, so how it behaves over 24 hours is really quite outstanding; in fact, it performs better at 10:00 at night than the prostaglandins do. It is one of the best performers for nighttime efficacy.”

She explained, “It is like putting the puzzle together: if you add together the 24-hour control, the fact that the CAI has no detrimental effect upon BP at night, and the fact that it may increase blood flow, it becomes a very powerful drug to continue to think about.” She concluded that its ability to lower IOP is sufficient on its own to merit close attention.