Introduction

At the "Glaucoma: The Pendulum Swings" Subspecialty Day immediately preceding the 2008 meeting of the American Academy of Ophthalmology in Atlanta, Joint Meeting with the European Society of Ophthalmology, topics included ocular blood flow and perfusion pressure and "normal tension" glaucoma and angle-closure glaucoma.

In "Clinical Studies on Blood Flow," Dr. Louis Cantor from Indianapolis, Indiana, asked, "Why be concerned about blood pressure?" Glaucoma is a multifactorial disease; although intraocular pressure (IOP) is its primary risk factor, and the only one proven to be modifiable, glaucoma can develop with "usual" IOP, and glaucoma damage can progress even though IOP has been decreased substantially. Are there vascular risk factors for glaucoma, such as vascular disease, hypertension, vasospasm, and ocular perfusion pressure (OPP, the difference between systolic, diastolic, or mean arterial blood pressure and ocular pressure)?

The Baltimore Eye Survey^[1] suggested that diastolic perfusion pressure (DDP) is a risk factor for glaucoma. The odds ratio for developing glaucoma increased from 1.0 with a DPP > 50 mm Hg, to 1.72 with a DPP of 40-49 mm Hg, to 2.14 with a DPP of 30-39 mm Hg, to 6.22 with a DPP < 30 mm Hg. In the Early Manifest Glaucoma Trial,^[2] patients with a systolic perfusion pressure (SPP) > 125.5 mm Hg had a progression rate of 64%, compared with 71% for an SPP ≤ 125.5 mm Hg. The median time to progression was 69 and 48 months, respectively. In a subset of patients with a higher IOP, the odds ratio for glaucoma progression was 1.55 in patients who had a lower compared with those who had a higher SPP.

Vascular abnormalities are important risk factors for glaucoma development and possibly for progression, concluded Dr. Cantor. Clinicians do not need sophisticated technologies to assess the OPP; rather, they need only the information provided by a tonometer and a sphygmomanometer. Regular blood pressure measurements combined with other factors might suggest different ways to treat at least some patients and might improve detection and treatment for patients with blood pressure that is too high or too low.

Dr. Cantor recommended that ophthalmologists regularly measure their patients' blood pressures, calculate the DPP, closely follow patients with a DPP < 60 mm Hg (especially those whose DPP is < 50 mm Hg), and refer patients with blood pressure anomalies for further evaluation and appropriate treatment.^[3]

Dr. Rohit Varma from Los Angeles, California, presented "Epidemiologic and Clinical Trial Evidence for the Importance of Ocular Perfusion Pressure (OPP) in Glaucoma." Expanding on the preceding findings, Dr. Varma reported data from several studies. The Egna-Neumarkt study^[4] indicated that glaucoma prevalence increased rapidly as DPP decreased to < 70 mm Hg. The data from the Proyecto VER Mexican study^[5] showed that patients with a DPP < 50 mm Hg had a 4-fold higher risk for glaucoma compared with those whose DPP was 80 mm Hg. The Barbados Eye Study^[3] (conducted in an African-Caribbean population) concluded that at 4 and 9 years, low DPP, SPP, and mean perfusion pressure were all associated with increased risk for glaucoma progression. Finally, the Los Angeles Latino Eye Study^[6] showed that glaucoma prevalence increased rapidly and linearly when DPP decreased to < 50 mm Hg.

Do these findings have clinical implications? Ophthalmologists should be able to easily measure SPP and DPP and to calculate mean perfusion pressure,^[1] which appear to be significant hemodynamic risk factors associated with glaucoma. The goal becomes avoiding a low perfusion pressure by reducing IOP and by detecting patients with low blood pressure. If the latter is due to overzealous treatment of systemic hypertension, collaboration with general practitioners and physicians should be able to rectify it by altering the amount or the timing of antihypertensive agents.

Another concern Dr. Varma raised is that some topical antiglaucoma agents actually might reduce blood pressure, thus paradoxically decreasing OPP. Although prostaglandin agents and carbonic anhydrase inhibitors effectively controlled perfusion pressure "around the clock," beta-blockers were effective during daylight hours but less so during sleep. Patients receiving alpha-agonists had the lowest OPP overall because of these drugs' effect on systemic blood pressure.^[7]

Moderator Dr. Joe Caprioli from Los Angeles argued that SPP, DPP, and mean arterial ocular perfusion pressure are not real entities; rather, they are surrogates for real OPP because brachial arterial pressure is not ophthalmic artery pressure. It is ophthalmic artery pressure that determines real OPP. We need to know real OPP, said Dr. Caprioli, and to detect patients for whom this is an important contributor to disease progression. Even though we might not know this, clinicians need to look for and treat raised IOP and to identify and to treat, where possible, reduced blood pressure.

This information challenges clinicians to consider optic nerve head perfusion pressure in patients with glaucoma and to improve this beyond IOP control, which addresses only one part of the perfusion equation.

Dr. Angelo Tanna from Chicago, Illinois, defined normal-tension glaucoma as optic neuropathy with excavation, an associated visual field abnormality fitting the pattern of glaucomatous defects, an open drainage angle, and an IOP within 2 standard deviations of the population mean. A "normal" IOP for any population is arbitrary, he said, with problems correcting for central corneal thickness and the challenges posed by often widely fluctuating IOP.

Differential diagnoses include "high IOP" glaucoma with very thin corneas (in which the applanation tonometric measurement is artificially low), intermittent unrecognized or previously raised IOP, glaucoma-like discs (tilted, myopic, colobomatous, hypoplastic), and glaucoma-like visual field defects (optic disc drusen, chorio-retinal scars).

Dr. Douglas Anderson from Miami, Florida, and Dr. Bruce Shields from New Haven, Connecticut, debated whether normal-tension glaucoma differs from primary open-angle glaucoma. In favor of such a difference, Dr. Anderson said that normal-tension glaucoma manifested an abundance of nerve-damage-relevant, IOP-unrelated pathologic mechanisms, including "weak" lamina cribrosa, abnormal astrocytes, vascular dysregulation (cold extremities, visual migraine, low blood pressure, and reduced thirst), cardiovascular disease, and sleep apnea. Although these factors might be present (but not particularly conspicuous) in primary open-angle glaucoma, they are almost or entirely absent in ocular hypertension.

Although major, IOP is but one risk factor for glaucoma, and it makes no sense to separate diseases on the basis of an arbitrary threshold in this single factor, said Dr. Shields. Glaucoma is a group of optic neuropathies to which a variety of pathologic processes contribute, with variable IOPs. Each risk factor lies on a continuum; for example, a certain IOP no longer defines glaucoma. Reduction of IOP, even if "normal," helps to slow the disease. We base the diagnosis on all available evidence, with little emphasis on IOP, said Dr. Shields, then we tailor the treatment to the mechanisms believed to be responsible for damage in that patient.

Dr. Kuldev Singh from San Francisco, California, outlined his approach to determine the likely extent of IOP reduction needed; it depends more on the historical rate of disease progression for the individual patient than on the baseline IOP. Because approximately half the untreated patients in the Collaborative Normal Tension Glaucoma Study^[8,9] did not progress over 8 years, Dr. Singh is more likely to offer IOP reduction without evidence of progression for patients with glaucoma-like optic discs if the IOP is elevated. If IOP is "normal," Dr. Singh might withhold treatment until progressive cupping or visual field loss has been recorded. If progressive glaucoma damage has been recorded, the situation is different, said Dr. Singh. In this scenario, IOP is reduced no matter what its starting level.

Although an arbitrary IOP reduction from baseline, such as 30%, is sometimes recommended, Dr. Singh feels that consideration of the side effects that may occur is important. Degree of desired IOP reduction, Dr. Singh argued, should be based on expected risks and benefits of each treatment step, recognizing disease severity, documented rates of progression, life expectancy, and the patient's willingness to accept possible side effects. Balancing risks and benefits is a dynamic process for each patient.

Dr. Singh does not follow a complex diagnostic process for patients with a diagnosis of normal-tension glaucoma if disc damage and visual field loss match one another and if both appear to be glaucomatous. Additional investigations of any patient with "glaucoma" should follow the same principles, regardless of the IOP. Dr. Anderson's recommendations for patients requiring further investigations included those with visual acuity < 6/12, visual field loss pattern respecting the vertical meridian, disc neural rim pallor outside the cupped area, and unexplained unilateral disease. This applies to all patients, regardless of IOP.

Because angle-closure glaucoma causes as much blindness as does open-angle glaucoma,^[10] it warrants attention, said Dr. Tin Aung from Singapore. Pupil block is the primary mechanism, and mandates laser peripheral iridotomy (LPI) as the primary treatment strategy. However, LPI does not open the drainage angle in all cases, and it can still be associated with a high rate of increased IOP and progression of glaucomatous optic neuropathy.^[11] Other mechanisms of angle-closure glaucoma discussed by Dr. Aung include plateau iris (a large ciliary body or anteriorly rotated ciliary processes, which hold the peripheral iris forward against the meshwork despite a patent peripheral iridotomy)^[12,13] and uveal/choroidal effusion or even choroidal expansion, any of which might precede or even precipitate acute angle closure.^[14]

With ultrasound biomicroscopy, plateau iris has been identified in > 30% of angle-closure eyes. Clearly, non-pupil block or combined mechanisms play a significant role in pathogenesis. Uveal effusions have been found in 9% of Japanese patients with chronic angle closure, in 58% of those with acute angle closure, and in 23% of fellow eyes of those with acute angle closure.^[15] Similarly, in Singapore, said Dr. Aung, 15% of eyes with angle-closure glaucoma had uveal effusion, including newly diagnosed cases before LPI.^[16] What is the significance of uveal effusion in angle-closure glaucoma? Is it cause or effect?

Angle-closure glaucoma is not a homogeneous disease, said Dr. Aung, and combined mechanisms are common. To eliminate pupil block, LPI remains the primary strategy, but it might not be the only treatment necessary. Other mechanisms contributing to ongoing angle closure in an eye need to be identified and treated as well.

In "Insights From Epidemiological Studies," Dr. Paul Foster categorized^[17] the angle-closure spectrum into primary angle-closure suspect ("occludable" angle with normal IOP, optic disc and visual field, and no peripheral anterior synechiae [PAS]), primary angle-closure ("occludable" angle with increased IOP or PAS, with normal disc and field), and primary angle-closure glaucoma (PACG) (primary angle closure [PAC] with disc and field damage). PAC is the central diagnostic entity. Glaucomatous optic neuropathy from angle closure, said Dr. Foster, can be typical glaucomatous excavated optic atrophy or a flat pale optic disc from rapid, profound, and perhaps prolonged IOP elevation. Most commonly, angle closure is chronic and asymptomatic: according to Dr. Foster, even in London, for example, the ratio of asymptomatic to symptomatic disease is 10:1.

"Who gets angle-closure?" asked Dr. Foster. It occurs more frequently in older than young people (ratio of cases in those >60 years to those < 60 years is 9.1:1), in women than men (female-to-male ratio is 2:4), and in Asian populations (especially Chinese) than white persons.^[18] Globally, the ratio of open-angle glaucoma to angle-closure glaucoma is 3:1, while the blindness rate is 1:1. PACG is a more rapidly progressive and visually destructive condition than primary open-angle glaucoma. This is what makes PACG so important.

Clinical trials in angle-closure glaucoma increasingly guide management, said Dr. David Friedman from Baltimore, Maryland. LPI prevents PAC from progressing to PACG in most cases. Exact data will be available over the next few years. For acute angle-closure crisis, LPI normalized IOP faster than did medications, with similar longer-term IOP levels. Cataract extraction might well offer better long-term outcomes than LPI; a randomized study is about to start.

In all ethnic groups, primary angle-closure suspect status, angle closure, and angle-closure glaucoma are much more common than is usually appreciated. Therefore, advances in management are important for all clinicians. Regular, accurate gonioscopy is indispensable for detection and monitoring, and appropriately indicated, performed, and timely laser peripheral iridotomy is essential to protect individuals from preventable visual loss. For additional information, see the newly released second edition of the Asia Pacific Glaucoma Guidelines at www.seagig.org and visit the wonderful gonioscopy Website www.gonioscopy.org. Management of an acute angle-closure crisis has changed significantly. Medical control remains an option, but LPI as early as possible, with or without argon laser peripheral iridoplasty as necessary, can control IOP faster and more effectively, with fewer potential side effects. The Asia Pacific Glaucoma Guidelines are a valuable resource for this too.

Dr. Robert Weinreb from San Diego, California, discussed functional assessments of glaucoma damage and its progression. All trial data, he said, showed a remarkably variable rate of progressive damage between individuals. Therefore, clinicians need to measure rates of any progression for each individual. This has major implications for prognosis: while a slowly progressing older patient needs different treatment from that of a more rapidly progressing younger patient, even a slowly progressing 30-year-old could give rise for concern. Dr. Weinreb spoke of the ability of the newly released Glaucoma Progression Analysis II software for the Humphrey perimeter to facilitate such individualized progression rate measurement.

On the basis of a measure of visual sensitivity, the Visual Field Index (VFI) is calculated from a single visual field; the VFI emphasizes sensitivity of central compared with more peripheral points, and neutralizes the effects of media opacities such as developing cataracts. It is very different from the mean deviation. Once the VFI has been calculated for an eye over time, a gradient is calculated for progressive visual decline. From this, a prediction is made for future progression. When something significant is done for an eye (such as surgical intervention to reduce IOP markedly), the baseline needs to be reset and a new prediction graph constructed. By combining aids such as this with the individual patient's life expectancy, a clinician can more effectively manage glaucoma.

References