• Professor of Ophthalmology and Douglas R. Anderson Chair in Ophthalmology at the Bascom Palmer Eye Institute, University of Miami School of Medicine
• Member of the Steering Committee, Optic Disc and Visual Field Reading Committee, and Data and Safety Monitoring Committee for the Normal-Tension Glaucoma Study (1988 to 1999), which received International Glaucoma Review Global Glaucoma Special Recognition in 2002
• Trustee of ARVO, 1983 to 1988; President of ARVO, 1987; recipient of Mildred Weisenfeld Award, 1997; and Chairman of the ARVO Committee on Ethics and Regulations for Clinical Research, 2001 to 2004
• Founding member of the American Glaucoma Society and President, 1990 to 1992
• Recipient of the Hans Goldmann Medal, Glaucoma Society of the International Congress of Ophthalmology, 2003
• Recipient of the Georg von Bartisch Medal for Contributions to Glaucoma Research, 2002
What is your current opinion about the participation of vascular phenomena in the pathogenesis of glaucoma?
I am inclined to think that glaucomatous optic nerve damage is, at least in part, the result of intermittent minor ischemic events, perhaps often due to abnormal physiologic local control of blood flow in patients with vasospastic tendencies and possibly compounded by problems such as vascular occlusive disease and clotting abnormalities. I am drawn to the hypothesis that, at times when circulation is challenged (eg, low blood pressure, raised IOP), there may be an episode of ischemia if, at that moment, there are vasospastic stimuli, small thrombi, unusual circulatory vasoactive hormones, dehydration, or who knows what that together render inadequate the compensatory dilation normally provided by local autoregulation of blood flow. It has been suggested that, if such an episode is transient, there may be local damage during a reperfusion stage.1 All of this is conjecture, but I suspect that, by causing damage to the lamina cribrosa and axons, such mechanisms initiate events that account for cupping and vision loss.
Which is your favorite technique for detecting early glaucomatous visual field loss and why?
At present, the traditional careful examination of the optic nerve with stereoscopic documentation and standard white-on-white perimetry remain my usual clinical tools. Some of the new methods for testing particular visual functions at multiple visual field locations and methods for quantifying the retinal nerve fiber or ganglion cell layers seem promising. Researchers have yet to obtain and validate normal values fully, however, or to confirm that early changes detected with these methods predict a dim future for the patient. As a result, like the rest of the glaucoma community, I am intensely interested in how investigators are improving and validating these methods.
During patient care, I trust the disc appearance as giving me the most dependable early evidence of glaucomatous damage, but I do find meaningful, early field changes in some patients whose discs would not be convincingly abnormal without the corroborating visual field information. When new testing methods provide suggestive information, I am in a state of heightened alert, but I do not feel compelled to intervene therapeutically unless more traditional changes arise. For example, a thinning of the disc rim over time or declining visual field thresholds, especially in the face of suggestive findings with one of the new tests, may cause me to conclude that the process of glaucomatous optic nerve damage has begun, even if the disc morphology and standard visual field test are still technically within normal limits. Asymmetric but normal findings between a patient's two eyes is also meaningful if his eyes are otherwise symmetric (and especially if the IOP is asymmetric as well), but these findings are unimportant if the discs are of different size, anisometropia is present, or there is some other explanation for ocular asymmetry.
What prompted your interest in developmental glaucoma, and how has your perspective on the subject changed?
My initiation into research was through electron microscopy as it began to improve scientists' understanding of cell (and ultimately molecular) biology. The opportunity arose for me to examine normal human eyes from different gestational ages by scanning and transmission electron microscopy. At the same time, trabeculotomy was introduced as an alternative to goniotomy for primary infantile glaucoma. I created two radial incisions in order to perform trabeculotomies in the two directions, thereby leaving a segment in between that I could excise. I compared the normal and abnormal tissue with magnification and methods not before available, and I was able to identify porous but thickened trabecular tissue (not an impermeable membrane) as the underlying abnormality. By simultaneously performing goniotomy on the contralateral eye in bilateral cases, I was able to show that the two operations yielded the same outcome.
Little has changed in the last 3 decades with regard to primary glaucoma, except that infantile glaucoma seems to occur even less frequently than it used to (perhaps owing to a reduction in the incidence of congenital rubella), and the remaining cases (secondary or associated with severe anterior segment anomalies) are more difficult to manage.
What are your views on managing low-tension glaucoma?
The distinction between primary open-angle glaucoma and normal-tension glaucoma (NTG) has blurred. Both seem to be some sort of abnormal pathophysiologic process in the optic nerve, with the rate and degree of damage dependent upon the level of IOP. Whether or not the pressure is abnormal, the treatment principles seem to be the same and to focus on lowering the IOP.
Many cases of NTG are not progressive, even without treatment. As a result, with mild cases, practitioners have the option of observing the course of the disease for a while before deciding whether to commit to long-term lowering of the IOP therapeutically. In severe cases of NTG, the need for treatment is more obvious, and physicians are much less willing to observe patients in order to determine whether their condition is progressive. In uncertain situations, monocular treatment may help indicate the natural course of the disease in one eye of a patient and the benefit of treatment in the other. The goal of treatment may be to lower the patient's IOP 20% to 40%, depending on the clinician's sense of the disease's severity and its ongoing rate of progression. Practitioners are now able to achieve such pressure reductions more easily, either medically or with laser treatment, than they could in the past.
The pathophysiology within the optic nerve—the process that lowering the IOP can decelerate—is presumably more abnormal in eyes in which damage occurs with, for example, an IOP in the high teens compared with those that suffer damage only when the IOP is in the mid-20s or higher. It is tempting to guess what the pathophysiology might be and what treatments might address this abnormality and reduce the impact of the IOP level. Without a proper understanding of the vascular connective tissue and/or neuronal events, however, such efforts at neuroprotection lack a validated rationale and, in any event, have no clearly demonstrated clinical benefit.
What led to your early focus on the relationship between IOP and damage to the optic nerve? How has the understanding of this matter changed, and where do you see related research headed in the next few years?
When I entered the field of ophthalmology from a background that included early ultrastructural studies, I worked to understand the normal structure and cell biology of the trabecular meshwork and optic nerve. My efforts evolved into studies of the events during optic nerve diseases like papilledema, optic atrophy, and glaucomatous cupping. Gradually, with a clinical focus on glaucoma, my laboratory work became almost exclusively devoted to understanding the pathogenic process of glaucomatous optic atrophy—first, by determining that an elevation of IOP affected axonal transport and, later, by showing that this event likely related to the impairment of blood flow.
Further work of mine focused on the role of capillary pericytes in controlling microvascular blood flow; my hypothesis was that ischemia might result when something (such as IOP) challenged blood flow and local control mechanisms were inadequate to maintain blood flow. This theory was in keeping with studies on normal human subjects that showed individual variation in the ability to maintain blood flow in the face of an IOP challenge, which also varied in different sectors of the same optic disc.
Among other subjects, I have developed a heightened interest in catalyzing the development and validation of quantitative means by which to document progressive optic nerve damage and visual loss. I hope to find a method for meaningfully quantifying the rate of progression, as opposed to defining criteria for establishing the fact than an event of progression of unspecified magnitude has occurred. I expect this work to be a multicenter, collaborative effort that will require contributions from many glaucoma scientists.
In the future, practitioners should possess a better understanding of vascular events that may affect the optic nerve, as well as of any cascade of destructive tissue and cellular processes that may result. Therapy may be directed at preventing the ischemia or, alternatively, at reducing its harmful consequences. This therapy may be used to augment the lowering of IOP or, in some cases, to replace IOP lowering as the focus of treatment. A better understanding of the pathogenic mechanisms should assist the development of means by which to interfere with these injurious events.
1. Flammer J, Pache M. Resink T. Vasospasm, its role in the pathogenesis of diseases with particular reference to the eye. Prog Retin Eye Res. 2001;20:319-349.
