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Editorial IGR 9-3

Editorial
R.N. Weinreb

A pulse for ocular blood flow in glaucoma

It seems like forever that the glaucoma community has debated the merits of a relationship between ocular blood flow and glaucoma. Like any debate, this putative relationship has strong supporters and also has equally strong detractors. The good science has often been muddled by poor science, and claims of the superiority of one therapy compared with another based on their ocular blood flow attributes have obfuscated any relationship even more. Let me share with you the good fortune that I had in participating in a symposium that comprehensively discussed the relationship between ocular blood flow and glaucoma.

Like the general glaucoma community, I often ponder whether there is a relationship, and have been steadfast in occupying a central position in the debate. I have been fully cognizant of the attractiveness of this relationship and the numerous studies that have suggested that certain blood flow parameters are risk factors for the development of glaucoma and/or glaucoma progression. However, I also have recognized that much of the scientific inquiry on the subject has lacked rigor. For these reasons, I was particularly delighted to receive a telephone call several months ago from Neeru Gupta, who invited me to participate in a symposium at the University of Toronto that she and Yeni Yücel were organizing on Ocular Blood Flow and its relationship to glaucoma. She asked me to introduce the subject and set the stage for the discussion to follow. "But Neeru," I recall saying, " you have so many bona fide experts participating and I know so little about the subject. Why don't you invite one of them and I can lecture on a subject with which I am more comfortable?" "But Bob," she said in reply, "that is precisely why I would like you to introduce the subject. You should critically review the subject and set the stage for the discussion that surely will follow."

Systematically reviewing this literature was an onerous and tedious experience, and one which I cannot recommend to any colleague unless they have a compelling reason to do so. Glaringly apparent in the course of the review, I came across emerging, but compelling, epidemiologic research by Leske and colleagues who have identified some blood flow parameters and cardiovascular history as risk factors for the development of glaucoma and glaucoma progression. I also learned that changes in blood pressure can cause changes in intraocular pressure, something that I am often asked by my patients, but that these changes are quite small. However, it became evident that many, but not all, of the clinical investigations on this subject are ripe with methodologic flaws and faulty assumptions. Some of these problems relate to the available technologies for measuring ocular blood flow. Questionable study designs also are rampant.

Ferid Murad MD, PhD, Nobel Laureate in 1998 for his seminal contributions in understanding the ubiquitous biological roles of nitric oxide, opened the symposium with inspirational and encouraging words for all of us engaged in scientific inquiry and discovery. And then came my opportunity to share the fruits of my review and introduce a critique of the field that I thought would help to focus the symposium, provoke discussion, and might even stimulate those in the field or those who are considering entering it.

Each of the current methods for assessing ocular blood flow have limitations in their accuracy and variability.

See also: WGC 2007 - Debate: Ocular Blood Flow in Glaucoma

Comment: The specific vascular bed(s) or vessel(s) relevant to glaucomatous optic neuropathy remains unknown.

Comment: Is perfusion of inner retina (central retinal artery) or optic nerve (ophthalmic artery) most important, or should perfusion of both be measured?

The most robust and clinically relevant blood flow parameter remains unknown.

Comment: Measurement of blood flow seems desirable, but a reproducible, accurate and practical clinical method for this is not available.

The available technology is costly and not widely available.

Use of IOP-lowering drugs, systemic medications, and systemic disease obfuscate relationships between ocular blood flow parameters and glaucoma.

Comment: Most, but not all, clinical studies of ocular blood flow and glaucoma do not have controls for these factors, all of which can have effects on ocular blood flow independent of the disease.

There is a compelling need for high quality and longitudinal studies of vasoprotection of glaucoma.

Comment: Such studies might be multi-centered, and include masked reading centers and rigorous methods.

Comment: Use of multiple technologies and standardization of measurement techniques for assessing progression and ocular blood flow parameters are desirable.

Comment: As glaucoma is slowly progressive, the studies will be lengthy, costly and, most likely, include a large number of patients.

There is no agreed upon method for identifying those glaucoma patients who have dysfunctional ocular blood flow that damages, even in part, their optic nerve.

Comment: Those patients, if any, in whom ocular blood flow is dysfunctional, are those who might be particularly amenable to vasoprotective therapies.

These areas were just a small part of a marvelous symposium during which bonhomie prevailed throughout. Although I learned much from the experts (Drance, Flammer, Araie, Harris, Schmetterer, Cioffi, Pillunat, Org�l, Nicolela, Flanagan, Tsai, Lesk), I cannot say that I was convinced that I should prescribe magnesium, ginkgo, and chocolate (preferably the dark type and, not surprisingly, from Switzerland) singly or in combination to treat some glaucoma patients, or even convinced of the strident claims of calcium channel blocking agent effectiveness. Are these surreal or are they veridical?

Even more than before though, I have the sense that there may be a meaningful relationship between ocular blood flow and glaucoma. However, I still remain to be convinced, as summarized brilliantly by Roger Hitchings with his closing symposium remarks, by the body of evidence. This surely will take time, but good science should prevail. And this is an area deserving of great science!

This issue of IGR

Apart from the fascinating comments in the Editors Selection - a.o. on a groundbreaking study by Thorleifsson et al. that describes a gene encoding for LOXL1 having strong genetic association with exfoliation glaucoma; the gene confers high risk for exfoliation glaucoma in patients with exfoliation syndrome -, this issue contains:

Two new sections in IGR: 'Glaucoma Dialogue' and `Glaucoma Opinion'

For the 'Glaucoma Dialogue' section, published manuscripts of import and potential impact for discussion will be selected. Solicited comments of experts will be sent to the authors of a selected manuscript for a response. Both comments and responses will be published in IGR in their entirety. The 'Glaucoma Opinion' section will contain reports

World Glaucoma Congress 2007, Singapore reports

There are reports on 14 debates and symposia from the World Glaucoma Congress in Singapore which deal with such important topics as:

• How early should we detect glaucoma?

• Is glaucoma a neurodegenerative disease?

• Medical treatment of laser first?

• Should gonioscopy be replaced by ant segment OCT?

• Where do fixed combinations fit in our therapeutic armamentarium?

• New surgical procedures.

And much more.