Ocular blood flow and glaucoma

Ocular blood flow and glaucoma

George A. Cioffi

Discoveries in Sight, Devers Eye Institute, Portland, OR, USA

Introduction

Despite extensive investigations into the relationship between the circulation of the eye and glaucoma, there remains substantial debate. The issue becomes more confused when the potential effects, either beneficial or detrimental, of medical therapy are included in the discussion. It is generally believed that circulatory abnormalities occur in greater frequency in individuals with glaucoma, and that vascular insufficiency leads to the development of glaucomatous optic neuropathy. Many studies are based on the premise that the vascular perfusion of the optic nerve or retina can be measured, and that ischemia within these tissues leads to retinal ganglion cell death. In fact, the relative benefit of various therapeutic agents is often evaluated by the perceived influence of the drug on the vascular status of the ocular tissues. When considering the potential effects of topical medications on the eye, there remains controversy regarding the ability of drugs to penetrate the eye and to reach the posterior segment in pharmacologically active levels. There are a myriad of important unanswered questions regarding research into the relationship between ocular blood flow and glaucoma. While investigating potential therapeutic agents that may enhance or diminish the circulatory status of the eye is important, we must remember that there are a series of sequential assumptions upon which all ‘glaucoma blood flow’ studies are based. Only by recognizing these assumptions and by realizing that they are hypotheses not fact, can we evaluate the relevance of the investigations.1

The three common assumptions are: 1. optic nerve ischemia directly causes or increases the susceptibility of the optic nerve to glaucomatous damage; 2. present knowledge of the optic nerve vascular anatomy and physiology allows investigators to identify the vascular beds of importance in this neuropathy; and 3. current measurement techniques provide the ability to monitor these vascular beds.

The vascular hypothesis of glaucoma is based upon these three critically important, but unproven, assumptions.2 Experimental investigations examining each of these assumptions will allow a better understanding of the potential role of vascular abnormalities in the development of glaucomatous optic neuropathy. Care-

Address for correspondence: G.A. Cioffi, MD, Devers Eye Institute, 1040 NW 22nd Avenue, N200, Portland, OR 97210, USA

Glaucoma in the New Millennium, pp. 29–36

Proceedings of the 50th Annual Symposium of the New Orleans Academy of Ophthalmology, New Orleans, LA, USA, April 6-8, 2001

edited by Jonathan Nussdorf

© 2003 Kugler Publications, The Hague, The Netherlands

fully examining our current knowledge of each of these three assumptions will allow better interpretation of a plethora of publications describing vascular phenomena in glaucoma.

The relationship between ischemia and glaucomatous optic neuropathy

Abnormalities in the circulation of blood to the anterior optic nerve have been cited by many investigators as being potential causative factors in the development of glaucomatous optic neuropathy.2-5 There are many clinical reasons to believe that microvascular factors are important. Microvascular diseases, including systemic hypertension, peripheral vascular disease and possibly diabetes mellitus, are associated with glaucomatous optic neuropathy.2,6,7 Studies have shown a higher incidence of systemic vascular diseases, including systemic hypotension,4,8 nocturnal hypotension,9-11 and systemic hypertension,6,12 in glaucoma patients. Systemic hypertension, particularly in its late stages, has been epidemiologically related to glaucoma.13 Disorders associated with vasospasm, such as migraine headache or cold hands and feet, are more commonly seen in patients with glaucoma, both with and without elevated intraocular pressure.14-17 Studies of glaucoma patients have shown abnormalities in blood rheology,3,18-23 with increased blood viscosity and reduced erythrocyte deformability. Additional studies have suggested that the blood flow in the peripapillary region24-30 and the retrobulbar space31-39 is significantly reduced in eyes exhibiting glaucomatous optic nerve damage. In the optic nerve, evidence of decreased blood flow accompanied by visual field damage has been reported in glaucoma patients.40-47 Many of these studies remain controversial, as the validity of the various hemodynamic measurement techniques is still under investigation. The hypothesis that circulatory abnormalities are related to the development of glaucomatous optic neuropathy is well supported by these clinical associations. As reasonable as this hypothesis may be, ischemia has never actually been demonstrated to cause, or even contribute to, glaucomatous optic neuropathy. Direct evidence that ischemia is related to glaucoma, as a causative factor, is lacking. Vascular disease may be merely an associated finding.

While the available clinical evidence supports the argument that circulatory anomalies are involved in the development of glaucomatous optic neuropathy, direct evidence that ischemia is related to glaucoma is considerably more suspect. The clinical arguments that vascular insufficiency has a role in the pathogenesis of glaucoma have been well rehearsed by myself and others. The belief that intraocular pressure alone does not account for the development of all glaucomatous optic neuropathy is now commonly accepted. The ischemic hypothesis states that ischemia of the ganglion cell, most likely in the anterior optic nerve, results in ganglion cell death, either directly or in conjunction with other factors. Each of the hypotheses relating ischemia and ganglion cell death provides a potential, yet unproven, mechanism by which apoptotic ganglion cell death may be initiated in glaucoma. We know that acute ischemic damage of the optic nerve (i.e., anterior ischemic optic neuropathy) has a very different clinical appearance from glaucomatous optic neuropathy. The effects of chronic optic nerve ischemia or prolonged blood flow insufficiency have not been documented. Direct evidence of a link between glaucoma and ocular ischemia may require a laboratory model or a more convincing clinical association. If ischemia is related to the development of glau-

comatous optic neuropathy, certain observations should be possible. Every ‘blood flow’ study is based upon the fundamental assumption that optic nerve ischemia can, either directly or indirectly, cause glaucomatous optic neuropathy. However, the causal relationship between optic nerve ischemia and glaucomatous optic neuropathy remains an attractive, yet unproven, hypothesis.

The ocular vascular anatomy and physiology related to glaucoma

The second assumption may be more mundane, but is no less important. If we propose to monitor circulatory aberrations in the optic nerve that are associated with the development of glaucoma, our understanding of vascular anatomy and physiology must be sufficient to tell us where to look. The anterior optic nerve vasculature is a complex network of blood vessels with a dual arterial supply and a single vessel providing the bulk of venous outflow. The majority of the anterior optic nerve derives its blood from the posterior ciliary arteries, which unfortunately are less accessible to our investigative techniques than the retinal circulation. The complexity of the optic nerve vasculature, the peripapillary choroidal vasculature, and the retinal vasculature has perplexed scientists for more than a century. The possibility of interactions and collateralizations between these vascular beds remains controversial, and the physiological mechanisms that control the blood flow to the anterior optic nerve are still under investigation. At this time, it is unknown whether an increased blood flow volume in one vessel, such as the central retinal artery or ophthalmic artery, has any influence on the health of the optic nerve and the development of glaucomatous optic neuropathy. It is also unknown whether increased blood flow to one vascular bed positively or negatively affects blood flow to the other vascular beds. Continued investigations of ocular vascular physiology and anatomy in health and disease must underpin the interpretation of future ‘blood flow’ studies.

The anterior optic nerve may be anatomically divided into four regions: the superficial nerve fiber layer, prelaminar region, laminar cribrosa, and retrolaminar region. Many laboratories have demonstrated that the optic nerve vascular supply varies, depending on the region. The superficial nerve fiber layer is principally supplied from the arterioles in the adjacent retina, which derive from the central retinal artery. The central retinal artery does not usually contribute to either the prelaminar or laminar region, although it may contribute occasional small branches within the retrolaminar optic nerve. The prelaminar, laminar, and retrolaminar regions are supplied by branches of the pial arteries and the short posterior ciliary arteries, both originating from the posterior ciliary arteries. The venous drainage of the anterior optic nerve is almost exclusively via the central retinal vein and its tributaries. Although the vascular anatomy of the anterior optic nerve is now well described in the normal primate (human and non-human) eye, the vascular anatomy in human and experimental glaucoma is not well understood.

The capillary beds are anatomically confluent and form a continuous vascular network along the length of the anterior optic nerve. The blood flow within the capillaries of the more anterior regions (the superficial nerve fiber layer, prelaminar region, and laminar region) is normally higher than the blood flow within the posterior regions. The longitudinal anastomoses of capillaries throughout the

anterior optic nerve might be viewed as a protective mechanism against regional ischemic insult. However, the blood supply from the posterior ciliary system cannot completely compensate for an experimental occlusion of the central retinal artery.57,58 Part of the reason for this may be the lack of large vessel collateral communication between the two vascular systems in the optic nerve. Moreover, flow resistance may be so high in these fine capillary networks that collateral flow is limited. To maintain adequate perfusion with changes in intraocular pressure, an autoregulatory mechanism is required. Local metabolic and myogenic autoregulation, integrated with the autonomic nervous system and circulating hormones, maintains the blood flow in the anterior optic nerve at a relatively constant level, over a wide range of changes in perfusion pressure. Perfusion pressure is determined by the blood pressure, intraocular pressure, and vascular resistance.5962 Since the density of capillaries within all the regions of the anterior optic nerve does not differ as significantly as the flow rates, it is thought that different regulatory mechanisms may exist in the various regions of the anterior optic nerve. The regulation of blood flow within these various regions and between the two arterial systems (central retinal artery and posterior ciliary arteries) remains poorly understood.

The coexistence of glaucomatous optic nerve damage and any physiological abnormalities does not establish a causal relationship. We need to have a better understanding of the vascular anatomy of the anterior optic nerve in glaucoma (human and experimental). We also need to enhance our understanding of the complex regulatory system that governs optic nerve perfusion.

Ocular hemodynamic measurement techniques

The final assumption is that current investigative techniques provide reliable and accurate information about the circulatory status of the optic nerve. If we accept that ischemia is related to the development of glaucomatous optic neuropathy and we establish which vascular beds are important to the health of the optic nerve, do current measurement techniques provide the necessary tools for the assessment of these vascular beds?

Non-invasive monitoring of ocular blood flow in humans is an example of technology in need of validation. Over the past two decades, many highly technical methods have been developed to examine in vivo ocular hemodynamics, but the validity of each of these methods has not been fully demonstrated, which has resulted in limited clinical and experimental utility of many of these devices.63,64 Failure to validate these technologies has led to a conceptual stagnation, as unsupportable conclusions have confused our understanding of the relationship between blood flow and glaucoma. These technologies include Doppler ultrasound, laser Doppler flowmetry, and scanning laser angiography. Color Doppler imaging and transcranial Doppler ultrasound are the two principal methods used to assess the retrobulbar hemodynamics. With these techniques, the retrobulbar vessels that contribute to the vascular supply of the anterior optic nerve (ophthalmic artery, central retinal artery, and posterior ciliary arteries) can be imaged. These Doppler techniques measure blood flow velocity within the imaged vessels. Fluorescein fundus angiography is a conventional method used to describe a two-dimensional vascular filling pattern of the retina, choroid, and anterior optic nerve. Fluorescein

angiography of the optic nerve and peripapillary region has been widely used in the study of glaucoma.45,46 Vascular filling times, similar to blood flow velocity measurements, can also be derived from fluorescein angiography. However, relatively low resolution limits the usefulness of this method. Recently developed scanning laser ophthalmoscopy can be coupled with fluorescein angiography to enhance resolution.63

Laser Doppler flowmetry provides a measure of blood cell velocity in a volume of tissue, and estimates of volumetric blood flow can be derived.65 Laser Doppler flowmetry has also been combined with scanning laser ophthalmoscopy (Heidelberg Retinal Flowmeter) to provide two-dimensional blood flow perfusion maps.66 From these two techniques, volumes of clinical information about the blood flow within the retina and anterior optic nerve of the glaucomatous eye have been derived.29,30,40,41,55,67 However, the reproducibility and the depth of penetration of the these techniques have been points of controversy. Based on in vitro experiments, laser Doppler flowmetry has the potential to penetrate 1000 m.68,69 Theoretically, scanning laser Doppler flowmetry can measure to a depth of approximately 300400 m.30,66,70 It remains doubtful whether either of these techniques can penetrate in vivo beyond the superficial layers of the optic nerve.64,71 The importance of a limited depth of penetration is that the vasculature within the lamina cribrosa (potentially the primary site of altered perfusion in glaucoma) may be inaccessible.

Only with validation of these machines will we better understand ocular hemodynamics in health and disease. Deciphering the myriad of numerical values produced by these instruments has become a daunting task. In a recent article, Hayreh examined the scope of these techniques, and elucidated questions of validity, reproducibility, variability, accuracy, confounding agents, and clinical pertinence which still exist.64 Does the high variability of measurement techniques limit their usefulness and contribute to the misinterpretation of their measurements? Do measurements reflect only changes in the circulation or do con-founders, such as intraocular pressure variations, alter the measurements? Is blood flow velocity directly, indirectly, or not related to volumetric blood flow in the vessel of interest? These questions are only a few of the current issues under investigation. Presently, there is no single method to assess the circulatory status of the human optic nerve, and familiarity with the technique in question is always necessary to be able to interpret the resulting data.

Summary

This manuscript is not intended to discourage investigation of the possibility that hemodynamic abnormalities are associated with glaucoma. In fact, I hope to stimulate more intense and rational ‘blood flow’ research. Investigators and observers must remember that the validity of each investigation is based upon acceptance of the assumptions listed above. In the future, each of these assumptions must be validated independently, if hemodynamic-modifying therapy is to be applied in the treatment of glaucoma. However, we must always be willing to accept the null hypothesis, that ischemia and glaucoma are not related.

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