(IGR: 19-2) | International Glaucoma Review #

Consensus 6

Ocular Blood Flow in Glaucoma

edited by:R.N. Weinreb and A. Harris
2009

“Obtaining consensus on the relationship of blood flow to glaucoma was a daunting task. So much has been studied and written, but how much do we really know? As with the previous WGA consensuses, the Glaucoma Blood Flow consensus is based on the published literature and expert opinion.

Although consensus does not replace and is not a surrogate for scientific investigation, it does provide considerable value, especially when the desired evidence is lacking. The goal of this consensus was to establish a foundation for ocular blood flow research of glaucoma and the best practice for its testing in clinical practice. Identification of those areas for which we have little evidence and, therefore, need additional research was a high priority. We hope that this consensus will serve as a benchmark of our understanding, and that it will be revised and improved with the emergence of new evidence.”

Preface

Welcome

ANATOMY AND PHYSIOLOGY
L. Pasquale, J. Jonas, D. Anderson

Anatomy of blood from the heart to the eye
Blood supply of the optic nerve
Overview of blood flow regulation in general
The mediators of autoregulation
The anatomic underpinning of ocular blood flow control
The ocular vasculature and its role in regulating blood flow to the optic nerve and retina

CLINICAL MEASUREMENT OF OCULAR BLOOD FLOW
A. Harris, I. Januleviciene, B. Siesky, L. Schmetterer, L. Kageman, I. Stalmans, A. Hafez, M. Araie, C. Hudson, J. Flanagan, S.T. Venkataraman, E.D. Gilmore, G. Feke, D. Huang, E. Stefánsson

Color Doppler Imaging
Laser Doppler Flowmetry and Scanning Laser Flowmetry
Retinal Vessel Analyzer
Blue Field Entopic Stimulation
Laser Interferometric Measurement of Fundus Pulsation
Dynamic Contour Tonometry and Ocular Pulse Amplitude
Ocular Blood Flow (POBF) Analyzer
Laser Speckle Method (Laser Speckle Flowgraphy)
Digital Scanning Laser Ophthalmoscope Angiography
Bi-directional Laser Doppler Velocimetry and Simultaneous Vessel Densitometry
Doppler Optical Coherence Tomography
Retinal Oximetry

CLINICAL RELEVANCE OF OCULAR BLOOD FLOW (OBF) MEASUREMENTS INCLUDING EFFECTS OF GENERAL MEDICATIONS OR SPECIFIC GLAUCOMA TREATMENT
M. Araie, J. Crowston, A. Iwase, A. Tomidokoro, C. Leung, O. Zeitz, A. Vingris, L. Schmetterer, R. Ritch, M. Kook, A. Harris, R. Ehrlich, D. Gherghel, S. Graham

What is the evidence supporting a role for ocular blood flow in glaucoma patients?
Clinical evidence derived from different measurement parameters
Evidence from experimental animal studies
What disease mechanisms lead to impaired blood flow in glaucoma?
Ocular versus systemic causes
Systemic factors
Vascular dysregulation/perfusion instability
What is the impact of medication and other modifiable factors on ocular blood flow?
IOP-lowering topical medication
Systemic drugs
Ocular surgery, exercise
Does modulation of blood flow alter glaucoma progression?
Glaucoma and systemic vascular disease
Systemic disease and glaucoma patients
Diabetes
Cardiovascular diseases

SHOULD MEASUREMENTS OF OCULAR BLOOD FLOW BE IMPLEMENTED INTO CLINICAL PRACTICE?
N. Gupta, R.N. Weinreb

Interpreting clinical studies

WHAT DO WE STILL NEED TO KNOW?
A. Harris, F. Medeiros, R. Ehrlich, V. Costa, B. Siesky, I. Januleviciene, C. Burgoyne

Ocular blood flow and visual function in glaucoma patients
Ocular perfusion pressure and prevalence and progression of glaucoma
Ocular blood flow and optic nerve head structure
The relationship between intraocular pressure and ocular blood flow
The relationship between cerebrospinal fluid pressure and glaucoma

Future research

Summary of Consensus Points

Index of Authors

Consensus 6 Summary Consensus Points

ANATOMY AND PHYSIOLOGY

Blood supply to the retinal nerve fiber layer invariably comes from the central retinal artery and, when present, from the cilioretinal artery(ies).
Comment: There are no anastomotic connections between the arteries, which function as end-vessels even though the capillaries are a continuous bed.
Blood supply to the prelaminar and laminar portion of the optic nerve head comes from branches of the short posterior ciliary arteries.
Comment: These often form an incomplete vascular ring around the optic nerve head (‘Vascular ring of Zinn and Haller’), before giving off branches into the tissue of the optic nerve head located inside of the peripapillary scleral ring of Elschnig. These vessels feature an anastomotic blood supply.
Retinal vessels are not fenestrated and are not innervated. Since they lack a continuous tunica musculosa, the retinal ‘arteries’, except for the main central retinal vessel trunk, are anatomically arterioles.
Comment: These anatomical features may have implications for understanding how blood flow is regulated in this vascular bed.
It is unclear whether the branches of the posterior ciliary artery that feed the intrascleral portion of the optic nerve are innervated and/or fenestrated.
Comment: Such knowledge is essential to understand how the intrascleral papillary tissue responds to various insults, including abnormally high IOP.
Branches of the short posterior ciliary arteries supply the choroidal vasculature. The majority of total ocular blood volume and flow (~80-90%) is derived from the choroidal vascular. The capillaries are among the largest in the body and are fenestrated. The arteries that feed them are innervated.
Comment: These features have important implications for how the choroidal vasculature is regulated. It has remained unclear whether there is a clinically relevant anastomotic blood exchange between the choroidal vasculature bed and the vascular system of the ciliary body, which is fed by the two long posterior ciliary arteries and the 7 anterior ciliary arteries.
The central retinal vein drains all blood from the entire retina and the optic nerve head.
Comment: Upon contact-free ophthalmoscopy, a spontaneous pulsation of the central retinal vein can be detected in ~80 to 90% of normal eyes. Since the central retinal vein passes through the optic nerve and then through the cerebrospinal fluid space before piercing through the optic nerve meninges in the orbit, the blood pressure in the central retinal vein should be at least as high as the cerebrospinal fluid pressure within the optic nerve meninges in the orbit plus a (hypothetical) trans-lamina cribrosa outflow resistance.
Blood flow to the optic nerve and retina is dominated primarily by myogenic and metabolic regulation. The blood flow to the choroid is believed to be primarily regulated mainly by hormonal and neuronal mechanisms. The extent of autoregulation in the choroid is not known.
Comment: Ocular vascular autoregulation maintains adequate blood flow that provides nutrients and oxygen, as well as adequate tissue turgor, to ocular structures in the face of changing metabolic needs and altered ocular perfusion pressure. Such functions are all designed to allow sharp vision at all times.

CLINICAL MEASUREMENT OF OCULAR BLOOD FLOW

Color Doppler imaging of the ophthalmic artery, central retinal artery and posterior ciliary arteries measures blood flow velocity noninvasively and calculates resistive index.
Comment: Color Doppler imaging does not measure flow.
Comment: With careful interpretation, color Doppler imaging measures blood flow velocity and vascular resistivity in the retrobulbar blood vessels. The exact relationship between vascular resistivity index and resistance is not fully understood.
Comment: The measurements with one color Doppler instrument are not necessarily compatible with those of another.
Scanning laser Doppler flowmetry measures velocity, volume and flow limited to the retinal microcirculation and the optic nerve head.
Comment: There is a lack of standardization for analysis, and flow is limited to arbitrary units of measure.
Comment: The depth of the measurements is not known and may not be comparable among subjects.
The retinal vessel analyzer provides a dynamic assessment of retinal vessel diameters of branch retinal arterioles and venules.
Comment: The retinal vessel analyzer does not evaluate either velocity or blood flow.
Comment: At the current time, vessels with a diameter of 90 micrometers or larger are measured.
The relationship between ocular pulse amplitude and total blood flow to the eye and, specifically, to the optic nerve is uncertain.
Laser speckle flowgraphy provides 2-dimensional in vivo measurements of blood velocity in the optic nerve head and subfoveal choroid.
Comment: Measurements in human eyes of the retina and iris have been problematic.
Comment: Measurement with laser speckle flowgraphy is not clearly understood.
Digital scanning laser ophthalmoscope angiography allows direct visualization of retinal and choroidal microvasculature.
Comment: Various aspects of observed blood flow parameters and filling characteristics can be quantified, including retinal velocity and circulation times with fluorescein dye, and relative regional choroidal filling delays with indocyanine green dye.
Comment: At the current time, scanning laser ophthalmoscope angiography requires an intravenous dye injection.
By combining bidirectional laser Doppler velocimetry with simultaneous measures of retinal vessel diameter and centerline blood velocity, it is possible to calculate retinal blood flow in absolute units.
Comment: These measurements require clear optical media and pupil dilation.
Comment: The method is limited to vessels greater than 60 micrometers.
Doppler Fourier Domain Optical Coherence Tomography provides rapid measurements of volumetric flow rate, velocity, and cross-sectional area in branch retinal vessels.
Comment: At the current time, the method is limited to vessels greater than 60 micrometers and there are limited data.
Retinal oximetry is a non-invasive measurement of oxygen saturation.
Comment: At the current time, there are limited data. The method is limited to retinal vessels greater than 60 micrometers. It may be applicable also to the optic nerve head..
At the present time, there is no single method for measuring all aspects of ocular blood flow and its regulation in glaucoma.
Comment: A comprehensive approach, ideally implemented in a single device, may be required to assess the relevant pathophysiology of glaucoma.

CLINICAL RELEVANCE OF OCULAR BLOOD FLOW (OBF) MEASUREMENTS INCLUDING EFFECTS OF GENERAL MEDICATIONS OR SPECIFIC GLAUCOMA TREATMENT

Blood pressure (BP) is positively correlated with IOP.
It is unclear whether the level of BP is a risk factor for having or progressing open-angle glaucoma (OAG) in an individual patient.
Comment: It has been hypothesized that low blood pressure is a risk factor for patients with abnormal autoregulation.
Lower ocular perfusion pressure (OPP = BP – IOP) is a risk factor for primary OAG.
OBF parameters measured with various methods are impaired in OAG, especially in NTG, compared with healthy subjects.
Comment: Reduction of OBF with aging has been confirmed by various methods.
Comment: The optic nerve head blood flow may be reduced during the nocturnal period.
Vascular dysregulation may contribute to the pathogenesis of glaucoma, more likely in people with lower intraocular pressure.
Certain drugs, even when formulated in an eye drop, may have an impact on ocular blood flow and its regulation.
Comment: The impact of eye drop related changes in ocular blood flow on the development and progression of glaucoma is unknown.
Comment: Some data support increased blood flow and the enhancement of ocular blood flow regulation with carbonic anhydrase inhibitors. These appear to exceed what one would expect from their ocular hypotensive effect alone.
Some systemic medications may have an impact on ocular blood flow and its regulation.
Comment: The impact of systemic medications altering ocular blood flow on the development of glaucoma and the progression of glaucoma is unknown.
Comment: Classes of systemic medications with agents that have been reported to increase ocular blood flow include calcium-channel blockers, angiotensin-converting enzyme inhibitors, angiotensin- receptor inhibitors, carbonic-anhydrase inhibitors, phospodiesterase-5 inhibitors.
The association between diabetes and cardiovascular diseases with OAG still remains unclear.

SHOULD MEASUREMENTS OF OCULAR BLOOD FLOW BE IMPLEMENTED INTO CLINICAL PRACTICE?

Measurements of ocular blood flow are currently research tools for the study of glaucoma.
Comment: Assessing ocular blood flow has been of interest to clinicians and scientists over several decades, and sophisticated diagnostics directed at measuring ocular perfusion have emerged.
Comment: Before deciding whether to implement measurements of blood flow into clinical practice for glaucoma management, however, these measurements need to be critically assessed in clinical studies.
Although there is an association between measurements of ocular blood flow and glaucoma progression, a causal relationship has not been established.
There are insufficient data to support the measurement of ocular blood flow for clinical decision making in glaucoma practice.
Comment: Prior studies of ocular blood flow in glaucoma have varied considerably in their methodologies, numbers of patients, and study design pertaining to design, conduct and analysis.
Evidence that measurement of blood flow leads to better clinical outcomes for the glaucoma patient is lacking.
There is no evidence that altering blood pressure changes the course of glaucoma.

WHAT DO WE STILL NEED TO KNOW?

Clinical studies are essential to establish the clinical application of ocular blood flow measurements in glaucoma.
Comment: Appropriately designed studies utilizing standardized measurement techniques are needed to ascertain the relationships among ocular blood flow, metabolism and glaucoma progression.
Comment: Future studies should ascertain the relationship between blood pressure and glaucoma.
The physiology of ocular blood flow regulation needs to be elucidated. Laboratory studies designed to detect molecular and cellular mechanisms in vitro and in vivo that support the presence of ischemia are needed.
Comment: Experimental research is needed to elicit the existence and role of hypoxia/ischemia in relevant glaucoma models.
Longitudinal studies are necessary to confirm whether blood flow abnormalities precede visual field defects and correlate with their severity.
The hypothesis should be tested that treatment of OPP, rather than IOP alone, is beneficial in glaucoma.
There is a need to determine at what levels IOP and OPP increase the risk for the onset and/or progression of glaucoma for an individual eye.
The clinical outcome of ocular blood flow fluctuation, perfusion pressure and their impact on glaucoma needs to be investigated.
Comment: The contribution of the blood flow within the entire central visual pathway is unknown and still needs to be determined.
A normative database for ocular blood flow measurements that can be used in research and clinical practice should be established.