Research indicates that optic nerve ischemia may contribute to glaucomatous damage8,9 and establishes links between glaucoma and microvascular disease, systemic vascular disease, and vasospasm.10-12 According to evidence-based medicine, diastolic perfusion pressure is the only vascular parameter that meets the criteria necessary to be considered clinically. The relationship between perfusion pressure and glaucoma is not known, but the existence of a relationship begs the question, are vascular deficits and ischemia involved in the pathogenesis and progression of glaucoma? This article examines the current understanding of the role of vascular factors in glaucoma.
EVIDENCE-BASED STUDIES OF A VASCULAR ROLE IN GLAUCOMA
Population-based studies have found that vascular-related factors are also risk factors in glaucoma. In 1983, Framingham Eye Study participants with open-angle glaucoma (OAG) were reported to have significantly low blood pressure (BP)/IOP ratios.13 In addition, persons with definite glaucomatous visual field defects had lower ratios than those with suspect defects or no defects. Low perfusion pressure was also an OAG risk factor in the Baltimore Eye Survey, Egna-Neumarkt, Proyecto VER, and, most recently, the Barbados Incidence Study of Eye Diseases.14-17
The Baltimore Eye Survey found a diastolic perfusion pressure (diastolic perfusion pressure = diastolic BP - IOP) of less than 30 mm Hg to be strongly associated with OAG (risk ratio = 6), whereas systolic perfusion pressure (systolic perfusion pressure = systolic BP - IOP) and mean perfusion pressure (mean perfusion pressure = mean BP - IOP) were only mildly associated.14 In the Egna-Neumarkt study, the OAG prevalence increased progressively with decreased diastolic perfusion pressure,15 and the Proyecto VER study reported similar results at a low diastolic perfusion pressure.16 The Barbados Incidence Study of Eye Diseases found all three factors (diastolic perfusion pressure, systolic perfusion pressure, and mean perfusion pressure) to be related to OAG, but a low diastolic perfusion pressure had the strongest correlation, approximately tripling subjects' risk ratio of developing OAG.17
CLINICAL EVIDENCE OF VASCULAR DEFICITS
Clinical studies have detected numerous ocular blood flow deficits in some patients with primary open-angle glaucoma (POAG). Several different methodologies have been used to assess blood flow. Fluorescein angiography has demonstrated reduced total retinal blood flow and dye leakage from optic nerve head (ONH) capillaries,8 findings suggesting peripapillary ischemia in glaucoma.9
Scanning laser Doppler flowmetry combines laser flowmetry over a defined area of points and creates a 2-D perfusion map. The penetration depth is approximately 400 µm and only measures the flow in the microcirculation. The velocity limit is 10 mm/second and is therefore inaccurate for large vessels. Researchers have used this technology to demonstrate reduced blood flow in a number of conditions, but the findings have been variable. Investigators have demonstrated (1) lower optic nerve blood flow in POAG compared to OHT subjects,18 (2) an inverse relation between C/D ratio and ONH flow,18,19 (3) reduced ONH flow in patients with normal-tension glaucoma (NTG),19 and (4) decreased ONH flow with worsened mean defect or corrected pattern standard deviation.20,21
Studies have also shown that the choroidal circulation in glaucoma fails to vasodilate appropriately,22 and delays in choroidal filling may be associated with a thinning of the entire choroid.23 In addition, the retrobulbar vessels in both NTG and POAG patients exhibited increased resistance indices during color Doppler imaging.10,24 Such imaging measures retrobulbar blood velocities and resistivity index in the ophthalmic artery, ciliary arteries, and central retinal artery. These vascular abnormalities may be among the earliest manifestations of glaucoma.25-27
Investigators including myself are evaluating the usefulness of retinal oximetry for assessing tissue ischemia. The measurement of blood oxygen saturation in the retinal vasculature may provide physicians with a better understanding of the relationship between vascular deficits, metabolic events, and glaucoma. The clinical measurement of oxygen saturation in humans is accomplished noninvasively by optical means. Via the different optical characteristics of oxygenated and deoxygenated hemoglobin, the wavelength-dependent transmission of light through perfused tissue allows us to calculate the ratio of oxygenated hemoglobin to total hemoglobin concentration.28
Reduced perfusion pressure to the eye (potentially nocturnal) may cause disease progression, regardless of an individual's well-controlled IOP.11 Despite accumulating evidence that glaucoma patients suffer from inadequate ocular blood flow, the current clinical treatment of the illness involves neither documentation nor treatment of these deficits.29
CELLULAR EFFECTS OF ISCHEMIA
Recent evidence suggests that glaucoma characteristically damages the photoreceptors and the horizontal cells, as well as the retinal ganglion cells.30,31 Retinal circulation nourishes the retinal ganglion cells, whereas the photoreceptors receive their blood supply from the underlying choroid. In order to define how enhanced blood flow improves visual function, therefore, it is essential to evaluate blood flow to the retina and choroid, for the retinal ganglion cells and photoreceptor cells, respectively. If specific damage to retinal ganglion cells indeed causes visual function deterioration in glaucoma,31 then enhancing retinal blood flow should improve this deficit. If, instead, photoreceptor deterioration underlies the decline in visual function, then improving choroidal blood flow should mitigate this process. Finally, if a loss of both cell types occurs in glaucoma,11,29-33 then improving retinal and choroidal blood flow may have a beneficial effect.
In animal models of glaucoma, retinal ganglion cells die via apoptosis,33,34 a process in which ischemia may play a role.34 In vivo and in vitro models of retinal ischemic/reperfusion injury emphasize the impact of the loss of nutrient delivery, especially to the apparently highly sensitive retinal ganglion cells.35,36 In this context, improving blood flow may deliver immediate neuroprotection to these cells. Also, relieving ischemia and increasing oxygen may be another route to providing immediate neuroprotection in glaucoma.
Clinical studies of glaucoma and diabetes have linked visual function to hemodynamics. Hyperoxia acutely improved contrast sensitivity in diabetic patients who possessed a substantial initial contrast sensitivity defect.37 The acute enhancement of ocular perfusion may improve visual function in some patients with NTG.12,38-41 In a series of experiments with NTG patients, breathing CO2 for several minutes (sufficient to increase end-tidal PCO2 by 15%) reduced resistance indices in their ophthalmic arteries to normal levels, a discovery suggesting the existence of a reversible ocular vasospasm.42 Investigators have obtained findings similar to these short-term results with CO2 breathing both acutely and over 6 months in NTG patients treated with calcium channel blockers.39-41,43,44 These studies imply that improving ocular perfusion may simultaneously and immediately enhance glaucoma patients' visual function, but the mechanism for this action is not yet defined.
CONCLUSION
Today, the role of vascular factors in the management of glaucoma is as undetermined as the role of IOP was 10 years ago. The only vascular factor consistently meeting the criteria required for clinical consideration is diastolic perfusion pressure. Currently, no evidence supports the role of ischemia in the clinical management of the disease, despite numerous small, clinical findings supporting the role of vascular deficits and ischemia in glaucoma. Technology for the comprehensive assessment of vascular hemodynamics exists in the clinical research environment, and a large-scale, prospective, ocular hemodynamic study in glaucoma could yield useful findings. In the future, such technology and research may assist glaucoma management.
Supported in part by an unrestricted grant from Research to Prevent Blindness.
Alon Harris, PhD, is Director Glaucoma Research and Diagnostic Center, Department of Ophthalmology, Indiana University School of Medicine, Indianapolis, Indiana. He disclosed no financial interest in the technology, companies, and subject matter described herein. Dr. Harris may be reached at (317) 278-0177; alharris@indiana.edu.
1. Tielsch JM. The epidemiology and control of open-angle glaucoma: a population-based perspective. Ann Rev Public Health. 1996;17:121-136.
2. Heijl A, Leske MC, Bengtsson B, et al. Early Manifest Glaucoma Trial Group. Reduction of intraocular pressure and glaucoma progression. Arch Ophthalmol. 2002;120:1268-1279.
3. The Advanced Glaucoma Intervention Study (AGIS): 7. The relationship between control of intraocular pressure and visual field deterioration. The AGIS Investigators. Am J Ophthalmol. 2000;130:429-440.
4. Kass MA, Heuer DK, Higginbotham EJ, et al. The Ocular Hypertension Treatment Study: a randomized trial determines that topical ocular hypotensive medication delays or prevents the onset of primary open-angle glaucoma. Arch Ophthalmol. 2002;120:701-713; discussion:829-830.
5. Anderson DR. Collaborative Normal Tension Glaucoma Study. Curr Opin Ophthalmol. 2003;14:86-90.
6. The effectiveness of intraocular pressure reduction in the treatment of normal-tension glaucoma. Collaborative Normal-Tension Glaucoma Study Group. Am J Ophthalmol. 1998;126:498-505.
7. Goldberg I. Relationship between intraocular pressure and preservation of visual field in glaucoma. Surv Ophthalmol. 2003;48(suppl 1):3-7.
8. Nanba K, Schwartz B. Nerve fiber layer and optic disk fluorescein defects in glaucoma and ocular hypertension. Ophthalmology. 1988;95:1227-1233.
9. O'Brart DPS, de Souza Lima M, Bartsch D-U, et al. Indocyanine green angiography of the peripapillary region in glaucomatous eyes by confocal scanning laser ophthalmoscopy. Am J Ophthalmol. 1997;123:657-666.
10. Rankin SJ, Walman BE, Buckley AR, Drance SM. Color Doppler imaging and spectral analysis of the optic nerve vasculature in glaucoma. Am J Ophthalmol. 1995;119:685-693.
11. Tielsch JM, Katz J, Sommer A, et al. Hypertension, perfusion pressure, and primary open-angle glaucoma. A population-based assessment. Arch Ophthalmol. 1995;113:216-221.
12. Harris A, Sergott RC, Spaeth GL, et al. Color Doppler analysis of ocular vessel blood velocity in normal tension glaucoma. Am J Ophthalmol. 1994;118:642-649.
13. Kahn HA, Leibowitz HM, Ganley JP, et al. The Framingham Eye Study. I. Outline and major prevalence findings. Am J Epidemiol. 1977;106:1:17-32.
14. Tielsch JM, Sommer A, Katz J, et al. Racial variations in the prevalence of primary open-angle glaucoma. The Baltimore Eye Survey. JAMA. 1991;266:369-374.
15. Bonomi L, Marchini G, Marraffa M, et al. Vascular risk factors for primary open-angle glaucoma: the Egna-Neumarkt Study. Ophthalmology. 2000;107:1287-1293.
16. Quigley HA, West SK, Rodriguez J, et al. The prevalence of glaucoma in a population-based study of Hispanic subjects: Proyecto VER. Arch Ophthalmol. 2001;119:1819-1826.
17. Leske MC, Wu SY, Nemesure B, Hennis A. Incident open-angle glaucoma and blood pressure. Arch Ophthalmol. 2002;120:954-959.
18. Hafez AS, Bizzarro RL, Lesk MR. Evaluation of optic nerve head and peripapillary retinal blood flow in glaucoma patients, ocular hypertensives, and normal subjects. Am J Ophthalmol. 2003;136:1022-1031.
19. Jonas JB, Harazny J, Budde WM, et al. Optic disc morphometry correlated with confocal laser scanning Doppler flowmetry measurements in normal-pressure glaucoma. J Glaucoma. 2003;12:260-265.
20. Ciancaglini M, Carpineto P, Costagliola C, Matropasqua L. Perfusion of the optic nerve head and visual field damage in glaucomatous patients. Graefes Arch Clin Exp Ophthalmol. 2001;239:549-555.
21. Chung HS, Harris A, Kagemann L, Martin B. Peripapillary retinal blood flow in normal-tension glaucoma. Br J Ophthalmol. 1999;83:466-469.
22. Duijm HFA, Thomas J, van den Berg TP, Greve EL. A comparison of retinal and choroidal hemodynamics in patients with primary open-angle glaucoma and normal-pressure glaucoma. Am J Ophthalmol. 1997:123:644-656.
23. Yin ZQ, Vaegan A, Millar TJ, et al. Widespread choroidal insufficiency in primary open-angle glaucoma. J Glaucoma 1997;6:23-32.
24. Kaiser TJ, Schoetzau A, Stümpfig D, Flammer J. Blood-flow velocities of the extraocular vessels in patients with high-tension and normal-tension open-angle glaucoma. Am J Ophthalmol. 1997;123:320-327.
25. Tuuolonen A, Nagin P, Schwartz B. Increase of pallor and fluorescein-filling defects of the optic disk in the follow-up of ocular hypertensives measured by computerized image analysis. Ophthalmology. 1987;94:558-563.
26. Tuuolonen A. Asymptomatic miniocclusions of the disc veins in glaucoma. Arch Ophthalmol. 1989;107:1475-1480.
27. Loebl M, Schwartz B. Fluorescein angiographic defects of the optic disk in ocular hypertension. Arch Ophthalmol. 1977;95:1980-1984.
28. Harris A, Dinn RB, Kagemann L, Rechtman E. A review of methods for human retinal oximetry. Ophthalmic Surg Lasers Imaging. 2003;34:152-158.
29. Wilensky JT. The role of brimonidine in the treatment of open-angle glaucoma. Surv Ophthalmol. 1996;41(suppl 1):3-7.
30. Janssen P, Naskar R, Moore S, et al. Evidence for glaucoma-induced horizontal cell alterations in the human retina. Ger J Ophthalmol. 1996;5:378-385.
31. Weiner A, Ripkin DJ, Adler RT, et al. Further studies of foveal outer retinal function in normal-pressure glaucoma (NPG) and primary open-angle glaucoma (POAG). Paper presented at: The Annual Meeting of the Association for Research in Vision and Ophthalmology; 1998; Fort Lauderdale, Florida.
32. Weiner A, Ripkin DJ, Patel S, et al. Foveal dysfunction and central visual field loss in glaucoma. Arch Ophthalmol. 1998;116:1169-1174.
33. Quigley HA, Nickells RW, Kerrigan LA, et al. Retinal ganglion cell death in experimental glaucoma and after axotomy occurs by apoptosis. Invest Ophthalmol Vis Sci. 1995;36:774-786.
34. Nickells RW. Retinal ganglion cell death in glaucoma: the how, the why, and the maybe. J Glaucoma. 1996;5:345-356.
35. Romano C, Price MT, Almli T, Olney JW. Excitotoxic neurodegeneration induced by deprivation of oxygen and glucose in isolated retina. Invest Ophthalmol Vis Sci. 1998;39:416-423.
36. Kuroiwa S, Katai N, Shibuki H, et al. Expression of cell cycle related genes in dying cells in retinal ischemic injury. Invest Ophthalmol Vis Sci. 1998;39:610-617.
37. Harris A, Arend O, Danis R, et al. Hyperoxia improves contrast sensitivity in early diabetic retinopathy. Br J Ophthalmol. 1996;80:209-213.
38. Pillunat L, Lang GK, Harris A. The visual response to increased ocular blood flow in normal pressure glaucoma. Surv Ophthalmol. 1994;38(suppl 1):139-147.
39. Pillunat LE, Lang GK, Harris A. Ocular carbon dioxide reactivity and calcium channel blockers in normal tension glaucoma. In: Drance SM, ed. Glaucoma, Ocular Blood Flow, and Drug Treatment. Amsterdam: Kugler; 1995: 67-71.
40. Bose S, Piltz JR, Breton ME. Nimodipine, a centrally active calcium antagonist, exerts a beneficial effect on contrast sensitivity in patients with normal-tension glaucoma and in control subjects. Ophthalmology. 1995;102:1236-1241.
41. Harris A, Evans DW, Cantor LB, Martin B. Hemodynamic and visual function effects of oral nifedipine in normal-tension glaucoma. Am J Ophthalmol. 1997;124:296-302.
42. Netland PA, Chaturvedi N, Dreyer EB. Calcium channel blockers in the management of low-tension and open-angle glaucoma. Am J Ophthalmol. 1993;118:608-613.
43. Kitazawa Y, Shirai H, Go F. The effect of Ca2+-antagonist on visual field in low-tension glaucoma. Graefe's Arch Clin Exp Ophthalmol. 1989;227:408-412.
44. Sawada A, Kitazawa Y, Yamamoto T, et al. Prevention of visual field defect progression with brovincamine in eyes with normal-tension glaucoma. Ophthalmology. 1996;103:283-288.
