RESEARCH RESULTS Perfusion Pressure and Glaucoma Work is ongoing toward understanding the participation of vascular phenomena in the pathophysiology of glaucoma. BY ALON HARRIS, PHD laucoma remains a multifactorial optic neu- ropathy of unknown etiology and sometimes “Clinical studies have detected inadequate treatment.1 Several large-scale G studies published during the past several numerous ocular blood flow deficits in years have provided substantial proof that reducing IOP benefits patients with glaucoma,2-6 and, presently, the some patients with primary only definitive treatment for glaucoma is to lower IOP open-angle glaucoma.” surgically and/or medically, thus slowing disease pro- gression. This finding holds true for glaucoma patients with IOPs above and within the normal range.7 The Baltimore Eye Survey found a diastolic perfusion Research indicates that optic nerve ischemia may pressure (diastolic perfusion pressure = diastolic BP - contribute to glaucomatous damage8,9 and establishes IOP) of less than 30 mm Hg to be strongly associated links between glaucoma and microvascular disease, sys- with OAG (risk ratio = 6), whereas systolic perfusion temic vascular disease, and vasospasm.10-12 According to pressure (systolic perfusion pressure = systolic BP - IOP) evidence-based medicine, diastolic perfusion pressure is and mean perfusion pressure (mean perfusion pressure the only vascular parameter that meets the criteria nec- = mean BP - IOP) were only mildly associated.14 In the essary to be considered clinically. The relationship be- Egna-Neumarkt study, the OAG prevalence increased tween perfusion pressure and glaucoma is not known, progressively with decreased diastolic perfusion pres- but the existence of a relationship begs the question, sure,15 and the Proyecto VER study reported similar are vascular deficits and ischemia involved in the patho- results at a low diastolic perfusion pressure.16 The Bar- genesis and progression of glaucoma? This article exam- bados Incidence Study of Eye Diseases found all three ines the current understanding of the role of vascular factors (diastolic perfusion pressure, systolic perfusion factors in glaucoma. pressure, and mean perfusion pressure) to be related to OAG, but a low diastolic perfusion pressure had the EVIDENCE-BASED STUDIES OF A strongest correlation, approximately tripling subjects’ VASCULAR ROLE IN GLAUCOMA risk ratio of developing OAG.17 Population-based studies have found that vascular- related factors are also risk factors in glaucoma. In 1983, CLINICAL EVIDENCE OF VASCULAR Framingham Eye Study participants with open-angle DEFICITS glaucoma (OAG) were reported to have significantly Clinical studies have detected numerous ocular blood low blood pressure (BP)/IOP ratios.13 In addition, per- flow deficits in some patients with primary open-angle sons with definite glaucomatous visual field defects had glaucoma (POAG). Several different methodologies have lower ratios than those with suspect defects or no de- been used to assess blood flow. Fluorescein angiography fects. Low perfusion pressure was also an OAG risk fac- has demonstrated reduced total retinal blood flow and tor in the Baltimore Eye Survey, Egna-Neumarkt, Proyec- dye leakage from optic nerve head (ONH) capillaries,8 to VER, and, most recently, the Barbados Incidence findings suggesting peripapillary ischemia in glaucoma.9 Study of Eye Diseases.14-17 Scanning laser Doppler flowmetry combines laser flow- 12 IGLAUCOMA TODAYIMARCH/APRIL 2004 RESEARCH RESULTS metry over a defined area of points and creates a 2-D underlying choroid. In order to define how enhanced perfusion map. The penetration depth is approximately blood flow improves visual function, therefore, it is 400 µm and only measures the flow in the microcircula- essential to evaluate blood flow to the retina and cho- tion. The velocity limit is 10 mm/second and is therefore roid, for the retinal ganglion cells and photoreceptor inaccurate for large vessels. Researchers have used this cells, respectively. If specific damage to retinal ganglion technology to demonstrate reduced blood flow in a cells indeed causes visual function deterioration in glau- number of conditions, but the findings have been vari- coma,31 then enhancing retinal blood flow should im- able. Investigators have demonstrated (1) lower optic prove this deficit. If, instead, photoreceptor deteriora- nerve blood flow in POAG compared to OHT subjects,18 tion underlies the decline in visual function, then im- (2) an inverse relation between C/D ratio and ONH proving choroidal blood flow should mitigate this pro- flow,18,19 (3) reduced ONH flow in patients with normal- cess. Finally, if a loss of both cell types occurs in glauco- tension glaucoma (NTG),19 and (4) decreased ONH flow ma,11,29-33 then improving retinal and choroidal blood with worsened mean defect or corrected pattern stan- flow may have a beneficial effect. dard deviation.20,21 Studies have also shown that the choroidal circula- tion in glaucoma fails to vasodilate appropriately,22 and “Reduced perfusion pressure to the eye delays in choroidal filling may be associated with a thin- ning of the entire choroid.23 In addition, the retrobulbar (potentially nocturnal) may cause vessels in both NTG and POAG patients exhibited in- disease progression, regardless of an creased resistance indices during color Doppler im- aging.10,24 Such imaging measures retrobulbar blood individual’s well-controlled IOP.” velocities and resistivity index in the ophthalmic artery, ciliary arteries, and central retinal artery. These vascular abnormalities may be among the earliest manifestations In animal models of glaucoma, retinal ganglion cells of glaucoma.25-27 die via apoptosis,33,34 a process in which ischemia may Investigators including myself are evaluating the use- play a role.34 In vivo and in vitro models of retinal fulness of retinal oximetry for assessing tissue ischemia. ischemic/reperfusion injury emphasize the impact of The measurement of blood oxygen saturation in the the loss of nutrient delivery, especially to the apparently retinal vasculature may provide physicians with a better highly sensitive retinal ganglion cells.35,36 In this context, understanding of the relationship between vascular improving blood flow may deliver immediate neuropro- deficits, metabolic events, and glaucoma. The clinical tection to these cells. Also, relieving ischemia and in- measurement of oxygen saturation in humans is accom- creasing oxygen may be another route to providing im- plished noninvasively by optical means. Via the different mediate neuroprotection in glaucoma. optical characteristics of oxygenated and deoxygenated Clinical studies of glaucoma and diabetes have linked hemoglobin, the wavelength-dependent transmission of visual function to hemodynamics. Hyperoxia acutely light through perfused tissue allows us to calculate the improved contrast sensitivity in diabetic patients who ratio of oxygenated hemoglobin to total hemoglobin possessed a substantial initial contrast sensitivity de- concentration.28 fect.37 The acute enhancement of ocular perfusion may Reduced perfusion pressure to the eye (potentially improve visual function in some patients with NTG.12,38-41 nocturnal) may cause disease progression, regardless of In a series of experiments with NTG patients, breathing 11 an individual’s well-controlled IOP. Despite accumulat- CO2 for several minutes (sufficient to increase end-tidal ing evidence that glaucoma patients suffer from inade- PCO2 by 15%) reduced resistance indices in their oph- quate ocular blood flow, the current clinical treatment thalmic arteries to normal levels, a discovery suggesting of the illness involves neither documentation nor treat- the existence of a reversible ocular vasospasm.42 In- ment of these deficits.29 vestigators have obtained findings similar to these short-term results with CO2 breathing both acutely and CELLULAR EFFECTS OF ISCHEMIA over 6 months in NTG patients treated with calcium Recent evidence suggests that glaucoma characteristi- channel blockers.39-41,43,44 These studies imply that cally damages the photoreceptors and the horizontal improving ocular perfusion may simultaneously and cells, as well as the retinal ganglion cells.30,31 Retinal cir- immediately enhance glaucoma patients’ visual func- culation nourishes the retinal ganglion cells, whereas tion, but the mechanism for this action is not yet the photoreceptors receive their blood supply from the defined. MARCH/APRIL 2004 IGLAUCOMA TODAYI 13 RESEARCH RESULTS CONCLUSION 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- Today, the role of vascular factors in the management based study of Hispanic subjects: Proyecto VER. Arch Ophthalmol. 2001;119:1819-1826. of glaucoma is as undetermined as the role of IOP was 17. Leske MC, Wu SY, Nemesure B, Hennis A. Incident open-angle glaucoma and blood 10 years ago. The only vascular factor consistently meet- pressure. Arch Ophthalmol. 2002;120:954-959. 18. Hafez AS, Bizzarro RL, Lesk MR. Evaluation of optic nerve head and peripapillary reti- ing the criteria required for clinical consideration is dias- nal blood flow in glaucoma patients, ocular hypertensives, and normal subjects. Am J tolic perfusion pressure. Currently, no evidence sup- Ophthalmol. 2003;136:1022-1031. 19. Jonas JB, Harazny J, Budde WM, et al. Optic disc morphometry correlated with con- ports the role of ischemia