Glaucoma and ocular blood flow: an anatomical perspective

Abstract

Open-angle glaucoma (OAG) is a chronic progressive optic neuropathy that is increasing in prevalence worldwide. Currently, intraocular pressure is the only known modifiable risk factor. With lowering of intraocular pressure, the proportion of individuals who experience progression of visual field defects is reduced but continues to occur in some individuals. Many other risk factors have been identified, including decreased ocular perfusion pressure and decreased ocular blood flow. Various imaging methodologies have shown an association between OAG and altered blood flow in the various circulations: retrobulbar, retinal, optic nerve head and choroidal. In addition, different morphological alterations have been found to be associated with OAG. This review will cover the evidence that supports the association between altered ocular blood flow and glaucoma. Furthermore, it serves to describe the future methodologies that will assess ocular metabolism, which will strive to move the field closer to definitively understanding the effect of vascular changes on OAG.

Keywords::

• ischemia
• metabolism
• ocular blood flow
• open-angle glaucoma
• perfusion pressure
• visual function

Figure 1. Color Doppler imaging measures velocity in retrobulbar blood vessels.

Outcome parameters include peak systolic (PSV) and end diastolic (EDV) blood flow velocities, and also calculated vascular resistance index, which is equal to (PSV-EDV)/PSV.

Color figure can be found online at www.expert-reviews.com/doi/full/10.1586/eop.12.41

Figure 2. Doppler optical coherence tomography.

(A) Fundus photograph showing the double circular pattern of the optical coherence tomography (OCT) beam scanning across retinal blood vessels emerging from the optic disc. (B) The relative position of a blood vessel in the two OCT cross-sections is used to calculate the Doppler angle θ between the beam and the blood vessel. (C) Color Doppler OCT image showing the unfolded cross-section from a circular scan. Arteries and veins could be distinguished by the direction of flow as determined by the signs (blue or red color) of the Doppler shift and the angle θ.

Color figure can be found online at www.expert-reviews.com/doi/full/10.1586/eop.12.41

Figure 3. Color overlay of oxygen saturation in the retinal vessels.

Color figure can be found online at www.expert-reviews.com/doi/full/10.1586/eop.12.41

Figure 4. Simultaneously recorded images of the human retinal vessels using a single flash.

(A) Oxygen-sensitive image at 600 nm. (B) Oxygen-insensitive image at 570 nm. The arteries are lighter in (A) because oxyhemoglobin light absorption is relatively low.

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Medscape, LLC designates this Journal-based CME activity for a maximum of 1 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

All other clinicians completing this activity will be issued a certificate of participation. To participate in this journal CME activity: (1) review the learning objectives and author disclosures; (2) study the education content; (3) take the post-test with a 70% minimum passing score and complete the evaluation at www.medscape.org/journal/expertop; (4) view/print certificate.

Release date: 26 September 2012; Expiration date: 26 September 2013

Learning objectives

Upon completion of this activity, participants will be able to:

• • Evaluate the relationship between OAG and ocular blood flow

• • Distinguish ocular circulatory systems affected by OAG

• • Analyze the effect of OAG on ocular blood flow in particular ocular circulation systems

• • Assess methods to evaluate ocular blood flow

Financial & competing interests disclosure

PUBLISHER

Elisa Manzotti

Publisher, Future Science Group, London, UK.

Disclosure: Elisa Manzotti has disclosed no relevant financial relationships.

CME Author

Charles P Vega, MD

Health Sciences Clinical Professor; Residency Director, Department of Family Medicine, University of California, Irvine, CA, USA.

Disclosure: Charles P Vega, MD, has disclosed no relevant financial relationships.

Authors and Credentials

Brent A Siesky, PhD

Eugene and Marilyn Glick Eye Institute, Indiana University School of Medicine, Indianapolis, IN, USA.

Disclosure: Brent A Siesky, PhD, has disclosed no relevant financial relationships.

Alon Harris, MS, PhD

Eugene and Marilyn Glick Eye Institute, Indiana University School of Medicine, Indianapolis, IN, USA.

Disclosure: Alon Harris, MS, PhD, has disclosed the following financial relationships: he receives renumeration from MSD and Alcon for serving as a lecturer for the outside entities, and he also receives renumeration for serving as a consultant for MSD, Alcon and Sucampo Pharmaceuticals.

Annahita Amireskandari, MD

Eugene and Marilyn Glick Eye Institute, Indiana University School of Medicine, Indianapolis, IN, USA.

Disclosure: Annahita Amireskandari, MD, has disclosed no relevant financial relationships.

Brian Marek, BS

Eugene and Marilyn Glick Eye Institute, Indiana University School of Medicine, Indianapolis, IN, USA.

Disclosure: Brian Marek, BS, has disclosed no relevant financial relationships.

Historical perspective

Glaucoma is currently the second leading cause of blindness worldwide, second only to cataracts, and the prevalence is expected to increase [1,2]. In 2010, there were an estimated 60.5 million people with open-angle glaucoma (OAG) worldwide [2]. As the world population ages, it is expected that this number will to rise to 79.6 million by 2020. Such an increase in OAG has been documented in the USA, with a 25% increase in prevalence from 2002 to 2010 (2.22–2.79 million estimated cases). Moreover, it was estimated that in the year 2000, 8.8 million physician office visits and US$440 million were attributable to glaucoma in the USA [3].

Intraocular pressure & glaucoma

Despite its prevalence, much remains to be determined about this chronic progressive optic neuropathy [4]. It has been over 100 years since intraocular pressure (IOP) was first included in the disease description of an optic neuropathy that resulted in blindness [5]. Large-scale studies have demonstrated that lowering IOP is a beneficial treatment but also that a portion of patients experience progression of the disease despite low IOP. Currently, elevated IOP continues to be the only modifiable risk factor for the development and progression of glaucoma [6].

Results from the Advanced Glaucoma Intervention Study assessed the effect of IOP reduction after surgical intervention on the progression of visual field (VF) deficits [5]. Even with reduction of IOP to less than 18 mmHg, 14.4% of patients had VF deterioration after 7 years. However, the Early Manifest Glaucoma Trial showed that treatment was helpful in slowing progression, with 45% of the treatment group (trabeculoplasty plus topical betaxolol) compared with 62% of the control group (observation) progressing [7,8]. Furthermore, the Ocular Hypertensive Study showed that topical ocular hypotensive medications were successful at preventing or delaying the onset of OAG in patients with ocular hypertension (OHT) [9]. The lowering of IOP reduced the 5-year risk of developing glaucoma from 9.5% in the observation group to 4.4% in the treatment group. Different modalities of treatment have also been compared [10]. For example, one study demonstrated that surgical and medical interventions were able to achieve IOP reductions of 48 and 35%, respectively [7,8]. However, at 8 years, 21.3% of the surgical and 25.5% of the medicine groups still had worsening of their VFs. In a trial looking at a 30% reduction of IOP, 12% of treated normal-tension glaucoma (NTG) patients continued to have VF progression, although 35% of the control group had VF progression [11].

The continued disease progression, despite treatment in the aforementioned studies, has led to the idea that OAG is a multifactorial disease with inadequate methods of treatment [4]. Thus, much effort has been directed at identifying other risk factors. A variety of risk factors have been discovered including age [5,12], race [9], male sex [12], BMI [12], increased cup-to-disc (CD) ratio [5,9,13], pattern standard deviation [13], central corneal thickness [8,9,13] and pseudoexfoliation syndrome [5,13]. Moreover, vascular disturbances such as ischemia [14,15], vascular dysregulation [16–18] and low ocular perfusion pressure (OPP) [19,20] have been identified as risk factors. It is difficult to establish causality in the study of glaucoma in humans, as one cannot isolate a specific trait [13]. Also, it is not always clear whether the disease or the risk factor came first: a problem known as temporal ambiguity. It is possible that some findings are a result of the glaucomatous disease process and not a cause of it. However, having a background of knowledge about glaucoma and performing prospective studies helps to clarify the relationship [13].

Ocular perfusion pressure

OPP is defined as arterial blood pressure (BP) minus IOP [21]. Mean ocular perfusion pressure is generally calculated as two-thirds of mean arterial pressure minus IOP [22]. Occasionally, OPP is further divided into systolic perfusion pressure (SBP minus IOP) and diastolic perfusion pressure (DPP; diastolic BP [DBP] minus IOP). Large population-based studies have determined that reduced OPP is strongly associated with increased prevalence of glaucoma [16–18]. Low DPP has the strongest correlation with the development of glaucoma [16,18]. The Baltimore Eye Survey found that those with DPP <30 mmHg had a six-times higher risk of disease development than those with DPP >50 mmHg [17]. Furthermore, the Barbados Eye Study showed that individuals with the lowest 20% of DPP were 3.3-times more likely to develop glaucoma [12]. In a subgroup of patients from the Barbados Eye Study followed for 9 years, lower OPPs and lower systolic BPs were again identified as risk factors [23,24]. In a different study, low mean ocular perfusion pressure (<42 mmHg), systolic perfusion pressure (<101 mmHg) and DPP (<55 mmHg) were all shown to be risk factors for the development of glaucoma, with relative risks of 3.1, 2.6 and 3.2, respectively [18]. The Egna-Neumarkt Study reported a 4.5% increase in glaucoma prevalence in patients with DPPs <50 mmHG compared with patients with DPPs ≥66 mmHg [16]. Despite the fact that these studies are from varying populations, they all found that reduced DPP is an important risk factor for the development of glaucoma.

BP & cerebrospinal fluid pressure as it relates to glaucoma

The Thessaloniki Eye Study assessed the relationship between BP in patients without glaucoma and optic disc morphology, as measured by Heidelberg retinal flowmetry (HRF) [25]. It concluded that being on antihypertensive therapy with DBP <90 mmHg was positively correlated with cup area and CD ratio when compared with both patients with high DBP and patients with untreated, normal DBP. Also, low OPP was positively associated with cup area and CD ratio. The results did not change after adjusting for cardiovascular disease, diabetes, age, IOP and duration of antihypertensive treatment. These results suggest that BP could be an independent risk factor glaucomatous damage [25]. Also, it brings up the question of whether there is a particular time of day to administer antihypertensive medication for the best treatment outcome [26]. It is unknown whether treating systemic hypertension is better in the morning than at night due to the possibility of worse nocturnal hypotension with treating in the evening.

In addition, the European Glaucoma Prevention Study concluded that the use of systemic diuretics was significantly associated with the development of glaucoma in OHT patients with a hazard ratio of 2.41 [27,28]. The combination of antihypertensives with diuretics worsened the prognosis further, with a hazard ratio of 3.07. In contrast to the Thessaloniki Eye Study and the European Glaucoma Prevention Study, systemic hypertension has also been described as a risk factor. This could be due to the association between hypertension and increased IOP. As the Thessaloniki Eye Study adjusted for IOP, it may have more appropriately assessed the relationship between BP and CD ratios [25]. Furthermore, the Thessaloniki Eye Study showed that optic disc changes occurred only when a hypertensive patient was on antihypertensive medication, and thus had normal DBP. Optic disc changes were only found with this combination and were not associated with solely antihypertensive use or BP status, thus implying a connection between these two variables and glaucomatous change.

Recently, more attention has been focused on the cerebrospinal fluid (CSF) surrounding the optic nerve (ON). The balance between the anterior force of the CSF pressure and the posterior force of the IOP in the area of the optic nerve head called the lamina cribrosa is known as the trans-lamina cribrosa pressure difference [29]. The concern is that variations in this pressure difference can apply damaging force to the optic disk [30]. This is related to blood flow in that the CSF pressure is thought to have a positive correlation with BP. With high BPs, the CSF pressure rises to prevent dangerously high pressures in the cerebral vasculature. As the BP falls, the CSF pressure also decreases in order to allow for continued perfusion of the brain and associated structures. Thus, at low BPs, the trans-lamina cribrosa pressure difference is increased due to the low CSF pressure. If BP is medically reduced, CSF pressure may also fall so that even with normal IOP, the trans-lamina cribrosa pressure difference will be elevated, such as in high-pressure glaucoma [25]. Furthermore, several studies have concluded that CSF pressure is reduced in some patients with NTG and primary open-angle glaucoma (POAG) [29,31]. Interestingly, some studies have continued to look at the role of CSF in glaucoma and have hypothesized that there is a ‘compartment syndrome’ within the subarachnoid space of the ON [32]. It has been proposed that there are variations in the CSF pressure on the ON with possible areas of increased pressure. Also, reductions in CSF flow in the region of the ON have resulted in hypotheses that variations in the CSF composition, whether it is decreased nutrients or increased toxic metabolites, may be involved in the pathogenesis of ON damage [32].

Ocular blood flow

Over the years, many clinical studies have detected ocular blood flow (OBF) deficits in OAG patients. Blood flow parameters in OAG patients have been shown to be reduced in the retrobulbar [33], retinal [34], optic nerve head (ONH) [35] and choroidal [36] circulations. These vascular deficits may be one of the first manifestations of glaucoma [37,38]. Changes in BP [39] and OPP [16,17,39] have been associated with OAG. This is also true of other vascular abnormalities such as nocturnal hypotension [40], optic disc hemorrhage [41], aging of the vasculature [42] and diabetes [41]. Also, vascular dysregulation, which can result in vasospasm, may participate in the pathophysiology of glaucoma [19,20]. Vasospasm and systemic hypotension may be distinct risk factors for glaucomatous VF progression [43]. It has been proposed that disturbances in OBF in OAG are partly related to systemic vascular dysregulation [20]. Dysfunction of the innermost layer of the blood vessels, the endothelium, is thought to play a role in this vascular dysregulation [44]. Vascular tone and blood flow are partially regulated by the endothelium through the release of vasoactive substances such as nitric oxide and endothelin-1. Endothelial dysfunction has been shown in glaucoma by demonstrating an imbalance of vasoactive substances such as nitric oxide and endothelin-1. There has also been shown to be decreased flow-mediated vasodialation in the forearm of NTG patients, indicating that endothelial dysfunction is present in the ocular and systemic vasculature of NTG patients, and is thus not likely only a consequence of the disease process [44].

Despite the fact that evidence from many studies has demonstrated the association between reduced OBF and OAG in various circulations, the current clinical treatment of the disease involves neither documentation nor treatment of the deficits [42]. This is partly due to the need for larger scale clinical studies that will allow the precise relationship between blood flow and glaucomatous damage to be understood. The remainder of this review will cover the latest evidence of the relationship of OBF to glaucoma. It will look at specific anatomical blood supplies to the eye: the retrobulbar, retinal, ONH and choroidal circulations. With each circulation, the relevant anatomy, background on imaging methodologies and functional or structural changes will be discussed.

Ischemia of retinal nerve ganglion cells

Glaucoma, being an optic neuropathy, is associated with the loss of retinal ganglion cells (RGCs). With the increased acceptance of the concept of altered blood flow in OAG, one must consider the possibility of ocular tissue ischemia and that ischemia may play a central role in RGC death [14,15]. In animal models of glaucoma, RGCs have been shown to die mainly by apoptosis [14,45]. Ischemic injury of RGCs is thought to occur through accumulation of glutamate, leading to glutamate excitotoxicity [46]. In vitro models have shown that neuroprotection of the ischemic RGCs can be obtained through blockage of both of the N-methyl-d-aspartate and non-N-methyl-d-aspartate glutamate receptors, or by the delivery of a minimal amount of glucose [46]. During ischemia, RGC cytoskeleton components have been shown to suffer derangements and could be an important cause of neuronal dysfunction [47]. In addition, these changes are observed before the signs of apoptosis within the RGCs. In the context of ischemia, neuroprotection could be achieved by increasing blood flow, whether it is by better autoregulation or increased OPP. And if indeed RGCs glaucoma are entering apoptosis from ischemia, improving oxygen and nutrient delivery to the eye could offer neuroprotection.

Furthermore, visual function has been correlated to ocular hemodynamics in clinical studies of patients with both diabetes and glaucoma. Contrast sensitivity has been shown to improve with hyperoxia in diabetic patients with substantial initial defect [48]. Moreover, acute enhancement of ocular perfusion in NTG patients may improve visual function [33,49–51]. Similarly, calcium channel blockers have been shown to benefit visual function acutely and over 6 months in some patients with NTG [49–53]. Also, calcium channel blockers may reduce progression of VF defects NTG patients [54]. While these studies suggest improving ocular perfusion may benefit visual function, the mechanism for the improvement has not been determined.

Retrobulbar blood flow

The first branch of the internal carotid artery is the ophthalmic artery (OA), the only extracranial branch of the internal carotid artery [55]. The OA progresses to run inferiorly to the ON and enters the orbit through the optic canal. While in the orbit, the OA crosses superior to the ON and continues nasally and anteriorly. The OA terminates after giving off the central retinal artery (CRA) and the posterior ciliary arteries, and branches to the extraocular muscles.

The CRA supplies the inner two-thirds of the retina, the anterior segment of the ONH and portions of the retrolaminar ON [55]. It penetrates the ON 10–15 mm behind the globe to run adjacent to the central retinal vein in the middle of the ON. The medial and lateral posterior ciliary arteries then branch off the OA. Each posterior ciliary artery further divides to one long posterior ciliary artery (LPCA) and seven to ten short posterior ciliary arteries (SPCAs). The SPCAs supply the peripaillary and posterior choroid, while the LPCA and the anterior ciliary arteries (branches of the muscular arteries) supply the anterior choroid. These retrobulbar vessels provide the majority of the blood to the eye [55].

Currently, color Doppler imaging (CDI) remains the method of choice for measuring blood flow parameters in the retrobulbar vessels (Figure 1). CDI is a commonly used technology with applications in radiology, cardiology and obstetrics [56]. It utilizes 2D ultrasound images in conjunction with velocity measurements derived from the Doppler shift of sound waves reflected from erythrocytes, as they travel through blood vessels. A typical protocol for CDI involves evaluation of the OA, CRA and SPCAs. The peak systolic velocity (PSV) and end diastolic velocity (EDV) are measured and used to calculate Pourcelot’s index of resistivity (RI), an estimate of downstream resistance [57,58]. RI is calculated using the equation: (PSV−EDV)/PSV. In addition, the pulsitality index (PI) is calculated by the equation: (PSV−EDV)/T_max. A shortcoming of CDI is its inability to measure net blood flow volumes due to not being able to accurately measure vessel diameter [56].

The retrobulbar circulation has been extensively studied with CDI, and there have been numerous studies that have concluded that there is an association between decreased blood flow velocities in the retrobulbar circulation and glaucomatous damage [59–64]. For instance, the retrobulbar vessels in both NTG and POAG patients exhibit increased RI during CDI [54,65]. Also, there is a correlation between glaucomatous VF progression and decreased blood flow velocities in the SPCAs [62,66] and an increased OA RI [66]. The rate of progression of VF defects also relates to blood flow, with more rapid progression correlating with a lower CRA velocity and a higher RI in the CRA [61,63]. In patients with asymmetric VF defects, the more severely affected eye has been shown to have reduced blood flow velocities in the PSV of the CRA and OA, and in the EDV of the CRA [64,67]. Furthermore, in patients with unilateral VF loss, the RI in the CRA of both eyes was higher than that in controls [64]. Also, the PSV and EDV of the CRA and SPCA in the eye with normal VFs and the eye with VF loss were both lower than in healthy controls [64]. This leads to the possibility that reduced blood flow may precede detectable VF damage.

Several studies have also demonstrated that changes in RI can be used to predict glaucomatous VF progression [59,60]. In one such study, the RI of the OA and SPCA was shown to reliably predict glaucomatous VF progression [59]. Similarly, Galassi et al. found a higher EDV and a lower RI in the OA in patients with stable VF when compared with patients with a deteriorating VF (p < 0.001) [60]. Patients with an RI of ≥0.78 in the OA were six-times more likely to have VF deterioration than those with an RI <0.78. A recent study used CDI to assess the OA waveform as it relates to glaucoma, and found that patients with glaucoma had decreased early systolic acceleration and decreased systolic/diastolic mean velocity ratios [68]. The study suggested that altered pattern of blood flow velocities could be a sign of inadequate mechanisms of autoregulation in patients with glaucoma. Also in support of the relationship between vascular dysregulation and glaucoma, Garhöfer et al. demonstrated an increased correlation between OPP and retrobulbar blood flow velocities [69].

In addition, studies have shown relationships between glaucoma treatment, OBF and VF progression. Martinez and Sanchez performed a study where OAG patients with asymmetric VF defects were given dorzolamide 2% twice a day (b.i.d.) added to timolol maleate 0.5% b.i.d. in the eye with larger VF defect and only timolol in the eye with the smaller defect [70]. The result was that the eye receiving dorzolamide and timolol had a significantly reduced IOP, increased EDV in the OA and SPCA and reduced RI in the OA and SPCA when compared with baseline. Also, the dorzolamide plus timolol eye had significantly reduced VF progression compared with the timolol eye. However, there were several limitations to the study. First, it is expected that the eye with less damage will progress faster than the more damaged eye due to the regression to the mean effect. Second, the dozolamide plus timolol in the eye with the worse VF defect was associated with a further reduction in IOP, which itself can reduce the rate of VF defect progression.

In a study by Martinez and Sanchez-Salorio, predictors of VF progression were analyzed in patients being treated with timolol plus either dorzolamide or brinzolamide [71]. It was found that patients with decreased EDV and increased RI in the OA and SPCA were predictors for VF progression. The risk of progression decreased 30 and 20% with each cm/s increase in EDV of the OA and SPCA, respectively. Also, the risk decreased 20% for every 0.01-unit decrease in the RI of the OA or SPCA [71]. However, the study is limited in that the statistical power may be low and that the inclusion of bilateral glaucoma, systemic hypertension and cardiovascular disease was uneven. Interestingly, a 1-year study comparing OAG patients taking either latanoprost and timolol fixed combination or dorzolamide and timolol fixed combination found that despite both a significant decrease in the RI of the OA and SPCA in the dorzolamide and timolol fixed combination group, there was no change between the groups in VFs or retinal nerve fiber layer (RNFL) thickness between groups [72]. In addition, both groups had significant IOP reductions.

Retinal blood flow

The retina receives its nourishment through intricately arranged blood flow from two sources: the CRA and the uveal system [55]. The CRA supplies the inner two-thirds of the retina. The uveal system supplies the remainder of the retina by diffusion of molecules from the choroid, through the retinal pigment epithelium, and into the retina, supplying the bipolar cells and photoreceptors. The uveal system will be discussed further when the choroidal blood flow is addressed.

The CRA eventually terminates in four major trunks, each of which supplies a quadrant of the retina [55]. The retinal arteries and veins course within the RNFL, and eventually the capillaries and fibers of the RNFL run in parallel. Considering that the RGCs are supplied by the retinal circulation and that the RGCs are lost in glaucoma, retinal blood flow is of great importance in understanding the pathophysiology of glaucoma.

Retinal blood flow alterations & visual function

Currently, a variety of technologies are used to assess retinal blood flow. These include laser Doppler flowmetry (LDF), digital scanning laser ophthalmoscope (SLO) angiography, laser speckle flowgraphy, Fourier-domain optical coherence tomography (FD-OCT), retinal vessel analyzer and retinal oximetry. These imaging technologies have been able to demonstrate an association between retinal blood flow and visual function. The following is a description of this evidence.

Using HRF, it has been determined that reductions in retinal blood flow were associated with reductions in visual function [35]. HRF is a commercially available system that combines LDF and scanning laser tomography to provide a 2D map of blood flow to the ON and surrounding retina. In patients with asymmetric glaucomatous damage, this technology was used to show that both blood flow and velocity are significantly decreased in eyes with worse damage compared with the fellow eye with less damage [73]. Moreover, blood velocity was found to be significantly reduced in hemifields with greater damage. This correlation was not present when blood flow or blood flow volume was assessed. It is hypothesized that once glaucomatous field damage is initiated in an eye, both superior and inferior disk rims are exposed to similar blood flow alterations despite asymmetric hemifields.

Using SLO angiography, similar conclusions have been drawn. In SLO angiography, the retinal blood flow is directly visualized using sodium fluorescein dye that is injected intravenously. The time from dye injection to its first appearance in a retinal artery and associated vein is referred to as the arteriovenous passage (AVP) time. SLO with fluorescein has been used to demonstrate reduced retinal blood flow, along with narrower vessels and a smaller vascular bed in patients with glaucoma [74], as demonstrated by prolonged AVP times [75,76] and fluorescein-filling defects [75]. The association between altered blood flow and worsening VFs has additionally been demonstrated with SLO angiography. Areas of more severe VF defects are associated with prolonged AVP compared with areas of less damage [77,78]. In a study by Arend et al., dorzolamide was found to significantly shorten AVP times in patients with OAG, suggesting that dorzolamide may enhance retinal perfusion and possibly enhance visual function in this manner [79].

Two relatively new and exciting technologies for ocular imaging are FD-OCT and retinal oximetry. FD-OCT represents a recent improvement in Doppler OCT, which allows for more rapid and higher resolution images. Thus, FD-OCT combines the structural measurements of OCT with the retinal blood flow measurements of laser Doppler in a single device. It is possible to capture high-resolution Doppler information from retinal vessels in three dimensions within a fraction of the cardiac cycle [80,81]. Retinal blood flow scans (Figure 2) transect all retinal branch arteries and veins that emerge from the ONH, providing the basis for total retinal blood flow measurement. An advantage to this technology is that blood flow can be measured as an absolute value (µl/min). Also, blood flow can be measured several times per second and averaged to give a repeatable value (consensus). More research into FD-OCT needs to take place before it can be used to its full potential, possibly for the development of standardized OBF measurements and making retinal blood flow analysis a part of everyday clinical practice. Thus far, it has been determined to be a reproducible method of determining total retinal blood flow [80]. Using FD-OCT, a pilot study looking at blood flow differences in various retinal diseases and normal eyes found that in patients with glaucoma, the average blood flow and arterial and venous velocities were significantly lower than healthy controls [82]. Also, the decrease in blood flow was highly correlated with the mean deviation of VFs.

OBF measurements remain a substitute for retinal tissue metabolic status. Therefore, such measurements make it impossible to interpret the impact of varying degrees of ischemia on retinal metabolism. Methods of direct measurement of tissue oxygenation are a step toward revealing the impact of ischemia on retinal photoreceptor ganglion cells. The methodology of photographic retinal oximetry moves in this direction and provides a more direct way to measure tissue oxygenation and metabolism. Retinal oximetry uses a modified fundus camera or similar device and developed algorithms to measure oxygen saturation in the arteries and veins, the difference of which is informative about tissue oxygenation and metabolism (Figure 3). Current technology permits the clinician to determine artery and vein saturations over using a single set of oxygen-sensitive and oxygen-insensitive images (Figure 4). As this technology develops and more is known about the complex optical environment in the ocular fundus, its application to understand the differences in oxygen utilization will be more valuable. The most significant limitation of retinal oximetry lies in that it has not been sufficiently validated [83]. However, one study has shown it to be repeatable, with a standard deviation between measurements of average oxygen saturation of 0.8% in the arterioles and 1.3% in the venules [84].

In terms of its contribution to the understanding of glaucoma, retinal oximetry in one study has shown that NTG patients had significantly reduced arterial oxygen saturation [85]. However, these findings were not found in POAG patients. On the other hand, in all examined eyes arteriolar oxygen saturation and the retinal arteriovenous differences in oxygen correlated strongly with the patient’s rim area. Olafsdottir et al. found that deeper VF defects in patients with POAG were associated with decreased arteriovenous difference in retinal oxygen saturation and increased oxygen saturation in venules [86]. No correlation was present concerning retinal arterioles and VF defects. It was concluded that these results suggest that oxygen metabolism is altered in the retina of patients with glaucoma [86].

Retinal morphologic changes

The pathological loss of RGCs in glaucoma is something that can be morphologically seen as thinning of the RNFL and excavation of the ONH. Fortunately, some of the current imaging technologies that can be used to assess blood flow can also measure these morphologic changes, and the association between altered blood flow and these changes have been documented.

Using scanning laser polarimetry and CDI, patients with OAG were shown to have reduced retrobulbar blood flow and reduced RNFL thickness compared with healthy controls [87]. This correlation was present in relation to the CRA EDV and CRA PI. In patients with obstructive sleep apnea, a condition known for causing nocturnal hypoxia, RNFL thickness was also found to be reduced [88]. However, in patients with early OAG, one study found that a thinner RNFL was associated with increased retinal blood flow [89]. Also, patients with OHT had an association of increased retinal blood flow in thinner segments of the RNFL [90].

Several theories have been proposed to explain this contradiction in regards to OBF and RNFL thickness. Intuitively, it makes sense that a thinning of the RNFL would be associated with reduced blood flow. As the neural tissue is lost, there are likely reduced metabolic demands; therefore, fewer capillaries are required to nourish the retina. While some studies have supported this reasoning by showing that a thinner RNFL is associated with reduced OBF measures [87,88], others have demonstrated increased OBF in areas of RNFL thinning [89,90]. An autoregulatory compensatory response concept has been proposed to explain the varying results. Blood flow may initially increase in a region of RNFL thinning, but then blood flow may gradually decrease as glaucomatous damage progresses. Unfortunately, this progression has not been yet shown in the literature. On the other hand, the finding of increased blood flow could be an artifact in the imaging as the thinner RNFL could alter the tissue depth sampled by LDF. However, this is less likely given that glaucoma patients have been extensively shown to have reduced retinal blood flow compared with controls, even though glaucoma patients have RNFL thinning [90]. Therefore, the autoregulation compensatory response concept is the best explanation for the varied findings.

Rather than a constant underperfusion, it has been suggested that fluctuating or unstable blood flow may account for the glaucomatous damage [91]. Steady underperfusion of tissue could result in cell death, or it could result in tissue adaptation in the form of atrophy. However, with unstable perfusion, oxidative stress occurs from the recurrence of underperfusion followed by reperfusion. This oxidative stress could be critical to cellular damage and death in glaucoma. This idea of unstable blood flow from vascular dysregulation has been described in patients with glaucoma. A study looking at short-term BP and choroidal blood flow variability found that patients with POAG had significantly increased short-term variability in these parameters compared with healthy controls [92].

Also, POAG patients have been shown to have increased circadian OPP variation than healthy controls [22]. Circadian fluctuations in mean OPP and mean arterial pressure have also been demonstrated in NTG [93]. Larger fluctuations in OPP and arterial pressure were correlated with reduced RNFL thickness, suggesting faulty autoregulation. In addition, wider fluctuations have been correlated with worse VFs [93]. Choi et al. noted that wider circadian OPP fluctuations in NTG patients were associated with excessive nocturnal BP dipping as well as worse VFs [94]. However, a nocturnal dip of BP by more than 10% of mean daytime BP is seen in two-thirds of healthy individuals [95]. Interestingly, Liu et al. showed that healthy volunteers of various ages had increased OPP nocturnally despite also having a nocturnal peak in IOP [96]. It is thought that an intact autoregulatory response is able to maintain OPP in these patients despite decreased BP and increased IOP. In patients with glaucoma, however, OPP is lowest at 7:00 am, in conjunction with the relative period of decreased BP and increased IOP [22]. Therefore, patients with glaucoma may lack the regulatory capacity to maintain OPP in spite of BP and IOP changes. This could lead to periods of ischemia followed by reperfusion injury [93]. Further work into OPP fluctuations and their effects on OBF and glaucoma progression over time are merited to further understand these relationships and define treatment strategies that will minimize OPP fluctuation in patients with glaucoma.

With regard to altered blood flow, it appears that all areas of the retina may not be equally affected. This is supported by evidence that shows that the inferior retina is more susceptible to functional and structural damage in glaucoma. For example, VF defects are more commonly localized to the superior VF, thus corresponding to the inferior retina [97]. In terms of structural damage in glaucoma, the location also tends to be in the inferior retina when considering loss of large ganglion cells [98], disc hemorrhage [99], peripapillary atrophy [100] and rim notching [101]. In addition, the inferior retina has a thicker RNFL compared with the superior retina, which may mean that the inferior retina requires more blood flow to nourish the enlarged RNFL [102]. However, the blood supply appears to be increased in the inferior retina to meet the suspected increased metabolic demand. In fact, it has been shown that the inferior retina has reduced blood flow per unit of nerve tissue volume compared with the superior retina [102]. Also, Chung et al. found that the inferior temporal quadrant of the peripapillary retina is more responsive to vasoconstriction and less responsive to vasodilation than the respective location in the superior temporal quadrant [103]. Reduced flow per unit of nerve tissue along with decreased responsiveness of the vasculature to increase blood flow suggests that the inferior retina is more susceptible to ischemic insult.

In addition to the loss of RGCs in glaucoma, capillaries within the neural tissue have been shown to be reduced in density and number in OAG. Histological specimens taken at autopsy from individuals with POAG demonstrated reduced capillary density and reduced number of capillaries in the postbulbar retrolaminar portion of the ON. Fluorescein angiography in NTG and POAG patients has shown filling defects signifying capillary dropout [104]. Moreover, the extent of the defects correlates to VF defects and CD ratios. Other morphological correlates with increased filling defects include increased cup area, reduced rim area, reduced rim volume and reduced RNFL thickness [105]. Although it has been demonstrated that a decrease in capillaries occurs with glaucomatous atrophy, this evidence does not indicate whether the capillary loss is primary or secondary to the atrophy. This evidence, however, indicates an ischemic component to the neural loss in glaucoma.

Using a methodology called retinal vessel analyzer, a marginal negative correlation has been found between retinal vessel diameter and ON damage [106]. Also, Kotliar et al. found that patients with glaucoma had a local vessel wall difference compared with age-matched controls [107]. This vessel wall difference may increase resistance to blood flow. Another study found that a brief increase in IOP leads to less retinal vessel reaction in glaucomatous eyes than in eyes of healthy controls and OHT patients [30]. The authors concluded that this might be from impaired autoregulation to ocular perfusion changes in patients with glaucoma.

ONH blood flow

The ONH has a complicated blood supply that originates from several sources. The ONH is separated into four segments: superficial nerve layer, prelaminar region, laminar region and retrolaminar region [55]. The superficial nerve layer is continuous with the RNFL and is the only layer visible during the fundus exam. Likewise, the superficial nerve layer is supplied by branches of the retinal arteries. The second region moving posteriorly, the prelaminar region, lies adjacent to the peripapillary choroid. This region is mostly supplied by branches of SPCAs directly and by branches off the circle of Haller and Zinn, an arterial ring formed by SPCA branches. Next is the laminar region, which has the same blood supply as the prelaminar region. The laminar region contains the lamina cribrosa, a connective tissue ring though which the neural fibers pass through. Finally, the retrolaminar region marks the start of axonal myelination. Its blood supply comes from the CRA and the pial system (derived from the SPCAs and the circle of Haller and Zinn).

ONH blood flow alterations

Using HRF, it has been determined that blood flow to the peripapillary retina [34,108] and neuroretinal rim [109,110] are reduced in glaucoma. In addition, blood flow at the neuroretinal rim corresponded to regional VF defects in patients with NTG [35] and POAG [106]. Moreover, patients with glaucoma have faulty autoregulation in response to the lowering of IOP [111]. A study looking at ONH vascular reactivity to normoxic hypercapnia showed that patients with untreated POAG had reduced vascular reactivity to healthy controls, thus supporting the concept of vascular dysregulation in glaucoma [112].

In patients with glaucoma, SLO angiography has shown reduced total retinal blood flow and dye leakage from ONH capillaries [113] has been demonstrated, suggesting peripapillary ischemia [114]. Using laser speckle flowgraphy, Yaoeda et al. compared blood flow to the ONH in patients with NTG and POAG to healthy controls and found that ONH circulation in NTG patients correlated with VF defects while statistical significance was not reached with POAG [115]. Similarly, with OAG patients, Deokule et al. did not find a correlation between peripapillary blood flow and VF defects using LDF [116].

ONH morphologic changes

In addition to RNFL thinning and capillary dropout, various studies have found OBF changes to be associated with optic disk changes. Relating to ONH morphologic changes in glaucoma, the characteristic of increasing CD ratio has been correlated to alterations in retinal circulation using LDF. Patients with OAG have been shown to have a significantly negative correlation between neuroretinal blood flow and CD ratio [106,117,118]. However, this relationship was not present with juxtapapillary blood flow. OHT patients with larger CD ratios had significantly less neuroretinal rim blood flow, suggesting that reduced neuroretinal rim perfusion could be a precursor to the manifestation of VF deficits [118].

Using CDI, it was shown that the CRA and central retinal vein velocities were positively correlated with the size of the neuroretinal rim of the optic disk [119]. In a study of patients with NTG, decreasing neuroretinal rim area was associated with reduced blood flow in the neuroretinal rim and optic disk border [109]. Similar findings have been reported in exfoliative glaucoma in that decreased neuroretinal rim area was found to be correlated with decreased blood flow to the lamina cribrosa and rim, but not the peripapillary retina [120]. However, it has been shown that neuroretinal rim damage is associated with local blood flow reduction in OAG patients [121]. Abnormalities in ONH morphology were shown to be localized to quadrants that corresponded to lower blood flow. Also, peripapillary retinal blood flow in quadrants with normal optic disc morphology had significantly lower blood flow in OAG patients compared with the same regions in controls. Therefore, vascular alterations may occur and possibly be detected before morphologic damage. Furthermore, reduced ONH blood flow has been shown to be associated with VF defects [106]. This concept was also discussed with the finding that patients with glaucoma with asymmetric VF deficits had blood flow in both eyes that were reduced from controls [64].

Choroidal blood flow

The blood supply to the choroid is divided into anterior and posterior divisions [55]. The choroid in the posterior half of the globe is supplied by the SPCAs, which also supply much of the ONH. The anterior half of the choroid is supplied by the LPCAs and anterior ciliary arteries. There has not been shown to be any anastomosis between these two circulations, and therefore there is a watershed area where the two circulations meet. The outer choroid contains larger nonfenestrated blood vessels, whereas the inner choroid contains small fenestrated capillaries. The fenestration allows for diffusion of substances into and out of the capillaries and then active transport across the retinal pigment epithelium layer, thus nourishing the outer third of the retina.

Choroidal blood flow & morphologic alterations

Fewer imaging methodologies are able to measure choroidal circulation, which include SLO angiography, dynamic contour tonometry (DCT) and laser interferometric measurement of fundus pulsation. Of these, only SLO angiography is able to directly measure choroidal blood flow. Whereas SLO angiography with fluorescein dye is used to assess retinal blood flow, indocycanine green dye is used for choroidal blood flow. Indocyanine green angiography has been used in patients with glaucoma to demonstrate slow choroidal filling and sluggish movement of blood into and out of the choroid [122]. Slowing has also been shown specifically in NTG patients [123]. Yin et al. found morphological changes in patients with POAG with reduced choroidal thickness due to a reduction in size of the choriocapillaris [36].

Indirect measurements of choroidal blood flow are accomplished by DCT and laser interferometric measurement of fundus pulsation. DCT is a noninvasive method of measuring IOP continuously over time. The difference between the highest and lowest IOP measurements is the ocular pulse amplitude (OPA), which is believed to be the result of changing blood volume in the eye. It is thought that volumetric pulsations in the choroidal vasculature are a main contributor to the OPA. OPA has been shown to be reduced in NTG and POAG compared with healthy controls [124]. OPA has also been shown to increase with IOP. However, Punjabi et al. demonstrated that it is increased in OHT patients, which has been hypothesized to be due to increased choroidal blood flow and accounts for the protection from glaucomatous damage [125]. Also, they did not show that OPA was reduced in NTG and POAG as the healthy controls had the lowest OPA. A correlation has been demonstrated between a small OPA and moderate-to-severe glaucomatous VF loss [126]. Also, a small OPA may be a risk factor for the development of VF defects. Given that this technique does not directly measure OBF in a particular circulation, its clinical significance is controversial in terms of diagnosis and management of glaucoma [56]. Therefore, more research into OPA and its associations with glaucoma are needed.

Conclusion

Other than IOP, many other risk factors for OAG have been identified, including those pertaining to vascular alterations. As described earlier, decreased blood flow parameters in the retrobulbar, retinal, ONH and choroidal circulations have all been shown to correlate with VF defects. In addition, morphologic changes in the retina, ONH and choroid are associated with altered blood flow. These findings, along with concepts such as fluctuations in perfusion, promote the possibility of ischemic injury in OAG.

Expert commentary

The understanding of glaucoma has come a long way from the identification of IOP as a risk factor for glaucoma. Numerous other risk factors have been identified including decreased OPP, decreased OBF, circadian fluctuations in vascular parameters and vascular dysregulation. However, increased IOP continues to be the only modifiable risk factor for the progression of glaucoma. The association between altered OBF and glaucoma has been repeatedly defined; however, the pathophysiologic effect of altered blood flow on glaucomatous damage remains to be understood. Moreover, there are a lack of progression data for parameters such as OPP and OBF. Owing to a lack of large-scale longitudinal clinical trials, more evidence needs to be present before a recommendation can be made about measuring OBF in a clinical setting. Some of the aforementioned studies have small sample sizes and do not possess large statistical power, which could cause confusion due to reduced reproducibility of the studies. OBF measurements remain to be a research methodology to understand more about the pathophysiology of glaucoma. Nevertheless, the use of the methodologies of to assess OBF are continually providing more information that will be used to further understand the pathophysiology of glaucoma.

From the use of CDI for measuring retrobulbar vessels to SLO angiography measuring retinal and choroidal circulations, the blood flow methodologies are each able to assess a subset of the ocular circulation. However, none are comprehensive in their assessment and a combination of the various methodologies must be used to thoroughly analyze OBF. Furthermore, each methodology has its disadvantages, such as CDI’s inability to measure blood flow volume. The relatively new technologies of retinal oximetry and FD-OCT have shown promise to provide continued useful information, with retinal oximetry’s ability to more directly measure tissue metabolism and FD-OCT’s ability to provide accurate measurements of blood flow in absolute units. For further usefulness of OBF data, a comprehensive and standardized approach needs to be implemented [56].

Five-year view

The future of understanding the effect of OBF on glaucoma will be enhanced by both the quality of studies and the improvement of imaging methodologies. In the next 5 years, more large-scale, multicenter, longitudinal studies will be underway. Future studies will take more comprehensive and normalized measurements of blood flow and structural morphology. The standardized imaging techniques will allow comparisons to be drawn from data from between different studies [56]. These measurements will utilize the technologies that are currently in use but are also continuing to improve, as with retinal oximetry and FD-OCT. Also, MRI is starting to be used to assess blood flow to the retina and choroid [127,128] with the ability to image multiple layers without depth limitation and provide multiple clinically relevant data in a single setting [127,129]. Building on retinal oximetry, the future of imaging also lies in moving away from measuring solely OBF, a surrogate measure of tissue oxygenation and metabolism, to more direct methods of measuring these parameters. This involves non invasively measuring oxygen saturation, redox potential, glucose uptake, carbon dioxide levels, oxygen utilization and metabolite accumulation [56]. In addition, in the future, a normative database of blood flow parameters could ideally be established for the various technologies and corrected for age, gender, IOP and BP. This way, it may be possible to screen individuals to determine whether they have an altered vascular profile that could increase their risk of developing glaucoma. Ideally, there should be a way to comprehensively measure OBF with a single device. Many of these future concepts are currently in the process of becoming a reality. With enhanced understanding, new modifiable risk factors dealing with altered blood flow and vascular pathology could be discovered. Improving blood flow could involve treating vascular comorbidities and lifestyle changes. Individuals with increased physical activity have been shown to have increased OPP compared with more sedentary individuals, but further research is needed to understand the potential benefit of physical activity in glaucoma [130]. If lifestyle changes prove to be beneficial in modifying glaucoma risk in a safe manner, they can prove difficult to incorporate into one’s life. New medications such as statins, which not only improve a vascular profile in general but also have neuroprotective properties and improve endothelial cell dysfunction, may be used in the future for the treatment of glaucoma after more is understood about this disease process [44,131].

Key issues

• • Intraocular pressure is the only known treatable risk factor to decrease progression of open-angle glaucoma.

• • Sufficient evidence exists from clinical trials to conclude that ocular blood flow deficits are associated with glaucoma.

• • Recent evidence has shown that blood flow deficits lead to structural and functional damage.

• • In large population trials, decreased ocular perfusion pressure has been associated with the prevalence and progression of glaucoma.

• • Greater fluctuations in ocular blood flow and ocular perfusion pressure have been shown to be associated with the development of glaucoma and progression of visual field loss.

• • Currently, there is insufficient evidence to conclude that insufficient blood flow directly causes glaucoma progression.

• • Future studies will look at glaucoma progression as it relates to ocular blood flow parameters in longitudinal studies involving an increased number of patients, and more standardized methods.

• • Assessment of blood flow will need to move away from surrogate measurers of blood flow and more towards measurement of oxygenation and metabolism of ocular tissues.

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Glaucoma and ocular blood flow: an anatomical perspective

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Activity Evaluation: Where 1 is strongly disagree and 5 is strongly agree

	1	2	3	4	5
1. The activity supported the learning objectives.
2. The material was organized clearly for learning to occur.
3. The content learned from this activity will impact my practice.
4. The activity was presented objectively and free of commercial bias.

1. You are seeing a 62-year-old man in your clinic with a recent diagnosis of primary open-angle glaucoma (OAG). His past medical history includes diagnoses of hypertension, hyperlipidemia, and migraine headache. What should you consider regarding the general relationship between OAG and ocular blood flow (OBF)?

• □ A Mean ocular perfusion pressure is calculated as one quarter of the mean arterial pressure minus intraocular pressure (IOP)

• □ B Mean ocular perfusion pressure is calculated as one quarter of the mean arterial pressure minus intraocular pressure (IOP)

• □ C Low OPP is associated with a low cup-to-disc (CD) ratio

• □ D Systemic diuretic therapy reduces the risk of incident OAG

2. OBF has been demonstrated to be reduced in all of the following ocular circulation systems except:

• □ A Choroidal

• □ B Choroidal

• □ C Retrobulbar

• □ D Cavernous sinus

3. Which of the following statements regarding altered ocular blood flow in particular circulation systems is most accurate?

• □ A Laser speckle flowgraphy is the method of choice to measure blood flow in the retrobulbar vessels

• □ B The rate of progression of visual field defects is unrelated to central retinal artery velocity

• □ C Blood flow at the neuroretinal rim is increased in cases of OAG

• □ D Only scanning laser ophthalmoscope angiography (SLO) is able to directly measure choroidal blood flow

4. What should you consider regarding retinal blood flow in OAG?

• □ A Blood flow to the optic nerve does not correlate with the degree of damage

• □ B OAG is associated with faster arterio-venous passage times

• □ C Fourier-domain optical coherence tomography (FD-OCT) allows for more rapid and higher resolution images compared with Doppler OCT

• □ D Retinal oximetry is now widely employed as the best means to measure retinal oxygenation and metabolism