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The Role of Ocular Perfusion Pressure in the Pathogenesis of Glaucoma

Yen Cheng “Joey” Hsia, MD; Sanjay Asrani, MD; and Yvonne Ou, MD

Although many risk factors, such as elevated intraocular pressure (IOP), have been implicated in the pathogenesis of open-angle glaucoma (OAG), the exact mechanisms remain unclear. There are 2 theories that have gained the most traction over time: the mechanical theory suggests that IOP directly damages the lamina cribrosa and retinal ganglion cell axons, whereas the vascular theory hypothesizes that insufficient ocular blood flow predisposes the optic nerve to damage, especially in the setting of increased IOP.^1,2 While these 2 theories are presented as distinct, they are not mutually exclusive, and in many clinical scenarios, both mechanisms may be at play.

In many glaucomatous conditions, including congenital glaucoma and secondary glaucomas, such as angle-recession glaucoma, it is clear that increased IOP is a major factor in the development of glaucomatous optic neuropathy. According to the mechanical theory, increased IOP leads to biomechanical forces that stretch and collapse the laminar beams of the lamina cribrosa and result in posterior bowing.^3–5 This may lead to secondary reactive changes in the optic nerve head that results in the withdrawal of trophic factors and possibly the generation of neurotoxic molecules that leads to the degeneration of the retinal ganglion cell axons. The exact pathogenic process is still under investigation and will be critical in the development of neuroprotective and regenerative treatment.⁶

However, elevated IOP cannot be the only risk factor involved in the development of glaucomatous optic neuropathy because there is a subset of patients with glaucoma without elevated IOP. Traditionally, this subset has been termed low- or normal-tension glaucoma (NTG), and it is now widely recognized that vascular abnormalities play an important role in the pathogenesis and progression in this subgroup of OAG despite having normal IOP.^7,8 It has been hypothesized that autonomic dysfunction and systemic vascular dysregulation contribute to low ocular perfusion and subsequent optic nerve head ischemia. Furthermore, vascular risk factors, including migraine, significant blood loss requiring transfusion, Raynaud’s phenomenon, sleep apnea, and nocturnal hypotension, have been implicated in the development of glaucoma.

While the evidence regarding systemic blood pressure (BP) and glaucoma has been inconsistent, nocturnal hypotension and unstable ocular perfusion pressure (OPP) may be involved in the pathogenesis and progression of glaucomatous optic neuropathy. Multiple large population-based studies have shown an association between lower diastolic BP and diastolic OPP to the prevalence, incidence, and progression of OAG.^9–12 In order to better understand the role of OPP in the pathogenesis of glaucoma, it is important to review the definition of OPP and the anatomy and physiology of ocular blood flow.

VASCULAR SUPPLY OF THE OPTIC NERVE

Perfusion pressure of a tissue is equal to the difference between arterial and venous pressure. In the eye, IOP is the surrogate for venous pressure, and thus, BP and IOP are the main components of OPP. OPP is defined by the following different parameters:

• Systolic ocular perfusion pressure (SOPP = SBP – IOP) where SBP is the systolic BP
  
• Diastolic ocular perfusion pressure (DOPP = DBP – IOP) where DBP is diastolic BP

Blood supply to the optic nerve head (ONH) categorized by anatomical regions (Figure 73-1):

• Retinal: retinal arterioles from the central retinal artery (CRA)
  
• Prelaminar: peripapillary choroidal branches from the posterior ciliary artery (PCA)
  
• Laminar: centripetal branches from the short PCAs
  
• Retrolaminar: pial branches from the PCAs and CRA

As evident by the above description, the main blood supply to the ONH is from the ciliary circulation (PCA branches). While retinal circulation is characterized by a low flow and high level of oxygen extraction, choroidal circulation is characterized by a high flow and low level of oxygen extraction. Additionally, retinal circulation is autoregulated and thus somewhat independent of perfusion pressure, whereas choroidal circulation is more dependent on perfusion pressure.⁸ In particular, the watershed zone between the PCA branches is especially vulnerable to decreases in the OPP. Although there is marked variability in the location of watershed zones between eyes, the majority have a watershed zone that passes though the ONH.¹³ In NTG, eyes with a watershed zone involving a greater part of the ONH have greater mean deviation on visual fields.¹⁴

Given the complexity of ocular blood flow, many mechanisms have been suggested to play a role in the poor perfusion of the optic nerve. These include alterations in the microvasculature and changes in retinal or choroidal blood flow that interfere with the delivery of nutrients or removal of waste products, failure in autoregulation, and release of toxic vasoactive substances that injure the optic nerve.¹⁵ In particular, the failure in autoregulation has been suggested to result in ischemic damage and reperfusion injury to the optic nerve.⁸

A detailed discussion of the methods used to measure ocular blood flow is beyond the scope of this chapter, and one is directed to comprehensive reviews on this subject.^15,16 Methods include fluorescein angiography, laser Doppler flowmetry, and color Doppler imaging. The limitations of these imaging techniques are high interoperator variability and the inability to analyze the circulation of ONH in its entirety as they mainly provide circulatory information on the superficial circulation of the ONH but not the deeper layers.^13,17 Based on these imaging methods, there is evidence that there is reduced retinal blood flow and dye leakage from optic nerve capillaries, as well as abnormal retrobulbar flow velocities in glaucoma.¹⁵ Recently, the development of optical coherence tomography angiography (OCTA) using a split-spectrum amplitude-decorrelation angiography algorithm enables quantification of optic disc perfusion rapidly and noninvasively with high repeatability and reproducibility.¹⁸ In glaucomatous eyes, reduced peripapillary perfusion can both be visualized as focal defects and quantified via flow index and vessel density.¹⁹ Future research is needed to determine the utility of OCTA in diagnosing and monitoring glaucoma.

EPIDEMIOLOGIC EVIDENCE

While large clinical trials have shown that lowering IOP slows progression of glaucomatous optic neuropathy, it is also clear that some glaucoma patients will continue to progress despite lowering of IOP. The Early Manifest Glaucoma Trial²⁰ (EMGT) demonstrated that lowering IOP resulted in decreasing the rate of progression in the treatment group (45%) as compared to the control group (62%). Subsequent analysis of data from the EMGT revealed that risk factors for disease progression included lower systolic perfusion pressure, lower systolic BP, and cardiovascular disease history.²¹

Vascular-related risk factors, including low OPP, have been associated with OAG in numerous large population-based studies throughout the world. In the Baltimore Eye Study,⁹ systemic BP and IOP were significantly although modestly correlated. The authors hypothesized that earlier stages of hypertension might be protective against optic nerve damage because of increased perfusion but that later stages of hypertension would damage the optic nerve as peripheral resistance increased. Using age as a surrogate for the duration of hypertension, they showed that age modified the effect of systemic hypertension on the prevalence of primary open-angle glaucoma (POAG), with a stronger association as age increased. Perhaps most interestingly, lower diastolic perfusion pressure was strongly associated with a higher prevalence of POAG (Table 73-1).

Later studies supported this relationship between low OPP and prevalence of OAG. In the Rotterdam Study,²² patients with an OPP lower than 50 mm Hg had a 4-times-greater risk of developing OAG than those with a perfusion pressure of 80 mm Hg. This finding was supported in the Egna-Neumarkt Glaucoma Study,11 which found that lower diastolic perfusion pressure was associated with hypertensive glaucoma.

The 9-year follow-up data from the Barbados Eye Study²³ demonstrated that patients with low OPP at baseline had a significantly increased risk of developing OAG over time. The relative risks for the development of incident OAG ranged from 2 to 2.6 for systolic, diastolic, and mean OPP. More recently, the Thessaloniki Eye Study²⁴ showed low DOPP was associated with increased risk for POAG in patients on systemic antihypertensive treatment, suggesting the status of ocular perfusion may be more important. The group theorized that patients on hypertensive treatment may experience greater nocturnal hypotension and end-organ vascular resistance secondary to arteriole thickening.

While the association between DOPP and OAG has been established, the relationship between SOPP and OAG is less definitive. In the Blue Mountains Eye Study,²⁵ there was a marginal association between elevated SOPP and prevalence of OAG. In both the Rotterdam Study²⁶ and the Thessaloniki Eye Study,²⁴ SOPP was not associated with an increased risk for OAG. The Barbados Eye Study,^10,23 however, reported the opposite finding, with low SOPP increasing the relative risk of OAG at 4 and 9 years of follow-up. The EMGT,²¹ in which the authors controlled for IOP as well as IOP- and BP-lowering treatments, also revealed that lower SOPP was a significant risk factor for progression of glaucoma. One of the limitations of assessing OPP in large population studies is that systemic blood pressure (brachial arterial pressure) is being used as a surrogate for ocular arterial pressure in the calculation of OPP. The brachial arterial pressure is typically lower than ocular arterial pressure in sitting or standing position due to the effect of gravity. Therefore, the calculated OPP and the physiological OPP are not truly equivalent.¹⁷

VASCULAR DYSREGULATION AND OPEN-ANGLE GLAUCOMA

Given the definition of OPP, an abnormal OPP could be due to low blood pressure (SBP or DBP) or an elevated IOP. Appropriate vascular autoregulation in healthy patients likely provides consistent OBF over a wide range of perfusion pressures. Animal study of ONH perfusion using primate models showed that ONH blood flow declined significantly more by lowering BP than by elevating the IOP.²⁷ In a separate study using rat models, He and colleagues²⁸ evaluated the influence of OPP on retinal ganglion cell function using electroretinogram. The study showed in animals with lower BP, milder IOP elevations were needed to compromise retinal function compared to control. Conversely, animals with an acute increase in BP endured a greater IOP challenge before retinal dysfunction occurred. These results suggest a sufficient level of BP is important for maintaining autoregulation of ONH blood flow and that higher BP may enhance BP autoregulation while lower BP weakens it. However, the relationship between BP and OAG remains unclear as various studies have reported both positive and negative associations. As mentioned earlier, authors from the Baltimore Eye Study⁹ theorized that early in the course of systemic hypertension the elevated BP may improve OPP and offer protection against elevated IOP, but over time it exacerbates vascular dysfunction by narrowing arteriole lumen and affecting vascular tone (resistance). Interestingly, in the Blue Mountains Eye Study,³⁰ eyes with a narrowed retinal arteriolar caliber exhibited greater risk of developing OAG.

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