The impact of ocular blood flow in glaucoma
Introduction
The term glaucoma is used to cover a wide range of diseases, traditionally including any and all conditions associated with increased intraocular pressure (IOP). However, by virtue of the fact that not all patients with glaucomatous optic neuropathy (GON) have increased IOP, and not all patients with increased IOP suffer from GON, new definitions were introduced. Some authors equate glaucoma with GON (van Buskirk and Cioffi, 1992). In practice it has proven useful to speak about glaucoma patients if they present either with elevated IOP, GON or both (Flammer, 2001a). Whereas a number of indisputable risk factors (RFs), including elevated IOP, have been described, the pathogenesis leading to GON remains poorly understood.
In the past, two theories were presented, the mechanical and the vascular (Fechtner and Weinreb, 1994). The mechanical theory supposes that GON is a direct consequence of IOP, damaging the laminar cribrosa and neural axons (Yan et al., 1994). The vascular theory considers GON as a consequence of insufficient blood supply due to either increased IOP or other RFs reducing ocular blood flow (OBF) (Flammer, 1994). The differentiation between mechanical and vascular theories had little clinical impact so far, as IOP reduction was the only intervention available for treatment of glaucoma. However the introduction of new therapeutic options, such as pharmacological blood flow modulation, call for a more detailed description of the RFs and a better understanding of GON pathogenesis. The purpose of this review is to summarize some of the present knowledge of the pathogenesis of GON, with special emphasis on the role of OBF.
Section snippets
Historical review
Elevation of IOP as a distinct sign of ocular disease recognizable by undue eyeball resistance to indentation by the physician's finger, was first clearly mentioned in the breviary of the itinerant English oculist Bannister in 1626 in a book titled “A worthy treatise of the eyes” (Shaffer, 1996). In the early 1800s firmness of the eyeball was generally accepted as a distinct disease entity, which McKenzie described as glaucoma (MacKenzie, 1830).
In 1851, the invention of the ophthalmoscope by
The role of IOP in glaucoma
A number of conditions such as congenital glaucoma, angle-closure glaucoma or secondary glaucomas clearly show that increased IOP is sufficient to lead to GON. According to the mechanical theory an increased pressure leads to elongation, stretching and collapse of the laminar beams and their posterial displacement (bowing). The axons of the retinal ganglion cells become damaged either directly, by increased pressure and pressure gradient, or indirectly, by tissue deformation. The axoplasmatic
Anatomy and physiology of OBF
The anatomy and physiology of OBF, including the ONH blood flow has been reviewed previously (Flammer and Orgül, 1998; Hayreh, 1996; Bill and Nilsson, 1985; Buechi, 1995). In order to enable a better appreciation of the vascular insufficiency occurring in glaucoma, a summary of the anatomy and physiology of OBF is presented here.
Ocular circulation is complex, because of the necessity to supply different ocular structures with nutrients without interfering with the visual pathway. OBF is highly
Techniques for evaluating OBF
Many different methods are used to visualize and measure directly or calculate indirectly in vivo OBF. Although there have been many advances in techniques over the past 20 years, there is still no single method that can provide all the relevant information in one reading. The fact that the different methods available also measure different aspects of ocular perfusion (for example flow velocity or vessel size, etc.) and at different locations in the eye makes direct comparisons between
OBF in glaucoma
To summarize the findings of OBF studies in glaucoma is difficult for the following reasons: the authors use different techniques and therefore measuring different aspects of ocular circulation (Carter et al., 1990); they include glaucoma patients at different stages (e.g. early vs. late); different types of glaucoma are studied (e.g. NTG vs. high-tension glaucoma (HTG)); some include provocation tests, while others do not. Nevertheless, the vast majority of studies published find on average a
Indirect signs of altered blood flow
There are a number of signs that point indirectly to the fact that at least in some glaucoma patients, blood flow is compromised. In the eye, changes in conjunctival capillaries (Unger and Jankovsky, 1967; Orgül and Flammer, 1995), local vasoconstriction in the retina (Rankin and Drance, 1996), increased prevalence of ONH hemorrhages (Drance et al., 2001; Begg et al., 1970; Kottler and Drance, 1976; Susanna et al., 1979; Drance et al., 1997; Siegner and Netland, 1996; Sugiyama et al., 1997;
Primary cause or secondary effect?
We have shown evidence to support the view that OBF is indeed reduced in at least a sub-group of glaucoma patients. Reduction was found in all ocular tissues tested so far, but especially in the choroid, the ONH and peripapillary area (Ulrich et al., 1993; Duijm et al., 1997; Wolf et al., 1993). The question arises whether this alteration of blood flow is just a consequence of the glaucomatous disease (either due to increased IOP or due to the GON) or whether there is a primary vascular
Potential causes of OBF reduction
There is enough evidence to assume a primary (i.e. not caused by GON or IOP) component to the OBF reduction in glaucoma patients, and we must ask what this might be caused by. Theoretically there are three possibilities: (a) increased resistance to flow, (b) reduced perfusion pressure, (c) and increased blood viscosity. While there is little support in the literature to assume a change in blood viscosity, there are many indications for both increased resistivity to flow and decreased perfusion
Arteriosclerosis
Arteriosclerosis occurs very frequently, especially in older subjects, and is the major cause of the most important cardiovascular events like myocardial infarction or cerebral vascular insults. Arteriosclerosis is also clearly associated with ocular diseases like central retinal arterial occlusions (Ahuja et al., 1999), anterior ischemic optic neuropathy (AION) (Lieberman et al., 1978; Bertram et al., 1994; Hayreh, 1999), venous occlusion (Pliszkiewicz et al., 1984) and possibly even with
Perfusion pressure
Perfusion pressure is defined as the difference between the arterial and venous pressure. In the eye, venous pressure is equal to or slightly higher than IOP. We have already discussed the role of increased IOP. We will now focus on blood pressure. While IOP is very weakly positively correlated with blood pressure (Bonomi et al., 2000), it is systemic hypotension which is clearly a RF for GON (Bonomi et al., 2000; Drance et al., 1973a; Demailly et al., 1984; Kaiser et al (1993a), Kaiser et al
Vascular dysregulation
Blood flow through an organ is regulated by perfusion pressure and local resistance to flow. Local resistance in turn is controlled by the size of the local vessels. The regulation serves the purpose of ensuring an adequate supply of oxygen and nutrients reaching the tissues, as well as temperature and volume regulation. Many systems, like the autonomic nervous system, circulating hormones and endothelial cell layer, among others, are involved in this regulation.
Considering the complexity of
Vascular dysregulation and OBF
Involvement of ocular circulation in vasospastic syndrome was postulated in the early 1980s when it was noted that patients with a primary vasospastic syndrome often had diffuse or glaucomatous-like visual field defects which the patients were not aware (Gasser et al., 1986; Gasser and Flammer, 1987). In these patients the ONHs were mostly normal, or sometimes pale. It was assumed that the reduction of blood flow occurred mostly in the choroid (Flammer and Guthauser, 1987). The visual field
Vascular dysregulation and glaucoma
Due to the fact that primary vasospastic syndrome can involve the eye and can induce glaucomatous-like visual field defects, it was postulated that this syndrome might also be an RF for GON—especially in patients with NTG (Flammer et al., 1987a; Broadway and Drance, 1998). Subsequent studies have indeed shown that glaucoma patients are more often vasospastic than controls (Gasser and Flammer, 1991; Rojanapongpun and Drance, 1993b; O’Brien, 1998).
The fact that we see improvements in circulation
Rheological factors
Theoretically not only low perfusion pressure or increased local resistance, but also systemic or local increases in blood viscosity can lead to reduced blood flow. Whereas some authors find slight changes (Liu et al., 1997; Wu and Li, 1993; Ge et al., 1993; Ge, 1992), this could not be demonstrated in all studies (Carter et al., 1990). However, this does not exclude local increase in blood viscosity. Decreased erythrocyte deformability (Ates et al., 1998), hyperaggregability of the
Ocular blood flow and glaucomatous optic neuropathy
The functional loss of vision in glaucoma is caused by cell death of retinal nerve cells and their axons. This is at least partially due to apoptosis (Garcia-Valenzuela et al., 1995; Murakami and Okisaka, 1998), a genetically predetermined program of cell death, which can be activated by many different factors depending on the situation. It is important to appreciate that apoptosis is a fundamental biological process and is part of the natural cell life cycle. Its inappropriate activation can,
The concept of reperfusion damage
It has been known for a long time that IOP fluctuations are more strongly correlated to progression of visual field damage than the level of mean IOP (Asrani et al., 2000; Flammer et al., 1982; Weber et al., 1993), with different therapies exerting different effects on this fluctuation (Orzalesi et al., 2000). Likewise, blood pressure fluctuations are more damaging than a steady decrease in blood pressure (Kashiwagi et al., 2001). Furthermore, as we have seen previously, while arteriosclerosis
Conclusions and therapeutic consequences
Although it remains somewhat difficult to clinically measure OBF in the eye, techniques now exist which enable ophthalmologists to assess hemodynamic properties in and behind the eye at least for research purposes. All the different studies, using different types of instruments, point in the same general direction indicating that on average blood flow is decreased in some glaucoma patients, especially in NTG patients and in patients that progress despite normalized IOP. Furthermore this
Future directions
In looking forward, we need to look at several aspects. The first is the technology we use to measure OBF. Although this has improved greatly, there is still much improvement needed. Using current techniques most measurements are of blood velocity. What is missing to a greater extent are direct data on blood flow in specific tissues of the eye.
Different sub-groups of glaucoma patients may behave in unique ways. More information about these sub-populations is needed.
Blood flow in an individual
Acknowledgements
The authors would like to thank Prof. David Briers for his contribution to the section on Laser Speckle Phenomenon.
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