Ординатура / Офтальмология / Английские материалы / Mechanisms of the Glaucomas_Shields, Tombran-Tink, Barnstable_2008

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II

MECHANISMS OF INTRAOCULAR PRESSURE

ELEVATION IN THE GLAUCOMAS

INTRODUCTION

When we classify the various clinical forms of glaucoma by most of the currently used systems, in reality we are only addressing the mechanisms by which the intraocular pressure (IOP) is abnormally elevated. And, of course, this is only part of the glaucomatous process. We have assumed that the remainder of the process follows a common pathway of optic neuropathy and visual loss. But this may not be entirely accurate, as we learn more about the different mechanisms of glaucomatous optic neuropathy, discussed later in this text, especially between glaucomas with high pressures and those with normal pressure. Nevertheless, classifications that focus only on mechanisms of IOP elevation may, for the present at least, be justified on two counts. First, a level of IOP appears to be a major causative risk factor for the optic neuropathy in virtually all forms of glaucoma, even in cases of normal-tension glaucoma. And, second, the reduction of IOP is presently the only proven treatment for preventing glaucomatous optic neuropathy. Therefore, in this section, we will consider various clinical forms of glaucoma from the standpoint of mechanisms of elevated IOP.

There are several systems by which the glaucomas can be classified. The two most commonly used are based on (i) the event that initiates the glaucomatous process or (ii) the alteration in aqueous humor dynamics that causes the elevated IOP. The former is used in most textbooks, because it provides a more complete picture of the clinical entity, that is, from the initial event, such as a genetic defect, ocular configuration, infection, trauma, and so on through the various tissue alterations responsible for the elevated IOP, to the optic neuropathy and visual loss. In addition, some of the clinical entities have more than one mechanism of IOP elevation at different stages of the disorder, for example, an open-angle mechanism initially and a closed-angle mechanism in the more advanced stage. However, as the purpose of this book is to focus more on the mechanisms of the glaucomas, the second classification, which provides a better opportunity to consider this aspect of the disorders, will be used in this section.

It was once thought that the mechanism of elevated IOP in some forms of glaucoma was increased aqueous production, but it now appears that virtually all forms are due to obstruction of aqueous outflow. One classification for the mechanisms of outflow obstruction, and the one used in this section, is to first divide them into open-angle and closed-angle forms. These two divisions are subsequently divided into

three subdivisions each. In the open-angle forms, the subdivisions are pretrabecular, trabecular, and posttrabecular. In the pretrabecular forms, an obstructive element, such as a fibrovascular, endothelial, epithelial, fibrous, or inflammatory layer, covers the internal portion of the trabecular meshwork. In the trabecular forms, the obstructive element is within the meshwork and may represent either a clogging element, such as red blood cells, pigment, protein, and so on, or an alteration of the actual meshwork, such as swelling or collapse of the trabecular beams. The latter is probably the mechanism of chronic open-angle glaucoma although the precise mechanism of the alterations has yet to be determined. In the post-trabecular forms, the obstruction is either in Schlemm’s canal (which may be another mechanism of chronic open-angle glaucoma, i.e., collapse of the canal) or in the scleral outlet channels or episcleral veins, with elevated episcleral venous pressure being the best understood of these mechanisms.

In the closed-angle mechanisms of aqueous outflow obstruction, the three subdivisions are anterior (pulling) forms, posterior (pushing) forms with pupillary block, and posterior (pushing) forms without pupillary block. In the anterior forms, there is an element in the anterior chamber angle, which contracts to pull the peripheral iris into apposition with the trabecular meshwork. This element could be an inflammatory precipitate or one of the layers described above in the pretrabecular forms of open-angle glaucoma. In both of the posterior forms, there is a pressure behind the iris, which pushes it into apposition with the meshwork. In the posterior form with pupillary block, there is either functional or synechial obstruction to aqueous flow between the lens and pupillary portion of the iris, which causes a relative increase in pressure in the posterior chamber, pushing the peripheral iris forward. In the posterior form without pupillary block, the obstruction is either at the level of the ciliary body, lens, or posterior segment, each of which can cause a forward shift of the lens–iris diaphragm, with closure of the anterior chamber angle.

Initiating Factors

The two most common initiating conditions leading to the retinal hypoxia are diabetic retinopathy and central retinal vein occlusion (CRVO). Approximately, one-third of the cases of rubeosis iridis and subsequent NVG are related to diabetic retinopathy (1,2), and the frequency of this association is increased with pars plana vitrectomy for proliferative retinopathy (3), an unrepaired retinal detachment after vitrectomy (4), and cataract extraction, especially with an open posterior capsule (5). CRVO accounts for approximately another one-third of cases of NVG (1). Predisposing conditions for CRVO include elevated intraocular pressure (IOP) and systemic hypertension. Other retinal vascular occlusive events that less commonly lead to NVG include central retinal artery disease, branch retinal vein occlusion, and branch retinal artery occlusion. The third most common initiating event is carotid artery obstructive disease, with subsequent retinal ischemia, which accounted for 13% of NVG in one series (2). Other conditions that may lead to retinal hypoxia and subsequent rubeosis irides include rhegmatogenous retinal detachment, a choroidal melanoma beneath a retinal detachment, sickle-cell retinopathy, and carotid-cavernous fistula. One initiating event for rubeosis iridis, that is not associated with retinal hypoxia, is chronic anterior uveitis, which was seen in 11% of one series (1) and 1.5% of another series (2) of NVG.

Theories of Angiogenesis

In all of the initiating events, with the exception of anterior uveitis, a common feature is the retinal hypoxia. This appears to stimulate the release of the diffusible angiogenic peptides, such as vascular endothelial growth factor (VEGF), which is synthesized by several types of retinal cells although Müller cells appear to be the main source of VEGF under conditions of retinal ischemia (6,7). Evidence supporting the role of VEGF in ocular neovascularization include the observations that elevated levels of VEGF have been identified in the aqueous humor of patients with NVG (8), and neutralizing VEGF antibodies prevented NVI in a nonhuman primate model of retinal vein occlusion (9).

Although VEGF is the most extensively studied proangiogenic factor in the mechanism of NVG, others factors are also released by endothelial cells in response to specific stimuli, such as hypoxia, including basic fibroblast growth factor, tumor necrosis factor- , insulin-like growth factor, and platelet-derived growth factor.

Physiologically, the vasculature appears to be maintained in a quiescent state through a delicate balance between proangiogenic and antiangiogenic factors. In the eye, this balance is largely between VEGF and the antiangiogenic factor, pigment epitheliumderived growth factor (PEDF) (10). An imbalance of the VEGF–PEDF equilibrium has been documented in the vitreous of eyes with proliferative diabetic retinopathy, that is, increased VEGF and decreased PEDF (11). This process in turn stimulates a cascade that results in the activation, proliferation, and migration of endothelial cells, resulting in the formation of new, leaky, fragile blood vessels. The diffusible nature of the angiogenic peptides may explain the increased risk for rubeosis iridis following removal of the vitreous or lens, that is, elimination of barriers between the posterior and anterior segments. An alternative theory is that vasoinhibitory factors may be released by the vitreous (12) or lens (13).

It has also been suggested that chronic dilation of vessels in response to hypoxia or other stimuli that cause vessels to dilate may lead to new vessel growth (14). Although this theory has less support than that of diffusible angiogenesis factors, it might provide an explanation for the rubeosis iridis in association with chronic anterior uveitis.

Clinicopathological Course

The clinical and histologic sequence of events that lead from the initiating factor through the anterior chamber neovascularization to NVG might be thought of in four stages: (i) prerubeosis, (ii) preglaucoma, (iii) open-angle glaucoma, and (iv) angleclosure glaucoma (see Fig. 1).

In the prerubeosis stage, the principal clinical finding is the initial retinal ischemic disorder, such as proliferative diabetic retinopathy or CRVO, and the anterior segment findings by slit-lamp examination and gonioscopy are grossly normal (unless the initiating factor is uveitis). At this stage, the patient is at risk of developing rubeosis iridis, and it is important to be aware of the factors that may increase this risk, such as those previously discussed for diabetic retinopathy. In eyes with CRVO, factors that increase the risk of developing rubeosis iridis include retinal capillary nonperfusion, as documented by fluorescein angiography, relative afferent pupillary defect, and abnormal electroretinography.

In the preglaucoma stage, rubeosis iridis is now present, but the IOP is still normal, unless the patient has preexisting chronic open-angle glaucoma. This appears first as fine peri-pupillary vessels on the iris stroma. In a monkey model of retinal vein occlusion, these new vessels developed intrastromally from dilated normal iris vessels, which show marked increase in endothelial cell metabolism, followed by new vessel formation (15). The anterior chamber neovascularization eventually appears in the anterior chamber angle, which is seen gonioscopically as single vascular trunks that grow from the peripheral iris across the scleral spur to the trabecular meshwork, where they arborize along the meshwork. Although the NVI typically precedes the NVA, the reverse can occur, prompting the need for careful gonioscopy when following patients for early evidence of anterior chamber neovascularization.

In the open-angle stage of NVG, both the NVI and NVA have become much more prominent, and the IOP is elevated. The new vessels may cover the iris stroma from the pupillary margin to the iris root (see Fig. 2) and may be associated with inflammation and hemorrhage, for which the condition was once called congestive or hemorrhagic glaucoma. In the angle, the new vessels are more numerous, but the angle is still open. The histologic hallmark of this stage is a fibrovascular membrane on the surface of the iris and in the anterior chamber angle, the latter of which is most likely responsible for the obstruction to aqueous outflow and the elevated IOP. Glaucomatous optic neuropathy may ensue at this stage, as in all forms of glaucoma.

In the angle-closure stage of NVG, the fibrovascular membrane undergoes contracture. On the iris, this is seen clinically and histologically as flattening of the stroma, with ectropion uvea, pupillary dilation, and a forward displacement of the iris (see Fig. 3). In the anterior chamber angle, the contracture of the fibrovascular membrane pulls the peripheral iris into the angle (see Fig. 4), further obstructing

Fig. 2. Slit-lamp view of extensive iris neovascularization (rubeosis iridis) in open-angle glaucoma stage of neovascular glaucoma.

Fig. 3. Slit-lamp view of angle-closure glaucoma stage of neovascular glaucoma, with rubeosis iridis, ectropion uvea, and corectopia.

Fig. 4. Light microscopic view of angle-closure stage of neovascular glaucoma with peripheral anterior synechia (iris adherent to cornea) from contracture of fibrovascular membrane.

aqueous by progressive peripheral anterior synechia and rendering the elevated IOP more difficult to control.

Management

Although glaucoma is defined as an optic neuropathy in which a level of IOP is a major risk factor, patients in the NVG process require close observation and frequent intervention at each stage of the disorder. By the time they reach the angle-closure

stage, the glaucoma is very difficult to control, and the optimum treatment approach is to anticipate and prevent the NVG from developing or to treat it aggressively in the earliest possible stage.

In the prerubeosis stage, it is often necessary to treat the initiating event, such as the proliferative diabetic retinopathy or a chronic uveitis. In other cases, however, such as CRVO, the standard of practice is to follow the patient closely for evidence of rubeosis iridis, which is an indication to treat. With both diabetic retinopathy and CRVO, as well as several other retinal ischemic disorders, the preferred treatment has traditionally been panretinal photocoagulation (PRP). The mechanism by which PRP is believed to influence neovascularization is through a reduction in the retinal oxygen demand, thereby reducing the hypoxia and the stimulus for release of VEGF.

The effect of PRP is to reduce or eliminate the anterior segment neovascularization although this may take several weeks. If done prophylactically in the preglaucoma (rubeosis iridis) stage, it may prevent the development of NVG, whereas in the early open-angle glaucoma stage, it may reverse the glaucoma or at least make it easier to control. Even in the angle-closure stage, it may have value by reducing the NVI and NVA, so that incisional glaucoma surgery has a better chance of success. More recently, the use of intravitreal injections of VEGF inhibitors for the treatment of wet macular degeneration has also been found to have a profound effect on the anterior chamber neovascularization, further supporting the theory that the latter is caused by diffusible angiogenic factors from the posterior segment. This effect of a single injection on NVI and NVA, however, is time limited, so that any planned surgical intervention should be performed within a window of 4–6 weeks.

When NVG is present, that is, stages 3 or 4, control of the IOP is required in addition to the PRP. In some cases, this can be accomplished medically. The preferred drugs are those which reduce aqueous production, such as beta blockers, alpha-2 agonists, and carbonic anhydrase inhibitors. Neither prostaglandins, which increase uveoscleral outflow, nor miotics, which increase trabecular outflow, are likely to be effective, as the mechanical obstruction of the anterior chamber angle reduces aqueous humor access to these routes of outflow. In addition, both of the latter classes of drugs may increase the ocular inflammation. Topical corticosteroids may be useful in minimizing the inflammation and pain.

When the IOP cannot be controlled medically, surgical intervention is required. Filtering surgery is complicated by intraoperative bleeding and a high-risk postoperative bleb failure when the rubeosis iridis is active. For this reason, it is preferable to eliminate the neovascularization with PRP and/or intravitreal injections of VEGF inhibitors preoperatively. When incisional surgery is necessary in the face of active rubeosis iridis, a drainage implant device may be preferable to trabeculectomy. Alternatively, especially in patients with limited visual potential or who are too sick for incisional surgery, diode transscleral cyclophotocoagulation may be in the patient’s best interest.

Future treatment of NVG will most likely focus more on the underlying mechanisms of the disorder, specifically by preventing the effects of the angiogenic factors. In addition to the potential value of PEDF and other antiangiogenic factors, as previously discussed, other therapeutic possibilities include systemic -interferon, a polypeptide that inhibits neovascularization (16), and troxerutin, a semisynthetic,