Ординатура / Офтальмология / Английские материалы / Shields Textbook of Glaucoma, 6th edition_Allingham, Damji, Freedman_2010

Slitlamp Biomicroscopic Findings Corneal Findings

Pigment dispersion occurs throughout the anterior ocular segment but is seen by slitlamp examination primarily on the cornea and iris. Krukenberg spindle is an accumulation of pigment on the posterior surface of the central cornea in a vertical, spindle-shaped pattern (Fig. 17.1). Dispersed pigment is deposited on the cornea in this pattern because of aqueous convection currents and is then phagocytosed by adjacent endothelial cells (3). This feature is commonly seen in eyes with pigmentary glaucoma, but it is neither invariable nor pathognomonic of the disorder. In one study, only 2 of 43 patients with Krukenberg spindles developed field loss during a follow-up that averaged 5.8 years (16). Krukenberg spindle is more common in women and may have a hormonal relationship (16, 17). Specular microscopy of the corneal endothelium reveals distinct pleomorphism and polymegathism (i.e., abnormality in shape and size of cells); however, normal cell counts and central corneal thickness are found (18, 19).

Figure 17.2 Transillumination of the iris in a patient with pigmentary glaucoma showing typical midperipheral spoke-like defects.

Figure 17.3 Pigment granules on iris stroma in a patient with pigmentary glaucoma. Iris Findings

Iris transillumination is a valuable diagnostic clinical feature of pigmentary glaucoma because it represents areas where pigment has been dispersed. The characteristic appearance is a radial spoke-like pattern in the midperiphery of the iris (20) (Fig. 17.2). This feature can be seen during slitlamp biomicroscopy by directing the light beam through the pupil perpendicular to the plane of the iris or by using scleral transillumination and observing the retinal light reflex through the defects in the iris. In some patients, however, a dark, thick iris stroma may prevent transillumination of the defects, and the absence of this finding therefore does not rule out the diagnosis of pigmentary glaucoma. This could explain the absence of iris transillumination in black patients with pigmentary glaucoma (14). An infrared videographic technique has been developed that allows visualization of discrete iris transillumination defects not visible by slitlamp examination (21).

Pigment granules are frequently dispersed on the stroma of the iris, which may give the iris a progressively darker appearance or create heterochromia in asymmetric cases (9) (Fig. 17.3). Asymmetric pigment dispersion has also been reported in association with unilateral cataract formation or extraction (22). Patients with PDS may also have anisocoria, in which the eye with the larger pupil is on the side with the greater iris transillumination. The iris heterochromia and anisocoria of PDS may mimic Horner syndrome (23).

Other anterior segment locations where pigment dispersion may be seen by slitlamp examination include the posterior lens capsule (Fig. 17.4), lens zonules, and the interior of a glaucoma filtering bleb (9). Gonioscopic Findings

The principal gonioscopic feature of pigmentary glaucoma is a dense, homogeneous band of dark brown pigment in the full circumference of the trabecular meshwork (Fig. 17.5A). The

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dispersed pigment may also accumulate along the Schwalbe line, especially inferiorly, creating a thin, dark band.

Figure 17.4 Pigmented line on posterior lens capsule at the insertion of zonules. This is termed the Zentmayer line or a Scheie stripe.

throughout the anterior ocular segment, glaucoma was present in 42 (26), whereas in another study of 407 patients with the dispersion syndrome, only one fourth had glaucoma (11). In a long-term study that spanned 5 to 35 years, 13 of 37 patients with PDS (35%) converted to pigmentary glaucoma (6). The glaucoma usually develops within 15 years of the presentation of the PDS, although some may take more than 20 years (6). In another study, with follow-up averaging 27 months, progression of the iris transillumination defects and pigment dispersion could be documented in 31 of 55 patients and correlated with worsening of the glaucoma in most of these (27). A study of 111 patients with PDS or pigmentary glaucoma identified male sex, black race, high myopia, and Krukenberg spindles as risk factors for the development and severity of glaucoma in this population (10). However, another study found that sex did not influence the development or severity of glaucoma among patients with PDS (6). In some patients, strenuous exercise, such as jogging, or spontaneous changes in the pupillary diameter may be associated with marked pigment release into the anterior chamber, although this does not appear to significantly elevate the IOP in most cases (28). In patients in whom exercise-induced pigment dispersion causes a significant IOP rise, use of pilocarpine has effectively inhibited this phenomenon. Phenylephrine-induced mydriasis also causes a significant shower of pigment into the anterior chamber in some patients with pigmentary glaucoma or PDS, although this transient liberation of pigment is not consistently associated with IOP elevations (28).

After pigmentary glaucoma becomes established, it may be somewhat more difficult to control than chronic open-angle glaucoma (COAG) is. In one long-term follow-up study of 38 patients (75 eyes), 39 eyes were controlled medically, 15 required laser trabeculoplasty, and 20 underwent a trabeculectomy (29). However, 67 eyes (89%) retained normal vision during the study (mean follow-up, 10 years). With increasing age, there is a tendency for the glaucoma to become less severe, but the condition must be treated aggressively during the active years to avoid irreversible loss of vision in later life.

Theories of Mechanism

Two fundamental questions must be considered regarding the pathogenesis of PDS and the mechanism of pigmentary glaucoma. What are the factors leading to the pigment dispersion and how do the dispersed pigment and additional features cause the glaucoma?

Mechanism of Pigment Dispersion

An inherent weakness or degeneration in the iris pigment epithelium was first proposed as a cause of PDS by Scheie and Fleischauer in 1958 (26). Subsequently, histopathologic observations of the iris in eyes with the PDS or pigmentary glaucoma have revealed changes in the iris pigment epithelium, which include focal atrophy and hypopigmentation, an apparent delay in melanogenesis, and hyperplasia of the dilator muscle (26, 30, 31 and 32). In contrast, eyes with COAG and various degrees of pigment dispersion had minimal hypopigmentation of the iris epithelium with normal dilator muscle and melanogenesis (32). These observations have led some observers to think that a developmental abnormality of the iris pigment epithelium is the fundamental defect in PDS (30, 31 and 32). The additional observation of retinal pigment epithelial dystrophy in two brothers with pigmentary glaucoma raises the possibility of an inherited defect of pigment epithelium in the anterior and posterior ocular segments (33). On the basis of fluorescein angiography of the iris, hypovascularity of the iris may also play a role in PDS (34, 35).

Campbell (36) proposed an alternative mechanical theory for the mechanism of pigment liberation from the iris (Fig. 17.5B). He observed that the peripheral radial defects of the iris corresponded in location and number to anterior packets of lens zonules and suggested that a background bowing of the peripheral iris led to the mechanical rubbing of the lens zonules against the iris pigment epithelium with the subsequent dispersion of pigment. This hypothesis was supported by histologic studies showing a correlation between packets of zonules and deep groves in the iris pigment epithelium and posterior stroma (36, 37). Sugar (7) suggested that the radial folds of iris pigment epithelium rubbing against the lens capsule itself might be an additional mechanism of pigment release.

The mechanical theory of Campbell is also supported by biometric and photogrammetric studies of anterior chamber dimensions, which revealed deeper anterior chambers and flatter lenses in the involved

eyes of unilateral cases and a deeper-than-normal midperipheral chamber depth with corresponding concavity of the iris in eyes with the PDS (38, 39). Further support for the mechanical theory comes from studies with ultrasonographic biomicroscopy indicating that the distance between the base of the trabecular meshwork and the point of insertion of the iris is greater in eyes with PDS than in healthy controls. Ultrasonographic biomicroscopy studies in patients with PDS have shown that the radial width of the iris compared with the size of the anterior segment is larger than normal (40). This larger size results in a floppier iris, which may predispose to iridozonular contact when combined with the posterior iris insertion. The mechanical theory is also consistent with clinical observations and helps to explain certain features of the disease. For example, the low incidence of the condition among nonwhite persons may be because of the heavy pigmentation and compactness of the iris stroma in these individuals, which prevents posterior sagging of the midperipheral iris (41). The tendency for the disease to ameliorate with increasing age may be attributed to the increasing axial length of the lens, which pulls the peripheral iris away from the zonules (5, 36). A case has also been reported in which subluxation of the lens apparently caused remission of pigmentary glaucoma (42).

The mechanical theory must include an explanation of the mechanism by which the peripheral iris is bowed backward. This missing piece of the puzzle came with the observation that a laser iridotomy relieves the posterior bowing, which led to the concept of reverse pupillary block (43). This concept suggests

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that aqueous is moved into the anterior chamber against the normal pressure gradient, possibly by the movement of the peripheral iris in response to movement of the eye (e.g., blinking) or accommodation. Once in the anterior chamber, the aqueous is prevented from returning to the posterior chamber by a oneway valve effect between the iris and lens, resulting in a relatively greater pressure in the anterior chamber and subsequent backward bowing of the peripheral iris. The theory of reverse pupillary block has been supported by studies with ultrasound biomicroscopy and Scheimpflug photography, both of which demonstrate the posterior bowing of the iris in patients with PDS and pigmentary glaucoma (28). The posterior bowing is eliminated by a peripheral iridotomy, miotic therapy, or prevention of blinking. Exercise, however, increases the iris concavity (44). The observations regarding blinking and exercise appear to support the concept that eye movement is responsible for the pumping of aqueous into the anterior chamber. It has also been observed that accommodation in patients with PDS leads to increased posterior bowing of the iris, which the investigators explain by the forward movement of the lens, which reduces the volume, thereby increasing the pressure in the anterior chamber (45). Iridotomy abolishes the change in the iris profile that is normally seen with accommodation in patients with PDS (46). The mechanical theory, however, does not fully explain why not all eyes with myopia are subject to PDS, and it may be that additional iris defects (as previously discussed) are necessary for development of this syndrome.

Another mechanism of pigment dispersion involves elongated anterior zonules that may be pigmented (Fig. 17.6A,B), encroaching in the central visual axis (47, 48). Normally, the anterior zonular insertion leaves a zonule-free zone of 6.9 mm (49). The clinical appearance and electron microscopic appearance (Fig. 17.6C) of an anterior capsule specimen obtained during cataract surgery suggest a mechanism of pigment release from the pigmented epithelium located at the papillary ruff and the central iris, which are close to the elongated zonules (48). This mechanism appears to be distinct from PDS in which iridozonular contact occurs in the region of the posterior chamber between the midperipheral iris and anterior zonule bundles (36). The zonules appear normal, as standard phacoemulsification did not indicate fragility (48, 50). Although subtle and easily missed on biomicroscopy, long anterior zonules may be more common than suspected but not previously recognized as a distinct entity associated with pigment dispersion.

Figure 17.6 Variant of pigment dispersion syndrome in a patient with African ancestry and hyperopia illustrating a distinct mechanism of pigment dispersion. A: Long anterior zonules are visible on the anterior capsule surface following dilation with direct and retroillumination. B: Pigment is commonly noted with some of the long anterior zonules. C: Transmission electron microscopy shows central anterior lens capsule covered by an irregular zonule lamella with pigment granules and degenerative lens epithelium in pigmented long anterior zonules. (Courtesy of Ursula Schlötzer Schrehardt, PhD.)

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Mechanism of Intraocular Pressure Elevation

In 1963, Grant (51) demonstrated that pigment granules perfused in human autopsy eyes caused a significant obstruction to aqueous outflow. Clinical studies have also shown that pigment release caused by pharmacologically induced movement of the iris causes a transient pressure rise in some eyes and that the number of aqueous melanin granules (as quantified by the cell count mode of a laser flare-cell meter) is strongly correlated with high IOP and visual field loss (52, 53 and 54). However, perfusion of living monkey eyes with uveal pigment particles caused only a transient obstruction to aqueous outflow (55), and histologic studies of human eyes with pigmentary glaucoma showed that only 3.5% of the pigment in the trabecular meshwork was in the juxtacanalicular tissue, which was thought to be insufficient to account for the outflow obstruction (56). It appears that other or additional factors must be involved in the mechanism of pigmentary glaucoma.

Although many histopathologic studies of eyes with pigmentary glaucoma have revealed excessive amounts of pigment granules and cell debris in the trabecular meshwork, it is the associated changes in the trabecular endothelial cells and collagen beams that are believed to lead to the glaucoma (28) (Fig. 17.7). On the basis of these observations, the following pathophysiologic sequence of events has been

proposed for the development of pigmentary glaucoma (57). Trabecular cells engulf melanin, which eventually leads to cell injury and death from phagocytic overload. Because melanoprotein is only partially digested, it is retained in intracellular storage vacuoles, where it generates deleterious oxygenfree radicals. Macrophages migrate to the necrotic trabecular cells, possibly in response to cytokines released by the injured cells, and carry off the pigment and debris through the Schlemm canal and into the circulation. The trabecular cell loss leaves the collagen beams denuded and vulnerable to fusion, with obliteration of the aqueous channels. Histologic studies reveal that the culde-sacs, which normally terminate in aqueous channels, are markedly reduced in pigmentary glaucoma, accounting for a major portion of the increased resistance to aqueous outflow.

Figure 17.7 Light microscopic view of trabecular meshwork from a patient with pigmentary glaucoma showing free pigment granules primarily in the uveal meshwork and in the inner portion of the corneoscleral meshwork, with intracellular pigment in the deeper portions of the meshwork. (Reprinted with permission from Richardson TM. Pigmentary glaucoma. In: Ritch R, Shields MB, eds. The Secondary Glaucomas. St. Louis: CV Mosby; 1982.)

An alternative theory suggests that a primary developmental anomaly of the anterior chamber angle may lead to aqueous outflow obstruction (9). This concept is based on the previously described abundant iris processes that have been seen in some cases. However, this is not a consistent finding and probably plays little or no role in the mechanism of pigmentary glaucoma.

A third hypothesis is that pigmentary glaucoma represents a variation of COAG. This theory was derived from observations that COAG and pigmentary glaucoma could be seen in the same family. In one study, individuals with Krukenberg spindles had topical corticosteroid responses that were similar to those seen in close relatives of patients with COAG (58). However, patients with pigmentary glaucoma were not found to have the same corticosteroid sensitivity to in vitro inhibition of lymphocyte transformation as COAG patients (59). Human leukocyte antigen testing revealed differences between PDS, pigmentary glaucoma, and COAG (60), but another study showed no significant difference among patients with pigmentary glaucoma, patients with PDS, and healthy controls (61). The bulk of the current evidence suggests that pigmentary glaucoma and COAG are separate entities.

Differential Diagnosis

In several disorders, an excessive dispersion of pigment may be associated with glaucoma, with or without a cause-and-effect relationship. These conditions constitute the differential diagnosis for pigmentary glaucoma. One such condition is the exfoliation syndrome (see Chapter 15), in which rubbing between the midperipheral lens and peripupillary iris leads to the pigment dispersion. This condition is usually distinguished from pigmentary glaucoma by the typical lens appearance and older age of the patients, although the two conditions have occurred together (62). Other conditions associated with increased anterior segment pigmentation and glaucoma include some forms of uveitis (see Chapter 22), trauma (Chapter 25), ocular melanosis and melanoma (Chapter 21), ciliary body melanocytoma (63), complications of intraocular surgery (Chapter 26), and COAG with excessive pigment dispersion (Chapter 11). Unilateral PDS may be evident after implantation of posterior chamber phakic refractive intraocular lenses, after anterior rotation or displacement of posterior chamber intraocular lens, and in the case of unilateral angle recession (64, 65 and 66).

Management Medical Therapy

The mechanical theory of Campbell (36) suggests that taking measures to eliminate contact between the iris and lens zonules is the most appropriate way to prevent the progressive development of pigmentary glaucoma. Pilocarpine has the theoretical

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advantage of relieving this mechanism of pigment dispersion by creating miosis, while at the same time lowering the IOP by the direct effect on aqueous outflow. However, it is usually not tolerated by the young patient with myopia because of further induced myopia. Pilocarpine may provide the desired miosis and improved facility of outflow without excessive induced myopia in some patients with pigmentary glaucoma. When using cholinergic agonists in patients with pigmentary glaucoma, special attention must be given to the risk of retinal detachment, which is more common in this population (24). The a-adrenergic antagonist thymoxamine has been advocated because it produces miosis without cyclotropia (36); however, the drug is not available in most parts of the world. An alternative a-blocker, dapiprazole, was proposed for this use, but it was found to be less effective than pilocarpine, 1.6%, in constricting the pupil or relieving posterior iris bowing in patients with PDS (67). Dapiprazole is no longer commercially available for use in the United States.

Alternative medications to miotic therapy include prostaglandin analogues, ß-adrenergic antagonists, and carbonic anhydrase inhibitors. With all of these nonmiotic drugs, the IOP may be reduced, but the mechanism of continued pigment dispersion is not eliminated.

Laser Surgery

In 1991, Campbell reported that a laser iridotomy (suggested initially by Dr. B. Kurwa) effectively relieved the posterior iris bowing in pigmentary glaucoma (Campbell DG, lecture honoring H. Saul Sugar, MD, American Glaucoma Society Fourth Annual Scientific Meeting, San Diego, CA, December 1991). This was confirmed by Karickhoff the following year in a report of six patients (43). This effect, however, has not been observed in all cases (68), and iridotomy did not completely eliminate exerciseinduced pigment dispersion in a patient with PDS (69). An ultrasound biomicroscopic study of patients with PDS and peripheral iris concavity has shown that the iris flattens after peripheral iridotomy (70). In a study of 21 patients with PDS and IOP less than 18 mm Hg in both eyes, an Nd:YAG laser iridotomy was randomly performed in one eye, and the fellow eye was used as a control (71). After 2 years of follow-up, one treated eye (4.7%), compared with 11 untreated eyes (52.3%), demonstrated an IOP elevation of more than 5 mm Hg. This difference in IOP elevation was inversely related to patient age. A retrospective review of 46 patients with pigmentary glaucoma who underwent unilateral laser iridotomy and were followed up for 2 or more years found that the mean IOP decreased by 4 mm Hg, compared with 1.9 mm Hg in the fellow eye; however, a higher mean baseline IOP in the treated eye accounted for the apparent treatment effect, and the authors concede that their data are inconclusive regarding whether laser iridotomy is beneficial in this group of patients (72). If performing a laser iridotomy in patients with PDS, it may be prudent to use only dilute pilocarpine, because these patients are at increased risk