Secondary open angle glaucoma

Pigmentary glaucoma

Pigmentary glaucoma is a secondary form of open-angle glaucoma produced by pigment dispersion in the anterior segment of the eye.1,2 This condition constitutes 1.0–2.5% of the glaucomas seen in many Western countries.3 Pigmentary glaucoma generally occurs in young adults but has been described in adolescents and older individuals as well.1,4 The disease preferentially involves men, and the women affected usually are a decade older than the men.4–6 Pigmentary glaucoma occurs most often in white individuals: it is diagnosed rarely in blacks and Asians.1,5,6 There is a strong association between pigmentary glaucoma and myopia: the typical pigmentary glaucoma patient is a myopic white man in his twenties or thirties. One study of black patients found that the average age of onset was 73 years, and the patients were more often hyperopic than myopic, indicating that there may be a different mechanism of disease in this subgroup.7 Although there have been a few reports of familial pigmentary glaucoma,1,6,8 most cases appear to be sporadic.

Pigmentary glaucoma is characterized by the release of pigment particles from the pigment epithelium of the iris. These particles are carried by the aqueous humor convection currents and then deposited on a variety of tissues in the anterior segment of the eye, including the corneal endothelium (Fig. 18-1), trabecular meshwork (Fig. 18-2), anterior iris surface, zonules (Fig. 18-3), and lens. The loss of pigment from the iris is detected as a series of radial, spokelike, midperipheral transillumination defects. These defects can range in number from 1 or 2 to 65 or 70 and can be thin slits

or coalescent areas. They are best seen in a darkened room by a dark-adapted observer. The defects can be highlighted by shining a small slit beam through the pupil with the light perpendicular to the plane of the iris. On rare occasions, transillumination defects are hidden by very heavy iris pigmentation. Patients with pigmentary glaucoma have very deep anterior chambers, a concave appearance of the peripheral iris, and mild iridodonesis.9–11

The deposition of pigment on the corneal endothelium generally takes the form of a vertically oriented spindle called Krukenberg’s

Fig. 18-2  Goniophotograph of dense pigment in the anterior chamber angle.

Fig. 18-1  Deposition of pigment on the corneal endothelium, referred to as

Krukenberg’s spindle.

(From Alward WLM: Color atlas of gonioscopy, St Louis, Mosby, 1994.)

Fig. 18-3  Pigment deposit on the zonules.

(From Campbell DG, Netland PN: Stereo atlas of glaucoma, St Louis, Mosby, 1998.)

spindle (see Fig. 18-1), which can range in appearance from faint to striking. The spindle is neither pathognomonic of the disease nor invariably present, but it is a very useful sign.The spindle consists of extracellular as well as intracellular pigment granules phago-cytized by the corneal endothelium.12,13 Pigment also accumulates in the trabecular meshwork. In early cases of pigmentary glaucoma, the trabecular meshwork is moderately pigmented, with pigments varying from one portion of the meshwork to another. In advanced cases, the trabecular meshwork appears as a dark-brown velvet band that extends uniformly about the circumference of the angle (see Fig. 18-2). The pigment can cover the entire width of the angle from the ciliary face to the peripheral cornea; a pigment line ­anterior to Schwalbe’s line is often referred to as Sampaolesi’s line.

Pigment is also deposited on the zonules, posterior lens surface (Zentmayer’s ring or Scheie’s line), and anterior iris surface.The pigment on the anterior iris surface accumulates in the circumferential folds and can be sufficient to give a dull or even a heterochromic appearance if the pigment dispersion is asymmetric in the two eyes.5

The anterior chamber is very deep and the peripheral iris has a concave configuration when viewed at the slit lamp or with gonioscopy (Fig. 18-4).With the exception of pigmentary dispersion, pigmentary glaucoma resembles primary open-angle glaucoma (POAG) in most aspects, including elevated intraocular pressure (IOP), decreased outflow facility, optic nerve cupping, and visual field loss. Large diurnal IOP fluctuations are thought to occur more often in pigmentary glaucoma and can be sufficient to cause corneal edema, blurring, and halo vision. Patients with pigmentary glaucoma can have a sudden release of pigment with severe IOP elevations after pupillary dilation or exercise.14–18 At times, this release of pigment can be confused with active anterior segment inflammation. Pigment release and marked IOP elevation after exercise can be blocked by topical pilocarpine therapy.19

Several reports have indicated that pigment dispersion lessens with time so that Krukenberg’s spindles and trabecular pigmentation become less prominent.4,5 In some cases, this is accompanied by an improvement in aqueous humor dynamics. Ritch has proposed that this disappearance of pigment may explain some nonprogressive cases of normal-tension glaucoma.20 That is, a patient who has optic nerve cupping, visual field loss, and normal IOP may have had pigmentary glaucoma and elevated IOP in the past.

Fig. 18-4  Concave peripheral iris illustrated by an inferior slit beam in a patient with pigmentary glaucoma.

Remission of pigmentary dispersion also has been reported after glaucoma surgery6 and lens subluxation.21

The differential diagnosis of pigmentary glaucoma includes any condition that produces pigmentation of the trabecular meshwork. These include normal eyes with aging, POAG, uveitis, cysts of the iris and ciliary body, pigmented intraocular tumors, previous surgery (including laser surgery), trauma, angle-closure glaucoma, amyloidosis, diabetes mellitus, herpes zoster, megalocornea, radiation, siderosis, and hemosiderosis.These conditions should be readily distinguished from pigmentary glaucoma by the history and physical examination. The condition most likely to be confused with pigmentary glaucoma is exfoliation syndrome. However, the pattern of iris atrophy in exfoliation syndrome is usually central and geographic, and the pigment accumulation in the trabecular meshwork consists of larger particles that are unevenly distributed about the angle.

It is important to emphasize that many individuals have pigment dispersion without glaucoma or abnormal aqueous humor dynamics.22 Pigment dispersion syndrome (PDS) was found in 2.45% of 934 patients undergoing glaucoma screening,23 and is thus much more common than pigmentary glaucoma, which results from a decreased facility of outflow following pigment deposition in the trabecular meshwork in a subset of patients with PDS. Pigment dispersion syndrome can be asymptomatic, and have varying levels of expression, and is therefore likely to be overlooked or underdiagnosed.The true prevalence of PDS in the population is not known; most cases of mild pigment dispersion are probably never detected. Pigment dispersion appears to be at least as common as pigmentary glaucoma and occurs with equal frequency in both sexes. In some cases, pigment dispersion progresses to pigmentary glaucoma over time, which can be as long as 12–20 years.1 However, most individuals with PDS maintain normal visual fields and aqueous humor dynamics, even on long-term follow-up.This good prognosis is especially likely if the patient has a normal tonographic outflow facility when first seen.16 Generally the degree of pigment dispersion does not correlate well with the presence or future development of glaucoma.8 Patients with PDS and normal IOPs should receive a careful initial examination, including visual field examinations and optic nerve photographs.These individuals should then be followed up periodically without treatment.

Any theory about the pathogenesis of pigmentary glaucoma must explain two phenomena: pigment release and diminished outflow facility. Campbell has proposed a mechanical theory to explain pigment dispersion.9 He postulated that the concave shape of the peripheral iris allows it to rub against the zonules, causing pigment release and dispersion. Campbell noted that the pattern of iris transillumination defects corresponds with the arrangement of the anterior zonular packets.9 He also noted that the number and extent of the iris transillumination defects correlate with the progression of pigmentary glaucoma.9 When patients receive miotic treatment, the ensuing pupillary block lifts the peripheral iris off the zonules and allows the transillumination defects to fill in and even disappear. Lord and colleagues measured refraction, keratometry, and axial length of 13 patients with pigmentary glaucoma and 17 controls.24 They found that the pigmentary glaucoma and PDS patients had flatter keratometry than myopic controls, suggesting a difference in their anterior segment architecture.

Not all patients with a diagnosis of pigmentary glaucoma show iridozonular contact on ultrasound biomicroscopy. Pillunat and colleagues studied 28 eyes of 28 patients with pigmentary glaucoma and found that iridozonular contact was present in only 10.25 In these 10 eyes, laser peripheral iridectomy predictably relieved the

characteristic reverse pupillary block, and interestingly led to a 25% decrease in IOP (from a pretreatment mean of 24.6 mmHg to a post-treatment mean of 18.3). In the 18 eyes without iridozonular contact, the pressure dropped only slightly, from 25.1 to 23.1.These findings differ from our experience in that we have had no success in lowering pressures in patients with pigmentary glaucoma and ultrasonically confirmed iridozonular contact. Perhaps iridectomy may help during phases of the syndrome when pigment granules are being liberated actively, but iridectomy seems unlikely to benefit established cases when the damage has been done. Richter and colleagues observed active pigment dispersion in 31 of 55 PDS and pigmentary glaucoma patients followed for between 6 and 43 months (mean 27 months).26 Active pigment dispersion was defined as an increase in transillumination, an increase in corneal pigmentation, or the presence of pigment granules on the surface of the lens in the pupil.There were no differences in frequency of active dispersion or worsening of glaucoma in patients less than 44 years old, between 45 and 64, or over 65. Although we have not seen pressure lowering in pigmentary glaucoma patients following laser peripheral iridectomy, iridectomy may have prevented or limited future pressure rise.

In addition to the mechanical theory of pigment dispersion, Anderson and colleagues found that DBA/2J(D2) mice develop a form of pigmentary glaucoma involving pigment dispersion and iris stromal atrophy.27 Using high-resolution mapping techniques, sequencing, and functional genetic tests, they showed that these conditions resulted from mutations in genes encoding melanosomal proteins.They postulate that pigment production and mutant melanosomal protein genes may contribute to human pigmentary glaucoma. Further study is needed to confirm this hypothesis.

When iris pigment is infused into animal or enucleated human eyes, outflow facility decreases and IOP increases.16,28 Repeated infusions of pigment, however, do not produce chronic glaucoma in animal eyes.29 Some authorities believe that patients with pigmentary glaucoma must have an underlying developmental abnormality of the outflow channels. As evidence for this theory, they cite

(1) the high prevalence of prominent iris processes in patients with pigmentary glaucoma;5 (2) patients with pigmentary glaucoma who have angles that resemble infantile glaucoma, and (3) families who have some members with pigmentary glaucoma and other members with congenital glaucoma.

Other authorities propose that pigmentary glaucoma is a variant of POAG. These investigators point to families that have members with both pigmentary glaucoma and POAG.5 However, patients with pigmentary glaucoma do not resemble those with POAG when corticosteroid testing is considered.30

Histopathologic examination of specimens from eyes with pigmentary glaucoma demonstrates pigment and debris in the trabecular meshwork cells.31–33 With advanced disease, the trabecular cells degenerate and wander from their beams, allowing sclerosis and eventual fusion of the trabecular meshwork.31,33 Some propose that excessive phagocytosis of foreign material damages the trabecular endothelial cells and causes them to migrate.34

The treatment of pigmentary glaucoma resembles that of POAG in that the usual progression is from medical therapy to argon laser trabeculoplasty (ALT) to filtering surgery. -Adrenergic antagonists, adrenaline (epinephrine), dipivefrin, and carbonic anhydrase inhibitors (CAIs) are useful in the management of pigmentary glaucoma. Miotic agents reduce IOP in pigmentary glaucoma and are theoretically appealing because they increase pupillary block and lift the peripheral iris from the zonules. However, cholinergic drugs are generally poorly tolerated by these young patients. Some reports

also indicate that patients with pigmentary glaucoma have a high incidence of retinal detachment;6 thus a careful peripheral retinal examination is mandatory before cholinergic agents can be prescribed.Thymoxamine, an -adrenergic antagonist, might be useful in this situation because it constricts the pupil without inducing a myopic shift in refraction.35

The most intriguing therapy for pigmentary glaucoma is peripheral iridectomy to cure the ‘reverse’ pupillary block that is responsible for the characteristic peripheral iris concavity.36 Ultrasonic biomicroscopy is helpful in indicating those eyes that are most likely to benefit from iridectomy.11 In eyes with deep peripheral concavity, the effects of peripheral iridectomy are almost immediate. Within seconds of completing the iridectomy the peripheral iris moves forward and assumes a more normal configuration (Fig. 18-5).The long-term effects of peripheral iridectomy are unclear. Ideally peripheral iridectomy would provide effective prophylaxis for patients with PDS before they develop glaucomatous visual field loss. Although it is impossible to determine exactly which patients with pigmentary dispersion syndrome will develop glaucoma,37 it may be most appropriate to treat patients at the first sign of significant IOP elevation. Patients who show elevation following exercise may also be good candidates for peripheral iridectomy.18 Pilocarpine and other miotics can reduce exercise-induced pressure rises, but parasympathetics routinely cause significant ocular side effects in the young adults most likely to have pigmentary glaucoma. Peripheral iridectomy has the same beneficial effects and is well tolerated by patients of all ages.

If medical management does not control IOP, ALT should be performed.38 Because of the heavy pigmentation of the angle, ALT is done with relatively low energy settings in the range of 200–600 mW. Selective laser trabeculoplasty also works.

Many individuals with pigmentary glaucoma eventually require filtering surgery. Despite the young age of these patients, the results of surgery are generally successful.

As mentioned previously, pigment dispersion may diminish with age. Some patients require less medical therapy and eventually discontinue therapy as they reach 60 or 70 years of age.This does not occur invariably, however, and some individuals with pigmentary glaucoma require life-long treatment.

There have been several reports of pigment dispersion and secondary glaucoma from posterior chamber intraocular lenses (IOLs). This subject is discussed in the section on glaucoma after cataract surgery, p. 273.

Fig. 18-5  Ultrasonic biomicroscopy of the anterior segment showing the iris before (A) and after (B) peripheral iridectomy in the same patient as in Figure 18-1. The iris configuration changes from concave to slightly convex.

Exfoliation syndrome (pseudoexfoliation syndrome)

Exfoliative syndrome (previously or classically known as pseudoexfoliation syndrome) occurs when several ocular tissues synthesize an abnormal protein. This protein may obstruct the trabecular meshwork and cause glaucoma. Exfoliation syndrome and its associated glaucoma are known by a variety of other names, including pseudo­ exfoliation, senile exfoliation, senile uveal exfoliation, glaucoma capsulare, and iridociliary exfoliation.39 At one time, most cases of exfoliation syndrome were diagnosed in Scandinavia. Although it is now clear that this condition occurs throughout the world, some

areas seem to have a higher prevalence of the disease than do others, with particularly high rates in Scandinavia and parts of Africa.40,41

It is, however, difficult to compare the published prevalence of exfoliation syndrome precisely because various studies used different techniques and definitions and did not match the patients for

age.The prevalence of exfoliation syndrome is closely linked to age, reaching a maximum in the seventh to ninth decades of life.42–44

The prevalence of exfoliation syndrome in the Framingham study was 0.6% in patients younger than 65 years of age, 2.6% in patients 65–74 years of age and 5.0% in patients 75–85 years of age.45 Others have reported that exfoliation syndrome occurs in 3–28% of

patients with open-angle glaucoma in the United States, with most estimates in the range of 3–10%.42–44,46 In the Blue Mountains Eye

Study, the exfoliation syndrome prevalence was 2.7% of the entire population of 3645 that participated.47 The prevalence of glaucoma among exfoliation syndrome patients was 14.7%. In contrast, in some areas of Scandinavia, more than 50% of patients with openangle glaucoma have evidence of exfoliation. Exfoliation syndrome appears to be common among Russian immigrants to the U.S.A.

Exfoliation syndrome is more common in women than in men, but the combination of exfoliation syndrome and glaucoma occurs equally in both sexes.48 Most cases appear to be sporadic, but Allingham and associates found a series of Icelandic families in which there appears to be an X-linked inheritance pattern.49 In their study, Allingham and colleagues identified six Icelandic families that met the entry criteria of having at least three members over 70 years of age, at least one of whom had exfoliation syndrome. In each of these families, at least one person in the next generation had pseudoexfoliation and glaucoma. In all cases in

which a parent and child were found to have exfoliation syndrome, the parent was always the mother.40,49

Recently, a polymorphism in exon 1 of the LOXL1 gene has been found to be highly associated with exfoliative syndrome in Iceland and in Sweden where the prevalence of exfoliative syndrome is very high.The same polymorphisms have been confirmed in populations with exfoliative syndrome in other parts of Europe, India, the United States,Australia, and Japan.51–56 These same polymorphisms are NOT associated with POAG and appear to be specific for exfoliative syndrome and glaucoma.57 Unfortunately, the polymorphisms can not be used for diagnostic purposes since they appear quite frequently in the ‘normal’ population.58 Whether these polymorphisms in normal individuals are truly markers for future development of exfoliative syndrome or glaucoma or whether some other genetic or environmental facilitator must be present to generate the syndrome remains unknown at this time.That some ‘second hit’, either genetic or environmental, must be present is hinted at by the study of Hewitt and co-workers55 which suggests that Australians of European extraction have a much lower penetrance from the polymorphisms than in the

Nordic peoples. The LOXL1 family of proteins is associated with extracellular matrix formation and stability so it is not surprising that formation of abnormal proteins by genetic variants might affect trabecular outflow and the lens epithelium, among other structures.59 Inhibitors of matrix metalloproteinases have been found to be upregulated and actual matrix metalloproteins have been found to be downregulated in the aqueous humor of eyes with exfoliative syndrome compared to eyes without.60

One-third to one-half of the cases of exfoliation syndrome are unilateral at detection, but 14–43% of these cases become bilateral over 5–10 years.48,61 The prevalence of glaucoma in exfoliation syndrome is reportedly 0–93%.48 However, many of these studies diagnosed glaucoma on the basis of elevated IOP or even abnormal provocative tests. Using strict definitions, recent studies detected glau-

coma in 6–7% of patients with exfoliation syndrome and detected elevated IOP in an additional 15%.48,62,63 In patients who had exfo-

liation syndrome and normal IOPs at diagnosis, glaucoma developed in 3–15% over 3–15 years.41,48,61 In the Ocular Hypertension

Treatment Study, the rate of new glaucoma among untreated ocular hypertensive patients was approximately 2% per year.

Exfoliation syndrome is not associated with any known systemic disorder. However, a retrospective study suggests that patients with exfoliative syndrome have a higher risk of developing acute cerebro­ vascular diseases and chronic cerebral conditions such as Alzheimer disease than those with POAG.64 However, this same group was unable to show any overall increase in mortality associated with exfoliative syndrome except as related to use of acetazolamide.65

Another study showed higher levels of plasma homocysteine in exfoliative patients compared to those with normal-tension glaucoma.66 Increased levels of plasma homocysteine have been associated with increased risk of cardiovascular disease. It is clear that prospective longitudinal studies are needed to determine if these associations noted in retrospective and cross-sectional studies are truly clinically important.

The clinical presentation of exfoliation syndrome includes a classic pattern on the anterior lens surface consisting of a central translucent disc surrounded by a clear zone, which in turn is surrounded by a granular grey-white ring with scalloped edges (Fig. 18-6).This is best appreciated when the lens is examined with the slit lamp after pupillary dilation; if the pupil is not dilated, many cases can be missed because the characteristic ring may not be visible within a small pupil. The central and peripheral zones can be entirely separate or can be joined by bridges of material. It has

Fig. 18-6  Exfoliation material on the lens.

(From Alward WLM: Color atlas of gonioscopy, San Francisco, 2000, Foundation of American Academy of Ophthalmology.)