A basement membrane separates the polarized endothelial cells from the underlying collagenous core and, not infrequently, patches of this basement membrane present a periodic structure (banded basement membrane) measuring 100 nm (1 µm = 1000 nm = 10,000 Å).

D. Lying within the tightly packed collagenous cores of the trabeculae are many aggregates of filamentous and homogenous elastic tissue whose density increases with age (the aggregates also take stains for elastic tissue).

E. The endothelial cells covering the connective tissue core have apical surfaces, line intertrabecular spaces, and therefore are bathed by aqueous.

F. The trabeculae of the meshwork are roughly arranged into circumferential sheets lying superimposed one on the other.

Trabeculae can be fairly easily separated from one another mechanically, especially in the uveal meshwork. The spaces between adjacent sheets are called intertrabecular spaces. Large oval apertures traverse each trabecular sheet and may be called transtrabecular spaces. The transtrabecular apertures are not superimposed, and they decrease in size in the direction of the corneoscleral meshwork. The corneoscleral sheets differ only slightly from the uveal in having somewhat flatter trabeculae as observed in cross-section and in lacking the staining characteristics for elastic fibers. The transtrabecular apertures here are more circular and smaller than those of the uveal meshwork. All intertrabecular and transtrabecular spaces thus may be considered extensions of the anterior chamber.

G. Spaces between individual sheets are well seen in proper meridional section, and here they are termed the intertrabecular spaces.

In the uveal meshwork, the intertrabecular spaces pass the scleral roll to continue with the tissue spaces lying between the smooth muscle cells of the ciliary muscles—especially those of the meridional (longitudinal) ciliary muscle. If serially sectioned in a frontal or coronal plane, the spaces can be seen as large-apertured, relatively straight, short tubes. Such a grouping of tubes with apertured walls might be termed a system of compound aqueous tubes. In the corneoscleral meshwork, which blends posteriorly with the region of the scleral roll, the intertrabecular spaces (tubes) abut the canalicular extensions of the canal of Schlemm. Such extensions are frequent in this region.

H. The blind inpouchings of the canal of Schlemm (canals of Sondermann), here termed canaliculi, are endothelium-lined and do not appear to be in continuity with the intertrabecular spaces. Their function, presumably, is to drain off aqueous passing laterally along the corneoscleral trabecular meshwork (i.e., along the intertrabecular spaces).

Fig. 16.1 Normal adult angle. Schematic representation of meridional section of corneoscleral coat. Circumferential shallow outer sulcus (1) and deeper, inner sulcus (2) are present in region of union of sclera with cornea. Posterior boundary of inner sulcus is thickened by scleral roll (posterior border ring of Schwalbe).

Fig. 16.2 Normal adult angle. The trabecular meshwork is a loose collagenous meshwork that fills the inner scleral sulcus and extends as an open fan to the root of the iris. The meshwork may be separated into two parts by an imaginary line extending from the end of Descemet’s membrane (1) to the scleral roll (2). The meshwork lying external to the line and extending from cornea to sclera is known as the corneoscleral (cs) meshwork. The meshwork lying internal to the line and in continuity with the uveal tract posteriorly (3) is known as the uveal (u) meshwork. A third part, which rests on the inner wall of the canal of Schlemm (s), is a thin or patchy basement membrane associated with a zone of delicate connective tissue called the juxtacanalicular connective tissue (jct).

Fig. 16.3 Normal adult angle. A, Scanning electron microscopy shows the main aqueous drainage area [i.e., the angle (a) of the anterior chamber]. Aqueous drains through the trabecular meshwork ™ into Schlemm’s canal (sc), the collector channels (cc), and the aqueous veins, as well as into the uveal tract and out through the anterior ciliary and vortex veins. Some aqueous also drains into the iris and out through the iris vessels (c, cornea; pc, posterior surface of cornea; sr, scleral roll/spur; i, iris; ix, iris in cross-section; ip, iris pigment epithelium). B, In an adult, the scleral roll becomes thickened by compacting of the uveal meshwork to form the scleral spur (s), a bipartite structure. Between the scleral portion and the cornea lies the corneoscleral trabecular meshwork ™. Just posterior lies the uveal trabecular meshwork, and just anterior, adjacent to Schlemm’s canal (sc), lies the juxtacanalicular connective tissue (see Fig. 16.11A) (c, cornea; i, iris; cb, ciliary body). C, We usually view the transtrabecular and intertrabecular trabecular meshwork spaces meridionally. A section perpendicular to this plane, through the dotted lines, results in an anterior–posterior (coronal or frontal) view of the trabecular meshwork intertrabecular drainage spaces or canals, as seen in D (see Figs. 16.9A and 16.9C). (A, Courtesy of Dr. RC Eagle, Jr.)

Introduction

The cell and molecular biology and gene rearrangement aspects of the glaucomas are fascinating, but an in-depth analysis of these matters is beyond the scope of our discussion. For example, genome-wide expression profiling of patients with primary open-angle glaucoma (POAG) identified 563 genes that were significantly dysregulated in POAG compared with normal controls. These genes impacted numerous functions, including nucleoside, nucleotide, and nucleic acid metabolism; the mitogen-activated protein kinase kinase kinase (MAPKKK) cascade; apoptosis; protein synthesis; cell cycle; intracellular signaling cascade; and nervous system development and function. Therefore, we highlight only a few salient facts regarding these areas.

Currently, 15 chromosome loci, which are designated GLC1A to GLC10, are associated with POAG. Candidate genes include myocilin (GLC1A), WD40-repeat36 (GLC1G), optineurin (GLC1E), and neurotrophin-4 (NTF-4) (optineurin is discussed with normal pressure glaucoma later in this chapter). Nevertheless, it has been estimated that mutations in known glaucoma genes account for less than 15% of cases. The prevalence of heterozygous cytochrome p450 1B1 (CY1B1) gene changes in a mixed glaucoma population suggests that the pathogenesis of glaucoma is genetically heterogeneous and may be polygenic. Single nucleotide polymorphisms (SNPs) between the CAV1 and CAV2 genes on chromosome 7q31 code for two members of the caveolin family of proteins are associated with POAG in white Americans, particularly women. These proteins impact modulation of endothelial cell membranes, which could alter the process of ocular aqueous fluid drainage. In general, however, SNPs are not discussed in any detail, but they have been described elsewhere (see Bibliography). Gene copy number variations also may play a role in the development of POAG. For example, homozygous deletions that reduce galactosylceramidase activity may increase the risk of POAG.

I. Glaucoma is characterized by an intraocular pressure (IOP) sufficient to produce ocular tissue damage, either transient or permanent.

A. Glaucoma is a “family” of diseases having in common a type of optic atrophy called optic nerve head cupping or excavation.

1. Various systemic abnormalities have been associated with glaucoma, including elevation of the 20S proteasome α subunit of leukocytes. Certain class I HLA haplotypes (A9–B12, A2–B40, A1–B8) are associated with progression of optic nerve head changes in glaucoma.

2. The appearance of the optic disc is an important diagnostic finding in glaucoma. The ratio of the optic cup to disc is moderately heritable.

A more appropriate name may be glaucomatous optic neuropathy because the primary defect, especially in chronic open-angle glaucoma, appears to be within the optic nerve head.

B. Although most individuals associate glaucoma with an elevated IOP, the pressure may, in fact, be within the statistically “normal” range and still cause ocular tissue damage in normal-tension (improperly called low-tension) glaucoma.

1. IOP is a risk factor for glaucoma, and the higher the pressure, the greater the probability of the development of the disorder.

a. The accurate measurement of IOP is vital to the proper diagnosis and treatment of glaucoma.

b. Central corneal thickness (CCT) impacts the validity of IOP measurements, particularly in the diagnosis of ocular hypertension.

Thicker corneas of normal composition produce an artificially high IOP measurement compared to manometrically measured “true” IOP. Conversely, thinner corneas produce an inappropriately low pressure on Goldmann applanation tonometry. Decreased CCT is present in normal-tension glaucoma and the CCT is thinner than in POAG. Similarly, CCT is thinner in patients with vascular risk factors for glaucoma. Patients with congenital aniridia have CCT that is significantly thicker than normal. This abnormality is not secondary to corneal edema resulting from endothelial dysfunction.

c. CCT is increased in children with ocular hypertension.

There is considerable racial variation in CCT. Osteogenesis imperfecta may be associated with an abnormally thin CCT. Alterations in corneal thickness related to forkhead gene dosage can result in errors in IOP measurement. Increased CCT is associated with segmental gene duplication.

d. Glaucoma, therefore, is not an IOP reading; it is a syndrome. In fact, the cause of the glaucoma may be due to factors (mostly poorly understood) other than IOP. IOP is simply one risk factor.

2. Normal-tension glaucoma probably accounts for approximately one-third of all cases of POAG.

Optineurin
Currently, 15 gene loci, designated GLC1A to GLC10, are associated with POAG. The optinuerin gene is associated with several disorders, including glaucoma, amyotrophic lateral sclerosis, other neurodegenerative disorders, and Paget’s disease of bone. A glaucoma-causing gene has been identified at GLC1E, and sequence variations in this optineurin (OPTN) gene on GLC1E have been found to be associated with the development of normal-tension glaucoma. The gene is located on chromosome 10. The glaucoma associated with optineurin is not characterized by marked IOP elevation. Rather, the E50K mutation in the optineurin gene is associated with increased severity of normal-tension glaucoma in white and Latino populations. There may be racial differences in glaucoma-associated optineurin genotypes. Its primary effect may be to increase susceptibility of retinal ganglion cells to premature cell death. Thus, optineurin may serve an optic nerve protective effect that is lost through mutation. Optineurin gene alterations do not appear to have a significant role in typical POAG.

Disc hemorrhage is a significantly negative prognostic factor in normal-tension glaucoma.

3. Optic atrophy type 1 (OPA1) on chromosome 3 is the gene responsible for dominant optic atrophy. It encodes for an inner mitochondrial membrane protein that is crucial for normal mitochondrial function. Mutations in this gene are of importance in glaucoma target retinal ganglion cells. OPA1 is downregulated in POAG, but it is most associated with damage from normal-pressure glaucoma. Some cases of normal-tension glaucoma are associated with polymorphisms of the OPA1 gene. This association raises the possibility that normal-tension glaucoma may result from mitochondrial dysfunction. OPA1 polymorphisms vary with ethnicity. The gene can modulate retinal ganglion cell survival. Alterations in this gene may facilitate ganglion cell death through glutamate excitotoxicity and oxidative stress, and also mitochondrial dysfunction. Apoptosis ensues.

4. More than 6% (4/62) of patients with normal-tension glaucoma may have relevant intracranial compressive lesions. Such lesions are usually lacking in POAG.

5. Predictive factors for progression of normal-tension glaucoma differ from those of POAG, possibly suggesting different pathobiologic mechanisms for these disorders.

Papillorenal syndrome is associated with optic disc and visual field anomalies that may lead to an erroneous diagnosis of normal-tension glaucoma.

II. Glaucoma suspect

A. Increased IOP without detectable ocular tissue damage or visual functional impairment is called ocular hypertension. An individual who has some features of glaucoma, but in whom a definitive diagnosis has not yet been confirmed, is termed a glaucoma suspect.

B. Ocular hypertension may be tolerated by the person, or eventually it may lead to ocular tissue damage and hence to glaucoma.

The prevalence of glaucoma suspect in the general adult population is approximately 8% depending on age and race. The incidence of or progression to glaucoma among glaucoma suspects is approximately 1% per year.

III. Glaucoma is the leading cause of blindness among the 500,000 legally blind people in the United States—approximately 14% (1 in 7) of blind people.

The second leading cause of blindness is retinal disease (exclusive of diabetic retinopathy), mainly age-related macular degeneration, followed by cataract. Optic nerve disease is fourth; diabetic retinopathy, fifth; uveitis, sixth; and corneal and scleral disease, seventh. Leading causes of new cases of blindness, in order of importance, are macular degeneration, glaucoma, diabetic retinopathy, and cataract.

A. Glaucoma of all types affects approximately 0.5–1% of the general population, 2% of people age 35 years or older, and 3% of people age 65 years or older.

B. POAG accounts for approximately two-thirds of all glaucoma seen in white patients.

1. The prevalence of POAG in white patients ranges from approximately 0.9% in people 40–49 years of age to approximately 2.2% in those 80 years of age or older.

2. The prevalence of POAG in black patients ranges from approximately 1.2% in people 40–49 years of age to approximately 11.3% in those 80 years of age old or older.

IV. Primary closed-angle glaucoma, which has a prevalence of less than 0.5%, is much less common in black patients than in white patients. A high percentage of black patients who develop angle-closure, however, have chronic closed-angle glaucoma instead of the acute type.

The prevalence of primary closed-angle glaucoma is highest among Inuits (~2 or 3%), followed by Asians (~1%).

V. There is considerable racial and genetic variation in the incidence and prevalence of the various forms of glaucoma.

Normal Outflow

Hypersecretion

I. Hypersecretion glaucoma is rare and has no antecedent cause.

II. Outflow facility is normal. The elevated IOP is presumed to be caused by an increased production of aqueous humor.

III. The glaucoma mainly affects middle-aged women, especially when they have neurogenic systemic hypertension.

IV. Histologically, the angle of the anterior chamber shows no abnormalities.

Impaired Outflow

Congenital Glaucoma

I. General information

A. The rate of congenital glaucoma is from 1 : 5000 to 1 : 10,000 live births.

B. It is usually inherited as an autosomal-recessive trait, but it can have an infectious cause (e.g., rubella).

C. Approximately 60–70% of affected children are boys.

D. The disease is bilateral in 64–88% of cases.

E. Age of onset: (1) present at birth, 40%; (2) between birth and six months, 34%; (3) between six months and one year, 12%; (4) between one and six years, 11%; (5) older than six years, 2%; and (6) no information, 1%.

II. Pathogenesis (many theories)

A. Barkan’s membrane (mesodermal surface membrane or imperforate innermost uveal sheet) mechanically prevents the aqueous from leaving the anterior chamber (histologic proof for this theory is scarce).

B. Congenital absence of Schlemm’s canal is very rare, if it exists at all. Most often, the canal is compressed or collapsed as a secondary change resulting from chronically elevated IOP. The canal, therefore, may be difficult to find histologically.

C. An “embryonic” anterior chamber angle that results from faulty cleavage of tissue during embryonic development of the eye prevents the aqueous from leaving the anterior chamber.

1. Histologically, the angle shows an anterior “insertion” of the iris root, anteriorly displaced ciliary processes, insertion of the ciliary meridional muscles into the trabecular meshwork instead of into (or over) the scleral roll, and mesenchymal tissue in the anterior chamber angle (Fig. 16.4).

Fig. 16.4 Congenital glaucoma. A and B from premature infants (A, 700 g—died soon after birth; B, 1050 g—lived one day); neither had clinical or histologic evidence of glaucoma. Note each has anterior “insertion” of iris root, anteriorly displaced ciliary processes, continuity of ciliary meridional muscles with uveal trabecular meshwork, and mesenchymal tissue in anterior chamber angle. C, Eye obtained from two-year-old child at time of accidental drowning but sectioned tangentially. Bilateral congenital glaucoma well documented; goniotomy and goniopuncture had been performed in another area of eye; pressure well controlled after surgery. Note similarity to nonglaucomatous premature eyes shown in A and B. D, However, when eye shown in C is sectioned properly (meridionally), the angle appears completely normal compared with that other two-year-olds.

2. Many nonglaucomatous infant eyes show a similar anterior chamber angle structure.

3. To interpret angle histology accurately, it is necessary to study truly meridional sections through the anterior chamber angle.

a. Tangential sectioning makes interpretation difficult (see Figs. 16.4C and 16.4D).

b. Unfortunately, in the usual serial sectioning of a whole eye, because of the continuously curved surface, only a few sections from the center of the embedded tissue are truly meridional.

D. The actual cause or causes of congenital glaucoma probably remain unknown.

1. Polymorphism in the cytochrome p450 1B1 (CYP1B1) gene is a predominant cause of primary congenital glaucoma.

2. The distribution of mutations in the CYP1B1 gene suggests that ethnic and geographic differences in primary congenital glaucoma may be associated with different CYP1B1 mutation patterns.

The site or sites of impaired outflow may vary from eye to eye. The major obstruction may lie near the entrance to the meshwork, in the meshwork, near the efferent vessels of the drainage angle, or any combination thereof. Congenital glaucoma, therefore, will probably be shown to have a number of causes. For example, a case of congenital glaucoma associated with the chromosomal defect of deletion of the short arm of the 10th chromosome (10p-) showed aberrant trabecular pillars¹ extending from the iris root toward Schwalbe’s line. Also, as mentioned previously, a form of autosomal-dominant juvenile glaucoma has been mapped to the long arm of chromosome 1 (1q21–q31).

III. Associated diseases and conditions

A. Iris anomalies (see Chapter 9)

1. Hypoplasia of the iris (“aniridia”) and iris coloboma may be associated with congenital glaucoma.

a. The PAX6 point mutation defect (1630A > T) on band p13 of chromosome 11 has been associated with some cases of aniridia. PAX6 mutations result in alterations in corneal cytokeratin expression, cell adhesion, and glycoconjugate expression. There is also corneal stem cell deficiency, which contributes to associated keratopathy.

1) Glaucoma may result from congenital abnormalities in the differentiation of the angle structures or from progressive angle-closure caused by the residual stump of iris.

b. Aniridia may be found in Brachmann–de Lange syndrome, which may also include conjunctivitis, blepharitis, microcornea, and corectopia.

B. Axenfeld’s anomaly and Rieger’s syndrome (see Chapter 8)

1. Anterior segment dysgenesis phenotypes are associated with mutations in genes expressed during neural crest development. Forkhead box D3 (FOXD3) variants increase the risk of anterior segment dysgenesis phenotypes in humans.

C. Peters’ anomaly (see Chapters 2 and 8). Peters’ anomaly and primary congenital glaucoma may share a common molecular pathophysiology. Both of these disorders can be associated with mutation in the cytochrome P4501B1 (CYP1B1) gene (discussed previously).

D. Phakomatoses

1. Sturge–Weber syndrome (see Chapter 2)

a. Phakomatosis pigmentovascularis (PPV) types II A and B are associated with melanosis bulbi and glaucoma. Ectodermal and mesodermal migration disorders have been postulated to be involved in the pathogenesis of this disorder. PPV II B is also associated with iris mamillations, Sturge–Weber syndrome, hemifacial, and hemicorporal, or limb hypertrophy without venous insufficiency.

2. Neurofibromatosis (see Chapter 2)

E. Lowe’s syndrome (see Chapter 10)

F. Pierre Robin syndrome—hypoplasia of the mandible, glossoptosis, cleft palate, and ocular anomalies such as glaucoma, high myopia, cataract, neural retinal detachment, and microphthalmos

G. Rubella (see Chapter 2)

H. Marfan’s syndrome (see Chapter 10)

I. Homocystinuria (see Chapter 10)

J. Microcornea (see Chapter 8)

K. Spherophakia (see Chapter 10)

1. Homozygous mutation in the LTBP2 gene is associated with some cases of microspherophakia. Young children with the findings of megalocornea, spherophakia, and/or lens dislocation may develop Marfanoid features as they age and may develop elevated IOP. This syndrome is marked by homozygous truncating mutations of LTBP2 gene.

L. Chromosomal abnormalities (e.g., trisomy 13; see Chapter 2)

M. Persistent hyperplastic primary vitreous (see Chapter 18)

N. Retinopathy of prematurity (see Chapter 18)

O. Retinoblastoma (see Chapter 18)

P. Juvenile xanthogranuloma (see Chapter 9)

Q. Hennekam syndrome, which includes lymphedema, lymphangiectasis, and developmental delay. Other associated findings are dental anomalies, hearing loss, and renal anomalies.

R. Nail–patella syndrome is characterized by dysplasia of the nails, patellar aplasia or hypoplasia, iliac horns, dysplasia of the elbows, and frequently glaucoma and progressive nephropathy. The underlying gene involved is LMX1B, which is a LIM-homeodomain transcription factor. The gene is located at 9q34.

S. Congenital glaucoma can accompany Marshall–Smith syndrome, which is characterized by orofacial dysmorphism, failure to thrive, and accelerated osseous maturation.

T. Subtelomeric deletion of chromosome 6p results in a syndrome characterized by ptosis, posterior embryotoxin, optic nerve abnormalities, mild glaucoma, Dandy–Walker malformation, hydrocephalus, atrial septal defect, patent ductus arteriosus, and mild mental retardation. This syndrome phenotypically overlaps Ritscher–Schinzel [or craniocerebellocardiac (3C) syndrome].

U. An autosomal-recessive syndrome phenotypically resembles Ivemark syndrome (hepatorenal–pancreatic syndrome) and is characterized by neonatal diabetes mellitus, congenital hypothyroidism, hepatic fibrosis, polycystic kidneys, and congenital glaucoma.

V. Neurofibromatosis type 1 should be excluded in newborns with unilateral congenital glaucoma.

W. Subepithelial amyloid deposits, in a recessive form of congenital hereditary endothelial dystrophy, can be associated with congenital glaucoma.

IV. Secondary histologic ocular effects in young eyes (<10 years of age)

A. Buphthalmos (“large eye”) is caused by an enlargement, stretching, and thinning of the coats of the eye, especially marked in the anterior segment, resulting in a deep anterior chamber (Fig. 16.5). Subluxated lenses may develop in these enlarged eyes.

Fig. 16.5 Congenital glaucoma. A, Child with congenital glaucoma and enlarged eyes (buphthalmos) shows bilateral aniridia. The markedly enlarged corneas are caused by glaucoma. B, Histologic section shows that most of the enlargement of the globe in buphthalmos takes place in the anterior segment. Note stretching and thinning of cornea and sclera, especially in the limbal region (limbal ectasia). C, Anterior stretching and thinning of cornea, limbal region, and anterior sclera are quite marked. D, Deep glaucomatous optic nerve head excavation present in buphthalmic eye removed from a seven-year-old girl who had congenital glaucoma and multiple surgical procedures. Note that secondary anterior iris synchia has caused the ectatic limbus to be lined by iris (limbal staphyloma). (A, Courtesy of Dr. HG Scheie.)

B. Ruptures of Descemet’s membrane (Haab’s striae) may be found in the enlarged corneas (Fig. 16.6), are usually horizontal in the central cornea but concentric toward the limbus, are located mainly in the lower half, and are often associated with corneal edema.

Ruptures of Descemet’s membrane secondary to birth trauma tend to be unilateral, most often in the left eye (most common fetal presentation is left occiput anterior), and usually run in a diagonal direction across the central cornea.

Fig. 16.6 Ruptures of Descemet’s membrane (Haab’s striae). A, Rupture extends from 10 o’clock toward 4 o’clock. B, Red fundus reflex of another case shows a horizontal Haab’s stria. C, Histologic section shows two breaks in Descemet’s membrane. The one on the right is shown with increased magnification in D. D, The ruptured end of Descemet’s membrane has healed over. Scroll-like extension of Descemet’s membrane, covered by endothelium, hangs into the anterior chamber. (A, Courtesy of Dr. HG Scheie; B, courtesy of Dr. DB Schaffer.)

C. The limbal region becomes stretched and thin, with a resultant limbal ectasia (see Fig. 16.5).

When the limbal ectasia is lined by uvea (e.g., with peripheral anterior synechiae), it is called a limbal staphyloma (see Fig. 16.5). When it extends posteriorly to involve the sclera over the ciliary body, it is called an intercalary staphyloma.

D. Fibrosis of the iris root and trabecular meshwork is a late manifestation, as is disappearance of Schlemm’s canal.

E. Continued high IOP may cause atrophy of the ciliary body, choroid, and retina; cupping of the optic disc (see Fig. 16.5); and atrophy of the optic nerve.

Cupping of the optic nerve head secondary to glaucoma develops more rapidly in infant eyes than in adult eyes. Unlike in the adult eye, however, cupping in the infant eye is often reversible when the IOP normalizes. Restoration of a normal cup is most rare with glaucomatous cupping in adults.

Primary Glaucoma (Closed- and Open-Angle)

I. The classification of the various forms of glaucoma depends on the clinical examination of the anterior chamber angle by gonioscopy. It is important that the clinician be able to correlate the clinical findings with their histologic counterparts.

II. Optical coherence tomography and ultrasound biomicroscopy can be utilized to evaluate the anatomic configuration of the anterior chamber angle and adjacent structures for the classification of the pathophysiology of the glaucomas.

A. Specific features with such imaging studies that may contribute to angle-closure include:

1. Increased iris convexity and thickness with accompanying anterior iris bowing and secondary crowding of the anterior chamber angle

2. Greater lens vault

3. Smaller anterior chamber width, area, and volume

4. Dynamic increase or lesser reduction in iris volume during dilation

5. Choroidal expansion accompanying angle-closure

Primary open- and closed-angle glaucoma occur more often in diabetic patients than in nondiabetic individuals.

III. Closed-angle (narrow-angle; angle-closure; acute congestive) glaucoma (Figs. 16.7 and 16.8)

A. In anatomically predisposed eyes, primary closed-angle glaucoma develops.

1. The surface of the peripheral iris is close to the inner surface of the trabecular meshwork, causing a narrow or shallow anterior chamber angle.

Plateau iris configuration is a much rarer cause of closed-angle glaucoma than is the typical narrow anterior chamber angle configuration in white populations. In the former condition, closed-angle glaucoma occurs, but direct examination with a slit lamp shows a normal-depth central anterior chamber and a flat iris plane except at the extreme periphery. A vertical section through the iris displays a “hockey stick” configuration to the iris contour. Gonioscopic examination, during the acute glaucomatous attack, shows a closed anterior chamber angle. Rarely, multiple ciliary body cysts can cause a plateau iris configuration to the anterior chamber angle.

2. Small, hypermetropic eyes are especially vulnerable to angle-closure.
A founder gene effect is probably related to two families of the Faroe Islands with hereditary high hyperopia, angle-closure glaucoma, uveal effusion, cataract, esotropia, and amblyopia.

Closed-angle glaucoma may be a prominent feature of the oculodentodigital dysplasia (ODDD) syndrome, associated with microcornea, and iris atrophy. It is a rare inherited disorder that impacts the development of the face, teeth, and limbs, including narrow nose, hypoplastic alae nasi, anteverted nostrils, syndactyly, and hypoplasia and yellowing of the dental enamel. Other less common findings are intracranial calcification and conductive deafness secondary to recurrent otitis media. This syndrome can be associated with a mutation (P59H) in the GJ1A gene. It can have an autosomal-recessive inheritance.

3. The lens is normal-sized or large.

If the lens becomes large enough (e.g., a swollen, intumescent lens), it may push the iris diaphragm anteriorly so that angle-closure can result even though the anterior chamber angle had been of normal or average depth.

4. Closed-angle glaucoma is usually a disorder affecting older individuals; however, it may be found even in individuals 40 years of age or younger. The most common causes (in decreasing order of frequency) in this young age group are plateau iris syndrome, iridociliary cysts, retinopathy of prematurity, uveitis, isolated nanophthamlos, relative pupillary block, and Weil–Marchesani syndrome.

B. The trabecular meshwork is normal before an initial attack of acute primary closed-angle glaucoma. After repeated attacks (often at subclinical levels), the still-open anterior chamber angle may become damaged (fibrotic) and, therefore, may simulate chronic simple (open-angle) glaucoma. Pigment accumulation within trabecular cells and loss of trabecular endothelial cells are also common findings following angle-closure.

C. A sudden rise in IOP results from the peripheral iris being in apposition to the filtering trabecular meshwork from the pupillary block mechanisms except in the plateau iris syndrome, which in its pure form does not involve pupillary block.
The association of typical acute closed-angle glaucoma with increasing age is due, in part, to progressive pupillary block from the increase in lens size as it adds layers of lens fibers over time.

Malignant glaucoma is a rare postoperative complication that follows ocular surgery to control glaucoma (or even after cataract surgery) in eyes that have shallow anterior chambers, often chronic angle-closure, and usually peripheral anterior synechiae. Miotics tend to aggravate the condition and, rarely, may precipitate malignant glaucoma even without previous surgery. The condition results from misdirection of aqueous into the posterior segment of the globe, thereby shifting the iris lens diaphragm anteriorly and resulting in angle-closure.

D. There may be specific gene loci involved in the pathogenesis of primary angle closure in various racial groups. For example, the CALCRL gene may be important for Australian whites. Other specific geographically distributed gene loci associated with primary angle-closure glaucoma have been reported.

E. The overall aging of the population is expected to result in a 9–19% increase in the prevalence of primary angle-closure glaucoma in the United States, Europe, and the United Kingdom within the next decade.

F. Histology

1. Segmental iris atrophy

a. Swelling of the iris root and occlusion of the greater arterial circle of the iris or its branches result in occlusion of the arterial supply to the iris stroma and subsequent necrosis.

b. Segmental iris atrophy is usually seen in the upper half of the iris in a sector configuration.

Segmental iris atrophy following closed-angle glaucoma resembles that of herpes zoster iritis. Iris atrophy can also be seen in pseudoexfoliation syndrome and after trauma. The atrophy may be extreme, resulting in a through-and-through iris hole, thereby curing the acute attack of glaucoma.

c. Histologically, there is marked atrophy of the iris stromal layer and, often, of iris pigment epithelium.

2. Irregular pupil results from necrosis of the dilator and sphincter muscles.

a. Histologically, segments of the dilator muscle or its entire length are absent.

b. The sphincter muscle shows varying degrees of atrophy.

3. Glaukomflecken (cataracta disseminata subcapsularis glaukomatosa; see Fig. 16.8)

a. Glaukomflecken probably results from interference with the normal metabolism of the anterior lens cells due to a stagnation of aqueous humor that contains toxic products of necrosis or from foci of pressure necrosis (see Chapter 10).

b. Anterior subcapsular, multiple, tiny gray-white lenticular opacities are seen.

c. Histologically, small areas of epithelial cell necrosis together with tiny adjacent areas of subcapsular cortical degeneration are found.

4. Optic disc edema

a. The nerve fibers in the optic nerve are more susceptible to an acute rise in IOP than are the retinal ganglion cells (RGC).

b. Irreversible vision impairment after an acute attack is mainly caused by optic nerve damage.

Optic disc edema occurs early, probably from temporary obstruction of the venous return at the nerve head caused by the abrupt increase in IOP. If the associated corneal edema is cleared with glycerol during an acute attack, the optic disc edema can be seen ophthalmoscopically in many cases.

c. Histology (see Fig. 13.7B)

5. Neovascularization of iris

a. Neovascularization of iris (clinical rubeosis iridis) is usually secondary to a central retinal vein or artery thrombosis caused by elevated IOP during the acute attack.

b. Histologically, fibrovascular tissue is found in the anterior chamber angle and on the anterior surface of the iris.

Familial amyloidotic polyneuropathy type I (Met 30) has presented with neovascular glaucoma.

G. Failure to reverse the initial attack of angle closure can result in chronic angle-closure glaucoma.

1. This entity can be confused clinically with chronic open-angle glaucoma unless careful gonioscopy is performed routinely on all suspected cases of glaucoma.
Chronic angle-closure glaucoma is associated with the necessity of continued treatment and subsequent procedures even in the presence of a patent iridotomy.

2. Histology
There is disorganization of the trabecular architecture, narrowing or loss of trabecular spaces, scarring of the trabecular beams, trabecular endothelial cell loss, deposition of banded fibrillar material, and melanin pigment deposition.

Fig. 16.7 Closed-angle glaucoma. A, Patient complained of pain, photophobia, and seeing halos around lights. Right eye shows a semidilated pupil and ciliary injection. B, Histologic section shows peripheral iris surface compressing trabecular meshwork. C, Histologic section of another case shows that eyes prone to acute attacks have a characteristic “crowded” anterior segment.

Fig. 16.8 Closed-angle glaucoma. A, After acute attack, glaukomflecken (i.e., tiny, white anterior subcapsular lens opacities) present. B, Histologic section shows that glaukomflecken are characterized by small areas of lens epithelial necrosis and tiny adjacent areas of subcapsular cortical degeneration. C, Another case demonstrates triad of irregular pupil, segmental iris atrophy (only brown iris from 5:30 to 9 o’clock relatively normal), and glaukomflecken. D, Histologic section of another case shows that loss of iris dilator muscle, absence of considerable amount of iris stroma in necrotic iris, and loss of pupillary iris pigment epithelium are responsible for clinically seen triad.

IV. Chronic open-angle (chronic simple) glaucoma (POAG) (Figs. 16.9 and 16.10)

A. The angle appears normal gonioscopically.

B. The site or sites of resistance to aqueous humor outflow lie within the structures of the drainage angle of the anterior chamber probably in the juxtacanalicular region.

C. The condition is most often bilateral.

1. Glaucoma may develop in one eye months to years before the fellow eye.

Patients who have POAG show a significantly higher prevalence of splinter hemorrhages on the optic nerve than do patients who do not have glaucoma. These splinter hemorrhages are associated with an increased incidence of field defects. Disc hemorrhages in glaucomatous or glaucoma suspect eyes are often associated with progressive changes of the optic nerves and of the visual fields.

2. One eye may be more severely affected than the other eye.

a. Open-angle glaucoma with dilated episcleral vessels may be seen unilaterally in orbital and lid hemangioma (Sturge–Weber syndrome) or bilaterally in carotid cavernous fistula, familial cases, or idiopathic cases.

b. Unilateral open-angle glaucoma may occur in association with lid thickening caused by neurofibromatosis.

D. Prevalence (see section Introduction)

E. Heredity and genetics

1. In most cases, the condition is probably inherited as an autosomal-recessive trait.

2. Myocilin
Myocilin was the first gene to be associated with glaucoma. Myocilin is the most frequently mutated gene in POAG patients worldwide. There are myocilin genotype–phenotype correlations, such as age of diagnosis, maximum IOP, and response to medical therapy. Mutations in the myocilin gene are present in 1–4% of POAG patients but not in patients with pseudoexfoliation. Myocilin gene is located on chromosome 1, localized to the olfactomedin domain, and was the first gene identified for POAG in the GLC1A locus. Its associated glaucoma is transmitted as an autosomal-dominant trait. There appears to be compromised stability of the protein, which categorizes the resulting disorder as a disease of protein misfolding. There is strong evidence that myocilin polymorphisms are related to POAG susceptibility with significant racial variation such that for whites Q368x is most important, whereas T353I is not important for Asians. The Gln48His mutation is unique to Indian patients. There is a low prevalence of myocilin mutations in African-Americans with POAG.

a. The GLC1A Thr377Met mutation in the myocilin gene has been associated with glaucoma that has a younger age of onset and higher peak IOP than in pedigrees with the more common Gln368STOP mutation. In addition, individuals with the Thr377Met mutation are more likely to undergo filtration surgery.

b. It is probable that accumulation of mutant myocilin in the rough endoplasmic reticulum in glaucoma stresses the endoplasmic reticulum and may produce cytotoxicity in the human trabecular meshwork cells. Most known myocilin mutations localize to the C-terminus, an olfactomedin-like domain.

A more appropriate name for POAG might be glaucomatous optic neuropathy because the primary defect is probably in the optic nerve.

F. Normal-tension (improperly called low-tension) glaucoma is a subdivision of POAG (see section Introduction in this chapter).

G. Histology and pathophysiology

1. Optic nerve (see later in this chapter)

2. Little is known about the early histologic changes that take place in the region of the drainage angle because the number of human eyes that have well-characterized early open-angle glaucoma available for histologic examination is small (see Fig. 16.9).

3. Very little meaningful information can be derived from long-standing, “end-stage” diseased eyes or from tiny biopsies taken during surgery for control of glaucoma.

Many reported histologic changes, such as “sclerosis” of the trabecular meshwork, compression or absence of Schlemm’s canal, or decrease in number of macrovacuoles in the endothelial lining of Schlemm’s canal, are probably end-stage changes, artifacts, or misinterpretations.

4. Aging changes in the drainage angle of the anterior chamber

a. Chronic open-angle glaucoma (COAG) is usually associated with a progressive decrease in the facility of outflow of aqueous humor from the anterior chamber.

b. The resulting IOP becomes incompatible with the continued health of the tissues of the optic nerve head.

c. Decreased facility of outflow results from an obstruction produced by excessive aging changes in the drainage angle.

d. The degree of obstruction is a quantitative problem; two extremes of excessive obstruction are:

1) Proliferation of the endothelium (and possibly of juxtacanalicular connective tissue cells) lining Schlemm’s canal into its lumen for much of its circumference

2) Compaction of the uveal meshwork against the scleral roll, producing a prominent scleral spur (“hyalinization” of adjacent ciliary muscle and atrophy of the iris root also occur)

e. The two major aging changes—each may be seen in almost pure form, or they may be combined.

1) They may also be associated with proliferations of trabecular endothelial cells in the meshwork.

2) COAG depends on the amount of aqueous inflow and the degree of obstruction to outflow caused by the aging changes (see Fig. 16.10).

f. Other changes in the trabecular meshwork in POAG include loss of cells, increased accumulation of extracellular matrix, changes in cytoskeleton, cellular senescence, and the process of subclinical inflammation.

Oxidative stress is likely to be one important mechanism in the pathogenesis of POAG.

g. Molecular analysis of human trabecular meshwork in glaucoma demonstrates oxidative DNA damage in glaucoma.

The aging changes listed here as occurring in the tissues of the drainage angle are mostly irreversible. Their obstructive nature may be circumvented for short or long periods with a variety of pharmacologic agents. Thus, whether glaucoma develops is a quantitative problem based on whether aging changes of decreased outflow exceed aging changes of decreased inflow.

5. Ischemia involving the aqueous outflow pathway has been postulated to contribute to the development of POAG.

Fig. 16.9 Open-angle glaucoma. A, The normal anterior chamber angle shows a loose arrangement of trabecular meshwork in both the corneoscleral and uveal components (ctm, corneoscleral trabecular meshwork; utm, uveal trabecular meshwork). The juxtacanalicular connective tissue (j) of the trabecular meshwork is adjacent to Schlemm’s canal (sc) (sr, scleral roll). B, An eye removed from a patient who had chronic open-angle glaucoma shows the results of the aging process. The normally loose tissue in the uveal trabecular meshwork and angle recess has compacted (c, compressed trabecular meshwork), producing a prominent scleral roll/spur (sr) (sc, Schlemm’s canal). C, A coronal section taken through normal trabecular meshwork shows that the loose beams of the meshwork form large tubes running in an anterior–posterior direction. D, Coronal sections through the trabecular meshwork in a patient who had chronic open-angle glaucoma show that the aging process has caused marked compaction of the trabecular meshwork beams, resulting in occlusion of most of the tubes. (A, Rhesus monkey; A–D, PD stain; case reported in Fine BS, Yanoff M, Stone RA: A clinicopathologic study of four cases of primary open-angle glaucoma compared to normal eyes. Am J Ophthalmol 91:88. © Elsevier 1981.)

Fig. 16.10 A, Diagram shows theoretical situation of aqueous inflow and outflow in normal (left) and in aging (right) persons. B, If outflow facility decreases faster than does aqueous inflow, glaucoma results (left). The opposite situation results in hypotony (right).

Secondary Closed-Angle Glaucoma

Causes

I. Chronic primary angle-closure glaucoma

A. Repeated attacks of primary closed-angle glaucoma may give rise either to peripheral anterior synechiae and secondary closed-angle glaucoma or to trabecular damage and secondary COAG.

In black patients, the acute attacks may be subclinical while the closure of the angle progresses relentlessly.

B. Histologically, peripheral anterior synechiae are seen, sometimes broad based.

C. Chronic trabecular iris contact or peripheral anterior synechias may block aqueous outflow and may result in progressive endothelial cell damage and Schlemm’s canal occlusion. Trabecular cell damage may be secondary to impairment of mitochondrial function and subsequent fusion of trabecular beams.

II. Phacomorphic

A. Swelling of the lens may cause peripheral anterior synechiae (through pupillary block and iris bombé).

B. More frequently, a maturing cataractous lens swells rapidly and simulates primary closed-angle glaucoma.

III. Subluxated or anteriorly dislocated lens can cause a pupillary block that, if not relieved, leads to iris bombé, peripheral anterior synechiae, and secondary angle-closure.

IV. Persistent flat chamber after surgical or nonsurgical trauma may lead to broad-based peripheral anterior synechiae, occasionally causing total anterior synechiae.

V. Iridocorneal endothelial (ICE) syndrome

A. The ICE syndrome consists of a spectrum of changes that include the iris nevus (Cogan–Reese) syndrome, Chandler’s syndrome, and essential iris atrophy.

Antibody titers to the Epstein–Barr virus are increased in patients who have the ICE syndrome; the significance of this increase remains to be clarified.

1. All three entities share a basic corneal endothelial defect and iris involvement.

a. Specular microscopy shows abnormal cells, called ICE cells, that are larger and more pleomorphic than normal endothelial cells and whose specular reflex shows light–dark reversal (i.e., the cell surface is dark instead of light, often with a central light spot, and the intercellular junctions are light instead of dark).

Electron microscopically, ICE cells show epithelial features (e.g., tonofilaments, desmosomes, multilayering, microvilli, and conspicuous “blebs”). Also, immunohistochemical stains of the corneal endothelium are positive for AE1 and AE3 (epidermal keratins) and vimentin, which, again, suggests an “epithelialization” of the endothelium and may explain, at least in part, the aggressive proliferative nature of the corneal endothelium in the ICE syndrome.

b. The abnormal endothelial cells may coexist with normal endothelial cells, a condition called subtotal ICE, when 25–75% of the total cells are ICE cells.

c. On specular microscopy, the clinically uninvolved contralateral eye often demonstrates subclinical corneal abnormalities such as a relatively low percentage of hexagonal cells and a relatively high coefficient of variation of cell area.

2. All ICE syndrome entities tend to be unilateral, occur in young women, and cause corneal edema when the IOP is only slightly elevated or even normal.

3. Glaucoma occurs in approximately 50% of cases.

4. Although in their pure forms the three entities are distinct clinicopathologic types, findings overlap so much in many cases that they are considered variants of the same process.

5. Each variant is described separately, but all are considered to belong to the ICE syndrome.

Posterior polymorphous dystrophy (PPMD; see Chapter 8) shares some characteristics with the ICE syndrome (Table 16.1), such as endothelial degeneration, corneal edema, iridocorneal adhesions, endothelialization of the anterior chamber angle, and glaucoma. Differences between the entities include the structure of the corneal endothelium (epithelial-like in PPMD), hereditary transmission (positive in PPMD), laterality (bilateral in PPMD), and progression (relatively stable in PPMD).

TABLE 16.1

Comparison of Posterior Polymorphous Dystrophy and Iridocorneal Endothelial Syndrome

	Posterior Polymorphous Dystrophy	Iridocorneal Endothelial Syndrome
Cornea
Edema	Common	Common
Endothelial surface	Vesicles, ridges, plaques, guttata	Fine guttata-like lesions common
Iridocorneal Adhesions	25%	100%
Iris
Stromal atrophy	Minimal or none	Marked (essential iris atrophy), moderate (iris nevus syndrome), or mild (Chandler’s syndrome)
Ectropion uveae	Occasional	Occasional to common
Glaucoma	13%	∼80%
Hereditary Transmission	Present (autosomal-dominant)	None
Laterality	Bilateral	Unilateral
Sex Distribution	Equal	Women > men
Onset of Symptoms	Any age, including congenital	Third and fourth decades
Progression	Corneal changes often progress to edema and degeneration; iridocorneal adhesions may progress very slowly	Fairly rapid formation of synechiae and severe glaucoma
Histopathology
Cornea	Thickened, multilayered Descemet’s membrane; endothelial cells resemble epithelial cells (microvilli, desmosomes, cytoplasmic tonofilaments)	Thickened, multilayered Descemet’s membrane; endothelial cells attenuated, reduced in number, and missing in areas
Chamber angle	Corneal endothelium and Descemet’s membrane over trabecular meshwork and iris	Corneal endothelium and Descemet’s membrane over trabecular meshwork and iris

(Modified from Rodrigues MM, Phelps CD, Krachmer JH et al.: Glaucoma due to endothelialization of the anterior chamber angle: A comparison of posterior polymorphous dystrophy of the cornea and Chandler’s syndrome. Arch Ophthalmol 98:688, 1980. © American Medical Association. All rights reserved.)

B. Iris nevus syndrome (Figs. 16.11 and 16.12)

1. The iris nevus syndrome mainly occurs in young women, and it is characterized by several of the following signs: peripheral anterior synechiae, often associated with atrophic defects in adjacent iris stroma; matted appearance of iris stroma; a velvety, whorl-like iris surface; loss of iris crypts; fine iris nodules; pupillary eversion (ectropion uveae); heterochromia; secondary glaucoma; and corneal edema at only slightly elevated, or even normal, IOP.

2. Histologically, the two main features are (1) a diffuse or nodular, or both, nevus of the anterior surface of the iris and (2) corneal endothelialization of the anterior chamber angle and anterior surface of the iris.

Fig. 16.11 Iridocorneal endothelial (ICE) syndrome (iris nevus syndrome variant). A, Patient had unilateral corneal edema and heterochromia iridum. Normal iris pattern on right side and effaced pattern on left caused by overgrowth of corneal endothelium Descemet’s (“glass”) membrane on left side (m, membrane over nasal iris; e, edge of membrane). B, Close-up view shows start of glass membrane inferiorly (b, corneal blebs; m, membrane; i, inferior temporal membrane edge). C, Periodic acid–Schiff (PAS)-stained histologic section of another eye shows a diffuse nevus on the anterior surface of the iris. Endothelium has partially grown over trabecular meshwork and laid down a new basement (Descemet’s) membrane. D, Another PAS-stained section of the same case shows a diffuse iris nevus and a peripheral anterior synechia. Endothelium has migrated posteriorly over trabecular meshwork and has laid down new Descemet’s membrane. (C and D, From Yanoff M: Glaucoma mechanisms in ocular malignant melanomas. Am J Ophthalmol 70:898. © Elsevier 1970.)

Fig. 16.12 Iridocorneal endothelial (ICE) syndrome (iris nevus syndrome variant). A, Small iris nevus at half past 10 o’clock in the right eye causes distortion of pupil, effacing of iris pattern around nevus, and ectropion uveae. A sector iridectomy was performed. B, Biopsy shows deep stromal pigmentation. Bleached sections demonstrated nevus cells. C, Another section of the same case shows a fragment of peripheral Descemet’s membrane (on the right) adherent to the iris by means of a bridge. Endothelial cells have migrated and proliferated, cover both sides of the synechia, and have grown onto the anterior surface of the iris up to the pupil on the left, causing an ectropion uveae. Note normal stromal architecture and absence of inflammation or degeneration. (From Jakobiec FA, Yanoff M, Mottow L et al.: Solitary iris nevus with peripheral anterior synechias and iris endothelialization: A variant of the iris nevus syndrome. Am J Ophthalmol 83:884. © Elsevier 1977.)

C. Chandler’s syndrome (Fig. 16.13)

1. The condition, probably the most common variant of the ICE syndrome, is unilateral and occurs mainly in young women. The glaucoma is usually mild.

2. Endothelial dystrophy causes corneal edema to develop at a slightly elevated or normal IOP.

Patients with Chandler’s syndrome tend to have worse corneal edema and less glaucoma than patients with the other two variants.

3. Small peripheral anterior synechiae and mild pupillary distortion are found.

4. Small areas of iris stromal thinning may be found, but through-and-through holes are rare.

5. Histology

a. The iris stroma is atrophic.

b. In the areas of iris hole formation, the stroma and pigment epithelium are absent.

Fig. 16.13 Iridocorneal endothelial (ICE) syndrome (Chandler’s syndrome variant). A, Left eye shows focal, peripheral, angle-closure superonasally. B, Irregular layer of filamentous Descemet’s membrane (asterisk) between attenuated corneal endothelium (e) and trabecular meshwork ™. Inset, thin (1.5 µm) section shows peripheral extension of Descemet’s membrane (arrows) lining indentations of uveal meshwork. (From Rodrigues MM, Streeten BW, Spaeth GL: Chandler’s syndrome as a variant of essential iris atrophy: A clinicopathologic study. Arch Ophthalmol 96:643, 1978, with permission. © American Medical Association. All rights reserved.)

D. Endothelialization of the anterior chamber angle, often extending over the anterior surface of the iris, and formation of new Descemet’s membrane are characteristic components.

Iris nodules may appear late in the course of the disease. At first, they appear small and yellow, but then they increase in number and become dark brown.

E. Essential iris atrophy (Fig. 16.14)

1. Essential iris atrophy is usually unilateral, is found most often in women, and is of unknown cause.

2. The onset is usually in the third decade.

3. Corneal edema often develops when IOP is slightly elevated or even normal.
The corneal endothelium shows a fine, hammered-silver appearance, similar to cornea guttata but less coarse.

4. The initial event is the formation of a peripheral anterior synechia distorting the pupil to that side.

a. The pupil becomes more distorted, sometimes with the development of an ectropion uveae.

b. Through-and-through holes develop in the iris, usually opposite to the distorted pupil.

The holes seem to be caused by mechanical traction, related to sector corneal endothelial iris overgrowth.

5. Peripheral anterior synechiae increase circumferentially, and an intractable glaucoma develops.
Corneal endothelial overgrowth is a feature common to all three variants included in the ICE syndrome.

Fig. 16.14 Iridocorneal endothelial (ICE) syndrome (essential iris atrophy variant). A, Slit-lamp and (B) red-reflex views of the same eye show migration of the iris nasally toward the initial synechia and stretching of the iris temporally, causing holes clear through the iris. C, Histologic section of another eye with essential iris atrophy shows a peripheral anterior synechia (p), various degrees of degeneration and loss of the central iris stroma, and total loss of the central iris pigment epithelium (ip) (c, cornea; ir, iris root; cb, ciliary body; l, lens). D, In an area away from the peripheral anterior synechia, the anterior chamber angle is open but the trabecular meshwork is covered by proliferated corneal endothelium and Descemet’s membrane. (A and B, Courtesy of Dr. HG Scheie; C and D, reported in Scheie HG, Yanoff M, Kellogg WT: Essential iris atrophy: Report of a case. Arch Ophthalmol 94:1315, 1976. © American Medical Association. All rights reserved.)

VI. Iridoschisis (Fig. 16.15)

A. The condition starts mainly in the seventh decade of life and is usually bilateral; the sexes are equally affected.

B. The pupil is not displaced and remains reactive.

C. The anterior iris stromal layers separate widely from the deeper layers, resembling spaghetti.

1. The lower half of the iris is most frequently involved.

2. Initially, the loosened stromal fibers remain attached centrally and peripherally so that the delicate middle part of the fibers bows forward into the anterior chamber. Ultimately, the fibers break, and the free ends float in the aqueous.

D. Glaucoma develops in approximately 50% of affected eyes; it begins as peripheral anterior synechiae develop.

E. The cause seems to be a peculiar type of aging change. It may follow trauma. Rarely, it may occur with POAG.

Fig. 16.15 Iridoschisis. A, The iris is in disarray, with long rolled strips from the 3 o’clock to the 6 o’clock position. B, The gross specimen from another eye shows separation and breakage of the collagenous columns of the iris stroma. C, Histologic section of the eye shown in B demonstrates epithelial blebs (bullous corneal edema) and separation of the iris stroma into elongated lamellae. (A, Courtesy of Prof. GOH Naumann.)

VII. Anterior uveitis (see Figs. 3.11 and 3.12)—anterior uveitis from any cause [e.g., trauma, infection, “allergy,” sympathetic uveitis (phacoanaphylactic endophthalmitis)] may result in posterior synechiae, iris bombé, and, finally, peripheral anterior synechiae.

VIII. Retinopathy of prematurity

A. The retrolental mass of neovascular tissue pushes the lens forward and causes “crowding” of the anterior chamber angle.

B. Closed-angle glaucoma may result, sometimes years after the initial damage.

IX. Spherophakia (Weill–Marchesani syndrome; see Chapter 10)

X. Persistent hyperplastic primary vitreous (see Chapter 18)

A. Repeated hemorrhages result in organization and iridocorneal synechiae.

B. Less often, swelling of the lens or iris bombé can produce a closed angle.

XI. Epithelialization of anterior chamber angle (see Chapter 5)

XII. Endothelialization of anterior chamber angle (see Fig. 5.34)

A. Endothelialization of the anterior chamber angle (or pseudoangle in the presence of peripheral anterior synechiae) is seen histologically in 20% of enucleated eyes.

B. Most of the eyes with endothelialization have peripheral anterior synechiae; slightly less than half of the eyes are associated with neovascularization of iris.

C. Histologically, the endothelial cells possess junctional complexes, apical villi, prominent basement membranes, and myoblastic differentiation.

XIII. Neovascularization of anterior surface of the iris (clinically termed rubeosis iridis; see Figs. 9.13, 9.14, and 15.5)

The many causes include diabetes mellitus, central retinal vein or artery occlusion, branch retinal artery occlusion, diffuse retinal vascular disease, carotid artery ischemia, retinoblastoma, malignant melanoma of uvea (Table 16.2), long-standing retinal detachment, any chronic retinal disease, penetrating or contusive ocular injuries, metastatic tumors to the retina and vitreous including cutaneous melanoma, and Fuchs’ heterochromic iridocyclitis (see Chapter 3).

TABLE 16.2

Histopathologic Mechanisms Producing Secondary Glaucoma in Eyes Containing Uveal Malignant Melanomas

Mechanism	Underlying Cause
Peripheral anterior synechiae and angle-closure	1. Posterior synechiae, iris bombé, and peripheral anterior synechiae 2. Iris neovascularization and peripheral anterior synechiae 3. Diffuse iris nevus or melanoma and peripheral anterior synechiae
Cellular obstruction of aqueous drainage area of an open angle	1. Seeding of neoplasm into anterior chamber angle 2. Ring melanoma with invasion of anterior chamber angle structures 3. Melanin phagocytosis by macrophages with obstruction of anterior chamber angle (melanomalytic glaucoma)

Mechanism

Underlying Cause

Peripheral anterior synechiae and angle-closure

1. Posterior synechiae, iris bombé, and peripheral anterior synechiae

2. Iris neovascularization and peripheral anterior synechiae

3. Diffuse iris nevus or melanoma and peripheral anterior synechiae

Cellular obstruction of aqueous drainage area of an open angle

1. Seeding of neoplasm into anterior chamber angle

2. Ring melanoma with invasion of anterior chamber angle structures

3. Melanin phagocytosis by macrophages with obstruction of anterior chamber angle (melanomalytic glaucoma)

(Modified from Yanoff M: Glaucoma mechanisms in ocular malignant melanomas. Am J Ophthalmol 70:898. © Elsevier 1970.)

XIV. Cysts of iris and anterior ciliary body (see Figs. 9.9 and 9.10)

A. Multiple cysts of the iris and ciliary epithelium can cause both secondary acute and chronic closed-angle glaucoma.

1. Congenital cysts of the iris are extremely rare but may cause secondary glaucoma when they enlarge, and they can even be confused with iris melanoma.

2. Primary angle-closure glaucoma is uncommon in younger individuals such as teenagers. Therefore, such individuals who present with angle-closure should be evaluated to exclude secondary causes of angle-closure such as ciliary body cysts.

The cysts may be idiopathic or may be associated with late syphilitic interstitial keratitis. Another cause of glaucoma in late syphilitic interstitial keratitis is secondary chronic angle-closure due to peripheral anterior synechiae.

B. Histologically, a proliferation of the posterior layer of the iris pigment epithelium or of the inner layer of ciliary epithelium lines the cyst (see Chapter 9).

XV. Juvenile xanthogranuloma (see Chapter 9)

XVI. Secondary to uveal malignant melanoma (Figs. 16.16–16.18)

A. Posterior synechiae and iris bombé (see Fig. 16.16)
A large posterior malignant melanoma and a total neural retinal detachment may combine to displace the iris lens diaphragm anteriorly, resulting in posterior synechiae and iris bombé followed by secondary peripheral anterior synechiae. Similar changes may occur with a large posterior metastatic neoplasm.

B. Neovascularization of iris (see Fig. 16.17)
Neovascularization of the iris may occur with a large posterior choroidal malignant melanoma and cause peripheral anterior synechias. Similar changes may occur with a large posterior metastatic lesion.

C. Diffuse iris malignant melanoma (see Fig. 16.18)
A diffuse iris malignant melanoma, or even a diffuse iris nevus, may induce peripheral anterior synechiae, although diffuse melanomas do not usually present with such changes. The condition may simulate the ICE syndrome.

Rarely, an aggressive iris nevus can involve the angle, cause synechiae, and result in secondary angle-closure glaucoma.

Fig. 16.16 Closed-angle glaucoma secondary to uveal melanoma. A, Patient presented with signs and symptoms of acute closed-angle glaucoma in right eye. Left eye had shallow anterior chamber and narrow angle. Ultrasonography showed solid tumor in choroid. B, Enucleated right eye shows large posterior melanoma and neural retinal detachment. C, Histologic section shows a closed angle secondary to iris bombé and secondary peripheral anterior synechia. Melanoma should be suspected in any glaucomatous eye that contains neural retinal detachment.

Fig. 16.17 Closed-angle glaucoma secondary to uveal melanoma. A, Histologic section shows large, mushroom-shaped melanoma and complete neural retinal detachment. B, Iris neovascularization and secondary peripheral anterior synechia have closed the angle. (From Yanoff M: Glaucoma mechanisms in ocular malignant melanomas. Am J Ophthalmol 70:898. © Elsevier 1970.)

Fig. 16.18 Closed-angle glaucoma secondary to uveal melanoma. A, Diffuse iris malignant melanoma has involved the angle for 360°, resulting in secondary angle-closure. Infiltration by melanoma also can produce a form of secondary open-angle glaucoma (see Figs. 16.23 and 16.24). B, Most iris melanomas show a rather bland cytology and can be considered as spindle nevi.

XVII. Immune recovery resulting from highly active antiretroviral therapy (HAART) has been associated with severe vitritis resulting in acute angle-closure secondary to posterior synechias in a patient with inactive AIDS and inactive cytomegalovirus retinitis.

XVIII. Dense vitreous hemorrhage can result in angle-closure, presumably from anterior displacement of the iris lens diaphragm.

XIX. Snake bite is an unusual cause of bilateral angle-closure glaucoma.

XX. Autosomal vitreoretinochoroidopathy can be associated with angle-closure secondary to microcornea and shallow anterior chamber without microphthalmia.

Secondary Open-Angle Glaucoma

I. Secondary to cells or debris in angle

A. Hyphema (see Chapter 5)

B. Uveitis

1. Cyclitis (or iridocyclitis) may lead to excessive cellular production that obstructs the open angle.

Anterior uveitis usually causes a decrease in aqueous inflow so that glaucoma rarely ensues. Glaucoma is also less likely if the cyclitis is segmental rather than circumferential. Glaucoma is most unlikely with a posterior cyclitis or pars planitis. Intractable glaucoma may complicate herpes simplex ocular infection even in the absence of obvious keratitis. Such infection can be confirmed by polymerase chain reaction analysis of aqueous humor.

In various types of uveitic glaucoma, including Fuchs’ heterochromic iridocyclitis, herpes simplex-associated uveitis, and juvenile idiopathic arthritis-associated uveitis, common features include increased extracellular material in the subendothelial region of Schlemm’s canal with some signs of lytic activity in the trabecular meshwork.

2. Glaucomatocyclitic crisis (Posner–Schlossman syndrome)

a. The condition mainly occurs as a unilateral acute rise in IOP in people in their third through fifth decades; it may recur. The disease is self-limited and subsides in 1–3 weeks.

Although the cause is unknown, an abnormal instability of the ciliary vascular system may be related to the development of the acute glaucoma. Indirect evidence suggests that the herpes simplex virus may play a role in the origin of Posner–Schlossman syndrome. Glaucomatocyclitic crisis appears to have a predilection for patients who have POAG or in whom it will develop.

b. Epithelial edema and one or more keratic precipitates (tiny and fine at first but may become mutton-fat) are seen clinically.

c. Little or no reaction occurs in the aqueous humor, and the angle usually appears normal.

d. The histology is unknown.

3. In oculodermal melanocytosis, in the involved eye, glaucoma may result from a low-grade chronic anterior uveitis of unknown cause.

C. Phacolytic glaucoma (see Chapter 10)

D. Nondenatured lens material-induced glaucoma usually follows a very recent traumatic rupture of the lens.

1. If glaucoma develops after needling of a soft cataract, it occurs within the first week.

2. After penetrating ocular injury

3. The glaucoma is caused by occlusion of the open anterior chamber angle by the swollen lens material, and it is not related to phagocytic action.

The ruptured lens may not release its material but may swell and result in pupillary block and a secondary acute or chronic closed-angle glaucoma.

E. Hemolytic (ghost cell) glaucoma (Figs. 16.19 and 16.20)

1. Hemolytic glaucoma presents as an acute open-angle glaucoma.

2. The glaucoma results as a complication of long-standing vitreous or, rarely, anterior chamber hemorrhage from any cause.

Glaucoma may be caused by macrophages and red blood cell (RBC) debris, especially hemoglobin aggregates, or by hemolyzed RBCs (ghost cells). Both RBC debris and ghost cells result from hemolysis; therefore, hemolytic glaucoma is a more accurate term than ghost cell glaucoma. Neither fresh RBCs nor ghost cells seem able to pass from the vitreous compartment through an intact anterior hyaloid face into the aqueous compartment; a rent or passageway is necessary.

3. Histologically, the anterior chamber angle is obstructed by debris, hemoglobin, ghost cells, and macrophages filled mainly with hemoglobin but also containing some hemosiderin.

Fig. 16.19 Hemolytic (ghost cell) glaucoma. A, Macroscopic appearance of fresh blood in subvitreal area (dark red) and old blood in vitreous (yellow-red). B, Histologic section shows intact erythrocytes (toward lower left). Hemolysis of the erythrocytes releases the hemoglobin particles and leaves empty shells (“ghost cells”) behind (toward right).

Fig. 16.20 Hemolytic (ghost cell) glaucoma. A, Histologic section shows fragmented erythrocytes, hemoglobin particles, debris, and ghost cells (all the result of hemolysis, hence the name hemolytic glaucoma) lying free or within macrophages (shown with increased magnification in B) in anterior chamber angle. C, Scanning electron micrograph shows macrophage “balls” in anterior chamber and between ciliary processes. D, Each ball is a macrophage filled with hemolyzed erythrocytes (ghost cells). E, Heinz bodies (precipitation of hemoglobin) can be seen in the erythrocytes. (Courtesy of Dr. RC Eagle, Jr.)

F. Pigment dispersion syndrome (pigmentary glaucoma; Figs. 16.21 and 16.22)

1. The pigment dispersion syndrome is found most often in young, myopic, adult, white men.

Pigment dispersion may result from iris chafing on foreign material such as an intraocular lens. More commonly, posterior bowing of the iris causes rubbing of the posterior iris against the patient’s own lens structures.

The insertion of the iris into the ciliary body is more posterior in pigment dispersion syndrome than in control eyes. A low prevalence of pigment dispersion syndrome and pigmentary glaucoma occurs in blacks, Latinos, and Asians. In black patients, pigmentary glaucoma tends to develop in an older age group (average, 73 years), mainly in hyperopes and women, shows no iris transillumination, and occurs in irises that have a relatively flat connection to the anterior face of the ciliary body.

2. Depigmentation of the iris epithelium, especially peripherally, results in circumferential foci of increased iris transillumination where the peripheral third of the iris meets the middle third.

The eye on the side of greatest increased iris transillumination may contain a larger pupil than the other eye (anisocoria). By slit-lamp biomicroscopy, a band of increased granular iris pigmentation can be seen overlying the ring of increased retroillumination. The band is presumably caused by the many pigment-filled macrophages in this region of stroma. In predisposed eyes, because of a basic abnormality of the iris pigment epithelium, an important factor in the loss of posterior iris pigment may be the rubbing between anterior packets of zonules and peripheral iris.

3. Iridodonesis may be present.

4. Krukenberg’s spindle consists of a vertical band of melanin pigment phagocytosed by the central and inferior corneal endothelium, most often bilateral.

Pigment may be released into the aqueous compartment after pupillary dilatation or after physical exercise. When a Krukenberg’s spindle is present unilaterally, ocular trauma may be the cause.

5. The pigment is deposited on the iris surface, lens, zonules, and in the trabecular meshwork.

The disease seems to ameliorate with increasing age in some patients. In these patients, the corneal and trabecular meshwork pigmentation decreases. The picture resembles that of pseudoexfoliation of the lens. Rarely, the pigment dispersion syndrome can coexist with the pseudoexfoliation syndrome.

6. Incidence of neural retinal detachments and of retinal lattice degeneration is increased in patients who have pigment dispersion syndrome.

Glaucoma seems to be present in approximately 10% of cases. Perhaps the relationship of the iris pigment epithelial defect to the glaucoma is a matter of two independent gene loci that are very close together on the same chromosome and tend to be inherited together, but not necessarily so. Furthermore, patients with pigment dispersion syndrome and glaucoma are the same age (~49 years) as patients with the syndrome but without glaucoma. If glaucoma resulted from the dispersion of pigment, patients with glaucoma should have a higher average age than patients without glaucoma. The number of aqueous melanin granules (measured with the laser-flare cell meter) correlates with increased IOP.

7. Compared with normal eyes, pigment dispersion syndrome eyes have a larger iris, a midperipheral posterior iris concavity that increases with accommodation, a more posterior iris insertion, increased iridolenticular contact that is reversed by inhibition of blinking, and possibly an inherent weakness of iris pigment epithelium.

The most likely cause of the aforementioned constellation of findings is a gene affecting some aspect of the development of the middle third of the eye.

8. Histologically, the posterior layer of iris pigment epithelium, mainly at the junction of middle and peripheral thirds of the iris, atrophies in foci that correspond to the clinically observed peripheral foci of increased iris transillumination.

a. The dilator muscle may be dysplastic, present in excessive amounts, atrophic, or absent.

b. The adjacent iris stroma contains pigment-filled macrophages.

c. Neuroepithelial melanin granules are widely distributed in the endothelium of both the posterior cornea (Krukenberg’s spindle) and the trabecular meshwork.

9. Familial occurrence of pigment dispersion syndrome has been reported.

Fig. 16.21 Pigment dispersion syndrome. A, A Krukenberg’s spindle (k) is seen as a vertical linear deposition of melanin pigment in the central inferior cornea. B, Granules of melanin pigment are present in corneal endothelial cells (s, stroma; d, Descemet’s membrane; e, endothelium containing pigment). C, The anterior chamber angle (a) is deeply pigmented. D, Melanin pigment (p) is present in the endothelial cells lining the beams of the trabecular meshwork (t) (s, stroma; sc, Schlemm’s canal).

Fig. 16.22 Pigment dispersion syndrome. A, Extensive increased iris transillumination is present, predominantly in the middle third of the iris, best seen toward the left of the figure. B, The area of increased transillumination corresponds to the area of loss of pigment epithelium from the back of the iris. C, The gross specimen confirms this, as does D, a scanning electron microscopic view of the posterior surface of the iris (d, defects of pigment epithelium in iris; c, ciliary processes; a, area devoid of pigment epithelium; p, posterior surface of iris).

G. Pseudoexfoliation syndrome (see Chapter 10)

1. LOXL1 (lysyl oxidase-like 1) promoter haplotype is associated with pseudoexfoliation syndrome and pseudoexfoliation glaucoma in the U.S. white population, which is similar to most non-African populations.

Single nucleotide polymorphisms in exon 1 of the LOXL1 gene have been identified as strong genetic risk factors for both pseudoexfoliation syndrome and pseudoexfoliation glaucoma.

2. Polymorphisms in elastin are not associated with pseudoexfoliation syndrome and glaucoma.

H. Secondary to uveal malignant melanomas (Figs. 16.23–16.25; see Table 16.2)

1. Seeded malignant melanoma cells (see Fig. 16.23) may block the anterior chamber angle.

Similar seeding can occur with metastatic neoplastic cells or juvenile xanthogranuloma cells. Rarely, an aggressive nevus can infiltrate an open angle, resulting in secondary open-angle glaucoma.

2. A ring malignant melanoma (see Fig. 16.24) may directly invade the anterior chamber angle structures and block the open angle. Therefore, glaucoma may be the presenting finding.

A ring melanoma arises from the root of the iris and anterior ciliary body for 360° and should not be confused with a segmental iris or ciliary body melanoma that may seed the anterior chamber angle for 360°.

3. Melanomalytic glaucoma (see Fig. 16.25)

a. Necrosis (partial or complete) of a malignant melanoma (or a melanocytoma), usually of the ciliary body, causes the liberation of melanin pigment.

A similar process, called melanocytomalytic glaucoma, has been reported with necrotic iris melanocytomas.

b. The liberated melanin induces phagocytosis by macrophages.

c. The melanin-laden macrophages then obstruct the open angle of the anterior chamber.

4. Epithelialization or endothelialization of anterior chamber angle (see Chapter 5)

5. Diffuse iris melanoma presents with glaucoma in 56% of cases, and 32% of cases have had laser or incisional glaucoma surgery at the time of presentation.

Fig. 16.23 Open-angle glaucoma secondary to uveal melanoma. A, Histologic section shows seeding of iris melanoma onto anterior surface of iris. B, Melanoma cells also cover angle recess and trabecular meshwork. (From Yanoff M: Glaucoma mechanisms in ocular malignant melanomas. Am J Ophthalmol 70:898. © Elsevier 1970.)

Fig. 16.24 Open-angle glaucoma secondary to uveal melanoma. A, Histologic section shows a ring melanoma involving the iris root and anterior ciliary body for 360° and invading the anterior chamber angle structures. B, Increased magnification shows the melanoma cells invading the trabecular meshwork. (From Yanoff M: Glaucoma mechanisms in ocular malignant melanomas. Am J Ophthalmol 70:898. © Elsevier 1970.)

Fig. 16.25 Open-angle glaucoma secondary to uveal melanoma—melanomalytic glaucoma. A, Patient presented with symptoms of acute closed-angle glaucoma. By gonioscopy, angle wide open, except 8 to 9 o’clock, in area of tumor. Eye enucleated because intraocular pressure uncontrollable. B, Histologic section shows small, completely necrotic ciliary body melanoma. C, Scanning electron micrograph shows many round “balls” on trabecular meshwork (top), angle recess (middle dark groove), and anterior iris surface (bottom). D, Histologic section shows an open anterior chamber angle heavily infiltrated by pigment-laden macrophages (balls seen in C). It is impossible to determine whether the large pigmented cells are melanoma cells or macrophages. E, Bleached section shows clearly that cells have macrophagic features (abundant cytoplasm and tiny, innocuous nuclei). (Modified with permission from Yanoff M, Scheie HG: Melanomalytic glaucoma: Report of patient. Arch Ophthalmol 84:471, 1970. © American Medical Association. All rights reserved.)

II. Secondary to damaged outflow channels

A. Old uveitis may result in “scarring” of the tissues in the drainage angle.

B. Repeated attacks of acute closed-angle glaucoma may cause damage to the trabecular meshwork so that even though the angle appears open, the facility of outflow is decreased.

C. Repeated hyphema may damage the aqueous outflow tissue.

D. In both siderosis and hemosiderosis bulbi, iron has a “toxic,” sclerosing effect on tissues within the drainage angle.

E. Trauma

1. It may have a direct effect on the tissues of the drainage angle by inducing scarring (sclerosis) of the trabecular meshwork, or it may cause a postcontusion deformity of the anterior chamber angle (see Chapter 5).

2. Iris melanocytes may proliferate over the trabecular meshwork and occlude an open anterior chamber angle.

F. Cornea guttata [Fuchs (see Chapter 8)]

G. In early iris neovascularization, before peripheral anterior synechiae form, an open anterior chamber angle may be obstructed by an almost transparent, delicate fibrovascular membrane arising from vessels near the iris root or near the anterior face of the ciliary body.

III. Secondary to corneoscleral and extraocular diseases such as interstitial keratitis, orbital venous thrombosis, cavernous sinus thrombosis, carotid–cavernous fistula, encircling band after retinal detachment surgery, retrobulbar mass, leukemia, and mediastinal syndromes

Carotid–cavernous fistula may also cause closed-angle glaucoma by a pupillary-block mechanism.

IV. Unknown mechanisms (usually reversible)

A. Corticosteroid-induced glaucoma (either oral or inhaled)

There is accumulation of basement membrane-like and fine fibrillar-like material in the outer trabecular meshwork in steroid glaucoma. In addition, type IV collagen, heparin sulfate proteoglycan, and fibronectin stain more prominently in the outer trabecular meshwork in steroid glaucoma compared to POAG and nonglaucomatous eyes.

B. α-Chymotrypsin-induced glaucoma

Tissue Changes Caused by Elevated Intraocular Pressure

Melanin pigment liberated from pigment epithelium or uveal melanocytes does not usually exist “free” on surfaces but is present in cells (e.g., in macrophages in iris or in endothelium on posterior cornea or trabecular meshwork).

II. Fibrosis of stroma

III. Atrophy or necrosis of stroma dilator muscle and pigment epithelium

IV. Ectropion uveae (usually secondary to neovascularization of iris ²)

V. Iris hyperpigmentation is a side effect of topical prostaglandin therapy for glaucoma. Histologic evaluation of involved irides demonstrates increased melanin production by melanocytes without melanocytic proliferation or atypia.

Ciliary Body

I. Fibrosis and hyalinization of the core of fibrovascular tissue in the ciliary processes of the pars plicata

II. Atrophy of pars plicata

Lens

Cataract, especially after glaucoma surgery or after an acute attack of glaucoma (e.g., glaukomflecken with acute closed-angle glaucoma)

Sclera

Ectasia (thinning) or, if lined by uvea, staphyloma (Fig. 16.30)

Neural Retina (Fig. 16.31)

I. Degeneration of inner layers, predominantly nerve fiber and ganglion cell layer

Mechanisms that have been proposed for the apoptotic cell death of RGC in glaucoma include neurotrophic factor deprivation, glutamate excitotoxicity, ischemia, glial cell activation, and immune response.

II. Retinal ganglion cell loss (particularly affecting large ganglion cells and those directly adjacent to the optic nerve) may be present in glaucoma.

A link exists between apoptosis of RGC, matrix metalloproteinase (MMP-9), laminin degradation, and IOP. Abnormal extracellular matrix remodeling in the glaucomatous retina may relate to RGC death. Corpora amylacea in the RGC layer may decrease in number with advancing glaucoma.

III. Photoreceptors are not lost in substantial numbers in POAG.

IV. There is gliosis, especially with secondary glaucoma.

V. Changes in macular thickness and volume correlate with the severity of glaucoma.

Fig. 16.31 Retina. A, Histologic section of the nasal neural retina shows that only an occasional ganglion cell remains instead of the normally seen continuous single layer. The atrophic inner neural retinal layers are still identifiable, unlike the neural retina after central retinal artery occlusion, where the inner layers appear as a homogeneous scar (i, internal limiting membrane; a, atrophic nerve fiber and ganglion cell layers; rc, rods and cones; rpe, retinal pigment epithelium; c, choroid). B, Another case shows more marked glaucomatous atrophy of the inner layers (compare with the inner nuclear layer in A).

Optic Nerve

I. The normal optic nerve fiber count decreases with advancing age; this process is accelerated by glaucoma.

II. Optic nerve atrophy results from a loss of the nerve fibers of the inner neural retina and optic nerve.

A. Whether the neural damage is caused by local or distant astrocytic damage or by vascular insufficiency is not known.
Astrocyte metabolism is altered in glaucoma or in cells cultured at elevated IOP.

B. The exact effect or role that the blockage of axoplasmic transport (flow) has on the process is not known.

C. Although optic nerve cupping and atrophy result from glaucoma, some cupping may not result from permanent axonal damage. For example, cupping may be reversible in congenital glaucoma following normalization of IOP, particularly in younger patients. Improved neural rim area can also be seen after IOP normalization, even in adults.

D. Premature loss of estrogen associated with menopause may be a risk factor for glaucomatous optic nerve damage in women.

III. Atrophy results in loss of substance from the optic nerve head, leading to cupping (Fig. 16.32) or, if the loss is extensive, to excavation of the optic nerve head. Cup enlargement, in turn, results in increased visibility of lamina cribrosa pores.

Fig. 16.32 Glaucoma cupping. Right (A) and left (B) eyes of the same patient. The right optic nerve is cupped, secondary to glaucoma. The left optic nerve is less involved (or “less cupped”). C, The optic nerve head is deeply cupped. Atrophy of the optic nerve is determined by comparing the diameter of the optic nerve at its internal surface and posteriorly, where it should double in size. Here, it is the same size because of a loss of axons and myelin, which also causes an increase in size of the subarachnoid space and a proliferation of glial cells, resulting in an increased cellularity of the optic nerve.

IV. Cavernous (Schnabel’s) optic atrophy (Fig. 16.33) consists of cystoid spaces, usually posterior to scleral lamina cribrosa. The cystoid spaces are filled with hyaluronic acid (see Chapter 13).

Vitreous passes through the atrophic optic nerve head into the substance of the scleral portion of the optic nerve. Changes resembling Schnabel’s optic atrophy have been seen in nonglaucomatous eyes that contain primary or metastatic melanomas.

Fig. 16.33 Cavernous (Schnabel’s) optic atrophy. A, The optic nerve head shows cupping of its surface and large cystic spaces in its parenchyma on right side. B, Special stain to test for the presence of acid mucopolysaccharides (AMP) shows that the cystic spaces are filled with a blue-staining material. Predigestion of the section with hyaluronidase produced empty spaces, demonstrating that they had contained hyaluronic acid. (B, AMP stain.)

V. Parapapillary chorioretinal atrophy is associated with glaucoma.

A. Alpha parapapillary chorioretinal atrophy shows irregular hypopigmentation and hyperpigmentation.

B. Beta parapapillary chorioretinal atrophy shows complete chorioretinal atrophy with visible large choroidal vessels and sclera.

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Glaucoma

Normal Anatomy (Figs. 16.1–16.3)

A. The posterior boundary of the inner scleral sulcus is a ridge, mainly composed of circumferentially oriented bundles of collagen fibrils, the scleral roll or Schwalbe’s posterior-border ring.

B. A short distance posteriorly, the ridge or roll tapers and finally blends with the more predominant, obliquely arranged collagenous lamellae of the sclera.

C. Deep within this inner sulcus and applied closely to the collagenous tissue of the corneosclera lies the large vessel called the canal of Schlemm.

2. The outer wall of the canal also rests on a basement membrane that is separated from the dense collagenous lamellae of cornea and sclera by a few loose cells.

3. The inner wall rests on a thinner or patchy basement membrane that is associated with a zone of delicate connective tissue, the juxtacanalicular connective tissue.

b. Examination of trabeculectomy specimens containing the external portion of the trabecular meshwork reveals severely decreased cellularity in glaucoma.

4. Pores are present in the wall of Schlemm’s canal.

5. Ultrastructural analysis of ocular basement membrane components fails to demonstrate significant differences between the characteristics of these structures in normal and glaucomatous eyes.

If the collector channels reach the surface of the sclera unconnected, they can be observed in vivo as the clear aqueous veins of Ascher.

II. The trabecular meshwork

B. The meshwork may be easily and usefully separated into two parts by an imaginary line extending from the scleral roll to the end of Descemet’s membrane (see Fig. 16.2).

1. The meshwork lying external to the line and extending from cornea to sclera is known as the corneoscleral meshwork.

2. The meshwork lying internal to the line and in continuity with the uveal tract posteriorly is known as the uveal meshwork.

C. A single trabecula of uveal meshwork consists of a collagenous core surrounded by a single layer of polarized cells (“endothelium”—in reality a mesothelium).

E. The endothelial cells covering the connective tissue core have apical surfaces, line intertrabecular spaces, and therefore are bathed by aqueous.

F. The trabeculae of the meshwork are roughly arranged into circumferential sheets lying superimposed one on the other.

G. Spaces between individual sheets are well seen in proper meridional section, and here they are termed the intertrabecular spaces.

Introduction

I. Glaucoma is characterized by an intraocular pressure (IOP) sufficient to produce ocular tissue damage, either transient or permanent.

A. Glaucoma is a “family” of diseases having in common a type of optic atrophy called optic nerve head cupping or excavation.

2. The appearance of the optic disc is an important diagnostic finding in glaucoma. The ratio of the optic cup to disc is moderately heritable.

A more appropriate name may be glaucomatous optic neuropathy because the primary defect, especially in chronic open-angle glaucoma, appears to be within the optic nerve head.

1. IOP is a risk factor for glaucoma, and the higher the pressure, the greater the probability of the development of the disorder.

a. The accurate measurement of IOP is vital to the proper diagnosis and treatment of glaucoma.

b. Central corneal thickness (CCT) impacts the validity of IOP measurements, particularly in the diagnosis of ocular hypertension.

c. CCT is increased in children with ocular hypertension.

d. Glaucoma, therefore, is not an IOP reading; it is a syndrome. In fact, the cause of the glaucoma may be due to factors (mostly poorly understood) other than IOP. IOP is simply one risk factor.

2. Normal-tension glaucoma probably accounts for approximately one-third of all cases of POAG.

Disc hemorrhage is a significantly negative prognostic factor in normal-tension glaucoma.

4. More than 6% (4/62) of patients with normal-tension glaucoma may have relevant intracranial compressive lesions. Such lesions are usually lacking in POAG.

5. Predictive factors for progression of normal-tension glaucoma differ from those of POAG, possibly suggesting different pathobiologic mechanisms for these disorders.

Papillorenal syndrome is associated with optic disc and visual field anomalies that may lead to an erroneous diagnosis of normal-tension glaucoma.

II. Glaucoma suspect

B. Ocular hypertension may be tolerated by the person, or eventually it may lead to ocular tissue damage and hence to glaucoma.

III. Glaucoma is the leading cause of blindness among the 500,000 legally blind people in the United States—approximately 14% (1 in 7) of blind people.

A. Glaucoma of all types affects approximately 0.5–1% of the general population, 2% of people age 35 years or older, and 3% of people age 65 years or older.

B. POAG accounts for approximately two-thirds of all glaucoma seen in white patients.

1. The prevalence of POAG in white patients ranges from approximately 0.9% in people 40–49 years of age to approximately 2.2% in those 80 years of age or older.

2. The prevalence of POAG in black patients ranges from approximately 1.2% in people 40–49 years of age to approximately 11.3% in those 80 years of age old or older.

The prevalence of primary closed-angle glaucoma is highest among Inuits (~2 or 3%), followed by Asians (~1%).

V. There is considerable racial and genetic variation in the incidence and prevalence of the various forms of glaucoma.

Normal Outflow

Hypersecretion

I. Hypersecretion glaucoma is rare and has no antecedent cause.

II. Outflow facility is normal. The elevated IOP is presumed to be caused by an increased production of aqueous humor.

III. The glaucoma mainly affects middle-aged women, especially when they have neurogenic systemic hypertension.

IV. Histologically, the angle of the anterior chamber shows no abnormalities.

Impaired Outflow

Congenital Glaucoma

I. General information

A. The rate of congenital glaucoma is from 1 : 5000 to 1 : 10,000 live births.

B. It is usually inherited as an autosomal-recessive trait, but it can have an infectious cause (e.g., rubella).

C. Approximately 60–70% of affected children are boys.

D. The disease is bilateral in 64–88% of cases.

II. Pathogenesis (many theories)

C. An “embryonic” anterior chamber angle that results from faulty cleavage of tissue during embryonic development of the eye prevents the aqueous from leaving the anterior chamber.

2. Many nonglaucomatous infant eyes show a similar anterior chamber angle structure.

3. To interpret angle histology accurately, it is necessary to study truly meridional sections through the anterior chamber angle.

a. Tangential sectioning makes interpretation difficult (see Figs. 16.4C and 16.4D).

b. Unfortunately, in the usual serial sectioning of a whole eye, because of the continuously curved surface, only a few sections from the center of the embedded tissue are truly meridional.

D. The actual cause or causes of congenital glaucoma probably remain unknown.

1. Polymorphism in the cytochrome p450 1B1 (CYP1B1) gene is a predominant cause of primary congenital glaucoma.

2. The distribution of mutations in the CYP1B1 gene suggests that ethnic and geographic differences in primary congenital glaucoma may be associated with different CYP1B1 mutation patterns.

III. Associated diseases and conditions

A. Iris anomalies (see Chapter 9)

1. Hypoplasia of the iris (“aniridia”) and iris coloboma may be associated with congenital glaucoma.

1) Glaucoma may result from congenital abnormalities in the differentiation of the angle structures or from progressive angle-closure caused by the residual stump of iris.

b. Aniridia may be found in Brachmann–de Lange syndrome, which may also include conjunctivitis, blepharitis, microcornea, and corectopia.

B. Axenfeld’s anomaly and Rieger’s syndrome (see Chapter 8)

D. Phakomatoses

1. Sturge–Weber syndrome (see Chapter 2)

2. Neurofibromatosis (see Chapter 2)

E. Lowe’s syndrome (see Chapter 10)

F. Pierre Robin syndrome—hypoplasia of the mandible, glossoptosis, cleft palate, and ocular anomalies such as glaucoma, high myopia, cataract, neural retinal detachment, and microphthalmos

G. Rubella (see Chapter 2)

H. Marfan’s syndrome (see Chapter 10)

I. Homocystinuria (see Chapter 10)

J. Microcornea (see Chapter 8)

K. Spherophakia (see Chapter 10)

L. Chromosomal abnormalities (e.g., trisomy 13; see Chapter 2)

M. Persistent hyperplastic primary vitreous (see Chapter 18)

N. Retinopathy of prematurity (see Chapter 18)

O. Retinoblastoma (see Chapter 18)

P. Juvenile xanthogranuloma (see Chapter 9)

Q. Hennekam syndrome, which includes lymphedema, lymphangiectasis, and developmental delay. Other associated findings are dental anomalies, hearing loss, and renal anomalies.

S. Congenital glaucoma can accompany Marshall–Smith syndrome, which is characterized by orofacial dysmorphism, failure to thrive, and accelerated osseous maturation.

V. Neurofibromatosis type 1 should be excluded in newborns with unilateral congenital glaucoma.

W. Subepithelial amyloid deposits, in a recessive form of congenital hereditary endothelial dystrophy, can be associated with congenital glaucoma.

IV. Secondary histologic ocular effects in young eyes (<10 years of age)

C. The limbal region becomes stretched and thin, with a resultant limbal ectasia (see Fig. 16.5).

D. Fibrosis of the iris root and trabecular meshwork is a late manifestation, as is disappearance of Schlemm’s canal.

E. Continued high IOP may cause atrophy of the ciliary body, choroid, and retina; cupping of the optic disc (see Fig. 16.5); and atrophy of the optic nerve.

Primary Glaucoma (Closed- and Open-Angle)

A. Specific features with such imaging studies that may contribute to angle-closure include:

1. Increased iris convexity and thickness with accompanying anterior iris bowing and secondary crowding of the anterior chamber angle

2. Greater lens vault

3. Smaller anterior chamber width, area, and volume

4. Dynamic increase or lesser reduction in iris volume during dilation

5. Choroidal expansion accompanying angle-closure

Primary open- and closed-angle glaucoma occur more often in diabetic patients than in nondiabetic individuals.

III. Closed-angle (narrow-angle; angle-closure; acute congestive) glaucoma (Figs. 16.7 and 16.8)

A. In anatomically predisposed eyes, primary closed-angle glaucoma develops.

1. The surface of the peripheral iris is close to the inner surface of the trabecular meshwork, causing a narrow or shallow anterior chamber angle.

3. The lens is normal-sized or large.

F. Histology

1. Segmental iris atrophy

a. Swelling of the iris root and occlusion of the greater arterial circle of the iris or its branches result in occlusion of the arterial supply to the iris stroma and subsequent necrosis.

b. Segmental iris atrophy is usually seen in the upper half of the iris in a sector configuration.

c. Histologically, there is marked atrophy of the iris stromal layer and, often, of iris pigment epithelium.

2. Irregular pupil results from necrosis of the dilator and sphincter muscles.

a. Histologically, segments of the dilator muscle or its entire length are absent.

b. The sphincter muscle shows varying degrees of atrophy.

3. Glaukomflecken (cataracta disseminata subcapsularis glaukomatosa; see Fig. 16.8)

b. Anterior subcapsular, multiple, tiny gray-white lenticular opacities are seen.

c. Histologically, small areas of epithelial cell necrosis together with tiny adjacent areas of subcapsular cortical degeneration are found.

4. Optic disc edema

a. The nerve fibers in the optic nerve are more susceptible to an acute rise in IOP than are the retinal ganglion cells (RGC).

b. Irreversible vision impairment after an acute attack is mainly caused by optic nerve damage.

c. Histology (see Fig. 13.7B)

5. Neovascularization of iris

a. Neovascularization of iris (clinical rubeosis iridis) is usually secondary to a central retinal vein or artery thrombosis caused by elevated IOP during the acute attack.

b. Histologically, fibrovascular tissue is found in the anterior chamber angle and on the anterior surface of the iris.

Familial amyloidotic polyneuropathy type I (Met 30) has presented with neovascular glaucoma.

G. Failure to reverse the initial attack of angle closure can result in chronic angle-closure glaucoma.

IV. Chronic open-angle (chronic simple) glaucoma (POAG) (Figs. 16.9 and 16.10)

A. The angle appears normal gonioscopically.

B. The site or sites of resistance to aqueous humor outflow lie within the structures of the drainage angle of the anterior chamber probably in the juxtacanalicular region.

C. The condition is most often bilateral.

1. Glaucoma may develop in one eye months to years before the fellow eye.

2. One eye may be more severely affected than the other eye.

b. Unilateral open-angle glaucoma may occur in association with lid thickening caused by neurofibromatosis.

D. Prevalence (see section Introduction)

E. Heredity and genetics

1. In most cases, the condition is probably inherited as an autosomal-recessive trait.

A more appropriate name for POAG might be glaucomatous optic neuropathy because the primary defect is probably in the optic nerve.

F. Normal-tension (improperly called low-tension) glaucoma is a subdivision of POAG (see section Introduction in this chapter).

G. Histology and pathophysiology

1. Optic nerve (see later in this chapter)

3. Very little meaningful information can be derived from long-standing, “end-stage” diseased eyes or from tiny biopsies taken during surgery for control of glaucoma.

4. Aging changes in the drainage angle of the anterior chamber

a. Chronic open-angle glaucoma (COAG) is usually associated with a progressive decrease in the facility of outflow of aqueous humor from the anterior chamber.

b. The resulting IOP becomes incompatible with the continued health of the tissues of the optic nerve head.

c. Decreased facility of outflow results from an obstruction produced by excessive aging changes in the drainage angle.

d. The degree of obstruction is a quantitative problem; two extremes of excessive obstruction are:

1) Proliferation of the endothelium (and possibly of juxtacanalicular connective tissue cells) lining Schlemm’s canal into its lumen for much of its circumference

2) Compaction of the uveal meshwork against the scleral roll, producing a prominent scleral spur (“hyalinization” of adjacent ciliary muscle and atrophy of the iris root also occur)

e. The two major aging changes—each may be seen in almost pure form, or they may be combined.

1) They may also be associated with proliferations of trabecular endothelial cells in the meshwork.

2) COAG depends on the amount of aqueous inflow and the degree of obstruction to outflow caused by the aging changes (see Fig. 16.10).

Oxidative stress is likely to be one important mechanism in the pathogenesis of POAG.

g. Molecular analysis of human trabecular meshwork in glaucoma demonstrates oxidative DNA damage in glaucoma.

5. Ischemia involving the aqueous outflow pathway has been postulated to contribute to the development of POAG.

Secondary Closed-Angle Glaucoma

Causes

I. Chronic primary angle-closure glaucoma

A. Repeated attacks of primary closed-angle glaucoma may give rise either to peripheral anterior synechiae and secondary closed-angle glaucoma or to trabecular damage and secondary COAG.

In black patients, the acute attacks may be subclinical while the closure of the angle progresses relentlessly.

B. Histologically, peripheral anterior synechiae are seen, sometimes broad based.

II. Phacomorphic

A. Swelling of the lens may cause peripheral anterior synechiae (through pupillary block and iris bombé).

B. More frequently, a maturing cataractous lens swells rapidly and simulates primary closed-angle glaucoma.

III. Subluxated or anteriorly dislocated lens can cause a pupillary block that, if not relieved, leads to iris bombé, peripheral anterior synechiae, and secondary angle-closure.

IV. Persistent flat chamber after surgical or nonsurgical trauma may lead to broad-based peripheral anterior synechiae, occasionally causing total anterior synechiae.

V. Iridocorneal endothelial (ICE) syndrome

A. The ICE syndrome consists of a spectrum of changes that include the iris nevus (Cogan–Reese) syndrome, Chandler’s syndrome, and essential iris atrophy.

Antibody titers to the Epstein–Barr virus are increased in patients who have the ICE syndrome; the significance of this increase remains to be clarified.

1. All three entities share a basic corneal endothelial defect and iris involvement.

b. The abnormal endothelial cells may coexist with normal endothelial cells, a condition called subtotal ICE, when 25–75% of the total cells are ICE cells.

2. All ICE syndrome entities tend to be unilateral, occur in young women, and cause corneal edema when the IOP is only slightly elevated or even normal.

3. Glaucoma occurs in approximately 50% of cases.

4. Although in their pure forms the three entities are distinct clinicopathologic types, findings overlap so much in many cases that they are considered variants of the same process.

5. Each variant is described separately, but all are considered to belong to the ICE syndrome.

Posterior polymorphous dystrophy (PPMD; see Chapter 8) shares some characteristics with the ICE syndrome (Table 16.1

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Glaucoma

Glaucoma

Normal Anatomy (Figs. 16.1–16.3)

Introduction

Normal Outflow

Hypersecretion

Impaired Outflow

Congenital Glaucoma

Primary Glaucoma (Closed- and Open-Angle)

Secondary Closed-Angle Glaucoma

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Tissue Changes Caused by Elevated Intraocular Pressure

Cornea (Figs. 16.26–16.28; see also Fig. 8.55)

Anterior Chamber Angle

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Neural Retina (Fig. 16.31)

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Glaucoma

Normal Anatomy (Figs. 16.1–16.3)

Introduction

Normal Outflow

Hypersecretion

Impaired Outflow

Congenital Glaucoma

Primary Glaucoma (Closed- and Open-Angle)

Secondary Closed-Angle Glaucoma

Causes