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

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