Primary refers to the absence of a local or systemic predisposing condition.
Primary open-angle glaucoma (POAG) represents approximately 70% of all glaucoma.1 Prevalence ranges from
0.42% in Wales to 14.7% in St. Lucia with the United States having a prevalence of approximately 2.1%.2
In America, the incidence of POAG rises from 0.7% for individuals less than 40 to 4.8% in people over 65.2
POAG is the result of faulty drainage of aqueous humor, although the exact mechanism remains unknown. One
finding which could be important in the pathogenesis of POAG is the decline in trabecular cell numbers in
the meshwork with aging and even more so with glaucoma.3,4, Alterations in juxtacanalicular tissue, in
the meshwork channels and in the canal of Schlemm also have received attention.5 Genetic studies of POAG
patients have shown up to 4.6% have a mutation in the gene for myocilin.6 This substance is present in
the trabecular meshwork and in other ocular tissues and organ systems. How myocilin works is unknown. Five
additional loci related to POAG (GLC1B-GLC1F) have been found on a variety of chromosomes, indicating the
involvement of multiple genes in the development of POAG.
On routine histology, few changes are seen anteriorly. The trabecular beams may be slightly thickened and
the trabecular cells reduced in number but these findings are subtle. The histologic diagnosis of POAG,
therefore, relies on the absence of debris, pigment or cells within the meshwork, as would be seen in
secondary open angle glaucoma. Damage to the optic nerve occurs first at the lamina cribrosa, possibly due
to mechanical distortion of the latter by pressure, resulting in compression of axons. Axonal damage may be
diffuse or focal and the largest axons are affected first.7 While increased IOP is important, varied
clinical pictures suggest other factors are involved and the roles of optic nerve extracellular matrix and
optic nerve microcirculation need to be clarified.
Treatment of POAG includes both medical and surgical therapies.8 Drugs aim to increase aqueous outflow
(topical cholinergic agents, prostaglandin analogues) or decrease aqueous production (adrenergic agonists,
carbonic anhydrase inhibitors). Laser trabeculoplasty, trabeculectomy (which may or may not be sent for
histological assessment), ciliodestructive procedures, and drainage devices9 may be employed, and
findings related to these procedures may be visible in enucleated glaucoma eyes.
Primary angle closure glaucoma comprises approximately 6% of glaucoma cases, mostly in individuals older
than age 50 and more frequently in women.10 These patients have shallow anterior chambers and narrow
angles. As the lens ages, it enlarges and can assume a more anterior placement; as the iris dilates, it can
press against the lens, inhibiting aqueous flow. This then pushes the iris forward, blocking the angle.
Acute glaucoma with pain, nausea and vomiting due to rapid IOP rise can result; the eye is red, feels hard
and the pupil is unresponsive to light. Treatment involves medications to constrict the pupil and laser
iridotomy or surgical peripheral iridectomy. Histologically, following episodes of angle closure glaucoma,
segmental iris atrophy may be present, related to pressure on the iris's arterial supply during an attack.
Necrosis of portions of sphincter and dilator muscles can result in an irregular pupil. The lens can
develop foci of epithelial cell necrosis together with tiny areas of anterior cortical degeneration
(glaukomflecken). The optic disc is edematous.
Secondary open angle glaucoma is characterized by trapping of cells and debris in the trabecular meshwork
which impedes aqueous outflow and occurs in a variety of forms.
The exfoliation (pseudoexfoliation) syndrome is a relatively common age-related disease characterized by
fibrillar extracellular deposits within the eye and in a variety of organs including: lung, liver, heart,
kidney, meninges, and gallbladder.11-13 Clinically, white fluffy deposits involve structures of the
anterior segment. Deposits may also be found on intraocular lens implants, and in conjunctival and orbital
biopsies.11 Also characteristic is loss of pigment from the iris sphincter region and pigment deposits
on anterior chamber structures. Patients with exfoliation syndrome are at substantially increased risk of
developing open angle glaucoma as the trabecular meshwork, may be obstructed by fibrillar material. They
also are predisposed to angle-closure glaucoma and ocular surgical complications.11 Other associations
include cataract, retinal vein occlusion and iris blood vessel abnormalities. On histology, the deposits
are composed of short eosinophilic PAS positive feathery fibrils. Ultrastructurally, two types of electron
dense banded fibrils are seen embedded in an amorphous ground substance.11 The chemical composition of
this material is unknown but it appears to be a complex glycoprotein/proteoglycan structure with a protein
core surrounded by glycosaminoglycans.11 Recent genetic studies have linked the exfoliation syndrome to
Phacolytic glaucoma occurs when the cortex of a hypermature cataract liquefies, lens material escapes into
anterior and posterior chambers and is engulfed by macrophages which then, along with lens debris, becomes
trapped in the trabecular meshwork. Patients present with acute glaucoma and aspiration of aqueous confirms
cholesterol crystals and macrophages containing lens protein.15,16 The lens capsule may be intact or
disrupted and, in a few cases, there may be vitreous hemorrhage, a neutrophilic response or
Ghost cell glaucoma results from vitreous hemorrhage, with or without anterior chamber hemorrhage, in
association with an anterior vitreous defect permitting passage of blood anteriorly. Fresh red blood cells
easily can pass through the trabecular meshwork; however, over several weeks, they age into less pliable,
spherical cells with clumped intracellular hemoglobin (Heinz bodies).17 These cells can persist within
vitreous for months following the initial hemorrhage. If the anterior hyaloid face is intact, macrophages
gradually ingest these cells along with extracellular hemoglobin but if it is interrupted, the ghost cells
can pass anteriorly and clog the trabecular meshwork. Aqueous aspirates examined by phase contrast
microscopy contain degenerated erythrocytes which can be seen as well in cell block preparations.18 If
trabeculectomy is performed, ghost cells can be identified in the meshwork and, if the eye is enucleated
because of traumatic complications, ghost cells also can be detected within vitreous, along with macrophages
and an opening in the anterior hyaloid face.17 Two other forms of glaucoma related to vitreous
hemorrhage are hemolytic glaucoma, where red blood cell debris and hemosiderin-laden macrophages obstruct
the trabecular meshwork,19,20 and hemosiderotic glaucoma in which iron from hemorrhage or an intraocular
foreign body is deposited in iris stroma and in the trabecular meshwork inducing sclerosis with obliteration
of intertrabecular spaces.20
Necrotic malignant melanomas and melanocytomas can have a marked associated macrophage response, with
melanophages blocking the trabecular meshwork and producing melanomalytic/melanocytomalytic glaucoma.21-23
Small clusters of tumor cells may also be evident in the meshwork. Additionally, malignant
melanomas can induce open-angle glaucoma by direct invasion of angle structures and seeding of tumor cells
into the anterior chamber angle.24 Pigment dispersion syndrome is a common form of secondary open angle
glaucoma, typically affecting young myopic Caucasian males.25 Midpheripheral iris transillumination
defects and pigment dispersion on the surfaces of anterior segment structures and in the trabecular meshwork
are observed. Secondary open angle glaucoma also can occur if pressure in episcleral vessels exceeds normal
values, as it may in thyroid orbitopathy, cavernous sinus thrombosis and Sturge-Weber syndrome.26
Secondary angle closure glaucoma, comprising about 10% of glaucoma cases, is related to previous ocular
problems such as diabetic retinopathy, central retinal vessel occlusion, and inflammation. New vessels
proliferate on the anterior iris surface (rubeosis iridis), adhesions form between iris and
meshwork/posterior cornea (peripheral anterior synechiae), and the angle becomes obliterated; this is termed
neovascular glaucoma. Whenever adhesions block the angle, endothelial cells from the posterior corneal
surface can proliferate and extend over the pseudoangle onto anterior iris (endothelialization) with, or
more commonly without, Descemet's membrane (descemetization).27
After surgery (86% post-cataract extraction, 12% post-penetrating keratoplasty) and trauma, corneal or
conjunctival epithelium can grow down through the wound in the form of sheets and/or cysts (epithelial
downgrowth) and cover angle structures.28 Damage to corneal endothelium and corneal stromal
vascularization are frequent accompaniments. As well, fibrous tissue from a wound may extend into the
anterior chamber (stromal downgrowth or overgrowth). A poorly closed or fistulous wound may aid this
process but is not a prerequisite. In addition, following trauma there may be contusion angle deformities
which may result in decreased aqueous outflow.
Secondary angle closure glaucoma may result from obstruction to aqueous as it flows from posterior to
anterior chamber (pupillary block). An inflamed iris may develop adhesions to the anterior lens surface
(posterior synechiae) which, when circumferential, block aqueous entering the anterior chamber, resulting in
a bulging forward of the iris (iris bombé), compressing the angle. Iridotomy can relieve this problem as
can disruption of the posterior synechiae. Anterior lens displacement from trauma or conditions such as
Marfan's syndrome, lens swelling or displacement of an implanted intraocular lens also can produce pupillary
Congenital glaucoma is present at birth or early childhood and is associated with visible anterior segment
abnormalities. Both primary and secondary forms may occur; causes are diverse.
Primary congenital glaucoma results from maldevelopment of trabecular meshwork (trabeculodysgenesis). Most
cases are sporadic but a few are inherited as autosomal recessive with variable penetrance, mapping to at
least two chromosomal loci, 2p21 and 1p36.29 Signs of glaucoma may be evident at birth and most patients
have increased IOP by 12 months. The condition is more frequently bilateral than unilateral, but signs in
the second eye may be subtle and late. Since the eye is distensible in infancy, elevated IOP can cause it
to enlarge (buphthalmos). Corneal enlargement can occur up to age three while the sclera may expand until
approximately age 10.30 Foci of scleral thinning (ectasia) and bulging bluish areas of thinned sclera
lined by uveal tract (staphyloma) may be seen. The corneal horizontal diameter increases from the normal of
10.5 mm to 16 mm or greater, resulting in ruptures in Descemet's membrane, visible as scrolls and ridges,
and a deep anterior chamber. Histologically, an abnormal trabecular meshwork, compact with thickened
collagenous beams, is evident. Abnormal insertions of the iris, forward placement of ciliary processes and
poorly developed scleral spur also may be noted. Eyes enucleated for long-standing congenital glaucoma
often have other changes including fibrosis of iris root and meshwork and disappearance of Schlemm's canal.
Other causes of congenital glaucoma include:
Histological features of these conditions are diverse. Mechanisms of glaucoma vary from increased epibulbar
vessel pressure (Sturge-Weber syndrome), to developmental abnormalities (iridotrabeculocorneodysgenesis), to
secondary angle-closure from rubeosis with peripheral anterior synechiae in inflammatory states. Several
gene mutations have recently been described for some of the dysgenesis disorders.14 Whether enlargement
of the eye occurs depends on the age at onset of the glaucoma, as in primary congenital glaucoma.
- Dysgenesis of iris, angle and peripheral cornea with or without systemic abnormalities
e.g. Reiger's anomaly/syndrome; Axenfeld's anomaly/syndrome; Peter's anomaly; aniridia; Marfan's syndrome; Weill-Marchesani syndrome
e.g. neurofibromatosis; Sturge-Weber syndrome
- Metabolic disease
e.g. oculocerebrorenal syndrome (Lowe's disease); homocystinuria
- Chromosomal deletion/duplication
e.g. Turner's syndrome; trisomy 13-15
e.g. rubella; juvenile xanthogranuloma
- Richards RD: Glaucoma. AFP 1987;35:212-220.
- Tielsch JM: The epidemiology of primary open-angle glaucoma. Ophthalmol Clin N A 1991;4:649-657.
- Alvarado J, Murphy C, Juster R: Trabecular meshwork cellularity in primary open-angle glaucoma and
nonglaucomatous normals. Ophthalmology 1984;91:564-579.
- Alvarado JA, Murphy CG: Outflow obstruction in pigmentary and primary open angle glaucoma. Arch
- Grierson I, et al: Pathological dilemmas in the outflow system in primary open-angle glaucoma.
Acta Ophthalmol Scand Suppl 1997;220:7-12.
- Alward WLM: The genetics of open angle glaucoma: the story of GLC1A and myocilin. Eye
- Fechtner RD, Weinreb RN: Mechanisms of optic nerve damage in primary open angle glaucoma. Surv
- Coleman AL: Glaucoma. Lancet 1999;354:1803-1810.
- Lim KS, et al: Glaucoma drainage devices; past, present and future. Br J Ophthalmol
- Greenidge KC: Angle-closure glaucoma. Int Ophthalmol Clin 1990;30:177-186.
- Ritch R, Schlötzer-Schrehardt U: Exfoliation syndrome. Surv Ophthalmol 2001;45:265-315.
- Naumann GOH, Schlötzer-Schrehardt U, Küchle M: Pseudoexfoliation syndrome for the comprehensive
ophthalmologist. Intraocular and systemic manifestations. Ophthalmology 1998;105:951-968.
- Streeten BW, et al: Pseudoexfoliative fibrillopathy in visceral organs of a patient with
pseudoexfoliation syndrome. Arch Ophthalmol 1992;110:1757-1762.
- Friedman JS, Walter MA: Glaucoma genetics, present and future. Clin Genet 1999;55:7;1-79.
- Brooks AMV, Grant G, Gillies WE: Comparison of specular microscopy and examination of aspirate in
phacolytic glaucoma. Ophthalmology 1990;97:85-89.
- Flocks M, Littwin CS, Zimmerman LE: Phacolytic glaucoma. A clinicopathologic study of one hundred
thirty-eight cases of glaucoma associated with hypermature cataract. Arch Ophthalmol 1955;54:37-45.
- Campbell DG: Ghost cell glaucoma following trauma. Ophthalmology 1981;88:1151-1158.
- Cameron JD, Havener VR: Histologic confirmation of ghost cell glaucoma by routine light microscopy. Am
J Ophthalmol 1983;96:251-252.
- Fenton RH, Zimmerman LE: Hemolytic glaucoma. An unusual cause of acute open-angle secondary glaucoma.
Arch Ophthalmol 1963;70:236-239.
- Spraul CW, Grossniklaus HE: Vitreous hemorrhage. Surv Ophthalmol 1997;42:3-39.
- McMenamin PG, Lee WR: Ultrastructural pathology of melanomalytic glaucoma. Br J Ophthalmol
- El Baba F, et al: Choroidal melanoma with pigment dispersion in vitreous and melanomalytic
glaucoma. Ophthalmology 1988;95:370-377.
- Fineman MS, et al: Melanocytomalytic glaucoma in eyes with necrotic iris melanocytoma.
- Yanoff M: Mechanisms of glaucoma in eyes with uveal malignant melanomas. Int Ophthalmol Clin
- Farrar SM, Shields MB: Current concepts in pigmentary glaucoma. Surv Ophthalmol 1993;37:233-252.
- Margo CE, Grossniklaus H: Ocular histopathology: a guide to differential diagnosis. 1991 W B Saunders
- Gartner S, Taffet S, Friedman AH: The association of rubeosis iridis with endothelialization of the
anterior chamber: report of a clinical case with histopathological review of 16 additional cases. Br J
- Weiner MJ, et al: Epithelial downgrowth: a 30-year clinicopathological review. Br J Ophthalmol
- Raymond V: Molecular genetics of the glaucomas: mapping of the first five "GLC" loci. Am J Hum Genet
- deLuise VP, Anderson DR: Primary infantile glaucoma (congenital glaucoma). Surv Ophthalmol