—  SHORT COURSE  —

OPHTHALMIC PATHOLOGY FOR THE NON-SPECIALIST


CASE 11 – CONGENITAL GLAUCOMA (BUPHTHALMOS)

J. Godfrey Heathcote, M.B.,Ph.D.  —  Janice R. Safneck, M.D.




History
A 28-year-old woman had an abnormal left eye from infancy that became blind and painful.

Diagnosis
Congenital glaucoma, with
(i) anterior uveitis
(ii) cystoid macular edema

Histopathology
The eye measures 29 mm x 23 mm x 23mm while the bulging, cloudy cornea measures 14 mm x 12 mm. Three white spots are visible on the cornea. Staphylomas are noted posteriorly and semicircumferentially 4 mm from the limbus. Opening the eye reveals a pale, cupped optic nerve head and pallor around the macula. The anterior chamber is deep with peripheral anterior synechiae.


Case 11, Slide 28 - Congenital Glaucoma (Buphthalmos): The enlarged cornea shows a small ulcer, white areas corresponding microscopically to band keratopathy and fibrosis, laterally at the limbus an elevated area of Salzmann's nodular degeneration and peripheral vascularization. Conjunctival and episcleral vessels are congested.
Case 11, Slide 29 - Congenital Glaucoma (Buphthalmos): Pupil-optic nerve section of the globe with enlarged anterior chamber, peripheral anterior synechiae, staphyloma posteriorly in relation to the macula and cupped optic nerve head.
Case 11, Slide 30 - Congenital Glaucoma (Buphthalmos): Retina with loss of ganglion cell layer.

On microscopy, the enlarged, bulging cornea displays band keratopathy, fibrosis, vascularization, ulceration, pannus, chronic non-granulomatous inflammation and, peripherally, Salzmann's nodular degeneration. Ridges in Descemet's membrane are observed. The anterior chamber is deep. A compact sclerotic focus that may have been trabecular meshwork is seen, covered by iris. No canal of Schlemm is visible. The iris contains chronic non-granulomatous inflammation, shows focal ectropion uveae but no rubeosis, is irregularly shaped and in areas has an irregular and incomplete sphincter muscle. Ciliary processes are small. The lens shows mild cataractous change. The retina reveals loss of the ganglion cell layer and posterior staphyloma formation in the region of the macula and around the optic nerve. Cystoid macular edema also is present as is perivascular inflammation and peripheral retinal non-cystoid degenerative changes. The choroid shows no significant findings. The optic nerve head is cupped and the optic nerve is atrophic. The sclera is thinned, particularly in areas corresponding to the staphylomas.

Discussion
Glaucoma represents a group of disorders with optic nerve head damage and visual field loss, usually but not always accompanied by increased intraocular pressure (IOP). Glaucoma is one of the leading causes of blindness in the Western world, in large part because it is generally asymptomatic until significant visual loss has occurred. The clinical signs of raised IOP depend on the rate and severity of pressure rise. If pressure increases slowly, no symptoms may be noticed until a considerable decrease in vision has taken place. On the other hand, someone with acute glaucoma and a sudden dramatic rise in pressure will develop a red painful eye and usually seek medical attention. The incidence of glaucoma increases with age and most affected individuals are older than age 40. IOP is normally between 10-22 mm Hg and is maintained through proper secretion, circulation and removal of aqueous humor. Aqueous humor is secreted by the ciliary body epithelium and then passes through the space behind the iris and surrounding the lens equator. It moves through the pupil into the anterior chamber and leaves the eye via the trabecular meshwork and canal of Schlemm into episcleral vessels. Any blockage of this pathway can result in increased IOP. While theoretically increased aqueous secretion also could produce glaucoma, this mechanism rarely is implicated.

Certain histologic findings are common to all forms of glaucoma. The most striking changes relate to the optic nerve head and retina. In the former there is progressive loss of axons accompanied by remodeling and compression of the lamina cribrosa, resulting in cupping. In the latter, degeneration of ganglion cells and the nerve fiber layer occur, yielding inner retinal atrophy; however, the supporting cells are not affected and so the layered architecture of the retina is preserved. Gliosis is not seen. Additional changes may be evident with long-standing glaucoma. The cornea may show evidence of edema, and bullous keratopathy. If the latter occurs, ulceration and inflammation may result. Corneal vascularization also may be present. The ciliary body may exhibit atrophy and hyalinization. The sclera may display foci of thinning, particularly in younger individuals.

Glaucoma is classified basically into the following categories:
1. Primary glaucoma
(a)open-angle glaucoma
(b)angle closure glaucoma
2. Secondary glaucoma
(a)open-angle glaucoma
(b)angle closure glaucoma
3. Congenital glaucoma
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 chromosome 2p16.14 

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 iritis/iridocyclitis.16 

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 block.

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:

  1. 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
  2. Phakomatoses
    e.g. neurofibromatosis; Sturge-Weber syndrome
  3. Metabolic disease
    e.g. oculocerebrorenal syndrome (Lowe's disease); homocystinuria
  4. Chromosomal deletion/duplication
    e.g. Turner's syndrome; trisomy 13-15
  5. Inflammatory
    e.g. rubella; juvenile xanthogranuloma
  6. Neoplastic
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.

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