The open-angle glaucomas are characterized by the presence of a wide angle between the cornea and the iris that allows for unimpeded outflow of aqueous and for unobstructed visualization of the trabecular meshwork by gonioscopy.
Primary Open-Angle Glaucoma
In patients with primary open-angle glaucoma (POAG), the iridocorneal angle is open and appears entirely normal with no evidence of excessive pigmentation or other structural changes. POAG is by far the most common form of glaucoma in the United States.
Diagnosis of POAG is based on elevated intraocular pressure, the presence of cupping of the optic nerve head demonstrated by ophthalmoscopy, and loss of peripheral vision in an optic nerve-related pattern.
The four major risk factors for the development of POAG are age, race, elevated intraocular pressure, and family history.2 POAG is uncommon before the age of 40, and when diagnosed before age 40, the disorder is considered a separate subcategory of glaucoma known as JOAG. The prevalence of glaucoma increases with age, and in some studies, advanced age is a more important risk factor than elevated intraocular pressure.2,3 In the United States, patients of African heritage develop glaucoma earlier and have a more severe form of the disease. African-Americans have four to five times the prevalence of glaucoma than European-Americans.4 Elevated intraocular pressure, while not absolutely required for the diagnosis of glaucoma, is a major risk factor for its development.5 The majority of patients with POAG have an elevated intraocular pressure. The higher the intraocular pressure, the greater the risk of developing glaucoma. Patients with a positive family history of POAG are at an increased risk of developing the disease.6-8
Other risk factors for the development of glaucoma are minor and more variable, and include myopia, diabetes mellitus, and cardiovascular disease.2
Genetics and Molecular Biology.
Although the suggestion that some cases of POAG are inherited was first made over 150 years ago,9,10 acceptance of POAG as an inherited disease became widespread only after a number of glaucoma disease loci were successfully identified. Prior to these molecular studies, the familial nature of POAG was supported mainly by epidemiologic studies, reports of concordance in twins, and reports of families in which the disorder segregated in a Mendelian fashion. Formal segregation analyses have not been reported. Several studies reported a high incidence of glaucoma among individuals with a family history.6,8,11-13 In these studies, prevalence rates were reported to be five- to twentyfold higher in individuals with a first-degree relative with glaucoma as compared to the general population. Variations in these studies can be attributed to population differences and differences in study design. Twin studies also support a genetic component of glaucoma, although no large twin studies (i.e., with statistically significant data) have been reported.14 Case reports of twins showing both concordance14-18 and discordance14,19,20 for POAG have been reported, suggesting that both genetic and nongenetic factors play a role in this form of glaucoma. Numerous extended kindreds in which glaucoma segregates in a Mendelian manner (both autosomal dominant and autosomal recessive) have been reported.21-25 Such families are perhaps the strongest evidence that glaucoma is heritable. The percentage of cases of POAG that are classified as hereditary in the literature ranges from 5 percent to 50 percent.2
Factors associated with glaucoma, such as intraocular pressure,8,26 outflow facility,27 cup-to-disc ratio,28,29 and hypertensive response to corticosteroids,30 have all been shown to have a heritable component.
A number of different loci involved in POAG have been identified, clearly demonstrating it is genetically heterogeneous. By convention, each locus has been given the prefix designation “GLC” referring to glaucoma, followed by the number “1,” which refers to the open-angle subtype of glaucoma. Finally, each locus has been given a letter designation (i.e., A, B, C, etc.) which refers to the order in which the loci were identified. Sheffield et al. reported the first genetic linkage of a POAG locus to chromosome 1 with a large autosomal dominant pedigree consisting of 22 individuals affected with JOAG.31 This locus, designated GLC1A, is linked to the disease in almost all pedigrees with juvenile-onset glaucoma,32-34 and to some pedigrees that display a range of phenotypes from ocular hypertension to POAG with an onset after the age of 40 years.35 Efforts to fine map the disease locus resulted in the narrowing of the candidate interval.36 As discussed more fully below, the gene responsible for GLC1A glaucoma was recently identified.37
Stoilova et al. mapped a locus for adult-onset POAG to 2cen-q13. This locus is designated GLC1B.38 The clinical characteristics of the families mapping to the GLC1B locus include autosomal dominant inheritance, low to moderate intraocular pressure, onset in the fifth decade of life, and good response to medical treatment.38 Wirtz et al. used a single large pedigree to map a third autosomal dominant POAG locus (GLC1C) to chromosome 3q21 to 3q24.39 To date, other families mapping to this locus have not been reported. Sarfarazi and coworkers recently reported the mapping of two additional adult-onset glaucoma loci (GLC1D and GLC1E) to chromosomes 8 and 10.40,41 The genes causing GLC1B through GLC1E glaucoma have yet to be identified.
The majority of cases of POAG are thought to be the result of multifactorial inheritance, although some studies have suggested that POAG is inherited as an autosomal dominant with reduced penetrance.42 A number of studies using affected pedigree member and affected sib pair study designs are ongoing but have not yet yielded any new statistically established loci. An alternative approach for identifying POAG genes that is likely to be fruitful is the use of mouse models. John and coworkers recently reported strain differences in intraocular pressure between inbred mouse strains.43 Crosses between these strains should allow mapping of loci controlling intraocular pressure.
Using a combination of positional cloning and candidate gene screening, Stone et al. identified a gene on the long arm of chromosome 1 that causes most cases of autosomal dominant JOAG. The gene was initially mapped to a 23 cM interval on chromosome 1.37 The interval was narrowed to about 1 cM using several extended pedigrees and comparison of haplotypes between affected kindreds. A physical map of the interval was constructed, and genes mapping to the narrowed interval were considered to be candidates and were screened for mutations.36,37 Initial identification of the GLC1A gene was based on mutation identification in extended pedigrees segregating juvenile-onset disease. Later, screening of unrelated probands with adult-onset POAG revealed GLC1A sequence variation that was significantly greater than that present in controls, further supporting GLC1A as an important glaucoma-causing gene.37 A follow-up study of 716 primarily Caucasian patients with adult-onset POAG and 596 ethnically matched controls identified 16 probable disease-causing mutations.44 These mutations accounted for 4.6 percent of the glaucoma cases in probands. The most common mutation, Gln368ter, was found to account for almost half of the cases. The age at which the diagnosis was made in patients with GLC1A mutations ranged from 8 years to 77 years. The Q368ter mutation is associated with a significantly later age of onset (range 36 to 77 years; average age = 59 years) compared to the other reported mutations.44 These data demonstrate that adult-onset glaucoma can be inherited as an autosomal dominant disorder. Due to the late onset of the disease in some cases, a positive family history may not be apparent. Morissette et al. recently reported a sequence variant (K423E) in the GLC1A gene, found in a large extended kindred, which appears to cause disease when found in the heterozygous state, but not in the homozygous state.45
The GLC1A gene encodes a 504-amino acid protein referred to initially as the trabecular meshwork-induced glucocorticoid response protein (TIGR). Upon the recommendation of the Human Genome Organization Nomenclature Committee, the protein is now officially referred to as myocilin. This protein has a molecular mass of 57 kDa and is expressed in a wide range of tissues.46,47 Myocilin has an aminoterminal hydrophobic region, a domain displaying 25 percent homology with myocin heavy chain, and an olfactomedin-like domain at the C-terminus. In addition, a leucine zipper-like motif with a leucine at every seventh position is found between amino acids 117 to 169. Arginine residues are found at every eleventh position from amino acid 125 to amino acid 169. The normal role of myocilin and the mechanism by which mutations in this gene cause glaucoma are not yet known. The gene consists of three exons. Of interest is that nearly all glaucoma-associated mutations in this gene are in exon three (Fig. 242-4), which suggests that alterations elsewhere in the gene only rarely cause glaucoma. The mechanism by which GLC1A mutations cause increased intraocular pressure and glaucoma has not yet been demonstrated.
Diagram of the GLC1A structural gene with three exons. Most disease-causing mutations are in exon 3.
The optic neuropathy of glaucoma cannot be treated directly at the present time. Treatment is, therefore, directed at the one major risk factor that can be altered, elevated intraocular pressure. Intraocular pressure is usually lowered by one or more topical medications, which include β-adrenergic antagonists, prostaglandin analogs, adrenergic agonists, carbonic anhydrase inhibitors, and cholinergic agonists. These medications either decrease aqueous humor production or increase aqueous humor outflow. Oral carbonic anhydrase inhibitors can be used to decrease aqueous humor production, but these agents have been almost completely replaced by topical drugs that have fewer systemic side effects. If the intraocular pressure is not adequately controlled with medications, argon laser can be applied to the trabecular meshwork to increase aqueous outflow. This procedure, called argon laser trabeculoplasty, decreases intraocular pressure in about 80 percent of patients, but the effect may be lost after a few years.48 If medical and laser therapy fails to control intraocular pressure, a new route of aqueous egress can be created surgically in the form of a trabeculectomy or by insertion of a drainage tube (a seton or valve).
Lowering intraocular pressure has been shown to slow glaucomatous damage and to protect the optic nerve head from further damage.49,50
Normal tension glaucoma is a subtype of primary open-angle glaucoma. It is arbitrarily defined as glaucomatous optic neuropathy and visual field loss in a patient whose intraocular pressure has never been recorded above the normal range (up to 21 mm Hg). It is felt that the optic nerve head damage in normal-tension glaucoma may have a more vascular etiology than the nerve head damage that occurs in high-pressure glaucomas.
Normal-tension glaucoma is associated with a normal appearing anterior segment. The trabecular meshwork is readily visualized on gonioscopy and appears normal. The optic nerve head cupping tends to be more focal than that seen in high-pressure glaucoma and is more likely to selectively involve the inferotemporal and superotemporal portions of the optic nerve head. The visual fields show optic nerve-related field loss. When compared with high-pressure glaucomas the visual field loss is more central and denser.
Patients with normal-tension glaucoma are on average much older than patients with POAG. They are also more likely than the general population to have a history of vasospastic disease such as migraine headache51 or Raynaud's phenomenon.52 There is evidence that patients with progressive normal-tension glaucoma may have impaired circulation to the optic nerve head associated with nocturnal systemic hypotension.53
Genetics and Molecular Biology.
There have been few genetic studies of normal-tension glaucoma. Evidence that normal-tension glaucoma has a genetic component is based on prevalence differences between races and populations, as well as the segregation of normal-tension glaucoma as an autosomal dominant disorder in a few reported kindreds.54 The prevalence of normal-tension glaucoma in Japan is reported to exceed 2 percent of the population over the age of 40, much greater than the prevalence seen in the United States.55 Like POAG, normal-tension glaucoma is likely to be a genetically heterogeneous disorder. In most cases of normal-tension glaucoma, there is not a strong family history, the lack of which suggests either polygenic or multifactorial inheritance.
Sarfarazi et al. recently reported the identification of a locus (GLC1E) on chromosome 10p14-p15 in a large British family with a phenotype consistent with normal-tension glaucoma.41 The maximum lod score when an “affected only” analysis was performed was 3.57 at D10S506. A maximum lod score of 10 at a recombination fraction of zero was observed at marker D10S1216 when unaffected individuals were also included in the analysis. No genes involved in this form of glaucoma have yet been identified. The existence of the normal-tension glaucoma entity stresses the important concept that glaucoma is not simply a disorder of increased intraocular pressure, but that factors involved in susceptibility and resistance to ganglion cell death also play a role.
Like POAG, the treatment of normal tension glaucoma is directed at lowering intraocular pressure. A large collaborative randomized trial studying the benefits and risks of treating normal-tension glaucoma has shown that a 30 percent reduction of intraocular pressure slows the progression this disease.56 Some researchers have suggested that oral calcium channel blockers be used to improve optic nerve head blood flow.57 There is concern that the systemic hypotension induced by these medications may be detrimental to the optic nerve head.53
Pigmentary glaucoma (MIM 600510) is a form of “secondary” open-angle glaucoma in which the trabecular meshwork is visible on gonioscopy but is filled with dense black pigment. The pigment originates from the posterior surface of the iris.58 The mechanism of pigment dispersion syndrome appears to be the following. First, during a blink, aqueous is expressed from the posterior chamber into the anterior chamber of the eye. In susceptible eyes, this excess aqueous in the anterior chamber pushes the iris posteriorly. This posterior bowing of the iris brings the pigment epithelium of the iris into contact with the lens zonules.59 Abrasion of the zonules against the pigment epithelium causes the epithelium to be disrupted, dispersing melanosomes into the aqueous humor.58 This pigment is then deposited in several areas. A vertical stripe of pigment is deposited on the corneal endothelium (Krukenberg spindle). Pigment can also be deposited over the anterior surface of the iris as well as at the junction of the posterior lens capsule and zonules. It is the deposition of pigment granules in the trabecular meshwork that can lead to an elevated intraocular pressure and, ultimately, to glaucoma. If all of the signs of pigment dispersion and deposition are present but there is no glaucoma, the disorder is called pigment dispersion syndrome. When glaucoma ensues, it is called pigmentary glaucoma.
The diagnosis of pigmentary glaucoma is made by recognizing the deposition of pigment on the cornea, anterior iris, trabecular meshwork, and the lens-zonule interface. In addition, on retroillumination there are transillumination defects visible in the iris where light shines through areas that have lost their pigmented epithelium.
Pigment dispersion syndrome is most commonly seen in Caucasians; it is rare in other races.60 It is a disease that is more frequently seen in myopic individuals and is uncommon in patients who are not myopic.60 It is a disease that occurs earlier in life than most glaucomas, being most common in persons between the ages of 20 and 40 years.60 Men and women appear to have equal rates of pigment dispersion, but men are more likely to develop glaucoma and, when they do, to develop glaucoma at a younger age.60
Genetics and Molecular Biology.
Evidence that pigment dispersion syndrome is genetic is limited to studies of a few extended pedigrees in which it appears to be inherited as an autosomal dominant disorder.61,62 Most cases of pigment dispersion appear to be isolated. Three autosomal dominant pigment dispersion pedigrees were used to map a locus on chromosome 7q35-q36.62 A single pedigree yielded a maximum 2-point lod score of 5.72 at a recombination fraction of zero.62 A second locus was recently reported to map to chromosome 18q11-q21 with a maximum lod score of 3.3 (theta = 0) in a single pedigree.61
Pigmentary glaucoma is treated like POAG. There is some theoretical advantage to using cholinergic agonists because of their ability to reverse the iris backbowing and to stop the dispersion of pigment.63 Laser trabeculoplasty also works well because the marked trabecular pigmentation absorbs the laser energy well.64 More recently, laser iridotomies have been performed in selected patients to eliminate the iris backbowing and to prevent the iris pigment from being abraded.65
Exfoliative glaucoma (also called pseudoexfoliative or glaucoma capsulare) is a common form of secondary glaucoma in which a fibrillar material is deposited throughout the anterior segment of the eye, as well as in tissues throughout the body. Elevated intraocular pressure results from physical blockage of the trabecular meshwork and damage to trabecular endothelial cells.
Exfoliation is a disease of the elderly. These patients are typically older than patients with POAG. They have somewhat more marked elevation of the intraocular pressure and that may be more difficult to control. Exfoliative glaucoma is frequently unilateral or markedly asymmetrical.
In exfoliation syndrome, there is a deposition of fibrillar material throughout the anterior segment of the eye. This is deposited as a ground-glass-appearing coating on the anterior lens capsule. The chaffing of the iris against the lens causes the material to be worn off in the zone of iris-lens touch, creating a bull's-eye pattern on the anterior lens capsule. The material that is rubbed free can appear as flaky debris at the pupillary margin. The pigment epithelium of the iris is rubbed away near the pupil and creates transillumination defects in the iris. In the iridocorneal angle, the trabecular meshwork is heavily pigmented. The exfoliative material is found throughout the body, although it appears to cause pathology in the eye alone.66,67
Exfoliation syndrome is most common among the elderly.68 It clusters in populations but is found to some degree in most populations. It is the most common cause of glaucoma in Scandinavian countries.69 It is not seen in Eskimos but is found in up to 38 percent of Navajo Indians.70,71 Women are more likely to develop exfoliative glaucoma than men, but this may in part be due to an increased life span.72
Gifford described a father and son with exfoliative glaucoma.73 No large pedigrees have been reported. There are some pedigrees that contain members with both exfoliative and POAG.74 This observation, coupled with the variation in disease prevalence among different populations, is consistent with a role for genetic factors in the pathogenesis of this disease.
Exfoliative glaucoma is treated in the same way as POAG. It is more likely to be poorly controlled by medical means and require surgical intervention. Laser trabeculoplasty can be quite effective in patients with exfoliation syndrome.75
It is well-established that many eyes will mount an ocular hypertensive response to corticosteroids.76,77 The response can be low, intermediate, or high.
Elevated intraocular pressure is found weeks to months after initiation of corticosteroid therapy. The response is greatest when the corticosteroids are administered topically or injected into the tissues surrounding the eye. There is also some elevation in intraocular pressure noted with oral, dermatological, and inhaled corticosteroids. The elevated intraocular pressure is not associated with any visible structural change in the eye.
Careful follow-up is critical in patients placed on chronic corticosteroids. The intraocular pressure rise generally takes a few weeks to occur, but can be seen at any time from a few days to many months following the initiation of therapy.
Patients with primary open-angle glaucoma77 and their relatives78 are at high risk of demonstrating an elevated intraocular pressure when treated with corticosteroids.
Based on steroid challenges to families, Becker and Armaly suggested that corticosteroid responsiveness was inherited through a single recessive gene.78,79 Other authors have questioned the single-gene theory.80-82
When possible, the corticosteroids are discontinued or reduced. If the corticosteroids cannot be reduced, then the patient is treated like a patient with primary open-angle glaucoma.