Clinical background
Glaucoma is a disease characterized by “a progressive, chronic optic neuropathy in adults where IOP [intraocular pressure] and other unknown factors contribute to damage and which in the absence of other identifiable causes, there is characteristic acquired atrophy of the optic nerve and loss of retinal ganglion cells (RGCs).” The progressive loss of RGCs and their axons produces characteristic damage of optic nerve (e.g., disc cupping and/or retinal nerve fiber layer defects) and corresponding visual field defects. Based upon its definition of a multifactorial optic neuropathy, glaucoma is diagnosed based on structural and functional criteria rather than the IOP level ( Box 23.1 ). A recently proposed “glaucoma continuum” hypothesis characterizes patients along a path from undetectable disease to early mildly symptomatic disease to profound functional impairment.
Glaucoma is likely caused by several or more contributing risk factors, not all of which will be present to the same degree in every patient. While our current definition of open-angle glaucoma is no longer synonymous with “elevated intraocular pressure,” multiple randomized prospective clinical studies conducted across the glaucoma continuum have demonstrated the pressure-associated nature of the disease
In the majority of cases, primary open-angle glaucoma (POAG) has few detectable symptoms until considerable vision loss and/or visual field loss has occurred. However, in certain patients, patients may become aware of early visual defects close to central fixation. In patients with POAG, the elevated pressure may not cause the eye discomfort associated with cases of angle closure glaucoma attack. Table 23.1 outlines some ocular areas that deserve special attention during clinical slit-lamp examination of patients with POAG, including the presence of open normal-appearing anterior-chamber angles. Nevertheless, the best means to diagnose glaucoma is to have a high level of suspicion for patients with progressive optic nerve damage ( Table 23.2 ).
| Ocular structure | Possible abnormalities |
|---|---|
| Cornea (epithelium and endothelium) | Edema, abnormal stromal thickness, Fuchs’ corneal endothelial dystrophy, peripheral anterior synechiae associated with iridocorneal endothelial syndromes, pigment deposition on the corneal endothelium, keratic precipitates |
| Anterior chamber | Peripheral and axial anterior-chamber depth to establish normal values and to rule out a narrow chamber; axial depth to determine position of lens and possible narrowing of angle; changes in axial anterior-chamber depth that may be indicative of malignant glaucoma |
| Iris | Transpupillary iris transillumination to uncover peripupillary defects and pigmentary dispersion syndrome; evaluate texture of iris, and determine presence of nevi or membranes |
| Lens | Exfoliation on anterior surface of lens; exfoliation or pigment on the zonules; pigment deposited between posterior lens surface, zonules, and hyaloid; all other lenticular opacities |
|
It is important to note that a high percentage of glaucoma is found in patients who never manifest elevated IOPs. Historically, “glaucoma” was defined as a disease of elevated IOP above 21 mmHg (the statistical upper 95th percentile of IOP in normal subjects). Blockage of the trabecular meshwork (TM) to aqueous flow was believed to lead to chronic IOP elevation that directly caused the observed optic nerve damage and corresponding loss of peripheral vision. However, population-based studies have shown that one-third or more of persons with open-angle glaucoma (OAG) have normal levels of IOP. Thus, the current definition of OAG is no longer synonymous with “elevated IOP” but that of a pressure-associated optic neuropathy. While POAG is known to occur throughout the entire spectrum of IOP, the Collaborative Normal Tension Glaucoma Study Group designation may be clinically useful since it may denote patients in whom there may be additional non-IOP risk factors.
POAG affects more than 2.5 million Americans over the age of 40 with 130 000 functionally blind (defined by central vision < 20/200 or constricted visual field less than 10°). Table 23.3 demonstrates the incidence and prevalence of OAG with age and race. Glaucoma is the second leading cause of blindness worldwide, affecting an estimated 60.5 million people worldwide by 2010. The percentage of undiagnosed patients in the USA ranges from 56% to 92%. African-Americans are four to six times more likely to develop glaucoma and subsequent blindness, while older Hispanic patients have a severalfold increase.
| Study | Incidence for all ages | Prevalence |
|---|---|---|
| Quigley ‡ | 1.1 per 100 000/year among whites | 1.55% among whites over 40 * |
| 3.9 per 100 000/year among blacks | 4.6% among blacks over 40 † | |
| Baltimore Eye Survey § | Not applicable | 1.29% among whites over 40 |
| 4.3% among blacks over 40 | ||
| The Beaver Dam Eye Study ¶ | Not applicable | 2.9% among whites |
* Median age–adjusted prevalence.
† Overall age-adjusted prevalence.
‡ Quigley HA, Vitale S. Models of open-angle glaucoma prevalence and incidence in the United States. Invest Ophthalmol Vis Sci 1997;38:83–91.
§ Tielsch JM, Sommer A, Katz J, et al. Racial variations in the prevalence of primary open-angle glaucoma. The Baltimore Eye Survey. JAMA 1991;266:369–374.
¶ Klein BEK, et al. Prevalence of glaucoma. The Beaver Dam Eye Study. Ophthalmology 1992;99:1499–1504.
Pathology
The visible portion of the optic nerve head (ONH) is referred to as the optic disc. The physiologic cup, a central depression in the optic disc, is a pale area partially or completely devoid of axons with exposure of the lamina cribrosa, pores in the posterior sclera that allow passage of the RGC axons and central vessels ( Figure 23.1 ). The nerve tissue between the cup and the disc margin is defined as the neuroretinal rim, an important landmark for assessment of the integrity of the disc structure.
Glaucomatous optic neuropathy (GON) refers to excavation (depression) of the physiologic cup at the lamina cribrosa associated with chronic degeneration of the neuroretinal rim and subsequent loss of RGCs (visible as nerve fiber layer defects). Amyloid precursor protein (amyloid-beta) has also been observed to be present, similar to that observed in Alzheimer’s disease and other neurodegenerative diseases. While initial experimental primate studies showed a selective loss of magnocellular bodies and axons, recent contrast sensitivity testing of glaucoma patients suggests nonselective impairment of the low-spatial-frequency components of both magnocellular and parvocellular pathways, presumably mediated by cells with larger receptive fields.
In addition to death of RGCs, there is atrophy and loss of target neurons in the lateral geniculate nucleus of the brain. Studies utilizing experimental primate models of glaucoma show reduced dendrite complexity by 47% and 41% in magnocellular layer 1 and parvocellular layer 6, respectively in experimental animals compared to controls. Clinicopathology demonstrates neural degeneration in the brain involving the intracranial optic nerve, lateral geniculate nucleus, and visual cortex.
Etiology
Randomized, prospective, multicenter clinical trials conducted across the glaucoma continuum (i.e., ocular hypertension to advanced OAG) demonstrate the benefits of lowered IOP. Based upon the results of multiple prospective studies, IOP has been shown to be the major risk factor for the development and progression of POAG. In particular, these studies showed that normal IOP is part of the pathogenic process of OAG and that IOP reduction favorably influences the disease course. In the Collaborative Normal Tension Glaucoma Study, over 20% of patients continued to progress despite adequate IOP reduction of greater than 30%. Approximately 50% of untreated normal-tension glaucoma patients did not progress over the 5-year period, while 5% rapidly progressed, and 45% slowly progressed. Moreover, a faster rate of progression occurred in women and in patients with migraine and optic disc hemorrhages.
In eyes with early glaucoma, diurnal IOP is higher, 24-hour change of habitual IOP less, and posture-dependent IOP pattern around normal awakening time different when compared to normal eyes. In the Early Manifest Glaucoma Trial (EMGT), long-term IOP variation was not found to be an independent risk factor for glaucomatous progression after accounting for mean IOP in statistical models. A retrospective analysis of data from the Advanced Glaucoma Intervention Study (AGIS) showed that long-term IOP fluctuation was associated with visual field progression in patients with low mean IOP but not in patients with high mean IOP. Further study is needed to explain the discrepancy among these various studies regarding the relative importance of IOP variation (independent of mean IOP) for glaucomatous progression.
Goldmann applanation tonometry is the most precise method for IOP measurement though its accuracy is affected by central corneal thickness (CCT). Increased CCT alters the tonometrically measured IOP by overestimating its value, while thinner CCT may be a risk factor for OAG independent of the tonometric artifact. Randomized clinical trials have demonstrated the importance of CCT in risk models for glaucoma in patients with ocular hypertension and for visual field progression in patients with OAG. At present, it is unclear whether CCT might serve as an additional surrogate factor and/or be associated with ONH structural characteristics that may affect glaucoma risk and/or progression (e.g., posterior sclera thickness near the lamina cribrosa region).
Genetic risk factors
The genetic contributions to POAG are complex, resulting from interactions of multiple genetic factors and susceptibility to environmental exposures. Abundant evidence supports a familial aggregation for POAG and its increased risk among first-degree relatives. When juvenile OAG is detected in families, the disease generally exhibits autosomal-dominant inheritance, whereas when primary congenital glaucoma is detected in families, it generally exhibits autosomal-recessive inheritance. Based on later onset and heterogeneous factors, POAG is not a simple genetic trait, but has a complex multifactorial pattern of inheritance from the interplay of multiple genetic and environmental factors. However, specific environmental modifying features have not been clearly identified in patients with POAG.
A small number of single-gene defects are associated with a small proportion of OAG overall. While at least 14 genetic loci are associated with POAG, glaucoma-predisposing genes have only been identified in three of these loci (MYOC, OPTN, WDR36). Defects in myocilin (MYOC) were observed in 20% of patients with juvenile OAG and 3–5% of adult-onset POAG. MYOC is one of the olfactomedin domain-containing glycoproteins involved in the extracellular matrix of the aqueous outflow pathways. Specific mutations in MYOC are linked to gain-of-function association with the peroxisomal targeting signal type 1 receptor (PTS1R). Mutations in WDR36 on 5q22.1, located within the chromosomal region GLC1G, were initially reported with POAG, though subsequent studies have failed to confirm this original finding. Finally, mutations in optineurin (OPTN) are observed in patients with normal IOP levels, though these mutations have not been seen with increased frequency in more typical high-tension POAG.
Genes for OAG have been identified by candidate gene screening (e.g., MYOC) and by linkage analysis (e.g., OPTN). A recent genome-wide search yielded multiple single-nucleotide polymorphisms (SNPs) in the 15q24.1 region associated with exfoliation glaucoma, a common secondary OAG characterized by abnormal fibrillar deposits on the lens and in the TM. Two nonsynonymous SNPs identified in exon 1 of the gene lysyl oxidase-like 1 (LOXL1) account for more than 99% of the disease. The LOXL1 gene product catalyzes the formation of elastin fibers that are major components of the deposits in exfoliation glaucoma. Exfoliation is discussed further in Chapter 24 .
Vascular factors
Vascular dysregulation, leading to low perfusion pressure and/or insufficient autoregulation, may play a role in the pathogenesis of OAG. Though previous prevalence surveys and clinical trials have failed to show an association between cardiovascular disease and the occurrence or progression of OAG, the Barbados Eye Studies and the EMGT reported positive associations. In the African-descent participants of the Barbados Eye Studies, risk factors for long-term OAG incidence included lower systolic blood pressure, and particularly lower ocular perfusion pressures, which more than doubled risk. In the EMGT, predictive factors for long-term glaucoma progression included lower systolic perfusion pressure, cardiovascular disease history in patients with higher baseline IOP, and lower systolic blood pressure in patients with lower baseline IOP.
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