Open-angle glaucoma: Epidemiology, clinical presentation, and diagnosis Author Deborah S Jacobs, MD Section Editor Jonathan Trobe, MD Deputy

Editor Pracha Eamranond, MD, MPH Disclosures Last literature review version 19.3: Fri Sep 30 00:00:00 GMT 2011 | This topic last updated: Tue Feb 15 00:00:00 GMT 2011 (More) INTRODUCTION Glaucoma is a group of eye diseases traditionally characterized by elevated intraocular pressure (IOP). However, glaucoma is more accurately defined as an optic neuropathy than a disease of high pressure. In open-angle glaucoma, optic nerve damage results in a progressive loss of retinal ganglion cell axons, which is manifested initially as visual field loss and, ultimately, irreversible blindness if left untreated [1]. This topic will discuss the epidemiology, clinical presentation, and diagnosis of openangle glaucoma in adults. Glaucoma in children, angle-closure glaucoma, and treatment and prevention of open-angle glaucoma are discussed elsewhere. (See "Overview of glaucoma in infants and children" and "Angle-closure glaucoma" and "Open-angle glaucoma: Treatment".) CLASSIFICATION There are different types of glaucoma, generally categorized by the anterior chamber (iridocorneal) angle (figure 1) and the underlying etiology, if known: Open-angle glaucoma is an optic neuropathy characterized by progressive peripheral visual field loss followed by central field loss, in a characteristic pattern. This is usually but not always in the presence of elevated intraocular pressure (IOP), perhaps in part related to increased aqueous production and decreased outflow (figure 2). The optic nerve or "disc" takes on a hollowed-out appearance on ophthalmoscopic examination, which is described as "cupping." Cupping is associated with the loss of ganglion cell axons. Angle-closure glaucoma is characterized by narrowing or closure of the anterior chamber angle. The normal anterior chamber angle provides drainage for the aqueous humor (the fluid that fills the eyeball). When this drainage pathway is narrowed or closed, inadequate drainage leads to elevated intraocular pressure and damage to the optic nerve (figure 3). Acute angle-closure glaucoma occurs in eyes with a certain anatomical predisposition. It presents as a painful red eye and must be treated within 24 hours to prevent permanent blindness. (See "Angleclosure glaucoma".) Developmental glaucoma occurs in infants and children and is discussed elsewhere. (See "Overview of glaucoma in infants and children" and "Primary infantile glaucoma".) Both open-angle and angle-closure glaucoma can be divided into primary and secondary forms. Secondary glaucoma has many subtypes with elevated IOP resulting from uveitis, trauma, glucocorticoid therapy, vasoproliferative retinopathy, or ocular syndromes such as pigment dispersion or pseudoexfoliation (the deposition of white fluffy material within the anterior segment of the eye).

Glaucoma can also be categorized based on timing (ie, acute, subacute, and chronic). Mixed mechanism glaucoma refers to glaucoma with several etiologies (eg, openangle glaucoma complicated by superimposed angle-closure, or open-angle glaucoma with superimposed uveitis).

EPIDEMIOLOGY Glaucoma is the second leading cause of blindness in the world (after cataracts) [2] and the leading cause of blindness among African-Americans [3]. Open-angle glaucoma is the most common type of glaucoma among populations of European or African descent, whereas angle-closure glaucoma is more common among populations of Asian descent [2]. It is estimated that there are 44.7 million people with open-angle glaucoma worldwide in 2010, and that this number will increase to 58.6 million in 2020 [4]. It is estimated that there are 2.8 million people with open-angle glaucoma in the United States (US) in 2010 [4], and that the number will increase to 3.4 million in 2020 [5]. Patients with open-angle glaucoma report decreased quality-of-life and difficulties with daily functioning, including driving [6,7]. Patients with glaucoma are also more likely to report falls and motor vehicle collisions [8]. One meta-analysis found no association between open-angle glaucoma and all-cause mortality [9]. In the US, the cost of glaucoma to society has been estimated to be about $1.5 billion per year, including benefits, lost tax revenues, and health expenses [10]. Risk factors The major risk factors for developing open-angle glaucoma include age, black race, family history, and elevated intraocular pressure [11,12]. Age The incidence of open-angle glaucoma increases with age, particularly in patients of Caucasian and African ancestry [13-15]. The prevalence of open-angle glaucoma is below 1 percent in individuals under 55 years of age, approaches 2 percent at age 65, and reaches approximately 4 percent at age 80 [5]. The rate of blindness from open-angle glaucoma also increases with age [3]. Race Race is an important risk factor for development and progression of open-angle glaucoma. The estimated prevalence of open-angle glaucoma is approximately three times higher in blacks, compared to whites [5]. The ageadjusted rate of blindness from glaucoma among blacks was 6.6 times that among whites, with blindness beginning 10 years earlier in blacks [3]. Family history Family history is a significant risk factor for open-angle glaucoma in several population studies [16-19]. The Baltimore Eye Survey found that the relative risk of open-angle glaucoma increased 3.7- and 2.2-fold for individuals with an affected sibling or parent, respectively [16]. Several earlyonset glaucoma syndromes are inherited as Mendelian dominant or recessive traits; open-angle glaucoma, however, has a complex inheritance pattern, with the likelihood that multiple genes interact with environmental factors [17]. Elevated intraocular pressure (IOP) There is a large body of literature illustrating the association between elevated IOP and both development and progression of open-angle glaucoma [19-24]. As an example, the Early Manifest Glaucoma Trial followed 255 patients with a diagnosis of open-angle glaucoma over a mean of eight years; mean IOP was a significant risk factor for progression of glaucoma (HR 1.11, 95% CI 1.06-1.17), even when IOP was within the "normal" range of 8 to 22 mg Hg [25].

Approximately one-sixth of patients in the US with otherwise characteristic openangle glaucoma will have a consistently normal IOP [26]. These patients constitute a subgroup commonly referred to as low-tension or normal-tension glaucoma. While a small proportion of open-angle glaucoma in the US may be classified as normal tension, the majority of patients with open-angle glaucoma in Asia have normal tension glaucoma [27]. In contrast, many patients with elevated pressures never develop the optic nerve and field changes characteristic of glaucoma [20,21]. Thus, although high pressure is clearly associated with open-angle glaucoma, it is neither necessary nor sufficient for the diagnosis and is therefore termed a "risk factor" for the condition. Other factors Other possible risk factors for developing open-angle glaucoma include myopia, pseudoexfoliation, low diastolic perfusion pressure, cardiovascular disease, systemic hypertension, diabetes mellitus, and hypothyroidism [28-34].

Although risk factors for the development of open-angle glaucoma have been welldocumented, risk factors for progression of open-angle glaucoma have not been as conclusively established [35]. Results conflict whether fluctuation in IOP is predictive of glaucoma progression [23,24]. Even in patients with documented findings of glaucoma on comprehensive eye examination (eg, visual field deficits, optic disc changes), it is unclear which patients go on to develop loss of visual acuity and blindness [36]. PATHOGENESIS The pathogenesis of primary open-angle glaucoma is not clear. Optic nerve axon loss may be related to ganglion cell susceptibility, microcirculatory deficiency at the optic nerve head, or extracellular matrix factors [11,37]. These factors may play a combined role: circulatory or extracellular matrix factors could account for both high pressures and axon loss; variation in axon susceptibility might explain why the disease state does not correlate well with elevated IOP [38]. It is not clear if elevated IOP is caused by factors related to aqueous production, aqueous outflow, or to anatomic or physiologic features of the trabecular meshwork and other outflow structures. Mutations in the myocilin gene (MYOC) have been identified in about 4 percent of adults with open-angle glaucoma and more than 10 percent of cases of juvenile open-angle glaucoma, a rare autosomal dominant condition with glaucoma onset between 3 and 40 years of age [11]. MYOC mutations alter the myocilin protein. Myocilin-associated glaucoma is characterized by elevated IOP, with IOP >40 mmHg in some patients with juvenile open-angle glaucoma. Myocilin is produced in the ciliary body and trabecular meshwork, but its precise role in regulating intraocular pressure is unknown. CLINICAL PRESENTATION Individuals with open-angle glaucoma rarely experience symptoms. Thus, open-angle glaucoma is generally detected incidentally during comprehensive ophthalmic examination. This is in contrast to angle-closure glaucoma in which patients present with symptoms and signs including loss of visual acuity, pain, conjunctival erythema, and corneal edema. (See"Angle-closure glaucoma", section on 'Clinical presentation'.) High elevations of intraocular pressure (IOP), up to 40 mmHg in patients with openangle glaucoma, generally cause no pain, redness, or visual symptoms. There is no loss of visual acuity as long as central vision is preserved. Central visual field loss is a late manifestation of open-angle glaucoma, usually preceded by ganglion cell loss and optic nerve damage. Some patients are unaware of field loss even when it has progressed to

central "tunnel vision" of 10 to 20 degrees. Visual field loss cannot be recovered once it has occurred. The mean progression rate from a full field of vision to blindness takes approximately 25 years in untreated patients [39]. However, it is important to note that the median progression rate is much slower (approximately 70 years), since only a small minority of patients progress rapidly to blindness. SCREENING Intraocular pressure (IOP) testing remains the most available and best studied means of screening for glaucoma. However, as mentioned below, no diagnostic test has ideal sensitivity or specificity for screening in the general population, alone or in combination [40]. It remains controversial which populations should be screened, what screening tests should be performed, and with what frequency. (See 'Diagnosis' below.) Evidence for treating elevated intraocular pressure Randomized trials that investigated the effect of lowering IOP in patients with elevated IOP without visual defects have found some benefit in delaying or preventing the onset of open-angle glaucoma [41,42]. In a meta-analysis of five randomized trials in adults with elevated IOP (n = 2318), those randomly assigned to topical IOP lowering medication were less likely to develop open-angle glaucoma compared to those randomly assigned to placebo (HR 0.56, 95% CI 0.39-0.81) [41]. The study further estimated that 12 subjects with elevated IOP would need to be treated to prevent one case of glaucoma within five years of treatment. One large randomized trial (n = 1636) found that IOP lowering medication reduced the risk of both optic disc deterioration (HR 0.36, 95% CI 0.23-0.56) and the perhaps more clinically important outcome of visual field abnormalities (HR 0.45, 95% CI 0.27-0.76) [43]. Since the prevalence of elevated IOP in the general population is approximately 4 percent among individuals age 40 years [44] and 12 patients would be needed to treat to prevent one case of glaucoma, 300 individuals would need to be screened to prevent one case of glaucoma within five years of treatment. Cost-effectiveness In the absence of randomized trials assessing screening strategies, several studies have attempted to determine the cost-effectiveness of glaucoma screening, with more recent studies using Markov modelling [45-48]. One study in the United Kingdom found that neither IOP measurement alone nor comprehensive eye examination were cost-effective in subjects age 40 years, but that screening in older or other higher risk populations might be cost-effective [47]. Another study in Finland found that screening with combined fundus examination, visual field testing, and intraocular pressure measurement in persons age 50 to 89 was costeffective for preventing visual disability (32,603 Euros per one year of avoided visual disability) and quality-adjusted life years (9,023 Euros per one QALY gained by screening) [48]. There is a great deal of uncertainty in the assumptions of these models, particularly with regard to which is the optimal screening protocol, the harms and benefits associated with early detection, and the thresholds for different treatments in relation to cost (determining follow-up, adherence, and additional testing) [45,47,48]. Recommendations of others There is significant variation in screening recommendations from different organizations, partly since no randomized trials have evaluated screening strategies for the prevention of open-angle glaucoma [49]. The American Academy of Ophthalmology (AAO) recommends a comprehensive eye examination for every patient over age 40 by an ophthalmologist or an optometrist skilled in the assessment of the optic nerve and knowledgeable about

glaucoma [26]. Screening only by measuring IOP is not appropriate since a substantial number of patients with glaucomatous visual field changes have normal IOP [20]. A typical frequency for repeat evaluation for individuals between ages 40 and 60 is every three to five years for those without risk factors, and every one to two years for those with one or more risk factors such as borderline pressures, cupping, black race, and family history. The AAO also suggests periodic examination for black men and women between ages 20 to 39. After age 60, a comprehensive eye examination should be performed every one to two years. Field testing is performed by the ophthalmologist once the patient falls into the diagnostic category of "glaucoma suspect" based upon the other risk factors. (See 'Risk factors' above.) The US Preventive Services Task Force (USPSTF) found insufficient evidence to recommend for or against screening adults for glaucoma [50]. While they felt there was good evidence that screening could detect increased IOP and early open-angle glaucoma, and that early treatment reduces the development and progression of visual field defects, they also felt that the evidence was insufficient to determine the extent to which screening would reduce impairment in visionrelated function or quality of life. They noted that harms associated with treatment for increased IOP and early open-angle glaucoma include local eye irritation and an increased risk for cataracts. The Canadian Task Force on the Periodic Health Examination also concluded that there was insufficient evidence to recommend for or against screening for glaucoma in the periodic health examination. Referral of high-risk individuals to a specialist was deemed "clinically prudent" [51].

Synthesis Given the risk of blindness with untreated glaucoma, the effectiveness of treatment, and that early open angle glaucoma is asymptomatic, we suggest that individuals over age 40 be screened for glaucoma. Earlier screening may be appropriate for individuals with significant risk factors for glaucoma. Although the randomized trials cited in this section performed IOP-based screening only, we suggest screening with a comprehensive eye examination since individual tests such as fundus examination or measurement of intraocular pressure alone will likely fail to detect many cases of glaucoma [52-54]. DIAGNOSIS Glaucoma is diagnosed in patients with characteristic nerve damage on fundus examination (picture 1A-B) and visual field testing, typically in the presence of elevated intraocular pressures. Some authorities consider either characteristic optic nerve change OR visual field defects as sufficient criteria for diagnosis of open-angle glaucoma [55,56]. The American Academy of Ophthalmology (AAO) Preferred Practice Pattern defines primary open-angle glaucoma as a chronic, generally bilateral, and often asymmetrical disease, which is characterized (in at least one eye) by all of the following [26]: Evidence of glaucomatous optic nerve damage from either or both of the following: the appearance of the disc or retinal nerve fiber layer (eg, thinning, cupping, or notching of the disc rim, progressive change, nerve fiber layer defects); the presence of characteristic abnormalities in the visual field (eg, arcuate defect, nasal step paracentral scotoma, generalized depression) in the absence of other causes or explanations for a field defect. Adult onset.

Open, normal appearing anterior chamber angles. Absence of known (eg, secondary) causes of open-angle glaucoma.

Who should be referred for comprehensive eye examination? Patients with abnormal cupping should be referred for a comprehensive eye examination. Any patient with high IOP detected during community-based screening or spectacle/contact lens evaluation should also be referred for comprehensive eye examination. Diagnostic tests Fundus examination The primary care clinician should be attentive to the presence of cupping seen in the fundus. Cupping describes a hollowed-out appearance of the optic nerve or "disc" on fundus examination. A cup whose diameter is greater than 50 percent of the vertical disc diameter is indicative of glaucoma. Although cupping has the highest sensitivity and specificity of any other finding on eye examination, there is no single cutoff criteria that yields sufficiently high sensitivity and specificity to make cupping a useful diagnostic test [57]. One study found that ophthalmologists, using direct ophthalmoscopy, detected less than one-half of cases of glaucoma [52]. Combining cupping with other diagnostic criteria increased diagnostic yield. Other findings on fundus examination indicative of glaucoma include thinning or notching of the disc rim, progressive change of the size or shape of the cup, and nerve fiber layer defects. Visual field testing Open-angle glaucoma ideally should be diagnosed before there is significant visual field loss. However, confrontational field testing, using the examiners fingers, is not useful in the detection of glaucoma. Automated perimetry is an important diagnostic tool that is much more reliable at detecting visual field loss in glaucoma compared to confrontational field testing [58]. There are several types of automated perimetry technologies, including standard threshold automated perimetry, frequency doubling technology perimetry, and short wavelength automated perimetry [53]. Automated perimetry has become the standard of care for optometric and ophthalmic practice in the detection and monitoring of glaucoma, although there is a role for careful manual perimetry in some cases, particularly in patients with advanced field loss or dementia. Reliable field testing requires comprehension and cooperation on the part of the patient. Dementia and other mental or physical problems may preclude testing in certain individuals, forcing the clinician to rely upon other variables in diagnostic and therapeutic decision-making. Visual field testing can be time consuming and of variable specificity and sensitivity, depending on user characteristics and the type of test being used. Intraocular pressure Elevated intraocular pressure (IOP) alone does not establish the diagnosis of open-angle glaucoma [26,59]. One-third to one-half of individuals with glaucoma field defects have intraocular pressures 21 mmHg when first detected (normal IOP 8 to 21 mmHg) [60]. In addition, over 90 percent of adults with pressures >21 mmHg have no optic nerve damage. However, patients with elevated IOP should be referred to an ophthalmologist given their higher risk of open-angle glaucoma. (See 'Risk factors' above.) A prospective population study of risk factors associated with glaucomatous field loss found that during a period of five years, 99 percent of eyes with an initial pressure <20

mmHg continued to be free of glaucomatous field defects, compared with 93 percent of eyes with an initial pressure 20 mmHg [61]. The sensitivity for the diagnosis of openangle glaucoma by IOP measurement was 47.1 percent and the specificity over 90 percent at an IOP cutoff point of >21 mmHg [54]. The presence of either increased IOP (>21 mmHg) or increased vertical cup/disc ratio (0.5) increased the sensitivity to 61 percent but decreased the specificity to 84 percent. There was no cutoff value for IOP that had reasonable sensitivity and specificity as a screening tool for the diagnosis of open-angle glaucoma. Ophthalmologists and optometrists can measure IOP by applanation tonometry, pneumotonometry, or air-puff tonometry. Applanation tonometry is a method that determines the intraocular pressure from the force required to flatten (applanate) a constant area of the cornea (picture 2). Applanation tonometry is most accurate and less subject to artifact. All tonometry methods require specialized equipment and skill, and thus fall out of the realm of the primary care clinician. Due to the effects of central corneal thickness on the mechanics of applanation tonometry, falsely higher measurements occur in patients with thicker corneas and falsely lower measurements in those with thinner corneas [62]. This can be partially corrected with pachymetry. (See 'Pachymetry' below.) Schiotz tonometry is a handheld device that is relatively inexpensive, but requires frequent use for reliable results. Generalists who practice in populations that do not have access to optometric or ophthalmic care can learn Schiotz tonometry and use it in conjunction with the optic disc examination in deciding whom to treat or refer. In developed countries, it is less common for primary care providers to measure IOP. There is some evidence that wearing a tight necktie may temporarily increase IOP [63]. The clinical implications of these findings require further study. Regardless, it is prudent to ask patients to loosen collars and ties prior to measuring IOP. Pressure parameters for referral There are no standard criteria for referral to an ophthalmologist for patients with elevated pressures. Primary open-angle glaucoma rarely presents with IOP >30mmHg, which is more common among patients with angleclosure glaucoma or secondary (rather than primary) open-angle glaucoma. (see "Angleclosure glaucoma" and "Evaluation of the red eye"). The following represent indications for ophthalmologic referral based on clinical practice experience: IOP >40 mmHg: Emergency referral IOP 30 to 40 mmHg: Urgent referral (within 24 hours) if no symptoms suggesting acute glaucoma IOP 25 to 29 mmHg: Evaluation within one week IOP 23-24 mmHg warrants repeat measurement to confirm and/or referral for comprehensive eye examination

These indications are not absolute, and should be interpreted in the context of patient history and examination findings. As an example, a patient with an IOP of 28 and advanced open-angle glaucoma including field loss and cupping may represent an emergency because of risk of imminent field loss, while a patient with a healthy nerve could withstand an IOP at that level for weeks with little risk of further nerve damage. Pachymetry Pachymetry is the measurement of corneal thickness; it can be performed by ultrasound or other methods. Patients with thin corneas are at higher risk

for the development of open-angle glaucoma [43,64]. Ophthalmologists may perform pachymetry in patients with suspected or diagnosed open-angle glaucoma to further evaluate their risk for development or progression of open-angle glaucoma [65]. Additionally, corneal thickness affects the results of applanation tonometry, and pachymetry may adjust for this effect. (see 'Intraocular pressure' above). Newer technologies for fundus evaluation Several newer technologies have been developed to evaluate the optic disc and retinal nerve fiber layer. These may aid in the early detection of glaucoma, as well as other eye diseases. Optical coherence tomography (OCT), Heidelberg retinal tomography (HRT), and scanning laser polarimetry are non-invasive imaging techniques that analyze light reflected off the fundus [66,67]. The need for pupil dilation varies with the particular device and the part of the fundus being studied. These tests are well-tolerated by patients. The devices generate a digital image and quantification of specific features of optic nerve head anatomy. One study compared OCT, HRT, scanning laser polarimetry, and conventional qualitative assessment of stereoscopic photographs of the optic disc [68]. The three newer technologies performed as well as, but not better than, stereoscopic photographs. Accuracy of results from stereoscopic images is dependent on the experience and skill of the interpreter, whereas the newer technologies provide more quantitative data that is less user dependent. INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, The Basics and Beyond the Basics. The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on patient info and the keyword(s) of interest.) Basics topics (see "Patient information: Age-related vision loss (The Basics)" and "Patient information: Glaucoma (The Basics)")

SUMMARY AND RECOMMENDATIONS Open-angle glaucoma is an optic neuropathy characterized by progressive peripheral visual field loss followed by central field loss, in a characteristic pattern. This is usually but not always in the presence of elevated intraocular pressure (IOP), perhaps in part related to increased aqueous production and decreased outflow (figure 2). (See 'Classification' above.) Open-angle glaucoma is a leading cause of irreversible blindness in the world. The major risk factors for developing open-angle glaucoma include age, black race, family history, and elevated intraocular pressure. (See 'Epidemiology' above.)

Individuals with open-angle glaucoma rarely experience symptoms. Some patients are unaware of field loss even when it has progressed to central "tunnel vision." Thus, open-angle glaucoma is generally detected incidentally on comprehensive ophthalmic examination. (See 'Clinical presentation' above.) We suggest that all individuals over age 40 be screened for glaucoma (Grade 2B). If the decision is made to undergo screening, we suggest performing a comprehensive eye examination rather than screening with individual tests (eg, fundus examination or measurement or intraocular pressure alone) (Grade 2C). Earlier screening may be appropriate for individuals with significant risk factors for glaucoma. (See 'Screening' above.) Patients with abnormal cupping on fundus examination should be referred for a comprehensive eye examination. (See 'Who should be referred for comprehensive eye examination?' above.) Glaucoma is diagnosed in patients with characteristic nerve damage on fundus examination and on visual field testing (picture 1A-B), typically in the presence of elevated intraocular pressures. Some authorities consider either characteristic optic nerve change OR visual field defects as sufficient criteria for diagnosis of open-angle glaucoma. (See 'Diagnosis' above.) Use of UpToDate is subject to the Subscription and License Agreement. REFERENCES

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