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Figure 1.
Aqueous Humor Drainage Pathways of Healthy and Glaucomatous Eyes
Aqueous Humor Drainage Pathways of Healthy and Glaucomatous Eyes
Figure 2.
Schematic Illustration of Normal Anatomy and Neurodegenerative Changes Associated With Glaucomatous Optic Neuropathy
Schematic Illustration of Normal Anatomy and Neurodegenerative Changes Associated With Glaucomatous Optic Neuropathy

A, The optic disc is composed of neural, vascular, and connective tissues. The convergence of the axons of retinal ganglion (RG) cells at the optic disc creates the neuroretinal rim; the rim surrounds the cup, a central shallow depression in the optic disc. Retinal ganglion cell axons exit the eye through the lamina cribrosa (LC), forming the optic nerve, and travel to the left and right lateral geniculate nucleus, the thalamic relay nuclei for vision.
B, Glaucomatous optic neuropathy involves damage and remodeling of the optic disc tissues and LC that lead to vision loss. With elevated intraocular pressure, the LC is posteriorly displaced and thinned, leading to deepening of the cup and narrowing of the rim. Distortions within the LC may initiate or contribute to the blockade of axonal transport of neurotrophic factors within the RG cell axons followed by apoptotic degeneration of the RG cells. Strain placed on this region also causes molecular and functional changes to the resident cell population in the optic nerve (eg, astrocytes, microglia), remodeling of the extracellular matrix, alterations of the microcirculation and to shrinkage and atrophy of target relay neurons in the lateral geniculate nucleus.

Figure 3.
Normal, Glaucomatous, and Severe Glaucomatous Optic Nerve Heads and Visual Field Test Results
Normal, Glaucomatous, and Severe Glaucomatous Optic Nerve Heads and Visual Field Test Results

A, The pink area of neural tissue forms the neuroretinal rim, whereas the central empty space corresponds to the cup. B, Glaucomatous optic nerve showing loss of superior neural retinal rim (thinning) and excavation with enlargement of the cup. The arrowheads point to an associated retinal nerve fiber layer defect, which appears as a wedge-shaped dark area emanating from the optic nerve head. The superior neural losses correspond to the inferior defect (black scotoma) seen on the visual field. There is also a small retinal nerve fiber layer defect inferiorly, but the corresponding hemifield of the visual field remains within normal limits. C, More extensive neural tissue loss from glaucoma with severe neuroretinal rim loss, excavation, and enlargement of the cup. There is severe loss of visual field both in the superior as well as in the inferior hemifield.

Figure 4.
Imaging Assessment of the Optic Nerve and Retinal Nerve Fiber Layer Using Spectral-Domain Optical Coherence Tomography
Imaging Assessment of the Optic Nerve and Retinal Nerve Fiber Layer Using Spectral-Domain Optical Coherence Tomography

A, The arrowheads point to a retinal nerve fiber layer (RNFL) defect. B, Areas of thicker RNFL appear in yellow and red. Arrowheads point to the RNFL defect. A deviation map compares the RNFL thickness values with a normative database and highlights the defect. E, Arrowheads point to a visual field defect.

Figure 5.
Gonioscopic Imaging and Optical Coherence Tomographic Imaging of Open-Angle and Closed-Angle
Gonioscopic Imaging and Optical Coherence Tomographic Imaging of Open-Angle and Closed-Angle

A lens with a prism is placed on the eye during gonioscopy, a process during which the examiner is able to examine the angle configuration and assess for the presence of angle closure. A, The arrowhead points to the lack of contact between the iris and angle. Image on the right shows the anterior segment captured by optical coherence tomography. The arrowheads point to visible trabecular meshwork. B, The angle is closed with the trabecular meshwork not visible due to apposition of the iris to the angle. In the right image, the arrowheads indicate apposition of the iris to the angle wall; the anterior chamber is shallow and the iris has a slightly convex configuration. This is more noticeable in the region of the iris on the right.

Figure 6.
Closed-Angle Glaucoma Treatment by Laser Peripheral Iridotomy
Closed-Angle Glaucoma Treatment by Laser Peripheral Iridotomy

C, Arrowhead points to the full-thickness hole in the iris.

Table 1.  
Major Randomized Clinical Trials Evaluating the Role of Intraocular Pressure in Preventing or Delaying Glaucoma Development and Progression
Major Randomized Clinical Trials Evaluating the Role of Intraocular Pressure in Preventing or Delaying Glaucoma Development and Progression
Table 2.  
Classes of Medications Used to Lower Intraocular Pressure
Classes of Medications Used to Lower Intraocular Pressure
1.
Weinreb  RN, Khaw  PT.  Primary open-angle glaucoma. Lancet. 2004;363(9422):1711-1720.
PubMedArticle
2.
Nickells  RW, Howell  GR, Soto  I, John  SW.  Under pressure: cellular and molecular responses during glaucoma, a common neurodegeneration with axonopathy. Annu Rev Neurosci. 2012;35:153-179.
PubMedArticle
3.
Quigley  HA, Broman  AT.  The number of people with glaucoma worldwide in 2010 and 2020. Br J Ophthalmol. 2006;90(3):262-267.
PubMedArticle
4.
Leite  MT, Sakata  LM, Medeiros  FA.  Managing glaucoma in developing countries. Arq Bras Oftalmol. 2011;74(2):83-84.
PubMedArticle
5.
Rotchford  AP, Kirwan  JF, Muller  MA, Johnson  GJ, Roux  P.  Temba glaucoma study: a population-based cross-sectional survey in urban South Africa. Ophthalmology. 2003;110(2):376-382.
PubMedArticle
6.
Hennis  A, Wu  SY, Nemesure  B, Honkanen  R, Leske  MC; Barbados Eye Studies Group.  Awareness of incident open-angle glaucoma in a population study: the Barbados Eye Studies. Ophthalmology. 2007;114(10):1816-1821.
PubMedArticle
7.
Sathyamangalam  RV, Paul  PG, George  R,  et al.  Determinants of glaucoma awareness and knowledge in urban Chennai. Indian J Ophthalmol. 2009;57(5):355-360.
PubMedArticle
8.
Budenz  DL, Barton  K, Whiteside-de Vos  J,  et al; Tema Eye Survey Study Group.  Prevalence of glaucoma in an urban West African population: the Tema Eye Survey. JAMA Ophthalmol. 2013;131(5):651-658.
PubMedArticle
9.
Friedman  DS, Wolfs  RC, O’Colmain  BJ,  et al; Eye Diseases Prevalence Research Group.  Prevalence of open-angle glaucoma among adults in the United States. Arch Ophthalmol. 2004;122(4):532-538.
PubMedArticle
10.
Day  AC, Baio  G, Gazzard  G,  et al.  The prevalence of primary angle closure glaucoma in European derived populations: a systematic review. Br J Ophthalmol. 2012;96(9):1162-1167.
PubMedArticle
11.
Hollands  H, Johnson  D, Hollands  S, Simel  DL, Jinapriya  D, Sharma  S.  Do findings on routine examination identify patients at risk for primary open-angle glaucoma? JAMA. 2013;309(19):2035-2042.
PubMedArticle
12.
Kersey  JP, Broadway  DC.  Corticosteroid-induced glaucoma: a review of the literature. Eye (Lond). 2006;20(4):407-416.
PubMedArticle
13.
Quigley  HA, Addicks  EM, Green  WR, Maumenee  AE.  Optic nerve damage in human glaucoma, II: the site of injury and susceptibility to damage. Arch Ophthalmol. 1981;99(4):635-649.
PubMedArticle
14.
Fechtner  RD, Weinreb  RN.  Mechanisms of optic nerve damage in primary open angle glaucoma. Surv Ophthalmol. 1994;39(1):23-42.
PubMedArticle
15.
Burgoyne  CF, Downs  JC, Bellezza  AJ, Suh  JK, Hart  RT.  The optic nerve head as a biomechanical structure: a new paradigm for understanding the role of IOP-related stress and strain in the pathophysiology of glaucomatous optic nerve head damage. Prog Retin Eye Res. 2005;24(1):39-73.
PubMedArticle
16.
Quigley  HA, McKinnon  SJ, Zack  DJ,  et al.  Retrograde axonal transport of BDNF in retinal ganglion cells is blocked by acute IOP elevation in rats. Invest Ophthalmol Vis Sci. 2000;41(11):3460-3466.
PubMed
17.
Ju  WK, Kim  KY, Lindsey  JD,  et al.  Intraocular pressure elevation induces mitochondrial fission and triggers OPA1 release in glaucomatous optic nerve. Invest Ophthalmol Vis Sci. 2008;49(11):4903-4911.
PubMedArticle
18.
Wang  N, Xie  X, Yang  D,  et al Orbital cerebrospinal fluid space in glaucoma: the Beijing Intracranial and Intraocular Pressure (iCOP) study. Ophthalmology. 2012;119(10):2065e1-2073e1.
PubMedArticle
19.
Ren  R, Jonas  JB, Tian  G,  et al.  Cerebrospinal fluid pressure in glaucoma: a prospective study. Ophthalmology. 2010;117(2):259-266.
PubMedArticle
20.
Almasieh  M, Wilson  AM, Morquette  B, Cueva Vargas  JL, Di Polo  A.  The molecular basis of retinal ganglion cell death in glaucoma. Prog Retin Eye Res. 2012;31(2):152-181.
PubMedArticle
21.
Stone  EM, Fingert  JH, Alward  WL,  et al.  Identification of a gene that causes primary open angle glaucoma. Science. 1997;275(5300):668-670.
PubMedArticle
22.
Rezaie  T, Child  A, Hitchings  R,  et al.  Adult-onset primary open-angle glaucoma caused by mutations in optineurin. Science. 2002;295(5557):1077-1079.
PubMedArticle
23.
Monemi  S, Spaeth  G, DaSilva  A,  et al.  Identification of a novel adult-onset primary open-angle glaucoma (POAG) gene on 5q22.1. Hum Mol Genet. 2005;14(6):725-733.
PubMedArticle
24.
Kwon  YH, Fingert  JH, Kuehn  MH, Alward  WL.  Primary open-angle glaucoma. N Engl J Med. 2009;360(11):1113-1124.
PubMedArticle
25.
Thorleifsson  G, Walters  GB, Hewitt  AW,  et al.  Common variants near CAV1 and CAV2 are associated with primary open-angle glaucoma. Nat Genet. 2010;42(10):906-909.
PubMedArticle
26.
Wiggs  JL, Yaspan  BL, Hauser  MA,  et al.  Common variants at 9p21 and 8q22 are associated with increased susceptibility to optic nerve degeneration in glaucoma. PLoS Genet. 2012;8(4):e1002654.
PubMedArticle
27.
Harwerth  RS, Wheat  JL, Fredette  MJ, Anderson  DR.  Linking structure and function in glaucoma. Prog Retin Eye Res. 2010;29(4):249-271.
PubMedArticle
28.
Medeiros  FA, Alencar  LM, Zangwill  LM, Bowd  C, Sample  PA, Weinreb  RN.  Prediction of functional loss in glaucoma from progressive optic disc damage. Arch Ophthalmol. 2009;127(10):1250-1256.
PubMedArticle
29.
Jampel  HD, Friedman  D, Quigley  H,  et al Agreement among glaucoma specialists in assessing progressive disc changes from photographs in open-angle glaucoma patients. Am J Ophthalmol. 2009;147(1):39e1-44 e1. .
PubMedArticle
30.
Medeiros  FA, Vizzeri  G, Zangwill  LM, Alencar  LM, Sample  PA, Weinreb  RN.  Comparison of retinal nerve fiber layer and optic disc imaging for diagnosing glaucoma in patients suspected of having the disease. Ophthalmology. 2008;115(8):1340-1346.
PubMedArticle
31.
Medeiros  FA, Zangwill  LM, Bowd  C, Weinreb  RN.  Comparison of the GDx VCC scanning laser polarimeter, HRT II confocal scanning laser ophthalmoscope, and stratus OCT optical coherence tomograph for the detection of glaucoma. Arch Ophthalmol. 2004;122(6):827-837.
PubMedArticle
32.
Chauhan  BC, O’Leary  N, Almobarak  FA,  et al.  Enhanced detection of open-angle glaucoma with an anatomically accurate optical coherence tomography-derived neuroretinal rim parameter. Ophthalmology. 2013;120(3):535-543.
PubMedArticle
33.
Medeiros  FA, Zangwill  LM, Anderson  DR,  et al Estimating the rate of retinal ganglion cell loss in glaucoma. Am J Ophthalmol. 2012;154(5):814e1-24e1.
PubMedArticle
34.
Strouthidis  NG, Gardiner  SK, Sinapis  C, Burgoyne  CF, Garway-Heath  DF.  The spatial pattern of neuroretinal rim loss in ocular hypertension. Invest Ophthalmol Vis Sci. 2009;50(8):3737-3742.
PubMedArticle
35.
McKean-Cowdin  R, Wang  Y, Wu  J,  et al.  Impact of visual field loss on health-related quality of life in glaucoma: the Los Angeles Latino Eye Study. Ophthalmology. 2008;115(6):941e1-948e1.
PubMedArticle
36.
Boland  MV, Ervin  AM, Friedman  DS,  et al.  Comparative effectiveness of treatments for open-angle glaucoma: a systematic review for the US Preventive Services Task Force. Ann Intern Med. 2013;158(4):271-279.
PubMedArticle
37.
Kass  MA, Heuer  DK, Higginbotham  EJ,  et al.  The Ocular Hypertension Treatment Study: a randomized trial determines that topical ocular hypotensive medication delays or prevents the onset of primary open-angle glaucoma. Arch Ophthalmol. 2002;120(6):701-713.
PubMedArticle
38.
Heijl  A, Leske  MC, Bengtsson  B, Hyman  L, Bengtsson  B, Hussein  M; Early Manifest Glaucoma Trial Group.  Reduction of intraocular pressure and glaucoma progression. Arch Ophthalmol. 2002;120(10):1268-1279.
PubMedArticle
39.
The AGIS Investigators.  The Advanced Glaucoma Intervention Study (AGIS), 7: the relationship between control of intraocular pressure and visual field deterioration. Am J Ophthalmol. 2000;130(4):429-440.
PubMedArticle
40.
Lichter  PR, Musch  DC, Gillespie  BW,  et al; CIGTS Study Group.  Interim clinical outcomes in the Collaborative Initial Glaucoma Treatment Study comparing initial treatment randomized to medications or surgery. Ophthalmology. 2001;108(11):1943-1953.
PubMedArticle
41.
Collaborative Normal-Tension Glaucoma Study Group.  Comparison of glaucomatous progression between untreated patients with normal-tension glaucoma and patients with therapeutically reduced intraocular pressures. Am J Ophthalmol. 1998;126(4):487-497.
PubMedArticle
42.
American Academy of Ophthalmology Preferred Practice Patterns Committee GP. Preferred practice pattern: primary open-angle glaucoma. In: Ophthalmology. Chicago, Illinois: American Academy of Ophtalmology: 2010.
43.
Gaton  DD, Sagara  T, Lindsey  JD, Gabelt  BT, Kaufman  PL, Weinreb  RN.  Increased matrix metalloproteinases 1, 2, and 3 in the monkey uveoscleral outflow pathway after topical prostaglandin F(2 alpha)-isopropyl ester treatment. Arch Ophthalmol. 2001;119(8):1165-1170.
PubMedArticle
44.
Stewart  WC, Konstas  AG, Nelson  LA, Kruft  B.  Meta-analysis of 24-hour intraocular pressure studies evaluating the efficacy of glaucoma medicines. Ophthalmology. 2008;115(7):1117e1-1122e1.
PubMedArticle
45.
Liu  JH, Kripke  DF, Weinreb  RN.  Comparison of the nocturnal effects of once-daily timolol and latanoprost on intraocular pressure. Am J Ophthalmol. 2004;138(3):389-395.
PubMedArticle
46.
Weinreb  RN, Kaufman  PL.  Glaucoma research community and FDA look to the future, II: NEI/FDA Glaucoma Clinical Trial Design and Endpoints Symposium: measures of structural change and visual function. Invest Ophthalmol Vis Sci. 2011;52(11):7842-7851.
PubMedArticle
47.
Mansouri  K, Medeiros  FA, Weinreb  RN.  Global rates of glaucoma surgery. Graefes Arch Clin Exp Ophthalmol. 2013;251(11):2609-2615.
PubMedArticle
48.
Odberg  T, Sandvik  L.  The medium and long-term efficacy of primary argon laser trabeculoplasty in avoiding topical medication in open angle glaucoma. Acta Ophthalmol Scand. 1999;77(2):176-181.
PubMedArticle
49.
Shingleton  BJ, Richter  CU, Dharma  SK,  et al.  Long-term efficacy of argon laser trabeculoplasty: a 10-year follow-up study. Ophthalmology. 1993;100(9):1324-1329.
PubMedArticle
50.
Shingleton  BJ, Richter  CU, Bellows  AR, Hutchinson  BT, Glynn  RJ.  Long-term efficacy of argon laser trabeculoplasty. Ophthalmology. 1987;94(12):1513-1518.
PubMedArticle
51.
Gedde  SJ, Schiffman  JC, Feuer  WJ,  et al.  Treatment outcomes in the Tube Versus Trabeculectomy (TVT) study after five years of follow-up. Am J Ophthalmol. 2012;153(15):789e2-803e2.
PubMed
52.
Ayyala  RS, Chaudhry  AL, Okogbaa  CB, Zurakowski  D.  Comparison of surgical outcomes between canaloplasty and trabeculectomy at 12 months’ follow-up. Ophthalmology. 2011;118(12):2427-2433.
PubMedArticle
53.
Rulli  E, Biagioli  E, Riva  I,  et al.  Efficacy and safety of trabeculectomy vs nonpenetrating surgical procedures: a systematic review and meta-analysis. JAMA Ophthalmol. 2013;131(12):1573-1582.
PubMedArticle
54.
He  M, Foster  PJ, Johnson  GJ, Khaw  PT.  Angle-closure glaucoma in East Asian and European people: different diseases? Eye (Lond). 2006;20(1):3-12.
PubMedArticle
55.
Sakai  H, Morine-Shinjyo  S, Shinzato  M, Nakamura  Y, Sakai  M, Sawaguchi  S.  Uveal effusion in primary angle-closure glaucoma. Ophthalmology. 2005;112(3):413-419.
PubMedArticle
56.
Lavanya  R, Wong  TY, Friedman  DS,  et al.  Determinants of angle closure in older Singaporeans. Arch Ophthalmol. 2008;126(5):686-691.
PubMedArticle
57.
Nongpiur  ME, Ku  JY, Aung  T.  Angle closure glaucoma: a mechanistic review. Curr Opin Ophthalmol. 2011;22(2):96-101.
PubMedArticle
58.
Amerasinghe  N, Zhang  J, Thalamuthu  A,  et al.  The heritability and sibling risk of angle closure in Asians. Ophthalmology. 2011;118(3):480-485.
PubMedArticle
59.
Vithana  EN, Khor  CC, Qiao  C,  et al.  Genome-wide association analyses identify three new susceptibility loci for primary angle closure glaucoma. Nat Genet. 2012;44(10):1142-1146.
PubMedArticle
60.
Sakata  LM, Lavanya  R, Friedman  DS,  et al.  Comparison of gonioscopy and anterior segment ocular coherence tomography in detecting angle closure in different quadrants of the anterior chamber angle. Ophthalmology. 2008;115(5):769-774.
PubMedArticle
61.
Wong  HT, Lim  MC, Sakata  LM,  et al.  High-definition optical coherence tomography imaging of the iridocorneal angle of the eye. Arch Ophthalmol. 2009;127(3):256-260.
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62.
Alsagoff  Z, Aung  T, Ang  LP, Chew  PT.  Long-term clinical course of primary angle-closure glaucoma in an Asian population. Ophthalmology. 2000;107(12):2300-2304.
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63.
Aung  T, Ang  LP, Chan  SP, Chew  PT.  Acute primary angle-closure: long-term intraocular pressure outcome in Asian eyes. Am J Ophthalmol. 2001;131(1):7-12.
PubMedArticle
Review
May 14, 2014

The Pathophysiology and Treatment of GlaucomaA Review

Author Affiliations
  • 1Hamilton Glaucoma Center, Shiley Eye Center and Department of Ophthalmology, University of California, San Diego, La Jolla
  • 2Singapore National Eye Center, Singapore, Singapore
  • 3Yong Loo Lin School of Medicine, National University of Singapore, Singapore
JAMA. 2014;311(18):1901-1911. doi:10.1001/jama.2014.3192
Abstract

Importance  Glaucoma is a worldwide leading cause of irreversible vision loss. Because it may be asymptomatic until a relatively late stage, diagnosis is frequently delayed. A general understanding of the disease pathophysiology, diagnosis, and treatment may assist primary care physicians in referring high-risk patients for comprehensive ophthalmologic examination and in more actively participating in the care of patients affected by this condition.

Objective  To describe current evidence regarding the pathophysiology and treatment of open-angle glaucoma and angle-closure glaucoma.

Evidence Review  A literature search was conducted using MEDLINE, the Cochrane Library, and manuscript references for studies published in English between January 2000 and September 2013 on the topics open-angle glaucoma and angle-closure glaucoma. From the 4334 abstracts screened, 210 articles were selected that contained information on pathophysiology and treatment with relevance to primary care physicians.

Findings  The glaucomas are a group of progressive optic neuropathies characterized by degeneration of retinal ganglion cells and resulting changes in the optic nerve head. Loss of ganglion cells is related to the level of intraocular pressure, but other factors may also play a role. Reduction of intraocular pressure is the only proven method to treat the disease. Although treatment is usually initiated with ocular hypotensive drops, laser trabeculoplasty and surgery may also be used to slow disease progression.

Conclusions and Relevance  Primary care physicians can play an important role in the diagnosis of glaucoma by referring patients with positive family history or with suspicious optic nerve head findings for complete ophthalmologic examination. They can improve treatment outcomes by reinforcing the importance of medication adherence and persistence and by recognizing adverse reactions from glaucoma medications and surgeries.

The glaucomas are a group of optic neuropathies characterized by progressive degeneration of retinal ganglion cells. These are central nervous system neurons that have their cell bodies in the inner retina and axons in the optic nerve. Degeneration of these nerves results in cupping, a characteristic appearance of the optic disc and visual loss.1 The biological basis of glaucoma is poorly understood and the factors contributing to its progression have not been fully characterized.2

Glaucoma affects more than 70 million people worldwide with approximately 10% being bilaterally blind,3 making it the leading cause of irreversible blindness in the world. Glaucoma can remain asymptomatic until it is severe, resulting in a high likelihood that the number of affected individuals is much higher than the number known to have it.4,5 Population-level surveys suggest that only 10% to 50% of people with glaucoma are aware they have it.48Glaucomas can be classified into 2 broad categories: open-angle glaucoma and angle-closure glaucoma. In the United States, more than 80% of cases are open-angle glaucoma; however, angle-closure glaucoma is responsible for a disproportionate number of patients with severe vision loss.9,10 Both open-angle and angle-closure glaucoma can be primary diseases. Secondary glaucoma can result from trauma, certain medications such as corticosteroids, inflammation, tumor, or conditions such as pigment dispersion or pseudo-exfoliation.

A recent JAMA Rational Clinical Examination systematic review of primary open-angle glaucoma diagnosis found that the risk of glaucoma was highest when examination revealed an increased cup-disk ratio (CDR), CDR asymmetry, disc hemorrhage, or elevated intraocular pressure.11 Primary open-angle glaucoma was also more likely when there was a family history of the disease, black race, or advanced age (Box). The primary care physician also should be aware of the risk of developing glaucoma in patients being treated with systemic or topical corticosteroids.12 Patients at risk should be referred to an eye care practitioner. This review explores pathophysiology of the disease and its treatment.

Box Section Ref ID
Box 1.

Risk Factors That Should Prompt Referral to an Eye Care Practitioner for Evaluation for Glaucoma

  • Older age

  • Family history of glaucoma

  • Black race

  • Use of systemic or topical corticosteroids

  • High intraocular pressure

Methods

A literature search was conducted using MEDLINE, the Cochrane Library, and manuscript references for studies published in English between January 2000 and September 2013 on the topics open-angle and angle-closure glaucoma. From the 4334 abstracts screened, 210 articles were selected that contained information on pathophysiology and treatment with relevance to primary care physicians.

Primary Open-Angle Glaucoma
Pathophysiology

Although the pathogenesis of glaucoma is not fully understood, the level of intraocular pressure is related to retinal ganglion cell death. The balance between secretion of aqueous humor by the ciliary body and its drainage through 2 independent pathways—the trabecular meshwork and uveoscleral outflow pathway—determines the intraocular pressure. In patients with open-angle glaucoma, there is increased resistance to aqueous outflow through the trabecular meshwork. In contrast, the access to the drainage pathways is obstructed typically by the iris in patients with angle-closure glaucoma (Figure 1).

Intraocular pressure can cause mechanical stress and strain on the posterior structures of the eye, notably the lamina cribrosa and adjacent tissues (Figure 2).13 The sclera is perforated at the lamina where the optic nerve fibers (retinal ganglion cell axons) exit the eye. The lamina is the weakest point in the wall of the pressurized eye. Intraocular pressure–induced stress and strain may result in compression, deformation, and remodeling of the lamina cribrosa with consequent mechanical axonal damage and disruption of axonal transport14,15 that interrupts retrograde delivery of essential trophic factors to retinal ganglion cells from their brainstem target (relay neurons of the lateral geniculate nucleus). Studies involving cats and monkeys with experimentally induced ocular hypertension have demonstrated blockade of both orthograde and retrograde axonal transport at the level of the lamina cribrosa.16 Disrupted axonal transport occurs early in the pathogenesis of glaucoma in experimental systems resulting in collections of vesicles and disorganization of microtubules and neurofilaments in the prelaminar and postlaminar regions. Similar ultrastructural changes in optic nerve fibers are seen in postmortem human eyes that have glaucoma.13 Because there also may be mitochondrial dysfunction in retinal ganglion cells and astrocytes,17 high levels of energy demand may be difficult to meet during periods of intraocular pressure–induced metabolic stress.

Glaucomatous optic neuropathy can occur in individuals with intraocular pressures within the normal range. In such patients, there may be an abnormally low cerebrospinal fluid pressure in the optic nerve subarachnoid space resulting in a large pressure gradient across the lamina.18,19 Impaired microcirculation, altered immunity, excitotoxicity, and oxidative stress may also cause glaucoma. Primary neural pathological processes may cause secondary neurodegeneration of other retinal neurons and cells in the central visual pathway by altering their environment and increasing susceptibility to damage.20.

Genetics

Several genes—including myocilin (MYOC, GLC1A) (CCDS1297.1),21 optineurin (OPTN, GLC1E) (CCDS7094.1),22 and WD repeat domain 36 (GLC1G) (CCDS4102.1)23—are associated with a monogenic, autosomal dominant trait; however, these genes account for less than 10% of all glaucoma cases.24 The first reported locus for primary open-angle glaucoma was located on chromosome 1 (GLC1A). The relevant gene at the GLC1A locus is MYOC, which encodes the protein myocilin. Disease-associated mutations of myocilin generally occur in the juvenile or early adult form of primary open-angle glaucoma, usually characterized by very high levels of intraocular pressure. In populations of adults with primary open-angle glaucoma, the prevalence of myocilin mutations varies from 3% to 5%.24 Carriers of disease-associated mutations develop the glaucoma phenotype in an estimated 90% of the cases.24 The mechanism of myocilin-related glaucoma has not been fully elucidated.24 It appears that mutations alter the myocilin protein in a way that disrupts normal regulation of intraocular pressure. Disease-associated forms of myocilin interfere with protein trafficking and result in intracellular accumulation of misfolded protein. Failure to adequately secrete the protein is thought to somehow cause the intraocular pressure to increase.

In contrast to individuals with the MYOC gene, those with the OPTN gene have normal levels of intraocular pressure.22 Although the mechanism relating the OPTN gene variants to glaucoma have not been elucidated, there is evidence suggesting that optineurin may have a neuroprotective role by reducing the susceptibility of retinal ganglion cells to apoptotic stimuli.

A growing number of studies use genome-wide scans to look for glaucoma susceptibility loci. The CAV1/CAV2 (HGNC:1527/HGNC:1528) locus on 7q34 may be associated with primary open-angle glaucoma in European-derived populations. This finding has been replicated by independent studies.25 These genes encode proteins (caveolins) involved in the generation and function of caveola, which are invaginations of the cell membrane involved in cell signaling and endocytosis. The CDKN2BAS (HGNC:34341) locus on 9p21 was shown to be related to glaucoma risk in multiple cohorts.26 The mechanism by which these genes might contribute to primary open-angle glaucoma is not clear, but they may interact with transforming growth factor β, a molecule regulating cell growth and survival throughout the body. Despite promising results, susceptibility genes that have been identified to date for primary open-angle glaucoma only have a modest effect size in explaining glaucoma risk.

Clinical Presentation and Diagnosis

Although elevated intraocular pressure is a very consistent risk factor for the presence of glaucoma, several population-based studies found intraocular pressure was lower than 22 mm Hg in 25% to 50% of individuals with glaucoma.1,14 Despite the strong association between elevated intraocular pressure and glaucoma, substantial numbers of people with elevated intraocular pressure never develop glaucoma even during lengthy follow-up.1 Glaucoma progresses without causing symptoms until the disease is advanced with substantial amounts of neural damage. When symptoms do occur, the disease results in vision loss with concomitant reduction in quality of life and the ability to perform daily activities, such as driving. Early intervention is essential to slow the progression of the disease. Referral to an eye care practitioner should occur for patients at risk of glaucoma (Box 1).

With retinal ganglion cell death and optic nerve fiber loss in glaucoma, characteristic changes in the appearance of the optic nerve head and retinal nerve fiber layer occur.1 These changes are the most important aspect of a glaucoma diagnosis and can be identified during ophthalmoscopic examination of the optic nerve head (Figure 3). The importance of conducting an appropriate ophthalmologic examination of the eye cannot be overstated with respect to early detection of glaucoma. Retinal ganglion cell loss causes progressive deterioration of visual fields, which usually begins in the midperiphery and may progress in a centripetal manner until there remains only a central or peripheral island of vision.

Because there is no single perfect reference standard for establishing the diagnosis of glaucoma, early diagnosis can be challenging. Although examination of the optic nerve head can reveal signs of neuronal loss, wide variability of its appearance in the healthy population makes identification of early damage challenging. Presence of characteristic visual field defects can confirm the diagnosis, but as many as 30% to 50% of retinal ganglion cells may be lost before defects are detectable by standard visual field testing.13,27 Longitudinal evaluation and documentation of structural damage to the optic nerve is, therefore, a critical component of the diagnosis of the disease.28 Such an evaluation may be performed by observing the optic nerve head using an ophthalmoscope or by obtaining optic nerve head photographs. However, subjective identification of optic disc damage from glaucoma can be challenging, with large disagreement in grading observed even among glaucoma specialists.29 Several recently developed laser scanning imaging techniques provide more objective and quantitative information about the amount of optic nerve fiber (retinal ganglion cell axon) loss. These techniques, including confocal scanning laser ophthalmoscopy, scanning laser polarimetry, and optical coherence tomography, have improved the identification of early disease and also enhanced the observation of progressive optic nerve fiber loss over time (Figure 4).3034

Primary care physicians have an important role in the diagnosis of glaucoma by referring patients with a family history of glaucoma to undergo a complete ophthalmologic examination. Anyone with a family history of the disease and who has not had a dilated funduscopic examination of the optic nerve head in the past 2 years should be referred for examination. In addition, evaluation of the optic nerve with direct ophthalmoscopy performed by primary care physicians during a routine clinical visit, may reveal signs suspicious for optic nerve damage that should prompt referral to an ophthalmologist.11

Treatment

Slowing disease progression and preservation of quality of life are the main goals for glaucoma treatment. The decrease in quality of life associated with glaucoma may occur earlier than previously thought, underscoring the importance of early diagnosis and treatment.35 Reduction of intraocular pressure is the only proven method to treat glaucoma.36 Results from several multicenter clinical trials have demonstrated the benefit of lowering intraocular pressure in preventing the development and slowing the disease’s progression (Table 1).37,38,40 The Ocular Hypertension Treatment Study37 randomized patients with ocular hypertension (high intraocular pressure but no clinical signs of glaucomatous damage to the optic nerve or visual field) to treatment vs no treatment. At the end of 5 years of follow-up, 4.4% of patients in the medication group vs 9.5% in the untreated group developed signs of glaucoma. The Early Manifest Glaucoma Trial38 also randomized patients to treatment vs no treatment; however, all patients had a clear diagnosis of glaucoma at the baseline visit. After a median follow-up of 6 years, progression was less frequent in the treatment group (45%) than in the control group (62%).

Current management guidelines from the American Academy of Ophthalmology Preferred Practice Pattern recommend lowering the intraocular pressure toward a target level, which is a value or range of values at which the clinician believes that the rate of disease progression will be slowed sufficiently to avoid functional impairment from the disease.42 Target intraocular pressure levels for a particular eye are established from pretreatment pressure levels that were associated with retinal damage, the severity of damage, risk factors for progression, life expectancy, and potential for adverse effects from treatment. In general, the initial target aims for a 20% to 50% reduction in pressure; however, the target pressure needs to be continuously reassessed during patient follow-up, depending on the evolution of the disease.42 For example, if there is continued disease progression (optic nerve changes or visual field loss) despite pressure levels at the initial target value, the target will need to be lowered.

The target intraocular pressure should be achieved with the fewest medications and minimum adverse effects. Several different classes of pressure-lowering medications are available (Table 2). Medication choice may be influenced by cost, adverse effects, and dosing schedules. In general, prostaglandin analogues are the first-line of medical therapy. These drugs reduce intraocular pressure by reducing outflow resistance resulting in increased aqueous humor flow through the uveoscleral pathway.43 These drugs are administered once nightly and have few, if any, systemic adverse effects. However, they can cause local adverse effects such as conjunctival hyperemia, elongation and darkening of eyelashes, loss of orbital fat (so-called prostaglandin-associated periorbitopathy), induced iris darkening, and periocular skin pigmentation.

Other classes of topical medications are less effective in lowering intraocular pressure than prostaglandin analogues.44 They are used as second-line agents or when there is a contraindication or intolerance to the use of prostaglandin analogues (Table 2). Prostaglandin analogues and carbonic anhydrase inhibitors lower intraocular pressure during both the day and night. Other drugs such as the β-adrenergic blockers and α-adrenergic agonists are effective only during the day and not at night.45 Some of these agents, such as β-adrenergic blockers, may have significant systemic adverse effects and are contraindicated in patients with history of chronic pulmonary obstructive disease, asthma, or bradycardia. To decrease systemic absorption of topical medications, it is advisable for patients to use gentle punctal occlusion or eyelid closure for 2 minutes after drug instillation. General practitioners and internists should be aware that topical medications used by patients with glaucoma, including topical β-blockers, for example, may incur significant or even life-threatening adverse effects. Success of treatment can be enhanced by reinforcing the importance of compliance to the treatment regimen.

Considerable efforts have been made to develop neuroprotective glaucoma treatments that prevent optic nerve damage. Unfortunately, no good evidence exists that these agents can prevent disease progression in patients with glaucoma. In part, neuroprotection has not succeeded because of incomplete understanding of the pathophysiological mechanisms associated with optic nerve damage, the limited identification of drugs that can medicate the known pathways, and lack of a viable regulatory pathway for drug approval.46

When medical treatment does not achieve adequate intraocular pressure reduction with acceptable adverse effects, laser or incisional surgeries are indicated. The annual number of incisional glaucoma surgeries performed per million people in the United States has been estimated at 274.47 In poorly adherent patients or in those with severe disease, surgery may sometimes be offered as a first-line therapy. Laser trabeculoplasty lowers intraocular pressure by inducing biological changes in the trabecular meshwork resulting in increased aqueous outflow. The procedure has an excellent safety profile and is performed during an office visit. Although substantial intraocular pressure reductions can be achieved in the majority of patients, the effect decreases gradually over time with a failure rate of about 10% per year.4850

Trabeculectomy is the most commonly performed incisional surgical procedure to lower intraocular pressure. It consists of excision of a small portion of the trabecular meshwork and or adjacent corneoscleral tissue to provide a drainage route for aqueous humor from within the eye to underneath the conjunctiva where it is absorbed. Antiscarring agents are frequently applied to the surgical site to decrease fibroproliferative response and increase success rates of the surgery, but may increase the rate of complications such as infection and damage from very low intraocular pressure. Devices that drain aqueous humor to an external reservoir are an alternative to trabeculectomy that are similarly effective in lowering intraocular pressure.51 Several alternatives to these procedures have been proposed and are being investigated. These so-called minimally invasive glaucoma surgeries potentially incur less risk of sight-threatening complications.52 To date, these procedures have not had the same intraocular pressure–lowering efficacy as trabeculectomy; however, they may be indicated for selected cases for which risk-benefit considerations are more favorable than those with trabeculectomy. A recent meta-analysis comparing trabeculectomy with nonpenetrating surgeries (deep sclerectomy, viscocanalostomy, and canaloplasty) concluded that while trabeculectomy was more effective in reducing the pressure, it carried a higher risk of complications.53

Primary Closed-Angle Glaucoma

The main feature distinguishing primary closed-angle glaucoma from primary open-angle glaucoma is that the angle, the site of aqueous outflow in the eye, is obstructed by apposition of the iris, resulting in an anatomically closed angle (defined if at least 270° of the angle is occluded). Like open-angle glaucoma, closed-angle glaucoma is predominantly an asymptomatic disease with individuals often unaware they have the disorder until advanced visual loss has occurred. In less than a third of cases, patients may present with acute primary angle closure, a clinical condition characterized by marked conjunctival hyperemia, corneal edema, a middilated unreactive pupil, a shallow anterior chamber, and very high intraocular pressure, usually greater than 30 mm Hg. Such patients often complain of ocular pain, nausea, vomiting, and intermittent blurring of vision with haloes noticed around lights.

Primary closed-angle glaucoma is caused by disorders of the iris, the lens, and retrolenticular structures. Pupillary block is the most common mechanism of angle closure and is caused by resistance to aqueous humor flow from the posterior to anterior chambers at the pupil. Aqueous humor accumulates behind the iris increasing its convexity causing angle closure (Figure 1). Nonpupil block mechanisms such as a plateaulike iris configuration may be responsible for a significant proportion of angle closure in Asian patients.54 Closed-angle glaucoma may also be caused by dynamic physiological factors, such as an increase in iris volume with pupil dilation and choroidal effusion.55

Risk Factors

Risk factors for angle closure include female sex, older age, and Asian ethnicity (eg, Chinese). Eyes with angle closure tend to share certain biometric characteristics. The main ocular risk factor for angle closure involves having a crowded anterior segment in a small eye, with a shallow central anterior chamber depth, a thicker and more anteriorly positioned lens, and short axial length of the eye.5557 With anterior segment optical coherence tomography, other anatomical risk factors for angle closure have been recently identified such as smaller anterior chamber width, area and volume, thicker irides with greater iris curvature, and a greater lens vault.57

Genetics

A genetic etiology for angle closure is supported by epidemiological findings: first-degree relatives of patients with it are at greater risk than the general population, the high heritability of anatomical risk factors (such as anterior chamber depth), and ethnic variations in the prevalence.58,59 Recently, a genome-wide association study involving more than 20 000 individuals from 7 countries found 3 new genetic loci for angle closure: rs11024102 at PLEKHA7, rs3753841 at COL11A1 (HGNC:2186), and rs1015213 located between PCMTD1 (HGNC:30483) and ST18 (HGNC:18695) on chromosome 8q.59 This indicates that open-angle and closed-angle glaucoma are distinct genetic entities with different genes associated with each disease.

Clinical Presentation and Diagnosis

The distinctive clinical features of angle closure are observed in the angle of the eye by gonioscopy. A simple, handheld, mirrored instrument is placed on the patient’s eye, followed by examination of the angle using a slit-lamp biomicroscope (Figure 5). With indentation, the examiner is also able to determine if peripheral anterior synechiae (adhesions between the iris and trabecular meshwork) are present. Gonioscopy is highly subjective, with poor reproducibility, and gonioscopic findings may vary with the amount of light used during the examination or mechanical compression of the eye.

Several imaging methods have been recently developed that can be used to objectively assess eyes for the presence of angle closure. Ultrasound biomicroscopy allows for the acquisition of real-time images of the angle, with resolution of between 25 μm to 50 µm.60 With biomicroscopy, one is able to visualize posteriorly located structures such as the ciliary body, lens zonules, and the anterior choroid, making it useful for identifying specific causes of angle closure. Biomicroscopic imaging requires a skilled operator and cooperation from patients during the imaging. Anterior segment optical coherence tomography is a noncontact imaging device that acquires high-resolution cross-sectional images of the anterior chamber (Figure 5). The incorporation of automated image analysis software allows for rapid measurement of anterior segment parameters. Comparison studies found a higher rate of diagnosis of closed angles with tomography than with gonioscopy.61

Management

The management of patients with angle closure depends on the stage of disease and on correctly identifying the underlying mechanism. The first-line treatment of angle closure is laser peripheral iridotomy, a procedure in which a full thickness hole is created in the iris (Figure 6) to eliminate pupillary block. This procedure is generally easily performed in the office without adverse events. Rare complications of iridotomy include transient increases of intraocular pressure, cornea decompensation, posterior synechiae (adhesions of iris to lens) formation, and optically induced visual disturbances. Eyes treated with iridotomy may still develop increased pressure over time; thus, it is essential to have periodic follow-up after the procedure. Studies suggest that iridotomy is most effective in decreasing pressure in the early stages of disease, but once extensive synechial angle closure and glaucomatous optic neuropathy have developed, its effect is more subdued.62 If pressure remains high after iridotomy, long-term medical treatment (including topical β-blockers, α2–agonists, carbonic anhydrase inhibitors, and prostaglandin analogues) can be instituted, similar to the management of open-angle glaucoma.

Acute Primary Angle Closure

Acute primary angle closure is an ocular emergency and requires immediate management to avoid blindness. Patients usually present with a painful red eye associated with blurring of vision, headache, and nausea and vomiting. The cornea is usually hazy due to the very high intraocular pressure, and the pupil is frequently middilated and poorly reactive to light. The aims of the treatment are to achieve rapid pressure control with topical and systemic medications to limit optic nerve damage. This is followed by iridotomy to alleviate pupillary block. Iridotomy successfully aborts the attack in 42% to 72% of cases, and many patients recover without optic disc or visual field damage if the pressure is promptly and adequately controlled.63 Laser iridoplasty (contraction of the peripheral iris) can be performed if conventional medical treatment is not tolerated or does not abort the attack. If iridotomy is unsuccessful or difficult to perform because of a cloudy cornea, surgical iridectomy is indicated. Prophylactic iridotomy should be carried out for the fellow eye, which is at high risk of acute angle closure.

Angle Closure Suspects

Management of patients suspected of having angle closure and who do not have glaucoma (ie, anatomically narrow angles but normal intraocular pressure and optic discs) is aimed at modifying the anterior segment configuration, before development of irreversible trabecular meshwork damage and glaucomatous optic neuropathy. The current practice is to offer prophylactic iridotomy to such patients, especially in the presence of risk factors such as a family history of angle closure, and those with symptoms or signs suggestive of intermittent acute angle closure, those who require repeated dilatation (such as diabetics), or for patients who lack access to medical care or are available for limited follow-up care. Cataract extraction with intraocular lens implant is an alternative to iridotomy in those with visually significant cataract because the surgery can decrease intraocular pressure and also widens the angles, thereby improves vision.

Surgical Management

As in primary open-angle glaucoma, surgical management is indicated when there is inadequate intraocular pressure lowering or is indicated for those with progression of optic nerve or visual field damage despite medical and laser treatment. Trabeculectomy, either alone or in combination with lens extraction should be considered if the pressure control remains too high despite laser and medical treatment, especially in more advanced cases of open-angle glaucoma. Lens extraction is also performed when lens-related mechanisms predominate, especially in cases in which a significant cataract impairs vision. Finally, glaucoma drainage implants may be used in patients with chronic angle closure similarly to open-angle glaucoma when trabeculectomy has failed to control pressure, or in eyes that are deemed to be at high risk of failure with trabeculectomy.

Conclusions

Glaucoma is a leading cause of blindness. Early diagnosis and treatment can prevent vision loss from the disease. Primary care physicians should consider referring patients with a family history of the disease for a complete ophthalmologic examination. In addition, evaluation of the optic nerve by direct ophthalmoscopy may identify suspicious signs of optic nerve damage that should also prompt referral to an eye care specialist.

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Article Information
Section Editor: Mary McGrae McDermott, MD, Senior Editor.
Submissions:We encourage authors to submit papers for consideration as a Review. Please contact Mary McGrae McDermott, MD, at mdm608@northwestern.edu.

Corresponding Author: Robert N. Weinreb, MD, UC San Diego, Shiley Eye Center, 9500 Gilman Dr, MC 0946, La Jolla, CA 92093-0946 (rweinreb@ucsd.edu).

Author Contributions: Drs Weinreb, Aung, and Medeiros had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: All authors.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: All authors.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: All authors.

Obtained funding: Medeiros.

Administrative, technical, or material support: Weinreb, Medeiros.

Study supervision: All authors.

Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Weinreb reported that he has worked as a consultant for Alcon, Allergan, Anakem, Aquesys, Bausch and Lomb, Carl Zeiss Meditec, Quark, Sensimed, Solx, Topcon and has received research support from National Eye Institute, Nidek, Genentech, Quark, and Topcon. Dr Aung reported that he has worked as a consultant for Alcon, Allergan, Bausch and Lomb, MSD, and Quark; has received research support from Alcon, Allergan, Aquesys, Carl Zeiss Meditec, Ellex, and Ocular Therapeutics; and has received lecture fees from Alcon, Allergan, Carl Zeiss Meditec, Ellex, Pfizer, and Santen. Dr Medeiros reported that he has received research support from the National Eye Institute, Alcon, Allergan, Merck, Carl-Zeiss Meditec, Heidelberg Engineering, Sensimed, and Reichert.

Funding/Support: This study was supported in part by grants EY019692 (Weinreb), EY021818 (Medeiros), from the National Institutes of Health/National Eye Institute; and an unrestricted grant from Research to Prevent Blindness. Dr Aung is supported by grants from the National Medical Research Council, Singapore, and the National Research Foundation, Singapore.

Role of the Sponsor: The study sponsors had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

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