Seminar

Glaucoma
Harry A Quigley

Most medical practitioners have regular contact with adults who have one of the two forms of glaucoma: open-angle glaucoma or angle-closure glaucoma. Data from population-based surveys indicate that one in 40 adults older than 40 years has glaucoma with loss of visual function, which equates to 60 million people worldwide being aected and 84 million being bilaterally blind. Even in developed countries, half of glaucoma cases are undiagnosed. Glaucoma is mostly asymptomatic until late in the disease when visual problems arise. Vision loss from glaucoma cannot be recovered, and improved case-detection methods for glaucoma are needed. Glaucoma is commonly treated with daily eye-drop drugs, but adherence to treatment is often unsatisfactory. As a usually asymptomatic and chronic disease, glaucoma has similar treatment challenges to chronic systemic diseases. Similarities to the pathogenesis of common CNS diseases mean that common neuroprotective strategies might exist. Successful gene therapy, which has been used for other eye diseases might be possible for the treatment of glaucoma in the future.

Lancet 2011; 377: 136777 Published Online March 30, 2011 DOI:10.1016/S01406736(10)61423-7 Glaucoma Service and Dana Center for Preventive Ophthalmology, Wilmer Ophthalmological Institute, Johns Hopkins School of Medicine, Baltimore, MD, USA (H A Quigley MD) Correspondence to: Dr Harry A Quigley, Wilmer 122, Johns Hopkins Hospital, 600 North Wolfe Street, Baltimore, MD 21287, USA hquigley@jhmi.edu

Clinical denitions
In 2002, an international consensus panel published denitions of open-angle glaucoma and angle-closure glaucoma that are now widely accepted.1,2 For both disorders, glaucoma is now recognised to be an optic neuropathy and is thought to be present only when at least one eye has both typical structural and functional defects (optic disc damage and visual eld loss). This combination of damage has to be suciently characteristic to indicate the death of a substantial number of retinal ganglion cells in the inner retina and loss of their axons in the optic nerve. At the optic disc, nerve bres of retinal ganglion cells pass out of the eye, most often leaving a central depression or cup that is paler than the rim that contains these nerve bres. Clinicians can compare this cup with the overall disc size to establish the cup-to-disc ratio. As more retinal ganglion cells and their axons are aected by glaucoma, the cup-to-disc ratio progressively increases. The structural change that is most often recognised clinically by ophthalmoscopy (gure 1) and by imaging devices (gure 2) is the topographical deepening and widening (excavation) of the cup. This excavation consists of both loss of retinal ganglion cell axons and deformation of connective tissues supporting the optic disc (gure 1).3 The structural loss of axons can also be detected by thinning of the nerve bre layer surrounding the disc that consists of retinal ganglion cell axons, either by clinical examination or by imaging methods such as optical coherence tomography or scanning laser polarimetry. The characteristic functional loss is assessed by measuring light sensitivity at locations in the central 30 of vision (visual eld test; gure 3). The denition by the international consensus panel species that glaucoma is present when three or more locations of the eld test, in a particular pattern, are notably outside the limits of normal variability and when, in the same eye, the cup-todisc ratio is greater than that seen in 975% of the general population. These criteria assure that the structural nding is unlikely to be simply a typical variation in healthy individuals, and that both structural and functional injury has occurred.
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For open-angle glaucoma, the level of intraocular pressure, measured by tonometry at the cornea, is now recognised to not be a dening criterion. Open-angle glaucoma often occurs at an intraocular pressure that falls in the typical range. In Asia, most patients with open-angle glaucoma have similar pressure levels as those in healthy individuals,4 yet the higher this pressure, the more likely that open-angle glaucoma will occur. Thus, open-angle glaucoma is not a direct consequence of increased intraocular pressure, but is related to associated factors, such as the stress generated in the sclera and optic nerve head by this pressure and the interaction between blood ow and pressure level. Although patients with intraocular pressure above the normal range (ocular hypertension) have an increased risk for developing open-angle glaucoma, many of these patients will not develop the disease.5 Clinical research reports still commonly refer to patients with open-angle glaucoma and untreated intraocular pressure of less than 21 mm Hg as having normal tension glaucoma; however, there is no evidence that such dichotomous subdivision has a scientic basis, and investigators are now urged to treat intraocular pressure as a continuous variable in studies of open-angle glaucoma.6 Angle-closure glaucoma was formerly categorised as an acute attack of high intraocular pressure with symptoms

Search strategy and selection criteria I searched the PubMed and Google Scholar databases up to August, 2010, and the International Glaucoma Review Abstracts (2005 to 2010), with the following search terms: glaucoma, angle closure, open angle, pathogenesis, diagnosis, treatment, laser, surgery, genetics, childhood, secondary, and neovascular, both alone and in combinations. I mostly selected publications from the past 5 years, but did not exclude important older publications. I also searched the reference lists of articles identied by this search strategy and selected those judged relevant to this Seminar. Review articles were cited to provide readers with more detail. The reference list was modied on the basis of comments from peer reviewers.

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Figure 1: Typical features of the eye in healthy individuals and in patients with glaucoma The optic disc of individuals without glaucoma, as seen by ophthalmoscopy, has a central pale area (cup) that occupies about half or less of the optic disc with a surrounding orange rim of nerve tissue (A). With glaucoma damage the cup occupies an increasing proportion of the disc, the rim disappears, and the cup becomes excavated with a deep oor and a rim that is undermined (B). The typical histological appearance of the optic nerve head (C) changes in glaucoma with tissue loss from the rim and deepening of the cup (D). The connective tissues of the optic nerve head in healthy individuals when seen after digestion of neural tissue are like a thin meshwork across the nerve head, perforated by pores for nerve bundles (E). The disc in glaucoma deepens and widens with xed deformation of the connective tissue, leading to the characteristic excavation seen clinically (F).

the meshwork over more than half of the 360 angle. A later stage is primary angle closure, in which the structurally narrow angle is combined with one or more signs that the disease has caused damage. These signs are an intraocular pressure above the typical range for the general population, areas in which the iris is permanently adherent to the meshwork (peripheral anterior synechiae), or evidence that an event of very high intraocular pressure has occurred or is occurring (acute angle closure crisis). Changes in the optic disc and visual eld are similar between angle-closure glaucoma and open-angle glaucoma,8 although visual eld change is more diuse in patients with angle-closure glaucoma. Some patients with angle-closure glaucoma have an even more diuse form of optic atrophy than do most patients with this form of glaucoma, after the brief, severe increased intraocular pressure of angle closure attack. These patients have a pale, unexcavated disc, similar to that seen in some other non-glaucoma optic neuropathies.9 The prevalence of both open-angle glaucoma and angleclosure glaucoma is low before 40 years of age and increases exponentially with age.5 There are infrequent, but severe, examples of glaucoma occurring in infancy or childhood, some of which are associated with mutations in the CYP1B1 gene, coding for a molecule in the anterior eye tissues.10 The role of intraocular pressure in glaucoma will be further understood when monitoring devices to continuously monitor intraocular pressure, which are being tested in animals, can be implanted in human beings. This denition will establish the importance of uctuations in intraocular pressure compared with the mean pressure level and will enable study of the importance of nocturnal decreases in intraocular pressure and blood pressure in nerve damage attributable to glaucoma.

Open-angle glaucoma
Clinical features and risk factors
Open-angle glaucoma is distinguished from other optic neuropathies by slow progression over months to years.11 The clinical appearance of this form of glaucoma is distinguishable from ischaemic optic neuropathy12 or chiasmal tumour-induced neuropathy by the excavation or abnormal structural deepening of optic-disc connective tissue. Of retinal neurons, glaucoma aects only retinal ganglion cells13,14a loss that occurs selectively more rapidly in axons that pass through the upper and lower poles of the optic disc. Loss of function of the optic disc leads to characteristic mid-peripheral visual eld loss15 (gure 2 and gure 3). Loss of central visual acuity and the temporal visual eld typically occurs only in the end stage of disease (gure 4). Glaucoma functional loss is never substantially reversible, compared with chiasmal syndromes (eg, pituitary tumours) in which recovery of function is frequent. Open-angle glaucoma is most often bilateral, but asymmetric. On average, there is 50% as much damage in the better eye as in the worse eye.16
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of pain and sudden decreased vision. Most patients with this form of glaucoma are now recognised to not undergo acute attacks, but to have an asymptomatic, chronic disorder. For the diagnosis of angle-closure glaucoma, the appearance of the anterior chamber angle is very important. This angle is viewed during gonioscopy, during which a contact lens-like instrument containing a mirror is placed on the cornea to view the internal junction of the base of the iris with the trabecular meshwork. In some people, several contributing features that lead to obstruction of aqueous humour outoweg, small eye size, large lens, and congurations that increase resistance for uid movement from behind the iris to in front of the iris.7 In patients in whom primary angle closure is suspected, the iris blocks the clinical gonioscopic view of
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A
Quality: Poor (Imaging quality) Focus: 600 dpt Operator: SM Disc size: 176 mm (average) Cup Linear cup/disc ratio [] 050 (+001) p=039 Asymmetry 029 p=001 Cup shape measure [] 023 (001) p>05 Asymmetry 019 p=0002 004 (+004) p=0004 079 (+001) p=0005 Follow-up report Quality: Acceptable (SD 37 m) Focus: 1000 dpt Operator: SM Disc size: 178 mm (average)

OD

OS

Rim Rim area [mm] 132 (001) p>05 Asymmetry 066 p=0006 Rim volume [mm] 044 (007) p>05 Asymmetry 034 p=002 010 (+000) p<0001 066 (001) p<0001

MRA: within normal limits

MRA: outside normal limits

Figure 2: Diagnostic imaging of the optic nerve head to diagnose and monitor progressive change Confocal tomographic images (A) created by digital integration of reected light from successive planes of tissue show the excavation of glaucoma as enlargement of the cup in the left eye (red area in centre of disc image in upper right), compared with the right eye (upper left image) with a smaller red cup zone. Comparison with normative databases and with variation over time enables reasonable diagnostic and prognostic accuracy. Optical coherence tomography (B) uses sophisticated reprocessing of light reected from the retina to show individual layers and to measure loss of thickness in the retinal ganglion cell layer and retinal nerve bre layer in the zone, indicated by the green line in the left retinal image.

The mean age of onset is typically after the age of 60 years and the frequency of this disease rises with age.17,18 Because open-angle glaucoma does not spontaneously remit, the occurrence of this form of glaucoma is greater in elderly individuals than in younger people. Only a few patients with open-angle glaucoma develop bilateral blindness,16 even in the absence of treatment. However, because of the high prevalence of open-angle glaucoma and angle-closure glaucoma, together they are the second leading cause of world blindness after cataracts.19
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Genetic inuences have a role in both occurrence and morbidity of open-angle glaucoma, having a rst-degree relative who has open-angle glaucoma raises the likelihood for developing this disorder by ten times.20 The heritability index for open-angle glaucoma in studies of twins is signicant, but modest.21 Those with an aected family member should be advised to have regular examinations for open-angle glaucoma, including disc examination and visual eld testing. The high prevalence and morbidity of open-angle glaucoma in people of
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SUP

Central 24-2 threshold test Fixation monitor: blind spot Fixation target: central Fixation losses: 4/14 xx False POS errors: 5% False NEG errors: 18% Test duration: 05:13 Fovea: 33 dB Stimulus: III, white background: 315 ASB Strategy: SITA-fast Pupil diameter: Visual acuity: RX: +275 DS+150 DC20 Date: 10262001 Time: 8:48 AM Age: 69

25 26 27 27 27 24 29 27 27 16 30 <0 18 18 18 <0 <0 <0 <0 6

26 27 25 26 24 14 22 25 25 11 25 24 27 28 5 24 27 30

T E M

V A

N A S
1 0 1 1 2 4 1 4 4 10 11 13 14 34 29 31 21 34 26 24 17 10 34 9 4 4 2 1

5 14 22 <0 20 27 27 30 28

7 24 22 27 27 28 27 22 25

0 1 3 2 4 17 8 4 4 21 6 4 26 4 2 3 7 5 3 2 3 0

1 2 2 0 3 16 6 3 3 20 4 3 25 2 1 2 6 4 1 1

0 1

0 2 2

9 10 12 13 33 28 30 20 33 25 23 16 9 33 8 2 2 3 0

*** Low test reliability *** GHT Outside normal limits

25 7 8 3

24 6 7 1

MD 1103 dB p<05% PSD 1134 dB p<05%

Total deviation

Pattern deviation

<5% <2% <1% <05%

INF

Figure 3: Histological basis for selective loss of ganglion cells in glaucoma Loss of retinal ganglion cells and their axons occurs selectively, with upper and lower axons and their retinal ganglion cells being more aected than nasal and temporal axons, which is evident as an hour-glass shaped pattern in the optic nerve just behind the eye (A). Atrophic areas are lighter in colour than non-atrophic areas (B). The selective polar axon loss is indicative of lower density of connective tissue in the upper and lower quadrants of the optic nerve head (B). Visual eld result shows the corresponding upper and lower mid-peripheral loss of function from polar area axons at a moderate stage of glaucoma (C). V=vein. A=artery. SUP=superior. TEM=temporal. INF=inferior. NAS=nasal.

Central 24-2 threshold test Fixation monitor: blind spot Fixation target: central Fixation losses: 4/16 xx False POS errors: 4% False NEG errors: 2% Test duration: 06:04 Fovea: 38 dB Stimulus: III, white background: 315 ASB Strategy: SITA-standard Pupil diameter: Visual acuity: RX: +000 DS+175 DC175 Date: 07212004 Time: 3:11 PM Age: 62

Central 24-2 threshold test Fixation monitor: blind spot Fixation target: central Fixation losses: 4/16 xx False POS errors: 0% False NEG errors: 40% Test duration: 06:49 Fovea: 30 dB Stimulus: III, white background: 315 ASB Strategy: SITA-standard Pupil diameter: Visual acuity: RX: +375 DS+125 DC95 Date: 08032007 Time: 12:08 PM Age: 84

Central 24-2 threshold test Fixation monitor: blind spot Fixation target: central Fixation losses: 0/17 False POS errors: 0% False NEG errors: 8% Test duration: 06:46 Fovea: 32 dB
17 0 6

Stimulus: III, white background: 315 ASB Strategy: SITA-standard

Pupil diameter: Visual acuity: RX: +100 DS DC

Date: 04262006 Time: 3:03 PM Age: 75

25 30 27 29 26 27 28 30 28 30 19 32 33 30 27 0 31 32

22 28 28 29 25 30 30 30 23 31 31 29 26 32 28 21 14 31 21 7 <0 28 <0 30

15 19 25 24 26 23 27 24 27 28 23 27 29 30 28 0 26 28

2 6

7 <0 11 8 6 0 5 <0 <0 30

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21 22 <0 <0 23 0 12 4

<0 12 8 0

0 <0

29 <0 <0 <0 9 7 10 11

22 <0 23 25 19 <0 12 6 17 6 6 0 2

27 17 <0 <0 1 <0 <0 <0 5 0 <0

28 30 21 31 29 30 29 28 26

22 17 22 24 16 24 23 17 19

30 18 <0 16 22

<0 21 12 22 22

0 <0

0 1 3 2 4 17 8 4 4 21 6 4 26 4 2 3 7 5 3 2 3 0

1 2 2 0 3 16 6 3 3 20 4 3 25 2 1 2 6 4 1 1

9 6 1 3 2

25 21 14 10 17 6 6 31 29 6 15 32 22 27 2 33 32 30 27 22 23 19 17 32 9 16 7 5 2 2 2 1

7 4 0 1 0 1 0 1 3 1 1

23 19 12 8 15 3 4 28 26 4 13 29 19 24 0 31 30 28 25 19 21 17 15 30 6 14 4 3

25 24 10 22 22

1928 1820 21 32182922 23 31 30 30 27 5 153231 28 31333230 2530 31 2930 1 3 1

17 16 2 14 14 2 23 24 z 10 19 0 2

1120 10 12 13 24102114 1523222212 3 6242219 23252422 172223 2122

1 1 2 4 1 4 4 10 11 13 14 34 29 31 21 34 26 24 17 10 34 9 4 4 2 1

0 1

0 2 2

9 10 12 13 33 28 30 20 33 25 23 16 9 33 8 2 2 3 0

*** Low test reliability *** GHT Outside normal limits

4 1 5 3 0 1 3 2 4 2 13 6 7 12 9

*** Low test reliability *** GHT Outside normal limits

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*** Low test reliability *** GHT Outside normal limits

25 7 8 3

24 6 7 1

7 12 8 7

4 10 6 4 10 3 5 9 7

10 32 25 14

2 24 17 6 9 16 22 14 19

MD 433 dB p<05% PSD 800 dB p<05%

MD 1289 dB p<05% PSD 1135 dB p<05%

MD 2275 dB p<05% PSD 956 dB p<05%

Total deviation

Pattern deviation

Total deviation

Pattern deviation

Total deviation

Pattern deviation

<5% <2% <1% <05%

<5% <2% <1% <05%

<5% <2% <1% <05%

Figure 4: Visual eld test of the left eyes show early (A), moderate (B), and severe (C) stages of functional loss Damage starts in the nasal eld, most often in upper or lower half quadrants (A). Mid-stage disease has more worse loss in the initial hemield and also has loss in opposite hemield (B). At nearly end-stage disease, only a central island of vision remains (C).

African ethnic origin compared with European22,23 or Asian people is further evidence for the heritability of this glaucoma. Finally, mutations in multiple genes and additional genomic regions contribute to open-angle glaucoma24 or are associated with exfoliation syndrome; patients with this syndrome have a high risk of developing open-angle glaucoma.25,26 Although intraocular pressure is common in many patients with open-angle glaucoma, the higher this pressure,27 the greater the likelihood of developing the disorder and the more rapidly it progressively worsens. Nevertheless, most patients with intraocular pressure outside the typical range (ocular hypertension) in a population will not develop clinical open-angle glaucoma.28 Measurement of intraocular pressure by
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tonometry, during which tonometers are placed on the cornea, is now recognised to be more aected by the behaviour of the cornea than was previously thought. A thicker central cornea, as measured by ultrasonic pachymetry, leads to a higher measured intraocular pressure than is actually present, whereas a thinner central cornea not only understates the true intraocular pressure, but might itself be somehow associated with increased occurrence of open-angle glaucoma or more rapid progressive worsening.29,30 Thus, the biomechanical response of the eye to this pressure aects which eyes will develop glaucoma damage. Experimental or spontaneous increased intraocular pressure exacerbates retinal ganglion cell loss in animals (monkey, cat, rat, and mouse).31 The translation of stress in the ocular
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cornea and sclera to the retinal ganglion cell axons at the optic nerve head as they pass out of the eye to brain relay centres is one of the initiating features of the pathogenesis of open-angle glaucoma.32 Risk factors that increase strain from intraocular pressure include large eye size (axial myopia), larger disc diameter, and thinner central cornea thickness.33 Treatments that lower intraocular pressure slowed glaucoma progression in controlled clinical trials.34 Data from both population-based studies and controlled clinical trials indicate that vascular nutrition also aects the likelihood of development of open-angle glaucoma and its progression,35 although the increased risk is associated with reduced calculated perfusion pressure the dierence between blood pressure and intraocular pressure rather than the absolute level of blood pressure. However, attempts to raise blood pressure to benet patients with open-angle glaucoma are at present unproven and potentially dangerous.36 Methods to measure nutritional blood ow in human beings are inexact, but haemorrhages on the optic disc are seen in those progressing more rapidly,37 indicating microvascular damage. Use of risk calculation schemes based on longitudinal follow-up data in decision making for patients with glaucoma might improve treatment outcomes.3840

Pathogenesis
Alterations of the connective tissues at the optic disc cause the characteristic cup excavation of glaucoma and are coincident with the initial axon abnormalities in both human and experimental glaucoma.41 Axons grouped together at the optic disc undergo apoptosis together, indicating that this area is a prominent injury site, although damage in the retina and even in the optic nerve behind the eye are potential contributors. Various detrimental eects at the nerve head lead to axonal injury, and blockade of both anterograde and retrograde axonal transport occurs;42 some of these eects are associated with intraocular pressure. Responses mediated by axon injury are likely to be rapidly transmitted to the retinal ganglion cell body in the retina and distally to the brain through the axon. Retinal ganglion cells depend on neurotrophic support provided by their brain target neurons and by retinal interactions. Interruption of axonal transport reduces concentrations of trophic molecules. If survival mechanisms do not succeed, apoptosis of retinal ganglion cells is triggered, with early loss of axons by Wallerian degeneration and then somal death after an abortive attempt at regeneration.43 Cell survival can be enhanced by overexpression of neurotrophins,44 by knockout of the Bax protein associated with apoptosis,45 by inhibition of calcineurin generation,46 and by inhibition of cysteine protease enzyme eectors of apoptosis.47 Initial degeneration of some retinal ganglion cells seems to lead to a toxic environment with secondary retinal ganglion cell loss caused by events such as glutamate excitotoxicity,48 free radical
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generation,49 and dysfunctional immune responses.50 In a rat model of glaucoma, the local generation of nitric oxide at the optic nerve head was associated with damage from glaucoma, and mitigation of this damage was therapeutic.51 Astrocytic glia that lend support to the retinal ganglion cells and their axons probably have important roles in both protecting and damaging neurons, with strong evidence that tumour necrosis factor derived from astrocytes is pathogenic.52 Therapeutic approaches to these factors in experimental settings might also be relevant in human trials. One large trial of an N-methyl-D-aspartate acid receptor antagonist, memantine, has apparently not succeeded. As with CNS disorders, glaucoma has substantial barriers to the translation to human beings of neuroprotective strategies that seemed promising in animal experiments.53 There are some similarities in the pathways for neuronal dysfunction in glaucoma and Alzheimers diseaseboth have excess concentrations of amyloid54 and loss of thickness in the nerve bre layer.55 In patients with open-angle glaucoma whose intraocular pressure is above the normal range, deciencies in the ability of the trabecular meshwork to manage aqueous humour outow are probably partly attributable to loss of its lining cells, accumulation of extracellular molecules blocking outow,56 and, in a few patients, deleterious eects of mutated myocilin.57 Attempts at gene overexpression with viral vectors injected into the anterior chamber have suggested a possible new means to produce a longlasting reduction of intraocular pressure.58 Improvements in treatment of glaucoma in the future could come from one of four areas: improving intraocular pressure by enhancing outow of aqueous humour, changing the biomechanical response of the sclera and nerve head to stress induced by intraocular pressure, improving vascular micronutrition in the retina and optic disc, or redirecting glial responses to protective rather than detrimental ones. A potential treatment to preserve vision through methods other than lowering of intraocular pressure could be viral vector delivery of neurotrophins, as indicated in animal models of glaucoma44 and in short-term human clinical trials in patients with Lebers congenital amaurosis.59

Diagnosis
Glaucoma is undiagnosed in nine of ten aected people worldwide and is undiagnosed in 50% of those in developed countries;1 thus, improved case detection is needed. Population screening outside the health-care system is not cost eective because it needs detailed examination of optic disc structure and formal visual eld testing.60,61 Individuals without glaucoma vary widely in both types of testing, making the predictive power of screening too low. Preferred practice patterns from professional organisations suggest monitoring structural glaucoma damage by clinical observation of the optic disc and by photography or digital imaging of the optic disc
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and nerve bre layer. Data from studies have indicated that imaging instruments are useful determinants of the presence and progressive change in glaucoma.62,63 Automated visual eld testing with threshold strategies64 is repeated regularly to establish the rate of progressive worsening65 as a means to judge the success of treatments that lower intraocular pressure. To detect early retinal ganglion cell damage, potentially at a reversible stage of injury, imaging methods applicable to the living eye are needed. Techniques for such imaging are being developed in animals,66,67 and high priority should be given to translating these techniques into practical methods for clinical use and as outcomes in neuroprotection clinical trials.

Treatment
In controlled clinical trials, substantial benet of intraocular pressure-lowering treatment for patients suspected to have glaucoma were reported before initial damage was seen.68 A consensus panel in the UK based its recommendations for whether to treat patients with intraocular pressure greater than 21 mm Hg on assessment of risk factors, including age and central corneal thickness.69 Cost-eectiveness analyses conrm that some patients with ocular hypertension could be more properly followed up by detailed testing on the basis of risk factor assessment, without needing to lower intraocular pressure.70 For patients with established open-angle glaucoma (dened as having optic nerve damage), lowering of intraocular pressure is eective and always recommended, irrespective of whether intraocular pressure is abnormal.71 Lowering of this pressure is accomplished by daily eye drops, laser treatment to the trabecular meshwork, or operative surgical procedures. The eectiveness of the three approaches has been compared pairwise in randomised controlled trials, with the main dierences being the rate and type of side-eects.7274 For example, severe loss of vision was uncommon, but this side-eect only occurs after surgery, whereas laser treatment has the lowest rate of side-eects overall. In clinical practice, most patients begin treatment with eye drops, most often with prostaglandin analogue or -adrenergic antagonists. For every patient, the baseline intraocular pressure without treatment is assessed and this pressure is lowered to a target pressure unique to that individual,75 with lower targets for those with either greater initial damage or more risk factors for progression. When this pressure is lowered by 2040%, the average rate of progressive visual eld loss is reduced by half. Although this treatment reduces the rate of progressive vision loss over the lifetime of many patients, those with rapid rates of deterioration need to undergo an escalation of treatment to preserve vision. Adherence to treatment is not ideal and is similar to pill-based treatment for other chronic, asymptomatic diseases.76 Adherence research that used electronic
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monitoring and pharmacy-rell data indicated that only 6070% of prescribed doses of eye drops are taken by patients with glaucoma.76 Physician behaviour and attitudes of patients that aect adherence have been studied, and interventions with reminder systems show that substantial improvement is feasible.77 Laser delivery to the trabecular meshwork with either continuous wave or pulsed lasers (argon laser trabeculoplasty or selective laser trabeculoplasty) leads to some lowering of intraocular pressure with minimum risk and side-eects. These outpatient treatments are done under topical anaesthesia, and are sometimes repeated. The most common glaucoma operative surgery is trabeculectomy, which forms a controlled leaking area for aqueous humour from the anterior chamber to a zone of the upper eye overlying the sclera, sometimes visible as a thin area called a bleb. Trabeculectomy achieves the desired lowering of intraocular pressure in most patients operated on for at least 5 years. Adjuvant delivery of topical or injected antibrotic drugs (mitomycin and uorouracil) are often used when increased scarring is anticipated, to restrict trabeculectomy success by closing the outow channel. Late complications of trabeculectomy include overt leakage through the bleb with dysfunctionally low intraocular pressure or bacterial infection. Progressive worsening of cataracts is common in patients undergoing trabeculectomy.71 For patients who are less likely to benet from trabeculectomy, articial tubereservoir devices can be inserted surgically into the anterior chamber, leading uid to drain to the orbital surface of the eye (so-called tubeshunt surgery). This surgery had similar outcomes to trabeculectomy in a controlled clinical trial in patients who had had previous surgery and who would be expected to have high failure rates with trabeculectomy.78 In patients with advanced disease, intraocular pressure is lowered by decreasing aqueous inow through destruction of the ciliary body with laser energy from instruments outside or within the eye. Sustained delivery of treatment should be an active area of research, either through depot placement of sustained-release treatment or by placement of cells engineered to produce benecial substances.79 Visionthreatening complications of present surgical techniques, including dysfunctionally low intraocular pressure and late infection, mandate research into new approaches to glaucoma surgery.

Angle-closure glaucoma
Clinical features, risk factors, and pathogenesis
Although angle-closure glaucoma is often related to an acute, painful crisis associated with blurred vision, more than 75% of patients do not have an acute attack,80 instead they have an asymptomatic course with progressive loss of the visual eld similar to that in patients with open-angle glaucoma. Worldwide, a third of patients with primary glaucoma have angle-closure glaucoma.1
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The proportionate vision loss in angle-closure glaucoma might be as much as twice as great as open-angle glaucoma, so half of patients blinded by glaucoma have angle-closure glaucoma.81 Epidemiological observations by Alsbirk82 documented a high prevalence of angleclosure glaucoma in Greenland, and conrmed that small eye size was a major risk factor. Data from later population-based studies in China,83 India,84 Europe,85 and Africa86 indicated that risk of developing angleclosure glaucoma increases exponentially with age, is more common in women, and has a greater prevalence in people of Asian and Indian ethnic origin than in those of European and African descent.87 People of African and European ethnic origin have a similar prevalence of angle-closure glaucoma. Because of the ethnic distribution and the large populations in which angle-closure glaucoma is more prevalent, many patients with this type of glaucoma live in Asia and India. Because eye size is partly genetically determined,88 the fact that data from twin studies lend support to a genetic eect in the disease is not surprising. No specic gene has yet been associated with angle-closure glaucoma. Angle-closure glaucoma is distinguished from openangle glaucoma by the closure of the angle between the iris and cornea, obstructing outow of aqueous humour. This obstruction often results from high resistance for aqueous movement, through the doughnut-shaped channel between the iris and lens that is 25 m in height or less in eyes with denite angle closure. Increased resistance in this irislens channel leads the iris to bow forward, closing o access to the trabecular meshwork and decreasing aqueous humour outow. If present for days to weeks, this event leads to permanent adherence of the iris to the meshwork, chronically increased intraocular pressure, and eventually to glaucomatous neuropathy similar to that seen in open-angle glaucoma. The production of a hole through the iris with laser, iridotomy, removes this basic mechanism and is an initial treatment for patients with angle-closure glaucoma. Although people with angle-closure glaucoma have eyes of shorter overall length and with shallower anterior chambers than the mean in the general population, anatomic size does not explain why most people with narrow angles do not develop the disease. Additionally, small eye size alone does not explain the high prevalence of angle-closure glaucoma in Chinese people, who proportionately do not have smaller diameter eyes than do European people, but have ve times the prevalence of angle-closure glaucoma.89 Abnormalities in dynamic, physiological responses seem to be indicators of which smaller eyes develop angle-closure glaucoma.7 The iris gains and loses volume with pupil constriction and dilation, presumably by exchange of aqueous humour between the iris stroma and the anterior chamber90 (gure 5). Patients with angle closure, particularly those who have an acute high intraocular pressure, do not lose enough iris volume on pupil enlargement, increasing
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the likelihood that the iris obstructs the angle.91 Additionally, uid movement between the iris and lens meets greater resistance with forward movement of the lens. Individuals with angle closure seem to have expansion of the extravascular space of the choroid (between the retina and sclera), causing forward movement of the lens and intensifying the block of aqueous humour through the pupil.92

Diagnosis
The denitive clinical examination to identify people at risk for angle-closure glaucoma is gonioscopy. Although several systems for gonioscopic grading exist, none has
A

Figure 5: Optical coherence tomographic images showing features of angle-closure glaucoma Images from optical coherence tomography show a cross-section of the iris with a small pupil (A) that is dilated in dim light (B). The space between the iris and cornea narrows in this angle-closure eye. The failure of normal loss of iris cross-sectional area on dilation of pupil might contribute to closure of the angle. Optical coherence tomography image including the mid-section of the eye (C) shows the wall of the eye consisting of the sclera, choroid, and retina. In angle-closure eye (D), there is expansion of extravascular space in the choroid, seen as a dark cleft (arrow). This choroidal expansion probably contributes to internal forces that increase resistance to movement of the aqueous humour through the pupil.

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been validated in a prospective trial to measure its predictive power. Several lens types are in use, with some allowing dynamic viewing to look for scarring (synechiae) of the iris to the meshworksigns that permanent angle closure has begun. Present gonioscopic grading, ultrasound biomicroscopy, and optical coherence tomography evaluations cannot be used to predict with accuracy who will develop angle-closure glaucoma.93 Provocative tests for angle-closure glaucoma have been used in which the pupil is dilated, looking for an increased intraocular pressure as the outcome, but these tests have poor predictive power.94 Because the number of individuals suspected to have angle closure is greater than the number who will develop the disease, more people are treated with the initial step of iridotomy than actually need the treatment. New anterior segment optical coherence tomographic imaging measures of iris volume change and posterior segment optical coherence tomographic estimation of choroidal volume have promise as predictive tests for the development and progression of angle-closure glaucoma.

and the same type of chronic examination schedule is usedmonitoring the optic disc, nerve bre layer, and visual eld. There is controversy about the role of early lens removal in patients with angle-closure glaucoma, with some suggestions that the long-term outcome might be improved.99 Longitudinal studies are needed to establish risk factors for the occurrence and progression of angle-closure glaucoma.

Other forms of glaucoma

Glaucoma is uncommon in children, with an estimated prevalence in the USA of fewer than three per 100 000 for all forms of glaucoma in those younger than 20 years.100 Many of these cases are primary childhood-onset glaucoma, which presents during the rst year of life with symptoms of tearing and photophobia and signs of enlarged and cloudy corneas. There is substantial heritability, and three genetic loci have been identied for childhood glaucoma, with one gene clearly associated with the syndrome (CYP1B1).101 Diagnosis is made by examination of the anterior eye and optic disc, measurement of cornea and eye dimensions, and measurement of intraocular pressure, which has been made more convenient by a new tonometer for which the patient does not need anaesthesia.102 Although eyedrops are sometimes used temporarily, treatment is mainly surgical, by the specic operative procedures trabeculotomy and goniotomy used for eyes of children younger than 10 years, which improve outow through the trabecular meshwork. When these techniques do not succeed, trabeculectomy and tube-shunts that bypass existing outow are done, as for adult glaucoma.103,104 In addition to the primary glaucomas, several ocular disorders lead to an increase in intraocular pressure sucient to present a risk to optic nerve structure and function; these disorders are the secondary glaucomas. The common feature of their mechanisms is reduction in outow of aqueous humour, by causes such as inammatory debris, red blood cells from intraocular haemorrhage, and growth of new blood vessels in the angle (neovascular glaucoma) resulting from ocular vascular diseases of the eye. Neovascular glaucoma is most common in patients with diabetes, in people with occlusions of major retinal vessels, and in those with carotid artery obstructive disease. Initial treatment for secondary glaucoma is to stabilise or inhibit the inciting disorder. For neovascular glaucoma, this therapy can be laser treatment for the retina and, more recently, the injection of inhibitors of vascular endothelial growth factor.105 Exposure to corticosteroids can lead to secondary glaucoma, most often after oral delivery, but even after inhaled and nasal spray forms.106 Physicians prescribing corticosteroids in any form should elicit ocular history for patients with glaucoma and are advised that detailed eye examination is the only method to establish whether the treatment is leading to secondary glaucoma.
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Treatment
In many patients with angle-closure glaucoma, the resistance at the irislens channel is a dominant feature, and bypassing the pupil block by making a laser hole in the peripheral iris is curative. Both eyes of patients with primary angle closure are treated with iridotomy. Even patients who have an acute angle-closure crisis with very high intraocular pressure are initially treated to make a hole in the iris. Most eyes can have successful iridotomy under topical anaesthesia produced by laser treatment. Iridotomy is well tolerated and associated with few sideeects,95 but better methods are needed to limit iridotomy to those suspected to have angle-closure glaucoma who are most likely to benet.96 Although the angle appears more open after iridotomy in two-thirds of patients, the angle remains narrow after the iris hole in a third of patients; however, most of these patients who still have narrow-looking eyes do not go on to develop angle-closure glaucoma over ensuing years, even if the aected eye had an acute angle-closure crisis.97 Rarely, other mechanisms participate in continued angle-closure disease after iridotomy, involving direct blockade of the angle by the iris (plateau iris syndrome)98 and forward collapse of the vitreous humour (malignant glaucoma). Specic forms of laser treatment (iridoplasty) and operative surgery (vitrectomy) are used when these disorders arise, and their mechanisms and contribution to angle-closure glaucoma overall are still controversial. If angle closure has been active before iridotomy, and especially if adhesions of the iris to the meshwork have formed, glaucomatous neuropathy might have already occurred at the time of diagnosis. This advanced stage of disease necessitates the same type of treatments to lower intraocular pressure as that for open-angle glaucoma,
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Conclusions
Both open-angle and angle-closure glaucoma are commonly present in older people and, with the ageing of world populations, the number with both forms of glaucoma will substantially increase in the next decade.1 The diagnosis of glaucoma of each type requires a detailed eye examination, with tests of both structure and function of the eye. New developments in diagnostic testing might soon make this process more ecient. Therapy that lowers intraocular pressure slows the progress of open-angle and angle-closure glaucoma, but approaches that supplement this treatment by protecting retinal ganglion cells from death are actively being sought. Newer predictive tests are being evaluated to establish which suspects for angle-closure glaucoma merit initial laser iridotomy.
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