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SEMINAR

Glaucoma is a group of progressive optic neuropathiesthat have in common a slow progressive degeneration ofretinal ganglion cells and their axons, resulting in adistinct appearance of the optic disc and a concomitantpattern of visual loss. The biological basis of the disease isnot yet fully understood, and the factors contributing toits progression are not yet fully characterised. However,intraocular pressure is the only proven treatable riskfactor. Without adequate treatment, glaucoma canprogress to visual disability and eventual blindness. Thisseminar will address primary open-angle glaucoma, anage-related and insidious form of the disease.

EpidemiologyIt is estimated that glaucoma affects more than 66 millionindividuals worldwide with at least 6·8 million bilaterallyblind.1 Vision loss caused by glaucoma is irreversible, andglaucoma is the second leading cause of blindness in theworld. Of the many types of glaucoma, primary open-angle glaucoma is perhaps the most common, particularlyin populations of European and African ancestry.2,3 Thedisease is the leading cause of blindness in African-Americans.

In the USA, more than 7 million office visits occur peryear to monitor patients who have glaucoma or are at riskof developing the disease.3,4 Blindness from all forms ofglaucoma in the USA is estimated to cost in excess of$1·5 billion annually. However, the scope of the problemis probably larger than these numbers suggest, and asubstantial proportion of individuals remain eitherundiagnosed or inadequately treated. The number ofindividuals suspected to have glaucoma—usually thosewith raised intraocular pressure (ocular hypertension) orasymmetric optic disc appearance—far exceeds thenumber who have been diagnosed with the disease.

Lancet 2004; 363: 1711–20

Hamilton Glaucoma Center and Department of Ophthalmology,University of California San Diego, 9500 Gilman Drive, La Jolla CA92093-0946, USA (Prof R N Weinreb MD); and Glaucoma Unit andOcular Repair and Regeneration Biology Unit, Moorfields EyeHospital and Institute of Ophthalmology, University CollegeLondon, London, UK (Prof P T Khaw PhD)

Correspondence to: Prof R N Weinreb(e-mail: weinreb@eyecenter.ucsd.edu)

Moreover, the magnitude of the problem will increase asthe population ages.3

Anatomy and physiology Aqueous humour secretion and drainageIntraocular pressure is regulated by a balance between thesecretion and drainage of aqueous humour (figure 1).This fluid is secreted posterior to the iris by the ciliarybody and then flows anteriorly to the anterior chamber.Aqueous humour provides nutrients to the iris, lens, andcornea. It exits the eye into the venous circulation via thetrabecular meshwork and independently through theuveoscleral outflow pathway.

The optic nerve and inner retinaAxons of retinal ganglion cells comprise the retinal nervefibre layer, the innermost layer of the retina. The humanoptic nerve contains about one million nerve fibres(figure 2). These axons converge on the optic disc (alsoknown as the optic nerve head) and form the optic nerve.The fibres exit the eye after traversing the lamina cribrosa, aseries of perforated connective tissue sheets, and synapse inthe lateral geniculate nucleus of the brain. The optic disc isabout 1·5 mm in diameter and vertically oval. Its area variesup to sevenfold, and is largest in highly myopic individuals.The convergence of the axons forms a central depression inthe disc, known as the cup. Most, but not all, optic nerveshave a visible physiologic cup. The neuroretinal rim of theoptic nerve head is pink and surrounds the cup. Trophicfactors, including brain-derived neurotrophic factor, areretrogradely transported from the axonal terminals ofretinal ganglion cells to their cell bodies in the inner retina,and are essential for the survival of the cells. Glutamate, aneurotransmitter, is normally present in low concentrationsin the retina. Trophic factors also are transported via retinalganglion cell axons in an anterograde fashion to the lateralgeniculate nucleus.

Primary open-angle glaucoma

Robert N Weinreb, Peng Tee Khaw

Seminar

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Primary open-angle glaucoma is a progressive optic neuropathy and, perhaps, the most common form of glaucoma.Because the disease is treatable, and because the visual impairment caused by glaucoma is irreversible, earlydetection is essential. Early diagnosis depends on examination of the optic disc, retinal nerve fibre layer, and visualfield. New imaging and psychophysical tests can improve both detection and monitoring of the progression of thedisease. Recently completed long-term clinical trials provide convincing evidence that lowering intraocular pressureprevents progression at both the early and late stages of the disease. The degree of protection is related to the degreeto which intraocular pressure is lowered. Improvements in therapy consist of more effective and better-tolerated drugsto lower intraocular pressure, and more effective surgical procedures. New treatments to directly treat and protect theretinal ganglion cells that are damaged in glaucoma are also in development.

Search strategy and selection criteriaWe systematically searched MEDLINE with terminologyrelating to primary open-angle glaucoma discussed in thisreview. Keywords used were glaucoma, open-angle glaucoma,primary open-angle glaucoma, glaucoma blindness, ocularhypertension. Articles were reviewed up to June, 2003, andstudies reported in full and in abstract form have beenreported.

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PathophysiologyGlaucoma is a neurodegenerative disease characterised bythe slow, progressive degeneration of retinal ganglioncells.5 With glaucoma, the width of the neuroretinal rimdecreases with concomitant enlargement of the cup.Other optic neuropathies usually result in pallor of theoptic nerve head but, for unknown reasons, rarely showenlargement of the optic disc cup. Glaucomatousneuronal death is not limited to changes in the retinalganglion cell axons, soma, and dendrites;6 neurons in thelateral geniculate nucleus7–9 and the visual cortex9,10 arealso lost. Outcomes of both functional (psychophysical)testing11 and histological studies7,9 suggest that thepathological process does not discriminate among subsetsof retinal ganglion cells. Glial cells also are affected, and itis possible that astrocytes, perhaps activated by raisedintraocular pressure or by other mechanisms, alter theenvironment of the axons and produce a milieu thatcauses axonal degeneration or that prevents survival of thehealthy retinal ganglion cells.12,13

The pathophysiology of glaucomatous neurodegenera-tion is not fully understood. The level of intraocularpressure is unquestionably related to the death of retinal

ganglion cells and optic nerve fibres in some, if not all,patients with primary open-angle glaucoma. Although noobstruction can be seen with clinical examination,resistance to aqueous outflow through the trabecularmeshwork is increased in patients with this form ofglaucoma, often associated with high intraocular pressure.When pressure increases above physiological levels, thepressure gradient across the lamina cribrosa alsoincreases. As a result, the lamina cribrosa and the retinalganglion cell axons undergo deformation and mechanicalstress.14 In glaucoma, cupping of the optic disc andcompression, stretching, and remodelling12 of the laminacribrosa can arise in response to raised intraocularpressure. In experimental models of glaucoma, there is ablockade of retinal ganglion cell axonal protein transportdue to intraocular pressure-induced compression of opticnerve axons at the lamina cribrosa.5,15 In primary open-angle glaucoma, retinal ganglion cell axon compressioncan impair trophic factor axonal transport, causing deathof the cells by trophic insufficiency.

Independently or in addition to intraocular pressure,other factors can individually or collectively contribute todeath of retinal ganglion cells and optic nerve fibres inglaucoma (figure 3). The retina is dependent on its bloodsupply for meeting its high metabolic needs, and localischaemia-hypoxia, perhaps due to dysfunction of blood-flow autoregulation, has been implicated as one of thesefactors.16 However, the role of ischaemic-hypoxia has beendifficult to establish, since it is difficult to assessexperimentally and clinically. Excessive stimulation of theglutamatergic system, specifically the N-methyl-D-aspartate subtypes, has also been proposed to contributeto death of retinal ganglion cells in glaucoma.17–19

However, there is still debate on whether excess glutamatehas a positive or negative effect on retinal ganglion cells,and whether various classes of cells respond differently toglutamate. Other proposed contributors include poorlyfunctioning cellular pumps and glutamate transporters,oxidative stress and formation of free radicals,inflammatory cytokines (tumour necrosis factor and nitricoxide),20,21 and aberrant immunity.22,23 The response to aninitial optic nerve injury in glaucoma also can lead tosecondary neurodegeneration among surviving retinalganglion cells and their fibres. According to this view,although the primary insult does not directly affect allfibres and retinal ganglion cells, it causes alterations in theneuronal environment that in turn increase thevulnerability of spared neurons.20,22

Nonhuman primates have been the animal of choice forstudying glaucoma. Monkeys have been shown to developglaucomatous changes in the optic nerve when theirintraocular pressure is raised experimentally. Monkeyscan be trained to perform visual field tests, and those withexperimental glaucoma show deficits indicative ofglaucoma.10

Rodent models (both genetically engineered mice24–26

and experimental models of ocular hypertension inmice27,28 and rats29,30) enhance the potential to investigatemechanisms at the molecular and cellular levels. Theoptic nerve head of these animals is similar to that of theprimate, including the connective tissue and cellular(astrocyte) support structures of the optic nerve axonbundles, and the response of their optic nerve to injuryhas clinical and experimental features similar to those ofhumans beings with glaucoma. The dynamics of theaqueous humour in mice,31—including a diurnal variationof intraocular pressure,32 and responses to various drugsthat lower intraocular pressure—also are similar to thoseof human beings.

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Cornea

Trabecular meshwork

Uveos

cleral

outflo

w

Ciliary body

Iris

Anterior chamber

Figure 1: Physiology of aqueous humourIntraocular pressure is determined by the balance between secretion anddrainage of aqueous humour. Arrows show direction of flow; aqueoushumour is secreted by the ciliary body into the posterior chamber, passesposterior to the iris and through the pupil into the anterior chamber, andexits through the trabecular meshwork or uveoscleral outflow pathways.

Normal

Glaucoma

A

A

B

B

C

CFigure 2: Optic nerve in healthy and glaucomatous eyes(A) The normal optic disc has a small central cup. The central cup of theglaucomatous disc is enlarged and deepened, and the surroundingneuroretinal rim is thinned. Optic disc haemorrhage (arrow) is sometimesobserved in an eye with glaucoma. (B) Longitudinal cross-section ofnormal and glaucomatous optic nerve. The retinal nerve fibre layer (arrow)is the innermost layer of the retina, and is thin in the glaucomatous opticnerve. (C) Transverse cross-section of normal and glaucomatous opticnerve. The normal optic nerve has about 1 million optic nerve fibres. Asglaucoma progresses, the number of nerve fibres is reduced, andconcomitant reduction in diameter of the optic nerve is seen.

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DiagnosisPrimary open-angle glaucoma is a chronic, generallybilateral, but often asymmetrical, disease that is character-ised by progressive damage of the optic nerve as shown bychanges in the optic disc, retinal nerve fibre layer, or visualfield. The disease has an adult onset, with open anteriorchamber angles of normal appearance and an absence ofother known explanations for the change in the opticnerve. If detected early, disease progression can frequentlybe arrested or slowed with medical and surgical treatment.

Assessment of the optic disc Examination of the optic disc is the most valuable methodof diagnosing early glaucoma, because the optic nerveappearance often changes before visual field loss isdetectable. Some studies have shown that as many as halfof retinal ganglion cells and their axons can be lost beforethe visual field test shows evidence of glaucoma.33,34

Therefore, vision loss is usually not perceived until thedisease is quite advanced. The optic disc should beexamined with a magnified stereoscopic view. Thisexamination is best done at the slit lamp biomicroscopewith an indirect lens or a contact lens. The directophthalmoscope is less desirable for examining the opticdisc because it provides a view that lacks the depth of astereoscopic image. Optic disc changes consist of diffuseor focal narrowing or notching of the disc rim, especiallyat the inferior or superior poles (figure 4A). Typical opticdisc changes in glaucoma are described in the panel.

Examination of the retinal nerve fibre layer adjacent tothe optic disc also provides useful information about

glaucoma. In the healthy eye, there are broad and brightreflections from the relatively thick retinal nerve fibre layerin the superior and inferior bundles. In glaucoma,reflectivity in these regions is reduced and there are evenfocal areas where reflections are absent (figure 4B).

During the past decade, several objective andquantitative methods have emerged for assessment of theoptic disc and the retinal nerve fibre layer.35 Scanning laserpolarimetry is a clinical technique for assessing thethickness of the retinal nerve fibre layer (figure 4C). Thistechnology measures the retardation (phase shift) of apolarised laser light passing through the eye possessing thephysical property of form birefringence.36 Formbirefringence occurs in tissue that is composed of parallelstructures, each of which is of a smaller diameter than thewavelength of light used to image it. Birefringence in theretinal nerve fibre layer arises from the microtubulescontained within the individual nerve fibres.37 The greaterthe number of microtubules, the greater the retardation ofthe polarised laser light, indicating the presence of moretissue. Scanning laser polarimetry thus gives an indirectassessment of the thickness of the layer. Although thetechnology has been available for several years, recentadvances have enhanced the ability to identify and followthe progression of glaucoma.38–42 Another technique,confocal scanning laser ophthalmoscopy43–45 (figure 4D)allows layer-by-layer imaging to measure the topographyof the optic disc. This technology quantifies the area ofthe optic disc cup and neuroretinal rim, and thesemeasurements can be evaluated longitudinally to assesswhether the glaucoma is stable or progressing. A third

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Microcirculation

Retinalganglion

cell

TAstrocytes

Glial cells

Excessive glutamatestimulation

Lateral geniculate nucleus and other targets

Blockade ofneurotrophins and othertarget derived factors

Aberrantimmunity

Lamina cribrosa

Inflammatorycytokines

Ischaemia—hypoxia

Intraocularpressure

Figure 3: Factors contributing to pathophysiology of glaucomatous neurodegenerationIntraocular pressure can cause blockade at the lamina cribrosa of axonal protein transport, causing neuronal retinal ganglion cell death by trophicinsufficiency. Other implicated factors include local ischaemia-hypoxia, excessive stimulation of the glutamatergic system, alterations in glial cells orastrocytes, and aberrant immunity.

For personal use. Only reproduce with permission from The Lancet publishing Group.

technique, optical coherence tomography,46–49 assesses theecho time delay of reflected light and can measure bothretinal nerve fibre layer thickness and optic disctopography. With all these methods, the images are rapidlyacquired and rapidly processed to obtain a permanentrecord for future comparison. These three techniques havebeen shown to be highly effective for distinguishingbetween individuals with glaucoma and those without, andare undergoing longitudinal assessment for effectiveness inmonitoring glaucoma progression.

Assessment of the visual field Central visual acuity is relatively resistant to glaucomatousdamage and, therefore, is decreased late in glaucoma.Since peripheral vision is most susceptible toglaucomatous damage, marked changes arise in theperipheral field of vision before any changes are noted incentral visual acuity. The characteristic visual fieldabnormalities include a nasal step scotoma that respectsthe horizontal raphe, inferior or superior arcuate scotoma,paracentral scotoma, or generalised depression. Standardautomated perimetry, which employs a white stimulus ona white background (figure 4E), has been used for morethan two decades in routine clinical practice to quantifythe patient’s visual field. Although useful both fordiagnosing glaucoma and for determining whetherglaucoma is progressing, this method is insensitive to lossof retinal ganglion cells,33,34 especially early in the course ofthe disease.

Selective perimetry, which isolates specific retinalganglion cell populations (based on the target in the visualpathway of the cell axon), identifies glaucoma earlier than

standard visual field testing. Short wavelength automatedperimetry employs a blue stimulus against a yellowbackground, and selectively tests retinal ganglion cells thattarget the koniocellular sublayers of the lateral geniculatenucleus. In longitudinal studies, it can detect glaucoma asmany as 5 years earlier than standard perimetry.50,51

Frequency doubling perimetry, which tests retinal ganglioncells that target magnocellular layers of the lateralgeniculate nucleus, also can detect glaucoma early.11,52

Recognised risk factors for glaucomaThe overall risk of developing glaucoma increases with thenumber and strength of risk factors. It increasessubstantially with the level of intraocular pressureelevation and with increasing age.53,54 African-Americansare at greater risk than white Americans55—the onset ofoptic nerve damage comes at an earlier age, the damage ismore severe at the time of detection, and surgery can beless successful.56,57 Other strong risk factors include somevisual field abnormalities seen in otherwise usual baselinevisual field examinations,58,59 high myopia, and familyhistory of glaucoma.60,61 First-degree relatives ofindividuals with primary open-angle glaucoma have up toan eight-fold increased risk of developing the diseasecompared with the general population. Recently, a thincornea (central corneal thickness <556 �m) and a verticalor horizontal cup-to-disc ratio of greater than 0·4 (asdetermined from stereoscopic disc photographs) havebeen added to the list of risk factors for developingglaucoma.58,59 Other potential risk factors in thedevelopment of glaucomatous optic nerve damage includesystemic hypertension, cardiovascular disease, myopia,migraine headache, and peripheral vasospasm. Theevidence for these factors being associated with thedevelopment or progression of glaucoma is weaker.

GeneticsDetails about the inheritance of the disease remainunclear. No single Mendelian mode of inheritance canadequately describe primary open-angle glaucoma.Consequently, it has been proposed that the disorder has acomplex or multifactorial aetiology. Alternatively, primary

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A Optic diskphotograph

B Retinal nerve fibrelayer photograph

C Scanning laserpolarimetry

D Confocal scanningophthalmoscopy

E Standard automatedperimetry

Normal

Glaucoma

Figure 4: Assessment of the optic disc in healthy and glaucomatous eyes(A) Optic nerve photography: small central cup in healthy eye; enlarged cup and loss of inferotemporal neuroretinal rim in glaucomatous eye. (B) Retinalnerve fibre layer photography: uniform reflections in healthy eye; poor reflections in inferotemporal region (arrows) in glaucomatous eye. (C) Scanning laserpolarimetry: retinal nerve fibre layer thickness is reduced inferotemporally and superonasally. (D) Confocal scanning laser ophthalmoscopy: neuroretinal rimarea is within normal limits (ticks) in healthy eye, but reduced in inferior and superonasal regions (crosses) in glaucomatous eye. (E) Standard automatedperimetry: normal blind spot and superior scotomas (arrows) in glaucoma.

Optic disc changes in glaucoma

Large cup-to-disc ratio (thin neuroretinal rim)Progressive optic disc cuppingAsymmetric optic disc cupping (>0·2 difference)Optic disc haemorrhageAcquired pit of the optic nerveParapapillary retinal nerve fibre layer loss

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open-angle glaucoma might represent a collection ofclinically indistinguishable disorders. The chromosomallocations of several genes that can independently cause thedisease have been mapped, indicating that at least someportion of primary open-angle glaucoma is caused bysingle gene defects. The glaucoma gene at the GLC1Alocus (myocilin) has been shown to be associated withboth juvenile and adult-onset primary open-angleglaucoma.62–67 More than 43 different myocilin mutationshave been reported in open-angle glaucoma patients, andseveral large studies have suggested that as a group thesemutations are associated with 3–4% of patients with thecondition in populations worldwide.68 Due to the lowprevalence of myocilin-associated glaucoma in the generalpopulation, screening tests of whole populations formyocilin defects are not especially useful.69 However,testing might be warranted in those at extremely high risk,such as family members of patients with known myocilin-associated glaucoma and members of families with a stronghistory of inherited glaucoma.

Detection and screeningIn most cases, the loss of vision caused by glaucoma canbe limited or prevented by currently available therapies ifthe disease is identified in its early stages. Most cases ofglaucoma are not discovered until vision has already beenpermanently lost, because clinical signs of early glaucomaare subtle, even to an eye specialist.

Programmes to detect individuals at risk in the generalpopulation seek to identify those with glaucoma, thosewho are suspected of having glaucoma, or those who havea high risk of developing glaucoma. These activities maybe more efficient and cost-effective when targeted towardgroups that have a higher risk of disease. Age and race are

two risk factors, in particular, that select for individuals atrisk. Table 1 shows the recommended frequency of eyeexaminations for individuals in the general populationbased on age and race.

The measurement of intraocular pressure is not aneffective method for screening populations for glaucoma.Moreover, the most widely used method formeasurement, Goldmann tonometry, underestimates thetrue intraocular pressure of patients with thin corneas andoverestimates it in patients with thick ones. Half of allpatients with primary open-angle glaucoma have pressuresbelow 22 mm Hg at a single screening.54 Additionally,most individuals with raised pressures do not have, andmight never develop, optic nerve damage, although suchrisk increases with the level of intraocular pressure.Therefore, screening should not rely solely onmeasurement of intraocular pressure; assessments of theoptic disc, retinal nerve fibre layer, and visual functionprovide complementary information. Screening is anessential component of the comprehensive adult eyeassessment; it is the most effective way to identifyindividuals with glaucoma.

ManagementGoals of glaucoma managementAs described in the Preferred Practice Patterns of theAmerican Academy of Ophthalmology70 and otherguidelines, glaucoma care aims to enhance the patient’shealth and quality of life by preserving visual functionwithout causing untoward effects from treatment. Specificgoals are: (1) to document the status of optic nerve onpresentation and during follow-up by assessment of theappearance of the optic disc, retinal nerve fibre layer, orboth, and assessment of the visual field; (2) estimation andmaintainance, through appropriate therapeutic inter-vention, of an intraocular pressure below which furtheroptic nerve damage is unlikely to occur (the targetintraocular pressure); (3) to reset the target intraocularpressure to a lower level if deterioration arises; (4) tominimise the side-effects of management and their effecton the patient’s vision, general health, and quality of life(including the cost of treatment); and (5) to educate andengage the patient in the management of his or her disease.

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Asymptomatic Other asymptomatic patientsAfrican-Americans

Age (years)20–29 Every 3–5 years At least once30–39 Every 2–4 years At least twice40–64 Every 2–4 years Every 2–4 years�65 Every 1–2 years Every 1–2 years

Table 1: Frequency of examination to identify patients at risk70

Aim Result

Ocular Hypertension Efficacy and safety of topical ocular With mean IOP-lowering of 22·5%, the probability of developing glaucomatous Treatment Study58, 59 medications in preventing or delaying the change (optic disc or field change) was 4·4% in the medication group and 9·5% in

development of POAG in individuals with the observation group at 60 months. Baseline age, vertical cup disc ratio, visual raised IOP (1636 patients) field abnormalities, and IOP were good predictors of progression. Corneal

thickness was a powerful predictor of progression

Glaucoma Laser Trial75 Efficacy and safety of argon laser Eyes treated with laser trabeculoplasty had slightly reduced IOP (1·2 mm Hg) and trabeculoplasty or medicine as initial improved visual field (0·6 dB) after median follow-up of 7 yearstreatment in POAG (271 patients)

Collaborative Initial Effects of randomising patients to either Surgery lowered the IOP more than medical treatment (average during follow-up Glaucoma Treatment initial medical or surgical treatment 14–15 mm Hg vs 17–18 mm Hg), but with no statistical difference in visual field Study72 (607 patients) progression over 5 years

Early Manifest Glaucoma Effects of treatment with a topical � blocker Progression was less frequent in the treatment group (45% vs 62%) with median Treatment Trial71,76 and laser trabeculoplasty versus observation follow-up of 6 years, Other important predictors of glaucoma progression included

in patients with newly detected POAG lens exfoliation, bilateral glaucoma, IOP >21 mm Hg, more advanced visual field (255 patients) loss, disc haemorrhages, and age �68 years

Collaborative Normal Effect of pressure lowering (30%) on optic Only 12% of treated patients progressed (optic disc and visual field progression) Tension Glaucoma nerve damage and field loss in normal compared with 35% in the untreated group. Study77,78 tension glaucoma (140 patients)

Advanced Glaucoma Effect of treatment sequences of laser Outcome depended on race. In patients who had laser trabeculoplasty first, black Intervention Study79 trabeculoplasty and trabeculectomy patients were at a lower risk than white patients of failure. In patients who

(surgery) in advanced glaucoma (776 eyes received surgery first, black patients were at a higher risk of first failure than whiteof 581 patients) patients. Patients with lower IOP had less progression

POAG=primary open-angle glaucoma. IOP=intraocular pressure.

Table 2: Clinical trials in the past decade

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At present, treatment of primary open-angle glaucomais directed at lowering intraocular pressure, whichcontinues to be the only proven and treatable risk factorfor the disease. There are several modalities of treatmentfor lowering intraocular pressure, including drugs, lasersurgery, and incisional surgery. However, lowering ofintraocular pressure does not seem to halt all cases ofprogression.57,58,71,72 In some individuals with progession,it is not practical to sufficiently lower the intraocularpressure. In other individuals, factors other thanintraocular pressure may be damaging the optic nerve.

Current management of glaucoma is directed atestablishing and maintaining a target intraocularpressure70,73 (the degree of intraocular pressure at whichfurther glaucomatous damage is prevented). It is difficultto assess accurately and in advance the target intraocularpressure in every individual patient and eye.Furthermore, no degree of intraocular pressure is safefor every patient. In general, the initial target aims toachieve a 20–50% reduction from the initial pressure atwhich damage occurred. The least amount ofmedication and fewest side-effects to achieve thetherapeutic response are desirable goals. The greater thepre-existing damage due to glaucoma, the lower thetarget intraocular pressure should be. The likelihood ofprogressive damage is increased with high intraocularpressure, severe pre-existing damage, and the presenceof several risk factors. The target intraocular pressure ofan individual should be periodically re-assessed to judgeits appropriateness, by comparing optic nerve status withprevious (including baseline) examinations.

With the availability of practice guidelines,70,73 therehas also been interest in the extent to which actualpractice is consistent with recommended care. For somekey components of the examinations, patterns of care inthe USA are not consistent with the American Academyof Ophthalmology guidelines.74 For instance, nearly halfthe patients in one study did not have a photograph ordrawing of the optic disc at the time of their initialassessment. This problem is of particular concernbecause of the importance of having a baseline image forfuture comparison to assess progression. Anotheressential care process encouraged by recent guidelines isto document a specific target intraocular pressure.70,73

This process seems to be ignored by many eye-careproviders.74 This omission is especially problematic,since many of the recommendations for care depend onwhether the intraocular pressure is above or below thetarget. Primary open-angle glaucoma may be oftenundertreated, at least relative to the standards foroptimal preservation of vision established by recentclinical trials.

Clinical trial results Over the past decade, results from several multicentreclinical trials have confirmed the value of reducingintraocular pressure in patients with ocularhypertension58,59 (significantly raised intraocular pressurewithout glaucomatous visual field loss or optic discdamage) or primary open-angle glaucoma.56,57,71 Loweringthe intraocular pressure can reduce by one-half, onaverage, the number of ocular hypertensive patientsprogressing to glaucoma, and can also prevent progressionin patients with pre-existing glaucoma. However, not allpatients with ocular hypertension will progress toglaucoma. Therefore, the decision to treat depends on therisk of the individual patient progressing as well as thepatient’s preference for treatment. Several of these trialsare summarised in table 2.

Medical treatmentThe prostaglandin analogues and prostamides(latanoprost, travoprost, unoprostone, and bimatoprost)reduce intraocular pressure by increasing the outflow ofaqueous humour, primarily through the uveoscleralpathway.80,81 Some prostaglandins activate matrixmetalloproteinases, which then remodel extracellularmatrix and reduce outflow resistance, allowing theaqueous humour to flow out via this route.82,83 In general,these drugs have become the first line of treatmentbecause of their once daily application, minimal systemicside-effects, and effectiveness of intraocular pressurelowering. However, only latanoprost is currently approvedas a first line agent in Europe and the USA. These drugshave unusual side-effects, including a gradual irreversibledarkening of the iris in a small percentage of patients,most commonly visible in patients with hazel irides.84 Thiseffect seems to be due to an increase in melanosomesrather than a proliferation of melanocytes,85,86 and mightbe due to an upregulation of tyrosinase.87 Anotherinteresting side-effect is increased growth and darkness ofeyelashes.88

Several other classes of medications are used to lowerintraocular pressure in glaucoma. The �2 adrenergicagonists (brimonidine and apraclonidine) seem to reducesecretion of aqueous humour initially and then primarilyincrease aqueous outflow.89 They are less effective atlowering the intraocular pressure than are theprostaglandin analogues.90 Topical �-2 adrenergicagonists are associated with allergic conjunctivitis, cancause sedation, and have the potential for systemicsympathomimetic activity. Brimonidine should be usedwith caution in children because of the potential forrespiratory arrest.91 Carbonic anhydrase inhibitors reduceaqueous secretion. Topical forms of this medication

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Examples Side-effects

Agents that suppress aqueous inflow� adrenergic blockers Betaxolol, carteolol, levobunolol, Ocular irritation and dry eyes. Contraindicated in patients with bradycardia, heart

metipranolol, timolol block, heart failure, asthma, or obstructive airway disease� adrenergic agonists Apraclonidine, brimonidine Red eye and ocular irritation. CNS effects and respiratory arrest in young children

(brimonidine). Caution in patients with cerebral or coronary insufficiency, Raynauds, postural hypotension, hepatic or renal impairment

Carbonic anhydrase Dorzolamide and brinzolamide (topical), Oral form can cause transient myopia, nausea, diarrhoea, loss of appetite and inhibitors acetazolamide and methazolamide (oral) taste, parasthesiae, lassitude, renal stones, and haematological problems.

Topical forms much less likely to cause systemic side-effects but can cause local irritation and redness

Agents that increase aqueous inflowProstaglandin analogues, Latanoprost, travoprost, unoprostone, Brown discolouration of iris, lengthening and darkening of eyelashes, ocular (prostamide) (bimatoprost) irritation and redness, macular oedema or iritis in susceptible individuals Cholinergic agonists Pilocarpine, carbachol Ciliary spasm leading to headaches especially in younger patients, myopia, dim

vision (small pupil). Cataracts and iris-lens adhesions in long term

Table 3: Agents that reduce intraocular pressure

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(eg, dorzolamide, brinzolamide) have few systemic side-effects compared with oral acetazolamide. However, thetopical forms do not reduce intraocular pressure aseffectively as does the oral form, and they should not beused in individuals with known sulfa allergy. � blockers,which are still widely used, also reduce aqueous secretion.They can have substantial cardiovascular and respiratoryside-effects, especially in the elderly.92 Cholinergicagonists (eg, pilocarpine) increase aqueous outflow buthave substantial ocular side-effects, in particular blurringof vision due to the small pupil and induced myopia,which restrict their use. Table 3 shows available agentswith their actions.

A topical medication can enter the systemic circulationthrough the nasal mucosa via the nasolacrimal duct. Inthis case, it bypasses the hepatic circulation and the first-pass effect, and can have systemic side-effects. Theseside-effects can be reduced substantially with the use ofpunctual occlusion or gentle lid closure for 2 minutes tominimise drug absorption into the systemic circulation.

Since glaucoma is a chronic and progressive disease, thepatient’s compliance is essential for successful manage-ment. Compliance with glaucoma medications is muchlower than presumed by doctors, and many patients fail toattend follow-up appointments. Glaucoma patients arefrequently elderly and often have diminished cognitiveabilities, poor hearing, and other ailments, like arthritis,which may reduce their ability to take medication.

Neuroprotective agentsGeneral principles shared by related disorders can holdpromise for a common therapeutic approach.Neuroprotective molecules being studied in amyotrophiclateral sclerosis, Parkinson’s disease, and stroke are primecandidates for testing in glaucoma. Several drugs that arebeing screened for activity in neurological disorders couldbe tested in cell and animal models of glaucoma.Experimental retinal ganglion cell loss induced by highintraocular pressure, or by glutamate toxicity or acutecrush injury, can be reduced by vaccination with theimmunomodulatory drug copolymer 1 (glatiramer).93,94 AnN-methyl-D-aspartate antagonist, memantine, is beingassessed in two parallel large clinical trials. However, asyet no clinical evidence exists that any agent providesneuroprotection and prevents disease progression inpatients with glaucoma.

Laser treatmentSeveral types of laser treatment for glaucoma are available.In primary open-angle glaucoma, the most widely usedform is laser trabeculoplasty.95,96 In this technique, laserlight is directed at the trabecular meshwork to reduce theresistance to aqueous humour outflow. Although a highproportion of patients respond in the first few months afterlaser, most will gradually lose this effect. There is a 5-yearsuccess rate of about 50% with a failure rate of about 10%per year. Patients older than 40 years and those with moretrabecular pigmentation tend to respond better thanyounger patients. Trabeculoplasty increases aqueoushumour outflow by inducing a biological change in thetrabecular meshwork to facilitate aqueous outflow.97–99

Although various wavelengths have been used in lasertrabeculoplasty, there is no convincing evidence that anywavelength is superior in lowering the intraocularpressure.100

Another procedure, laser diode cyclophotocoagulation,is useful in advanced cases of primary open-angleglaucoma, usually when medical treatment and surgeryhave failed. Unlike laser trabeculoplasty, which is applied

through the clear cornea, the diode laser is appliedthrough the opaque white sclera. Light is preferentiallyabsorbed and damages the pigmented ciliary processes toreduce aqueous secretion. This treatment usually has atemporary effect and often needs to be repeated.101–103

Surgical treatmentTrabeculectomy, a surgical procedure that consists ofexcision of a minute portion of the trabecular meshworkor surrounding tissue, is the most widely used incisionalsurgery to enhance aqueous humour drainage. Previousstudies from the UK reported that surgery was superior tomedical or laser therapy in reducing intraocular pressureand preserving vision.104,105 By contrast, findings of amore recent study72 showed no significant differencein glaucoma progression between initial surgeryand medicine over 5 years, although cataract progressionwas greater in the surgical patients. Surgery as a primaryform of treatment is now rarely practised, even in theUK.106,107

Several techniques have been introduced to improve theresults of trabeculectomy and reduce the post-operativecomplications. Tight suturing with post-operative suturemanipulation reduces the risk of over-filtration andhaemorrhage. Although new procedures have beenintroduced to reduce complications associated withtrabeculectomy (eg, deep sclerectomy and viscocana-lostomy), prospective randomised studies at present allshow that these methods do not reduce the intraocularpressure as well as standard trabeculectomy.108–112

Glaucoma tube implants which drain aqueous humour toa reservoir that is sutured to the sclera can also be used.113

Typically, implants have been reserved for use in patientswho have failed trabeculectomy or in whom trabeculec-tomy cannot be done because of conjunctival scarring.

The most common cause for failure of trabeculectomyis episcleral fibroproliferation that blocks the egress ofaqueous humour. Anti-cancer agents, such as fluorouraciland mitomycin, have been applied intra-operatively assingle applications on a cellulose sponge for a fewminutes, or with post-operative subconjunctival injectionto reduce the proliferative response.114,115 These agentshave revolutionised surgery, especially in patients at a highrisk of failure due to scarring. In this group of patients (eg,those with previous failed filtration surgery), these agentshave halved the failure rate. In patients with primaryopen-angle glaucoma in Africa undergoing first timesurgery, prospective randomised trials have shown theirefficacy and relative safety.116–118 The use of anti-canceragents might be associated with an increase incomplications such as infection and vision impairmentdue to thin leaking tissues and low pressures.119–121

Changes in the method of application of these agentsmight greatly reduce long-term complications.122

Adjunctive use of a human antibody to transforminggrowth factor �2

123,124 and other agents are being studied assafer and more effective alternatives to the anti-canceragents.

ConclusionThe worldwide prevalence of primary open-angleglaucoma is increasing. Although the pathophysiology ofglaucoma is still not well understood, results of large-scalelong-term clinical trials have shown that reduction ofintraocular pressure prevents the progression of early andlate glaucoma. These findings clearly show theimportance of early diagnosis to initiate pressure-loweringtreatment and early detection of progression to advancethis treatment.

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Conflict of interest statementRNW is a consultant for Pfizer, Allergan, and Alcon and receives researchsupport from Zeiss-Meditec, Talia, Laser Diagnostic Technologies,Heidelberg Engineering, and Accumap. PTK receives research fundingfrom Cambridge Antibody Technology.

AcknowledgmentsRNW is or has been funded by the US National Eye Institute (EY05990and EY11158) and the Physician-Scientist Award from Research toPrevent Blindness (New York). PTK is funded by the UK MedicalResearch Council, the Wellcome Trust, the Guide Dogs for the BlindAssociation, Moorfields Trustees, the Eranda Trust, the Hayman Trust,the Helen Hamlyn Trust (in memory of Paul Hamlyn), and the Michaeland Ilse Katz Foundation. These sponsors had no role in the preparationof the manuscript, other than funding the authors.

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Diagnostic X-rays cause concernFebruary, 2004

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3 Comments on X-ray cancer risk (Jan 31, 2004)Herzog P, Rieger CT. Risk of cancer from diagnostic X-rays.DOI:10.1016/S0140-6736(04)15470-6. Lancet 2004; 363:340–41.

4 Exploiting RNA interference for therapy (Oct 25, 2003)Wall NR, Shi Y. Small RNA: can RNA interference be exploited fortherapy? DOI: 10.1016/S0140-6736(03)14637-5. Lancet 2003; 362:1401–03.

5 Migraine explained (Jan 31, 2004)Silberstein SD. Migraine. DOI:10.1016/S0140-6736(04)15440-8.Lancet 2003; 362: 381–91.

6 Questionable HABITS (Feb 7, 2004)Holmberg L, Anderson H. HABITS (hormonal replacement therapyafter breast cancer––is it safe?), a randomised comparison: trial stopped.DOI:10.1016/S0140-6736(04)15493-7. Lancet 2004; 363: 453–55.

7 Discussing HABITS (Feb 7, 2004)Chlebowski RT, Col N. Menopausal hormone therapy after breastcancer. DOI:10.1016/S0140-6736(04)15519-0. Lancet 2004; 363:410–11.

8 vCJD transmission via blood transfusion (Feb 7, 2004)Llewelyn CA, Hewitt PE , Knight RSG, et al. Possible transmissionof variant Creutzfeldt-Jakob disease by blood transfusion.DOI:10.1016/S0140-6736(04)15486-X. Lancet 2004; 363: 417–21.

9 A weighty issue (Jan 31, 2004)The Lancet. Who pays in the obesity war. DOI:10.1016/S0140-6736(04)15469-X. Lancet 2004; 363: 339.

10 BSE in primates (Feb 7, 2004)Herzog C, Salès PN, Etchegaray N, et al.Tissue distribution ofbovine spongiform encephalopathy agent in primates afterintravenous or oral infection. DOI:10.1016/S0140-6736(04)15487-1. Lancet 2004; 363: 422–28.

10most wanted

The 10 most wanted Lancet articles downloaded from ScienceDirect (see Lancet 2003; 361: 1265. DOI:10.1016/S0140-6736(03)12982-0).