SEMINAR Seminar Primary open-angle glaucoma Robert N Weinreb, Peng Tee Khaw 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, early detection is essential. Early diagnosis depends on examination of the optic disc, retinal nerve fibre layer, and visual field. New imaging and psychophysical tests can improve both detection and monitoring of the progression of the disease. Recently completed long-term clinical trials provide convincing evidence that lowering intraocular pressure prevents progression at both the early and late stages of the disease. The degree of protection is related to the degree to which intraocular pressure is lowered. Improvements in therapy consist of more effective and better-tolerated drugs to lower intraocular pressure, and more effective surgical procedures. New treatments to directly treat and protect the retinal ganglion cells that are damaged in glaucoma are also in development. Glaucoma is a group of progressive optic neuropathies that have in common a slow progressive degeneration of retinal ganglion cells and their axons, resulting in a distinct appearance of the optic disc and a concomitant pattern of visual loss. The biological basis of the disease is not yet fully understood, and the factors contributing to its progression are not yet fully characterised. However, intraocular pressure is the only proven treatable risk factor. Without adequate treatment, glaucoma can progress to visual disability and eventual blindness. This seminar will address primary open-angle glaucoma, an age-related and insidious form of the disease. Moreover, the magnitude of the problem will increase as the population ages.3 Anatomy and physiology Aqueous humour secretion and drainage Intraocular pressure is regulated by a balance between the secretion and drainage of aqueous humour (figure 1). This fluid is secreted posterior to the iris by the ciliary body and then flows anteriorly to the anterior chamber. Aqueous humour provides nutrients to the iris, lens, and cornea. It exits the eye into the venous circulation via the trabecular meshwork and independently through the uveoscleral outflow pathway. Epidemiology It is estimated that glaucoma affects more than 66 million individuals worldwide with at least 6·8 million bilaterally blind.1 Vision loss caused by glaucoma is irreversible, and glaucoma is the second leading cause of blindness in the world. Of the many types of glaucoma, primary openangle glaucoma is perhaps the most common, particularly in populations of European and African ancestry.2,3 The disease is the leading cause of blindness in AfricanAmericans. In the USA, more than 7 million office visits occur per year to monitor patients who have glaucoma or are at risk of developing the disease.3,4 Blindness from all forms of glaucoma in the USA is estimated to cost in excess of $1·5 billion annually. However, the scope of the problem is probably larger than these numbers suggest, and a substantial proportion of individuals remain either undiagnosed or inadequately treated. The number of individuals suspected to have glaucoma—usually those with raised intraocular pressure (ocular hypertension) or asymmetric optic disc appearance—far exceeds the number who have been diagnosed with the disease. The optic nerve and inner retina Axons of retinal ganglion cells comprise the retinal nerve fibre layer, the innermost layer of the retina. The human optic nerve contains about one million nerve fibres (figure 2). These axons converge on the optic disc (also known as the optic nerve head) and form the optic nerve. The fibres exit the eye after traversing the lamina cribrosa, a series of perforated connective tissue sheets, and synapse in the lateral geniculate nucleus of the brain. The optic disc is about 1·5 mm in diameter and vertically oval. Its area varies up to sevenfold, and is largest in highly myopic individuals. The convergence of the axons forms a central depression in the disc, known as the cup. Most, but not all, optic nerves have a visible physiologic cup. The neuroretinal rim of the optic nerve head is pink and surrounds the cup. Trophic factors, including brain-derived neurotrophic factor, are retrogradely transported from the axonal terminals of retinal ganglion cells to their cell bodies in the inner retina, and are essential for the survival of the cells. Glutamate, a neurotransmitter, is normally present in low concentrations in the retina. Trophic factors also are transported via retinal ganglion cell axons in an anterograde fashion to the lateral geniculate nucleus. Lancet 2004; 363: 1711–20 Search strategy and selection criteria Hamilton Glaucoma Center and Department of Ophthalmology, University of California San Diego, 9500 Gilman Drive, La Jolla CA 92093-0946, USA (Prof R N Weinreb MD); and Glaucoma Unit and Ocular Repair and Regeneration Biology Unit, Moorfields Eye Hospital and Institute of Ophthalmology, University College London, London, UK (Prof P T Khaw PhD) Correspondence to: Prof R N Weinreb (e-mail: [email protected]) THE LANCET • Vol 363 • May 22, 2004 • www.thelancet.com We systematically searched MEDLINE with terminology relating to primary open-angle glaucoma discussed in this review. Keywords used were glaucoma, open-angle glaucoma, primary open-angle glaucoma, glaucoma blindness, ocular hypertension. Articles were reviewed up to June, 2003, and studies reported in full and in abstract form have been reported. 1711 For personal use. Only reproduce with permission from The Lancet publishing Group. SEMINAR Cornea Anterior chamber Trabecular meshwork w flo ut o al r cle Iris s eo Uv dy y bo r Cilia Figure 1: Physiology of aqueous humour Intraocular pressure is determined by the balance between secretion and drainage of aqueous humour. Arrows show direction of flow; aqueous humour is secreted by the ciliary body into the posterior chamber, passes posterior to the iris and through the pupil into the anterior chamber, and exits through the trabecular meshwork or uveoscleral outflow pathways. Pathophysiology Glaucoma is a neurodegenerative disease characterised by the slow, progressive degeneration of retinal ganglion cells.5 With glaucoma, the width of the neuroretinal rim decreases with concomitant enlargement of the cup. Other optic neuropathies usually result in pallor of the optic nerve head but, for unknown reasons, rarely show enlargement of the optic disc cup. Glaucomatous neuronal death is not limited to changes in the retinal ganglion cell axons, soma, and dendrites;6 neurons in the lateral geniculate nucleus7–9 and the visual cortex9,10 are also lost. Outcomes of both functional (psychophysical) testing11 and histological studies7,9 suggest that the pathological process does not discriminate among subsets of retinal ganglion cells. Glial cells also are affected, and it is possible that astrocytes, perhaps activated by raised intraocular pressure or by other mechanisms, alter the environment of the axons and produce a milieu that causes axonal degeneration or that prevents survival of the healthy retinal ganglion cells.12,13 The pathophysiology of glaucomatous neurodegeneration is not fully understood. The level of intraocular pressure is unquestionably related to the death of retinal Normal A B C Glaucoma A C B Figure 2: Optic nerve in healthy and glaucomatous eyes (A) The normal optic disc has a small central cup. The central cup of the glaucomatous disc is enlarged and deepened, and the surrounding neuroretinal rim is thinned. Optic disc haemorrhage (arrow) is sometimes observed in an eye with glaucoma. (B) Longitudinal cross-section of normal and glaucomatous optic nerve. The retinal nerve fibre layer (arrow) is the innermost layer of the retina, and is thin in the glaucomatous optic nerve. (C) Transverse cross-section of normal and glaucomatous optic nerve. The normal optic nerve has about 1 million optic nerve fibres. As glaucoma progresses, the number of nerve fibres is reduced, and concomitant reduction in diameter of the optic nerve is seen. 1712 ganglion cells and optic nerve fibres in some, if not all, patients with primary open-angle glaucoma. Although no obstruction can be seen with clinical examination, resistance to aqueous outflow through the trabecular meshwork is increased in patients with this form of glaucoma, often associated with high intraocular pressure. When pressure increases above physiological levels, the pressure gradient across the lamina cribrosa also increases. As a result, the lamina cribrosa and the retinal ganglion cell axons undergo deformation and mechanical stress.14 In glaucoma, cupping of the optic disc and compression, stretching, and remodelling12 of the lamina cribrosa can arise in response to raised intraocular pressure. In experimental models of glaucoma, there is a blockade of retinal ganglion cell axonal protein transport due to intraocular pressure-induced compression of optic nerve axons at the lamina cribrosa.5,15 In primary openangle glaucoma, retinal ganglion cell axon compression can impair trophic factor axonal transport, causing death of the cells by trophic insufficiency. Independently or in addition to intraocular pressure, other factors can individually or collectively contribute to death of retinal ganglion cells and optic nerve fibres in glaucoma (figure 3). The retina is dependent on its blood supply for meeting its high metabolic needs, and local ischaemia-hypoxia, perhaps due to dysfunction of bloodflow autoregulation, has been implicated as one of these factors.16 However, the role of ischaemic-hypoxia has been difficult to establish, since it is difficult to assess experimentally and clinically. Excessive stimulation of the glutamatergic system, specifically the N-methyl-Daspartate subtypes, has also been proposed to contribute to death of retinal ganglion cells in glaucoma.17–19 However, there is still debate on whether excess glutamate has a positive or negative effect on retinal ganglion cells, and whether various classes of cells respond differently to glutamate. Other proposed contributors include poorly functioning cellular pumps and glutamate transporters, oxidative stress and formation of free radicals, inflammatory cytokines (tumour necrosis factor and nitric oxide),20,21 and aberrant immunity.22,23 The response to an initial optic nerve injury in glaucoma also can lead to secondary neurodegeneration among surviving retinal ganglion cells and their fibres. According to this view, although the primary insult does not directly affect all fibres and retinal ganglion cells, it causes alterations in the neuronal environment that in turn increase the vulnerability of spared neurons.20,22 Nonhuman primates have been the animal of choice for studying glaucoma. Monkeys have been shown to develop glaucomatous changes in the optic nerve when their intraocular pressure is raised experimentally. Monkeys can be trained to perform visual field tests, and those with experimental glaucoma show deficits indicative of glaucoma.10 Rodent models (both genetically engineered mice24–26 and experimental models of ocular hypertension in mice27,28 and rats29,30) enhance the potential to investigate mechanisms at the molecular and cellular levels. The optic nerve head of these animals is similar to that of the primate, including the connective tissue and cellular (astrocyte) support structures of the optic nerve axon bundles, and the response of their optic nerve to injury has clinical and experimental features similar to those of humans beings with glaucoma. The dynamics of the aqueous humour in mice,31—including a diurnal variation of intraocular pressure,32 and responses to various drugs that lower intraocular pressure—also are similar to those of human beings. THE LANCET • Vol 363 • May 22, 2004 • www.thelancet.com For personal use. Only reproduce with permission from The Lancet publishing Group. SEMINAR Microcirculation Intraocular pressure Lateral geniculate nucleus and other targets Ischaemia—hypoxia Retinal ganglion cell Lamina cribrosa Aberrant immunity Inflammatory cytokines Blockade of neurotrophins and other target derived factors T Astrocytes Excessive glutamate stimulation Glial cells Figure 3: Factors contributing to pathophysiology of glaucomatous neurodegeneration Intraocular pressure can cause blockade at the lamina cribrosa of axonal protein transport, causing neuronal retinal ganglion cell death by trophic insufficiency. Other implicated factors include local ischaemia-hypoxia, excessive stimulation of the glutamatergic system, alterations in glial cells or astrocytes, and aberrant immunity. Diagnosis Primary open-angle glaucoma is a chronic, generally bilateral, but often asymmetrical, disease that is characterised by progressive damage of the optic nerve as shown by changes in the optic disc, retinal nerve fibre layer, or visual field. The disease has an adult onset, with open anterior chamber angles of normal appearance and an absence of other known explanations for the change in the optic nerve. If detected early, disease progression can frequently be arrested or slowed with medical and surgical treatment. Assessment of the optic disc Examination of the optic disc is the most valuable method of diagnosing early glaucoma, because the optic nerve appearance often changes before visual field loss is detectable. Some studies have shown that as many as half of retinal ganglion cells and their axons can be lost before the visual field test shows evidence of glaucoma.33,34 Therefore, vision loss is usually not perceived until the disease is quite advanced. The optic disc should be examined with a magnified stereoscopic view. This examination is best done at the slit lamp biomicroscope with an indirect lens or a contact lens. The direct ophthalmoscope is less desirable for examining the optic disc because it provides a view that lacks the depth of a stereoscopic image. Optic disc changes consist of diffuse or focal narrowing or notching of the disc rim, especially at the inferior or superior poles (figure 4A). Typical optic disc changes in glaucoma are described in the panel. Examination of the retinal nerve fibre layer adjacent to the optic disc also provides useful information about THE LANCET • Vol 363 • May 22, 2004 • www.thelancet.com glaucoma. In the healthy eye, there are broad and bright reflections from the relatively thick retinal nerve fibre layer in the superior and inferior bundles. In glaucoma, reflectivity in these regions is reduced and there are even focal areas where reflections are absent (figure 4B). During the past decade, several objective and quantitative methods have emerged for assessment of the optic disc and the retinal nerve fibre layer.35 Scanning laser polarimetry is a clinical technique for assessing the thickness of the retinal nerve fibre layer (figure 4C). This technology measures the retardation (phase shift) of a polarised laser light passing through the eye possessing the physical property of form birefringence.36 Form birefringence occurs in tissue that is composed of parallel structures, each of which is of a smaller diameter than the wavelength of light used to image it. Birefringence in the retinal nerve fibre layer arises from the microtubules contained within the individual nerve fibres.37 The greater the number of microtubules, the greater the retardation of the polarised laser light, indicating the presence of more tissue. Scanning laser polarimetry thus gives an indirect assessment of the thickness of the layer. Although the technology has been available for several years, recent advances have enhanced the ability to identify and follow the progression of glaucoma.38–42 Another technique, confocal scanning laser ophthalmoscopy43–45 (figure 4D) allows layer-by-layer imaging to measure the topography of the optic disc. This technology quantifies the area of the optic disc cup and neuroretinal rim, and these measurements can be evaluated longitudinally to assess whether the glaucoma is stable or progressing. A third 1713 For personal use. Only reproduce with permission from The Lancet publishing Group. SEMINAR Normal Glaucoma A Optic disk photograph B Retinal nerve fibre layer photograph C Scanning laser polarimetry D Confocal scanning ophthalmoscopy E Standard automated perimetry 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) Retinal nerve fibre layer photography: uniform reflections in healthy eye; poor reflections in inferotemporal region (arrows) in glaucomatous eye. (C) Scanning laser polarimetry: retinal nerve fibre layer thickness is reduced inferotemporally and superonasally. (D) Confocal scanning laser ophthalmoscopy: neuroretinal rim area is within normal limits (ticks) in healthy eye, but reduced in inferior and superonasal regions (crosses) in glaucomatous eye. (E) Standard automated perimetry: normal blind spot and superior scotomas (arrows) in glaucoma. technique, optical coherence tomography,46–49 assesses the echo time delay of reflected light and can measure both retinal nerve fibre layer thickness and optic disc topography. With all these methods, the images are rapidly acquired and rapidly processed to obtain a permanent record for future comparison. These three techniques have been shown to be highly effective for distinguishing between individuals with glaucoma and those without, and are undergoing longitudinal assessment for effectiveness in monitoring glaucoma progression. Assessment of the visual field Central visual acuity is relatively resistant to glaucomatous damage and, therefore, is decreased late in glaucoma. Since peripheral vision is most susceptible to glaucomatous damage, marked changes arise in the peripheral field of vision before any changes are noted in central visual acuity. The characteristic visual field abnormalities include a nasal step scotoma that respects the horizontal raphe, inferior or superior arcuate scotoma, paracentral scotoma, or generalised depression. Standard automated perimetry, which employs a white stimulus on a white background (figure 4E), has been used for more than two decades in routine clinical practice to quantify the patient’s visual field. Although useful both for diagnosing glaucoma and for determining whether glaucoma is progressing, this method is insensitive to loss of retinal ganglion cells,33,34 especially early in the course of the disease. Selective perimetry, which isolates specific retinal ganglion cell populations (based on the target in the visual pathway of the cell axon), identifies glaucoma earlier than Optic disc changes in glaucoma Large cup-to-disc ratio (thin neuroretinal rim) Progressive optic disc cupping Asymmetric optic disc cupping (>0·2 difference) Optic disc haemorrhage Acquired pit of the optic nerve Parapapillary retinal nerve fibre layer loss 1714 standard visual field testing. Short wavelength automated perimetry employs a blue stimulus against a yellow background, and selectively tests retinal ganglion cells that target the koniocellular sublayers of the lateral geniculate nucleus. In longitudinal studies, it can detect glaucoma as many as 5 years earlier than standard perimetry.50,51 Frequency doubling perimetry, which tests retinal ganglion cells that target magnocellular layers of the lateral geniculate nucleus, also can detect glaucoma early.11,52 Recognised risk factors for glaucoma The overall risk of developing glaucoma increases with the number and strength of risk factors. It increases substantially with the level of intraocular pressure elevation and with increasing age.53,54 African-Americans are at greater risk than white Americans55—the onset of optic nerve damage comes at an earlier age, the damage is more severe at the time of detection, and surgery can be less successful.56,57 Other strong risk factors include some visual field abnormalities seen in otherwise usual baseline visual field examinations,58,59 high myopia, and family history of glaucoma.60,61 First-degree relatives of individuals with primary open-angle glaucoma have up to an eight-fold increased risk of developing the disease compared with the general population. Recently, a thin cornea (central corneal thickness <556 m) and a vertical or horizontal cup-to-disc ratio of greater than 0·4 (as determined from stereoscopic disc photographs) have been added to the list of risk factors for developing glaucoma.58,59 Other potential risk factors in the development of glaucomatous optic nerve damage include systemic hypertension, cardiovascular disease, myopia, migraine headache, and peripheral vasospasm. The evidence for these factors being associated with the development or progression of glaucoma is weaker. Genetics Details about the inheritance of the disease remain unclear. No single Mendelian mode of inheritance can adequately describe primary open-angle glaucoma. Consequently, it has been proposed that the disorder has a complex or multifactorial aetiology. Alternatively, primary THE LANCET • Vol 363 • May 22, 2004 • www.thelancet.com For personal use. Only reproduce with permission from The Lancet publishing Group. SEMINAR Age (years) 20–29 30–39 40–64 65 Asymptomatic African-Americans Other asymptomatic patients Every 3–5 years Every 2–4 years Every 2–4 years Every 1–2 years At least once At least twice Every 2–4 years Every 1–2 years Table 1: Frequency of examination to identify patients at risk70 open-angle glaucoma might represent a collection of clinically indistinguishable disorders. The chromosomal locations of several genes that can independently cause the disease have been mapped, indicating that at least some portion of primary open-angle glaucoma is caused by single gene defects. The glaucoma gene at the GLC1A locus (myocilin) has been shown to be associated with both juvenile and adult-onset primary open-angle glaucoma.62–67 More than 43 different myocilin mutations have been reported in open-angle glaucoma patients, and several large studies have suggested that as a group these mutations are associated with 3–4% of patients with the condition in populations worldwide.68 Due to the low prevalence of myocilin-associated glaucoma in the general population, screening tests of whole populations for myocilin 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 myocilinassociated glaucoma and members of families with a strong history of inherited glaucoma. Detection and screening In most cases, the loss of vision caused by glaucoma can be limited or prevented by currently available therapies if the disease is identified in its early stages. Most cases of glaucoma are not discovered until vision has already been permanently lost, because clinical signs of early glaucoma are subtle, even to an eye specialist. Programmes to detect individuals at risk in the general population seek to identify those with glaucoma, those who are suspected of having glaucoma, or those who have a high risk of developing glaucoma. These activities may be more efficient and cost-effective when targeted toward groups that have a higher risk of disease. Age and race are two risk factors, in particular, that select for individuals at risk. Table 1 shows the recommended frequency of eye examinations for individuals in the general population based on age and race. The measurement of intraocular pressure is not an effective method for screening populations for glaucoma. Moreover, the most widely used method for measurement, Goldmann tonometry, underestimates the true intraocular pressure of patients with thin corneas and overestimates it in patients with thick ones. Half of all patients with primary open-angle glaucoma have pressures below 22 mm Hg at a single screening.54 Additionally, most individuals with raised pressures do not have, and might never develop, optic nerve damage, although such risk increases with the level of intraocular pressure. Therefore, screening should not rely solely on measurement of intraocular pressure; assessments of the optic disc, retinal nerve fibre layer, and visual function provide complementary information. Screening is an essential component of the comprehensive adult eye assessment; it is the most effective way to identify individuals with glaucoma. Management Goals of glaucoma management As described in the Preferred Practice Patterns of the American Academy of Ophthalmology70 and other guidelines, glaucoma care aims to enhance the patient’s health and quality of life by preserving visual function without causing untoward effects from treatment. Specific goals are: (1) to document the status of optic nerve on presentation and during follow-up by assessment of the appearance of the optic disc, retinal nerve fibre layer, or both, and assessment of the visual field; (2) estimation and maintainance, through appropriate therapeutic intervention, of an intraocular pressure below which further optic nerve damage is unlikely to occur (the target intraocular pressure); (3) to reset the target intraocular pressure to a lower level if deterioration arises; (4) to minimise the side-effects of management and their effect on the patient’s vision, general health, and quality of life (including the cost of treatment); and (5) to educate and engage the patient in the management of his or her disease. Aim Result Ocular Hypertension Treatment Study58, 59 Efficacy and safety of topical ocular medications in preventing or delaying the development of POAG in individuals with raised IOP (1636 patients) With mean IOP-lowering of 22·5%, the probability of developing glaucomatous change (optic disc or field change) was 4·4% in the medication group and 9·5% in the observation group at 60 months. Baseline age, vertical cup disc ratio, visual 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 trabeculoplasty or medicine as initial treatment in POAG (271 patients) Eyes treated with laser trabeculoplasty had slightly reduced IOP (1·2 mm Hg) and improved visual field (0·6 dB) after median follow-up of 7 years Collaborative Initial Glaucoma Treatment Study72 Effects of randomising patients to either initial medical or surgical treatment (607 patients) Surgery lowered the IOP more than medical treatment (average during follow-up 14–15 mm Hg vs 17–18 mm Hg), but with no statistical difference in visual field progression over 5 years Early Manifest Glaucoma Treatment Trial71,76 Effects of treatment with a topical blocker and laser trabeculoplasty versus observation in patients with newly detected POAG (255 patients) Progression was less frequent in the treatment group (45% vs 62%) with median follow-up of 6 years, Other important predictors of glaucoma progression included lens exfoliation, bilateral glaucoma, IOP >21 mm Hg, more advanced visual field loss, disc haemorrhages, and age 68 years Collaborative Normal Tension Glaucoma Study77,78 Effect of pressure lowering (30%) on optic nerve damage and field loss in normal tension glaucoma (140 patients) Only 12% of treated patients progressed (optic disc and visual field progression) compared with 35% in the untreated group. Advanced Glaucoma Intervention Study79 Effect of treatment sequences of laser trabeculoplasty and trabeculectomy (surgery) in advanced glaucoma (776 eyes of 581 patients) Outcome depended on race. In patients who had laser trabeculoplasty first, black patients were at a lower risk than white patients of failure. In patients who received surgery first, black patients were at a higher risk of first failure than white patients. Patients with lower IOP had less progression POAG=primary open-angle glaucoma. IOP=intraocular pressure. Table 2: Clinical trials in the past decade THE LANCET • Vol 363 • May 22, 2004 • www.thelancet.com 1715 For personal use. Only reproduce with permission from The Lancet publishing Group. SEMINAR Examples Agents that suppress aqueous inflow adrenergic blockers Betaxolol, carteolol, levobunolol, metipranolol, timolol adrenergic agonists Apraclonidine, brimonidine Carbonic anhydrase inhibitors Dorzolamide and brinzolamide (topical), acetazolamide and methazolamide (oral) Agents that increase aqueous inflow Prostaglandin analogues, Latanoprost, travoprost, unoprostone, (prostamide) (bimatoprost) Cholinergic agonists Pilocarpine, carbachol Side-effects Ocular irritation and dry eyes. Contraindicated in patients with bradycardia, heart block, heart failure, asthma, or obstructive airway disease 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 Oral form can cause transient myopia, nausea, diarrhoea, loss of appetite and 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 Brown discolouration of iris, lengthening and darkening of eyelashes, ocular irritation and redness, macular oedema or iritis in susceptible individuals 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 At present, treatment of primary open-angle glaucoma is directed at lowering intraocular pressure, which continues to be the only proven and treatable risk factor for the disease. There are several modalities of treatment for lowering intraocular pressure, including drugs, laser surgery, and incisional surgery. However, lowering of intraocular pressure does not seem to halt all cases of progression.57,58,71,72 In some individuals with progession, it is not practical to sufficiently lower the intraocular pressure. In other individuals, factors other than intraocular pressure may be damaging the optic nerve. Current management of glaucoma is directed at establishing and maintaining a target intraocular pressure70,73 (the degree of intraocular pressure at which further glaucomatous damage is prevented). It is difficult to assess accurately and in advance the target intraocular pressure in every individual patient and eye. Furthermore, no degree of intraocular pressure is safe for every patient. In general, the initial target aims to achieve a 20–50% reduction from the initial pressure at which damage occurred. The least amount of medication and fewest side-effects to achieve the therapeutic response are desirable goals. The greater the pre-existing damage due to glaucoma, the lower the target intraocular pressure should be. The likelihood of progressive damage is increased with high intraocular pressure, severe pre-existing damage, and the presence of several risk factors. The target intraocular pressure of an individual should be periodically re-assessed to judge its appropriateness, by comparing optic nerve status with previous (including baseline) examinations. With the availability of practice guidelines,70,73 there has also been interest in the extent to which actual practice is consistent with recommended care. For some key components of the examinations, patterns of care in the USA are not consistent with the American Academy of Ophthalmology guidelines.74 For instance, nearly half the patients in one study did not have a photograph or drawing of the optic disc at the time of their initial assessment. This problem is of particular concern because of the importance of having a baseline image for future comparison to assess progression. Another essential care process encouraged by recent guidelines is to document a specific target intraocular pressure.70,73 This process seems to be ignored by many eye-care providers.74 This omission is especially problematic, since many of the recommendations for care depend on whether the intraocular pressure is above or below the target. Primary open-angle glaucoma may be often undertreated, at least relative to the standards for optimal preservation of vision established by recent clinical trials. 1716 Clinical trial results Over the past decade, results from several multicentre clinical trials have confirmed the value of reducing intraocular pressure in patients with ocular hypertension58,59 (significantly raised intraocular pressure without glaucomatous visual field loss or optic disc damage) or primary open-angle glaucoma.56,57,71 Lowering the intraocular pressure can reduce by one-half, on average, the number of ocular hypertensive patients progressing to glaucoma, and can also prevent progression in patients with pre-existing glaucoma. However, not all patients with ocular hypertension will progress to glaucoma. Therefore, the decision to treat depends on the risk of the individual patient progressing as well as the patient’s preference for treatment. Several of these trials are summarised in table 2. Medical treatment The prostaglandin analogues and prostamides (latanoprost, travoprost, unoprostone, and bimatoprost) reduce intraocular pressure by increasing the outflow of aqueous humour, primarily through the uveoscleral pathway.80,81 Some prostaglandins activate matrix metalloproteinases, which then remodel extracellular matrix and reduce outflow resistance, allowing the aqueous humour to flow out via this route.82,83 In general, these drugs have become the first line of treatment because of their once daily application, minimal systemic side-effects, and effectiveness of intraocular pressure lowering. However, only latanoprost is currently approved as a first line agent in Europe and the USA. These drugs have unusual side-effects, including a gradual irreversible darkening of the iris in a small percentage of patients, most commonly visible in patients with hazel irides.84 This effect seems to be due to an increase in melanosomes rather than a proliferation of melanocytes,85,86 and might be due to an upregulation of tyrosinase.87 Another interesting side-effect is increased growth and darkness of eyelashes.88 Several other classes of medications are used to lower intraocular pressure in glaucoma. The 2 adrenergic agonists (brimonidine and apraclonidine) seem to reduce secretion of aqueous humour initially and then primarily increase aqueous outflow.89 They are less effective at lowering the intraocular pressure than are the prostaglandin analogues.90 Topical -2 adrenergic agonists are associated with allergic conjunctivitis, can cause sedation, and have the potential for systemic sympathomimetic activity. Brimonidine should be used with caution in children because of the potential for respiratory arrest.91 Carbonic anhydrase inhibitors reduce aqueous secretion. Topical forms of this medication THE LANCET • Vol 363 • May 22, 2004 • www.thelancet.com For personal use. Only reproduce with permission from The Lancet publishing Group. SEMINAR (eg, dorzolamide, brinzolamide) have few systemic sideeffects compared with oral acetazolamide. However, the topical forms do not reduce intraocular pressure as effectively as does the oral form, and they should not be used in individuals with known sulfa allergy. blockers, which are still widely used, also reduce aqueous secretion. They can have substantial cardiovascular and respiratory side-effects, especially in the elderly.92 Cholinergic agonists (eg, pilocarpine) increase aqueous outflow but have substantial ocular side-effects, in particular blurring of vision due to the small pupil and induced myopia, which restrict their use. Table 3 shows available agents with their actions. A topical medication can enter the systemic circulation through the nasal mucosa via the nasolacrimal duct. In this case, it bypasses the hepatic circulation and the firstpass effect, and can have systemic side-effects. These side-effects can be reduced substantially with the use of punctual occlusion or gentle lid closure for 2 minutes to minimise drug absorption into the systemic circulation. Since glaucoma is a chronic and progressive disease, the patient’s compliance is essential for successful management. Compliance with glaucoma medications is much lower than presumed by doctors, and many patients fail to attend follow-up appointments. Glaucoma patients are frequently elderly and often have diminished cognitive abilities, poor hearing, and other ailments, like arthritis, which may reduce their ability to take medication. Neuroprotective agents General principles shared by related disorders can hold promise for a common therapeutic approach. Neuroprotective molecules being studied in amyotrophic lateral sclerosis, Parkinson’s disease, and stroke are prime candidates for testing in glaucoma. Several drugs that are being screened for activity in neurological disorders could be tested in cell and animal models of glaucoma. Experimental retinal ganglion cell loss induced by high intraocular pressure, or by glutamate toxicity or acute crush injury, can be reduced by vaccination with the immunomodulatory drug copolymer 1 (glatiramer).93,94 An N-methyl-D-aspartate antagonist, memantine, is being assessed in two parallel large clinical trials. However, as yet no clinical evidence exists that any agent provides neuroprotection and prevents disease progression in patients with glaucoma. Laser treatment Several types of laser treatment for glaucoma are available. In primary open-angle glaucoma, the most widely used form is laser trabeculoplasty.95,96 In this technique, laser light is directed at the trabecular meshwork to reduce the resistance to aqueous humour outflow. Although a high proportion of patients respond in the first few months after laser, most will gradually lose this effect. There is a 5-year success rate of about 50% with a failure rate of about 10% per year. Patients older than 40 years and those with more trabecular pigmentation tend to respond better than younger patients. Trabeculoplasty increases aqueous humour outflow by inducing a biological change in the trabecular meshwork to facilitate aqueous outflow.97–99 Although various wavelengths have been used in laser trabeculoplasty, there is no convincing evidence that any wavelength is superior in lowering the intraocular pressure.100 Another procedure, laser diode cyclophotocoagulation, is useful in advanced cases of primary open-angle glaucoma, usually when medical treatment and surgery have failed. Unlike laser trabeculoplasty, which is applied THE LANCET • Vol 363 • May 22, 2004 • www.thelancet.com through the clear cornea, the diode laser is applied through the opaque white sclera. Light is preferentially absorbed and damages the pigmented ciliary processes to reduce aqueous secretion. This treatment usually has a temporary effect and often needs to be repeated.101–103 Surgical treatment Trabeculectomy, a surgical procedure that consists of excision of a minute portion of the trabecular meshwork or surrounding tissue, is the most widely used incisional surgery to enhance aqueous humour drainage. Previous studies from the UK reported that surgery was superior to medical or laser therapy in reducing intraocular pressure and preserving vision.104,105 By contrast, findings of a more recent study72 showed no significant difference in glaucoma progression between initial surgery and medicine over 5 years, although cataract progression was greater in the surgical patients. Surgery as a primary form of treatment is now rarely practised, even in the UK.106,107 Several techniques have been introduced to improve the results of trabeculectomy and reduce the post-operative complications. Tight suturing with post-operative suture manipulation reduces the risk of over-filtration and haemorrhage. Although new procedures have been introduced to reduce complications associated with trabeculectomy (eg, deep sclerectomy and viscocanalostomy), prospective randomised studies at present all show that these methods do not reduce the intraocular pressure as well as standard trabeculectomy.108–112 Glaucoma tube implants which drain aqueous humour to a reservoir that is sutured to the sclera can also be used.113 Typically, implants have been reserved for use in patients who have failed trabeculectomy or in whom trabeculectomy cannot be done because of conjunctival scarring. The most common cause for failure of trabeculectomy is episcleral fibroproliferation that blocks the egress of aqueous humour. Anti-cancer agents, such as fluorouracil and mitomycin, have been applied intra-operatively as single applications on a cellulose sponge for a few minutes, or with post-operative subconjunctival injection to reduce the proliferative response.114,115 These agents have revolutionised surgery, especially in patients at a high risk of failure due to scarring. In this group of patients (eg, those with previous failed filtration surgery), these agents have halved the failure rate. In patients with primary open-angle glaucoma in Africa undergoing first time surgery, prospective randomised trials have shown their efficacy and relative safety.116–118 The use of anti-cancer agents might be associated with an increase in complications such as infection and vision impairment due to thin leaking tissues and low pressures.119–121 Changes in the method of application of these agents might greatly reduce long-term complications.122 Adjunctive use of a human antibody to transforming growth factor 2123,124 and other agents are being studied as safer and more effective alternatives to the anti-cancer agents. Conclusion The worldwide prevalence of primary open-angle glaucoma is increasing. Although the pathophysiology of glaucoma is still not well understood, results of large-scale long-term clinical trials have shown that reduction of intraocular pressure prevents the progression of early and late glaucoma. These findings clearly show the importance of early diagnosis to initiate pressure-lowering treatment and early detection of progression to advance this treatment. 1717 For personal use. Only reproduce with permission from The Lancet publishing Group. SEMINAR Conflict of interest statement RNW is a consultant for Pfizer, Allergan, and Alcon and receives research support from Zeiss-Meditec, Talia, Laser Diagnostic Technologies, Heidelberg Engineering, and Accumap. PTK receives research funding from Cambridge Antibody Technology. Acknowledgments RNW is or has been funded by the US National Eye Institute (EY05990 and EY11158) and the Physician-Scientist Award from Research to Prevent Blindness (New York). PTK is funded by the UK Medical Research Council, the Wellcome Trust, the Guide Dogs for the Blind Association, Moorfields Trustees, the Eranda Trust, the Hayman Trust, the Helen Hamlyn Trust (in memory of Paul Hamlyn), and the Michael and Ilse Katz Foundation. 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DOI:10.1016/S0140-6736(04)15440-8. Lancet 2003; 362: 381–91. Discussing HABITS (Feb 7, 2004) Chlebowski RT, Col N. Menopausal hormone therapy after breast cancer. DOI:10.1016/S0140-6736(04)15519-0. Lancet 2004; 363: 410–11. 8 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. Questionable HABITS (Feb 7, 2004) Holmberg L, Anderson H. HABITS (hormonal replacement therapy after breast cancer––is it safe?), a randomised comparison: trial stopped. DOI:10.1016/S0140-6736(04)15493-7. Lancet 2004; 363: 453–55. vCJD transmission via blood transfusion (Feb 7, 2004) Llewelyn CA, Hewitt PE , Knight RSG, et al. Possible transmission of 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/S01406736(04)15469-X. 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