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 affected and 8·4 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.
Clinical definitions In 2002, an international consensus panel published definitions 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 field loss). This combination of damage has to be sufficiently 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 fibres 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 fibres. 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 affected by glaucoma, the cup-to-disc ratio progressively increases. The structural change that is most often recognised clinically by ophthalmoscopy (figure 1) and by imaging devices (figure 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 (figure 1).3 The structural loss of axons can also be detected by thinning of the nerve fibre 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 field test; figure 3). The definition by the international consensus panel specifies that glaucoma is present when three or more locations of the field 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 97·5% of the general population. These criteria assure that the structural finding is unlikely to be simply a typical variation in healthy individuals, and that both structural and functional injury has occurred. www.thelancet.com Vol 377 April 16, 2011
For open-angle glaucoma, the level of intraocular pressure, measured by tonometry at the cornea, is now recognised to not be a defining 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 flow 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 scientific 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
Lancet 2011; 377: 1367–77 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
[email protected]
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 identified 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 modified on the basis of comments from peer reviewers.
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A
B
C
D
E
F
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 floor 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 fixed deformation of the connective tissue, leading to the characteristic excavation seen clinically (F).
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 outflow—eg, small eye size, large lens, and configurations that increase resistance for fluid 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 1368
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 field are similar between angle-closure glaucoma and open-angle glaucoma,8 although visual field change is more diffuse in patients with angle-closure glaucoma. Some patients with angle-closure glaucoma have an even more diffuse 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 definition will establish the importance of fluctuations 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 affects only retinal ganglion cells13,14—a 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 field loss15 (figure 2 and figure 3). Loss of central visual acuity and the temporal visual field typically occurs only in the end stage of disease (figure 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 www.thelancet.com Vol 377 April 16, 2011
Seminar
A Quality: Poor (Imaging quality) Focus: –6·00 dpt Operator: SM Disc size: 1·76 mm²
Follow-up report
OD
OS
(average)
Quality: Acceptable (SD 37 μm) Focus: –10·00 dpt Operator: SM Disc size: 1·78 mm²
(average)
Cup Linear cup/disc ratio [] 0·50 (+0·01)
Asymmetry –0·29
0·79 (+0·01)
p=0·39
p=0·01
p=0·005
Cup shape measure [] –0·23 (–0·01)
Asymmetry –0·19
–0·04 (+0·04)
p>0·5
p=0·002
p=0·004
Rim Rim area [mm²] 1·32 (–0·01)
Asymmetry 0·66
0·66 (–0·01)
p>0·5
p=0·006
p0·5
p=0·02
p
