1. health and fitness
2. disease

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: weinreb@eyecenter.ucsd.edu)
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
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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
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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
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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
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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
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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. These sponsors had no role in the preparation
of the manuscript, other than funding the authors.
References
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
Quigley HA. Number of people with glaucoma worldwide.
Br J Ophthalmol 1996; 80: 389–93.
Rahmani B, Tielsch JM, Katz J, et al. The cause-specific prevalence of
visual impairment in an urban population. The Baltimore Eye Survey.
Ophthalmology 1996; 103: 1721–26.
Quigley HA, Vitale S. Models of open-angle glaucoma prevalence and
incidence in the United States. Invest Ophthalmol Vis Sci 1997; 38:
83–91.
Javitt JC, Chiang YP. Preparing for managed competition: utilization
of ophthalmologic services varies by state. Arch Ophthalmol 1993; 111:
1469–70.
Fechtner RD, Weinreb RN. Mechanisms of optic nerve damage in
primary open angle glaucoma. Surv Ophthalmol 1994; 39: 23–42.
Weber AJ, Chen H, Hubbard WC, Kaufman PL. Experimental
glaucoma and cell size, density, and number in the primate lateral
geniculate nucleus. Invest Ophthalmol Vis Sci 2000; 41: 1370–79.
Yucel YH, Zhang Q, Gupta N, Kaufman PL, Weinreb RN. Loss of
neurons in magnocellular and parvocellular layers of the lateral
geniculate nucleus in glaucoma. Arch Ophthalmol 2000; 118: 378–84.
Yucel YH, Zhang Q, Weinreb RN, Kaufman PL, Gupta N. Atrophy
of relay neurons in magno- and parvocellular layers in the lateral
geniculate nucleus in experimental glaucoma.
Invest Ophthalmol Vis Sci 2001; 42: 3216–22.
Yucel YH, Zhang Q, Weinreb RN, Kaufman PL, Gupta N. Effects of
retinal ganglion cell loss on magno-, parvo-, koniocellular pathways in
the lateral geniculate nucleus and visual cortex in glaucoma.
Prog Retin Eye Res 2003; 22: 465–81.
Crawford ML, Harwerth RS, Smith EL 3rd, Mills S, Ewing B.
Experimental glaucoma in primates: changes in cytochrome oxidase
blobs in V1 cortex. Invest Ophthalmol Vis Sci 2001; 42: 358–64.
Sample PA, Bosworth CF, Blumenthal EZ, Girkin C, Weinreb RN.
Visual function-specific perimetry for indirect comparison of different
ganglion cell populations in glaucoma. Invest Ophthalmol Vis Sci 2000;
41: 1783–90.
Pena JD, Agapova O, Gabelt BT, et al. Increased elastin expression in
astrocytes of the lamina cribrosa in response to elevated intraocular
pressure. Invest Ophthalmol Vis Sci 2001; 42: 2303–14.
Wang L, Cioffi GA, Cull G, Dong J, Fortune B. Immunohistologic
evidence for retinal glial cell changes in human glaucoma.
Invest Ophthalmol Vis Sci 2002; 43: 1088–94.
Bellezza AJ, Rintalan CJ, Thompson HW, Downs JC, Hart RT,
Burgoyne CF. Deformation of the lamina cribrosa and anterior scleral
canal wall in early experimental glaucoma. Invest Ophthalmol Vis Sci
2003; 44: 623–37.
Quigley HA, McKinnon SJ, Zack DJ, et al. Retrograde axonal
transport of BDNF in retinal ganglion cells is blocked by acute IOP
elevation in rats. Invest Ophthalmol Vis Sci 2000; 41: 3460–66.
Weinreb RN, Cioffi GA, Harris A. Optic nerve blood flow. In:
Shields B, ed. 100 Years of progress in glaucoma. Philadelphia:
Lippincott Raven Healthcare, 1997; 59–78.
Lipton SA. Possible role for memantine in protecting retinal ganglion
cells from glaucomatous damage. Surv Ophthalmol 2003; 48(suppl 1):
S38–46.
Dreyer EB, Zurakowski D, Schumer RA, Podos SM, Lipton SA.
Elevated glutamate levels in the vitreous body of humans and
monkeys with glaucoma. Arch Ophthalmol 1996; 114: 299–305.
Yoles E, Schwartz M. Elevation of intraocular glutamate levels in rats
with partial lesion of the optic nerve. Arch Ophthalmol 1998; 116:
906–10.
Liu B, Neufeld AH. Nitric oxide synthase-2 in human optic nerve
head astrocytes induced by elevated pressure in vitro. Arch Ophthalmol
2001; 119: 240–45.
Yan X, Tezel G, Wax MB, Edward DP. Matrix metalloproteinases
and tumor necrosis factor alpha in glaucomatous optic nerve head.
Arch Ophthalmol 2000; 118: 666–73.
1718
22 Schwartz M. Neurodegeneration and neuroprotection in glaucoma:
development of a therapeutic neuroprotective vaccine—the
Friedenwald lecture. Invest Ophthalmol Vis Sci 2003; 44: 1407–11.
23 Tezel G, Edward DP, Wax MB. Serum autoantibodies to optic nerve
head glycosaminoglycans in patients with glaucoma. Arch Ophthalmol
1999; 117: 917–24.
24 John SW, Anderson MG, Smith RS. Mouse genetics: a tool to help
unlock the mechanisms of glaucoma. J Glaucoma 1999; 8: 400–12.
25 Aihara M, Lindsey JD, Weinreb RN. Ocular hypertension in mice
with a targeted type I collagen mutation. Invest Ophthalmol Vis Sci
2003; 44: 1581–85.
26 Danias J, Lee KC, Zamora MF, et al. Quantitative analysis of retinal
ganglion cell (RGC) loss in aging DBA/2NNia glaucomatous mice:
comparison with RGC loss in aging C57/BL6 mice.
Invest Ophthalmol Vis Sci 2003; 44: 5151–62.
27 Aihara M, Lindsey JD, Weinreb RN. Experimental mouse ocular
hypertension: establishment of the model. Invest Ophthalmol Vis Sci
2003; 44: 4314–20.
28 Mabuchi F, Aihara M, Mackey MR, Lindsey JD, Weinreb RN. Optic
nerve damage in experimental mouse ocular hypertension. Invest
Ophthalmol Vis Sci 2003; 44: 4321–30.
29 Morrison JC, Moore CG, Deppmeier LM, Gold BG, Meshul CK,
Johnson EC. A rat model of chronic pressure-induced optic nerve
damage. Exp Eye Res 1997; 64: 85–96.
30 Jia L, Cepurna WO, Johnson EC, Morrison JC. Patterns of
intraocular pressure elevation after aqueous humor outflow
obstruction in rats. Invest Ophthalmol Vis Sci 2000; 41: 1380–85.
31 Aihara M, Lindsey JD, Weinreb RN. Aqueous humor dynamics in
mice. Invest Ophthalmol Vis Sci 2003; 44: 5168–73.
32 Aihara M, Lindsey JD, Weinreb RN. Twenty-four-hour pattern of
mouse intraocular pressure. Exp Eye Res 2003; 77: 681–86.
33 Quigley HA, Dunkelberger GR, Green WR. Retinal ganglion cell
atrophy correlated with automated perimetry in human eyes with
glaucoma. Am J Ophthalmol 1989; 107: 453–64.
34 Quigley HA, Katz J, Derick RJ, Gilbert D, Sommer A. An evaluation
of optic disc and nerve fiber layer examinations in monitoring
progression of early glaucoma damage. Ophthalmology 1992; 99:
19–28.
35 Zangwill LM, Bowd C, Weinreb RN. Evaluating the optic disc and
retinal nerve fiber layer in glaucoma II: optical image analysis.
Sem Ophthalmol 2000; 15: 206–20.
36 Weinreb RN, Dreher AW, Coleman A, Quigley H, Shaw B, Reiter K.
Histopathologic validation of Fourier-ellipsometry measurements of
retinal nerve fiber layer thickness. Arch Ophthalmol 1990; 108:
557–60.
37 Knighton RW, Huang X, Zhou Q. Microtubule contribution to the
reflectance of the retinal nerve fiber layer. Invest Ophthalmol Vis Sci
1998; 39: 189–93.
38 Weinreb RN. Evaluating the retinal nerve fiber layer in glaucoma with
scanning laser polarimetry. Arch Ophthalmol 1999; 117: 1403–06.
39 Greenfield DS, Knighton RW, Huang XR. Effect of corneal
polarization axis on assessment of retinal nerve fiber layer thickness by
scanning laser polarimetry. Am J Ophthalmol 2000; 129: 715–22.
40 Zhou Q, Weinreb RN. Individualized compensation of anterior
segment birefringence during scanning laser polarimetry.
Invest Ophthalmol Vis Sci 2002; 43: 2221–28.
41 Weinreb RN, Bowd C, Zangwill LM. Glaucoma detection using
scanning laser polarimetry with variable corneal polarization
compensation. Arch Ophthalmol 2003; 121: 218–24.
42 Bowd C, Zangwill LM, Weinreb RN. Association between scanning
laser polarimetry measurements using variable corneal polarization
compensation and visual field sensitivity in glaucomatous eyes.
Arch Ophthalmol 2003; 121: 961–66.
43 Weinreb RN. Assessment of optic disc topography for diagnosing and
monitoring glaucoma. Arch Ophthalmol 1998; 116: 1229–31.
44 Chauhan BC, McCormick TA, Nicolela MT, LeBlanc RP. Optic disc
and visual field changes in a prospective longitudinal study of patients
with glaucoma: comparison of scanning laser tomography with
conventional perimetry and optic disc photography. Arch Ophthalmol
2001; 119: 1492–99.
45 Zangwill LM, Bowd C, Berry CC, et al. Discriminating between
normal and glaucomatous eyes using the Heidelberg Retina
Tomograph, GDx Nerve Fiber Analyzer, and Optical Coherence
Tomograph. Arch Ophthalmol 2001; 119: 985–93.
46 Schuman JS, Hee MR, Puliafito CA, et al. Quantification of nerve
fiber layer thickness in normal and glaucomatous eyes using optical
coherence tomography. Arch Ophthalmol 1995; 113: 586–96.
47 Zangwill LM, Williams J, Berry CC, Knauer S, Weinreb RN. A
comparison of optical coherence tomography and retinal nerve fiber
layer photography for detection of nerve fiber layer damage in
glaucoma. Ophthalmology 2000; 107: 1309–15.
48 Guedes V, Schuman JS, Hertzmark E, et al. Optical coherence
THE LANCET • Vol 363 • May 22, 2004 • www.thelancet.com
For personal use. Only reproduce with permission from The Lancet publishing Group.
SEMINAR
49
50
51
52
53
54
55
56
57
58
59
60
61
62
63
64
65
66
67
68
69
70
71
72
73
tomography measurement of macular and nerve fiber layer thickness
in normal and glaucomatous human eyes. Ophthalmology 2003; 110:
177–89.
Greenfield DS, Bagga H, Knighton RW. Macular thickness changes
in glaucomatous optic neuropathy detected using optical coherence
tomography. Arch Ophthalmol 2003; 121: 41–46.
Sample PA. Short-wavelength automated perimetry: its role in the
clinic and for understanding ganglion cell function. Prog Retin Eye Res
2000; 19: 369–83.
Polo V, Larrosa JM, Pinilla I, Perez S, Gonzalvo F, Honrubia FM.
Predictive value of short-wavelength automated perimetry: a 3-year
follow-up study. Ophthalmology 2002; 109: 761–65.
Landers J, Goldberg I, Graham S. A comparison of short wavelength
automated perimetry with frequency doubling perimetry for the early
detection of visual field loss in ocular hypertension.
Clin Experiment Ophthalmol 2000; 28: 248–52.
Sommer A, Tielsch JM, Katz J, et al. Relationship between
intraocular pressure and primary open angle glaucoma among white
and black Americans: the Baltimore eye survey. Arch Ophthalmol
1991; 109: 1090–95.
Mitchell P, Smith W, Attebo K, Healey PR. Prevalence of open-angle
glaucoma in Australia: the Blue Mountains eye study. Ophthalmology
1996; 103: 1661–69.
Tielsch JM, Katz J, Singh K, et al. A population-based evaluation of
glaucoma screening: the Baltimore eye survey. Am J Epidemiol 1991;
134: 1102–10.
Anon. The Advanced Glaucoma Intervention Study (AGIS): 3.
Baseline characteristics of black and white patients. Ophthalmology
1998; 105: 1137–45.
Anon. The Advanced Glaucoma Intervention Study (AGIS): 4.
Comparison of treatment outcomes within race. Seven-year results.
Ophthalmology 1998; 105: 1146–64.
Kass MA, Heuer DK, Higginbotham EJ, et al. The Ocular
Hypertension Treatment Study: a randomized trial determines that
topical ocular hypotensive medication delays or prevents the onset of
primary open-angle glaucoma. Arch Ophthalmol 2002; 120: 701–13.
Gordon MO, Beiser JA, Brandt JD, et al. The Ocular Hypertension
Treatment Study: baseline factors that predict the onset of primary
open-angle glaucoma. Arch Ophthalmol 2002; 120: 714–20.
Wolfs RC, Klaver CC, Ramrattan RS, van Duijn CM, Hofman A,
de Jong PT. Genetic risk of primary open-angle glaucoma.
Population-based familial aggregation study. Arch Ophthalmol 1998;
116: 1640–45.
Tielsch JM, Katz J, Sommer A, Quigley HA, Javitt JC. Family history
and risk of primary open angle glaucoma: the Baltimore eye survey.
Arch Ophthalmol 1994; 112: 69–73.
Sheffield VC, Stone EM, Alward WL, et al. Genetic linkage of
familial open angle glaucoma to chromosome 1q21-q31. Nat Genet
1993; 4: 47–50.
Stone EM, Fingert JH, Alward WL, et al. Identification of a gene that
causes primary open angle glaucoma. Science 1997; 275: 668–70.
Alward WL, Fingert JH, Coote MA, et al. Clinical features associated
with mutations in the chromosome 1 open-angle glaucoma gene
(GLC1A). N Engl J Med 1998; 338: 1022–27.
Fingert JH, Heon E, Liebmann JM, et al. Analysis of myocilin
mutations in 1703 glaucoma patients from five different populations.
Hum Mol Genet 1999; 8: 899–905.
Polansky JR, Fauss DJ, Zimmerman CC. Regulation of
TIGR/MYOC gene expression in human trabecular meshwork cells.
Eye 2000; 14: 503–14.
Clark AF, Kawase K, English-Wright S, et al. Expression of the
glaucoma gene myocilin (MYOC) in the human optic nerve head.
FASEB J 2001; 15: 1251–53.
Fingert JH, Stone EM, Sheffield VC, Alward WL. Myocilin
glaucoma. Surv Ophthalmol 2002; 47: 547–61.
Parrish RK. When does information become medically useful?: the
role of genetic testing in glaucoma. Arch Ophthalmol 2002; 120:
1204–05.
American Academy of Ophthalmology, Preferred Practice Patterns
Committee, Glaucoma Panel. Preferred practice pattern: primary
open-angle glaucoma. San Francisco, Calif: American Academy of
Ophthalmology, 2000.
Heijl A, Leske MC, Bengtsson B, Hyman L, Hussein M. Reduction
of intraocular pressure and glaucoma progression: results from the
Early Manifest Glaucoma Trial. Arch Ophthalmol 2002; 120:
1268–79.
Lichter PR, Musch DC, Gillespie BW, et al. Interim clinical
outcomes in the Collaborative Initial Glaucoma Treatment Study
comparing initial treatment randomized to medications or surgery.
Ophthalmology 2001; 108: 1943–53.
Terminology and Guidelines for Glaucoma (European Guidelines)
2nd ed. Savona, Italy: Editrice DOGMA, 2003.
THE LANCET • Vol 363 • May 22, 2004 • www.thelancet.com
74 Fremont AM, Lee PP, Mangione CM, et al. Patterns of care for
open-angle glaucoma in managed care. Arch Ophthalmol 2003; 121:
777–83.
75 The Glaucoma Laser Trial (GLT) and glaucoma laser trial follow-up
study: 7. Results. Glaucoma Laser Trial Research Group.
Am J Ophthalmol 1995; 120: 718–31.
76 Leske MC, Heijl A, Hussein M, Bengtsson B, Hyman L, Komaroff E.
Factors for glaucoma progression and the effect of treatment: the early
manifest glaucoma trial. Arch Ophthalmol 2003; 121: 48–56.
77 Comparison of glaucomatous progression between untreated patients
with normal-tension glaucoma and patients with therapeutically
reduced intraocular pressures. Collaborative Normal-Tension
Glaucoma Study Group. Am J Ophthalmol 1998; 126: 487–97.
78 The effectiveness of intraocular pressure reduction in the treatment of
normal-tension glaucoma. Collaborative Normal-Tension Glaucoma
Study Group. Am J Ophthalmol 1998; 126: 498–505.
79 The Advanced Glaucoma Intervention Study (AGIS): 9. Comparison
of glaucoma outcomes in black and white patients within treatment
groups. Am J Ophthalmol 2001; 132: 311–20.
80 Gabelt BT, Kaufman PL. Prostaglandin F2 alpha increases
uveoscleral outflow in the cynomolgus monkey. Exp Eye Res 1989; 49:
389–402.
81 Villumsen J, Alm A, Soderstrom M. Prostaglandin F2 alphaisopropylester eye drops: effect on intraocular pressure in open-angle
glaucoma. Br J Ophthalmol 1989; 73: 975–79.
82 Weinreb RN, Kashiwagi K, Kashiwagi F, Tsukahara S, Lindsey JD.
Prostaglandins increase matrix metalloproteinase release from human
ciliary smooth muscle cells. Invest Ophthalmol Vis Sci 1997; 38:
2772–80.
83 Weinreb RN, Toris CB, Gabelt BT, Lindsey JD, Kaufman PL.
Effects of prostaglandins on the aqueous humor outflow pathways.
Surv Ophthalmol 2002; 47(suppl 1): S53–64.
84 Wistrand PJ, Stjernschantz J, Olsson K. The incidence and timecourse of latanoprost-induced iridial pigmentation as a function of eye
color. Surv Ophthalmol 1997; 41(suppl 2): S129–38.
85 Grierson I, Pfeiffer N, Cracknell KP, Appleton P. Histology and fine
structure of the iris and outflow system following latanoprost therapy.
Surv Ophthalmol 2002; 47(suppl 1): S176–84.
86 Grierson I, Lee WR, Albert DM. The fine structure of an iridectomy
specimen from a patient with latanoprost-induced eye color change.
Arch Ophthalmol 1999; 117: 394–96.
87 Lindsey JD, Jones HL, Hewitt EG, Angert M, Weinreb RN.
Induction of tyrosinase gene transcription in human iris organ
cultures exposed to latanoprost. Arch Ophthalmol 2001; 119: 853–60.
88 Johnstone MA. Hypertrichosis and increased pigmentation of
eyelashes and adjacent hair in the region of the ipsilateral eyelids of
patients treated with unilateral topical latanoprost. Am J Ophthalmol
1997; 124: 544–47.
89 Toris CB, Camras CB, Yablonski ME. Acute versus chronic effects of
brimonidine on aqueous humor dynamics in ocular hypertensive
patients. Am J Ophthalmol 1999; 128: 8–14.
90 Einarson TR, Kulin NA, Tingey D, Iskedjian M. Meta-analysis of the
effect of latanoprost and brimonidine on intraocular pressure in the
treatment of glaucoma. Clin Ther 2000; 22: 1502–15.
91 Enyedi LB, Freedman SF. Safety and efficacy of brimonidine in
children with glaucoma. J AAPOS 2001; 5: 281–84.
92 Diggory P, Franks W. Medical treatment of glaucoma: a reappraisal
of the risks. Br J Ophthalmol 1996; 80: 85–89.
93 Schori H, Kipnis J, Yoles E, et al. Vaccination for protection of retinal
ganglion cells against death from glutamate cytotoxicity and ocular
hypertension: implications for glaucoma. Proc Natl Acad Sci USA
2001; 98: 3398–403.
94 Kipnis J, Yoles E, Porat Z, et al. T cell immunity to copolymer 1
confers neuroprotection on the damaged optic nerve: possible therapy
for optic neuropathies. Proc Natl Acad Sci USA 2000; 97: 7446–51.
95 Wise JB, Witter SL. Argon laser therapy for open-angle glaucoma: a
pilot study. Arch Ophthalmol 1979; 97: 319–22.
96 Weinreb RN, Tsai C, Morsman D. Laser trabeculoplasty. In:
Krupin T, ed. The Glaucomas, 2nd edition. St. Louis: CV Mosby,
1995; 1575–90.
97 Acott TS, Samples JR, Bradley JM, Bacon DR, Bylsma SS,
Van Buskirk EM. Trabecular repopulation by anterior trabecular
meshwork cells after laser trabeculoplasty. Am J Ophthalmol 1989;
107: 1–6.
98 Parshley DE, Bradley JM, Fisk A, et al. Laser trabeculoplasty induces
stromelysin expression by trabecular juxtacanalicular cells.
Invest Ophthalmol Vis Sci 1996; 37: 795–804.
99 Bradley JM, Anderssohn AM, Colvis CM, et al. Mediation of laser
trabeculoplasty-induced matrix metalloproteinase expression by
IL-1beta and TNFalpha. Invest Ophthalmol Vis Sci 2000; 41:
422–30.
100 Damji KF, Shah KC, Rock WJ, Bains HS, Hodge WG. Selective laser
1719
For personal use. Only reproduce with permission from The Lancet publishing Group.
SEMINAR
trabeculoplasty v argon laser trabeculoplasty: a prospective
randomised clinical trial. Br J Ophthalmol 1999; 83: 718–22.
101 Gaasterland DE, Pollack IP. Initial experience with a new method of
laser transscleral cyclophotocoagulation for ciliary ablation in severe
glaucoma. Trans Am Ophthalmol Soc 1992; 90: 225–43.
102 Gupta N, Weinreb RN. Diode laser transscleral
cyclophotocoagulation. J Glaucoma 1997; 6: 426–29.
103 Bloom PA, Tsai JC, Sharma K, et al. “Cyclodiode”. Trans-scleral
diode laser cyclophotocoagulation in the treatment of advanced
refractory glaucoma. Ophthalmology 1997; 104: 1508–19.
104 Jay JL, Murray SB. Early trabeculectomy versus conventional
management in primary open angle glaucoma. Br J Ophthalmol 1988;
72: 881–89.
105 Migdal C, Gregory W, Hitchings R. Long-term functional outcome
after early surgery compared with laser and medicine in open-angle
glaucoma. Ophthalmology 1994; 101: 1651–56.
106 Edmunds B, Thompson JR, Salmon JF, Wormald RP. The National
Survey of Trabeculectomy. I. Sample and methods. Eye 1999; 13:
524–30.
107 Edmunds B, Thompson JR, Salmon JF, Wormald RP. The National
Survey of Trabeculectomy. III. Early and late complications. Eye
2002; 16: 297–303.
108 El Sayyad F, Helal M, El-Kholify H, Khalil M, El-Maghraby A.
Nonpenetrating deep sclerectomy versus trabeculectomy in
bilateral primary open-angle glaucoma. Ophthalmology. 2000; 107:
1671–74.
109 Jonescu-Cuypers C, Jacobi P, Konen W, Krieglstein G. Primary
viscocanalostomy versus trabeculectomy in white patients with openangle glaucoma: a randomized clinical trial. Ophthalmology 2001;
108: 254–58.
110 Chiselita D. Non-penetrating deep sclerectomy versus
trabeculectomy in primary open-angle glaucoma surgery. Eye 2001;
15: 197–201.
111 O’Brart DP, Rowlands E, Islam N, Noury AM. A randomised,
prospective study comparing trabeculectomy augmented with
antimetabolites with a viscocanalostomy technique for the
management of open angle glaucoma uncontrolled by medical
therapy. Br J Ophthalmol 2002; 86: 748–54.
112 Carassa RG, Bettin P, Fiori M, Brancato R. Viscocanalostomy versus
trabeculectomy in white adults affected by open-angle glaucoma: a 2year randomized, controlled trial. Ophthalmology 2003; 110: 882–87.
113 Wilson MR, Mendis U, Paliwal A, Haynatzka V. Long-term followup of primary glaucoma surgery with Ahmed glaucoma valve implant
versus trabeculectomy. Am J Ophthalmol 2003; 136: 464–70.
114 Chen CW, Huang HT, Bair JS, Lee CC. Trabeculectomy with
simultaneous topical application of mitomycin-C in refractory
glaucoma. J Ocul Pharmacol 1990; 6: 175–82.
115 Smith MF, Sherwood MB, Doyle JW, Khaw PT. Results of
intraoperative 5-fluorouracil supplementation on trabeculectomy for
open-angle glaucoma. Am J Ophthalmol 1992; 114: 737–41.
116 Egbert PR, Williams AS, Singh K, Dadzie P, Egbert TB. A
prospective trial of intraoperative fluorouracil during trabeculectomy
in a black population. Am J Ophthalmol 1993; 116: 612–16.
117 Singh K, Egbert PR, Byrd S, et al. Trabeculectomy with
intraoperative 5-fluorouracil vs mitomycin C. Am J Ophthalmol 1997;
123: 48–53.
118 Yorston D, Khaw PT. A randomised trial of the effect of
intraoperative 5-FU on the outcome of trabeculectomy in east Africa.
Br J Ophthalmol 2001; 85: 1028–30.
119 Weinreb RN. Riding the Trojan horse of glaucoma surgery.
J Glaucoma 1995; 4: 2–4.
120 Higginbotham EJ, Stevens RK, Musch DC, et al. Bleb-related
endophthalmitis after trabeculectomy with mitomycin C.
Ophthalmology 1996; 103: 650–56.
121 Greenfield DS, Suner IJ, Miller MP, Kangas TA, Palmberg PF,
Flynn HW Jr. Endophthalmitis after filtering surgery with mitomycin.
Arch Ophthalmol 1996; 114: 943–49.
122 Wells AP, Cordeiro MF, Bunce C, Khaw PT. Cystic bleb formation
and related complications in limbus versus fornix based conjunctival
flaps in pediatric and young adult trabeculectomy with mitomycin C.
Ophthalmology 2003; 110: 2192–97.
123 Khaw PT. Antifibrotic agents in glaucoma surgery. In: Yanoff M, ed.
Ophthalmology:a practical textbook. London: Churchill Livingston,
2003.
124 Siriwardena D, Khaw PT, King AJ, et al. Human antitransforming
growth factor beta(2) monoclonal antibody: a new modulator of
wound healing in trabeculectomy—a randomized placebo controlled
clinical study. Ophthalmology 2002; 109: 427–31.
10
most wanted
Diagnostic X-rays cause concern
February, 2004
1
We can’t save the NHS (Nov 1, 2003)
6
Jeffcoate W. Contract for UK consultants––round 2: medical
profession KO’d, OK? DOI:10.1016/S0140-6736(03)14728-9.
Lancet 2003; 362: 1432.
2
X-rays and cancer (Jan 31, 2004)
Berrington de González A, Darby S. Risk of cancer from diagnostic
X-rays: estimates for the UK and 14 other countries.
DOI:10.1016/S0140-6736(04)15433-0. Lancet 2004; 363:
345–51.
3
4
Exploiting RNA interference for therapy (Oct 25, 2003)
Wall NR, Shi Y. Small RNA: can RNA interference be exploited for
therapy? DOI: 10.1016/S0140-6736(03)14637-5. Lancet 2003; 362:
1401–03.
5
7
Migraine explained (Jan 31, 2004)
Silberstein SD. Migraine. 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. Lancet 2004; 363: 339.
10 BSE in primates (Feb 7, 2004)
Herzog C, Salès PN, Etchegaray N, et al.Tissue distribution of
bovine spongiform encephalopathy agent in primates after
intravenous or oral infection. DOI:10.1016/S0140-6736(04)
15487-1. Lancet 2004; 363: 422–28.
The 10 most wanted Lancet articles downloaded from ScienceDirect (see Lancet 2003; 361: 1265. DOI:10.1016/S01406736(03)12982-0).
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