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Glaucoma

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 16TL4979
THELANCET-D-16-04979R3 Seminar
[PII_REPLACE]
SPa
Embargo: [add date when known]
This version saved: 10:49, 25-May-17

Glaucoma
Jost B Jonas, Tin Aung, Rupert R Bourne, Alain M Bron, Robert Ritch, Songhomitra Panda-Jonas

Glaucoma is a heterogeneous group of diseases characterised by cupping of the optic nerve head and visual-field Department of
damage. It is the most frequent cause of irreversible blindness worldwide. Progression usually stops if the intraocular Ophthalmology, Medical
Faculty Mannheim of the
pressure is lowered by 30–50% from baseline. Its worldwide age-standardised prevalence in the population aged Ruprecht-Karls-University of
40 years or older is about 3·5%. Chronic forms of glaucoma are painless and symptomatic visual-field defects occur Heidelberg, Heidelberg,
late. Early detection by ophthalmological examination is mandatory. Risk factors for primary open-angle glaucoma— Germany (Prof J B Jonas MD,
the most common form of glaucoma—include older age, elevated intraocular pressure, sub-Saharan African ethnic S Panda-Jonas MD); Singapore
Eye Research Institute,
origin, positive family history, and high myopia. Older age, hyperopia, and east Asian ethnic origin are the main risk Singapore (Prof T Aung MD);
factors for primary angle-closure glaucoma. Glaucoma is diagnosed using ophthalmoscopy, tonometry, and perimetry. Singapore National Eye Centre,
Treatment to lower intraocular pressure is based on topical drugs, laser therapy, and surgical intervention if other Singapore (Prof T Aung);
therapeutic modalities fail to prevent progression. Department of
Ophthalmology, Yong Loo Lin
School of Medicine, National
Introduction Because of the association with older age, the overall University of Singapore,
The term glaucoma includes a panoply of diseases that prevalence of glaucoma was lower in regions with Singapore (Prof T Aung); Vision
differ in their cause, risk factors, demographics, symptoms, younger populations than in high-income regions with and Eye Research Unit, Anglia
Ruskin University, Cambridge,
duration, treatment, and prognosis. Glaucoma has relatively old populations.4 The global prevalence of UK (Prof R R Bourne MD);
become the most frequent cause of irreversible blindness glaucoma was roughly 3·5% for people aged 40–80 years.3 Department of
worldwide.1–3 From a pathophysiological and therapeutic Primary open-angle glaucoma, with a global prevalence Ophthalmology, University
point of view, intraocular pressure is the primary of about 3·1%, was six times more common than primary Hospital, Dijon, France
(Prof A M Bron MD); Eye and
modifiable risk factor, since progression of glaucoma angle-closure glaucoma, which had a global prevalence Nutrition Research Group,
usually stops if this pressure is lowered by 30–50% from of about 0·5%.3 The prevalence of primary open-angle Bourgogne Franche-Comté
baseline. This association suggests that intraocular glaucoma was highest in Africa (4·2%), and primary University, Dijon, France
(Prof A M Bron); and Einhorn
pressure in glaucoma is too high in relation to the pressure angle-closure glaucoma was most prevalent in
Clinical Research Center, New
susceptibility of the optic nerve head, at which Asia (1·1%).3 In 2013, the number of people aged York Eye and Ear Infirmary of
glaucomatous optic-nerve damage occurs. 40–80 years and affected by glaucoma worldwide was Mount Sinai, New York, NY,
The common feature for all forms of glaucoma is loss estimated to be 64·3 million, and this number is USA (Prof R Ritch MD)
of retinal ganglion cells, thinning of the retinal nerve predicted to increase to 76 million in 2020 and to Correspondence to:
fibre layer, and cupping of the optic disc (figure 1; 112 million in 2040.3 With respect to primary open-angle Prof Jost Jonas,
Universitäts-Augenklinik,
figure 2). According to the morphology of the anterior glaucoma, men were more likely than women to have 68167 Mannheim, Germany
chamber angle, glaucoma can be divided into open-angle this disorder (odds ratio [OR] 1·36), as were people of jost.jonas@medma.
glaucoma and angle-closure glaucoma. The anterior African ancestry compared with people of European uni-heidelberg.de
chamber angle contains Schlemm’s canal, which is ancestry (OR 2·80).3 The prevalence of glaucoma-related
located between the peripheral cornea and the peripheral bilateral blindness was higher in people with primary
iris; the aqueous humour leaves the eye through angle-closure glaucoma than in those with open-angle
Schlemm’s canal (figure 3). In many patients, intraocular
pressure (as the most important risk factor for glaucoma)
either is increased only slightly or is within the normal Search strategy and selection criteria
range, and the rise in pressure—if present at all—is We searched the Cochrane library, MEDLINE, and Embase
usually painless. Since chronic glaucoma can progress between January, 2000, and December, 2016, with the terms:
unnoticed by the patient until central visual acuity and “glaucoma”, “primary open-angle glaucoma”, “secondary
reading ability are affected late in the disease, early open-angle glaucoma”, “angle-closure glaucoma”,
detection is important before subjective symptoms “intraocular pressure”, “optical coherence tomography”,
develop. In this Seminar, we aim to outline the “perimetry”, “optic disc”, “optic nerve head”, “retinal nerve
epidemiology, pathophysiology, symptoms, diagnosis, fiber layer”, “trabecular meshwork”, “glaucoma therapy”, and
and treatment of glaucoma, and we discuss potential “glaucoma surgery”. We largely selected publications from the
future developments in this area. past 5 years, but we did not exclude commonly referenced
and highly regarded older publications. We did not restrict
Epidemiology our search by language. We also searched the reference lists of
In 2010, of 32·4 million blind individuals worldwide, articles identified by this search strategy and selected those
glaucoma was the cause of blindness in 2·1 million we judged relevant. Review articles and book chapters are
(6·5%) people.4 Glaucoma caused visual impairment— cited to provide readers with further details and more
defined as visual acuity in the better eye between less references than this Seminar has room for. Our reference list
than 6/18 and 3/60 or greater—in 4·2 million (2·2%) of was modified on the basis of comments from peer reviewers.
191 million visually impaired individuals worldwide.4

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1
A B

5
Superior
Superior

10

Temporal Nasal Temporal Nasal

15
Inferior
Inferior

20

Figure 1: Ophthalmoscopic photographs of healthy and glaucomatous optic discs

Photographs were taken of the right eye. (A) In the healthy optic disc, the neuroretinal rim has its normal shape with its widest part in the inferior region, followed by
the superior region and the nasal region, and finally the temporal region (referred 25to as the ISNT rule). (B) In the glaucomatous optic disc, the neuroretinal rim is
strikingly thinner than in the healthy optic disc, and the optic cup is subsequently larger, and the cup is deeper.

glaucoma, suggesting that primary angle-closure

In angle-closure glaucoma, the peripheral iris is in
glaucoma has a worse prognosis.3 contact with the trabecular meshwork and the peripheral
30 cornea. The peripheral iris blocks the anterior chamber
Anatomy and pathophysiology angle so that aqueous humour no longer has access to
Intraocular pressure (normal range 10–21 mm Hg) is the outflow system (figure 3). In primary angle-closure
regulated by a balance between secretion of aqueous glaucoma, the iridocorneal contact is due to forward
humour by the ciliary body in the posterior chamber and bulging of the peripheral iris (so-called push mechanism),
drainage of aqueous humour from the anterior chamber 35 which is caused by a higher pressure in the posterior
angle, either through the trabecular meshwork and chamber behind the iris and a lower pressure in the
Schlemm’s canal or via the uveoscleral outflow pathway anterior chamber. The pressure difference is due to
through the iris root into the uveoscleral interface increased flow resistance for the aqueous humour
(figure 3). Increased intraocular pressure is due to a through the slit between the iris and lens in association
decreased outflow facility of aqueous humour. 40 with anatomical abnormalities, such as augmented
In open-angle glaucoma, the aqueous humour has forward bulging of the anterior lens pole (referred to as
free access to the trabecular meshwork and Schlemm’s anterior lens vault), an enlarged contact area between the
canal in the anterior chamber angle. In secondary open- posterior iris and the lens surface, and an abnormal
angle glaucoma, the outflow resistance through the insertion of the iris root on the ciliary body.9–11 The
trabecular meshwork and Schlemm’s canal is increased 45 condition is called primary angle-closure glaucoma when
due to a cause that is detectable by examination of the the raised intraocular pressure has caused damage to the
anterior ocular segment. These conditions include optic nerve. In secondary angle-closure glaucoma, the
pigmentary glaucoma and exfoliative glaucoma.5,6 In iridocorneal contact is caused by the iris being pulled
primary open-angle glaucoma, the anterior chamber forward (so-called pull mechanism) into the angle
angle seems to be unremarkable. The level of intraocular 50 because of, for example, neovascularisation in the iris
pressure can vary strikingly and could be as low as and uveitis. Iris neovascularisation is usually provoked
10 mm Hg. Optic-nerve damage in primary open-angle by ischaemic retinopathies such as diabetic retinopathy,
glaucoma can develop in the presence of normal levels with overproduction of vascular endothelial growth factor
of intraocular pressure, and this condition has been (referred to as neovascular glaucoma).12 In congenital
called normal-pressure glaucoma.7,8 In such situations, 55 glaucoma, the transtrabecular outflow is reduced, often
aqueous outflow resistance is normal or might only be due to an underdeveloped trabecular meshwork and
slightly increased. Schlemm’s canal.13 The increase in intraocular pressure

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 Seminar

in children younger than 2 years results in enlargement 1

A
of the globe, also called buphthalmos. Temporal
Common to all forms of glaucoma is glaucomatous optic superior
neuropathy, characterised by loss of the neuroretinal rim
and widening of the cup in the optic disc (figure 1; 5
figure 2).14–16 The optic disc (also called the optic nerve
head) is located 15° nasally to the fovea (ie, the centre of the
macula) and allows the exit of retinal ganglion cell axons
from the eye.17,18 The base of the optic nerve head consists
Fovea
of the lamina cribrosa, a perforated collagenous sieve-like 10
structure through which the optic nerve fibres and blood
vessels pass. Damage to optic nerve fibres occurs at the
lamina cribrosa (figure 4),19 which is the frontier between
the intraocular compartment and the retro-laminar
compartment.20–22 In eyes with raised intraocular pressure 15
in particular, the increased pressure difference across
Temporal
the lamina cribrosa causes stress and strain on this inferior
structure. This pressure difference results in eventual
23

compression, deformation, and remodelling of the lamina

cribrosa and impedes orthograde and retrograde axonal 20
transport within the optic-nerve fibres.19,24–27
Besides raised intraocular pressure, work is needed to
establish whether a low ocular perfusion pressure (the
difference between intraocular pressure and systemic
blood pressure) might be associated with glaucomatous 25 B
optic neuropathy.28–32 Findings of studies have suggested
an association between glaucomatous optic-nerve damage
and an abnormally low blood pressure at night;30,31
therefore, drugs that lower blood pressure might be best
administered to patients with glaucoma and arterial 30
hypertension in the morning. Studies are needed to
investigate whether mitochondria located in high
concentrations in the prelamina cribrosa region have a
direct role in pathogenesis of glaucomatous optic
neuropathy.33,34 In a similar manner, pathways from gene 35
mutations contributing to glaucoma, and eventual
dysfunction of the encoded proteins, have not yet been
analysed fully.35,36
Glaucoma-associated loss of neurons is not limited to
retinal ganglion cells but extends into the lateral 40
geniculate nucleus and the visual cortex.37,38 Findings of
clinical studies and histological investigations have
suggested that glaucomatous damage affects all subsets
of retinal ganglion cells in a similar manner.37,38 Study
Figure 2: Ophthalmoscopic photographs of the retinal nerve fibre layer of two different eyes
findings also showed that the glaucomatous loss of 45 (A) The photograph shows a healthy retinal nerve fibre layer. (B) The photograph shows the retinal nerve fibre
retinal ganglion cells and their axons was accompanied layer of an eye with glaucomatous optic-nerve damage, with localised retinal nerve fibre layer defects (light blue
by changes in the glial cell population, including arrows), in addition to a diffuse diminution of the retinal nerve fibre layer.
astrocytes and retinal microglial cells.40–42
preservation of visual field in patients with open-angle
Risk factors 50 glaucoma.51 In a meta-analysis of population-based studies,
The main risk factors for both development and progression the odds ratio for primary open-angle glaucoma was 1·73
of glaucoma are older age,3,43–46 an intraocular pressure too (95% CI 1·63–1·82) for each decade increase in age beyond
high in relation to the pressure sensitivity of the optic nerve 40 years.3 Similarly, the prevalence of primary angle-closure
head,7,47–51 ethnic background,44,52 a positive family history for glaucoma increased with older age. Across all ethnic
glaucoma, stage of disease, and high myopia.53–55 Findings 55 origins, individuals of African ancestry had the highest
of a randomised placebo-controlled trial showed that prevalence of glaucoma (6·11%, 95% CI 3·83–9·13) and
medical lowering of intraocular pressure resulted in primary open-angle glaucoma (5·40%, 3·17–8·27), whereas

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 Seminar

1 suggested that the main factor for the myopia-associated

A
increase in glaucoma susceptibility is the myopia-
associated enlargement of the optic disc.56 Secondary
6 stretching and thinning of the lamina cribrosa in
5 association with an elongation and thinning of the
7 parapapillary tissues could lead to pronounced changes
8
5 in the biomechanics of the optic nerve head and an
9 3
increase in glaucoma susceptibility. Another factor could
2
be the biomechanics of the optic nerve dura mater, which
10 pulls on the peripapillary sclera in eye movements and

1
increases the stress and strain of the lamina cribrosa.57
4
Socioeconomic status affects early detection of glaucoma
and initiation of and adherence to treatment;58,59 therefore,
this factor is associated with prognosis of the disease.
15 Whether nutritional status and diet have an effect on the
prevalence and incidence of any form of glaucoma is
unclear. The relation between primary open-angle
500 µm
glaucoma and diabetes mellitus,60,61 arterial hypertension,62,63
body-mass index,64 obstructive sleep apnoea,65 and oral
B Cornea 20 contraceptive use66 is uncertain. Although controversial,
low CSF pressure and low ocular perfusion pressure,
Closed anterior including a low systemic blood pressure, might potentially
chamber angle Lens
have a role in glaucoma.22,28–31,67–69
A thin central cornea has been deemed a risk factor for
25 glaucoma because a thin cornea leads to falsely low
measurements of intraocular pressure.43,70 Furthermore, a
Iris
thin cornea could be a structural risk factor because of a
hypothetical association with a thin lamina cribrosa.71–73
An association between corneal thickness and thickness
30 of the lamina cribrosa has, however, not been shown yet.71
Correspondingly, in an east Asian population,72,73 corneal
biomechanical variables—eg, corneal hysteresis and
Figure 3: Imaging of the anterior segment of the eye
(A) Histophotograph shows the anterior segment of a healthy eye with an open anterior chamber angle, with the
corneal resistance factor—were not correlated with the
ciliary body (1) in the posterior chamber, which is the site of aqueous humour production, and the slit (2) located severity of primary angle-closure glaucoma, nor was
between the posterior iris surface (3) and the anterior lens surface (4) and functioning as a connecting path for the 35 central corneal thickness associated with glaucoma.
aqueous humour to percolate (white line) from the posterior chamber into the anterior chamber through the pupil The main systemic risk factors for development of
(5). The anterior chamber angle is located between the peripheral cornea (6) and the peripheral iris and contains
the trabecular meshwork (7) and Schlemm’s canal (8). The aqueous humour leaves the eye through the trabecular
primary closure of the anterior chamber angle are older
meshwork and Schlemm’s canal and through the uveoscleral outflow pathway (9). (B) Optical coherence age, east Asian ethnic origin, and female sex, in addition
tomogram of the anterior segment of an eye with closed anterior chamber angle. to the main ocular risk factor of axial hyperopia. The
40 hyperopic eye has a small anterior chamber, a thick and
the Asian population had the highest prevalence of primary more anteriorly positioned lens, a thick iris, and greater
angle-closure glaucoma (1·20%, 0·46–2·55).3 Sex has been forward bulging of the anterior lens pole (or anterior lens
associated inconsistently with the prevalence of open-angle vault).9,10,74,75 The reduced space in the anterior chamber
glaucoma, yet in two meta-analyses of population-based leads to a higher risk of a blockage of the anterior chamber
glaucoma studies, a higher prevalence of primary open- 45 angle by peripheral iris tissue in mid-mydriasis. The angle
angle glaucoma was reported in men than in women.3,47 obstruction can occur acutely, leading to acute and painful
High myopia with a myopic refractive error of roughly angle-closure glaucoma, or it might develop chronically,
more than –8 diopters was another strong risk factor for associated with painless chronic angle-closure glaucoma.
glaucoma.53–56 Correspondingly, findings of the Singapore
Malay Eye Study showed an association between moderate 50 Genetics
or high myopia (worse than –4 diopters) and a higher Based on findings of genome-wide association studies,
prevalence of primary open-angle glaucoma.55 primary open-angle glaucoma is associated with several
Diagnosis of glaucomatous optic neuropathy can be genes: CDKN2B-AS1, CAV1 and CAV2, TMCO1, ABCA1,
missed in myopic eyes because intraocular pressure is AFAP1, GAS7, TXNRD2, ATXN2, the chromosome 8q22
typically within the normal range and the myopic 55 intergenic region, and SIX1 and SIX6.36,76–89 In particular,
appearance of the optic nerve head makes detection of myocilin, optineurin, and WDR36 are linked to adult
glaucomatous changes difficult. Study findings have glaucoma,77–79 CYP1B1 to glaucoma in children and

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 Seminar

younger adults,90 and LOXL1 to exfoliative glaucoma.80,81,91,92 1

This range of loci in primary open-angle glaucoma is
unexpectedly broad. Findings of genome-wide association
studies have also identified genetic loci associated with
quantitative glaucoma-related traits—eg, intraocular 5
pressure, central corneal thickness, and optic disc
size.90,92,93–97 Unexpectedly, the number of genetic loci
B A
shared between intraocular pressure and the primary
open-angle glaucoma phenotype was small (ie, CAV1 and
CAV2, TMCO1, ABCA1, and GAS7), suggesting that 10
genetic susceptibility to primary open-angle glaucoma is
not accounted for solely by raised intraocular pressure.
Genetic associations of glaucoma vary according to ethnic
group. Common glaucoma susceptibility alleles seen in
white European populations at the genome-wide level 15
C
(eg, CDKN2B-AS1, TMCO1, CAV1 and CAV2, chromo­
some 8q22 intergenic region, and SIX1 and SIX6) seem to
have weaker associations with primary open-angle
glaucoma in African-American populations.
D
Thus far, findings of genome-wide association studies 20
have implicated eight genetic loci that show strong
associations with primary angle-closure glaucoma.35,98
These loci suggest mechanisms of cell–cell adhesion and E
collagen metabolism, a type 2 diabetes-related pathway,
and acetylcholine-mediated signalling are important in 25
the primary angle-closure glaucoma disease process. Figure 4: Imaging of the optic nerve head
Considering the results of these genetic studies, Histophotograph shows a healthy optic nerve head with the lamina cribrosa (between the green stars) as the
assessment of family history of glaucoma is clinically bottom of the optic cup (A) and the neuroretinal rim (B) containing the retinal ganglion cell axons. The orbital CSF
important. Having a first-degree relative with glaucoma space (C) is between the pia mater of the optic nerve (D) and the dura mater of the optic nerve (E).
has been associated consistently with an increased risk 30
for primary open-angle glaucoma and primary angle- opportunistic case-finding to two proposed screening
closure glaucoma in prevalence surveys. Siblings of strategies for glaucoma in the UK. They found that general
affected individuals have nearly an eight times increased population screening was not cost-effective given the
risk of primary open-angle glaucoma and a five times disease prevalence and that targeted screening of specific
increased risk of angle closure when compared with 35 subgroups aligned with the established risk factors would
siblings of unaffected individuals. The risk for primary be needed to achieve cost-effectiveness. These same
open-angle glaucoma might be stronger when the reasons hold true for genetic screening for glaucoma.
affected relative is a sibling rather than a parent or child. Therefore, for screening programmes to be effective, it is
Although several genes are associated with glaucoma, important to select participants at substantial risk. If only
the connection between the gene mutation, the secondary 40 one screening technique could be applied, imaging of the
change in the encoded protein, and the tertiary alteration optic nerve and retinal nerve fibre layer would currently be
in the function of this protein are unclear. Genetic judged the best. One measurement of intraocular pressure
findings, therefore, have not yet contributed greatly to has a low sensitivity to detect glaucoma under screening
elucidate the pathogenesis of glaucoma. conditions.101
45
Screening Diagnosis
A large proportion (50–90%) of patients with glaucoma Because chronic forms of glaucoma are painless,
remain undiagnosed in developed, developing, and under­ measurable visual-field defects do not develop at an early
developed regions of the world.59,99 Although screening for stage of glaucoma, and defects generally do not occur at
glaucoma in the entire population would be an option, it 50 homonymous locations in both visual fields, self-detection
is not considered logistically feasible. Because of the fairly of glaucoma by affected individuals usually occurs at a
low prevalence of glaucoma (about 3·5% in individuals late stage of the disease. The mainstay of detection of
aged 40 years or older), and since diagnostic measures glaucoma is examination of the optic nerve head and
with sufficient precision are not yet available, general retinal nerve fibre layer.102–106 Glaucomatous changes of
screening for glaucoma would result in an unacceptably 55 the optic nerve head include loss of neuroretinal rim,
high number of false-positive diagnoses. Using a health leading to enlargement of the optic cup, deepening of the
economic model, Burr and colleagues100 compared optic cup (partly reversible if the intraocular pressure is

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 Seminar

reduced to normal or subnormal levels), development 1 glaucoma is caused by an acute pupillary block and is
and enlargement of the parapapillary beta zone, thinning characterised by an inflamed eye with pronounced
of the retinal nerve fibre layer, and optic disc hyperaemia of the conjunctiva, corneal oedema, a mid-
haemorrhages, which are signs of progression of the dilated unreactive pupil, a shallow anterior chamber, and
disease.107–109 These changes can be assessed by simple 5 high intraocular pressure. Acute angle-closure glaucoma
ophthalmoscopy or by imaging techniques such as is usually accompanied by severe ocular pain with
spectral-domain optical coherence tomography, which is blurring of vision, haloes noticed around lights, nausea,
useful in particular for follow-up examinations.106,110 and vomiting.
Tonometry is an essential part of the diagnosis and
follow-up of glaucoma, although intraocular pressure 10 Treatment
cannot be taken as the main criterion for diagnosis of Open-angle glaucoma
the disease because many patients with glaucoma can The only proven and generally accepted treatment to
present with normal intraocular pressure. In the Japanese reduce the risk of further progression of glaucomatous
population-based Tajimi study,111 intraocular pressure was optic neuropathy is to lower intraocular pressure.49,51,115
21 mm Hg or less in 92% of patients with primary open- 15 Reduction of intraocular pressure is achieved by drug
angle glaucoma. Intraocular pressure is the primary treatment, laser therapy, or surgery. The goal is to lower
modifiable risk factor and its modulation is central to the the intraocular pressure towards an individual target
management of glaucoma, but it is a fairly weak diagnostic level at which further progression of glaucomatous optic
criterion. The dependence of tonometric measurements nerve damage is unlikely. The target intraocular pressure
on the central corneal thickness and curvature has to be 20 for a particular eye is estimated based on the pretreatment
taken into account.112 In eyes with abnormally thick intraocular pressure, the severity of damage, presence of
corneas, tonometry gives falsely high readings, potentially risk factors for progression, life expectancy, and potential
leading to overdiagnosis, and in eyes with abnormally thin for adverse effects from treatment. The aim is usually for
corneas, tonometric measurements are falsely low, with a reduction in intraocular pressure of 20–50%. The
the risk of underdiagnosis of glaucoma. Central corneal 25 greater the pre-existing optic-nerve damage and the more
thickness and corneal curvature should, therefore, risk factors present, the lower the target pressure is set.
be measured once so that tonometric readings can be The target intraocular pressure should be reanalysed
corrected accordingly. periodically by assessing whether the optic-nerve damage
Perimetric visual-field examination is the second is stable or has progressed.
technique in the diagnosis and follow-up of glaucomatous 30 Several categories of topical drugs for lowering
optic-nerve damage.7,47,48 Many optic nerve fibres can be intraocular pressure are available. The choice of drug is
lost before perimetric defects are detected; therefore, the affected by cost, adverse effects, and dosing schedules.
diagnostic precision of this technique increases with the In general, prostaglandin analogues (eg, latanoprost,
stage of glaucoma.113 Perimetry describes the subjective tafluprost) are the first-line medical treatment; when
psychophysical defect as experienced by the patient, but 35 delivered once in the evening, these drugs lower
it has fairly high intervisit variability, so at least three intraocular pressure by improving uveoscleral outflow.
perimetric examinations could be necessary to detect Local side-effects include elongation and darkening of
visual-field deterioration reliably. Other psychophysical eyelashes, loss of orbital fat (prostaglandin-associated
tests—including assessment of glaucoma-related colour periorbitopathy) with resulting enophthalmos, iris
vision deficiency, impaired dark adaptation, increased 40 darkening in eyes with greenish-brown iris colour, and
photophobia, and decreased contrast sensitivity—are periocular skin pigmentation.
important for the quality of vision of the patient. These An alternative to prostaglandins are β adrenergic
modalities, however, are not measured routinely because blockers (eg, timolol, betaxolol), which reduce intraocular
of high interindividual and intraindividual variability. pressure by decreasing aqueous humour production.
A potential future development is application of optical 45 Applied once (in the morning) or twice (morning and
coherence tomography angiography to visualise the evening) daily, they can result in systemic side-effects
superficial and deep retinal vascular network and, in including bradycardia, arrhythmias, a drop in blood
particular, the peripapillary radial vascular network.114 pressure, reduced libido, and increased obstructive
Assessment of the peripapillary radial vascular network bronchial problems that can lead to an asthmatic attack.
could help in the diagnosis and follow-up of glaucomatous 50 Other groups of drugs include topical carbonic anhydrase
optic neuropathy in highly myopic eyes, in which most inhibitors (eg, dorzolamide, brinzolamide), which reduce
other diagnostic methods fail. aqueous humour production, and α adrenergic agonists
Open-angle glaucoma is distinguished from angle- (eg, brimonidine), which decrease aqueous humour
closure glaucoma by gonioscopic examination of the production and increase uveoscleral outflow. Miotics (eg,
anterior chamber angle. Angle-closure glaucoma in its 55 pilocarpine) have the longest history of application and
chronic form can be asymptomatic until visual-field reduce intraocular pressure by improving the
defects are noticed. In its acute form, angle-closure transtrabecular outflow. Local side-effects are a varying

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degree of annoying involuntary accommodation in 1 Similarly, trabeculectomy versus non-penetrating surgeries

patients younger than 45 years and pupillary constriction, (eg, deep sclerectomy, viscocanal­ostomy, and canaloplasty)
which is inconvenient at night and can reduce visual acuity is more effective at reducing the intraocular pressure but
in eyes with cataract, yet increases the depth of focus has a higher risk of complications.120,121
because of the stenopeic effect. Miotics can, therefore, be 5
useful in eyes with artificial intraocular lenses after cataract Primary angle-closure glaucoma
surgery. Miotics do not have major systemic side-effects. The treatment of acute angle closure differs profoundly
Prostaglandin analogues, carbonic anhydrase inhibitors, from the therapeutic regimen for open-angle glaucoma.
and miotics reduce intraocular pressure during both day In acute angle closure, acutely raised intraocular pressure
and night, whereas β adrenergic blockers and α adrenergic 10 is lowered first by drugs, including miotics as first-line
agonists are effective mostly during daytime. Most drug treatment (eg, pilocarpine), repeatedly instilled in short
groups can be combined with each other. intervals, and other drugs used in chronic open-angle
A new class of topically applied drugs is the ρ kinase glaucoma (eg, timolol, latanoprost, brimonidine). The
inhibitors (eg, ripasudil), which have finished phase 3 aim is to open up the angle by inducing a miosis and
trials and are expected to be approved in 2017.116–118 These 15 pulling the peripheral iris tissue out of the angle. An
drugs reduce intraocular pressure by increasing the alternative could be immediate laser iridoplasty.122 As
transtrabecular outflow and, potentially, by decreasing the definitive treatment, peripheral laser iridotomy, which
production of aqueous humour. forms a pathway for aqueous humour flow between the
After topical application of an eye drop, gentle occlusion posterior chamber and anterior chamber by creating a
of the lower lacrimal duct—or just to close the eyes for a 20 small hole in the peripheral iris, is mandatory for all
few minutes—is recommended. These measures greatly patients with primary angle-closure. This technique
reduce the amount of drug passing through the lacrimal reduces the pressure differences between both chambers
drainage system on to the mucosa of the oropharynx so that the peripheral iris can flatten and be retracted out
where the drugs are easily absorbed and, by avoiding of the anterior chamber angle. If done at an early stage,
breakdown by the hepatic system, can lead to systemic 25 one procedure can result in lifelong cure. If the procedure
side-effects. is delayed, peripheral anterior synechiae can form, and if
In eyes with an open anterior chamber angle, drug not released by surgical intervention within a few days to
treatment could be augmented by, or in some cases weeks, further circumferential adhesions can occur,
replaced by, laser therapy (laser trabeculoplasty) to resulting in an irreversible closure of the whole anterior
the trabecular meshwork, in particular if the target 30 chamber angle and blockage of the outflow system. Non-
intraocular pressure is not achieved by use of drugs pupillary block mechanisms (eg, plateau iris) can cause a
(particularly in poorly compliant patients). Independent considerable proportion of angle closure in people from
of concurrent drug treatment, laser intervention can east Asia, an ethnic group that has a higher propensity
reduce the intraocular pressure by a few additional mm for angle-closure glaucoma.
Hg. The good safety profile of laser trabeculoplasty is 35 Post-iridotomy procedures to further lower intraocular
combined with fairly low efficacy. pressure, if needed, are similar to those undertaken for the
If the intraocular pressure-lowering effect is not treatment of open-angle glaucoma. They include topical
sufficient, incisional glaucoma surgery has to be done, application of anti-glaucomatous drugs and incisional anti-
usually under local anaesthetic but occasionally under glaucoma surgery, including trabeculectomy or lens
topical anaesthesia. In patients with poor compliance or 40 extraction with implantation of glaucoma drainage
those intolerant to drug treatment, incisional surgery can implants. Since the risk of acute angle closure is usually
also be done as the first step in the treatment of glaucoma. similar between both eyes, laser peripheral iridotomy
A panoply of surgical antiglaucomatous procedures has should be done prophylactically in the contralateral eye of a
been developed in the past decade. Creating an additional patient presenting with unilateral primary angle closure.
outflow pathway from the eye for the aqueous humour, all 45 Evidence from a clinical trial shows that clear-lens
surgical techniques (eg, trabeculectomy) risk reduced long- extraction has greater efficacy and is more cost-effective
term success secondary to fibrosis around the than laser peripheral iridotomy for treatment of primary
subconjunctival exit point of the fistula. During and after angle-closure glaucoma,123 and this technique could be
surgery, antimetabolites are applied to the surgical site to considered as an option for first-line treatment. In more
decrease the fibrotic response and to keep the fistula site 50 than 400 patients with either newly diagnosed primary
open. Glaucoma implant drainage devices are another angle closure and an intraocular pressure of 30 mm Hg or
surgical option and act by channelling the aqueous humour greater or primary angle-closure glaucoma,123 individuals
through a tube out of the eye into the subconjunctival assigned to undergo clear-lens extraction versus standard
space. These devices are similarly effective in lowering care with laser peripheral iridotomy and topical medical
intraocular pressure to trabeculectomy.119 Minimally 55 treatment showed at study end a significantly higher mean
invasive glaucoma surgery, compared with standard health status score (p=0·005), a lower mean intraocular
trabeculectomy, has fewer side-effects but lower efficacy.120 pressure (p=0·004), and an incremental cost-effectiveness

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ratio of £14 284. The study findings agreed with those of a ganglion cell damage.130 Second, work is awaited to
1
previous investigation,124 in which cataract surgery elucidate secondary intracranial changes, including
combined with goniosynechiolysis successfully normalised cerebral neuroplasticity.37 Third, research is needed to
the intraocular pressure in patients with persisting examine the role of retinal vein pulsations and retinal
peripheral anterior synechiae between iris and cornea and 5 venous blood pressure in the pathogenesis and diagnosis
raised intraocular pressure after periphery iridotomy. of glaucomatous optic neuropathy.131 Fourth, an
assessment should be done of the cause of parapapillary
Congenital glaucoma beta zone.132 Fifth, investigations are needed into the
Treatment of congenital glaucomas is mainly surgical. reasons for increased glaucoma susceptibility in patients
Procedures used include goniotomy or trabeculotomy, in 10 with high myopia.53–56 Finally, research is awaited into the
which the inner wall of Schlemm’s canal is opened into biomechanics of the optic nerve dura mater and its effect
the anterior chamber. on the optic nerve head.57
Another area for future development is to further
Future developments investigate exfoliation syndrome, with respect to its
The noted growth in prevalence of cataract surgery and 15 genetics, proteomics, molecular biology, cellular processes,
the increase in prevalence of axial myopia, in particular and systemic manifestations.133,134
in Asia, might decrease the occurrence of angle-closure Several potential novel treatments for glaucoma are
glaucoma in the future.125 Ongoing studies that under investigation or could be explored. First, studies
investigate the benefits of iridotomy in patients with are underway to investigate induction of a re-sprouting
angle closure from east Asia will provide guidance on the 20 of retinal ganglion cell dendrites to increase the
efficacy of this treatment in these populations, in which receptive field of the still-existing ganglion cells.135
angle-closure is fairly prevalent among adults.126 Second, studies are in progress to refine the existing
Topically applied ρ kinase inhibitors might become an surgical techniques to reduce the risk of a postoperative
additional pillar in the medical treatment of glaucoma.116–119 scarring of the filtering bleb, leading to treatment
Novel sustained-release delivery systems—eg, intracameral 25 failure. Finally, work to further assess the application of
injection of slow-release intraocular pressure-lowering stem cells and gene therapy in patients with glaucoma
drug pellets or topically applied cyclodextrins—are being is needed.
tested in trials.127,128 Such systems might reduce the Contributors
problems associated with poor adherence and ocular JBJ, TA, RRB, AMB, RR, and SP-J jointly searched the literature and
surface damage that can occur with long-term use of 30 prepared and revised the manuscript and approved it.
topically applied eye drops. Declaration of interests
Better understanding of patient-reported outcomes and JBJ is a consultant for Mundipharma; holds a patent with
Biocompatibles UK (patent number 20120263794); and has applied for
experience might further improve the practical success a patent with the University of Heidelberg (Europäische
of glaucoma treatment. 129
Furthermore, improved Patentanmeldung 15 000 771.4). TA is a consultant for Alcon, Allergan,
awareness of the many forms of glaucoma among the 35 Belkin Lasers, Carl Zeiss Meditec, Pfizer, Roche, Quark, and Santen;
general population and health-care professionals, in has received lecture fees, travel grants, and research support from
Alcon, Allergan, Roche, Santen, and Tomey; has received lecture fees
particular among adults with a family history of and research support from Carl Zeiss Meditec; and has received
glaucoma, will address the large proportion of disease research support from Ellex, Ocular Therapeutics, and Quark. RRB is a
that has remained undetected so far, even in high-income consultant for and has received lecture fees, travel grants, and research
countries.59,99 40 support from Allergan and Tomey; and is a consultant for and has
received lecture fees and travel grants from Santen. AMB is a
Ongoing research will further refine the morphological consultant for Allergan, Bausch-Lomb, and Théa; and has received
diagnosis of glaucoma, in particular the measurement of research support from Théa and Horus. RR has received personal fees
the thickness of the retinal nerve fibre layer and the from Sensimed AG, iSonic Medical, Aeon Astron Europe, Santen
width of the neuroretinal rim. These data will help to Pharmaceutical, Ocular Instruments, Gerson Lehrman Group,
Gillis Zago Professional, Donahey Defossez & Beausay, and Tanoury,
improve precision in detecting progression of 45 Nauts, McKinney & Garbarino; other support [A: please explain what
glaucomatous optic nerve damage. 103–106
you mean by “other”] from Diopsys, GLIA, Guardion Health Sciences,
Ongoing studies will assess the hypothesis that in Mobius Therapeutics, Intelon Optics, Xoma, and The International Eye
patients with primary open-angle glaucoma and normal Wellness Institute; and holds a patent [A: please provide the patent
number] with royalties paid to The International Eye Wellness
intraocular pressure, the orbital CSF pressure could be Institute. SP-J holds a patent with Biocompatible UK (patent number
abnormally low, so that the translamina cribrosa pressure 50 20120263794) and has applied for a patent with the University of
difference would be raised.21,22,67,68 These studies might also Heidelberg (Europäische Patentanmeldung 15 000 771.4).
examine dynamic changes of the optic nerve head that References
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