PRIMER

Primary open-angle glaucoma

Robert N. Weinreb1, Christopher K. S. Leung2, Jonathan G. Crowston3,
Felipe A. Medeiros1, David S. Friedman4, Janey L. Wiggs5 and Keith R. Martin6
Abstract | Glaucoma is an optic neuropathy that is characterized by the progressive degeneration of
the optic nerve, leading to visual impairment. Glaucoma is the main cause of irreversible blindness
worldwide, but typically remains asymptomatic until very severe. Open-angle glaucoma comprises
the majority of cases in the United States and western Europe, of which, primary open-angle
glaucoma (POAG) is the most common type. By contrast, in China and other Asian countries,
angle-closure glaucoma is highly prevalent. These two types of glaucoma are characterized based on
the anatomic configuration of the aqueous humour outflow pathway. The pathophysiology of POAG
is not well understood, but it is an optic neuropathy that is thought to be associated with intraocular
pressure (IOP)-related damage to the optic nerve head and resultant loss of retinal ganglion cells
(RGCs). POAG is generally diagnosed during routine eye examination, which includes fundoscopic
evaluation and visual field assessment (using perimetry). An increase in IOP, measured by tonometry,
is not essential for diagnosis. Management of POAG includes topical drug therapies and surgery to
reduce IOP, although new therapies targeting neuroprotection of RGCs and axonal regeneration
are under development.

Correspondence to R.N.W.
Shiley Eye Institute, Hamilton
Glaucoma Center,
Department of
Ophthalmology, University
of California, San Diego,
9500 Gilman Drive, La Jolla,
California 92093, USA.
rweinreb@ucsd.edu
Article number: 16067
doi:10.1038/nrdp.2016.67
Published online 22 Sep 2016
Glaucoma is an optic neuropathy that is characterized
by the progressive degeneration and functional deterior­
ation of the optic nerve, including the optic nerve head
(ONH) and the retinal nerve fibre layer (RNFL) (FIG. 1a),
resulting in progressive reduction in visual sensitivity
and, in some patients, blindness1,2. More than ­70 ­million
people worldwide have glaucoma and it is the leading
cause worldwide of irreversible blindness 1. 10% of
individuals with glaucoma are thought to be bilaterally
blind1, but more than half are unaware that they are
affected as the disease often remains asymptomatic until
it is severe2.
There are different types of glaucoma (BOX 1). The
defining feature of this group of conditions is optic disc
excavation (also known as cupping), a characteristic
deformation and remodelling of the ONH in response to
intraocular pressure (IOP)-related biomechanical stress
and strain that can occur at any level of IOP (FIG. 1b,c).
The two main types are open-angle glaucoma and
angle-closure glaucoma, which are broadly distinguished
according to the anatomic configuration of the aque­
ous humour (that is, natural, clear fluid in the anterior
chamber in front of the lens) outflow pathway (FIG. 1a).
In open-angle glaucoma, the trabecular meshwork out­
flow pathway is accessible to the aqueous humour and
is often blocked internally, whereas it is blocked by the
iris in angle-closure glaucoma. If the trabecular mesh­
work outflow pathway is blocked internally or by the iris,
the IOP is increased and this might lead to ONH
damage. Glaucoma can also be classified as primary
(of unknown cause) or secondary (the cause can be
­identified by c­ linical examination)3 (BOX 1).
Open-angle glaucoma comprises the majority of
cases of glaucoma in individuals of European and
African descent, but angle-closure glaucoma is highly
prevalent in individuals of Chinese descent and other
populations from Asia4. The most common form of
open-angle glaucoma is primary open-angle glaucoma
(POAG). Most patients with POAG will not go blind
but often have substantial limitations in visual function
and quality of life (QOL). POAG is estimated to cause,
worldwide, approximately 6 million cases of blindness
in 2020 (REF. 1).
The pathophysiology of POAG and factors that con­
tribute to the worsening of disease are not well under­
stood. However, retinal ganglion cells (RGCs) and their
axons (that eventually converge in the optic nerve) are
known to be damaged early in the disease and their pro­
gressive death disrupts the visual pathway, which leads to
vision loss. Only a few risk factors for POAG have been
identified, including, for example, high IOP, older age and
a thin central cornea2. POAG management is directed at
lowering IOP by medical or surgical means. However,
many patients with POAG suffer progressive visual field
loss despite treatment with drug and surgical therapies.
Other forms of treatment, including neuroprotective

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PRIMER

Author addresses The primary role of IOP in glaucoma pathogenesis

1
Shiley Eye Institute, Hamilton Glaucoma Center,
Department of Ophthalmology, University of California,
San Diego, 9500 Gilman Drive, La Jolla, California 92093,
USA.
2
Department of Ophthalmology and Visual Sciences,
The Chinese University of Hong Kong, Hong Kong, China.
3
Department of Ophthalmology, Centre for Eye Research
Australia, University of Melbourne, Melbourne, Victoria,
Australia.
4
Dana Center for Preventive Ophthalmology, Johns
Hopkins Wilmer Eye Institute, Baltimore, Maryland, USA.
5
Department of Ophthalmology, Massachusetts Eye and
Ear, Harvard Medical School, Boston, Massachusetts, USA.
6
Department of Ophthalmology and Cambridge NIHR
Biomedical Research Centre, University of Cambridge,
Cambridge, UK.
strategies and therapies to promote regeneration of
injured RGC axons, are under investigation.
This Primer focuses on POAG, the most common
form of glaucoma, and discusses the mechanisms that
have been shown to underlie this disease, in addition to
diagnostic and management strategies.
Epidemiology
Prevalence
Between 35 and 58 million people were estimated to
have POAG worldwide in 2015. The prevalence of
POAG is expected to increase up to between 53 and
65.5 million affected individuals by 2020, owing to the
ageing world population4,5. The prevalence of POAG
varies widely across populations2,4,5 (FIG. 2). Prevalence
also differs according to ethnicity. Black individuals have
the highest prevalence of POAG, with >5% of individ­
uals 60 years of age compared to 2.7% among Hispanic
or Latino individuals, approximately 2% among Asian
populations and about 1.5% among white individuals5.
Moreover, the prevalence can vary within each ethnicity,
depending on the country of birth of the individual.
The prevalence of POAG is strongly correlated with
age; the highest prevalence is among older Hispanic or
Latino individuals (18%), followed by black individuals
(15%), white individuals (7%) and Asian individ­
uals (5%), all 85 years of age, and prevalence is even higher
in those >90 years of age5. Black individuals develop
POAG earlier than individuals of other ethnicities.
Risk factors
Age is a strong risk factor for the development of POAG6.
In addition, male sex is a risk factor; men have a 30%
increased risk of POAG compared with women, when
adjusted for age2. IOP is a strong risk factor for glau­
coma. The prevalence of POAG increases dramatically
at a higher IOP, but glaucoma can occur at all levels of
IOP7. The prevalence of POAG is lower in individuals
with lower IOP, but approximately half of all those diag­
nosed with POAG will have an IOP that is initially in the
normal range (between 10 and 20 mmHg)8. Moreover,
some individuals can have increased IOP (conven­
tionally >21 mmHg), without optic nerve damage.
in the presence of ‘population normal’ IOP is evidenced
by the reduced rates of glaucoma progression observed
in the Collaborative Normal Tension Glaucoma Trial
when IOP was reduced by 30% by medical or surgical
treatment 9. In this study, 12% of patients with glau­
coma at normal IOP who were treated had worsening
of disease, whereas a significantly greater proportion of
patients (35%) who were not treated worsened.
Ocular risk factors can further increase the risk of
POAG in individuals with high IOP10, such as changes
in connective tissue (for example, a thin central cornea11,
disc haemorrhage12 and corneal hysteresis13). Myopia
(short-sightedness), particularly high myopia, is also a
significant ocular risk factor for POAG14.
Systemic risk factors for POAG include blood pres­
sure and type 2 diabetes mellitus15,16. Hypertension
is associated with a 16% increased risk of POAG15.
Interestingly, low blood pressure might also be associ­
ated with risk of developing glaucoma by reducing ocu­
lar perfusion pressure (that is, the pressure by which
blood enters the eye, calculated by the arterial blood
pressure minus IOP)17. Low cerebral fluid pressure18,
resulting in increased trans-lamina cribrosa pressure
(IOP minus intracranial pressure), might also contrib­
ute to the optic nerve damage in glaucoma. A confirmed
family history of POAG is a strong risk factor, with an
approximate eightfold increase in risk among siblings7.
Early-onset glaucoma (defined as onset before 40 years
of age), specifically juvenile open-angle glaucoma and
familial normal-tension glaucoma19, has a strong genetic
component, whereas >15 genes are significantly associ­
ated with late-onset (defined as onset after 40 years of
age) POAG, but individual effect sizes are small.
Mechanisms/pathophysiology
Damage to the ONH
The characteristic pattern of RNFL loss with associated
arcuate visual field defects seen in glaucoma indicates the
ONH as being the primary site of injury in the disease.
In addition, studies of human post-mortem tissue and
primate models of experimental glaucoma have revealed
that glaucoma, in contrast to other optic neuropathies
such as ischaemic or traumatic optic neuropathy, is
character­ized by prelaminar thinning (that is, the loss of
RGC axons anterior to the lamina cribrosa), deforma­
tion of the lamina cribrosa20 and expansion of the scleral
­opening where RGC axons exit the globe of the eye (FIG. 1).
Mechanisms of injury in glaucoma
The characteristic damage to the ONH rather than
increased IOP is the defining feature of glaucoma.
Indeed, although glaucoma is frequently associated with
increased IOP, the condition can occur at any eye pres­
sure in susceptible individuals. Ocular hypertension is the
diagnosis applied when the IOP is above the statistically
normal range without evidence of optic nerve ­damage8.
Variations in IOP cause dynamic stresses and strains
within the ONH that is likely to vary in different individ­
uals according to the architecture and c­ omposition of
their connective tissue21.

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 PRIMER

Biomechanical deformation of the ONH might
adversely affect RGC function, including the transport
of crucial neurotrophic factors (FIG. 3). Axonal injury can
trigger signalling cascades that lead to death of RGCs
and degeneration of their axons. Although the ONH is
the primary site of injury, increased IOP can also affect
RGC somas. Indeed, RGCs have been shown to express
members of the transient receptor potential ion channel
family, which could contribute to calcium-­dependent
cell death22. In addition, effects that might be induced
or modulated by IOP23, such as vascular dysregula­
tion or ischaemia24, oxidative stress25,26, excitotoxicity 27,
inflammation 28,29, autophagy, autoimmunity 30 and
reactive gliosis31–34, might also have a role in glaucoma,
at least in animal models, and might be involved in
human disease23.

a Sclera
Vitreous humour Choroid
Conjunctiva Retina
Choroid
Optic
nerve

Cornea Lens

Iris
Retina
Aqueous humour Sclera
(in the anterior
chamber) Suprachoroidal
space
b Healthy
Optic disc
Internal limiting membrane
Retinal nerve fibres
Bruch’s membrane
Optic disc Choroid
Suprachoroidal space
Optic cup Sclera
Neuroretinal Lamina cribrosa
rim
Optic cup

Optic nerve

c Glaucoma

Optic disc

Optic cup

Figure 1 | Pathophysiology of glaucoma. a | Eye morphology. Intraocular pressure is generated by the balance between
aqueous humour production by the ciliary body and outflow via the trabecular meshworkNature Reviews
and the | Disease
uveoscleral Primers
outflow
pathway. Intraocular pressure is usually measured as the trans-corneal pressure gradient, but pressure generated in the
anterior chamber is transmitted to all compartments inside the eye and, when increased or in susceptible individuals,
might contribute to damage to the optical nerve head (ONH). b | ONH in a healthy eye. Unmyelinated axons of retinal
ganglion cells (RGCs) constitute the retinal nerve fibre layer of the inner retina. These axons converge at the ONH and
then exit the eye in the optic nerve where they become myelinated. The ONH consists of a neuroretinal rim, which
contains the RGC axons (also known as optic nerve fibres), a central depression known as the optic cup and a collagenous
structure, known as the lamina cribrosa, which provides physical support to the axon fibres. c | ONH in glaucoma.
Optic disc cupping, characterized by progressive neuroretinal rim narrowing, which increases the ratio between the optic
cup and disk (called the cup-to-disk ratio) is the characteristic ONH deformation in glaucoma. Biomechanical deformation
and remodelling of the ONH might lead to posterior displacement of the lamina cribrosa relative to the sclera and
changes in its thickness, with associated progressive loss of RGC axons and cell bodies.

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PRIMER

Role of IOP. IOP is determined by the balance between
aqueous humour production by the ciliary body and
aqueous humour outflow (FIG. 4). Aqueous humour exits
the eye through two drainage routes, the trabecular mesh­
work and the uveoscleral outflow pathway. IOP rises when
aqueous humour outflow is obstructed. In angle-closure
glaucoma, the trabecular meshwork is occluded, typically
by the iris. In open-angle glaucoma, there is increased
resistance to aqueous humour outflow at the level of the
trabecular meshwork or further downstream35. Reduced
outflow through the trabecular meshwork increases the
pressure in all compartments of the eye, raises the pres­
sure gradient across the lamina cribrosa and increases the
probability of progressive ONH damage.
Drainage of aqueous humour by the trabecular mesh­
work is thought to be an active process that depends on
mitochondrial function in trabecular meshwork cells.
Factors associated with increased resistance to aque­
ous humour outflow in POAG also might include a
reduction in the number and function of endothelial
cells in the trabecular meshwork, which occurs with
age and might be exacerbated in POAG35. Dysfunction
of mitochondria in trabecular meshwork cells has also
been demonstrated in tissue isolated from patients with
POAG36. Furthermore, the abnormal accumulation of
extra­cellular matrix mol­ecules and the development
Box 1 | Other types of glaucoma
Open-angle glaucoma is the most common form of
glaucoma, and it is often associated with an increase in
intraocular pressure (IOP). Normal-tension glaucoma is
a subtype in which there is normal IOP*. Angle-closure
glaucoma is more common in Asia.
Secondary open-angle glaucoma
• Pigmentary glaucoma: blockage of the aqueous
humour outflow tracts by pigment granules that are
released from the iris
• Exfoliative glaucoma: blockage of the aqueous humour
outflow tracts by exfoliative material that is also found
in the lens and other intraocular structures
Secondary angle-closure glaucoma
• Angle-closure glaucoma: glaucoma marked by an
increase in IOP that is typically caused by blockage of
the trabecular meshwork outflow pathway by the iris
• Neovascular glaucoma: blockage of the aqueous
humour outflow tracts by fibrovascular membranes
that leads to angle closure. This condition never occurs
on its own and is a complication of, for example,
diabetes mellitus
Other types of glaucoma that may be open-angle
or angle-closure
• Uveitic glaucoma: glaucoma associated with uveitis
(that is, inflammation of the uvea)
• Childhood glaucoma: early-onset glaucoma that is
often inherited
*Controversy exists as to whether normal-tension glaucoma is
a distinct disease entity or whether it is merely primary
open-angle glaucoma developing in a patient with their IOP
within the statistically normal range.
of crosslinked actin networks might affect the resist­
ance to outflow via the trabecular outflow pathway,
contributing to an increase in IOP37. After leaving the
eye through the trabec­ular meshwork in Schlemm’s
canal, aqueous humour enters the ­episcleral venous cir­
culation. Consequently, conditions that affect episcleral
venous pressure (such as carotid cavernous sinus fistula
or Sturge–Weber s­ yndrome) might also influence IOP.
Neurotrophins and axonal transport. Impaired axonal
transport in RGCs was identified in primates following
increased IOP38 and in rat models of glaucoma39. Axonal
transport was also impaired in post-mortem tissue from
12 patients with secondary glaucoma40. Impaired axonal
transport can adversely affect the survival of RGCs
by multiple mechanisms, including the disruption of
neuro­trophic factor signalling. For example, retrograde
transport of brain-derived neurotrophic factor (BDNF),
an important survival signal for RGCs, and its recep­
tor, BDNF/NT‑3 growth factors receptor (TrkB), to the
RGC soma was found to be reduced by increased IOP41.
Moreover, supplementation with BDNF or viral-mediated
expression of ciliary neurotrophic factor in inner retinal
cells has been shown to reduce RGC death and axonal loss
in animal models of glaucoma42,43.
Vascular factors and oxidative stress. Vascular insuffi­
ciency and ischaemia commonly cause neurodegener­
ation in the brain and might also contribute to the
pathophysiology of glaucoma23,24. Blood flow to the ONH
and retina are reduced in patients with glaucoma com­
pared with individuals without evidence of the disease44,45.
Moreover, the levels of endothelin 1 (a vaso­constrictor)
might be increased in the blood and aqueous humour of
some patients with glaucoma, which might affect ocular
blood flow and trabecular outflow 46.
RGC axon segments passing through the lamina cri­
brosa have relatively large energy demands as they have to
generate action potentials without the insulating support
of myelin sheaths, making them vulnerable to metabolic
stress47. Consequently, depleted energy resources might
contribute to neurodegeneration in glaucoma. High IOP
has been shown to be associated with decreased levels of
ATP in a mouse model of glaucoma, but the mechanisms
underlying this are incompletely understood48. Moreover,
increased IOP is associated with abnormal transport of
mitochondria and ATP production in patients with glau­
coma49 and in mouse models50. Increased IOP might also
increase resistance to blood flow in the fine capillaries
that supply axons within the lamina cribrosa, leading to
­further reduced metabolic support51.
Excitotoxicity. Excitotoxicity (that is, damage to neurons
owing to excessive stimulation by neurotransmitters,
including glutamate) can contribute to neurodegener­
ation in neurological disorders, including Alzheimer dis­
ease, and has been implicated in the pathophysio­logy of
glaucoma, but data are contradictory and controversial.
Systemic administration of memantine (an N‑methyl-
d‑aspartate (NMDA) receptor antagonist) has been shown
to reduce RGC death and functional loss in experimental

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 PRIMER

Prevalence (%)
<1.5
1.5–1.9
2–2.4
2.5–2.9
3–3.4
>3.5

Figure 2 | Global prevalence of primary open-angle glaucoma. For individuals ≥40 years of age, the population
prevalence data (%) in 2015 per region are colour-coded. Data from REF. 5. Nature Reviews | Disease Primers

glaucoma in rats52 and primates53,54, suggesting that sup­ the retina33. However, the nature of this response is not well
pressing excitotoxicity might be beneficial in glaucoma. understood as microglial activation can result in neuro­
However, phase III trials have failed to d ­ emonstrate protection or can exacerbate neuronal injury, ­depending
­protection of visual function55. on the subpopulations of microglia that predominate.

Role of glia. Astrocytes, which line the pores and blood
vessels of the lamina cribrosa, have an important role in
the pathogenesis of glaucoma. These astrocytes provide
support by secreting extracellular matrix molecules and
contribute to the blood–retinal barrier 56. In glaucoma,
astrocytes transform from mature, quiescent astrocytes
into a ‘reactive’ state, meaning they express high levels
of intermediate filament proteins, such as glial fibrillary
acidic protein. In mice with glaucoma, astrocytes in the
lamina cribrosa undergo morphological changes that
mimic the injury response of the central nervous system,
including hypertrophy of the soma and an increase in the
thickness of astrocytic processes57.
Astrocytes also cause extensive remodelling of the
extracellular matrix at the ONH via the release of matrix
metalloproteinases, as seen in glaucomatous eyes of both
humans and non-human primate models58. In monkeys
with experimentally induced glaucoma, abnormal astro­
cyte function leads to increased deposition of elastin,
which is associated with loss of collagen fibres58. These
alterations in the ONH extracellular matrix composition
could affect the ability of the ONH to withstand the bio­
mechanical stresses caused by IOP in glaucoma, leading
to disruption of RGC axonal function.
Microglia are the resident immune cells found in the
central nervous system and retina, where they have an
essential role in the innate immune response. Together
with astrocytes and Müller glia, microglia maintain
homeo­stasis in the retina via the regulation of ion
exchange and glucose levels and the transport of neuro­
transmitters. In experimental models of glaucoma, micro­
glial hypertrophy and proliferation have been noted in
Cellular processes involved in RGC death
Apoptosis and autophagy. The cumulative result of
injury in glaucoma is progressive RGC death, with
apoptosis as an important mechanism59,60. Increased
IOP in experimental models of glaucoma correlates
with the activation and/or upregulation of pro-apoptotic
molecules (such as mitogen-activated kinases, cellular
tumour antigen p53 and caspase 3)61, in conjunction
with the suppression of pro-survival molecules (such as
the apoptosis regulator BCL‑2 and BCL‑2‑like protein 1
(also known as BCL‑XL))62, and DNA fragmentation
in apoptotic RGCs59. Studies suggest that caspases are
the key regulators of apoptotic RGC death in glaucoma
and that the balance of proto-oncogene (specifically the
apoptosis regulator BAX and pro-survival BCL‑2 fam­
ily members) expression regulates the caspase cascade63.
Homozygous mutations in the gene encoding the homeo­
box protein SIX6 that confers an increased risk of POAG
have been shown to lead to RGC death in a mouse model
of increased IOP and in human POAG eyes64.
Autophagy (removal of proteins and organelles
from cells by lysosomal degradation), an alternative
pathway for cell death, might also be involved in glau­
coma. Mutations in an autophagy receptor gene (OPTN,
which encodes optineurin) are associated with glaucoma
(TABLE 1), but the precise role of autophagy in glaucoma is
unclear, as both activation and inhibition of autophagy
can exert neuroprotective effects on RGCs in different
experimental models of glaucoma. Interestingly, OPTN
and TBK1 (which encodes TANK-binding kinase 1),
two genes known to cause familial normal-tension
­glaucoma65,66, have important roles in autophagy 67–69.

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PRIMER

Healthy eye Glaucoma

ONH

• Reduced blood flow

• Oxidative stress

Lamina cribrosa
Astrocyte Reactive astrocyte

• Reactive gliosis
• ECM remodelling

ECM

↑IOP RGC axons

• Reduced axonal
Damage transport of
to ONH neurotropins
• Wallerian
Axon Myelin Myelin debris degeneration

RGC dendrites

Dendrites

Dendritic remodelling

Soma

RGC somas

• Excitotoxicity
• Autophagy
• Apoptosis
Autophagosome

RNFL

Figure 3 | Retinal ganglion cell injury and response in glaucoma. The optic nerve head Nature Reviews
(ONH) Disease Primers
is the| predominant
site of injury in glaucoma; ONH injury ultimately leads to retinal ganglion cell (RGC) damage. Multiple factors may
contribute to this cellular damage, including reactive gliosis and remodelling of the extracellular matrix (ECM) at the
lamina cribrosa, reduced axonal transport of neurotrophins and mitochondria, and reduced blood flow to the eye.
However, whether RGCs survive, a given level of axonal injury could potentially be influenced by many other factors,
including genetic predisposition, and the effect of other mechanisms, such as neurotrophic support, excitotoxicity or
autoimmune mechanisms within the retina. Responses to RGC damage include adaptive responses (such as dendritic
remodelling) that maintain function in surviving cells, or cellular mechanisms that result in the orderly breakdown
of RGC somas (by apoptosis) or axons (by Wallerian degeneration). Maintenance of visual function in the context of
glaucomatous injury requires maintenance of all compartments of the RGC from the dendritic field via the soma and
the axon to the final central synapses in the visual centres of the brain. IOP, intraocular pressure; RNFL, retinal nerve
fibre layer.

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 PRIMER

(overall risks are generally between 1.1 and 1.4), but

Conjunctiva
Intrascleral plexus
can suggest important biological pathways and pro­
Cornea
Anterior chamber
cesses involved in disease pathogenesis. The proteins
Aqueous vein Iris
(containing aqueous encoded by these loci are involved in different cellular
Episcleral vein humour) processes and biological systems79,80, including mem­
brane signalling, lipid metabolism, regulation of cell
Anterior Schlemm’s
canal growth and development and transforming growth
ciliary
vein factor-β (TGFβ) signalling.
Lens Sclera An evolutionarily conserved genomic region on
8q22 that is associated with normal-tension glaucoma81
contains regulatory enhancers that are highly active in
Vitreous the choroid plexus and the ocular ciliary body. These
findings might be relevant to recent studies that identi­
Ciliary process Ciliary body Suprachoroidal space fied low cerebrospinal fluid pressure in some patients
Figure 4 | Aqueous humour production and flow. Aqueous humour is produced by with normal-tension glaucoma, which might cause a
the ciliary processes of the ciliary body and flows fromNature | Diseaseof
Reviewschamber
the posterior Primers
the deleterious pressure gradient at the lamina cribrosa18.
eye (behind the iris) between the iris and lens via the pupil into the anterior chamber Although the genes influenced by these enhancers are
of the eye. Outflow of aqueous humour occurs either via the trabecular meshwork not yet known, genetic variants in this region might be
into Schlemm’s canal (the canalicular outflow tract), which ultimately drains into
involved in TGFβ signalling 82.
the episcleral vein, or via the uveoscleral outflow pathway into the suprachoroidal
space. In glaucoma, the canalicular outflow tract is blocked leading to increased
Three genes identified by familial linkage analysis
intraocular pressure, ultimately causing damage to the optic nerve head and retinal have been shown to cause POAG with an autosomal
ganglion cells. dominant inheritance pattern: mutations in MYOC
(encoding myocilin) and OPTN, and duplication of
TBK1. MYOC mutations have been shown to cause
Axonal degeneration and dendritic remodelling. high-tension juvenile-onset POAG and approximately
Axonal loss and death of the neuronal soma occur via 5% of late-onset POAG 83. Mutations in MYOC are
distinct mechanisms70. Axonal loss involves Wallerian primarily missense mutations that cause protein mis­
degeneration (an orderly process of axonal breakdown) folding and endoplasmic reticulum stress, leading to
or ‘dying back’ mechanisms (in which axons gradu­ trabecular meshwork dysfunction84. A missense muta­
ally retract from their central targets)59,71. In addition tion in OPTN can cause a familial form of POAG or
to axonal loss, changes to the dendrites of RGCs can normal-tension glaucoma85, as can TBK1 duplication86.
occur in glaucoma. Changes to the dendritic arbour of Glaucoma caused by mutations in OPTN or TBK1 is
RGCs are observed within 24 hours after an increase probably due to defective autophagy 67,87.
in IOP in experimental models of glaucoma and have
been shown to precede changes in RGC soma size and Diagnosis, screening and prevention
axon diameter 72,73. However, the timing of the dendritic POAG is diagnosed based on characteristic ONH and
changes of RGCs in response to raised IOP varies in RNFL changes examined by fundoscopic examin­
different models of glaucoma74. Furthermore, den­ ation and progressive reduction in visual sensitivity by
dritic changes have been observed in an experimental perimetry. However, the diagnosis of glaucoma does not
mouse model of glaucoma, including the simplifica­ require the detection of reduction in visual sensitivity.
tion and shrinkage of the RGC dendritic arbour 75 and Moreover, increased IOP is not a diagnostic requirement
loss of synapses, evidenced by reduced levels of disks of POAG.
large homologue 4 (also known as PSD‑95). This syn­
apse elimination was shown to be mediated by the Fundoscopic examination
­complement cascade76. POAG is frequently diagnosed when still asympto­
matic and before recognizable loss of vision during
Autoimmunity. Alterations in serum antibody profiles routine eye examination. Slit-lamp biomicroscopy is
of patients with glaucoma have been described, includ­ the standard technique for the evaluation of the ONH
ing the upregulation of antibodies against heat shock and the RNFL for the diagnosis of glaucoma. Direct and
protein 60 and myelin basic protein, as well as others77. ­indirect fundo­scopy is not adequate for ONH examin­
However, whether these autoantibodies in patients with ation; direct fundoscopy fails to provide a binocular
glaucoma are an epiphenomenon or causative remains view of the ONH, whereas the magnification of indirect
to be seen77,78. fundo­scopy is insufficient to allow reliable assessment
of the ONH. Diagnosis of glaucoma is predicated with
Genetic loci and related quantitative traits the detection of excavation (deformation and remodel­
Genome-wide association studies have identified vari­ ling) of the ONH, thinning of the RNFL and narrowing
ous loci associated with different types of glaucoma, of the neuroretinal rim (increasing the cup-to-disk ratio
including POAG, angle-closure glaucoma and early-­ (CDR)) (FIG. 5). ONH and RNFL changes in glaucoma
onset glaucoma, and related quantitative traits (TABLE 1). are typically localized at the inferotemporal followed
However, individually, the polymorphisms do not carry by the superotemporal quadrants of the ONH (FIG. 5).
more than a modest increase in the risk of glaucoma In general, POAG is a bilateral disease, although the

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Table 1 | Genes associated with the risk of primary open-angle glaucoma

Gene Protein Protein function Associations other than Refs
with POAG
8q22 Non-coding region Enhancer that is active in the ciliary body and the Normal-tension glaucoma 82
choroid plexus
ABCA1 ATP-binding cassette subfamily A Regulates lipid efflux and is involved in Associated with increased IOP 81,180,
member 1 membrane signalling 181
AFAP1 Actin filament-associated protein 1 Extracellular matrix protein – 181
ATXN2 Ataxin 2 Neurodegeneration Spinocerebellar ataxia 2 and 80,182,
amyotrophic lateral sclerosis 183
CAV1 Caveolin 1 Formation of the membrane caveolae (a type Associated with increased IOP 184–186
of lipid raft that influences the efficiency of
ABCA1‑mediated cholesterol transport and
sequesters endothelial nitric oxide synthase)
CDKN2B‑AS1 Cyclin-dependent kinase 4 Regulates cell division Associated with vertical 187,188
inhibtor B (CDKN2B) antisense cup‑to‑disc ratio and
RNA 1 normal-tension glaucoma
FNDC3B Fibronectin type III Extracellular matrix protein Associated with increased IOP 81
domain-containing protein 3B
FOXC1 Forkhead box protein C1 Ocular development Coding mutations cause 79,80,
early-onset glaucoma 189
GAS7 Growth arrest-specific 7 Regulates cell division Associated with increased IOP 80,81,190
GMDS GDP-mannose 4,6‑dehydratase N‑glycan biosynthesis – 181
PMM2 Phosphomannomutase 2 N‑glycan biosynthesis – 180
SIX6 Homeobox protein SIX6 Ocular development Associated with vertical 64,82,
cup‑to‑disc ratio and retinal 191,192
nerve fibre layer thickness
TGFBR3 TGFβ receptor 3 TGFβ signalling, which can regulate genes – 193
encoding extracellular matrix remodelling
TXNRD2 Thioredoxin reductase 2 Mitochondrial redox homeostasis – 80
TMCO1 Transmembrane and coiled-coil Endoplasmic reticulum calcium channel Associated with increased IOP 187,190,
domain-containing protein 1 194
IOP, intraocular pressure; TGFβ, transforming growth factor-β.

course of disease progression is often asymmetric, with
one eye more adversely affected than the other eye.
Small, typically flame-shaped haemorrhages near the
edge of RNFL defects as well as beta-zone parapapil­
lary atrophy (that is, atrophy of the retinal pigment epi­
thelium and choriocapillaris) are associated with, but
not diagnostic of, glaucoma. Mechanical damage to the
capillary network at the border of RNFL defects might
develop consequential to loss of axonal fibres (tissue
collapse), although the exact mechanism of optic disc
­haemorrhage in glaucoma remains obscure.
Dark room gonioscopy is used to assess the angle of
the anterior chamber to distinguish between open-angle
and angle-closure glaucoma88.
Slit-lamp biomicroscopy. A careful examination of the
neuroretinal rim colour and optic disc configuration
with slit-lamp biomicroscopy is important to differ­
entiate glaucomatous from non-glaucomatous optic
neuropathies. Although slit-lamp microscopy is effec­
tive to detect damage to the ONH and the RNFL in
glaucoma, large inter-observer variability in ONH and
RNFL assessment — particularly in the early stages of
glaucoma when the changes are subtle — poses major
challenges to clinicians. Anatomical variations in the
size and configuration of the ONH also complicate the
detection of ONH and RNFL abnormalities. Eyes with
tilted ONHs and parapapillary atrophy, signs that are
frequently seen in myopic eyes, can limit the ability to
identify neuroretinal rim loss and ONH excavation.
Likewise, visualization of the RNFL can be compromised
in eyes with hypopigmented fundus or in the presence
of media opacity.
Digital imaging. Although optic disc photography
remains useful to document the configuration of the
ONH and the RNFL, digital imaging technologies
have provided a more objective, quantitative and effi­
cient approach to assist clinicians in the diagnosis of
glaucoma. Confocal scanning laser ophthalmoscopy 89,
scanning laser polarimetry 90 and optical coherence
tomography (OCT)91,92 are the three commercially avail­
able imaging platforms for evaluation of the ONH and
RNFL structures. No consensus exists regarding which
imaging technique should be used for ONH and RNFL
imaging, but OCT has gained popularity in glaucoma
diagnostics in recent years because of its higher scan
speed and superior image resolution.

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OCT is a non-contact, optical imaging technique that
uses low coherence interferometry to measure the back­
scattered light from different layers of the retina and the
ONH. With a high scan speed, the latest OCT technology
allows three-dimensional reconstruction of the ONH
and the parapapillary RNFL in a few seconds. Three-
dimensional analysis of the RNFL in the para­papillary
optic disc region can reveal RNFL defects that are
missed by parapapillary RNFL measurements derived
from a circle scan (RNFL thicknesses are commonly
measured by OCT with reference to a circle scan with a
diameter of approximately 3.45 mm)93. RNFL defects in
glaucoma are commonly observed in the infero­temporal
followed by the superotemporal quadrants of the optic
disc in the RNFL thickness map94 (FIG. 5). As the macula
has the highest density of RGCs, their loss can also be
detected in the ganglion cell and inner plexiform layers
(the ­retinal layers containing the somas and dendritic
connections of RGCs) in the macular ganglion cell and
inner plexiform layer thickness map (FIG. 5d,e). The
detection of progressive changes of the ONH and the
RNFL is also useful to confirm the diagnosis of glau­
coma95 (FIG. 6). Although software for the detection of
progressive RNFL thinning is available in OCT, consider­
ation of age-related ONH and RNFL changes is relevant
to differentiate disease-related from age-related loss96.
OCT can also be used to measure the minimum
rim width (that is, the minimum distance between the
Bruch’s membrane opening and the internal limiting
membrane of the eye), which is a useful measurement
to document neuroretinal rim loss in glaucoma 97.
Fourier-domain OCT, including spectral-domain and
swept-source OCT, is useful to distinguish the individ­
ual components of ONH deformation in glaucoma, but
measurements of prelaminar tissue thickness, ONH
surface depth and lamina cribrosa surface depth (that
is, the distance from the Bruch’s membrane opening
to the anterior surface of the lamina cribrosa) are not
routinely performed in clinical practice for the diag­
nosis of glaucoma, as these parameters cannot be reli­
ably measured with commercially available software in
many patients.
Perimetry
The diagnosis of glaucoma does not require the detec­
tion of visual field defects with perimetry, as RNFL and
ONH abnormalities identified from clinical examin­
ation or digital imaging instruments often precede
detectable visual field loss. A considerable reduction
in RNFL thickness measured by OCT can be detected
as long as 8 years before the development of visual
field defects in patients with glaucoma98. Nevertheless,

a Optic disc b OCT RNFL c OCT RNFL d OCT GCIPL e OCT GCIPL f Visual field
photograph thickness thickness thickness thickness greyscale plot
map deviation map map deviation map
Healthy eye
Advanced glaucoma Early-stage glaucoma

Figure 5 | Diagnostic imaging for primary open-angle glaucoma. Optical disc photographs (part a) show a narrowed
Nature Reviews | Disease Primers
neuroretinal rim with increased cup-to-disk ratio in early-stage glaucoma (middle panel) and even more so in advanced
glaucoma (bottom panel) compared with the healthy eye (upper panel). Optic nerve head (ONH) and retinal nerve fibre
layer (RNFL) changes are typically localized at the superotemporal (black arrow) and the inferotemporal (white arrow)
quadrants of the ONH. An area of beta-zone parapapillary atrophy is found in the eye with advanced glaucoma
(arrowheads). Optical coherence tomography (OCT) RNFL thickness maps (part b) and OCT RNFL thickness deviation
maps (part c) show loss of the RNFL in early-stage and advanced glaucoma. The warm colours on the RNFL thickness maps
represent a thicker RNFL and cooler colours represent a thinner RNFL. The deviation maps are constructed with reference
to data collected from healthy individuals. Areas coded in red and yellow represent measurements below the 99th and
95th percentile ranges, respectively. OCT ganglion cell inner plexiform layer (GCIPL) thickness maps (part d) and OCT
GCIPL thickness deviation maps (part e) show loss of the ganglion cell layer and the inner plexiform layer in early-stage
and advanced glaucoma. Maps are colour coded as described in part b and part c. The visual field greyscale plots show
early superonasal defects in early glaucoma and diffuse visual field loss in advanced glaucoma (part f).

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perimetry is indispensable for the documentation and
monitoring of functional decline in glaucoma.
The conventional approach for the evaluation of
visual sensitivity loss in glaucoma is standard auto­
mated perimetry performed over the central 24–30° of
the visual field. Standard automated perimetry meas­
ures the threshold light sensitivity (that is, the intensity
of the stimulus seen 50% of the time by the individ­
ual) at each tested location by projecting white light
stimuli with varying brightness on a white background.
Locations with reduced sensitivity are encoded in dif­
ferent probability values (P <0.5%, P <1%, P <2% and
P <5%) in the total deviation plot and the pattern devi­
ation plot. Reduction in visual sensitivity frequently
develops at the superonasal followed by the infero­
nasal field, which corresponds to the infero­temporal
followed by the superotemporal loss of the neuro­
retinal rim and the RNFL in glaucoma. Nevertheless,
paracentral scotoma (an island of visual sensitivity
a 2007 (baseline) 2012 2015
RNFL thickness
map
loss within 10° of fixation best detected by perform­
ing perimetry over the central 10°) and generalized
reduction in visual sensitiv­ity are not uncommon in
patients with early-stage glaucoma. Visual sensitivity
progressively declines in glaucoma, typically encroach­
ing one hemifield respecting the horizontal meridian
before affecting the other hemifield. Central vision is
generally preserved until the end stages of glaucoma.
As perimetry is a subjective examin­ation, the inter­
pretation of visual field data should take reliabil­
ity indices into account, especially the false-­positive
losses (when the individual reports the presence of a
stimulus when no stimulus is presented) and fixation
losses (when the individual reports the presence of a
stimulus in the area of the physiological blind spot).
Confirmation of the development of a new or worsen­
ing of an existing visual field defect with repeated test­
ing is always necessary. Frequency doubling technology
perimetry and short-wavelength automated perimetry
have been proposed to be able to detect glaucomatous
visual field abnormalities when standard automated
perimetry measurements are still normal99,100. However,
other studies suggest similar performance between
short-wavelength automated perimetry and standard
automated perimetry for the detection of visual field
defects101–103. Standard automated perimetry remains to
be the standard method for visual field testing in the
diagnostic evaluation of glaucoma.

Measurement of IOP
Increased IOP is not a diagnostic requirement of glau­
coma, although IOP is a risk factor for the develop­
ment and progression of glaucoma. Although various
RNFL thickness
change map contact and non-contact tonometers to measure IOP
are available in clinical practice, Goldmann applan­
ation tonometry is the most widely adopted approach.
However, IOP measurements via Goldmann applana­
tion tonometry are influenced by the geometry and
b 2007 2015 biomechanical properties of the cornea. IOP tends to
be underestimated in eyes with thin and/or soft cor­
neas and overestimated in eyes with thick and/or stiff
corneas104. To account for the difference in properties of
the cornea, clinical evaluation of glaucoma also includes
measurement of central corneal thickness, commonly
performed with corneal pachymetry (ultrasonography).
Validated instruments to assess corneal elasticity are not
yet available.

Figure 6 | Progressive retinal nerve fibre layer thinning in a patient with primary
Nature Reviews | Disease Primers
open-angle glaucoma. a | Serial retinal nerve fibre layer (RNFL) thickness maps and
RNFL thickness change maps measured by optical coherence tomography show
progressive RNFL thinning in a patient with primary open-angle glaucoma between 2007
and 2015. Progressive RNFL thinning is noted at the inferotemporal (white arrow) and the
superotemporal (black arrow) quadrants in the RNFL thickness change maps (bottom
right panel). b | Visual field greyscale plots obtained from the baseline visit in 2007 (left)
and the follow-up visit in 2015 (right). Progressive reduction in visual sensitivity is noted
at the superonasal quadrant, which corresponds to the progressive RNFL thinning at the
inferotemporal quadrant in 2015. The central 5° of the visual field and the visual acuity of
this patient were normal in 2015.
Genetics
Genetic testing can be used diagnostically in some
patients with glaucoma. Currently, these tests are most
beneficial for patients with early-onset glaucoma,
specific­ally juvenile open-angle glaucoma and familial
normal-tension glaucoma19, which are linked to muta­
tions in MYOC, OPTN and TBK1. For patients and
families with a mutation in one of these genes, genetic
testing has possible benefits, including informed
genetic counselling, pre-symptomatic risk assessment
and the development of appropriate treatment and sur­
veillance plans105,106. For patients with MYOC mutations,
gene‑based therapies are emerging 84,107.

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Box 2 | Software algorithms to predict glaucoma progression
Algorithms used for progression analysis can be classified into event-based and
trend-based approaches179. For event-based approaches, the progression of glaucoma
is identified when changes in results from perimetry or digital imaging assessment
between baseline and follow‑up examinations are larger than the parameter’s
test–retest variability. For trend-based approaches, a significant negative trend
between the investigated result and follow‑up time based on regression analysis
denotes the progression of glaucoma. Trend-based analysis of the visual field index
and event-based analysis of the visual sensitivity at individual locations of the visual
field are commonly used approaches for the assessment of visual field progression.
Several commercial available optical coherence tomography devices enable the
detection of progressive retinal nerve fibre layer (RNFL) thinning based on event-based
(FIG. 6a) and trend-based analyses of RNFL thickness. Progressive optic nerve head
surface deformation can also be assessed using the Topographic Change Analysis
algorithm with confocal scanning laser ophthalmoscopy.
As previously mentioned, 15 genes are associated
with late-onset POAG79,80 and, although the genetic
associations are robust, individual variants with small
effects on disease risk are not likely to have a diagnostic
impact unless they are in the context of other genetic
risk factors. In addition, DNA variants that contribute
to late-onset glaucoma are common and, although the
distribution between affected and unaffected individuals
is significant, a test based on a single variant would not
have adequate sensitivity and specificity. The develop­
ment of gene panels and perhaps combinations of gene
and environmental risk factors might yield useful
gene‑based tests, but these tests will need to be validated
in the clinical setting and should be correlated with
clinical outcomes before routinely used for ­diagnosis,
­prognosis or screening.
Detection of glaucoma progression
POAG typically worsens slowly over years or dec­
ades, but some patients exhibit a more rapid disease
course. Identifi­cation of patients at risk of vision loss
to ­enable the appropriate management of disease
requires repeated examination of ONH deformation
and/or RNFL loss, in addition to visual field testing 108.
Consensus from the World Glaucoma Association rec­
ommends at least two reliable visual field tests in the
first 6 months after diagnosis and then another 2–4
tests within the next 18 months to rule out the rapid
worsening of disease and to establish an optimal set of
baseline data108. The frequency of subsequent ONH and
RNFL imaging and visual field testing is based on the
risk of visual impairment. Patients with high IOP and
advanced glaucoma would need more frequent ONH
and/or RNFL imaging and visual field testing to ­monitor
disease progression.
Determining glaucoma progression should not rely
on subjective clinical evaluation of ONH deformation,
RNFL loss or a decline in visual sensitivity, as agreement
of subjective interpretation of glaucoma progression is
poor, even among glaucoma specialists109. The use of
software included in the perimetry and digital imaging
devices is useful for progression analysis (FIG. 6); differ­
ent software progression algorithms might give different
results (BOX 2).
Progressive ONH deformation and progressive RNFL
thinning are predictive of subsequent development of
visual field loss110,111. Individuals with suspected glau­
coma who have progressive ONH and RNFL changes
(evaluated with optic disc stereophotography) have a
>25‑fold increase in the risk of developing visual field
defects (hazard ratio: 25.8; 95% CI: 16–14.7)111. Similarly,
progressive RNFL thinning (assessed using OCT)110,112
and progressive neuroretinal rim loss (assessed by con­
focal scanning laser ophthalmoscopy)113 are associated
with a high risk of subsequent progressive visual field
loss. Progressive ONH deformation, RNFL loss and
visual field changes are more difficult to detect using dig­
ital imaging instruments in late-stage than in early-stage
glaucoma. Thus, perimetry might be more informative
than digital imaging techniques to monitor disease pro­
gression in patients with moderate and advanced glau­
coma. Combining OCT assessment of RNFL thickness
and visual field measurements for the estimation of RGC
loss is useful to stage glaucoma and might provide an
alternative to track glaucoma progression114.
Screening and prevention
Given the fact that glaucoma is largely asymptomatic and
a leading cause of irreversible blindness, an unmet need
exists to identify and treat individuals who are at risk of
visual impairment from glaucoma. In the United States,
Australia and Singapore, nearly half of all glaucoma
cases are not diagnosed, whereas in Japan and Korea, it is
closer to 90%, and in less-developed countries, >95% are
undiagnosed115–117. However, the US Preventive Services
Task Force currently does not recommend glaucoma
screening, owing to a lack of data supporting long-term
benefits from screening programmes, despite ample
evidence showing that treatment of detected glaucoma
is effective to slow down vision loss. Aside from the
United States, most other countries also do not have
­recommendations for glaucoma screening.
Questions remain regarding the optimal tests
(for example, ophthalmoscopy, tonometry and optic
nerve imaging), the criteria used to define an abnormal
test, the screening interval and the target population
for glaucoma screening. A meta-analysis showed that
no single test or group of tests was found to be opti­
mal118. Screening high-risk subjects (for example, those
>50 years of age and individuals with a family history
of glaucoma) is likely to be more cost-­effective than
population-based screening. Teleglaucoma — that is,
remotely detecting glaucoma via electronic transmission
of stereo­scopic fundus photographs to an ophthalmol­
ogist in a reference centre — in a high-risk population
showed that this tool was more cost-effective than
in‑person examination119.
The fact that a substantial proportion of patients with
glaucoma might not progress or progress very slowly
also complicates the cost-effective analysis of screening
programmes. For example, the Early Manifest Glaucoma
Treatment Study showed that 38% of patients with glau­
coma who were randomized to an observation without
treatment group had no identifiable progression of
visual field loss or ONH damage in 6 years8,120. In the

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Patient with POAG

Calculate target IOP

Administer therapies or perform surgery to reduce IOP

Has the target IOP been achieved?

Yes No

Has there been a progression of damage? Has there been a progression of damage?
Yes No No Yes

Reassess diagnosis Has IOP been Follow-up Decrease target IOP

Decrease target IOP controlled for 6 months?
Yes No

Follow-up Increase target IOP if the patient

is stable and requires or wishes
a reduction in medication

Follow-up

Figure 7 | Management algorithm of newly diagnosed primary open-angle glaucoma. The management strategy
Nature
for primary open-angle glaucoma (POAG). Achieving and maintaining the target intraocular Reviews
pressure | Disease
(IOP) Primers
is central.
Adapted from REF. 122.

Collaborative Normal Tension Glaucoma Study, 50% of
patients in the observation arm had no identifiable pro­
gression over 5–7 years of follow-up121. More research
is needed for the development, implementation and
cost-effective analysis of glaucoma screening.
Management
Overall goals of management
The goal of POAG treatment is to enhance the QOL of
the patient through the preservation of vision122. This
currently entails lowering the IOP to a level that is likely
to prevent further damage to the optic nerve123. Lowering
IOP slows disease progression across the glaucoma con­
tinuum: patients at higher risk of developing glaucoma
(the Ocular Hypertension Treatment Study 124) to early
disease (the Collaborative Initial Glaucoma Treatment
Study 125 and the Early Manifest Glaucoma Trial120) to
advanced stages of glaucoma (the Advanced Glaucoma
Intervention Study 126). Moreover, lowering IOP has also
been shown to delay progression in patients with ocular
hypertension and in patients with POAG in which the
baseline IOP was within the normal range9. The deci­
sion of when and how to treat glaucoma is often complex
(FIG. 7) and requires consideration of a range of factors,
including the stage of disease, the rate of glaucoma pro­
gression to symptomatic vision loss, the risk of disease
progression and the life expectancy of the patient.
Treatment modalities
Topical medications are conventionally regarded as the
first-line treatment for POAG despite numerous studies
showing equivalent or improved IOP control with i­ nitial
laser therapy (selective laser trabeculoplasty (SLT)) or
surgery 127,128. Despite the potential for excellent IOP
control, surgery has not been widely adopted in most
settings as a primary treatment owing to the associated
risks of complications.
Topical medications. Topical medications applied
directly to the ocular surface can lower IOP by pro­
moting aqueous humour outflow or by reducing aque­
ous humour production129 (TABLE 2). The absorption of
these drugs into the systemic circulation through the
nasolacrimal duct can be avoided through use of digital
punctal occlusion or eyelid closure for at least 1 minute
after application.
Prostaglandin analogues are generally used as
first-line treatments for glaucoma in many countries.
Advantages of prostaglandin analogues include the
once-daily application, the low risk of systemic adverse
effects and potent lowering of IOP. Adverse effects
include darkening of the periocular skin and iris (most
noticeable in individuals with green or hazel irides)
owing to melanosome proliferation130, atrophy of orbital
fat and elongation and darkening of eye lashes131.
Cholinergic agonists can be used for the management
of POAG but require repeat administration (up to four
times per day) and might result in ocular adverse effects.
Topical β‑blockers are widely used to lower IOP
through the reduction of aqueous secretion from the
ciliary body. These agents, like their systemic counter­
parts, can induce substantial respiratory and cardio­
vascular effects, including fatigue and bradycardia, and
need to be used with caution in elderly patients. IOP
lowering is limited during the nocturnal period and in
patients who are already using systemic β‑blockers132.

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α‑Adrenergic agonists also reduce aqueous secretion
and some might increase aqueous outflow. α ­ ‑Adrenergic
agonists are administered twice daily but have limited
IOP-lowering effects during the nocturnal period, sim­
ilar to β-blockers133. Dose-dependent allergic follicular
conjunctivitis can occur in one-third of individuals and
the onset might not be until after a few months after
starting therapy.
Carbonic anhydrase inhibitors reduce aqueous
secretion. Topical application is less effective at reduc­
ing IOP than oral administration, but is associated
with less-severe systemic adverse effects than the tablet
form. A combination of therapies can also be used for
the management of POAG. For example, prostaglandin
analogues in combination with β-blockers lower IOP
throughout a 24‑hour period134.
Long-term use of topical therapies for an often
asymptomatic disease can result in low adherence to
prescribed medications. Careful education and use of
technologies such as automated reminders have poten­
tial for improving patient adherence to these therapies135.
Devices (either placed within the anterior chamber, vit­
reous cavity or subconjunctival space) to enable the sus­
tained release of IOP-lowering medications are under
investigation. The use of combinations of topical thera­
pies containing one or more glaucoma therapy, or topical
drugs with less-toxic preservatives, can reduce the rates
of ocular surface disease136 and might improve patient
adherence to the medication.
Laser trabeculoplasty. Laser trabeculoplasty has an
important role in the management of POAG. Laser
treatments to the trabecular meshwork lower the IOP
by activating trabecular meshwork cells, which leads
to remodelling of the local extracellular matrix and
increases aqueous humour outflow. However, the pre­
cise mechanisms underlying IOP reductions are not fully
understood. Laser trabeculoplasty using an argon laser
(known as argon laser trabeculoplasty (ALT)) has been
adopted in clinical practice for >30 years, but SLT (using
a neodymium-doped yttrium aluminium garnet laser)
is increasing in popularity. SLT has a similar efficiency
to ALT at lowering IOP, but induces less mechanical
damage to the trabecular meshwork and fewer adverse
effects137. In one study from St Lucia, initial SLT treat­
ment in individuals with POAG of West African origin
resulted in sustained lowering of IOP138. Moreover, data
from a meta-analysis showed a reduction in IOP of
6.9–35.9% 1 year following SLT137.
Baseline IOP is the only known predictor of treat­
ment outcome for SLT, a higher baseline IOP is associ­
ated with a greater IOP reduction139. The most common
adverse effects of laser trabeculoplasty are anterior
chamber inflammation and transient IOP spikes, pho­
tophobia and ocular discomfort, which often subside
spontaneously. Moreover, peripheral anterior syn­
echiae (adhesions of the anterior iris to structures in
the angle of the anterior chamber) have been reported
after SLT, but are less-commonly observed than after
ALT. The favour­able safety profile and the feasibility
of retreatment have prompted studies evaluating SLT
as a first-line therapy for POAG140. New generations
of laser trabeculoplasty technologies, including pattern
laser trabeculoplasty, micropulse laser trabeculoplasty
and titanium-sapphire laser trabeculoplasty have been
developed, but studies are required to evaluate whether
these technologies have a similar efficacy and safety
­profile to ALT or SLT141.

Table 2 | Topical medications used for the treatment of primary open-angle glaucoma
Class Drugs Mechanisms of action Notes Refs
Aqueous humour outflow (uveoscleral pathway)
Prostaglandin Latanoprost, travoprost Increase in outflow of aqueous humour, • Normally used as a first-line therapy 195,
analogues bimatoprost and tafluprost primarily through the uveoscleral pathway • Highly effective and well tolerated 196
by matrix metalloproteinase expression, and
remodelling of the uveoscleral outflow tract
Aqueous humour outflow (conventional pathway)
Cholinergic Pilocarpine and carbachol Increase in aqueous humour outflow through Very effective, but the use is compromised 197
agonists the trabecular meshwork due to ciliary muscle by dim vision (owing to pupillary constriction),
contraction discomfort and myopia
Aqueous humour formation
β‑Adrenergic Timolol, betaxol, carteolol Reduce the secretion of aqueous humour Few ocular adverse effects but might cause 198
receptor and levobunolol secretion from the ciliary body systemic adverse effects, such as fatigue
blockers and bradycardia
α‑Adrenergic Apraclonidine and • Decrease aqueous humour inflow by • Sedation can be minimized by occluding 133
receptor brimonidine inactivating adenylyl cyclase in ciliary nasolacrimal tear duct (for up to 2 minutes)
agonists processes • These drugs might have neuroprotective
• Mediates the release of noradrenaline via effects, but can induce allergy, particularly
activation of α2‑adrenergic receptors and with the 0.2% formulation
might increase uveoscleral outflow
Carbonic Dorzolamide, brinzolamide, Decrease in aqueous humour formation by Application using eye drops is better 199
anhydrase acetazolamide and inhibiting the production of carbonic anhydrase tolerated than oral administration
inhibitors methazolamide and bicarbonate in the ciliary epithelium
Adapted from REF. 129, Nature Publishing Group.

NATURE REVIEWS | DISEASE PRIMERS VOLUME 2 | 2016 | 13

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PRIMER

Cataract extraction surgery (replacing a cloudy nat­ural

Conjunctiva
Cornea
Anterior
Iris
chamber
Scleral flap
Ciliary
Lens body
Sclera
Suprachoroidal
Vitreous space
Figure 8 | Trabeculectomy for the
Nature management
Reviews | DiseaseofPrimers
primary open-angle glaucoma. Trabeculectomy involves
making a small hole in the sclera, which is covered by a
partial thickness scleral flap.
Surgery. Trabeculectomy involves a sclerectomy (a small
hole in the sclera) covered by a partial-thickness scleral
flap to the aqueous humour from the anterior ­chamber
of the eye into the subconjunctival space (FIG.  8) .
Trabeculectomy has been the most frequently performed
glaucoma surgery for >40  years. Intraoperative  or
postoperative adjuvant application of mitomycin C
or 5‑fluoro­uracil can further improve postoperative IOP
control, by slowing the healing and fibrosis of the sub­
conjunctival tissues. Some studies have suggested that
mitomycin C is more effective than ­5‑fluorouracil in
attaining surgical success142. Trabeculectomy can result
in long-term control of IOP, with one study noting a
stable reduction in IOP in 57% of patients (without the
need for additional medication) and 88% of patients
(with the need for additional medication), 20 years
after trabeculectomy 143. Complications of trabeculec­
tomy include short-term adverse effects, such as infec­
tion, suprachoroidal haemorrhage and hypotony (low
IOP), and long-term effects, such as increased risk of
endophthal­mitis (that is, inflammation of the internal
chambers of the eye).
Placement of a glaucoma drainage device, an implant
that connects the anterior chamber and the subconjunc­
tival space, is another common option for the treatment
of glaucoma and demonstrates a similar efficiency of
IOP reduction to trabeculectomy 144. Clinical failure
(inadequate lowering of IOP) of the glaucoma drainage
devices has been estimated to occur at a rate of approx­
imately 10% per year 145. Nonetheless, the Tube Versus
Trabeculectomy Study showed that >60% of patients with
previous cataract surgery and/or unsuccessful trabeculec­
tomy for the treatment of glaucoma achieved an IOP
of ≤14 mmHg 5 years after trabeculectomy with mito­
mycin C or glaucoma drainage device surgery 146. Early
postoperative complications (such as wound leaks and
bleb leaks) developed more frequently and the reoper­
ation rate was higher in patients receiving trabeculectomy
than in those who received glaucoma drainage device146.
lens with a clear artificial intraocular lens147) can widen
the anterior chamber angle and lower IOP. However,
this effect is generally small and not sustained, so lens
extraction is not recommended for the ­management
of POAG.
Minimally invasive glaucoma surgeries have provided
new alternatives to bridge the gap between the use of
topical therapies and surgery for the control of IOP. The
development of the Trabectome (Neomedix, Tustin,
California, USA), a handheld device that incorporates
electro-surgical pulse with simultaneous irrigation and
aspiration to surgically remove the trabecular mesh­
work, can be effective before and after cataract extrac­
tion surgery and can even be combined with cataract
surgery 148. The trabecular bypass stent (iStent; Glaukos
Corporation, Laguna Hills, California, USA), which
can be administered using minimally invasive surgery,
received US FDA approval for the treatment of POAG in
2012. Combined with cataract extraction, implantation
of a trabecular bypass stent can reduce IOP minimally
compared with cataract extraction alone149. Other stents
(for example XEN stent, Allergan, Irvine, California,
USA, and CyPass stent, Transcend Medical Inc., Menlo
Park, California, USA) are currently under evaluation
for the management of glaucoma150,151.
Quality of life
As a major cause of visual impairment, glaucoma can
affect several aspects of QOL and can impair perfor­
mance on a broad array of activities of daily living,
such as reading, walking and driving 152. Patients with
glaucoma might also be at an increased risk for falls
and motor vehicle accidents153,154. As currently avail­able
treatments for glaucoma might have adverse effects,
know­ledge of when and how glaucoma produces dis­
ability is important to adapt the intensity of therapy
to the rate of functional deterioration and the risk
of disability.
Inability to drive is a major concern for patients with
glaucoma; driving is often fundamental for maintaining
independent living and QOL. Driving cessation in these
patients is associated with increased risk of depressive
symptoms, social isolation and the need for long-term
care155. In addition, patients with glaucoma have an
increased risk of motor vehicle accidents. However, clin­
ical assessment of the visual field (for example, using
traditional tests such as standard automated perimetry)
has a limited ability to predict driving impairments in
patients with glaucoma156–158. Alternative strat­egies for
predicting the risk associated with driving in patients
with glaucoma have been proposed, such as the use­
ful field of view assessment (UFOV)159, which is a
computer-­based test that assesses visual processing
speed under conditions of divided attention. UFOV
measurements have been shown to predict the risk of
involvement in motor vehicle collisions in older individ­
uals160, but a prospective longitudinal study showed only
limited value in patients with glaucoma158. Other strat­
egies for predicting risk of motor vehicle accidents in
patients with glaucoma include driving simulation and

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 PRIMER

mobile platforms to evaluate visual processing speed,
attention and contrast sensitivity 152,161,162. These tests
evaluate aspects of vision relevant to driving that are
not fully assessed by standard automated peri­metry
or are only partially evaluated by UFOV. However,
evidence-­based guidelines for assessing driving ability
in patients with glaucoma are lacking. Although many
patients with glaucoma cease to drive owing to safety
concerns, many individuals with advanced disease still
continue to drive and continue to drive after a collision,
which subjects both themselves and others to increased
morbidity and mortality 163,164.
Owing to the important role of vision in balance
control and environment navigation, it is not surpris­
ing that glaucoma has been implicated as a risk factor
for falls165,166. Glaucoma can impair balance and walking
ability and has been shown to increase the frequency
at which patients with bilateral visual loss bump into
objects. These factors might result in a 2–4‑fold higher
risk in individuals with glaucoma than in healthy
individ­uals. However, evidence has only shown a rela­
tively weak correlation between peripheral visual field
loss (assessed by standard automated perimetry) and
the risk of falls, which might be related to the lack of
standard automated perimetry to evaluate the complex
demands that are put on vision for adequate postural
control during daily activities and challenging lighting
conditions. Assessment of postural reactions to dynamic
visual stimuli using virtual reality in patients with
glaucoma performed better than standard automated
­perimetry at predicting the risk of falls167.
Although glaucoma affects several vision-related
activities, it is not clear how severe the disease must be
before considerable impairment is detected. Studies have
investigated which activities associated with vision loss
caused by glaucoma168 are of particular importance to
patients. Patients with glaucoma gave highest impor­
tance to reading and tasks that involve seeing fine details,
in addition to mobility outside the home (for example
driving and walking)168,169. In addition, visual alterations
that are related to lighting and adapting to different
­levels of light, such as glare, are frequent complaints in
patients with POAG168,169.
Some studies have attempted to clarify the relation­
ship between progressive structural damage in the eye,
functional loss and QOL in glaucoma170,171. A signifi­
cant relationship has been shown between the rates of
visual field loss (assessed by standard automated peri­
metry) and a progressive reduction of patient-reported
QOL (assessed using the National Eye Institute Visual
Function Questionnaire (NEI VFQ‑25)). Interestingly,
even for patients with the same level of visual field loss,
those who have faster decline report a worse reduction
of NEI VFQ‑25 scores. This observation suggests that,
besides the actual severity of visual field defects, the
speed at which these defects develop is crucially impor­
tant in determining the effect of disease on QOL170,172.
Patients with slowly progressing disease might have
more time to develop compensatory strategies and, as
such, are less likely to report decline in QOL. However,
the nature and effectiveness of these compensatory
behaviours have not yet been fully elucidated. In another
study, rates of change of RNFL thickness (assessed using
OCT) were associated with changes in QOL, even after
adjustment for the amount of visual field loss over time,
suggesting that the assessment of structural damage in
the eye might provide more information for predict­
ing change in patient QOL, in addition to information
­gathered by perimetry 173.
The choice of management strategy for glaucoma
might also lead to alterations in QOL. The effects of the
initial treatment choice on QOL and health economics
have not been adequately assessed in glaucoma. Results
of prospective randomized controlled trials address­
ing these end points following the use of initial topical
­medications or SLT are forthcoming 174.
Outlook
Diagnosis and patient stratification
Despite substantial improvements in diagnostic imag­
ing and functional testing of glaucoma, a large propor­
tion of patients remain undiagnosed, even in developed
­countries, as this disease can remain asymptomatic for
long periods of time. Moreover, many patients diagnosed
with glaucoma continue to worsen even after treatment
despite improvements in drug and surgical therapies.
The emergence of new diagnostic tools for the assess­
ment of IOP, functional testing, imaging and genetic
testing could change the diagnosis and monitor­ing of
patients with POAG. This should facilitate the evalu­
ation of new therapies that complement current IOP-
lowering treatments to better preserve vision-­related
QOL in patients with POAG. Further research to develop
and implement these new paradigms and t­ reatments
is needed.
POAG is probably a broad term that includes many
disease subtypes, each with distinct molecular causes.
In addition, the same glaucoma genotype probably leads
to several phenotypes. Although the causative genetic
mutations underlying POAG are only known for a
­relatively small proportion of patients, this might change.
The development of gene panels and possibly
combin­ations of gene and environmental risk factors
might yield useful genetic tests for POAG. However,
these tests will need validation in the clinical setting and
should be correlated with clinical outcomes of disease
before routine use for diagnosis, prognosis or screening
of glaucoma.
The development of time-effective and cost-­effective
DNA sequencing will result in large amounts of data,
which have the potential to dramatically alter and person­
alize the management of POAG. For example, identifica­
tion of the specific pathogenetic molecular mechanisms
of disease in individual patients will ­probably lead to the
development of individualized therapies.
Identification of biomarkers that can be used for the
quantification of disease activity, the prediction of glau­
coma progression and the risk of blindness could also
aid future clinical trial design. Biochemical, proteomic
and metabolomic biomarkers identified from the blood
cannot currently be used to predict clinical outcomes,
but research into this is underway.

NATURE REVIEWS | DISEASE PRIMERS VOLUME 2 | 2016 | 15

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PRIMER

The current framing of the diagnosis might be
restricting the optimal treatment options for patients
with POAG. New information from biomedical and clin­
ical research is available, particularly from OCT imaging
and the lifestyle habits of patients that are not integrated
into clinical practice. Incorporation of electronic med­
ical records should facilitate the association of medical
history with phenotypic and genotypic information, to
identify relationships between and among molecular and
other patient-specific data and clinical outcomes.
New therapies
The optimization of clinical trial design, patient selec­
tion and choice of outcome measures should enable
the assessment of the efficacy of new treatments in a
­reasonable time frame, with an appropriate number
of patients.
Clinical trials that more-sensitively detect worsening
of glaucoma and identify disease-related biomarkers will
expedite the development of neuroprotective agents that
could be complementary to IOP-lowering therapies.
Progressive ONH or RNFL changes could be used as
outcome measures in clinical trials for the evaluation of
neuroprotective treatments. However, some regulatory
authorities only consider structural parameters when
evidence supports the predictive value of structural
­outcome measures on functional change175.
inhibitors176 and cell transplantation (mesenchymal stem
cells and oligodendrocyte precursor cells)177. However,
these approaches have not shown a preservation of
visual function in patients with glaucoma in a phase III
clinical trial.
Regeneration and repair. Repairing the retina and
the optic nerve is a formidable challenge owing
to the intricate organization of RGCs in the retina and
the complexity and length of their projections to the cen­
tral nervous system. The injured optic nerve does not
regenerate under physiological conditions and so any
visual loss caused by glaucoma results in permanent loss
of function. However, extensive RGC axonal regener­
ation has been observed following a zymosan-­induced
inflammatory response in Ptenflx/flx mice (a transgenic
mouse strain in which Pten is flanked by two LoxP sites;
deletion of Pten can be induced following the delivery
of Cre recombinase)178. Although the degree to which
regenerating axons reach their central targets is contro­
versial, the number of regenerating axons that reach the
optic chiasm and the possibility of functional recovery
have stimulated much research in this field. Given that a
small loss of RGC axons in patients with advanced glau­
coma might have a severe effect on visual function, it is
possible that even limited optic nerve regeneration could
be of benefit in end-stage disease.

Neuroprotection. Many patients with glaucoma con­ Quality of life

tinue to lose vision even when IOP is seemingly well
controlled and thus there is a need for new treatments
that can halt this decline. Multiple strategies can pro­
tect RGCs against IOP-induced damage in animal
models of glaucoma, including glutamate antagonists,
neurotrophic factors 42, calcium antagonists, anti­
oxidants, inhibitors of apoptosis, nitric oxide synthase
Determining the cause of disability in patients with
glaucoma is paramount to enable more-effective disease
management and better allocation of resources to aid
with the management of this disability. Further research
is needed to develop guidelines to increase the safety
of patients with glaucoma and to evaluate ­potential
assistive and rehabilitative strategies.

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Acknowledgements
R.N.W. has received research support from the National Eye
Institute. D.S.F. has received research support from the
US  NIH and the US Centers of Disease Control and
Prevention. J.L.W. has received research support from the
NIH, March of Dimes and Research to Prevent Blindness.
Author contributions
Introduction (R.N.W.); Epidemiology (D.S.F.); Mechanisms/
pathophysiology (K.R.M. and J.L.W.); Diagnosis, screening
and prevention (C.K.S.L. and R.N.W.); Management (J.G.C.);
Quality of life (F.A.M.); Outlook (R.N.W. and J.G.C.); Overview
of the Primer (R.N.W.).
Competing interests
R.N.W. has received personal fees from Allergan, Alcon,
Ametek, Bausch + Lomb, Carl-Zeiss Meditec, ForSight
Vision5 and Topcon, and has received research support from
Genentech and Quark, in addition to research equipment
from Heidelberg Engineering, Konan, Optovue and Topcon.
C.K.S.L. has received research support from Carl-Zeiss
Meditec and Topcon. J.G.C. has served on advisory
committees for Allergan, Alcon, CERA Technologies, Pfizer,
Polyactiva and Seagull Technologies. F.A.M. has received
personal fees from Carl-Zeiss Meditec, Heidelberg
Engineering, Ametek, Alcon and Allergan, and research
support from Carl-Zeiss Meditec, Heidelberg Engineering,
Topcon, Ametek, Bausch + Lomb, Allergan and Sensimed.
D.S.F. has received consulting fees from Nidek and ForSight
Vision5. K.R.M. has received personal fees from Allergan,
Bausch + Lomb, MSD and Santen. J.L.W. declares no
competing interests.

NATURE REVIEWS | DISEASE PRIMERS VOLUME 2 | 2016 | 19

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