29 Primary Open-Angle Glaucoma
ALBERT S KHOURI and ROBERT D FECHTNER
Summary
Primary open-angle glaucoma is the most prevalent of the
open-angle glaucomas and a leading cause of worldwide
blindness. Risk factors for the development or progression of
POAG have been identified. A better understanding of risk
factors may allow more targeted aggressive therapy for those
patients at greatest risk of suffering visual disability before the
disease progresses. The treatment of POAG remains limited to
lowering of IOP by medical, laser surgery, or incisional surgery
approaches. Major clinical trials have demonstrated the benefit
of IOP-lowering.
The causes of primary open-angle glaucoma remain obscure.
When elevated IOP is present it seems due to increased
resistance to aqueous outflow at the trabecular meshwork. Yet
some surgical techniques to bypass or decrease trabecular
meshwork resistance are not highly effective, suggesting there
may be additional failure of the outflow pathways downstream.
Further, glaucomatous damage can occur at statistically normal
IOPs and patients can tolerate elevated IOPs without glaucoma-
tous damage. We have little understanding of the differential
susceptibilities to glaucoma.
Primary open-angle glaucoma remains a challenge to diagnose
and treat because the early disease is asymptomatic. Once
symptoms are noticeable to the patient the disease is usually
fairly advanced. No adequate simple screening method exists.
The best detection method remains the comprehensive eye
evaluation, a resource that is not universally available or
accessed. Since the damage of POAG is irreversible, eye treat-
ment should be directed to preserve a lifetime of sufficient visual
function to maintain quality of life.
Introduction
Glaucoma is a leading cause of irreversible visual loss. This
potentially blinding disease is a progressive optic neuropa-
thy associated with elevated intraocular pressure. Since
early primary open-angle glaucoma is asymptomatic the
diagnosis is often made late in the disease, after irreversible
visual damage has occurred. Preserving vision is best
achieved with diagnosis prior to perceived functional
damage by the patient. Often the diagnosis is presumptive,
based on characteristic optic nerve findings, or abnormali-
ties on psychophysical testing. The diagnosis becomes more
definitive once progression of disease is documented over
time. With the evolution of global risk assessment, and the
refinement of diagnostic tools and technologies, our ability
to detect early disease continues to improve. This allows
clinicians to identify patients earlier for institution of treat-
ment. Prospective randomized clinical trials such as
the Early Manifest Glaucoma Trial, Collaborative Initial
Glaucoma Treatment Study and Advanced Glaucoma
Intervention Study have provided pivotal data on natural
history, risk factors, and outcomes of treatment. The out-
comes of clinical trials are discussed in a later section.
Prevalence
A review of published data from population-based studies
of age-specific prevalence of primary open-angle glaucoma
(POAG) combined with United Nations world population
projections were analyzed to derive an estimate of the
number of people in the world with glaucoma. It was pro-
jected that by 2020 around 59 million people will have
POAG. Bilateral blindness will be present in 5.9 million
people with POAG by 2020 making glaucoma the second
leading cause of blindness worldwide.1
In the 2002 World Health Organization report on the
magnitude and causes of visual impairment more than 161
million people were visually impaired, of whom 124 million
people had low vision and 37 million were blind. In this
report published in 2004, glaucoma contributed to blind-
ness in about 4.5 million individuals. These figures repre-
sented the first global estimates since the early 1990s.
Country and regional variations were notable with more
than 90% of the world’s visually impaired living in develop-
ing countries. Although cataract remained among the
leading causes of blindness associated with aging in all
regions of the world (except for the most developed coun-
tries),2 glaucoma was reported as the second leading cause
of blindness globally as well as in most regions, with age-
related macular degeneration (AMD) ranking third on the
global scale.3
The prevalence of glaucoma is influenced by many vari-
ables particularly age and race. Several population-based
studies found the prevalence increased with age.4–9 Glau-
coma prevalence increases with age by as much as 5- to
10-fold from the fifth to the eighth decades. However, indi-
viduals older than 75 years are poorly represented in
population-based studies of glaucoma prevalence. Typically
younger individuals are included as older individuals are
the most difficult to bring in for screening and scheduled eye
examinations.10
It is also well known that age-adjusted prevalence rates
for POAG are higher in Blacks compared with Whites.4
Rates among Blacks in the Baltimore Eye Survey ranged
from 1.23% (in those aged 40–49 years) to 11.26% (in
those older than 80 years), whereas rates for Whites ranged
from 0.92% to 2.16%, respectively. In the more recent Salis-
bury Eye Evaluation Glaucoma Study a total of 1233
individuals were screened with eye examination.10 The
prevalence of POAG was 3.4% for white individuals aged 73
333
334 SECTION 4 • Types of Glaucoma
and 74 years, increasing to 9.4% for those older than 75
years. Among black persons, the prevalence was 5.7% in
those aged 73 and 74 years and increased tremendously to
23.2% in those 75 years and older. Thus, black persons
older than 75 years had substantially higher rates than
Whites the same age. These findings have important impli-
cations for public health initiatives and screening programs.
This may also reflect a different racial genetic basis or sus-
ceptibility to the disease. Prevalence data give a snapshot of
current conditions. As demographic patterns shift, preva-
lence will have a corresponding shift of burden of disease
and opportunity for targeted screening.11
Risk Factors
Consideration of risk factors for the development of glau-
coma has been highlighted by an increasing appreciation
of risk assessment, and the way it has affected management
decisions for glaucoma patients. The goal of identifying risk
factors for glaucoma is to recognize patients at greatest risk
for progression and symptomatic vision loss that may have
a detrimental effect on their quality of life. In that sense
glaucoma present an unusual situation where some of the
putative risk factors for the disease are actually early patho-
logic signs like optic nerve cupping for example.
The ophthalmologist treating patients with early glau-
coma is frequently faced with the clinical dilemma of how
vigorous treatment goals should be. Not all patients with
glaucoma will progress to symptomatic visual loss during
their expected life span. Many with glaucoma will maintain
useful vision for their entire lifetime. Simply put, risk assess-
ment should allow us to identify those at greatest risk
for glaucoma progression at a rate that will result in symp-
tomatic vision loss. Applying what we have learned from
longitudinal studies of patients will help in making indi-
vidualized risk assessment plans.
The literature has often described ‘risk factors for glau-
coma’ without specifying whether it is a risk for developing
the disease or a risk for progressing. To better understand
this issue, it is helpful to think of glaucoma as a spectrum
ranging from a previously healthy optic nerve with unde-
tectable damage (by current technologies), to early detect-
able damage with none to early asymptomatic vision loss,
to more advanced degrees of damage and blindness. We
should also not assume that all the risk factors remain the
same or carry the same weight at all stages of the disease.
Risk assessment in patients with ocular hypertension and
glaucoma has been the subject of several reviews.12–14
Some risk factors can be identified by patient history such
as age, race, and history taking, while others can be detected
by clinical examination and testing like intraocular pres-
sure and optic nerve cup-to-disc ratio. The strength of evi-
dence supporting risk factors varies from strong to weak
(Table 29-1). Several risk factors have been identified for
progression from ocular hypertension to glaucoma. Those
will be discussed in detail in another chapter. We have
focused the discussion below on risk factors mostly associ-
ated with POAG and its progression. Recently, a risk model
to predict visual field outcomes in patients with treated
glaucoma has been described.15 This may be useful for the
objective assessment of the risk of visual field progression.
Table 29-1 Risk Factors for Glaucoma by Strength
of Evidence14
Risk Factor Strength of Evidence
Optic nerve head alteration Strong
Elevated intraocular pressure Strong
Older age Strong
African origin Strong
Confirmed family history Moderate
Diabetes mellitus Modest
Hypertension Modest
Data from Fechtner RD, Khouri AS. Evolving global risk assessment of ocular
hypertension to glaucoma. Curr Opin Ophthalmol. 2007 Mar;18(2):104–
109. PubMed PMID: 17301610.
OPTIC NERVE HEAD
The optic nerve head appearance is perhaps the most sig-
nificant risk factor and diagnostic sign as its alteration basi-
cally defines glaucoma in most patients. With current
limitations in imaging technologies of the optic nerve head
as well as biologic variability it remains challenging to
isolate well-defined optic nerve head parameters as risk
factors. However, there exists strong evidence that increased
cup-to-disc ratio in itself represents a risk factor for progres-
sion of glaucoma.16,17 Whether an increased cup-to-disc
ratio represents a risk factor or undetected existing
glaucoma damage has been debated.18 Limitations in
early detection of structural damage make it difficult to
completely resolve this issue. Baseline confocal scanning
laser ophthalmoscopy (CSLO) indices in an ancillary study
to the ocular hypertension treatment study predicted the
development of POAG (hazard ratios 95% confidence inter-
val ranged from 2.92 to 3.74 for an outside normal limits
result).19 In a study compiling different imaging modalities
(CSLO, optimal coherence tomography [OCT], scanning
laser polarimetry) abnormal baseline ONH topography and
reduced inferior retinal nerve fiber layer thickness were pre-
dictive of visual field progression in glaucoma suspects
and in glaucomatous eyes.20 Optic disc hemorrhages were
associated with a faster rate of glaucoma progression in
the Collaborative Normal Tension Glaucoma Study,21 and
with a 6-fold increase (95% confidence interval 3.6–10.1;
p < 0.001) in risk of developing POAG in the Ocular Hyper-
tension Treatment Study participants.22
INTRAOCULAR PRESSURE
Intraocular pressure (IOP) is one of the strongest risk factors
for glaucoma progression.16,23–26 At high enough levels IOP
can be causative. It is still not clear which dimensions of
IOP contribute the greatest risk. Higher IOP levels are asso-
ciated with glaucoma progression. Variability in diurnal
IOP and large IOP differences between fellow eyes were
found to be more common in patients with POAG (36%)
than in normal subjects (6%).27 The diurnal IOP range, and
the IOP range over multiple days were found to be signifi-
cant risk factors for progression, even after adjusting for
age, race, and visual field damage (relative hazards and 95%

confidence intervals were 5.69 [1.86, 17.35] and 5.76
[2.21, 14.98]).28 In an analysis of the Early Manifest Glau-
coma Trial with a median follow-up of 8 years the results
confirmed the earlier findings that elevated IOP is a strong
factor for glaucoma progression, with a hazard ratio
increasing by 11% for every 1 mmHg of higher IOP (95%
confidence interval 1.06–1.17; p < 0.0001).29 In another
study examining IOP-dependent variables associated with
visual field progression, univariate analysis found associa-
tions with mean follow-up IOP, fluctuation, and peak IOP.
However, the multivariate analysis found only peak IOP to
be associated with progression (OR 1.13, p < 0.01).30
AGE
There is strong evidence that prevalence and incidence of
primary open-angle glaucoma (POAG) increases with the
age of the population being studied.26,31–33 This was also
confirmed in other population-based studies like the visual
impairment project,34 and the Barbados Family Study.35 In
the Los Angeles Latino Eye Study older age predicted the
development of POAG (odds ratio per decade, 2.19; 95%
confidence interval, 1.74–2.75; p < 0.001).9 Since glau-
coma is a progressive disease it makes sense that older age
is a risk for greater severity.
RACE
Primary open-angle glaucoma was found to be four to six
times more frequent among individuals of African-
American origin compared to Caucasian.4,36 On average
POAG also began at an earlier age in African-Americans
than Caucasians. Other studies have also reported a notably
higher prevalence of glaucoma in individuals of black race
when compared with other racial groups.10,37 In the Los
Angeles Latino Eye Study, the 4-year incidence of POAG in
Latinos was higher than in non-Hispanic Whites, but lower
than in Afro-Caribbeans (2.3%; 95% confidence interval,
1.8% to 2.8%).38
FAMILY HISTORY
Family history of glaucoma increases the risk of an indi-
vidual developing the disease. Although the exact inherit-
ance pattern is still unknown, POAG is a multifactorial
polygenetic disease. Several studies examined family history
as a risk factor for glaucoma. The Glaucoma Inheritance
Study in Tasmania compared the distribution of patients
with genealogically confirmed familial POAG and those
with sporadic POAG. The familial group was significantly
younger at diagnosis and had more severe disease than the
sporadic group.39 This finding is in support of the value of
tailored screening, particularly of family members of indi-
viduals with a positive family history.
Self-reporting can be unreliable, but in the Rotterdam
Study family history was ascertained by direct examination
of relatives and not by patient self-report.40 The lifetime
absolute risk of glaucoma at age 80 years was found to be
almost 10 times higher for individuals having relatives with
glaucoma than for patients with negative family history
(22.0% vs. 2.4%). The Barbados Family Study of Open-
angle Glaucoma investigated inheritance of POAG among
29 • Primary Open-Angle Glaucoma 335
families of black race and also found family history to be a
major risk factor for glaucoma confirmed by direct
examination of the relatives.35 The Barbados Eye Studies
identified family history as a risk factor for definite incident
glaucoma in its 9-year analysis (RR, 2.4; 95% CI, 1.3–
4.6).33 Still, family history alone cannot account for the
observed prevalence of the disease suggesting that non-
genetic factors play a significant role in the overall occur-
rence of glaucoma.23
DIABETES
Several studies investigated the possible relationship
between POAG and diabetes. Prevalence of POAG was
higher in diabetic individuals compared to non-diabetics
(4.2% versus 2.0%; p = 0.004).41 In the Blue Mountains Eye
Study glaucoma prevalence and OHT were more common
in people with diabetes (odds ratio 2.12, confidence interval
1.18–3.79, and 1.86 confidence interval 1.09–3.20 respec-
tively).42 Other prospective studies of glaucoma manage-
ment reported a greater likelihood of progression in patients
with diabetes.43,44
In the Baltimore Eye Survey the association between
glaucoma and diabetes was found to be weak (age-
race-adjusted odds ratio, 1.03; 95% confidence interval,
0.85, 1.25).
Persons whose POAG had been diagnosed before they
enrolled in the study showed a positive association with
diabetes (odds ratio, 1.7, 95% confidence interval, 1.03,
2.86), indicating that selection bias into the healthcare
system may have influenced the positive results of associa-
tions between diabetes and POAG in some studies.45 The
unexpected findings from the Ocular Hypertension Treat-
ment Study suggested that subjects with self-reported dia-
betes actually had lower risk of progression to POAG (hazard
ratio of 0.37 in the multivariate analysis with p < 0.05).23,24
Diabetes was not selected as a predictive factor in the
analysis of pooled Ocular Hypertension Treatment Study–
European Glaucoma Prevention Study dataset. The Blue
Mountain Eye Study reported a significant and consistent
association between diabetes (diagnosed by history or ele-
vated fasting plasma glucose level) and glaucoma.42 The
effect of diabetes on the development of POAG remains
controversial.46
HYPERTENSION
In the Blue Mountains Eye Study Participants with glau-
coma were more likely to have systemic hypertension than
participants without glaucoma: 65.7% (95% CI: 56.6–74.8)
versus 45.4% (95% CI: 43.8–47.1).47 Although a positive
association between elevated blood pressure and POAG was
reported,48 larger population-based studies like the Fram-
ingham Eye Study 49 and the Baltimore Eye Survey failed to
confirm the association. However, systolic and diastolic
blood pressure showed a modest, positive association with
POAG. Age-adjusted data indicated that individuals with a
systolic blood pressure >130 mmHg had a higher preva-
lence of POAG. Lower perfusion pressure (blood pressure–
intraocular pressure) was strongly associated with an
increased prevalence of POAG, with a six-fold excess for
those in the lowest category of perfusion pressure.50
336 SECTION 4 • Types of Glaucoma
OTHER RISK FACTORS
Various factors like myopia, pseudoexfoliation, migraine,
and caliber of retinal vasculature have been reported in the
literature as risk factors. There seems to be an increased
frequency of myopia among patients with OHT or POAG. In
one study, 60% of eyes progressing from OHT to glaucoma
were myopic.51 In the Beijing Eye Study, subjects with
myopic refractive error exceeding −6 diopters had a signifi-
cantly higher glaucoma frequency than groups with low
myopia (−0.5 to −3) or emmetropia.52 There is evidence for
pseudoexfoliation as a risk factor for glaucoma progres-
sion.43 Migraine has been reported as a risk factor for glau-
coma progression.53 The Blue Mountains Eye Study, after
adjusting for age, family history, diabetes, hypertension,
and cup-to-disc ratio found that a narrower central retinal
artery was associated with higher risk of incident POAG
(adjusted odds ratio, 1.77; 95% confidence interval,
1.12–2.79).54
Pathogenesis
Despite the fact that POAG is the most commonly studied
type of glaucoma, its pathogenesis remains unclear. Accord-
ingly POAG is by definition a primary disease with no iden-
tifiable cause. With the current definition, any time a cause
is identified for glaucoma, it is labeled a secondary glau-
coma rather than POAG. The final common pathway is
injury and loss of retinal ganglion cells. Several theories of
mechanism have been suggested and remain a subject of
debate.55 Among those are the vascular and mechanical
theories for optic nerve damage.
Abnormal resistance to aqueous outflow and alterations
at various levels of the trabecular meshwork have been
described. Among those were histologic abnormalities in
collagen structure, intertrabecular spaces, juxtacanalicular
connective tissue, and endothelial cell function in glaucoma
eyes.56,57 Collapse of Schlemm’s canal has been proposed as
a contributing factor to the increased resistance to outflow
in POAG.58 Interpretation of the various histologic findings
and their implications on outflow resistance and IOP is
difficult. The role of different components of the outflow
system in regulating IOP, and the segmental variability of
the system makes simple interpretations elusive.59 The
understanding of complex mechano-transduction mecha-
nisms of aqueous outflow continue to evolve with new
models proposed for outflow control and regulatory feed-
back of IOP.60 More recent advances in anterior segment
spectral domain OCT have improved our ability to study
components of the conventional outflow pathway from
Schlemm’s canal to the superficial intrascleral venous
plexus.61
Genetics
The advances in DNA-related technologies have led to sig-
nificant leaps in our knowledge of the genetics of ophthal-
mic diseases. This progress has accelerated with the
completion of the Human Genome Project in 2003 (aimed
to identify all of the approximately 25,000 genes in human
DNA, and to determine the sequences of approximately 3
billion base pairs that make up human DNA), and the Inter-
national HapMap Project in 2005.62–64 Perhaps a reason
why it has been challenging to discover the genes for POAG
relates to the fact that POAG (although thought of as a
single disease) does not consist of a single ‘phenotypic’
variant. For example, some patients with POAG suffer optic
nerve damage at IOP in the statistically normal range, while
others produce damage with higher levels of IOP.65
Genetic factors have long been implicated in the patho-
physiology of POAG. Myocilin for example was associated
with both juvenile open-angle glaucoma and POAG.
Although more than 40 different myocilin mutations have
been described in POAG patients, as a group these muta-
tions are associated with only 3–4% of POAG patients.66
Other genetic sequence variations for POAG have been
described but in general they still are responsible for only a
small minority of all POAG.67,68 In a study performing
a genome-wide scan of IOP using 486 pedigrees of a
population-based cohort from the Beaver Dam Eye Study,
Linkage analysis was achieved using regression models and
seven loci of interest were identified on chromosomes 2, 5,
6, 7, 12, 15, and 19. Two of the regions (chromosomes 2
and 19) were especially interesting since each has been
identified as a potential linkage region for blood pressure.69
Replicating these initial findings in other populations will
assist in identifying genes that may control IOP.
Diagnosis
PRESUMPTIVE VERSUS DEFINITIVE
Detecting glaucomatous optic neuropathy or the corre-
sponding characteristic visual field loss is the basis of diag-
nosis. Structural and functional tests are useful for detection
of glaucoma, and in its follow-up and management over
time. Detection of change on either modality may not only
indicate progression of disease, but also indicate with cer-
tainty the presence of POAG. It is no longer considered
essential to wait until there are structural and correspond-
ing functional abnormalities before making the diagnosis of
POAG. For example, in the Ocular Hypertension Treatment
Study,24 for those who progressed to a glaucoma endpoint,
the determination was based on confirmed stereo optic
nerve photo change in 55%, confirmed and reproducible
visual field defect in 35% and concurrent defects in 10%.
Classic optic nerve head findings like a large cup-to-disc
ratio may show considerable overlap between POAG and
normal subjects. Visual field sensitivity and performance
fluctuate over time, and suspicious findings frequently dis-
appear or decrease in intensity upon retesting. Frequently
the diagnosis of glaucoma is ‘presumptive’, based on char-
acteristic optic nerve or visual field findings. Having the
ability to detect the most subtle signs of progression of
disease once they occur constitutes the ‘definitive’ diagnosis
for most subjects.
SIGNS OF POAG
Clinical assessment of the optic nerve head to diagnose or
exclude glaucoma is challenging because of the biological

variability in appearance and extent of cup-to-disc ratio
between pathologic and normal subjects. Changes in the
observations made with follow-up of subjects over time are
a more sensitive indicator of progression of disease. Certain
findings on examination are very suggestive of POAG and
their presence even on a single observation can imply the
presumptive diagnosis of glaucoma. Among these observa-
tions are nerve fiber layer (NFL) defects, optic nerve rim
hemorrhages, and neuroretinal rim notching or relative
thinning (Figs 29-1–29-3). The ISNT rule can be used to
aid in the differentiation between normal and glaucoma-
tous optic nerves. In healthy eyes the neuroretinal rim often
follows a characteristic configuration whereby the inferior
(I) rim is thickest, followed by the superior (S), then nasal
(N), then temporal (T) rim, hence the ISNT rule. While this
is a useful guide it does not uniformly apply to healthy eyes.
The utility of this rule in glaucoma diagnosis has also been
Figure 29-1 Inferior and superior nerve fiber layer defects.
Figure 29-2 Inferior splinter hemorrhage with neural rim thinning
and a corresponding nerve fiber layer defect.
29 • Primary Open-Angle Glaucoma 337
challenged.70 In many patients glaucomatous optic neu-
ropathy may be advanced (Fig. 29-4) by the time visual
impairments are noted.
STRUCTURAL ABNORMALITIES
It has been demonstrated that significant optic nerve
damage may occur prior to the appearance of visual field
loss.71 In one study, nerve fiber layer defects were present in
88% of optic nerve photographs at the time field loss was
first detected, with 60% of eyes showing nerve fiber layer
defects 6 years before field loss.72 Stereoscopic examination
of the optic nerve allows detailed evaluation of the struc-
ture. Clinically, stereoscopic evaluation of the optic nerve is
most conveniently performed with the slit lamp biomicro-
scope and a handheld lens (typically 78D or 90D), or less
commonly through evaluation of stereoscopic optic nerve
Figure 29-3 Relative thickness of the neuroretinal rim is outlined at
the four poles of the disc in a patient with early POAG. Note the inferior
rim is thin, violating the ISNT rule.
Figure 29-4 Advanced glaucomatous optic neuropathy.
338 SECTION 4 • Types of Glaucoma
images. While stereo disc photography has long been
regarded as a very useful test, the transition to other digital
imaging technologies has made photography less practical
in most clinical settings (see below).
As mentioned earlier, the essential pathologic process in
glaucoma is loss of ganglion cell axons. The appearance of
the neural rim and configuration of the optic cup reflect the
amount of axon loss. A useful clinical approach includes
five parameters for optic nerve evaluation: optic disc size,
neuroretinal rim shape, retinal nerve fiber layer, presence
of peripapillary atrophy, and presence of optic disc hemor-
rhages.73 A large number of clinical features have been
characterized (Table 29-2). None however seem to be uni-
versally present or absent. Thus it remains essential to cor-
relate structural findings with functional changes in vision,
and to follow these alterations over time.
FUNCTIONAL DEFECTS
Visual field testing is the mainstay for the diagnosis and
management of POAG. Reproducible visual field defects
confirm a presumptive diagnosis of glaucoma. Certain
visual field patterns of loss have been classically associated
with glaucoma like arcuate and nasal step defects (Figs
29-5 & 29-6). Progression of visual field loss is probably the
most commonly recognized indicator of disease worsening.
However perimetric testing generally is not sensitive to very
small changes, and true progression usually reflects signifi-
cant loss of nerve tissue. It is important to realize that not
all defects detected on sensitive perimetric testing persist on
re-testing and imply a pathologic glaucomatous process.
It is less common for glaucoma to be diagnosed before the
appearance of visual field loss. The exception would be in
patients with recurrent optic disc hemorrhages prior to
manifesting visual field loss.74,75 Standard automated per-
imetry (SAP) with static techniques has almost completely
Table 29-2 Common Optic Disc and Nerve Fiber
Layer Signs of Glaucoma
Sign Description
Cup-to-disc ratio Increased, usually >0.6
Asymmetry between eyes, usually >0.2
Vertical elongation, usually denoting loss
of rim inferiorly or superiorly
Neuroretinal rim Notching or focal loss
Pallor
Sloped rim is common temporally and is
not a specific sign
Nerve fiber layer Localized wedge defects
Can be diffuse in advanced disease
Often in relation with splinter hemorrhage
Vascular Disc splinter hemorrhages
Overpass with loss of rim underneath
Bayonetting
Narrowing, can be diffuse or focal
Nasalization mostly with advanced
cupping
Peri-papillary atrophy Common but not specific to glaucoma
replaced kinetic manual perimetry in large part because of
the convenience of testing and quantitative measures pro-
vided by automated testing. In addition to white-on-white
SAP, several other automated perimetry tests and algo-
rithms exist for the diagnosis and detection of glaucoma
progression. Among those technologies are short-wave-
length automated perimetry (SWAP), and frequency dou-
bling technology perimetry (FDT). The utility of various
functional tests in the detection of glaucoma and glaucoma
progression is variable.76 However, SAP remains the most
commonly used clinical test for automated perimetry.
In brief, there is evidence that SWAP can detect visual
field loss earlier than SAP with a sensitivity and specificity
reported to be about 88% and 92% respectively. However,
SWAP testing can be lengthy when performed under a
standard algorithm speed. The Swedish Interactive Thresh-
olding Algorithms (SITA) for SWAP perimetry shortens
testing time compared to full threshold testing and per-
formed similarly when equated to specificity.77 SWAP is also
sensitive to media opacities like nuclear sclerosis. In addi-
tion, it showed greater long-term fluctuation compared
with SAP making it difficult to use in assessing accurate
disease progression. Testing with FDT perimetry showed
sensitivity and specificity of more than 97% for detecting
moderate and advanced glaucoma, and sensitivity of 85%
and specificity of 90% for early glaucoma when compared
to SAP. FDT was comparable to SAP in glaucoma detection,
and had higher sensitivity compared to SWAP at a compa-
rable level of specificity in one study.76 As FDT perimetry has
a short testing time and is resistant to blur and pupil size, it
may be a useful screening tool.78 It performed as well as SAP
in detecting glaucoma in one comparative study but is not
widely used clinically.
ANCILLARY TESTS
Functional and structural testing is covered in detail in
other sections. Below is an overview of tests that are used
in glaucoma diagnosis and follow-up, although some
clinicians continue to adopt newer technologies and retire
older ones. This can disrupt follow-up as results from one
computer-assisted imaging technology typically can not be
translated to a newer technology. One must establish a new
baseline.
Stereophotography
Optic nerve head stereo photography allows the objective
documentation of optic nerve findings,79 and is a strong
comparative tool when used for serial comparison of photos
over time.80 It has been used as an endpoint for major clini-
cal trials. The use of digital imaging is becoming common
in ophthalmology, and has all but replaced film. Digital
fundus cameras are widely available, and newer stereo
digital fundus cameras have been developed. Digital imaging
allows immediate feedback on the quality of obtained
images. Film and digital imaging seem comparable in the
assessment of glaucomatous optic neuropathy and a high-
quality image of the optic nerve at baseline can allow detec-
tion of subtle structural changes.81 Digital images can be
transmitted to reading centers as is done in clinical trials
and teleophthalmology without effects on clinical interpre-
tation or image quality.82 Digital images can also be

Figure 29-5 Standard automated perimetry showing a classic arcuate defect.
analyzed with software-driven digital filters to expedite
archiving and clinical assessment of images.83,84
OTHER IMAGING TECHNOLOGIES
Scanning Laser Polarimetry
This technique measures the peripillary NFL thickness by
shining a laser beam onto the retina and assessing the
change in polarization or retardation of the reflected beam.
29 • Primary Open-Angle Glaucoma 339
Laser retardation is due to the birefringent properties of the
neurotubules in ganglion cell axons. Individualized com-
pensation for corneal birefringence is performed. The GDx
(Carl Zeiss Meditec, Inc., Dublin, CA) utilizes scanning laser
polarimetry to generate a high-resolution image of the peri-
papillary retina. The NFL thickness is measured along a
circle located 3.2 mm in diameter around the disc. The
superior and inferior poles have the greatest NFL thickness,
and when thickness is plotted graphically this typically
manifests in a ‘double hump’ pattern in normal eyes.
340 SECTION 4 • Types of Glaucoma
Figure 29-6 Short-wavelength automated perimetery showing an early inferior nasal step defect.
Measurements with this technology correlate well with
glaucoma damage and visual field defects.85,86 This technol-
ogy is less commonly used since the introduction of newer
OCT instruments (see below).
Confocal Scanning Laser Topography
The principle of confocal scanning laser polarimetry is to
illuminate the optic nerve and retina through a single
pinhole and to allow light that returns from the point of
interest to pass through the pinhole and be detected. To
image a plane, rather than a point, an array of points in
that plane must be scanned point by point yielding an
optical plane or section. The Heidelberg Retina Tomograph
(Heidelberg Engineering GmbH, Heidelberg, Germany)
creates a topographic image by a reconstruction of up to 64
scanned image planes. A contour line is placed by an opera-
tor and a series of topographic analyses are performed on
the image. The latest HRT 3 software performs automated
analyses based on the three-dimensional modeling of the
entire topographical image. The constructed three-
dimensional models of the ONH shape do not require place-
ment of a contour line manually, and do not require a

reference plane for analysis.87 Many HRT parameters were
found to be associated with the development of POAG,
including large cup-to-disc area ratio, mean cup depth, cup
volume, and neuroretinal rim area and volume.88
Optical Coherence Tomography
The OCT has perhaps become the most widely adopted
imaging modality for the retinal nerve fiber layer (RNFL)
in recent years. Physical principles of this technology
are similar to those of ultrasound. Optical coherence tom-
ography uses a near infrared light that is reflected from the
retina and detected by an interferometer measuring wave-
lengths of backscattered light. This provides an axial cross-
sectional image (series of A scans) of tissues based on the
optical backscatter of low coherence laser light as it goes
through the retinal layers including the RNFL. Lateral and
axial resolutions are determined by the optics of the eye,
and the wavelength and bandwidth of the light source.
With spectral domain OCT a broadband light source is
employed which allows signal at all wavelengths to be
simultaneously recorded by the spectrometer which is then
transformed to spatial information (not possible with time
domain). This allows for improved resolution and speed of
image acquisition thus reducing eye movement artifacts.
This also permits the reconstruction of three-dimensional
sections (cube around the ONH) and improved image regis-
tration. As a reference, while time domain OCT had the
capability of acquiring a few hundred axial scans per second
(limited by the rotational speed of an internal mirror), spec-
tral domain OCT acquire tens to hundreds of thousands of
axial scans per second. This translates into an improved
resolution in the range of 5–7 microns.
The glaucoma algorithms measure RNFL thickness along
a circle centered around the disc, and provide a reconstruc-
tion of the ONH (Figures 29-7 A,B). Optic nerve head algo-
rithms generally rely on a predetermined reference plane set
at an arbitrary distance above the retinal pigment epithe-
lium. Measurements are then compared to a reference or
normative database. Because comparisons to the reference
database will determine the significance of the results, it is
Table 29-3 Optical Coherence Tomography Database Subject Collection by Manufacturer
RTVue
Study sites 11 worldwide contributed data
(15 initially recruited):
6 USA
3 Japan
1 India
1 England
# Subjects 480
Subject ethnicity Caucasian
African descent
Hispanic
Asian
Indian
Other
Subject age 18–84
Significance RNFL thickness
limits include Ganglion cell complex (GCC)
Macular retinal thickness
29 • Primary Open-Angle Glaucoma 341
important for the clinician to be cognizant of differences
and limitations of the reference databases on various com-
mercially available units. The subject characteristics, exclu-
sion criteria, and examination parameters for databases
available on different OCT units by manufacturer are sum-
marized in Tables 29-3–29-5. Parameters like cup-to-disc
ratio and rim area together with NFL measurement can
improve diagnostic accuracy for glaucoma detection using
this instrument.89
Each of the above technologies has its merits and limita-
tions in the diagnosis and detection of progression of POAG.
The clinician should never rely solely on imaging devices to
diagnose or follow-up patients. Interpretation of test results
is most accurate when made in light of the clinical assess-
ment of individual patients.
Treatment Options and
Sequencing of Therapy
The selection of POAG treatment is usually determined by
the stage of disease, the levels of IOP at which damage
occurred or continues to progress, and the estimated life-
time risk of visual disability for patients. Although estimat-
ing lifetime risk remains challenging our understanding of
global risk assessment continues to evolve. The reality
remains that IOP is the only risk factor currently modifiable
by treatment. The IOP can be lowered by medical treatment,
laser surgery, or incisional surgery. The choice of initial
therapy depends on numerous considerations that vary
depending on the severity of the disease, ocular and sys-
temic factors, as well as patient economic and lifestyle con-
siderations. All these factors go into the decision-making
process in formulating the best therapeutic strategy for an
individual patient. In the US, the majority of patients are
treated with topical medications first. More often, recently
selective laser trabeculoplasty has been considered for some
patients as first-line treatment. Incisional treatments are
needed if therapeutic goals are unmet. The concept of
Cirrus Spectralis
6 USA 1 Germany
1 China
284 201
African descent Caucasian
Chinese
European descent
Hispanic
19–84 18–78
Peripapillary RNFL thickness RNFL thickness
RNFL thickness for the optic nerve head scan cube
Optic nerve parameters
Macular ganglion cell + IPL thickness
Macular retinal thickness
 29 • Primary Open-Angle Glaucoma 341.e1

A
Figure 29-7 A, B: OCT showing glaucomatous focal loss of retinal nerve fiber layer in both eyes.
341.e2 SECTION 4 • Types of Glaucoma

B
Figure 29-7 Continued
342 SECTION 4 • Types of Glaucoma

Table 29-4 Optical Coherence Tomography Database Exclusion Criteria by Manufacturer

RTVue Cirrus Spectralis
Ocular history Active ocular disease Vitreoretinal disease Glaucoma
Congenital abnormalities Uncomplicated cataract and/or refractive surgery Vitreal, retinal, or choroidal
Anatomic narrow angle eye within 12 months diseases or disease of
Glaucoma or suspect Any complicated eye surgery the optic nerve
Diabetic retinopathy Amblyopia Any intraocular disease
Uncomplicated cataract surgery Glaucoma, ocular hypertension, glaucoma suspect Prior intraocular surgery
within 6 month Angle closure, disc hemorrhage (except cataract surgery)
Other previous intraocular surgery Infection or inflammation in the eye
Medical history Leukemia Leukemia Diabetes mellitus
AIDS AIDS
Dementia Dementia
Multiple sclerosis Multiple sclerosis
Arteriosclerosis Diabetes mellitus
Uncontrolled systemic hypertension
Family history Glaucoma 1st degree relative
Medication Hydroxychloroquine or chloroquine

Table 29-5 Optical Coherence Tomography Database Examination Parameters

RTVue Cirrus Spectralis
Refraction (exclusion) Outside +/− 8 D sph, +/− 2 D cyl Outside −12 D to +8 D sph Outside −7 D to +5 D sph
IOP <22 mmHg <22 mmHg ≤21 mmHg
Visual acuity BCVA 20/30 or better in each eye No less than 20/40 Snellen or 0.7 or better (~20/30)
Snellen equivalent either eye
Optic nerve and RNFL The appearance of the optic disc was not No disc hemorrhage, RNFL defects Normal appearance of optic disc
used as an exclusion criterion – 2 examiners
Visual field Normal Humphrey SAP (<25% FN, FP, FL) Normal Humphrey 24-2 visual field Normal visual field based on FDT,
normal GHT (normal Octopus visual field (15% or less FN, FP, FL) (normal Octopus or Goldman perimetry
also accepted) program 30-2 also accepted)

maximal medical therapy continues to evolve.90 For some
patients it may represent a single fixed combination therapy
with or without a prostaglandin analogue. A full discussion
of the therapeutics of glaucoma is beyond the scope of this
chapter and is discussed in detail in other sections.
TARGET INTRAOCULAR PRESSURE
Establishing an upper limit of a range of IOP at which it is
judged likely to retard further optic nerve damage is known
as a ‘target IOP’.91 While studies can identify IOP levels at
which damage was less likely to progress92 there exists
no algorithm by which physicians can determine an IOP
below which further optic nerve damage will be prevented
in any particular patient. Target IOP is usually determined
based on the clinician’s experience and on the knowledge
of outcomes data from clinical trials. It remains a largely
individual subjective process. If glaucoma progression
occurs at the pre-set ‘within target range’, then target IOP
should be lowered further. Patients may progress despite
achieving a very low target IOP. We must recognize there
may be an IOP-independent contribution to damage in
some patients.
It is helpful while choosing a target pressure to judge the
severity of glaucoma on a simplified scale of mild, moderate,
or severe. According to the most recent American Academy
of Ophthalmology preferred practice patterns published in
2010 the severity of glaucoma can be classified as follows:
MILD. Optic nerve abnormalities consistent with glau-
coma (as detailed in the PPP) and a normal visual field as
tested with standard automated perimetry.
MODERATE. Optic nerve abnormalities consistent with
glaucoma (as detailed in the PPP) and visual field abnor-
malities in one hemifield that are not within 5 degrees of
fixation as tested with standard automated perimetry
SEVERE. Optic nerve abnormalities consistent with glau-
coma (as detailed in the PPP) and visual field abnormalities
in both hemifields and/or loss within 5 degrees of fixation
in at least one hemifield as tested with standard automated
perimetry.93
There exists a large body of evidence supporting an initial
target pressure selected at least 20% lower than the pre-
treatment IOP.24,92,94 Additional reductions of the target IOP
are recommended in patients with advanced disease or with
rapid progression.95
MEDICAL TREATMENT
Economic and regulatory issues determine the IOP-lowering
medications available for the physician to prescribe for the
patient. Topical prostaglandin analogs and beta-adrenergic
antagonists are the most frequently used eye drops for initial
lowering IOP in patients with glaucoma. The topical pros-
taglandins are most preferred for efficacy, convenience of
dosing (once daily), and excellent systemic safety. Other
contemporary classes of topical agents include alpha 2

adrenergic agonists, carbonic anhydrase inhibitors, and the
older class of parasympathomimetics. Oral carbonic anyhy-
drase inhibitors can be effective but as associated with a
high frequency of systemic adverse effects. If a drug fails
to reduce IOP, it can be switched to another agent within
the same pharmacologic class. Simplifying therapy helps
patients avoid the burdens of complex therapeutic regi-
mens. If a single medication is effective in lowering IOP but
target pressure is not reached, combination therapy, or
switching to an alternate therapy may be appropriate.
Various fixed combinations are available. While convenient,
these do not allow individualization of concentration or
dosing frequency of the components. Finally, adequate
medical treatment of glaucoma requires a high level of
adherence to therapy.
Adherence with Medical Therapy
Adherence is the consistent use of prescribed medications
over time, while persistence is the continued use of pre-
scribed medications over time. Adherence and persistence
to treatment are vital in preventing visual loss, and subse-
quent loss of functioning and quality of life.96 Compliance
is often defined as how well patients follow physicians’ rec-
ommendations. In recent medical literature, less judgmen-
tal words like ‘adherence’ and ‘persistency’ have been
substituted for ‘compliance’ with glaucoma therapy.97,98
Reducing the complexity of an eye drop regimen helps to
improve the compliance, adherence, and persistence with
glaucoma treatment. This relationship however is by no
means direct.
Levels of patient adherence to chronic medications are
known to be variable and challenging to measure across
areas of medicine.99 Adherence studies are difficult to
conduct, and are riddled with potential bias. Evidence of
how different drug regimens may influence adherence is
mixed. Increasing complexity of eye drop regimens has
been linked to worsening of100,101 or no difference in adher-
ence.102 A review of non-adherence with glaucoma treat-
ment found only 29 original studies and concluded that few
clinically relevant guidelines could be discerned.103 It is
however generally accepted that simpler therapeutic regi-
mens with less frequent dosing may be preferred by patients
and could promote adherence.59 In that sense fixed combi-
nation medications offer patients better convenience. If a
single eye drop from a single bottle can deliver the same
efficacy as two separate drops from two separate bottles the
benefit to the patient is obvious.
LASER AND INCISIONAL SURGERY
Laser trabeculoplasty may be considered as a first-line inter-
vention for open-angle glaucoma in patients unable or
unwilling to use medications, or in certain conditions like
pseudoexfoliation or pigmentary glaucoma where it can be
very effective. Laser trabeculoplasty is more often performed
for additional IOP lowering as an adjunct to medical therapy.
At times it can serve as a temporizing procedure for control
of IOP in eyes awaiting filtering surgery. As compared to
eyes initially treated with medication, eyes initially treated
with argon laser trabeculoplasty had 1.2 mmHg greater
reduction in intraocular pressure.104 Selective laser trabecu-
loplasty (532 nm Nd:YAG laser) appears to be as effective
29 • Primary Open-Angle Glaucoma 343
as argon trabeculoplasty techniques in lowering IOP and,
in at least some patients, is effective when repeated.105–107
Incisional surgery continues to have a role in the control of
intraocular pressure. Aqueous diversion to the subconjuncti-
val space can be achieved under a scleral flap by creating an
ostium (trabeculectomy) or with a small drainage device.
There are several variations of tubes to external reservoirs
with or without an integrated resistance device. Other surgi-
cal techniques to lower IOP include non-penetrating glau-
coma surgery, canaloplasty, trabecular bypass devices,
suprachoroidal shunts, and other novel devices. Several sec-
tions of this textbook are dedicated to the full discussion of
medical and surgical treatments of glaucoma.
Access the text on Selected major POAG clinical
trials online at http://www.expertconsult.com
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Selected Major POAG
Clinical Trials
A great deal of the current understanding of risk of pro-
gression and outcomes of treatment in POAG comes from
the large prospective clinical trials supported by the National
Eye Institute (www.nei.nih.gov). The Ocular Hypertension
Treatment Study (OHTS) mainly focused on quantifying
risk factors for developing POAG among ocular hyperten-
sive subjects. Other clinical trials like the Early Manifest
Glaucoma Trial (EMGT) and the Collaborative Initial Glau-
coma Treatment Study (CIGTS) studied long-term effects of
treating newly diagnosed POAG patients. The Advanced
Glaucoma Intervention Study (AGIS) enrolled POAG
patients that were unsuccessfully controlled with medica-
tions, and assessed the long-term outcomes of different
sequences of interventions involving trabeculectomy
and argon laser trabeculoplasty. A summary is included in
Table 29-6.
EMGT
The main purpose was to compare the effect of medical
therapy to late or no treatment on the progression of newly
detected POAG, and to measure the extent of IOP reduction
and explore factors that may influence glaucoma progres-
sion. The EMGT was conducted in collaboration with the
University of Lund in Sweden. The study was initiated with
support from the Swedish Medical Research Council. A total
of 255 open-angle glaucoma patients were randomized to
argon laser trabeculoplasty plus topical betaxolol or no
immediate treatment (129 treated; 126 controls) and fol-
lowed up every 3 months. After 6 years, 53% of patients
progressed. Relative risk of progression decreased by about
10% with each millimeter of mercury of IOP reduction
from baseline to the first follow-up visit (hazard ratio = 0.90
per mmHg decrease; 95% confidence interval: 0.86–0.94).43
In a more recent analysis with a median follow-up time of
8 years (range 0.1–11.1), 68% of the patients had pro-
gressed. Similar to the earlier findings that elevated IOP is
a strong factor for glaucoma progression, the hazard ratio
Table 29-6 Selected Major POAG Clinical Trials
Study Goal Intervention
24
OHTS 20% IOP reduction Medications
CNTGS111 30% IOP reduction Medications and surgery
EGMT43 Protocol driven Trabeculoplasty (360 degree) +
Betaxolol BID
CIGTS108 Protocol driven Medications and surgery
AIGS94 Protocol driven Argon laser trabeculoplasty (A) and
trabeculectomy (T) sequences:
ATT and TAT
29 • Primary Open-Angle Glaucoma 343.e1
increased by 11% for every 1 mmHg of higher IOP (hazard
ratio = 1.11, 95% confidence interval 1.06–1.17, p <
0.0001). Intraocular pressure fluctuation however was not
related to progression (hazard ratio = 1.00, 95% confidence
interval 0.81–1.24, p = 0.999).29
CIGTS
The trial compared the long-term effects of treating newly
diagnosed POAG patients with the conventional approach
of topical pharmacologic agents or by immediate filtration
surgery.108 The CIGTS was a randomized, controlled trial
that randomized a total of 607 patients with an intraocular
pressure >20 mm-Hg and evidence of optic nerve damage
and/or visual field loss to receive either a stepped medica-
tion treatment regimen or filtration surgery to control their
OAG. All patients were seen postoperatively and for follow-
up examinations at 3 and 6 months after treatment and
every 6 months thereafter. The 5-year results showed
both treatment groups had substantial and sustained
reductions in IOP from baseline with the surgical group
running IOPs about 2–3 points lower than the medical
group. The surgical group had more visual field loss
and more visual acuity loss in the first 3 years of the
study, but these differences largely disappeared in years 4
and 5 of follow-up. The surgery group had more cataract
extractions than the medical group. The surgery group
reported more local eye symptoms, but most of the symp-
toms disappeared beyond 3 years of follow-up. The medical
group reported a variety of systemic symptoms. Results
from CIGTS do not support altering current treatment prac-
tices in the initial management of patients with primary
open-angle glaucoma.109
AGIS
In advanced glaucoma, medications alone frequently do not
reduce IOP to the set target. Many patients over time require
several therapeutic interventions for control of their glau-
coma. The AGIS assessed the long-term outcomes of
sequences of interventions involving trabeculectomy and
argon laser trabeculoplasty in eyes that have failed initial
Follow-up Outcome
5 years Probability of POAG:
Treated 4.4%
Untreated 9.5%
7 years Glaucoma progression:
Treated 12%
Untreated 35%
5 years POAG progression:
Treated 45%
Untreated 62%
4+ years No significant difference in visual field loss
between the medically and surgically
treated patients
10 years (ongoing) Visual function outcomes better in ATT
sequence in Blacks and better in TAT
sequence in Whites
343.e2 SECTION 4 • Types of Glaucoma
medical treatment for glaucoma.110 A total of 789 eyes with
advanced glaucoma were enrolled. All patients were fol-
lowed under a standardized protocol for a minimum of 5
years to determine the degree of visual function loss, failure
rates of interventions, rates of complications, and need for
supplemental therapy.
Eligible eyes were randomly assigned to one of two inter-
vention sequences:
1. Trabeculectomy, followed by argon laser trabeculoplasty
(ALT) if trabeculectomy failed, followed by a second trab-
eculectomy if ALT failed (TAT).
2. ALT, followed by trabeculectomy if ALT failed, followed
by another trabeculectomy if the first trabeculectomy
failed (ATT).
Antifibrosis agents were used as an adjunct to trabeculec-
tomy, but only in eyes with a previous history of invasive
surgery.
After 10 years of follow-up AGIS results revealed a differ-
ence between Blacks and Whites in the way they benefited
from the two treatment sequences. In black patients vision
tended to be better preserved in the ATT regimen. In white
patients after 18 months the average percent of eyes with
VF loss was less in the TAT sequence, a difference that
increased and became statistically significant in years 8 to
10. In both black and white patients, average IOP reduc-
tions were greater in the TAT sequence and the first-
intervention failure rates were substantially lower for
trabeculectomy than for trabeculoplasty. The 10-year
cumulative incidence of unilateral visual field impairment
comparable to legal blindness was modest in eyes of black
(ATT 11.9%, TAT 18.5%) and white (ATT 9.9%, TAT 7.3%)
patients. Thus although IOP was lowered in both sequences
in black and white patients, the long-term visual function
outcomes were better for the ATT sequence in black patients,
and better in the TAT sequence in white patients.94
Eyes with IOP less than 18 mmHg in 100% of visits over
6 years had mean changes from baseline in visual field
defect score close to zero compared to eyes with less
than 50% of visits with IOP less than 18 mmHg that had
an estimated worsening over follow-up of 0.63 units of
visual field defect score (p = 0.083).92 Accordingly, even
though the AGIS results did not heavily impact current
clinical practices the analysis of IOP effects supported the
evidence on the protective role of low IOP on visual field
deterioration.
344 SECTION 4 • Types of Glaucoma
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