Risk factors for primary open-angle glaucoma in Filipinos

GLAUCOMA afflicts more than 67 million people
worldwide, of whom about 10% are estimated to be blind.
1
It is the leading cause of irreversible blindness worldwide
and is second to cataract as the most common cause of
blindness in the developing world.
2
Even though
economic data on the cost of glaucoma are limited, it is
believed that the social and economic impact of glaucoma
is enormous. With increasing costs of medication,
consultation, and an aging population, the impact of
glaucoma is likely to increase and become a public-health
problem.
The Third National Survey on Blindness in the Philippines showed that glaucoma is the third major cause of
visual impairment, after cataract and refractive error, with
a prevalence of 3%.
3
This translates to approximately 2.38
million Filipinos who have visual impairment from
glaucoma in at least one eye.
To reduce the incidence of blindness from glaucoma,
screening large population has been suggested, but it is
costly and likely to yield false-positive and false-negative
errors. This is because the diagnosis of glaucoma in its
early stage is not straightforward and requires correlation
with structural changes in the optic-nerve head (ONH)
and functional defects in the visual field. Documenting
both structural and functional changes in a large
population requires expensive special equipment and
time-consuming procedures. Obtaining a single
intraocular-pressure ( IOP) measurement has only
moderate sensitivity and low specificity. In the Baltimore
Eye Survey (BES), less than half of those with diagnosed
glaucoma had IOP greater than 21.
4
Thus, using IOP
measurement as a screening tool is not sensitive enough
to detect majority of those at risk of developing glaucoma.
There are many factors that can affect the causation of
glaucoma. The literature has identified age,
5-10
elevated
IOP,
11-17
race,
6,18-21
and family history
22-27
with strong
supporting evidence as risk factors for primary open-angle
glaucoma (POAG). Increasing age is associated with a
higher incidence of the disease as shown in most
population-based studies. Clinical and experimental
studies have also shown that elevated IOP beyond a critical
level also leads to glaucomatous optic-nerve damage. An
individual’s susceptibility to the disease is influenced by
his genetic makeup, i.e. family history of the disease, as
supported by studies on twins and siblings. But the
expression of the susceptibility varies. Many glaucoma
patients deny any family history. This implies that there
are other factors that influence this susceptibility.
Other factors that can influence the development of
glaucoma are vascular in nature, supporting the contention
that ischemia is another mechanism by which glaucoma
damage can occur. Such conditions are systemic
hypertension,
28-34
diabetes mellitus,
35-42
thyroid diseases,
43-47
and migraine.
48-53
Literature review of these factors presents
conflicting data.
Myopia, specifically high myopia, has also been shown
to have an increased prevalence of POAG, possibly due to
the altered rigidity of the sclera at the level of the lamina
cribrosa
54-57
seen in an elongated eyeball. The relationship,
however, is confusing.
Screening those at risk for developing glaucoma is likely
to be more cost-effective. Hence, we determined the risk
factors (probability of an individual at risk of developing
the disease) for POAG in Filipinos. We evaluated whether
the following parameters are risk factors: (1) age, (2) sex,
(3) refractive error, (4) diabetes mellitus, (5) systemic
hypertension and other cardiovascular disorder, (6)
thyroid diseases, (7) migraine, (8) family history of
glaucoma, (9) smoking, (10) alcohol consumption.

METHODOLOGY
Glaucoma patients seen at the Glaucoma Clinic of the
Department of Ophthalmology, University of the
Philippines-Philippine General Hospital (UP-PGH) were
recruited to participate in the study after informed
consent was obtained. They were recruited as they come,
consecutive and purposive. They were defined as having
POAG based on the following inclusion criteria: (1) 40
years of age and older; (2) open angles on gonioscopy,
and (3) definitive glaucomatous optic neuropathy (GON)
based on the presence of at least one visual field and one
optic-disc criteria in at least one eye after ophthalmologic
exclusion on narrow angles, other types of glaucoma, and
other possible causes.
The visual-field criteria consisted of the following: (1)
distinctive glaucomatous visual field defects on 24–2 or
30–2 threshold test of the Humphrey perimeter; (2) if
visual-field threshold test could not be performed, other
test strategy such as full-field, 120-degree suprathreshold
test or kinetic perimetry may be done and there was
evidence of glaucomatous visual-field loss such as blindness
or severe visual impairment.
The optic-disc criteria consisted of the following: (1)
at least 2 signs of optic-disc damage present in fundus
photographs and/or ophthalmologic examination, such
as notching with associated neuroretinal-rim narrowing,
nonconformity of the ISNT
58
rule, prominent β-zone
peripapillary atrophy associated with neuroretinal-rim
thinning, disc hemorrhage, focal retinal-nerve-fiber-layer
(RNFL) defect, and asymmetry in cup-disc (CD) ratios
between eyes of more than 0.2; (2) if photographs were
not available, the ophthalmologic examination or other
clinical records documenting GON.
The ophthalmologic criteria consisted of the following:
(1) clinical POAG diagnosis after examination by the
ophthalmologist; the diagnosis was based on the
assessment of disc and field changes, not on IOP, after
excluding other causes; (2) confirmation of previous
clinical POAG diagnosis and treatment through record
review for participants who did not complete the
ophthalmologic examination.
The following were excluded: less than 40 years of age;
narrow or closed angle on gonioscopy; secondary types of
glaucoma, such as pseudoexfoliation, pigmentary, uveitic,
pseudophakic, aphakic, hemolytic, steroid-induced, angle
recession or traumatic glaucoma; angle-closure glaucoma;
congenital, developmental, or juvenile glaucoma.
The study protocol was reviewed and approved by the
Ethics Review Board of UP-PGH.

Recruitment of cases and controls
Glaucoma patients seen at the Glaucoma Clinic of UPPGH were recruited. On the day of their visit to the clinic,
their medical records consisting of prior eye evaluations
and previous automated perimetry were reviewed to
determine eligibility. This initial screening established the
presence or absence of POAG and inclusion as cases in
the study. Patients with either eye satisfying the inclusion criteria were included in the study.
Control subjects were recruited at UP-PGH. They
consisted largely of companions (“bantays”) of patients
seen at the eye department.
Controls were defined based on the following: 40 years
or older, open angle on gonioscopy with no evidence of
glaucoma of any type and normal visual-field and opticnerve-head findings. Those with narrow or closed angle
on gonioscopy, and less than 40 years of age, and “bantay”
of cases were excluded.
Informed consent was obtained from all eligible participants following the tenets of the Declaration of Helsinki.
The risks and benefits of the study and the procedures to
be done were explained.
Each underwent a comprehensive eye examination
consisting of the following: determination of best-
corrected visual acuity with refraction, applanation
tonometry, slitlamp biomicroscopy, gonioscopy, and
fundus evaluation. In addition, a questionnaire interviewv was performed by the same interviewer who was masked
as to the status of the eye findings and diagnosis. All
participants also underwent automated perimetry with the
Humphrey Field Analyzer (Carl Zeiss, San Dublin, CA,
USA) testing the threshold of the central 30-degree field.
The pupils were dilated for optic-disc photography.
All data were entered into a standard data collection form
by the examining ophthalmologist and the questionnaire
interviewer. All forms were further reviewed by a research
associate for consistency and completion. Coding was
performed for each parameter and data were entered into
MS Excel (Microsoft Corporation, Redmond, WA, USA).
The optic-disc photographs were graded by two
glaucoma specialists as to the presence or absence of
GON. The visual fields were assessed by the same
specialists as to the presence or absence of definite
glaucomatous field defect, following the minimum
criteria set in the American Academy of Ophthalmology
Preferred Practice Pattern.
59
The following risk factors were included in the
questionnaire interview adopted from the BES
22
and the
Beaver Dam Eye Study:
60
1. Family history of glaucoma in parents, siblings, children.
Participants were asked to identify their first-degree
relatives and whether each had a history of glaucoma. Only
positive responses were accepted as a positive history in
the relative. Negative answers or “don’t know” responses
were considered negative.
2. Smoking history. Participants were asked in the
interview if they currently smoke or had ever smoked
greater than 100 cigarettes, and if so, how many cigarettes
were smoked daily, for how many months and date of
stopping. For categorical analyses, participants who
smoked were classified as past or current smokers.
3. Alcohol use was determined by subdividing participants
into current drinkers (any positive response for drinking
in the past year) and current nondrinkers for each alcohol
type (beer, wine, and liquor).
4. Refractive error for each participant was based on bestcorrected spectacle correction using the spherical part of
the prescription.
5. Cardiovascular diseases such as essential hypertension,
ischemic heart disease, carotid-artery stenosis were
considered present if the participant was being treated
for such conditions with specific medications or had
specific laboratory exams that were positive, or based on
medical records or confirmation with the medical doctor.
Current systemic hypertension was defined as blood
pressure taken on two separate determinations greater
than or equal to 140 mm Hg systolic or 90 mm Hg diastolic
with or without medications.
6. Diabetes mellitus was defined as either a history of
diabetes treated with insulin or oral hypoglycemic agents
and/or diet, or glycosylated hemoglobin level greater than
two standard deviations above the mean of the relevant
age-sex group and a random blood-sugar level greater than
11.1 mmol/l.
7. Thyroid disease was checked from the interview
questionnaire and confirmed by the treating physician. Any
“don’t know” or “not sure” responses that could not be
verified by the treating physician were considered negative.
8. Migraine headaches were obtained from the questionnaire interview asking for specific questions as any
recurrent, severe or pulsating headaches that is unilateral
in character and may be associated with nausea, vomiting,
photophobia, and/or sometimes visual disturbance,
occurring in the past. A history of migraine headaches
was considered positive if it occurred more than 1 year
from the initial diagnosis of glaucoma to differentiate
associated ocular pain from elevated IOP of glaucoma.

Statistical methods
To determine the risk factors of POAG, multivariate
logistic regression analysis was performed with Stata
Release 6 (Stata Corporation, TX, USA) to identify the
effects of each variable adjusting for the effects of other
variables. Significance of the variables to be retained or
removed from the model was judged using the Likelihood
Ratio Test (LRT).

RESULTS
A total of 365 participants (164 males, 201 females)
examined from June 2001 to July 2005 were included in
the study. Mean age was 58.7 years. There were 193
controls (no glaucoma) and 172 cases with confirmed
POAG. The participants with glaucoma were older, with a
mean age of 62.1 years. Both sexes were equally affected.
Those with glaucoma also had poorer visual acuity, with
mean of 0.82 (20/25). More myopia was seen in those
with glaucoma, with a wider spread toward the higher
myopic refraction. Larger optic cupping, with a mean of
0.68, and higher values (or worse) for the global indices
(mean defect and corrected pattern standard deviation)
in the visual field were seen in the glaucoma group,
indicating GON (Table 1). The IOPs in both groups were
similar.
Univariate analysis showed that older age, worse visual
acuity, larger vertical cupping, and worse visual-field mean
defect were associated with POAG (Table 2). Those 60
years of age and over have an increased risk of having
POAG than those less than 60 years. For every increase in
age after 65 years, there is a 6% increase in risk per year
for developing POAG. For each unit decrease in visual
acuity as measured using the decimal system, there was
an almost 3 times increased association with POAG.
Enlarged vertical cupping of the optic disc, specifically
0.7 or greater, showed 5 times increased risk of association
with POAG. Likewise, for every decibel increase in mean
defect in the visual field, there was a 29% risk of association
with POAG.
The multivariate analysis showed the persistent effects
of global indices or higher mean defect and pattern
standard deviation of the visual field, indicating strong
association with POAG (Table 3). For every increase in
decibel of the pattern standard deviation, there was a 45%
increased risk of association with glaucoma.
Of the systemic diseases studied, including family
history of major medical conditions, only family history
of hypertension was strongly associated with POAG, with
2.5 odds of increased association with glaucoma. Smoking
and alcohol consumption were not associated with POAG.

DISCUSSION
Many chronic diseases, including POAG, are associated
with aging. This study showed that those over 60 years of
age are more likely to have glaucoma than those less than
60. For every increase in age after 65 years, there is a 6%
increase in the risk per year for developing POAG. All
population-based studies on prevalence and incidence
consistently show a steady increase with age,
5-8
with a doubling of the prevalence per decade. The effect of age
seemingly disappeared when other factors such as worse
visual-field mean defect and pattern standard deviation
were included in the model, both of which showed much
stronger association with POAG. The relatively younger
age (mean 62.5, median 64.5) of the glaucoma group in
this study could have resulted in a relatively weaker effect
of age on the risk of developing glaucoma compared to
other studies. Nevertheless, the effect of age in this
population was highly significant in the univariate analysis
(Table 2).
There was no predilection of POAG for either sex in
this study even though more females participated in both
groups. Among the population-based surveys done in the
last two decades, the Barbados Eye Study showed male
gender to be a major risk factor for POAG among its
predominantly black population.
29
Poorer visual acuity had almost 3 times the risk of
association with POAG. Many in the glaucoma group had
advanced glaucoma associated with poorer vision (less
than 20/40) and large visual-field defects.
The type of refractive error was not associated with
POAG even though there were more participants with
myopia in the glaucoma group. Distribution of the
refractive errors in both groups showed the same spread
of refraction, with majority of those in the control group
having 20/20 (6/6) vision and those in the glaucoma group
having low myopic refraction. Several case series
54-55
and
case-control studies
56-57
have reported an association of
POAG with myopia, particularly high myopia, which is
supported by several population-based prevalence
surveys
61-63
reporting a prevalence of POAG in those with
myopia ranging from 48 to 70%. However, individuals with
myopia were not found to have a higher incidence or
progression of glaucoma in the OHTS
64
or EMGT
42
respectively. A possible explanation for the difference is
that studies reporting associations have a higher prevalence of high myopia (≥ 6.0D). The participants in the
glaucoma group in this study have low myopia (≤ 3.0D)
with a mean of only –0.48D.
A vertical cupping greater than 0.7 was associated with
five times increased risk of developing POAG, significantly
shown in the univariate analysis (Table 2). This effect was
not seen in the multivariate analysis as the influence of
visual-field defect was much stronger. Moreover, there were
many in the normal group with large optic discs which
were associated with larger optic cups. More than half in
the normal group had vertical cupping between 0.5 to
0.7 with a mean of 0.54. In the glaucoma group, the mean
was approximately 0.7 with majority greater than or equal
to 0.7. Numerous studies have reported increased
incidence of glaucomatous visual-field defects among
those with larger CD ratios.
64-67
More recently, the OHTS
showed a 1.4-fold increase in the incidence of POAG
among ocular-hypertensive patients for every 0.1 unit
increase in the baseline CD ratio.
64
Caution, however,
should be exercised in the interpretation of studies that
use ONH parameters (i.e., CD ratio, vertical-disc diameter,
disc area) to define glaucoma. The estimates may be
inflated because the criteria for defining POAG may be
inherent in the parameter itself, such as defining glaucoma
as those with C/D ratio greater than 0.7.
Other ONH parameters, such as the presence of β-zone
peripapillary atrophy and disc hemorrhages, have received
attention in the glaucoma literature. In this study, none
in the glaucoma group was noted to have disc hemorrhage,
either examined clinically or in the disc photographs. The
prevalence of disc hemorrhage in glaucoma was reported
to be less than 30%68
and more common in normal-tension
than high-tension glaucoma. Disc hemorrhages are
evanescent and may easily be overlooked unless specifically
looked for. Moreover, its presence is a sign of active
progression of the disease. All glaucoma patients in this
study were already on glaucoma treatment or had filtering
surgery. The mean IOP in the glaucoma group was 13.0
versus 12.6 mm Hg for control, with slightly higher
standard deviation in the glaucoma group but with similar
range. With IOP less than 25 mm Hg in the glaucoma
group, the presence of disc hemorrhage was unlikely.
Observation for β-zone peripapillary atrophy was not done
in this study.
Worse global indices (higher mean defects and pattern
standard deviations) used to characterize the visual-field
defects were seen in the glaucoma group. The standard
deviations were wide depicting the range of field defects
in this group—from early to the advanced stage. Some of
the changes in the early stage may be due to short-term
fluctuations that were also present in the control group.
One of the limitations in this study was that a single field
was obtained. For a reliable diagnosis, a series of fields
should be obtained to eliminate the effect of learning curve.
Many studies in the past have shown consistent
association between IOP and glaucoma but it was only
recently that a strong dose-response relationship has been
shown in prev a lence sur vey s
4-7, 29, 32, 36, 39, 69-70
and in
longitudinal studies of incidence
17, 20, 25, 71
and progression.
71
The most decisive new evidence was the demonstration by
randomized clinical trials that IOP lowering decreased the
incidence
17
and progression of glaucoma
15-16
compared to
no treatment. In addition, there is support for at least one
biologic mechanism that links elevated IOP to apoptosis of
neurons of the optic nerve through blockage of retrograde
axonal transport.
72-73
Thus, IOP is both a risk factor for and
a cause of glaucoma. This study was not able to demonstrate
IOP as a risk factor primarily because the participants in
the glaucoma group had already been treated either
medically or surgically, such that the IOP range is similar
to that of the control group.
Other risk factors considered were systemic diseases
such as diabetes, hypertension, thyroid disease, migraine,
use of specific medications, and family history of the
systemic diseases mentioned earlier. None had significant
association except for family history of hypertension
(OR=2.58). A major limitation of questionnaire interview
is the relative inaccuracy of the participants’ responses.
Studies have shown that recall by patients versus actual
tests or confirmations by the primary-care physicians have
large discrepancies. There were attempts to contact the
attending doctors but the response rate was rather low,
with many patients not having a permanent one.
Family history of glaucoma did not show any significant
association with POAG in this study. Other studies have
reported a relative risk between 2 and 4 for first-degree
relatives.
22, 74-76
The odds ratio was higher if based on
patients with previously diagnosed glaucoma than if based
on newly detected cases,
76
suggesting that having a
diagnosis of POAG leads to a greater awareness of
glaucoma in the family. The population in this study was
from the lower socioeconomic group who were most likely
not as knowledgeable about their general health and that
of their family. Moreover, they were less likely to seek
medical consultation for an asymptomatic condition until
late in the course of the disease. Hence, the accuracy of
patients’ responses in the questionnaire interview may be
less reliable. Requesting examination of first-degree
relatives of participants is preferred but time-consuming.
Genetic-linkage studies are also more accurate but
expensive.
Limitations of this study include biases inherent in a
case-control study, such as the selection of cases and
controls. Both were drawn from the same population—
those who went to PGH for their health needs. Companions (“bantays”) were recruited as controls since several
ophthalmic factors were studied in association with POAG
and those seeking eye care were more likely to have a
higher prevalence of eye problems. Attempt at age
matching was done initially at the start of the study to
remove the effect of aging on systemic diseases and
glaucoma, but there was difficulty recruiting older
controls, especially those greater than 70 years with mild
to no cataract and no other ocular problems. The
recruitment of controls was done consecutively as they
come, similar to the glaucoma group, and the result was a
much younger control. For studying relatively rare diseases
such as glaucoma, a case-control study design is most
practical and economical and the information gathered
could provide the basis for future population studies.
In summary, the causes of POAG are multiple and
complex. Determining the risk factors for the disease is
necessary to identify the target population that needed
to be screened, such as the elderly (those older than 60),
those with poorer visual acuity, elevated IOP, worse global
indices on visual-field tests, large vertical disc cupping,
and family history of hypertension to prevent irreversible
blindness.