AUGUST 2007
PART 2 OF 2
Supported by an unrestricted
educational grant from
1 | Introduction
I would like to welcome you to the third edition of the Glaucoma
Handbook, a publication developed under the auspices of the
Optometric Glaucoma Society (OGS). This handbook is meant to
serve as a guide to the diagnosis and management of glaucoma.
The material includes a review of basics in regards to glaucoma diagnosis
and therapy while providing new insights into the condition.
Our goal with each new edition is to keep the material fresh
and up-to-date. In certain sections, there is a great deal of new information;
and in others, little has changed. Thus, certain chapters
are brand new and others have been updated. The new
sections for this issue relate to angle closure glaucoma and intraocular
pressure, while the chapter on new technology has been
updated significantly with the introduction of spectral optical coherence
tomographers.
Instruments that take an image of the optic nerve and retinal nerve
fiber layer have been available for 15 years, with significant changes occurring
approximately every 5­6 years. Beginning with confocal scanning
laser ophthalmoscopy, refinements led to the introduction of confocal
scanning laser polarimetry. Optical Coherence Tomography has been available
for a decade with the most recent version, the Stratus OCT, introduced
in 2002. The next version of the OCT is being introduced by not one but
several companies, who will push each other to develop the best instrument
possible. The newest OCTs use Fourier-Domain technology (also called
Spectral detection), which allows the entire A-Scan to be acquired at one
time rather than being done over a period of time. This leads to faster imaging
speed, allowing for a greater amount of information to be obtained
in shorter periods, with greater resolution. Retinal histologic details are
apparent with Spectral OCT which will allow for improved diagnosis of
glaucoma as well as other conditions. This development will be discussed
in Chapter 4.
A great deal of new information has recently become available in regards
to intraocular pressure (IOP). Much of what was once taken for granted
in regards to IOP is being evaluated again, such when it is highest and
what are the best tools to measure it. Recent work has highlighted IOP
fluctuation may not be the risk factor previously described, in part due to
the design of previous studies. Issues of corneal thickness and rigidity are
now better understood and, in particular, how they impact on IOP measurements.
The Association of International Glaucoma Societies (AIGS) held
a consensus meeting on intraocular pressure in May 2007, gathering experts
from around the world to discuss this subject. Highlights from this
meeting are available at www.globalaigs.org. Chapter 3 discusses new
thoughts in regards to IOP, and how we should incorporate this information
into our decision making process.
Angle closure glaucoma (ACG) has been described for as long as papers
have been written about glaucoma. Still, it is only recently that we have
come to understand the natural history and mechanisms, its severity, and
how common it is in certain populations. Most optometrists are under the
impression that sudden eye pain and intense symptoms are the classic
ways that ACG presents. In reality, chronic angle closure glaucoma is the
most common form of ACG, with elevated IOP and an extremely narrow angle
being present but devoid of symptoms. Gonioscopy is the only way one
can differentiate closed from open angle glaucoma, with the prognosis dependent
upon the proper diagnosis. The AIGS convened a consensus meeting
on angle closure glaucoma in May 2006 with highlights also available
online at www.globalaigs.org. Chapter 12 discusses new information in regard
to ACG and important points that optometrists should consider whenever
one encounters patients with elevated IOP.
I would like to thank the members of the OGS for their support and
help in developing these materials. Also, I would like to recommend the
OGS on-line e-journal, which is available free of charge. One may sign up
for this at www.optometricglaucomasociety.org. On behalf of the OGS, I
would like to thank our team of authors, who have contributed to this
effort. I would specifically like to welcome the new authors for this edition,
David Friedman, Albert Khouri and David Pye. I would also like to
thank Karen Fixler, Jill Burdge and Dennis Kowloski from Pfizer for their
continuing support of the OGS, and specifically for the unrestricted grant
that allowed us to continue with this publication. We hope that you find
this handbook useful.
Murray Fingeret, OD
President, Optometric Glaucoma Society
Editor, The Glaucoma Handbook
22 RREEVVIIEEWW OOFF OOPPTTOOMMEETTRRYY//OOPPTTOOMMEETTRRIICC GGLLAAUUCCOOMMAA SSOOCCIIEETTYY
CHAPTERS
1 | Introduction
Murray Fingeret, OD
2 | The Diagnosis of Glaucoma
John G. Flanagan, PhD, MCOptom
3 | New Thoughts on Tonometry and
Intraocular Pressure
David Pye, MOptom
4 | New Technologies in the Diagnosis
and Management of Glaucoma
John G. Flanagan, PhD, MCOptom
5 | Risk Assessment as an Emerging
Tool for Glaucoma Care
Robert D. Fechtner, MD, Albert S. Khouri, MD,
and Murray Fingeret, OD
6 | Understanding Glaucoma
Medications
Murray Fingeret, OD
7 | The Management of Glaucoma
Murray Fingeret, OD
8 | When Medical Therapy Fails: Surgical
Options for Glaucoma Management
Kathy Yang-Williams, OD
9 | Adherence in Glaucoma Therapy
Steven R. Hahn, MD
10 | Communication in the Management
of Glaucoma
Steven R. Hahn, MD
11 | Secondary Glaucomas
Mitchell W. Dul, OD, MS
12 | Primary Angle Closure Glaucoma
David S. Friedman, MD
OOPPTTOOMMEETTRRIICC GGLLAAUUCCOOMMAA SSOOCCIIEETTYY//RREEVVIIEEWW OOFF OOPPTTOOMMEETTRRYY 33
2 | The Diagnosis of Glaucoma
John G. Flanagan, PhD, MCOptom
Most glaucomas are asymptomatic until the late stages of the
disease, and therefore a careful, comprehensive eye examination,
including history, is essential to the early diagnosis. The majority
of information important in the patienťs history relates to our
knowledge of the disease's epidemiology and risk factor analyses.
Age and race have clear clinical implications for the risk of developing
glaucoma, with peoples of African descent showing a four to
five times greater prevalence, a higher risk of blindness and a tendency
to be diagnosed at a younger age. More recently it has been
shown that while younger Hispanic-Americans develop primary
open-angle glaucoma (POAG) at a rate similar to Caucasian-Americans,
the ratio increases dramatically in older age, eventually exceeding
even African-American rates after the age of 75.
Pigmentary glaucoma is more common in Caucasians, as is exfoliative
glaucoma--the latter appearing to cluster in certain regions;
for example, the Scandinavian countries. Age and ethnicity are also
important in regard to the angle closure glaucomas, which will be
discussed in Chapter 12. Older age, as well as individuals of Asian
heritage, are risk factors for the development of this condition.
Family history is well established as a risk factor for glaucoma.
Having a sibling with glaucoma increases a person's chance of developing
POAG 3.7-fold, according to some evidence. The prevalence
of POAG in people having a first-degree relative with POAG
is estimated to be between 4% and 16%. Up to 25% of patients
with glaucoma are reported to have a positive family history. The
overall proportion of POAG attributable to genetics is thought to
be around 16%.
Ocular history is very important, as well. An essential aspect of
any initial glaucoma diagnosis is a careful review of previous ocular
findings. Ocular hypertension is strongly associated with an increased
risk of POAG, as are specific aspects of the optic nerve and
nerve fiber layer appearance. Of less diagnostic
importance, but still worth
documenting, are myopia and a history
of systemic disease such as diabetes
mellitus, systemic hypertension, vasospastic
disease, autoimmune disease
and severe hypotension.
TONOMETRY
Intraocular pressure (IOP) remains
the single most important risk factor for
the development of glaucomatous optic
neuropathy, and its measurement is vital
in the initial diagnosis and management
of the glaucomas. It is also the
only major risk factor that can be treated.
In recognition of its clinical importance,
this edition of the Handbook
includes a new chapter dedicated to
Tonometry and IOP (see Chapter 3).
PACHYMETRY
The measurement of corneal thickness, or pachymetry, is generally
performed by an ultrasonic device. It should be measured in
both eyes prior to gonioscopy, preferably before dilation, and at
least two hours after awakening. Additional consideration should
be given to the stability of the cornea and pachymetry readings following
contact lens wear, cataract, corneal or refractive surgery.
The ultrasound probe should be held perpendicular to the cornea
and centered on the pupil. Take a minimum of three readings and
ensure a standard deviation of 5 microns or less. Device name and
time of day should also be recorded.
The normal population mean value for corneal thickness when
measured by ultrasound pachymetry is thought to be 544 34 microns.
Various correction factors for the influence of central corneal
thickness (CCT) on IOP have been proposed, but should be considered
guidelines rather than absolute corrections. Most corrections
are based on values of between 2.5mmHg and 3.5mmHg per 50 microns
of CCT from 545 microns. However, it should be noted that the
effect is not linear; on thinner corneas, the greater the deviation,
the greater the effect. It is increasingly likely that corneal thickness
itself is a risk factor for POAG, independent of its tendency to skew
tonometry results. The Ocular Hypertension Treatment Study
(OHTS) suggested that the influence of CCT as a risk factor was
much greater than that predicted by simply correcting the IOP reading
for thickness. The relative risk of disease progression per 40 microns
of CCT was shown to be 1.71; and the relative risk per 1mmHg
of elevated IOP was 1.10. Forty microns would generally be corrected
as being equivalent to less than 3mmHg. Therefore, if corneal
thickness is viewed only in terms of affecting pressure readings, at
least 40% of the relative risk would be unaccounted for.
GONIOSCOPY
The careful examination of the anterior chamber angle is essential
in evaluating glaucoma suspects and diagnosing glaucoma.
The process is called gonioscopy. Gonioscopy enables the visualization
of the anterior angle and its assessment
permits the exclusion of
angle closure, angle recession, plateau
iris or secondary angle block as the
cause of raised IOP. Gonioscopy is most
commonly performed indirectly by using
a contact lens with a mirror system
that overcomes the inherent total internal
reflection of the angle anatomy.
The angle is graded to relate information
of its visible anatomical features.
Several new, non-contact OCT devices
can be used to evaluate the angle;
these include the Visante (Carl Zeiss
Meditec) and the Slit Lamp (SL)-OCT
(Heidelberg Engineering) (Figure 1).
Although considerably more expensive
than a classic contact goniolens, they
have the advantage of being objective
and quantitative.
1. The anterior chamber as viewed using the Visante OCT. In the top
image, the angle is wide open; while in the bottom image, the angle is
narrow. (Used with permission Carl Zeiss Meditec, Inc.)
STRUCTURE
Evaluation of the optic nerve head and nerve fiber layer (NFL) is
important in identifying early structural damage. Such structural
changes frequently occur prior to the presence of repeatable visual
function deficits. Clinical evaluation should be performed at the
slit lamp using a magnified, stereoscopic view through a dilated
pupil. The lens should be handheld. Perform careful, systematic
documentation of the neuroretinal rim, including evaluation based
on the ISN'T mnemonic device. That is, healthy rim tissue should
always be thicker in the inferior (I) region, followed in decreasing
thickness by the superior (S), nasal (N) and temporal (T) regions.
It has recently been suggested that this clinical schema performs
better if the nasal quadrant is ignored, owing to the obscuration of
the nasal rim tissue by the nerve head vasculature, resulting in the
IST device. Other observations that require documentation include:
focal thinning of the rim tissue, vertical elongation of the cup,
concentric enlargement of the cup, increased cup depth, saucerization,
disc asymmetry, beta-zone parapapillary atrophy and vascular
signs such as disc hemorrhage, focal narrowing, baring of circumlinear
vessels, bayoneting and nasalization of the vascular tree. The
size of the optic disc needs to be evaluated because the cup size
correlates directly with the optic disc size. In a healthy individual,
the larger the optic disc, the larger the optic cup. The disc size may
be qualitatively measured with the small spot of a direct ophthalmoscope,
with a fundus lens at the slit lamp or with an optic nerve
imaging instrument. Practitioners should use a red-free filter to
evaluate the nerve fiber layer (NFL) within two disc diameters of the
optic nerve. However, it should be noted that modern digital fundus
cameras give unprecedented images of the nerve fiber layer and are
highly recommended. Several grading systems have been suggested,
with the aim of evaluating the level of diffuse NFL atrophy and the
identification of localized wedge or slit defects.
FUNCTION
Visual function is generally evaluated by measuring the visual
field via standard automated perimetry. In glaucoma, the central
vision is not affected until late in the disease process. Consequently,
there is little diagnostic value in evaluating only central visual
function by way of visual acuity. Clinical evaluation of automated
perimetry charts remains a standard for the detection of glaucoma.
Typical glaucomatous visual field defects were first described by
von Graefe in 1869 and result from apoptotic death of the retinal
ganglion cells. The field defects reflect damage to the NFL bundles
as they track toward the optic nerve, although the site of damage
is thought to be at the level of the lamina cribrosa within the optic
nerve. Classic defects include early isolated paracentral, arcuate,
nasal step and occasional temporal wedge defects. It is likely that
a generalized defect due to diffuse loss of axons is present in many
glaucomatous visual fields, but such defects have limited diagnostic
value, as they are difficult to distinguish from the effects of media
opacity and pupil size.
The standard clinical application of static threshold automated
perimetry entails the assessment of the central 30 degrees. A variety
of threshold estimation algorithms are available, with the newer,
faster strategies based on Baysian methods--for example, the
SITA strategy found on the Humphrey Field Analyzer (HFA). It is
important to re-test abnormal-looking visual fields to ensure repeatability,
particularly in the nave patient, as there is a clearly
defined learning curve that can mimic early defects. Interpretation
can be aided by statistical packages that analyze the data relative
to age-matched normal values (Total Deviation), and scan for focal
defects by removing the influence of diffuse loss (Pattern Deviation).
There are also analyses that judge subjects' intra-test reliability
and the symmetry between the upper and lower field, such
as the glaucoma hemifield test. It is essential to establish good
quality baseline data for both the early diagnosis and the management
of manifest disease. There are several specific analyses for
glaucomatous progression, the most common being the Humphrey
Field Analyzer's Glaucoma Progression Analysis (GPA). The analysis
empirically compares serial fields to results collected in a group of
patients with stable glaucoma. The original application used agematched
normal data to perform the analysis (Total Deviation), but
the Early Manifest Glaucoma Trial found results to be more accurate
when based on the Pattern Deviation analysis, by reducing the influence
of diffuse loss.
The relationship between structure and function has gained
much recent attention and is clearly not as simple as many would
hope. However, it is inevitable that we will soon be considering the
complexities of this relationship when attempting to diagnose and
manage our patients with glaucoma. Indeed, the first available
combined analysis of structure and function was recently launched
by Heidelberg Instruments by combining results from the Heidelberg
Retina Tomograph (HRT3) and the Heidelberg Edge Perimeter
(HEP) (see Chapter 4).
The diagnosis of glaucoma requires the clinician to perform a series
of tests, including a risk factor analysis, measurement of IOP,
assessment of corneal thickness and evaluation of the anterior
chamber angle, optic nerve, retinal nerve fiber layer and visual
field. The skilled clinician will integrate these results in an attempt
to diagnose glaucoma at its earliest manifestation.
Dr. Flanagan is a Professor at both the School of Optometry, University of
Waterloo, and the Department of Ophthalmology and Vision Sciences, University
of Toronto. He is Director of the Glaucoma Research Unit, Toronto
Western Research Institute and a Senior Scientist at the Toronto Western
Hospital.
Suggested Readings
1. Epstein DL, Allingham RR, Shuman JS, eds. Chandler and Granťs Glaucoma. 4th ed.Baltimore: Lippincott
Williams and Wilkins, 1996.
2. Ritch R, Shields MB, Krupin T, eds. The Glaucomas. 2nd ed. St. Louis: CV Mosby Co, 1995.
3. Fingeret M, Lewis TL, eds. Primary Care of the Glaucomas. 2nd ed. New York: McGraw Hill. 2001.
4. Litwak AB, ed. Glaucoma Handbook. Boston: Butterworth-Heinemann. 2001.
5. Preferred Practice Patterns: Primary Open Angle Glaucoma. American Academy of Ophthalmology. 2003.
6. Karim DF, Rajeev H, Munger RM. Influence of corneal variables on accuracy of intraocular pressure measurement.
J Glaucoma. 2003. 12:1. 69-80.
7. Anderson DR, Patella VM. Automated Static Perimetry. 2nd ed. St. Louis: CV Mosby Co, 1999.
8. Medeiros FA, Sample PA, Zangwill LM, Bowd C, Aihara M, Weinreb RN. Corneal thickness as a risk factor
for visual field loss in patients with preperimetric glaucomatous optic neuropathy. Am J Ophthalmol. 2003
Nov;136(5):805-13.
9. Hawerth RS and Quigley HA. Visual field defects and retinal ganglion cell losses in patients with glaucoma.
Arch Ophthalmol. 2006;124:853-859
10. Giangiacomo A, Garway-Heath D, Caprioli J. Diagnosing glaucoma progression: Current practice and
promising technologies. Current Opinions in Ophthalmology. 2006. 17: 153-162.
11. Weinreb RN, Friedman DS, eds.Angle Closure and Angle Closure Glaucoma. Kugler Publications, The
Hague, The Netherlands. 2007.
44 RREEVVIIEEWW OOFF OOPPTTOOMMEETTRRYY//OOPPTTOOMMEETTRRIICC GGLLAAUUCCOOMMAA SSOOCCIIEETTYY
3 | New Thoughts on Tonometry and
Intraocular Pressure
David Pye, MOptom
Intraocular pressure (IOP) is a risk factor for the development of
glaucoma, though the condition may develop at any IOP level. IOP
is the only modifiable risk factor and is determined by the amount
of aqueous humor produced along with trabecular outflow,
uveoscleral outflow and episcleral venous pressure. IOP shows
greater variability in individuals with glaucoma with IOP variation
correlated with higher mean pressures, but there is insufficient evidence
to support 24-hour IOP fluctuation as an independent risk
factor. IOP is higher in individuals in the supine position, and often
peaks just before awakening.
It is now 50 years since Goldmann and Schmidt published a paper
that described a new method for measuring the intraocular
pressure of the eye. The method had considerable appeal, as the
IOP could now be measured with the patient in a seated position
at a slit lamp. The probe could be relatively easily disinfected and
perhaps, above all, the instrument appeared to be based on sound
engineering principles. However, in their paper, Goldmann and
Schmidt acknowledged that their instrument would not be accurate
in all circumstances. In the conclusion to their paper they
wrote "under conditions which differ considerably from our measurement
conditions (abnormally thick or thin corneas, for example
keratoconus, animal eyes, severe epithelial edema), errors of
several millimeters are to be expected". In spite of the above, the
Goldmann applanation tonometer (GAT) has become the International
Standard reference tonometer to which other tonometers
are to be compared.
Corneal thickness was recognized as a confounding factor for
GAT measurements in 1975 when Ehlers et al published a paper
where they performed a cannulation study on patients prior to
cataract surgery. They found that GAT overestimated the IOP of
those patients who had thick corneas and underestimated the true
IOP of those patients with thin corneas. They found a linear relationship
between the effect of central corneal thickness (CCT) and
GAT measurements, suggesting that changes of CCT of 100 microns
could affect the GAT measurements by 7mmHg. Interestingly, the
next paper published on this matter was 18 years later, in 1993,
when Whitacre published a paper that tried to emulate the Ehlers
study, but with fewer subjects. Since this time, there have been a
number of papers published using either in vivo data, meta-analysis
or theoretical models to predict the effects of CCT on GAT and,
as a result, a number of algorithms now exist which attempt to predict
the "true" IOP of a patient from CCT and GAT data.
A complicating factor is that there may be racial differences in
CCT. Whilst a difference has been demonstrated between AfricanAmerican
and Caucasian populations in the Ocular Hypertension
Treatment Study, it is difficult to compare results obtained from
other countries due to the different instruments used to measure
corneal thickness and the reported population samples. However,
the measurement of the "true" IOP of a particular patient is now
proving to be more complex than allowing for CCT alone. This was
initially discussed in a paper in
1999 by Orssengo and Pye, but
more graphically illustrated in a
paper by Liu and Roberts who
developed a theoretical model
for investigating the manner in
which the material behavior of
the cornea may affect GAT results.
Liu and Roberts used
corneal behavior data published
in the literature, and showed
that variations in Young's modulus
of the human cornea could
produce GAT measurements of
13mmHg to 30mmHg for a true
IOP of 15mmHg. At this stage,
there is no way of measuring
the biomechanical properties of the individual human cornea in
vivo, although there is a theoretical method which performs a calculation
of Young's modulus on the basis that the cornea is normally
hydrated. In other words, the use of a correction factor for GAT
based on CCT alone may be in considerable error as the biomechanical
effects of the individual cornea cannot be included in the calculation.
As a result, some authors are recommending that
pachymetry be performed on patients who are then considered to
have thin, normal or thick corneas rather than using a specific CCT
correction nomogram for GAT.
This then leads to two approaches to attempting to measure the
IOP. One is to try to measure the biomechanical behavior of the
cornea and make an allowance for these material properties to better
determine the IOP, and the second is to develop a method of
tonometry which directly measures the IOP by being able to overcome
the biomechanical influences of the cornea.
The Reichert Ocular Response Analyzer (ORA) is a non-contact
tonometer which measures the time delay between the initial applanation,
as a result of the puff of air, and the second applanation,
which occurs as the cornea begins to regain its shape as a
result of the topographical change produced by the initial stimulus.
The instrument provides a measure of the corneal behavior, and
a "corrected" IOP measurement as a result.
The Pascal tonometer has a tip with a surface contour which, it
is claimed, resembles the corneal contour when the pressure on
both sides of the probe tip is equal (Figure 1). When this is done,
it is suggested that the biomechanical effects of the cornea on IOP
are significantly reduced, if not eliminated, and the small pressure
sensor located in the probe tip then gives an accurate measure of
the IOP. There is a considerable amount of literature which suggests
that the Pascal is less affected by corneal properties than GAT.
New tonometers such as the ICare seem to perform similarly to
GAT, and other forms of tonometry using acoustic, contact lens or
infra-red technologies may appear in the future.
It is difficult to compare studies which have investigated the relative
performance of tonometers. Often the protocols vary, the statistical
analyses are different, and differing populations are used
for the studies. However, Tonnu et al compared the "repeatability
OOPPTTOOMMEETTRRIICC GGLLAAUUCCOOMMAA SSOOCCIIEETTYY//RREEVVIIEEWW OOFF OOPPTTOOMMEETTRRYY 55
Figure 1. The Pascal Dynamic Contour Tonometer
is seen with a measurement being taken.
The IOP is displayed in the digital display.
coefficient" which is a measure of how repeatable two readings taken
by the same observer will be, and found GAT to be more repeatable
than non-contact tonometry, Ocular Blood Flow Tonography
and Tonopen.
Another approach has been to investigate the effects of changes
in the biomechanical behavior of the cornea on GAT, and this was
observed clinically by Kaufman in 1975 who suggested that GAT
measurements were often grossly misleading in patients who had
only moderate amounts of corneal epithelial edema. There is also
evidence from refractive surgery that water in the cornea can significantly
reduce GAT measurements. Earlier this year, Hamilton et
al reported on the effects on GAT of corneal swelling produced by
two hours of eye closure and thick soft contact lens wear. The results
seem to suggest that, at low levels of corneal edema, the
cornea becomes stiffer and the GAT results may overestimate the
true IOP. As the cornea swells beyond 6% to 10%, the cornea may
behave as a softer tissue, artificially lowering the GAT measure-
ment.
The direct clinical implications of these results are twofold. One
is that if patients wear contact lenses, an estimation of their IOP
with GAT will be less affected by corneal material properties if the
patient does not wear their contact lenses on the day of measurement.
If this is not possible, then trying to measure the IOP of the
patient after the same period of contact lens wear at each visit may
be appropriate. The second implication of the work relates to the
diurnal variation of IOP. On eye opening, the average CCT is thicker
than it will be for the rest of the daytime, and the measured IOP
with GAT is highest. Interestingly, the CCT and IOP measured in this
fashion reduce at a similar rate over the first two hours after eye
opening, suggesting a link between the two results. The increase in
CCT alone does not explain the increased GAT result, and the soft
contact lens swelling results suggest that some of the increased IOP
measurement is due to stiffening of the corneal tissue, and it may
be that as much as half of the increased GAT measurement of IOP
on eye opening may be as a result of increased CCT and Young's
modulus of the cornea.
To reduce the corneal effects on IOP measurements obtained with
GAT, it would be advisable to ensure that the measurements are
taken after the patient has been awake with eyes open for at least
two hours.
The biomechanical behavior of the cornea has been reported to
be affected by age. Earlier this year, Elsheikh reported on in vitro
studies of human corneas that were subjected to relatively slow and
rapid rates of corneal inflation to attempt to imitate GAT and noncontact
tonometry respectively. Overall, 39 corneas were tested and
categorized into three age groups: 50-64, 65-79 and 80-95 years.
The results demonstrated that corneas exhibit a time-related behavior
to an applied stress, called viscoelasticity, and that the
corneas became stiffer with age. The suggested corneal stiffening
suggested from this work could significantly affect GAT results.
It is difficult to know what a single IOP measurement actually
means and how it should be interpreted, as there seems much more
we need to know and understand before a meaningful determination
of IOP can be made. While research into the measurement of
the true IOP continues, IOP is still an important measurement in
clinical practice.
Mr. David Pye, MOptom, is Senior Lecturer and Clinic Director at the School
of Optometry and Vision Science, University of New South Wales, Australia.
Suggested Readings
1. Goldmann H, Schmidt T. Über applanationstonometrie. Ophthalmologica. 1957;134:221-242.
2. International Standards Organization. ISO8612:2001(E): Ophthalmic Instruments-tonometers. Switzerland:copyright
office;2001.
3. Ehlers N, Bramsen T, Sperling S. Applanation tonometry and central corneal thickness. Acta Ophthalmol
(Copenhag). 1975;53:34-43.
4. Whitacre MM, Stein RA, Hassanein K. The effect of corneal thickness on applanation tonometry. Am J
Ophthalmol. 1993;115:592-296.
5. Orssengo GJ, Pye DC. Determination of the true intraocular pressure and modulus of elasticity of the human
cornea in vivo. Bull Math Biol. 1999;61:551-572.
6. Doughty MJ, Zaman ML. Human corneal thickness and its impact on the intraocular pressure measures: a
review and meta-analysis approach. Surv Ophthalmol. 2000;44:367-408.
7. Feltgen N, Leifert D, Funk J. Correlation between central corneal thickness, applanation tonometry, and
direct intracameral IOP readings. Br J Ophthalmol. 2001;85:85-87.
8. Kohlhaas M, Boehm AG, Spoerl E, Pürsten A, Grein HJ, Pillunat LE. Effect of central corneal thickness,
corneal curvature, and axial length on applanation tonometry. Arch Ophthalmol. 2006;124:471-476.
9. Liu J, Roberts C. Influence of corneal biomechanical properties on intraocular pressure measurement:
Quantitative analysis. J Cataract Refract Surg. 2005;31:146-155.
10. Brandt JD, Beiser JA, Kass MA, Gordon MO. Central corneal thickness in the Ocular Hypertension Treatment
Study (OHTS). Ophthalmology. 2001;108:1779-1788.
11. Brandt JD. Central corneal thickness, tonometry, and glaucoma risk - a guide for the perplexed. Can J
Ophthalmol. 2007;42:1-5.
12. Luce D. Determining in vivo biomechanical properties of the cornea with an ocular response analyzer. J
Cataract Refract Surg. 2005;31:156-162.
13. Kangiesser HE, Kniestedt YC, Robert YC. Dynamic Contour Tonometry: Presentation of a New Tonometer.
J Glaucoma. 2005;14:344-350.
14. Kaufmann C, Bachmann LM, Thiel MA. Comparison of dynamic contour tonometry with goldmann applanation
tonometry. Invest Ophthalmol Vis Sci. 2004;45:3118-3121.
15. Pepose J, Feigenbaum SK, Qazi MA, Sanderson JP, Roberts CJ. Changes in corneal biomechanics and intraocular
pressure following LASIK using static, dynamic, and noncontact tonometry. Am J Ophthalmol.
2007;143:39-47.
16. Brusini P, Salvetat ML, Zeppieri M, Tosoni C, Parisi L. Comparison of Icare tonometer with Goldmann applanation
tonometer in glaucoma patients. J Glaucoma. 2006;15:213-217.
17. Tonnu PA, Ho T, Sharma K, White E, Bunce C, Garway-Heath D. A comparison of four methods of
tonometry: method agreement and interobserver variablility. Br J Ophthalmol. 2005;89:847-850.
18. Dawson DG, Hardten DR, Albert DM. Pocket of fluid in the lamellar interface after penetrating keratoplasty
and laser in situ keratomileusis. Arch Ophthalmol. 2003;121:894-896.
19. Hamilton KE, Pye DC, Hali A, Lin C, Kam P, Nguyen T. The effect of contact lens induced edema on
Goldmann applanation tonometry measurements. J Glaucoma. 2007;16:153-158.
20. Hamilton KE, Pye DC, Aggarwala S, Evian S, Khosla J, Perera R. Diurnal variation of central corneal
thickness and Goldmann applanation estimates of intraocular pressure. J Glaucoma. 2007;16:29-35.
21. Elsheikh A, Wang D, Brown M, Rama P, Campanelli M, Pye D. Assessment of corneal biomechanical properties
and their variation with age. Curr Eye Res. 2007;32:11-19.
4 | New Technologies in the Diagnosis and
Management of Glaucoma
John G. Flanagan, PhD, MCOptom
The last decade has seen an explosion of new technologies that
have begun to challenge our understanding of the structural and
functional relationships in early glaucoma, while at the same time
introducing potentially new standards of care. In this chapter, I
will review several of the latest technologies and developments.
Methods for the non-invasive, objective, quantitative, structural
assessment include scanning laser tomography and optical coherence
tomography for the optic nerve (ON) and retinal nerve fiber
layer (RNFL); and scanning laser polarimetry for exclusive RNFL
analysis. All three technologies are reported to have excellent diagnostic
performance in the detection of early glaucoma. These instruments
are not meant for stand-alone use but rather support the
clinical evaluation of the ON/RNFL. They may provide corroboration
of a working diagnosis or require the clinician to re-evaluate his or
her assessment of the ON/RNFL.
66 RREEVVIIEEWW OOFF OOPPTTOOMMEETTRRYY//OOPPTTOOMMEETTRRIICC GGLLAAUUCCOOMMAA SSOOCCIIEETTYY
Scanning laser tomographers (SLT) were first introduced in the
late 1980s and are among the most common of the new imaging
systems for use in glaucoma. The technology is based on the optical
principals of confocal microscopy. A series of images are recorded
along the axial axis of the eye, thus enabling three-dimensional
reconstruction of the surface of the retina and/or the optic nerve
head. The Heidelberg Retina Tomograph (Heidelberg Engineering) is
the most common of the SLTs (Figure 1a). The current, third-generation
model, the HRT3, was introduced toward the end of 2005.
The HRT3 is similar to the previous model in that it operates using
a 670nm diode laser light source and a field of view of 15 x 15 degrees,
with a two-dimensional resolution for each image plane of
384 x 384 pixels. The scan depth is automatically selected from a
range of 1.0mm to 4.0mm, and 16 scans are obtained per millimeter
of scan depth. A 2mm scan depth with 32 image scans has a
one-second acquisition time (24msec per scan). The HRT3 offers
several important developments over its predecessors. A sophisticated
image acquisition quality control system has been incorporated.
This considerably reduces the learning curve for new users,
and helps to ensure adequate image quality for future progression
analysis. There is a new alignment algorithm that has reduced the
intra-test variability, which in turn enables more sensitive analysis
of structural progression. The database for analysis of the stereometric
parameters and Moorfields Regression Analysis has been expanded
to include 700 of Caucasian descent, 200 of African descent
and 200 from Southeast Asia. This database is also used for the
new, contour independent Glaucoma Probability Score (GPS), which
is based upon automated analysis of the shape of both the optic
nerve head and the parapapillary retina in both normal and glaucomatous
eyes. The printout reflects these new measures and emphasizes
the analysis of cup, rim, retinal nerve fiber layer and
ocular asymmetry. There are additional improvements in the Topographic
Change Analysis (TCA) that can now display graded levels
of significance and Trend Analysis overview plots of cluster volOOPPTTOOMMEETTRRIICC
GGLLAAUUCCOOMMAA SSOOCCIIEETTYY//RREEVVIIEEWW OOFF OOPPTTOOMMEETTRRYY 77
Figure 1a (top left), b (top right), c (bottom). HRT (a), GDx (b) and OCT (c) images of a patient
with primary open-angle glaucoma. The loss is in the left eye only. All three technologies reveal
the damage to be in the superior portion of the left optic nerve and retinal nerve fiber layer. This is
seen as areas in the left eye that are flagged in the superior region. The GDx also shows loss in the
inferior portion of the left eye, which does not correspond to the other tests or visual fields.
A
C
B
Figure 2a (left). The 3D disk printout as it appears on the computer screen for the RTVue spectral domain OCT. The optic nerve cross-sectional images along with the 3-D view are seen in the
printout. Figure 2b (right). The NMH4 printout from the RTVue OCT is seen.
88 RREEVVIIEEWW OOFF OOPPTTOOMMEETTRRYY//OOPPTTOOMMEETTRRIICC GGLLAAUUCCOOMMAA SSOOCCIIEETTYY
ume and area. The HRT remains the only imaging
technology specifically designed to analyze progression,
and it has the added advantage of being backwardly
compatible to its very first model. This means
that some centers now have 15 years of consecutive
data. The HRT has the ability to both align and analyze
serial images. This is of particular importance, as
the greatest potential of the new imaging technologies
lies in their detection of subtle structural
changes early in the disease, rather than cross sectional
classification and staging of the disease. Recent
data from the ancillary study of the Ocular
Hypertension Treatment Trial has indicated that
baseline HRT measures were highly predictive for the
development of POAG during the course of the study
(Moorfielďs Regression Analysis for the temporal inferior
sector had a hazarďs ratio approaching 6.0).
Scanning laser polarimetry combines scanning laser
ophthalmoscopy with polarimetry to measure the retardation
of polarized laser light caused by the birefringent
properties of the retinal nerve fiber layer
(Figure 1b). The commercially available instrument is
called the GDx VCC (Carl Zeiss Meditec). It uses an
820nm diode laser source in which the state of polarization
is modulated. Image acquisition takes 0.7 seconds
and the scan field is 20 degrees. Results are
compared to an age-matched normative database, and
a machine classifier is used to define the likelihood
that a map is normal or glaucomatous. The current
GDx is a fifth-generation instrument and uses Variable
Corneal Compensation (VCC), which differs from its
predecessors in that it performs individual specific
compensation of the ocular birefringence, rather than
using a fixed, average compensation.
The consensus meeting of the Association of International
Glaucoma Societies (AIGS) on Glaucoma Diagnosis
stated that the VCC reduced the range of
normative data, thereby improving detection rates and correlation
with other structural measures. Further, recent literature has reported
solid reproducibility and an encouraging diagnostic performance
in the detection of early disease. There are two anticipated new developments
for the GDx. Later this year the long anticipated Guided
Progression Analysis (GPA) will be launched, enabling the alignment
and analysis of serial data. Next year, the Enhanced Corneal Compensation
will replace the VCC, with the idea of further reducing image
noise and the effect of atypical scans.
Optical coherence tomography is the one technology that has
changed exponentially since the publication of last year's Handbook
with the introduction of high resolution, fourier or spectral domain
optical coherence tomography (OCT). Presently, the most commonly
used of the OCTs is the Stratus OCT (Carl Zeiss Meditec) which is
a third generation, time domain OCT that employs low-coherence interferometry
to enable high-resolution, cross-sectional imaging of
the retina and optic nerve. A superluminescent 830nm diode provides
a near infrared, low-coherence source, which is divided and
beamed to a reference device in the eye. Each light path goes back
to a detector where the reference beam is compared to the measurement
beam.
The Stratus can be used in the diagnosis and management of
glaucoma by measuring retinal nerve fiber layer (RNFL) thickness
around the optic nerve head. Radial tomograms are then used to assess
the cross-sectional profile of the optic nerve (Figure 1c). The
OCŤs RNFL assessment correlates well with the clinical assessment
of focal defects and visual fields in patients with glaucoma and
demonstrates a significant difference between normal and glaucomatous
subjects. Results are compared to an age-matched normative
database. Recent studies have suggested that the OCT is capable of
detecting early disease progression.
Fourier domain (FD) OCT was recently launched by 9 different
companies, including Optovue (RTVue 100), Heidelberg Engineering
(Spectralis HRA-OCT), Carl Zeiss Meditec (Cirrus) and Topcon (Figure
2a, b). FD OCT uses a stationary reference mirror, as opposed to the
moving reference mirror found in time domain OCT. The interference
Figure 3a,b. These FDT Matrix 24-2 Full Threshold fields are from the patient seen in Figure 1. The right visual
field is within normal limits, and the loss in the left correlates with the images in Figure 1 and SITA SWAP field in
Figure 4.
Figure 4. These are SITA SWAP fields for the patient seen in Figure 1 and 3. The loss is in the left eye, with the
inferior points being flagged. The field in the right eye is consistent with a trial lens artifact.
OOPPTTOOMMEETTRRIICC GGLLAAUUCCOOMMAA SSOOCCIIEETTYY//RREEVVIIEEWW OOFF OOPPTTOOMMEETTRRYY 99
between the sample and reference reflections are split into a spectrum,
and all wavelengths are simultaneously analyzed using a spectrometer.
The resulting spectral interferogram is Fourier transformed
to provide an axial scan at a fraction of the time previously required.
This has resulted in up to a 100 times increase in the number of Ascans
per second (Spectralis at 40,000 scans per second compared to
the Stratus at 400 scans per second). The new technologies are
paired with complementary imaging modes; for example SLT, to enable
registration of all A-scans. This allows accurate image registration
and image alignment of serial images, essential for the analysis
of progression and therefore overcoming the most significant problems
associated with time domain OCT. The new generation instruments
are just being delivered and require considerable refinement
of their software to ensure good analysis in patients with glaucoma,
but they promise to make a substantial contribution to future disease
management.
New technologies for visual function have concentrated on selectively
testing specific anatomical and/or perceptual pathways. The
goal of such an approach is to detect loss of retinal ganglion cells
(RGCs) earlier and with improved repeatability.
Frequency Doubling Technology perimetry (FDT) is based on the
frequency-doubling illusion, whereby a low-spatial frequency grating
(<1 cycle/degree) is flickered in counterphase at a high temporal
frequency (>15Hz). When this occurs, the spatial frequency of
the grating appears to double. The technique has been applied clinically
using a grating of 0.25 cycles/degree and temporal frequency
of 25Hz. It was initially proposed that the illusion was due to
selective processing of the My cells, a subset of magnocellular projecting
RGCs. However, this is now thought unlikely, as there is no
evidence for such cells in primates--although the illusion does
preferentially stimulate the magnocellular system. It is likely that
the stimulus, as used clinically, is a flicker contrast threshold task.
The original FDT tested up to 19 large, 10 degrees x 10 degrees targets
in either a threshold mode or a rapid (<1 minute) screening test.
During testing, the stimulus flicker and spatial frequency are held
constant while the contrast is modified in a stepwise process similar
to the bracketing method used in conventional perimetry. In response
to concerns over the ability of such large targets to detect
subtle, early defects, a second-generation machine was developed,
the FDT Matrix, which uses smaller 5-degree targets and measures
with a standard 24-2 pattern (Figure 3). A video camera is incorporated
for fixation monitoring, and it is possible to view serial fields
and perform glaucoma change analysis. A ZEST-like strategy is used
to estimate the sensitivity and ensure a standardized test time, regardless
of defect.
FDT has been reported to have high sensitivity and specificity for
the detection of glaucoma. Even when used in the screening mode,
it may detect some defects earlier than standard automated perimetry
(SAP), and it offers good test-retest characteristics. FDT is relatively
resistant to optical blur, small pupils and the influence of
ambient illumination--all of which make it ideal in a screening environment.
Recent reports on the Matrix suggest that it is capable
of diagnosing early disease before SAP and often prior to SWAP. As
disease progresses, there is little difference with SAP results.
Short-wavelength automated perimetry (SWAP), or blue-yellow
perimetry, uses a large Goldmann size V blue stimulus (centered on
440nm) against a bright yellow background (100 cd/m2) (Figure
4). The rationale is to selectively test the blue cones and their projection
through the koniocellular pathway, thus taking advantage
of their reduced redundancy. Several longitudinal studies found
SWAP to be predictive of early glaucomatous SAP visual field defect,
in some cases by up to five years. SWAP is tested, analyzed
and displayed in a way intuitively similar to SAP. SWAP is limited
by the relatively greater influence of cataracts and other media
opacities, a compressed dynamic range, poor test-retest characteristics
and increased test time. The clinical application has also been
limited by the threshold estimation strategies presently available.
SITA SWAP has recently been developed for the HFA and will likely
improve its clinical usefulness. However, SWAP will probably not replace
SAP and should be considered a complementary test to be
used in selected situations, such as high-risk glaucoma suspects
with normal SAP results.
Heidelberg Engineering recently launched a new visual function
test called the Heidelberg Edge Perimeter (Figure 5A, B). This is
based upon an illusionary stimulus called flicker defined form, in
which a 5o
stimulus region within a background of random dots is
flickered at a high temporal frequency (15Hz) in counterphase.
This gives rise to an illusionary edge or border that is perceived as
5a (left). The Heidebelberg
Engineering HEP perimeter is
seen. 5b (center). A nasal
step is seen on the printout
from the Heidelberg HEP.
This printout has similarities
to that of the HFA perimeter.
5c (right). One unique
feature of the HRT HEP
perimeter is the structure
function map, which
correlates findings of the
HRT confocal scanning laser
ophthalmoscope with that of
the perimeter.
1100 RREEVVIIEEWW OOFF OOPPTTOOMMEETTRRYY//OOPPTTOOMMEETTRRIICC GGLLAAUUCCOOMMAA SSOOCCIIEETTYY
a gray circle against a mean luminance background. The stimulus
targets the magnocellular projecting retinal ganglion cells and is
proposed for the early detection of glaucomatous damage. Of particular
note is the availability of the first ever combined Structure
Function Map, in which the HRŤs MRA analysis is combined with
the visual field analysis of the equivalent ON sectors (Figure 5C).
Current methods for the analysis of visual field progression include
an expert inspection of the Overview printout and the Glaucoma
Progression Analysis (GPA), an updated version of the
original Glaucoma Change Probability (GCP) analysis. Both are empirically
based and compare a patienťs pattern of change to "typical"
change experienced by others with glaucoma. GCP was based
on the total deviation normal database, and was criticized for being
prone to error in the presence of developing cataract and
changing pupil size. The new GPA was developed for the Early Manifest
Glaucoma Treatment Trial (EMGT) and uses the pattern deviation
normal database, allowing an analysis that is less sensitive to
the effects of cataract and reduced pupil size. GPA is available on
the Humphrey Field Analyzer (HFA). The analysis uses estimates of
the inherent variability of glaucomatous visual fields from data collected
at 16 centers. This is combined with the EMGT criterion of
three significantly deteriorating points repeated over three examinations.
A minimum of two baseline and one follow-up examination
are required. Each exam is then compared to baseline and to
the two prior visual fields. Points outside the 95th percentile for
stability are highlighted, as are points that progress on two or
three consecutive examinations. Two additional qualifying statements
alert the clinician to the likelihood of "probable progression"
(3x2 consecutive) and "likely progression" (3x3 consecutive) (Figure
6a, b, c). An advantage of the GPA is that it permits progression
analysis across the full-threshold and SITA-standard threshold
estimation strategies, thus allowing analysis of pre-SITA visual
fields alongside SITA standard fields.
New technologies have been developed and are gaining clinical
acceptance. These new tests complement the examination and allow
a better understanding of the visual field, optic nerve or retinal
nerve fiber layer. The new technologies supplement tests we
have been using for many years. As we gain better understanding
of their use and strengths, they will only improve our ability to diagnose
and manage glaucoma.
Suggested Readings
1. Fingeret M., Flanagan J., Lieberman J. (eds). The Heidelberg Retina Tomograph II Primer. Jocoto, San
Ramon. 2005
2. Weinreb RN, Greve EL, eds. Glaucoma Diagnosis Structure and Function. The Hague, Kugler Publications. 2004.
3. Chauhan BC, McCormick TA, Nicolela MT, LeBlanc RP. Optic disc and visual field changes in a prospective
longitudinal study of patients with glaucoma: comparison of scanning laser tomography with conventional
perimetry and optic disc photography. Arch Ophthalmol. 2001;119(10):1492-9.
4. Zangwill LM, Weinreb RN, Berry CC, Smith AR, Dirkes KA, Liebmann JM, Brandt JD, Trick G, Cioffi GA,
Coleman AL, Piltz-Seymour JR, Gordon MO, Kass MA; OHTS CSLO Ancillary Study Group. The confocal scanning
laser ophthalmoscopy ancillary study to the ocular hypertension treatment study: study design and
baseline factors. Am J Ophthalmol. 2004;37(2):219-27.
5. Zangwill LM et al. The CSLO ancillary study to OHTS: Baseline measurements associated with development
of POAG. Arch. Ophthalmol. 2005;123:1188-97.
6. Medeiros FA, Zangwill LM, Bowd C, Weinreb RN. Comparison of the GDx VCC scanning laser polarimeter,
HRT II confocal scanning laser ophthalmoscope, and stratus OCT optical coherence tomograph for the detection
of glaucoma. Arch Ophthalmol. 2004;122(6):827-37.
7. Reus NJ, Zhou Q, Lemij HG. Enhanced Imaging Algorithm for Scanning Laser Polarimetry with Variable
Corneal Compensation. Invest Ophthalmol Vis Sci. 2006;47:3870-3877.
8. Paunescu LA, Schuman JS, Price LL, et al. Reproducibility of nerve fiber thickness, macular thickness,
and optic nerve head measurements using Stratus OCT. Invest Ophthalmol Vis Sci. 2004;45:1716-1724.
9. Wollstein G, Schuman JS, Price LL, et al. Optical coherence tomography longitudinal evaluation of retinal
nerve fiber layer thickness in glaucoma. Arch Ophthalmol. 2005;123:464-470.
10. Sample PA, Johnson CA, Haegerstrom-Portnoy G, Adams AJ. Optimum parameters for short-wavelength
automated perimetry. J Glauc. 5:6, pp. 375-383, Dec. 1996.
11. Johnson CA, Adams AJ, Casson EJ, Brandt JD. Blue-on-yellow perimetry can predict the development
of glaucomatous field loss, Arch Ophthalmol. 111;645-650, May 1993.
12. Sample PA, Taylor JDN, Martinez GA, Lusky M, Weinreb RN. Short-wavelength color visual fields in
glaucoma suspects at risk. Am. J. Ophthalmol. 115:225-233, Feb. 1993.
13. Heijl A, Leske MC, Bengtsson B, Bengtsson B, Hussein M, and the Early Manifest Glaucoma Trial
Group. Measuring visual field progression in the Early Manifest Glaucoma Trial. Acta Ophthalmol Scand.
2003;81:286-293.
Figure 6a (left) is the left visual field Glaucoma Progression Analysis (GPA) printout for a patient with open-angle glaucoma. Five fields performed between September 2001 and March 2005
are available for analysis. In 6a, the single field summary printout is seen. The box on the right side reveals that a few points have changed once, and one point changed two fields in a row.
This is consistent with potential change. In Figure 6b (center), the first page of the overview printout displays the two baseline fields. On the bottom of this page is a table that graphs out each
of the fields and displays a regression analysis. Over four years, the fields have improved slightly. Figure 6c (right) shows some progression may have occurred, but this must be confirmed with
subsequent field testing.
14. Haymes SA, Hutchison DM, McCormick TA, Varma DK, Nicolela MT, LeBlanc RP, Chauhan BC. Glaucomatous
visual field progression with frequency-doubling technology and standard automated perimetry in a
longitudinal prospective study. Invest Ophthalmol Vis Sci. 2005;46(2):547-54.
15. Fingeret M, Lewis TL, eds. Primary Care of the Glaucomas. 2nd ed. New York: McGraw Hill. 2001.
16. Anderson DR, Patella VM. Automated Static Perimetry. 2nd ed. St. Louis: CV Mosby Co, 1999.
5 | Risk Assessment as an Emerging Tool for
Glaucoma Care
Robert D. Fechtner, MD, Albert S. Khouri, MD, and Murray Fingeret, OD
The clinician treating patients with glaucoma or glaucoma suspects
is faced with the clinical challenges of whom to treat, when
to treat and to what extent to treat. Not all patients with glaucoma
will lose vision to the extent that quality of life will be compromised.
Our current model of diagnosing and treating glaucoma
is based on the principles of detecting damage, setting a target intraocular
pressure at which we believe the pressure-related component
of damage will be reduced or eliminated, then following the
patient to monitor for progression. This model has limitations. Early
changes are asymptomatic and only as the disease progresses are
detectable structural and functional changes observed. Also,
changes are irreversible and represent significant damage to the
optic nerve.
We treat patients with ocular hypertension and glaucoma by reducing
intraocular pressure (IOP). However, it is important to remember
that the goal of glaucoma care is not to reduce IOP, not to
preserve optic nerve and not to preserve visual field, but rather to
preserve sufficient vision for acceptable quality of life. It is the loss
of vision from glaucoma that impacts upon the quality of life for
our patients. If our tools allow us only to base our treatment decisions
on the degree of loss already present or on the detection of
additional loss, we are missing an opportunity to identify and treat
appropriately patients at greatest risk for losing vision.
Risk assessment is a well-accepted tool in other fields of medicine.
Perhaps the best known example is cardiovascular medicine.
Most adults are at least aware that elevated blood pressure and abnormal
blood lipid profile increase the risk of coronary heart disease
(CHD). Many have had blood pressure measured and a lipid
profile tested. Risk assessment and modification is the fundamental
tool for preventing coronary heart disease. No one wishes to
learn of their risk by having the first heart attack! True, the consequence
of gradual atherosclerosis is a cardiovascular event--
quite dramatic compared with the chronic optic neuropathy and
gradual loss of vision of glaucoma, but there are some parallels in
the underlying principles of risk assessment. We can use the example
of cholesterol and IOP.
The understanding of cholesterol as a risk factor has dramatically
evolved over time. Early in the evolution of risk assessment for
CHD, cholesterol was identified as a risk factor. Initially, normal cholesterol
levels were defined as being within 2 standard deviations
(SDs) of the mean (200 mg/dL to 310 mg/dL). Later, it was appreciated
that there was a continuous effect, even within normal
ranges. It soon became evident that subjects with the "normal
range" of cholesterol levels included an excessively high incidence
of CHD. In fact, the correlation between cholesterol levels and CHD
occurred in a continuous, graded fashion, and normal cholesterol
levels were still associated with increased risk of CHD.
For glaucoma, abnormal IOP was described as two standard deviations
from the mean (21 mmHg). We have subsequently learned
that IOP is a continuous risk factor, even at statistically normal levels.
Further, it is clear that one can have high IOP without glaucoma
and one can have glaucoma with statistically normal IOP.
With the emerging evidence from large, prospective glaucoma trials,
we are beginning to amass the data to allow us to be able to
identify risk factors for both the development of and the progression
of glaucoma. By applying risk assessment, we can begin to develop
models to identify those patients at highest risk of progression.
Models allow the creation of risk calculators, tools to estimate individual
rather than population risk. We can then determine who is
at greatest risk and offer earlier or more aggressive intervention.
The results of recent large-scale trials have encouraged a reassessment
of the way clinicians evaluate and manage patients
with ocular hypertension (OHT) or glaucoma. The potential benefits
of IOP reduction have been clearly demonstrated. The Ocular
Hypertension Treatment Study (OHTS) investigated the effect of
lowering IOP on progression to open-angle glaucoma (OAG) in over
1600 subjects with OHT but no evidence of glaucomatous damage.
Treatment with topical ocular-hypotensive medication reduced the
risk of progression to glaucoma by approximately half, from 9.5%
in untreated patients to 4.4% in patients receiving treatment. It
should be noted that the European Glaucoma Prevention Study
(EGPS) found no benefit from treatment of ocular hypertension
with dorzolamide compared with placebo (vehicle of dorzolamide).
However, the IOP reduction in the placebo group was nearly the
same as that in the dorzolamide treated group, a curious finding
that has not been fully explained.
A recent study to test the generalizability of the OHTS prediction
model for the development of primary open-angle glaucoma in a
large independent sample of untreated ocular hypertensive individuals
was reported. A prediction model was developed from the observation
group of the OHTS that was then tested on the placebo
group of the European Glaucoma Prevention Study (EGPS). A calculator
to estimate the 5-year risk of developing POAG, based on the
pooled OHTS-EGPS predictive model was found to have high precision
in assisting clinicians deciding on the frequency of tests and
examinations during follow-up and the advisability of initiating
preventive treatment.
Similarly, in subjects with early glaucoma (Early Manifest GlauOOPPTTOOMMEETTRRIICC
GGLLAAUUCCOOMMAA SSOOCCIIEETTYY//RREEVVIIEEWW OOFF OOPPTTOOMMEETTRRYY 1111
Figure 1. The Discoveries in Sight risk calculator, available on the Internet at
www.discoveriesinsight.org.
1122 RREEVVIIEEWW OOFF OOPPTTOOMMEETTRRYY//OOPPTTOOMMEETTRRIICC GGLLAAUUCCOOMMAA SSOOCCIIEETTYY
coma Trial [EMGT]) who were randomized to either treatment or observation,
IOP reduction slowed the rate of progression from 62%
in controls to 45% in the treated population (median follow-up of
6 years). Despite these encouraging findings, individualizing therapy
based on the results from large-scale clinical trials is difficult.
Although IOP reduction may decrease risk of glaucoma and vision
loss, treatment costs and potential side effects also need to be
considered. It would be helpful to know who is at greatest risk and
most likely to benefit from treatment.
For many, it is not surprising to get confirmation that lowering
IOP prevents or delays the progression from OHT to glaucoma or
from glaucoma to further visual field loss. Perhaps more important
than the clear demonstration of the benefits of IOP lowering was
the identification of risk factors for the development of glaucomatous
damage. Several risk factors were identified at baseline in
OHTS for the group who developed glaucoma. Older age was associated
with increased risk of developing the disease over the course
of the 5 year study. Despite this correlation, it is important to remember
that glaucoma takes many years to progress to visual loss.
Though increasing age is a risk factor, younger patients should have
frequent eye exams, since they have a greater remaining life span
over which to develop vision loss.
Higher untreated IOP in OHTS was also associated with a greater
frequency of developing glaucoma. This is not surprising since IOP
is a consistent risk factor in many studies. In the recent analysis of
the Early Manifest Glaucoma Trial with a median follow-up of 8 years,
the results confirmed 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 1.061.17;
P<0.0001). Patients with a greater cup-to-disc diameter (a
measure of optic nerve damage) were more likely to develop glaucoma.
It is not clear if some of the subjects with the larger cup-to-disc
diameters already had early glaucoma without demonstrable visual
field defects when they entered the study. In a recent analysis of
OHTS data, optic disc hemorrhages were associated with a 6-fold increase
(95% CI 3.6-10.1; p<0.001) in risk of developing POAG in ocular
hypertensive subjects. A new and fascinating observation was
that subjects with thinner corneas were at higher risk for glaucoma.
While we know that the thickness of the cornea affects IOP measurements,
this alone did not account for the increased risk. Thinner central
corneal thickness was an independent risk factor. This has
prompted clinicians to measure corneal thickness in patients with
ocular hypertension-and glaucoma-on a routine basis.
The OHTS publication included two 3 x 3 tables that included
central corneal thickness and either IOP or C/D ratios. We could
consider these as the first crude risk calculators. It was possible to
combine two risk factors to derive an individual risk for the development
of glaucoma. Steven Mansberger, MD, MPH, at Devers Eye
Institute, posted an interactive risk calculator on the internet at
www.discoveriesinsight.org/GlaucomaRisk.htm (Figure 1). This calculator
was based on the OHTS publication. It has undergone modification
since it was originally introduced. A version is available
for download.
The first validated risk calculation model was published in 2005.
This was also based on the OHTS risk model. The calculator was tested
on an independent population of ocular hypertensive subjects
followed at the University of California, San Diego. With support
from Pfizer Ophthalmics, a cardboard slide rule and then a digital
handheld risk calculator were produced (Figures 2 and 3). To be used
precisely as designed, these calculators require input of data just as
it was collected in the OHTS study. This data includes the age, intraocular
pressure, central corneal thickness, vertical cup-to-disc ratio,
pattern standard deviation (PSD) from a HFA II threshold visual
field and diabetes status. However, in clinical practice, a less stringent
use should still provide reasonable estimates of risk.
As mentioned earlier, a validated risk model from the OHTS study
was introduced in 2006 (http://ohts.wustl.edu/risk). This prediction
model was developed from the observation group of the OHTS
and then tested on the placebo group of the EGPS. The calculator
was tested and found useful in estimating the 5-year risk of developing
POAG, based on the pooled OHTS-EGPS predictive model.
One question when the risk calculator is used is whether to input
diabetes status. OHTS found having diabetes to be protective of developing
glaucoma, but only diabetics without retinopathy were allowed
into the study. Diabetes being protective of developing
glaucoma has not been validated in other studies; and until further
data is available, it may be better to ignore the diabetes panel on
the risk calculator and always keep it checked as "no." Diabetes was
not found to be a risk factor in the analysis of pooled OHTS-European
Glaucoma Prevention Study dataset. Thus the effect of diabetes
on the development of POAG remains controversial.
How can a risk calculator add to the quality of clinical care? At
the very least, we should be able to better determine whom to treat
and whom to follow without treatment. One consensus group published
suggestions that we should observe low-risk patients, consider
treatment for moderate risk patients, and treat those at highest
risk. The exact treatment threshold has not been clearly determined,
but this group selected ranges of <5% for low risk, 5-15% for
moderate risk, and >15% for high risk. The rationale is that a glaucoma
patient at highest risk to progress from OHT to glaucoma is
also probably at relatively high risk for developing a glaucomatous
visual disability in his or her lifetime. Other factors will influence
the decisions regarding treatment.
The EMGT study identified factors present at the baseline visit
that predicted who would progress. These included higher IOP, eligibility
in both eyes (glaucoma in both eyes), presence of exfoliation
material, worsening visual field (mean defect) and older age.
Once the patients returned for follow-up, factors that predicted
progression included initial response to treatment (better initial response
was protective), IOP at first visit and mean IOP at all followFigure
2. The paper STAR risk calculator that is distributed by Pfizer, Inc.
OOPPTTOOMMEETTRRIICC GGLLAAUUCCOOMMAA SSOOCCIIEETTYY//RREEVVIIEEWW OOFF OOPPTTOOMMEETTRRYY 1133
up visits, as well as percentage
of visits at which a disc
hemorrhage was detected.
Corneal thickness was not
identified as a risk factor in
this study, but these individuals
already had glaucomatous
damage, not OHT.
Risk calculators have not
yet been developed for progression
once a patient has
glaucoma. For now, we should evaluate our patients for known or
suspected risk factors and either test for progression more frequently
or treat more aggressively those we consider at higher risk.
Can we predict which glaucoma patient is at risk for progressing
and ultimately developing a visual disability? OHTS identified
risk factors for the progression from OHT to open-angle glaucoma
(OAG). Risk calculators are now available to help the clinician estimate
individual risk of progression. The EMGT study identifies
some of the risk factors for progression of OAG. As we refine models
of risk, we will be able to better determine which patients are
at highest risk and may need aggressive treatment. Conversely, we
should identify patients at low risk who can be followed closely
without treatment. This requires a fundamental change in our
view of glaucoma treatment. Rather than think of it simply as IOPlowering
treatment, we might start to consider it as risk reduction.
Of course, we must consider patient preferences and views about
risk in making these determinations.
Well-designed clinical trials in glaucoma will continue to advance
our understanding of the spectrum of this disease. It is not only reassuring
that many of our cherished traditions are now supported
by evidence, but also intriguing to explore new concepts about
glaucoma based on large, well designed studies. At first, we will
make qualitative determinations by identifying risk factors in our
patients and altering our treatment decisions. Eventually, we can
expect to have risk calculators as tools to help decide whom to
treat, when to treat and to what extent.
Dr. Fechtner is Professor at the Institute of Ophthalmology and Visual Science,
University of Medicine and Dentistry of New Jersey, New Jersey Medical
School, and Director of the Glaucoma Division, UMDNJ-New Jersey
Medical School.
Dr. Khouri is a Research Associate at the Institute of Ophthalmology and
Visual Science, University of Medicine and Dentistry of New Jersey, New Jersey
Medical School.
Dr. Fingeret is Chief of the Optometry Section, Dept Veterans Affairs New
York Harbor Health Care System, Brooklyn Campus and Clinical Professor,
SUNY College of Optometry. Dr. Fingeret sits on the board of directors of the
Glaucoma Foundation and is president of the Optometric Glaucoma Society.
Supported in part by Research to Prevent Blindness and the Glaucoma Research
and Education Foundation, Inc.
Suggested Readings
1. Brandt JD, Beiser JA, Kass MA, Gordon MO, and the Ocular Hypertension Treatment Study (OHTS) Group.
Central corneal thickness in the Ocular Hypertension Treatment Study (OHTS). Ophthalmology.
2001;108:1779-1788.
2. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive
summary of the third report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection,
Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA.
2001;285:2486-2497.
3. Girkin CA, Kannel WB, Friedman DS, Weinreb RN. Glaucoma risk factor assessment and prevention:
Lessons from coronary heart disease, American Journal of Ophthalmology, Volume 138, Issue 3, Supplement
1, September 2004, Pages 11-18.
4. Gordon MO, Beiser JA, Brandt JD, et al, for the Ocular Hypertension Treatment Study Group. The Ocular
Hypertension Treatment Study: baseline factors that predict the onset of primary open-angle glaucoma.
Arch Ophthalmol. 2002;120:714-720.
5. Grundy SM, Pasternak R, Greenland P, Smith S Jr, Fuster V. Assessment of cardiovascular risk by use of
multiple-risk-factor assessment equations: a statement for healthcare professionals from the American
Heart Association and the American College of Cardiology. J Am Coll Cardiol. 1999;34:1348-1359.
6. Hattenhauer MG, Johnson DH, Ing HH, et al. The probability of blindness from open-angle glaucoma.
Ophthalmology. 1998;105:2099-2104.
7. Kannel WB. Contributions of the Framingham Study to the conquest of coronary artery disease. Am J
Cardiol. 1988;62:1109-1112.
8. Medeiros FA, Sample PA, Weinreb RN. Corneal thickness measurements and visual function abnormalities
in ocular hypertensive patients. Am J Ophthalmol. 2003;135:131-137.
9. National Cholesterol Education Program (NCEP) Expert Panel. Detection, Evaluation, and Treatment of
High Blood Cholesterol in Adults (Adult Treatment Panel III). Final Report. NIH (National Institute of
Health); 2002. Publication no. 02-5215.
10. Heijl A, Leske MC, Bengtsson B, Hyman L, Bengtsson B, Hussein M, for the Early Manifest Glaucoma
Trial Group. Reduction of intraocular pressure and glaucoma progression: results from the Early Manifest
Glaucoma Trial. Arch Ophthalmol. 2002;120:1268-1279.
11. Kass MA, Heuer DK, Higginbotham EJ, et al, for the Ocular Hypertension Treatment Study Group. The
ocular hypertension treatment study: a randomized trial determines that topical ocular hypotensive medication
delays or prevents the onset of primary open-angle glaucoma. Arch Ophthalmol. 2002;120:701-713.
12. Weinreb RN, Friedman DS, Fechtner RD, et al. Risk assessment in the management of patients with ocular
hypertension, American Journal of Ophthalmology, Volume 138, Issue 3, September 2004, Pages 458-467.
13. Coleman AL, Singh K, Wilson R, et al. Applying an evidence-based approach to the management of patients
with ocular hypertension: Evaluating and synthesizing published evidence, American Journal of Ophthalmology,
Volume 138, Issue 3, Supplement 1, September 2004, Pages 3-10.
14. Friedman DS, Wilson MR, Liebmann JM, et al. An evidence-based assessment of risk factors for the progression
of ocular hypertension and glaucoma, American Journal of Ophthalmology, Volume 138, Issue 3,
Supplement 1, September 2004, Pages 19-31.
15. Weinreb RN, Ocular hypertension: Defining risks and clinical options, American Journal of Ophthalmology,
Volume 138, Issue 3, Supplement 1, September 2004, Pages 1-2.
16. Results of the European Glaucoma Prevention Study. Ophthalmology. 2005 Mar;112(3):366-75.
17. Medeiros FA, Weinreb RN, Sample PA, Gomi CF, Bowd C, Crowston JG, Zangwill LM. Validation of a predictive
model to estimate the risk of conversion from ocular hypertension to glaucoma. Arch Ophthalmol.
2005 Oct;123(10):1351-60
18. Ocular Hypertension Treatment Study Group, European Glaucoma Prevention Study Group. Validated
prediction model for the development of primary open-angle glaucoma in individuals with ocular hypertension.
Ophthalmology. 2007;114:10-19.
19. Bengtsson B, Leske MC, Hyman L, Heijl A. Fluctuation of intraocular pressure and glaucoma progression
in the early manifest glaucoma trial. Ophthalmology. 2007;114:205-9.
20. Budenz DL, Anderson DR, Feuer WJ, et al. Detection and prognostic significance of optic disc hemorrhages
during the Ocular Hypertension Treatment Study. Ophthalmology. 2006;113:2137-2143.
6 | Understanding Glaucoma Medications
Murray Fingeret, OD
Medical therapy is the most common method used for the reduction
of the intraocular pressure (IOP) associated with ocular hypertension
(OHT) and open-angle glaucoma (OAG). Several classes of
drugs (prostaglandin derivatives, beta-adrenergic antagonists, carbonic
anhydrase inhibitors, adrenergic agonists and cholinergic agonists)
may be used to reduce the IOP. Medications are classified
based upon several areas: efficacy, safety, tolerability and patient
acceptance. Efficacy refers to how well the medication reduces IOP,
both in the short- and long-term. What is the drug's response rate?
For example, how many individuals will have their IOPs reduced
from the baseline level by 15%, 20%, 25%, 30% or more? How often
will the IOP creep back towards pre-treatment levels months to
years later? Tolerability refers to how well the drug is tolerated and
accepted. How often does the patient or doctor feel that side effects
preclude continuing the medication? In the perfect world, the
clinician would like to select an agent that shows excellent efficacy
and persistency, as well as being safe and well-tolerated.
Cholinergic agents, such as pilocarpine, were the drug of choice
Figure 3. The STAR risk calculator, distributed by
Pfizer, Inc.
1144 RREEVVIIEEWW OOFF OOPPTTOOMMEETTRRYY//OOPPTTOOMMEETTRRIICC GGLLAAUUCCOOMMAA SSOOCCIIEETTYY
for many years. In 1978, beta-adrenergic antagonists were introduced
and soon thereafter became the drug of choice. Their popularity
stemmed from improved efficacy, reduced dosing schedule and
a favorable side effect profile. Over the next two decades, other drug
classes (topical carbonic anhydrase inhibitors, adrenergic agonists,
cholinergic agents) were used to complement beta-adrenergic blockers.
During this period, adrenergic agonists (epinephrine, dipivefrin)
became obsolete as newer drugs with significant advantages came to
the market. In 1996, a further evolution occurred with the introduction
of prostaglandins (PGs). The first PG introduced, latanoprost
(Xalatan), soon replaced beta-adrenergic blockers, such as timolol,
as the primary agent for the treatment of OHT and open-angle glaucoma.
With the use of PGs, IOPs once obtainable with multiple medications
were within reach using a single agent. In addition,
compliance improved, and diurnal IOP variation was reduced.
Beta-adrenergic antagonists were introduced in 1978 with the introduction
of timolol maleate. Since then, additional beta-adrenergic
antagonists include levobunolol, betaxolol, metipranolol and carteolol.
Betaxolol is different from other medications in this class in
that it is a cardio-selective agent that primarily blocks beta1 adrenergic
receptors. Carteolol is also unique in that, in addition to being
a nonselective beta-adrenergic antagonist, it has intrinsic sympathomimetic
activity (ISA).
Nonselective adrenergic antagonists are available in both solution
and gel formulations. A gel formulation increases the drug's contact
time, enhances efficacy and reduces systemic absorption, but it is
usually uncomfortable. Istalol is a specific formulation of timolol
maleate that increases the drug's penetration into the eye, allowing
it to be used once per day. The beta-adrenergic antagonists reduce
IOP between 22 -28% by inhibiting the production of aqueous humor.
While the dosage for solutions is listed as bid, the nighttime
dosage has little impact on IOP reduction. The morning instillation
is the more important for the patient to remember to perform. Topically,
the drugs are well-tolerated. The larger concern with the use
of topical adrenergic antagonists is their systemic absorption and
potential side effects. Side effects include confusion, lethargy, fatigue,
bronchospasm and bradycardia. While beta-adrenergic blockers
appear to be safe as long as patients with known
contraindications (such as pulmonary conditions) avoid them, their
use nonetheless has declined over the past decade with the introduction
of PGs. PGs are more efficacious with fewer side effects and
a better dosing schedule. Also, oral adrenergic antagonists are increasingly
being used by internists and cardiologists to treat many
cardiovascular conditions. When given systemically, they often reduce
the IOP, minimizing the impact if a topical beta blocker is also
utilized. In most situations when patients requiring IOP reduction
are on oral beta-adrenergic antagonists, PGs become the drug of
choice. Still, one advantage of this drug class is that drugs such as
timolol or levobunolol are available as generics, which are less expensive
than branded medications.
Apraclonidine (Iopidine) was the first drug in a class known as
adrenergic agonists. Brimonidine is the other member of this category.
Adrenergic agonists inhibit the production of aqueous humor
and enhance outflow mechanisms, which leads to an IOP reduction
of 22% to 28%. Several side effects occur with apraclonidine, including
the development of an allergic follicular conjunctivitis and
loss of effect over time (tachyphylaxis). Brimonidine is still affected
to some extent by these same side effects, but it has replaced
Apraclonidine as the adrenergic agonist of choice. One important
difference between adrenergic agonists and beta-adrenergic antagonists
is the duration of action. The short duration of action of
adrenergic agonists requires that they be used on a tid dosage when
they are the only medication utilized. This peak-and-trough effect
associated with adrenergic agonists is one reason why they are
commonly used in a secondary role. When used in conjunction with
other agents, they can be used on a bid basis. Brimonidine is available
in a branded product (Alphagan P, 0.10%, 0.15%) and a generic
formulation (0.2%). Adrenergic agonists are relatively safe
medications, though they should not be used in children due to
concerns regarding lethargy. Other side effects include dry mouth,
fatigue and drowsiness.
Topical carbonic anhydrase inhibitors (CAI) inhibit the production
of aqueous humor and reduce the IOP by 16% to 22%. Originally,
CAIs were available only in an oral form (acetazolamide,
methazolamide) and were known to induce systemic side effects,
such as paresthesias, depression, diarrhea, metallic taste, kidney
stones and aplastic anemia. Because CAIs reduce IOP so effectively,
a topical formulation was developed. With topical preparations, the
inhibition of the carbonic anhydrase enzyme is limited to the eye,
dramatically reducing systemic side effects. Dorzolamide 2% (Trusopt)
was the original drug in this class, followed by brinzolamide
1% (Azopt). These topical formulations have been shown to be
safe, with the most common side effects being local irritation, such
as burning and stinging (more pronounced with dorzolamide).
However, one concern is that the drugs are from the sulfa family
and are therefore contraindicated in individuals with sulfa allergies.
CAIs are rarely a primary medication and are almost always
used with other agents. Topical CAIs are quite effective when employed
in combination with other agents. When combined with
timolol to produce Cosopt (timolol-dorzolamide), they form half of
the only fixed-combination glaucoma medication approved by the
Food and Drug Administration (FDA). Cosopt is used twice per day.
Many individuals feel that the topical CAIs are the best secondary
agent to be used when the individuaľs primary drug is effective
and tolerated, but further IOP reduction is needed.
Cholinergic agents reduce the IOP by causing the ciliary muscle
to contract, leading to improved flow through the trabecular meshwork.
Pilocarpine is the most common of the agents making up this
class and is available in concentrations ranging from 0.5% to 12%.
The most frequently used strengths are 1%, 2% and 4%. Pilocarpine
is rarely used due to its qid dosing schedule and commonly induced
local side effects, including brow-ache, dim vision, blurred vision
and headache. It is an extremely safe drug, systemically, and can
reduce IOP up to 25%.
The introduction of timolol led to a quiet revolution in the way
glaucoma was managed. Therapy went from an irritating, difficultto-tolerate
agent (pilocarpine) to one that was well-tolerated and
effective (timolol). A further revolution occurred in 1996 with the
introduction of latanoprost. Dosage was reduced to once per day,
IOP reduction enhanced (26% to 34%) and systemic or local side ef-
OOPPTTOOMMEETTRRIICC GGLLAAUUCCOOMMAA SSOOCCIIEETTYY//RREEVVIIEEWW OOFF OOPPTTOOMMEETTRRYY 1155
fects reduced. PGs reduce the IOP by enhancing uveoscleral outflow,
leading to IOP levels never before seen with single topical agents.
The increase in uveoscleral outflow is caused by the elevated presence
of metalloproteinases, which break down the collagen matrix
within the uveoscleral region that surrounds the ciliary muscle bundles.
New channels for aqueous outflow are created, boosting
uveoscleral outflow to greater than 50% of total flow from the eye.
Since the introduction of latanoprost, additional PGs have become
available, including travoprost (Travatan) and bimatoprost (Lumigan).
Both latanoprost and bimatoprost are listed on the drug's
package insert as capable of being a primary agent. PGs have a long
duration of action, allowing them to be used once per day while still
maintaining a flattened diurnal curve throughout a 24-hour period.
If needed, other glaucoma agents may be added to PGs. Tachyphlaxis
and systemic side effects are rare with local side effects that,
while irritating, are not serious. Hyperemia is the most common side
effect and is seen least commonly with latanoprost, followed by
travoprost, with bimatoprost causing hyperemia most often. Other
side effects include iris darkening, which is most commonly seen in
individuals with mixed-colored iris, periorbital skin darkening, eyelash
growth, anterior uveitis, cystoid macula edema (CME) and irritation.
Travatan Z is a new form of travoprost, with Sofzia being
used as the preservative instead of benzalkonium chloride (BAK).
The intent with the introduction of a non-BAK preserved solution is
to reduce symptoms that may be associated with chronic BAK use.
CME and anterior uveitis are rare and, when present, almost always
occur in eyes with a risk factor, such as prior intraocular surgery or
a history of iritis. Eyelash growth is reasonably common, but fortunately
is only a cosmetic concern. The iris color change has received
a great deal of attention. It is caused by an increase in the size and
number of melanin granules within the iris stromal melanocytes.
The pigment is contained within the iris, and no signs of increased
pigmentation are seen anywhere else in the eye. Periorbital skin
darkening is another commonly encountered side effect that typically
disappears upon discontinuation of the agent.
There has been controversy as to which of the PGs most effectively
reduces IOP. Well-conducted studies have not demonstrated that
any of the PGs is superior in reducing IOP. For example, the XLT
study, evaluating all the PGs, showed that the three PGs were comparable
in regard to efficacy, while hyperemia was most common
with bimatoprost. A meta-analysis recently published by van der
Valk et al also showed PGs to be similar in efficacy. Another area of
question is whether switching PGs within the class is an effective
strategy. There are several reasons why a PG may not be effective in
a particular patient. Different studies have shown that approximately
9% of individuals will show <15% IOP reduction when any of the
PGs are utilized. Will switching from one PG to another lead to a
greater IOP drop? Possibly, but the studies used to evaluate this
question are confusing. Switch studies have shown that, no matter
what the first or second drug is, IOPs will be lower on the second
drug. Reasons why the IOP may be reduced include improved compliance
or a phenomenon called regression to the mean. Regression
to the mean describes the situation in which it takes several IOP
readings (data points) to know what the true IOP range is throughout
the day (diurnal variation). Whether a switch within class lowers
IOP over the long term is still open to question. We do know that
if a person is experiencing side effects from one PG, then switching
to another is an advisable first step in reducing these symptoms.
Glaucoma medications have evolved over time. We are now at a
point where PGs have become the primary agent for therapy, and
timolol is used less often in a primary role. Other agents may be
used to complement PGs, always with the aim of reducing the IOP
to the needed target levels while keeping side effects to a minimum.
Suggested Readings
1. Lama PJ. Systemic adverse effects of beta-adrenergic blockers: an evidence-based assessment. Am J Ophthalmol.
2002 Nov;134(5):749-60.
2. Camras CB, Hedman K; US Latanoprost Study Group. Rate of response to latanoprost or timolol in patients
with ocular hypertension or glaucoma. J Glaucoma. 2003 Dec;12(6):466-9.
3. Latanoprost treatment for glaucoma: effects of treating for 1 year and of switching from timolol. United
States Latanoprost Study Group. Latanoprost treatment for glaucoma: effects of treating for 1 year and of
switching from timolol. United States Latanoprost Study Group. Am J Ophthalmol. 1998 Sep;126(3):390-9.
4. Additive intraocular pressure lowering effect of various medications with latanoprost. Additive intraocular
pressure lowering effect of various medications with latanoprost. Am J Ophthalmol. 2002
Jun;133(6):836-7.
5. Netland PA, Landry T, Sullivan EK, Andrew R, Silver L, Weiner A, Mallick S, Dickerson J, Bergamini MV,
Robertson SM, Davis AA; Travoprost Study Group. Travoprost compared with latanoprost and timolol in patients
with open-angle glaucoma or ocular hypertension. Am J Ophthalmol. 2001 Oct;132(4):472-84.
6. Schumer RA, Camras CB, Mandahl AK. Putative side effects of prostaglandin analogs. Surv Ophthalmol.
2002 Aug;47 Suppl 1:S219.
7. Noecker RS, Dirks MS, Choplin N; Bimatoprost/Latanoprost Study Group. Comparison of latanoprost, bimatoprost,
and travoprost in patients with elevated intraocular pressure: a 12-week, randomized, maskedevaluator
multicenter study. Am J Ophthalmol. 2004 Jan;137(1):210-1.
8. Parrish RK, Palmberg P, Sheu WP; XLT Study Group. A comparison of latanoprost, bimatoprost, and travoprost
in patients with elevated intraocular pressure: a 12-week, randomized, masked-evaluator multicenter
study. Am J Ophthalmol. 2003 May;135(5):688-703.
9. Zimmerman TJ, Review of clinical studies of beta-blocking agents.Surv Ophthalmol. 1989 Apr;33 Suppl:461-2;
10. van der Valk R, Webers CA, Schouten JS, Zeegers MP, Hendrikse F, Prins MH. Intraocular Pressure-Lowering
Effects of All Commonly Used Glaucoma Drugs A Meta-analysis of Randomized Clinical Trials. Ophthalmology.
2005 July, 112 (7): 1-7.
11. Toris CB, Koepsell SA, Yablonski ME, Camras CB. Aqueous Humor Dynamics in Ocular Hypertensive Patients.
J Glaucoma. 2002 November; (1)53-258.
12. Toris CB, Yablonski ME, Wang YL, Camras CB. Aqueous Humor Dynamics in the Aging Human Eye. Am J
Ophthalmol 1999. April; 127 (4): 407-412.
13. Liu JH, Sit AJ, Weinreb RN. Variation of 24-hour intraocular pressure in healthy individuals: right eye
versus left eye. Ophthalmology. 2005 Oct;112(10):1670-5.
14. Mossaed S, Liu JH, Weinreb RN. Correlation between office and peak nocturnal intraocular pressures in
healthy subjects and glaucoma patients.
Am J Ophthalmol. 2005 Feb;139(2):320-4.
15. Liu JH, Zhang X, Kripke DF , Weinreb RN Twenty-four-hour intraocular pressure pattern associated with
early glaucomatous changes. Invest Ophthalmol Vis Sci. 2003 Apr;44(4):1586-90
7 | The Management of Glaucoma
Murray Fingeret, OD
There are many situations that confront the optometrist as
he/she decides whether to initiate therapy for ocular hypertension
(OHT) or glaucoma. For ocular hypertension, the decision process
is discussed in Chapter 5. In regard to glaucoma, when optic nerve
and/or visual field damage associated with glaucoma is recognized
and other causes of this loss are ruled out, therapy is in order. Before
therapy commences, a strategy is developed based upon the
stage of disease and IOP level, as well as other factors. A target intraocular
pressure (IOP) range is determined and a medication selected.
If therapy is not indicated, the patient is often classified as
a glaucoma suspect and followed once to twice per year, depending
upon the individuaľs characteristics. The category of glaucoma suspect
includes individuals with ocular hypertension as well as suspicious
optic nerves or visual fields.
When medical therapy is initiated, the selection of the initial
agent usually is decided between two classes of drugs:
1166 RREEVVIIEEWW OOFF OOPPTTOOMMEETTRRYY//OOPPTTOOMMEETTRRIICC GGLLAAUUCCOOMMAA SSOOCCIIEETTYY
prostaglandins (PGs) or topical beta-blockers. PGs have replaced
beta-adrenergic antagonists as the most commonly used agent for
initial therapy. This is due to their ability to reduce IOP efficiently
on a once-per-dosage schedule, without inducing serious side effects,
as well as their dampening IOP fluctuations that may occur
over a 24-hour period (diurnal curve). Beta-adrenergic antagonists
do not reduce IOP as effectively, especially when viewed over a 24hour
period, and have some additional contraindications. Recent
information from several clinical trials has highlighted the need for
reduced target IOPs, further cementing PG's role as first-line agents.
The initial medication selected is based upon its ability to reduce
IOP, its safety profile, tolerability and patient acceptance. The drug
needs to be matched to the patient. For example, a patient with a
history of anterior uveitis or macula edema would not be a good
candidate for PG therapy. Likewise, a patient with pulmonary disease
would not be a candidate for beta-adrenergic antagonist therapy.
Target IOPs must also be considered as a therapeutic agent is
selected. Target pressures refer to the range of IOP that we hope
will prevent further glaucomatous damage. A patienťs target IOP
may change over time, either as new knowledge becomes available,
indicating lower IOPs will be advantageous or if progression is confirmed.
Target IOPs are a best guess of what IOP will control the
condition. The best indicator to show that target IOP has been
achieved is when periodic optic nerve and visual field evaluations
reveal no change. If change is noted, additional reduction is necessary.
Target IOPs are based on the amount of damage present and
the highest IOP reading, with greater reduction required as damage
worsens. Recent clinical trials have provided evidence that lower
target IOPs are important, though no definitive study has shown
exactly what IOPs are optimal.
The Ocular Hypertension Treatment Study (OHTS), which had a
target IOP reduction of 20%, found that 4.4% of individuals in the
therapy group progressed. In a study of glaucoma patients, the Early
Manifest Glaucoma Trial (EMGT), in which the goal was 25% IOP
reduction, 45% of patients in the therapy group progressed over
time. The Collaborative Initial Glaucoma Treatment Study (CIGTS)
which had a similar group of patients with early glaucoma as the
EMGT, also monitored for progression. CIGTS found little change in
the group whose IOP was reduced 38%. In the Advanced Glaucoma
Intervention Study (AGIS), groups were broken down based on the
percentage of visits in which the IOP was reduced below 18mmHg.
One group with a mean IOP of 20.2mmHg showed significant deterioration,
while another group with a mean IOP of 12.3mmHg appeared
to be stable over an 8-year period. These studies, taken as
a group, do not provide proof that IOPs need to be reduced to the
low teens for all patients, but they do illustrate the need to reduce
IOPs to lower levels than previously thought.
The EMGT recognized that risk factors for glaucomatous progression
include higher IOP at the time of diagnosis, pseudoexfoliation,
bilateral disease, disc hemorrhages, older age and worse visual field
mean deviation. The AGIS found that an additional risk factor is
variation in IOP over a 24-hour period. This is a separate risk that
describes IOP fluctuation throughout the day, even when IOP is low
at certain time points. To recognize diurnal fluctuations, we should
record the time of each visit and schedule exams at varying times
during the day.
Often it is helpful to begin therapy with a monocular or unilateral
trial in which medication is begun in one eye for a few weeks,
with the contralateral eye serving as a control. The rationale is that
IOP, while often different between the two eyes, will rise and fall
over the day to a similar degree. Also, the response to a medication
should be similar in both eyes. Since non-responder rates vary from
8% to 25% depending on the class of medication, a monocular trial
is one way to ensure the medication is effective as well as determine
if side effects are occurring. Realini has questioned the use of
the monocular trial, in part because the IOP reduction in one eye
does not necessarily predict how the drug will perform in the other.
Moreover, monocular trials require at least one additional visit.
Nevertheless, many experts continue to recommend the monocular
trial, recognizing its limitations but also using it as a way to control
the initiation of a new drug.
At the outset of therapy, the patient needs to be educated in regard
to the optimal time for drop instillation(s) and potential side
effects. Also, it is important to demonstrate proper eyedrop instillation
technique and have the patient demonstrate that he/she
can properly instill the drops. If eyedrop instillation appears to be
a problem, there are devices to aid instillation. Also, a companion
or family member may aid in medication insertion. Finally, written
dosing schedules should be provided as reminders. The first followup
visit usually occurs 2 to 4 weeks after therapy commences. At
each visit, ask if any side effects have occurred and when the patient
last used the medication(s). Patient communication is discussed
in Chapter 10. Even when written schedules are provided,
some patients misunderstand how to use the medication. Questions
that should be addressed at every visit include whether the patient
is actually using the drug or if there are any problems or concerns.
The IOP is measured to assess whether the medication is effective
and pressure is at target level. If the drug is well-tolerated and effective,
then the patient is followed over time, watching for medication
side effects and/or progression. Patients are seen every 3 to
6 months depending on severity and type of disease. Ocular hypertensives
are monitored less often, and individuals with significant
loss, more often. Dilated optic nerve evaluation, imaging and visual
field testing should be performed at least yearly. Testing more
often is recommended in the first year after diagnosis, if a greater
degree of loss is present or a question of stability arises.
An important question that should be considered early in the
course of follow-up is the rate of change. If a patient is progressing
rapidly, we need to recognize this and modify our approach.
One way to measure rate of change is to perform perimetry on a 6month
basis for the first 2 years. This is best done with SITA visual
fields and the Glaucoma Progression Analysis (GPA) software
tool. If the fields are unchanged, the interval between field testing
can be increased to yearly. Several fields are needed before a decision
can be reached regarding stability, but once 5 fields are available,
trends will emerge.
One challenge occurs when a patient does not respond or side effects
develop with the initial medication. If side effects occur, what
are they? Are they caused by the medication? May they be reduced
if a switch occurs within the same class of drugs? An intra-class
OOPPTTOOMMEETTRRIICC GGLLAAUUCCOOMMAA SSOOCCIIEETTYY//RREEVVIIEEWW OOFF OOPPTTOOMMEETTRRYY 1177
switch may work if hyperemia develops with one PG. A more difficult
question is if the target IOP level is not reached with the initial
medication. In this case, the IOP response needs to be
evaluated. For example, if the IOP was very high and/or the damage
significant, leading to a target goal of 40% reduction, and the
drug provides 25% of the target reduction, then the medication appears
to be effective, but a second agent is needed. On the other
hand, if the reduction is 15% or less, the patient may be considered
a non-responder. Inadequate responses do occur and are not
often recognized, leading to unachieved target levels. We should
ask if progression may occur in 15 years at the present IOP level. It
may be then easier to appreciate the urgency of attempting to
achieve target IOP levels.
There are different reasons why the IOP may not have been reduced
with the initial agent, including lack of response or poor
compliance with the clinician faced with a decision of how to proceed.
Switching to a drug within the same class, such as going from
one PG to another (intra-class switches) is controversial, since it is
not proven that such switches work. Switch studies with PGs have
shown that the medication switched to always performs better.
However, one problem is that most switch studies have been conducted
over only short periods, usually about 30 days. The improved
efficacy may be due to the second drug's greater response,
but other possible reasons for this reduction include improved compliance
or fluctuations in IOP (regression to the mean).
If the medication is effective but further reduction is needed, either
because the IOP is above the target goal or progression is identified,
the practitioner may choose an additional medication. If a
PG is the initial agent, the second agent may be a beta-blocker, alpha
agonist or topical CAI. A beta-blocker offers the convenience
of once-per-day use; thus the patient would take it in the morning
and take the PG at nighttime. When added to a PG, topical CAIs
may be more effective at lowering IOP than beta-blockers. But, topical
CAIs require twice-per-day dosage. If a patient is on a PG along
with a beta-blocker or topical CAI and further IOP reduction is
needed, then either of these drugs may be discontinued and a
fixed-combination agent containing timolol and dorzolamide
(Cosopt) begun. It is important to stress to patients taking two
medications that they should wait five minutes before instilling the
second agent to avoid washing the first from the eye. Also, remember
to instruct patients taking beta-blockers to close their eyes or
occlude their punctum for three minutes. This will reduce systemic
absorption, improve efficacy and reduce side effects. Argon or Selective
Laser Trabeculoplasty and filter surgery become options when
the patient is progressing or the IOP is above the target level, and
several medical options have been tried (see chapter 8).
In some cases, even with patients who respond well to initial
therapy, the IOP may slowly rise over time. Such increases could be
due to the glaucoma worsening, problems with compliance or the
development of tachyphylaxis. The two questions to ask are: Is the
drug effective, and is it being used? If the IOP is elevated, instill
the medication and measure the IOP several hours later. Also, observe
the patienťs drop instillation technique to determine if the
drug is getting into the eye. And finally, the reverse monocular trial
may be helpful to address whether tachyphylaxis has developed.
In this trial, the drug is temporarily discontinued in one eye and
continued in the other. If tolerance has developed, there will be little
change in the untreated eye's IOP over the next several weeks.
However, a rising IOP proves the drug is effective and should be
continued, but an additional agent is necessary.
The management of ocular hypertension and glaucoma is an art
that requires the clinician to make an ongoing series of decisions
and adjustments over the patienťs lifetime to ensure the IOP remains
at acceptable levels and the condition does not worsen. Periodic
monitoring of the optic nerve and visual fields are also
necessary. The doctor needs to consider both the short and longterm
view to ensure occurs throughout the lifetime of their patient.
Suggested Readings
1. Realini T, Fechtner RD, Atreides SP, Gollance S. The uniocular drug trial and second-eye response to
glaucoma medications. Ophthalmology. 2004 Mar;111(3):421-6.
2. Realini T, Vickers WR. Symmetry of fellow-eye intraocular pressure responses to topical glaucoma medications.
Ophthalmology. 2005 Apr;112(4):599-602.
3. Kass MA, Heuer DK, Higginbotham EJ, Johnson CA, Keltner JL, Miller JP, Parrish RK 2nd, Wilson MR,
Gordon MO. The Ocular Hypertension Treatment Study: a randomized trial determines that topical ocular
hypotensive medication delays or prevents the onset of primary open-angle glaucoma. Arch Ophthalmol.
2002 Jun;120(6):701-13.
4. Gordon MO, Beiser JA, Brandt JD, Heuer DK, Higginbotham EJ, Johnson CA, Keltner JL, Miller JP, Parrish
RK 2nd, Wilson MR, Kass MA. Baseline visual field characteristics in the ocular hypertension treatment
study. Ophthalmology. 2002 Mar;109(3):432-7.
5. Higginbotham EJ, Gordon MO, Beiser JA, Drake MV, Bennett GR, Wilson MR, Kass MA; Ocular Hypertension
Treatment Study Group. The Ocular Hypertension Treatment Study: topical medication delays or prevents
primary open-angle glaucoma in African American individuals. Arch Ophthalmol. 2004
Jun;122(6):813-20.
6. Heijl A, Leske MC, Bengtsson B, Hyman L, Bengtsson B, Hussein M; Early Manifest Glaucoma Trial Group.
Reduction of intraocular pressure and glaucoma progression: results from the Early Manifest Glaucoma Trial.
Arch Ophthalmol. 2002 Oct;120(10):1268-79.
7. Heijl A, Leske MC, Bengtsson B, Bengtsson B, Hussein M; Early Manifest Glaucoma Trial Group. Measuring
visual field progression in the Early Manifest Glaucoma Trial. Acta Ophthalmol Scand. 2003 Jun;81(3):286-
93.
8. The Advanced Glaucoma Intervention Study (AGIS): 7. The relationship between control of intraocular
pressure and visual field deterioration. The AGIS Investigators. Am J Ophthalmol. 2000 Oct;130(4):429-40.
9. Feiner L, Piltz-Seymour JR; Collaborative Initial Glaucoma Treatment Study. Collaborative Initial Glaucoma
Treatment Study: a summary of results to date. Curr Opin Ophthalmol. 2003 Apr;14(2):106-11.
10. O'Connor DJ, Martone JF, Mead A. Additive intraocular pressure lowering effect of various medications
with latanoprost. Am J Ophthalmol. 2002 Jun;133(6):836-7.
11. Bengtsson B, Leske MC, Hyman L, Heijl A. Early Manifest Glaucoma Trial Group. Fluctuation of intraocular
pressure and glaucoma progression in the early manifest glaucoma trial. Ophthalmology. 2007
Feb;114(2):205-9.
8 | When Medical Therapy Fails: Surgical
Options for Glaucoma Management
Kathy Yang-Williams, OD
Surgical intervention becomes an option in the management of
open-angle glaucoma when the intraocular pressure (IOP) cannot
be sufficiently reduced with medical therapy to prevent progressive
optic nerve damage and/or visual field loss. A recent analysis of
glaucoma surgery utilization rates in Medicare beneficiaries showed
that surgical procedures employed in more advanced glaucoma
(trabeculectomy, glaucoma drainage devices, and cyclophotocoagulation)
have increased in frequency in the past decade. Recent innovations
in glaucoma management, such as the use of
prostaglandin analogs and selective laser trabeculoplasty, may have
allowed patients to delay more invasive glaucoma procedures.
Selective laser trabeculoplasty (SLT) is a newer procedure performed
with a Q-switched 532nm Nd:YAG laser to reduce IOP. Unlike
its predecessor, argon laser trabeculoplasty (ALT), SLT
1188 RREEVVIIEEWW OOFF OOPPTTOOMMEETTRRYY//OOPPTTOOMMEETTRRIICC GGLLAAUUCCOOMMAA SSOOCCIIEETTYY
"selectively" targets the pigmented cells of the trabecular meshwork
(TM) using a larger spot size, lower power setting and less total
energy than ALT. These laser settings cause less collateral
damage to adjacent TM cells yet reduce the IOP at a rate comparable
to ALT. Primary SLT has been shown to be as effective as latanoprost
monotherapy in several studies. Advantages of using SLT
as compared to ALT include the potential for repeat procedures, the
lack of thermal damage to the trabecular meshwork, less post-operative
pain and inflammation, and a lower dependence on pigmentation
of the angle. However, much like ALT, the success rate of SLT
declines over time. Studies of long-term efficacy of SLT have yet to
be completed.
Glaucoma filtering surgery is intended to provide long-term
control of IOP without medications; to maintain adequate diurnal
control with minimal post-operative complications or subjective
discomfort. The ideal procedure would be widely available and
easily taught without requiring excessive expense for instrumentation.
The current gold standard for glaucoma filtering surgery
is trabeculectomy, a procedure first popularized by Cairns in 1968.
During trabeculectomy, the surgeon creates a partial scleral flap
before excising a block of trabecular meshwork. This scleral tunnel
allows aqueous to escape from the eye to the subconjunctival
space. Trabeculectomy has been associated with a number of complications,
including bleb dysesthesia (symptomatic bleb),
cataract, bleb failure, hyphema, wound leak, flat anterior chamber,
ocular hypotony, hypotony maculopathy, choroidal detachment,
suprachoroidal hemorrhage, bleb infection and
endophthalmitis.
Surgical variations
of this procedure
have been designed
to reduce the frequency
of these
complications. The
use of anti-metabolite
therapy, such as
5-fluorouracil (5-FU)
and mitomycin-C
(MMC), reduces the
risk for bleb failure by controlling the formation of scar tissue at
the surgical site. Anti-metabolites are indicated for high-risk patients,
such as younger patients, those with a history of failed filtration
surgery, African-Americans and individuals with aphakic,
uveitic, neovascular or secondary angle closure glaucoma. One
concern is that anti-metabolites, particularly mitomycin, have
been associated with a higher risk for late wound leak, blebitis
and endophthalmitis. Patients may present initially with an infected
bleb, or "blebitis," associated with a painful red eye, photophobia
and discharge. If the infection extends into the eye
(bleb-associated endophthalmitis), significant anterior chamber
reaction or hypopyon can result. This is an ocular emergency requiring
immediate and aggressive antibiotic therapy. Even with
treatment, the prognosis for patients with bleb-associated endophthalmitis
is poor. Trabeculectomy is a well-established technique,
but it poses significant risk for early and late
post-operative complications. Frequent post-operative visits are
necessary, and additional interventions may be required to ensure
the success of the procedure.
Non-penetrating glaucoma surgery reduces the risk of a flat anterior
chamber in the immediate post-operative period by creating
an alternative outflow pathway without the anterior chamber being
penetrated as occurs in
trabeculectomy. These procedures
are more difficult
to teach, and there is often
a steep learning curve
for surgeons. Non-penetrating
glaucoma surgeries
do not usually result in
the formation of a filtering
bleb, and patients have
fewer complaints because
of the absence of a filtering bleb. However, studies evaluating nonpenetrating
glaucoma surgery show that intraocular pressure reduction
is generally less than what can be achieved with
trabeculectomy.
Several new glaucoma surgeries intended to reduce IOP without
the creation of a filtering bleb are in development. Unlike trabeculectomy
and glaucoma drainage devices that shunt aqueous
humor to the subconjunctival space where it is resorbed via an
episcleral bleb, these procedures either restore or modify existing
natural outflow pathways or redirect aqueous via alternative pathways.
One group of procedures bypasses TM to re-establish physiologic
outflow and avoid the juxtacanalicular TM, while another
diverts aqueous away from the anterior chamber into the suprachoroidal
space. (Figure 1).
When fluid is directed into the distal outflow channels, the
aqueous flows into the sub-scleral space rather than subconjunctival
space, as in trabeculectomy, so no bleb is created. There is
no risk of hypotony due to the inherent resistance of the distal
outflow system and episcleral venous pressure (believed to be in
the range of 12 mmHg). Initial results with these procedures suggest
that IOP can be significantly reduced although not to the
same degree as is achieved with trabeculectomy. But, complicaFigure
3. Ablation of TM by Trabectome. (Courtesy of
Neomedix Inc, Tustin CA).
Figure 1. Schematic representation of glaucoma surgery mechanisms. (Modified from Primary
Care of the Glaucomas, Fingeret, Lewis: 2001. McGraw Hill, NY).
Figure 2. Microcannulation of Schlemm's canal. (Courtesy of
iScience Interventional, Menlo Park CA).
OOPPTTOOMMEETTRRIICC GGLLAAUUCCOOMMAA SSOOCCIIEETTYY//RREEVVIIEEWW OOFF OOPPTTOOMMEETTRRYY 1199
tions such as hypotony
and flat anterior
chamber are
avoided. In canaloplasty
with tensioning
suture (iScience
Interventional, Menlo
Park, CA), Schlemm's
canal is circumferentially
dilated with
Healon GV (sodium
hyaluronate, Advanced
Medical Optics, Santa Ana, CA) using a microcannula 200
microns in diameter. An optic fiber allows the microcatheter to be
viewed through the sclera (Figure 2). Once the canal has undergone
viscodilation, a 10-0 Prolene suture (Ethicon Inc, Somerville,
N.J.) is attached to the cannula and advanced through the canal
as the cannula is withdrawn. This suture creates tension on the
TM, bringing it anteriorly to reduce resistance to outflow. The Trabectome
(NeoMedix, Tustin CA) accesses existing outflow channels
by creating a direct communication between the anterior chamber
and Schlemm's canal. This ab interno trabeculotomy combines an
electrosurgical device with irrigation, aspiration and a protective
footplate to ablate and remove TM and the inner wall of Schlemm's
canal (Figure 3). Transient intra-operative hyphema due to blood
reflux into Schlemm's canal is the most common complication of
this procedure. Initial results are promising, with IOP controlled in
the 15 to 16 mmHg range. There is no bleb formation or risk for
flat anterior chamber, and perilimbal conjunctiva is preserved if
further surgical intervention becomes necessary. A new, micro-invasive
procedure that restores the conventional outflow pathway
by bypassing TM resistance is the iStent (Glaukos Corp., Laguna
Hills, CA). This trabecular bypass micro stent is an L-shaped titanium
tube measuring 120 microns in diameter that is implanted
into Schlemm's canal using a tiny opening through TM (Figure 4).
The lumen of the stent restores aqueous flow from the anterior
chamber into Schlemm's canal. Prospective clinical studies demonstrate
post-operative intraocular pressures of 15mmHg-16mmHg at
12 months. Again, no bleb is formed and the placement of the iStent
preserves all future options for glaucoma filtering surgery.
Multiple implants may be used to further reduce IOP and to titrate
IOP reduction based upon individual patient target pressures. The
Solx Gold Shunt (Occulogix Inc, Mississauga, Ontario, Canada) is a
60 micron wafer made of two gold plates that is designed to increase
uveoscleral outflow by redirecting fluid from the anterior
chamber to the suprachoroidal space. This novel technology takes
advantage of a physiologically negative pressure differential between
these two areas and explores yet another pathway for aqueous
outflow.
A glaucoma drainage device (GDD) consists of an endplate of
varying surface area and design that is inserted into the subconjunctival
space. The end-plate is attached to a drainage tube inserted
into the anterior chamber or the posterior chamber via the
pars plana. This drainage tube may offer little resistance to aqueous
flow (such as Baerveldt, Molteno) or may be constructed with
a unidirectional valve (such as Ahmed, Krupin). Non-valved
drainage implants require the insertion of a removable stent within
the tube or a ligature around the tube to prevent immediate
post-operative hypotony. Drainage implants can reduce IOP 50%
below pre-operative levels. However, they are also associated with
complications including hypotony, corneal decompensation, encapsulation
of end-plate, erosion of tube, suprachoroidal hemorrhage
and diplopia. Drainage implants, or tube shunts, have
traditionally been reserved for patients who have uncontrolled IOP
and a history of failed filtration procedures, scleral buckling surgery,
extensive conjunctival scarring or exaggerated inflammatory
response (neovascular or uveitic glaucoma). Interestingly, implants
are being done more commonly, and some individuals are
using them as their primary filtration surgical modality. Early results
from the Tube versus Trabeculectomy Study (TVT) indicate
that both procedures produced approximately equal IOP reduction
at the end of the first year, but patients more often required the
use of supplemental medication to reach acceptable IOP following
the placement of a non-valved GDD. Future reports from the TVT
study will help to evaluate the role of tube surgery in glaucoma
management for this specific patient population.
Glaucoma surgery will continue to evolve with the development
of new imaging techniques and materials. The ultimate goal of surgical
intervention is to achieve long term IOP control with lower
risk for surgical complication.
Acknowledgements
The author would like to acknowledge Bruce Cameron, MD, and Annisa
Jamil, MD, for their discussions in the preparation of this article.
Suggested Readings
1. Bahler CK, Smedley GT, Zhou J, Johnson DH. Trabecular bypass stents decrease intraocular pressure in
cultured human anterior segments. Am J Ophthalmol. 2004; 138: 988-994.
2. Busbee BG. Recchia FM, Kaiser R, et al. Bleb-associated endophthalmitis: Clinical characteristics and visual
outcomes. Ophthalmology. 2004; 111: 1495-1503.
3. Cameron BD, Field MW, Ball S, Kearney J. Circumferential viscodilation of Schlemm's canal with a flexible
microcannula during non-penetrating surgery. Digital J Ophthalmol. 2006; 12.
4. Francis BA, Ianchulev T, Schofield JK et al. Selective laser trabeculoplasty as a replacement for medical
therapy in open-angle glaucoma. Am J Ophthalmol. 2005; 140: 524-525.
5. Francis BA, See RF, Rao NA et al. Ab interno trabeculectomy: Development of a novel device (Trabectome)
and surgery for open-angle glaucoma. J Glaucoma. 2006; 15: 68-73.
6. Gedde SJ, Schiffman JC, Feuer WJ et al. Treatment outcomes in the tube versus trabeculectomy study after
one year of follow-up. Am J Ophthalmol 2007: 143: 9-22.
7. Gedde SJ, Schiffman JC, Feuer WJ et al. Surgical complications in the tube versus trabeculectomy study
during the first year of follow-up. Am J Ophthalmol 2007: 143: 23-31.
8. Goldsmith JA, Ahmed IK, Crandall AS. Non-penetrating glaucoma surgery. Ophthalmol Clin N Am. 2005;
18: 443-460.
9. Hong CH, Arosemena A, Zurakowski D, Ayyala RS. Glaucoma drainage devices: A systematic literature review
and current controversies. Surv Ophthalmol. 2005; 50: 48-60.
10. Jamil AL, Mills RP. Editorial: Glaucoma tube or trabeculectomy? That is the question. Am J Ophthalmol.
2007; 143: 141-142.
11. McIlraith I, Strasfeld M, Colev G, Hutnik CM. Selective laser trabeculoplasty as initial and adjunctive
treatment for open-angle glaucoma. J Glaucoma. 2006; 15: 124-130.
12. Minckler DS, Baerveldt G, Ramirez Alfaro M, Francis BA. Clinical results with the Trabectome for treatment
of open-angle glaucoma. Ophthalmology. 2005; 962-967.
13. Nagar M, Ogunyomade A, O'Brart DP et al. A randomized, prospective study comparing selective laser
trabeculoplasty with latanoprost for the control of intraocular pressure in ocular hypertension and open
angle glaucoma. Br J Ophthalmol. 2005; 89: 1413-1417.
14. Ramulu PY, Corcoran KJ, Corcoran SL, Robin AL. Utilization of various glaucoma surgeries and procedures
in Medicare beneficiaries from 1995 to 2004. Ophthalmology. 2007; in press.
15. Sarodia U, Shaarawy T, Barton K. Nonpenetrating glaucoma surgery: a critical evaluation. Curr Opin
Ophthalmol. 2007; 18: 152-158.
16. Schwartz KS, Lee RK, Gedde S. Glaucoma drainage implants: a critical comparison of types. Curr Opin
Ophthalmol. 2006; 17: 181-189.
17. Spiegel D, Wetzel W, Haffner DS, Hill RA. Initial clinical experience with the trabecular micro-bypass
stent in patients with glaucoma. Adv Ther. 2007: 24:161-170.
18. Stein JD, Challa P. Mechanisms of action and efficacy of argon laser trabeculoplasty and selective laser
trabeculoplasty. Curr Opin Ophthalmol. 2007; 18: 140-145.
Figure 4. iStent trabecular bypass micro stent. (Courtesy of
Glaukos Corp, Laguna Hills CA).
2200 RREEVVIIEEWW OOFF OOPPTTOOMMEETTRRYY//OOPPTTOOMMEETTRRIICC GGLLAAUUCCOOMMAA SSOOCCIIEETTYY
9 | Adherence in Glaucoma Therapy
Steven R. Hahn, MD
Patients do not benefit from medicines they do not take, and
most clinicians are aware that patients commonly fail to take all
the medication that they are prescribed. Yet, nonadherence does
not receive attention proportionate to its recognized importance in
clinical practice. Although some physicians may need to be reminded
about the magnitude of the problem, it is not a fundamental ignorance
of nonadherence that explains the lack of attention it
receives. One answer may be that clinicians intuitively know what
research on adherence has demonstrated: Nonadherence is difficult
to detect, its causes may be hard to identify, and the factors that
determine adherence often seem to be beyond the clinician's control
or scope of clinical expertise. These beliefs may create a sense
of powerlessness that is ultimately rationalized by the feeling that
nonadherence is a revelation of the imperfection of human nature
and might as well be accepted. The goal of this chapter, and the
next one addressing doctor-patient communication, is to reverse
this pessimism and empower clinicians by providing necessary information
on the prevalence and causes of nonadherence.
"Patient compliance" was the term originally used to describe
the extent to which patients take medication and follow lifestyle
and behavioral recommendations prescribed by their clinicians. The
term "adherence" has largely supplanted "compliance" because the
latter carries the connotation of a paternalistic clinician-directed
relationship in which patients "comply" with the directives of their
doctor. By contrast, adherence connotes a patienťs willingness to
"stick to" a treatment that they have agreed upon with their clinician.
A consensus panel convened by the World Health Organization
chose to define adherence as "the extent to which a person's
behaviour--taking medication, following a diet, and/or executing
lifestyle changes, corresponds with agreed recommendations from
a health care provider." Persistence is one aspect of adherence and
refers to the extent to which patients sustain use of medication
and lifestyle changes and behavioral treatments over time.
The first, and probably most important, problem presented by
noncompliance is the difficulty of detecting it. Numerous studies
have demonstrated that patients consistently under report and, as
discussed in the next chapter, actively conceal nonadherence from
their clinicians. A meta analysis of 86 studies revealed that patients
consistently overestimated adherence to treatment compared to
non-self-report methods of measuring medication taking behavior.
Concordance between face to face interview-based self-report was
particularly low with electronic event monitors, and somewhat better
with adherence questionnaires and diaries, pill counts, insurance
claims analyses, and plasma drug concentrations. Clinicians'
assessments of adherence also consistently over-estimate adherence.
One reason for under detection in addition to relying on patients'
self-report may be reliance on measurement of rapidly
responsive physiological parameters such as intraocular pressure at
the time of a doctor visit, because patients are often more adherent
to medication just before their visits to the doctor. This socalled
"white coat adherence" has been observed in several
therapeutic areas, including glaucoma. Although self-report of
nonadherence may be an insensitive measure of the problem, it is
reasonably specific. A meta analysis of four studies comparing patient
self-report to pill count showed that asking patients if they
had missed any doses of any medication detected 55% of patients
defined as nonadherent by pill count (sensitivity), and had a specificity
of 87%. Nonadherence to treatment is common across therapeutic
areas. In a quantitative survey of 569 studies published
between 1966 and 1998, adherence ranged from 4.6% to 100%, with
a median of 76% and an overall average of 75.2%. Rates of adherence
varied significantly with the methods used to measure them,
from a low of 66.6% for collateral report and 69% for MEMS caps to
a high of 85% for pill count. Rates of adherence to behavioral interventions,
such as diet and exercise, are often as low as 10%.
Although there is no gold standard for adherence measurement,
the use of surreptitious electronic devices (MEMS recorders) that
record the opening of a pill bottle or use of a medication dispenser
is one of the most reliable methods. In studies of adherence to
glaucoma medications using MEMS devices, almost half of patients
(41%) miss 10% of three times daily pilocarpine doses, i.e. one dose
in every two days. In another study using the same technology,
more than a quarter of patients (27.3%) missed more than a quarter
of timolol doses when used either alone or in combination with
pilocarpine or another medication; and a small but significant
number of patients (8.2% and 15.2%) missed half or more of their
medications. Medications that are taken more than once per day
are also vulnerable to problems with the timing of doses. Morning
medications are taken more reliably than doses later in the day,
and noon doses are the most frequently omitted. Studies using
MEMS recorders are usually of short duration and typically over
sample more persistent patients and under sample those new to
treatment. In theory, analysis of pharmacy claims data presents an
opportunity to study patients who are new to treatment and to follow
adherence behaviors over a longer period of time. An early
study using this approach suggested that one quarter of 2,440 patients
who filled an initial prescription for glaucoma medication
never filled a second one and, overall, patients were without medication
for nearly a third (30%) of the 12 month period that was
studied. Another study of 3,623 patients with diagnosed glaucoma
and 1,677 glaucoma suspects, all apparently newly treated, revealed
that nearly half had discontinued all glaucoma medication
by the end of one year.
The Glaucoma Adherence and Persistence Study (GAPS), based
upon retrospective analysis of the pharmacy and medical claims data
of 13,956 patients on glaucoma medication revealed significant problems
with nonadherence consistent with previous studies. The principal
measure of adherence used in GAPS was the medication
possession ratio, or MPR, calculated by dividing the days of supply
of medication dispensed by the number of days between prescription
fulfillments. The MPR is therefore a ratio expressing the proportion
of days for which a patient possesses enough medication to use
drops as directed. Although 89% of subjects claimed to take their
glaucoma medication "every day," the average medication possession
ratio (MPR) observed in GAPS was 0.64 (median 0.57), meaning that
the average subject only had enough medication to take 64% of pre-
OOPPTTOOMMEETTRRIICC GGLLAAUUCCOOMMAA SSOOCCIIEETTYY//RREEVVIIEEWW OOFF OOPPTTOOMMEETTRRYY 2211
scribed doses. The most poorly adherent 25% of subjects possessed
enough medication to take no more than 36% of their prescribed
doses; by contrast, the most adherent 25% possessed enough medication
to take 88% of their doses. Over half (55%) of the 10,260 subjects
followed for at least one year stopped and restarted medications
within that 12-month period. Only 10% of subjects filled prescriptions
continuously for 12 months.
Our understanding of the causes of nonadherence has evolved
from the original "Health Beliefs Model" which proposes that adherence
to treatment is the result of a balance by the patienťs perception
of their vulnerability to and the threat of the illness, the
benefit of the treatment, the cost and burden of the treatment, and
social and instrumental support for adherence. This model has
evolved to focus on specific elements within these domains. For example,
the "Information, Motivation, and Behavioral Skills" (IMB)
model asserts that these are the three key independent determinants
of adherence. This model makes the observation that patients
can be motivated to adhere without being knowledgeable
about the illness and vice versa, but they must have the specific
information that supports critical behavioral skills, such as those
required for administration of drops, or for creating and integrating
behavioral triggers that prompt medication taking into their
daily routine. The closely related "Therapeutic Decision Model"
calls attention to the fact that patients' decisions about adherence
are dynamic and incorporate ongoing experience of side effects and
efficacy with their providers' recommendations and other sources of
information. Most patients engage in an active testing process that
usually remains obscure to clinicians because they do not actively
explore it with their patients.
Factors influencing adherence have generally been classified into
four categories: patient characteristics, provider characteristics,
characteristics of the medical regimen, and situational/logistical
factors, including cost. Tsai and colleagues identified 71 specific
barriers that patients reported interfered with using glaucoma
medication. Patients' socio-demographic characteristics have been
inconsistently associated; a review of early research in adherence
to glaucoma medication found that age and education were not associated
with nonadherence, and that ethnicity and male gender
probably were, but weakly and inconsistently. With regard to characteristics
of the regimen, increased frequency of dosing but not
number of medications, total number of medicines for all conditions,
and frequency of side effects have been related to nonadherence.
Several studies have documented better adherence for
prostaglandins compared to other classes of medication. Cost of
medication and the need to integrate medication taking with the
daily routine have been associated with adherence.
Emerging data from GAPS suggests that provider-patient communication
and concern about the future consequences of glaucoma are
important factors in driving adherence. Patients who do not have a
robust understanding of what glaucoma might do in the future are
less likely to adhere to treatment. Patients who passively depend
upon their providers and don't actively engage in developing their understanding
of the disease are less likely to be successful in sustaining
their motivation and in overcoming barriers to adherence.
Nonadherence to topical glaucoma medication is prevalent and
difficult to detect because nonadherence is a socially undesirable
behavior that patients are reluctant to reveal. Current understanding
of adherence behavior identifies the need for patients to understand
the progression of the disease over time in a way that
supports concern about future consequences. Patients also need to
have the behavioral skills necessary to remember and administer
medication. Patients who are actively engaged in learning about
glaucoma and interested in participating in decision making are
most likely to overcome barriers to adherence. Providers can screen
for active engagement in self-care and for the presence of a motivating
concern about consequences by asking patients to describe
their understanding and concerns about what glaucoma might do
in the future. The epidemiology of barriers to adherence support
the value of screening for specific barriers to adherence such as
cost of medication, taking medications while traveling and away
from home, and the mechanics of drop administration. Communication
strategies for addressing these factors are addressed in the
chapter on communication.
Suggested Readings
1. Sabate, E. Adherence to long-term therapy:Evidence for action. 2003. World Health Organization.
2. Aaker E, Knudsen A, Wynn R, Lund A. General practitioners' reactions to non-compliant patients. Scand
J Prim Health Care. 2001;19:103-106.
3. Patel UD, Davis MM. Physicians' attitudes and practices regarding adherence to medical regimens by patients
with chronic illness. Clin Pediatr Phila.. 2006;45:439-445.
4. Reif S, Smith SR, Golin CE. Medication adherence practices of HIV/AIDS case managers: a statewide survey
in North Carolina. AIDS Patient Care STDS. 2003;17:471-481.
5. Roberts KJ. Physician beliefs about antiretroviral adherence communication. AIDS Patient Care STDS.
2000;14:477-484.
6. Sahm G, Bartsch A, Witt E. Reliability of patient reports on compliance. Eur J Orthod. 1990;12:438-446.
7. Rand CS. Measuring adherence with therapy for chronic diseases: implications for the treatment of heterozygous
familial hypercholesterolemia. Am J Cardiol. 1993;72:68D-74D.
8. Garber MC, Nau DP, Erickson SR, Aikens JE, Lawrence JB. The concordance of self-report with other measures
of medication adherence: a summary of the literature. Med Care. 2004;42:649-652.
9. Gilbert JR, Evans CE, Haynes RB, Tugwell P. Predicting compliance with a regimen of digoxin therapy in
family practice. Can Med Assoc J. 1980;123:119-122.
10. Mazze RS, Shamoon H, Pasmantier R et al. Reliability of blood glucose monitoring by patients with diabetes
mellitus. Am J Med. 1984;77:211-217.
11. Miller LG, Liu H, Hays RD et al. How well do clinicians estimate patients' adherence to combination antiretroviral
therapy? J Gen Intern Med. 2002;17:1-11.
12. Carroll CL, Feldman SR, Camacho FT, Manuel JC, Balkrishnan R. Adherence to topical therapy decreases
during the course of an 8-week psoriasis clinical trial: Commonly used methods of measuring adherence to
topical therapy overestimate actual use. Journal of the American Academy of Dermatology. 2004;51:212-216.
13. Cramer JA, Scheyer RD, Mattson RH. Compliance declines between clinic visits. Arch Intern Med.
1990;150:1509-1510.
14. Kruse W. Patient compliance with drug treatment--new perspectives on an old problem. Clin Investig.
1992;70:163-166.
15. Schwed A, Fallab CL, Burnier M et al. Electronic monitoring of compliance to lipid-lowering therapy in
clinical practice. J Clin Pharmacol. 1999;39:402-409.
16. Simmons MS, Nides MA, Rand CS, Wise RA, Tashkin DP. Trends in compliance with bronchodilator inhaler
use between follow-up visits in a clinical trial. Chest. 1996;109:963-968.
17. Kass MA, Meltzer DW, Gordon M, Cooper D, Goldberg J. Compliance with topical pilocarpine treatment.
Am J Ophthalmol. 1986;101:515-523.
18. Stephenson BJ, Rowe BH, Haynes RB, Macharia WM, Leon G. The rational clinical examination. Is this
patient taking the treatment as prescribed? JAMA. 1993;269:2779-2781.
19. Cramer JA, Mattson RH, Prevey ML, Scheyer RD, Ouellette VL. How often is medication taken as prescribed?
A novel assessment technique. JAMA. 1989;261:3273-3277.
20. Haynes RB, Taylor DW, Sackett DL, Gibson ES, Bernholz CD, Mukherjee J. Can simple clinical measurements
detect patient noncompliance? Hypertension. 1980;2:757-764.
21. Stewart M. The validity of an interview to assess a patienťs drug taking. Am J Prev Med. 1987;3:95-100.
22. DiMatteo MR. Variations in patients' adherence to medical recommendations: a quantitative review of
50 years of research. Med Care. 2004;42:200-209.
23. Haynes RB. Improving patient adherence: State of the art, with special focus on medication taking for
cardiovascular disorders. Patient compliance in health care research: American Heart Association Monograph
Series. Futura Publishing Co; 2001:3-21.
24. Olthoff CM, Schouten JS, van de Borne BW, Webers CA. Noncompliance with ocular hypotensive treatment
in patients with glaucoma or ocular hypertension an evidence-based review. Ophthalmology.
2005;112:953-961.
25. Gurwitz JH, Glynn RJ, Monane M et al. Treatment for glaucoma: adherence by the elderly. Am J Public
Health. 1993;83:711-716.
26. Nordstrom BL, Friedman DS, Mozaffari E, Quigley HA, Walker AM. Persistence and adherence with topical
glaucoma therapy. Am J Ophthalmol. 2005;140:598-606.
27. Amico KR, Toro-Alfonso J, Fisher JD. An empirical test of the information, motivation and behavioral
skills model of antiretroviral therapy adherence. AIDS Care. 2005;17:661-673.
2222 RREEVVIIEEWW OOFF OOPPTTOOMMEETTRRYY//OOPPTTOOMMEETTRRIICC GGLLAAUUCCOOMMAA SSOOCCIIEETTYY
28. Fisher JD, Fisher WA, Williams SS, Malloy TE. Empirical tests of an information-motivation-behavioral
skills model of AIDS-preventive behavior with gay men and heterosexual university students. Health Psychol.
1994;13:238-250.
29. Carey MP, Braaten LS, Maisto SA et al. Using information, motivational enhancement, and skills training
to reduce the risk of HIV infection for low-income urban women: a second randomized clinical trial.
Health Psychol. 2000;19:3-11.
30. Carey MP, Maisto SA, Kalichman SC, Forsyth AD, Wright EM, Johnson BT. Enhancing motivation to reduce
the risk of HIV infection for economically disadvantaged urban women. J Consult Clin Psychol.
1997;65:531-541.
31. Starace F, Massa A, Amico KR, Fisher JD. Adherence to antiretroviral therapy: an empirical test of the
information-motivation-behavioral skills model. Health Psychol. 2006;25:153-162.
32. Dowell J, Hudson H. A qualitative study of medication-taking behaviour in primary care. Fam Pract.
1997;14:369-375.
33. Dowell J, Jones A, Snadden D. Exploring medication use to seek concordance with `non-adherenť patients:
a qualitative study. Br J Gen Pract. 2002;52:24-32.
34. Prochaska JO, Velicer WF, Redding C et al. Stage-based expert systems to guide a population of primary
care patients to quit smoking, eat healthier, prevent skin cancer, and receive regular mammograms. Prev
Med. 2005;41:406-416.
35. Prochaska JO, Velicer WF. The transtheoretical model of health behavior change. Am J Health Promot.
1997;12:38-48.
36. Prochaska JO, DiClemente CC, Norcross JC. In search of how people change. Applications to addictive
behaviors. Am Psychol. 1992;47:1102-1114.
37. Tsai JC. Medication adherence in glaucoma: approaches for optimizing patient compliance. Current
Opinion in Ophthalmology. 2006;17:190-195.
38. Dasgupta S, Oates V, Bookhart BK, Vaziri B, Schwartz GF, Mozaffari E. Population-based persistency
rates for topical glaucoma medications measured with pharmacy claims data. Am J Manag Care.
2002;8:S255-S261.
39. Schwartz GF, Reardon G, Mozaffari E. Persistency with latanoprost or timolol in primary open-angle
glaucoma suspects. Am J Ophthalmol. 2004;137:S13-S16.
40. Shaya FT, Mullins CD, Wong W, Cho J. Discontinuation rates of topical glaucoma medications in a managed
care population. Am J Manag Care. 2002;8:S271-S277.
41. Spooner JJ, Bullano MF, Ikeda LI et al. Rates of discontinuation and change of glaucoma therapy in a
managed care setting. Am J Manag Care. 2002;8:S262-S270.
10 | Communication in the Management of
Glaucoma
Steven R. Hahn, MD
A patienťs daily decision to use glaucoma medication is the result
of a balance between their understanding of the potential risks
of glaucoma, their belief in the benefit of medication and the burden
of taking their drops. For most patients, the risk of untreated
glaucoma is an idea about potential future loss of vision. On the
other hand, the burden of treatment is not an idea; it is a tangible
daily experience. Although not as burdensome as treatment for
many other conditions, glaucoma is vulnerable to all the barriers to
adherence associated with any chronic medication and some
unique ones as well. In addition to inconvenience, cost, and integration
into daily lifestyle, topical glaucoma medication is technically
more complex to administer than a pill and often associated
with unique nuisance side effects.
If patients' adherence is a balance between the patienťs understanding
of the risks of glaucoma and the benefits and burdens of
treatment, then it is very much the story of the struggle between
the effect of episodic communications with their clinicians and the
daily experience of taking drops, because the most important and
sometimes only source of understanding about glaucoma is what
clinicians communicate to them. In short, clinician-patient communication
is the foundation of adherence, and adherence is the
key factor in treatment outcome, for patients do not benefit from
medicines that they do not take.
There are significant barriers to the detection of nonadherence
in patients' prescribed chronic medications. Research has demonstrated
that physicians have no better than a 50-50 chance of detecting
nonadherence in their patients. Three studies of occult
nonadherence from studies of chronic diseases are illustrative:
Patients with "treatment resistant hypertension" who had told
their physicians that they were taking their medications consistently
were told to continue their current treatment regimen using
a pillbox that they knew would record when they took their pills.
Subjected to this scrutiny, one-third of the patients were instantly
"cured;" however, several had syncopal episodes when they complied
with regimens that had previously been intensified in the
mistaken belief that they been adherent. Another 20% of the subjects
remained uncontrolled, but the recording pill box demonstrated
that the cause was nonadherence. In another study using
surreptitious micro recording devices, Cramer et al demonstrated
that adherence to antiseizure treatment was 88% to 86% during
the week before and after a visit to the doctor, but was only 67%
one month later. Finally, home glucose diaries were compared to
memory chip values in 19 Type I diabetics who were surreptitiously
given the first generation of glucometers with a recording memory.
Over all, half the patients made up half the values, and
physicians had a 50-50 chance of predicting which patients and
values were fabricated.
Why should patients conceal nonadherence from their clinicians?
Patients realize that providing misinformation may lead to poor decisions
about treatment, but their behavior is shaped by a more
powerful force: Nonadherence is a "socially undesirable" behavior,
and patients want to be seen as "good patients." This desire is often
stronger than their concern that concealing nonadherence
might lead to bad decisions about treatment. This tendency is exacerbated
by the fact that patients expect their clinicians to be
judgmental. Unless the clinician does something to alter it, the default
perception of the patient is that the clinician will think they
are a bad patient and be unsympathetic to any reason they have
for not taking medication as directed. Understanding these key
features of the psychology of patient self-report of nonadherence
is the foundation for a four-step, semi-structured dialogue that reduces
barriers to admitting to nonadherence by reversing the judgmental
environment and redefining the "good patient" as one who
collaborates in solving treatment problems.
Learned from the first "ASK"
1. What the patient already knows that is correct and important.
2. What the patient doesn't know that they should.
3. The patienťs misconceptions and mistaken beliefs.
Focus of the "TELL"
Reinforce what the patient understands correctly, without wasting time.
Prioritize and present the next most important pieces of information.
Correct misconceptions and mistakes.
Learned from the second "ASK"
Assess improvement in confidence, self-efficacy,and commitment.
Assess comprehension and impact of new information.
Assess comprehension and impact of corrected understanding and beliefs.
OOPPTTOOMMEETTRRIICC GGLLAAUUCCOOMMAA SSOOCCIIEETTYY//RREEVVIIEEWW OOFF OOPPTTOOMMEETTRRYY 2233
THE FOUR STEPS OF THE ADHERENCE DETECTION
INTERVIEW
1. Begin with a directive open-ended question: "Tell me how
you've been taking your medications." The patienťs response will
reveal their level of understanding of their regimen. Follow up with
a question about how they organize their medication and remember
to take them. It is useful to have the patient describe the way
they use all of their medications (both topical and systemic), even
if the clinician asking is focused on the use of only some of them.
2. Change the patienťs expectation that you will be judgmental:
Tell the patient that you know that noncompliance is
"universal," everyone has difficulty adhering to a medication
regime, and it is "normal" or understandable if a dose is missed because
of problems such as cost, side effects, inconvenience, etc.
3. Explain how information about adherence will affect decisions
about medication: For example, "Your pressure is higher
than it should be. Before we change the prescription, leťs make sure
that you've been able to use the medications you're already on. Taking
too much medicine or changing to a second-choice medication
would not be the best thing if the real problem has been with taking
the medication you've already been prescribed." This intervention
is important because it changes the definition of a "good
patient" from the unrealistic expectation that the patient will always
be adherent, to an understanding that a "good patient" is one
who discusses and solve problems with adherence with the clinician.
4. Finally, ask about "forgetting" or "missing" medications:
The critical feature of the fourth step in the sequence is that it
comes last, after the stage has been set. If the patient claims to be
adherent before steps one through three, the task of getting the
real story becomes doubly difficult because the patient will have to
admit to having not told the whole truth on top of now having to
acknowledge their nonadherence.
When problems with adherence are detected, the clinician needs
to assess two things: the patienťs motivation to take the medicine
and the presence of specific barriers to adherence. Even a patient
who experiences no burden or barrier to taking a medication will
not take it without believing there is a good reason to do so. Therefore,
the strategy is to determine that the patient is concerned
about the consequences of glaucoma and believes that taking medications
will be beneficial. The tactic for this assessment is to use
"Open-Ended Questions" about concerns and perceived benefit in
an "Ask-Tell-Ask" sequence.
Consider the Following Dialogue:
Optometrist: "Are you concerned about the consequences of
glaucoma?"
Patient: "Yes."
Compared With:
Optometrist: "Tell me what you understand about glaucoma, and
what your concerns are?"
Patient: "Well, I'm not really sure because I haven't noticed any
difference in my vision except for what the new glasses corrected.
I mean, my vision is fine when I wear my glasses. I thought glaucoma
was where you had real problems seeing. I was told that my
pressure is too high by the last doctor who saw me, the one who
put me on the drops, but my pressure was high before and I was
told there was no need for treatment. So I don't really know what
to expect, or whether I should worry or not."
The first question is "closed-ended"; one that calls for a yes or
no answer. The second is an "open-ended question"; one that cannot
be answered yes or no, but rather calls for a broader response.
This open-ended question is still focused. It is a "directed" openended
question that points the patienťs response to a particular
domain--concerns about and understanding of glaucoma--but
does not constrain the way the patient answers.
The directed open-ended question, "Tell me what you understand
about glaucoma, and what your concerns are" is the first
"ask" in a three step "ask-tell-ask" pattern that forms the basic
building block of all patient education interventions. The first ask
of the sequence will tell you three things: What the patient already
knows; what the patient doesn't know; and the patienťs misconceptions
and mistaken beliefs.
In the sample dialogue above, the clinician learns that the patient:
* Knows his "pressure is too high" and that the last doctor recommended
medication.
* Doesn't understand why medication was started, specifically
why his high intraocular pressure wasn't a reason for starting medication
before but is now.
* Has the mistaken belief that he does not have glaucoma unless
he is experiencing noticeable vision loss.
It is far better to learn what the patient already knows than it
is to launch into a set patient-education speech for at least two
reasons. First, the clinician can avoid spending unnecessary time
on information the patient already has. Second, asking first allows
the clinician to overtly acknowledge the patienťs correct understanding,
thereby reinforcing his self-confidence, sense of self-efficacy,
and praising him for his ability to collaborate in self-care
and decision making.
In our sample dialogue, the clinician can tell the patient:
"You're right, your pressure is too high, and that does produce
the problem of glaucoma if it is not corrected. It is time for medication
in your case..."
The patienťs understanding of glaucoma and medication is like
a partially assembled jigsaw puzzle. Once the clinician understands
which pieces have been connected and which are not yet aligned,
it will become clear which piece of the puzzle needs to be put in
place next to allow the rest to fall into place. A set speech on glaucoma
may include the critical information, but if it is presented
along with too much information or at the wrong time the patient
will not be able to integrate it.
In our sample dialogue, the clinician can tell the patient:
"...But, high pressure in the fluid in your eye is not the whole story
of glaucoma and when you need treatment. The pressure causes
damage to the nerve that goes from the eye to the brain, and we detected
the beginning of damage in that nerve at the last visit by
testing your visual fields, the machine with the flashing lights.
Thaťs why we knew that you need treatment." Perhaps the most important
benefit of asking before telling is the opportunity to identify
the patienťs misconceptions and mistaken beliefs. Erroneous
beliefs dramatically interfere with patients' motivation to adhere and
2244 RREEVVIIEEWW OOFF OOPPTTOOMMEETTRRYY//OOPPTTOOMMEETTRRIICC GGLLAAUUCCOOMMAA SSOOCCIIEETTYY
self-care behaviors. An undiscovered error in understanding can render
all of the correct information a clinician might provide useless.
What is truly striking is how prevalent and unpredictable patients'
mistaken beliefs can be across all chronic diseases. The only way to
discover the patienťs mistaken ideas is to ask.
In our sample dialogue, the clinician can tell the patient;
"...A lot of people believe that they don't have glaucoma unless
they notice a problem with their vision in everyday life. We can detect
the problem of glaucoma before you can yourself, and thaťs a good
thing because it gives us a chance to prevent more serious damage."
If the first ask reveals the patienťs initial knowledge, missing
information, and misconceptions, the "second" ask reveals what
has happened to those dimensions of the patienťs understanding
as a result of the "tell", and also takes the dialogue on to the next
step of explanation or instruction. The second ask should take the
general form, "What questions or concerns do you have now that
you have heard what I just told you?" In our sample dialogue, the
patienťs response to this second question was: "So you mean I've
already got damage to my eye? How bad is it? You said `prevent
more serious damage,' the medicine will do that? And what was that
about the visual field test?"
The second ask continues the dialogue, and lets the clinician
know which parts of the "tell" got through and which didn't. Our
patienťs response to the second ask makes it clear that the patient
needs to learn a little more about the stage and severity of his problem,
is ready to hear a reassuring link between medication and preventing
vision loss, and didn't quite get the role of visual fields in
managing glaucoma.
Adherence is a result of the balance between a patienťs concern
about the consequences of glaucoma, their belief in the benefit of
treatment, and the burden of taking medication. Communication between
clinician and patient is the foundation of patients' understanding.
Communication about adherence to medication is challenging
because patients would rather conceal nonadherence than be perceived
as bad patients. This barrier can be lowered by using a four-step
semi-structured dialogue that addresses the psychology of acknowledging
socially undesirable behavior. Specific barriers can be discovered
and addressed using an "ask-tell-ask" interviewing sequence.
Dr. Hahn is Professor of clinical medicine and Instructor in psychiatry at
Albert Einstein College of Medicine in the Bronx, N.Y.
Suggested Readings
1. Burnier M, Schneider MP, Chiolero A, Fallab Stubi CL, Brunner HR. Electronic compliance monitoring in
resistant hypertension: the basis for rational therapeutic decisions. J Hypertens 2001;19:335-341
2. Cramer JA, Scheyer RD, Mattson RH. Compliance declines between visits. J. Hypertension. 1990;150:335-341
3. Mazze RS, Shamoon H, Pasmantier R, et al. Reliability of blood glucose monitoring by patients with diabetes
mellitus. Am J Med. 1984;77:211-217.
11 | Secondary Glaucomas
Mitchell W. Dul, OD, MS
Secondary glaucomas represent only a small percentage of all
glaucomas but these conditions are important to understand as there
are critical differences in their diagnosis and management. This section
will discuss several of the most common secondary glaucomas.
NEOVASCULAR GLAUCOMA (NVG)
NVG is a condition caused by new blood vessel growth on the iris
and in the anterior chamber angle usually resulting from retinal ischemia
and hypoxia. NVG is an unusual condition that is more common
in older populations. Retinal ischemia and hypoxia associated
with conditions such as central retinal vein occlusion and proliferative
diabetic retinopathy are implicated in the development of neovascularization
of the anterior segment. In the presence of retinal
ischemia, angiogenic factors such as vascular endothelial growth factor
(VEGF) stimulate the proliferation of new vessels. These angiogenic
factors diffuse into the anterior chamber and promote new
vessel growth, especially in tissues with prolonged exposure to the
aqueous. Obstruction of the angle occurs as a result of the formation
of fibrovascular membranes, which serve as scaffolding for the new
blood vessels. Subsequent contracture of this membrane can lead to
progressive peripheral anterior synechia and subsequent angle clo-
sure.
Due to its prolonged contact time with the aqueous, neovascularization
usually appears first on the surface of the iris adjacent to
the pupillary border. These vessels are fine in caliber and may have
aneurism-like out-pouchings. Gonioscopic evaluation may reveal
vessels in the anterior chamber angle, even in the absence of iris
vessels. One emerging treatment for the management of neovascular
glaucoma is the use of bevacizumab (Avastin). Avastin is a monoclonal
antibody that works by attaching to and inhibiting the
action of vascular endothelial growth factor (VEGF). When VEGF is
bound to Avastin, it cannot stimulate the formation and growth of
new blood vessels. Injected into the vitreous, this compound has
been shown to produce a rapid improvement of retinal and iris neovascularization
after a single injection. In addition to this emerging
therapy, treatment of the underlying retinal ischemia with panretinal
photocoagulation can also prevent anterior chamber neo-
vascularization.
Neovascular glaucoma can lead to a blind, painful eye. Management
includes the use of topical atropine 1% to decrease ocular
congestion and topical steroids to decrease inflammation along
with concurrent use of antiglaucoma medications. Still, surgery remains
the main form of therapy. Surgical procedures include cyclocryotherapy,
trabeculectomy and tube implant. In general,
outcomes are less successful compared to primary open angle glaucoma,
although used with Avastin, results may be improved.
GLAUCOMA ASSOCIATED WITH INFLAMMATION
Inflammation associated with different sectors of the eye (scleritis,
uveitis, keratitis, trabeculitis) may lead to an increase in IOP
substantial enough to cause glaucomatous optic atrophy. In addition,
the use of corticosteroid for the treatment of these conditions
may also be responsible for increased IOP (steroid responder). In
both the pediatric and adult populations, the prevalence of glaucoma
associated with uveitis ranges from 5% to 14%, although the
etiology of the uveitis varies between these populations. In the
general glaucoma population, inflammatory etiologies account for
only a small percentage (< 2%) of all glaucomas. Uveitis associated
with glaucoma can result from different conditions, such as anterior
uveitis (e.g. idiopathic, the spondylarthropathies, juvenile
OOPPTTOOMMEETTRRIICC GGLLAAUUCCOOMMAA SSOOCCIIEETTYY//RREEVVIIEEWW OOFF OOPPTTOOMMEETTRRYY 2255
rheumatoid arthritis associated uveitis), Fuch's Heterochromic
uveitis, Posner-Schlossman, Herpetic uveitis, traumatic uveitis, and
lens-induced uveitis. In most cases of glaucoma associated with inflammation,
the anterior chamber angle is open and the increase
in IOP results from direct involvement of the trabecular meshwork
as a consequence of local inflammation (e.g. secondary trabeculitis),
spill-over from more generalized inflammation (e.g. panuveitis),
or as a consequence of accumulation of inflammatory
debris. Less commonly, local inflammation causes an increase in
IOP as result of a secondary angle closure (see section on angle closure
glaucoma).
The pathogenesis of steroid induced glaucoma is not fully understood.
Theories include the accumulation of glycosaminoglycans in
the anterior chamber angle and increased production of the
TIGR/Myoc protein. The result produces increased resistance to
aqueous outflow.
In addition to the treatment of the underlying cause of the
uveitis, in most cases, the treatment of the ocular component of
these conditions will involve both anti-inflammatory (topical corticosteroids)
and anti-glaucoma medications (aqueous suppressants).
Cycloplegics are used to prevent or manage posterior
synechia, secondary neovascular glaucoma and choroidal effusion.
Miotics are avoided because their use may exacerbate ciliary spasm,
inflammation and increase the likelihood of synechia.
Prostaglandins are also avoided, as this group of medications may
exacerbate the inflammatory component. If the patient is found to
be a steroid responder (IOP elevates over time), the initial consideration
is to discontinue or change the steroid medication. If this
is not feasible, given the nature of the patienťs condition, then
more aggressive management of the intraocular pressure may be
warranted until the steroid can be discontinued. In general, surgical
(trabeculectomy and tube shunts) have less successful outcomes
compared to primary open angle glaucoma.
TRAUMATIC GLAUCOMA
Angle recession glaucoma is the most common form of glaucoma
associated with trauma. Other forms include: glaucoma associated
with hyphema (acute) or later onset (ghost cell glaucoma), trabeculitis,
phacolytic glaucoma, and glaucoma associated with lens
dislocation. In the acute phase, the presence of blood in the anterior
chamber (hyphema) or inflammation as a result of injury (e.g.
traumatic iridocyclitis) may cause an increase in intraocular pressure
that mandates treatment. The long term effects of ocular trauma
associated with the pathogenesis of glaucoma often occur as a
result of the initial damage (angle recession) and subsequent healing
of the anterior chamber angle (Figure 1). Since most patients
with traumatic angle recession will not develop glaucoma (5% to
20% develops glaucoma), and elevated IOP occurs long after the antecedent
trauma, it is conceivable that many cases are overlooked.
Angle recession glaucoma is relatively uncommon when the recession
is less than 180 degrees. Angle recession glaucoma often presents
as a unilateral, or asymmetric, glaucoma without symptoms
unless in an advanced stage. The patient may not recall a history
of blunt ocular trauma. Diagnosis requires a 360 degree gonioscopic
assessment of each eye.
Since acute increases
in intraocular pressure in
the setting of blunt trauma
may be of short duration,
observation and
careful follow-up may be
all that is required (assuming
the presence of a
healthy optic nerve prior
to injury). If treatment is
indicated, aqueous suppressants
(e.g. beta
blockers, alpha agonists) are the mainstay of treatment. Angle recession
glaucoma should be treated in a similar fashion as primary open
angle glaucoma (POAG). If customary glaucoma management does not
produce an adequate IOP reduction, a course of cycloplegia may produce
positive results. Surgical washout of the anterior chamber may
be indicated in the presence of hyphema, especially if the corneal endothelium
shows signs of compromise (e.g. corneal blood staining), if
the hyphema does not resolve over time, or if a subsequent new hypema
occurs (rebleed).
For angle recession glaucoma, in general, the results of laser and
surgical procedures have less successful outcomes compared to primary
open angle glaucoma.
Patients with sickle cell disease are more sensitive to increases
in IOP, even of short duration (2 to 4 days). These conditions are
capable of occluding the central retinal artery (due, in part, to
stagnation of blood in small vessels, excessive deoxygenation of
erythrocytes, erythrostasis, sickling and increased blood viscosity).
It is, therefore, prudent to order a sickle prep (Sickledex) or hemoglobin
electrophoresis on all patients suspected of having sickle
cell disease or trait (more common among African Americans and
people of Mediterranean descent) in the presence of increased IOP
associated with hyphema.
PSEUDOEXFOLIATIVE GLAUCOMA (PXG)
PXG occurs throughout the world. In the United States, the
prevalence ranges from 5% to 15% of all glaucoma cases. It is
more common in patients > 60 y/o and uncommon in patients
<40. Pseudoexfoliation syndrome is a systemic disease associated
with abnormalities of the basement membrane in epithelial cells,
which are found throughout the body. The accumulation of pseudoexfoliative
material in the trabecular meshwork and the juxtacanicular
tissue next to the Schlemm's canal leads to obstruction
of aqueous.
Pseudoexfoliation
syndrome typically presents
unilaterally but
may become bilateral
and can be an aggressive
form of glaucoma
that can progress rapidly.
The initial signs are
usually noted with slit
lamp exam by observing
Figure 1. Gonioscopic appearance of angle recession
due to blunt trauma.
Figure 2. Pseudoexfoliation pattern on the crystalline lens.
2266 RREEVVIIEEWW OOFF OOPPTTOOMMEETTRRYY//OOPPTTOOMMEETTRRIICC GGLLAAUUCCOOMMAA SSOOCCIIEETTYY
the deposition of white, flaky material on the anterior lens capsule
(Figure 3) and iris border.
Treatment of PXG is similar to that of POAG. In general, patients
respond well to argon laser trabeculoplasty (ALT). Unfortunately,
within five years, approximately half are back to baseline
IOPs and some will have a rapid sustained increase in IOP within
two years.
PIGMENTARY GLAUCOMA
Pigmentary syndrome
and glaucoma
tend to occur at a relatively
early age (20 to
45 years) with most individuals
being myopic
(80%), Caucasian and
male. Pigment is released
from the iris due
to lens-iris contact,
leaving radially oriented transillumination defects. The pigment
circulates in the convection currents of the aqueous before adhering
to the corneal endothelium forming Krukenburg's spindle and
depositing in the anterior chamber angle. PDS is generally bilateral
and asymptomatic. Common signs include a Krukenburg spindle,
radially oriented iris transillumination defects, and heavy
pigment in the anterior chamber). In some instances, a concave
iris may be present (Figure 3).
PDS can resemble postoperative conditions such as IOL-iris chafing
and pseudoexfoliation; however, these are often unilateral and
present with less and unevenly dispersed pigment.
Treatment should take into account the needs of the patient
and the extent of glaucomatous optic neuropathy and/or visual
field loss. Like pseudoexfoliative glaucoma, patients typically respond
well to ALT at least initially. Laser iridotomy may alter the
pressure gradient associated with a concave iris, allowing it to flatten
in the anterior chamber thereby decreasing the likelihood of
contact. When medical and laser intervention fail, surgical intervention
is considered.
Suggested Readings
1. Vatavuk Z, Bencic G, Mandic Z. Intravitreal bevacizumab for neovascular glaucoma following central retinal
artery occlusion. Eur J Ophthalmol. 2007 Mar-Apr;17(2):269-71.
2. Lynch SS, Cheng CM. Bevacizumab for neovascular ocular diseases.
Ann Pharmacother. 2007 Apr;41(4):614-25.
3. Iliev ME, Domig D, Wolf-Schnurrbursch U, Wolf S, Sarra GM. Intravitreal bevacizumab (Avastin) in the
treatment of neovascular glaucoma. Am J Ophthalmol. 2006 Dec;142(6):1054-6.
4. Davidorf FH, Mouser JG, Derick RJ. Rapid improvement of rubeosis iridis from a single bevacizumab
(Avastin) injection. Retina. 2006 Mar;26(3):354-6.
5. Jonas JB, Spandau UH, Schlichtenbrede F. Intravitreal bevacizumab for filtering surgery. Ophthalmic Res.
2007;39(2):121-2.
6. Roberts DK, Winters JE, Castells DD, Teitelbaum BA, Alexander CC. A cross-sectional study of Krukenberg
spindles and pigmented lens striae in a predominately black population: two highly associated clinical signs
of anterior segment pigment dispersal. J Glaucoma. 2005 Feb;14(1):57-63.
7. Papadaki TG, Zacharopoulos IP, Pasquale LR, Christen WB, Netland PA, Foster CS. Long-term Results of
Ahmed Glaucoma Valve Implantation for Uveitic Glaucoma.
Am J Ophthalmol. 2007 Jul;144(1):62-69.
8. Kuchtey RW, Lowder CY, Smith SD. Glaucoma in patients with ocular inflammatory disease. Ophthalmol
Clin North Am. 2005 Sep;18(3):421-30.
9. Sung VC, Barton K. Management of inflammatory glaucomas. Curr Opin Ophthalmol. 2004 Apr;15(2):136-40.
10. Walton W, Von Hagen S, Grigorian R, Zarbin M. Management of traumatic hyphema. Surv Ophthalmol.
2002 Jul-Aug;47(4):297-334.
11. Schlotzer-Schrehardt U, Naumann GO. Ocular and systemic pseudoexfoliation syndrome. Am J Ophthalmol.
2006 May;141(5):921-937.
12 | Primary Angle Closure Glaucoma
David S. Friedman, MD
Primary angle closure glaucoma (PACG) is a leading cause of blindness
worldwide. In China, it is estimated that nearly one in six individuals
over the age of 50 has an angle appearance that puts
him/her at risk of PACG and acute angle closure attacks. Asian populations
are aging so the number of people with PACG will increase
dramatically in the coming decades. While it is often said that Chinese
populations (and others in East Asia) have ten times the risk
of PACG as Europeans, the truth is that in carefully conducted studies
the number is closer to four times as much, and nearly one in
200 Europeans over the age of 40 has PACG. PACG is often missed in
these populations, and efforts must be taken to identify it so that
needless loss of vision is avoided. Furthermore, it is essential that
adequate evaluation is given to the higher risk populations (older
persons, Asians, and in particular, older women).
In order to focus this chapter, I will first review the terminology
used when referring to patients with PACG and then will discuss the
epidemiology of PACG. The remainder of this chapter will cover diagnosis
and treatment strategies for PACG. Terminology to describe
PACG is confusing, and this lack of clarity influences how we think
about the disease. Much of this confusion stems from the literature
that developed when gonioscopy first became widely available in
the 1950s. Little was known about PACG and the natural history of
the disease, so a wide range of terms were used.
In order to allow for more uniform reporting, and to improve how
we think about the mechanisms of angle closure, a new terminology
was proposed and subsequently modified during a consensus
panel meeting involving over 100 glaucoma specialists from around
the world. There are currently four categories for describing persons
with angle closure, three of which require specific gonioscopic findings.
Each of these requires that the pigmented trabecular meshwork
is blocked by iris (what is termed "iridotrabecular contact or
ITC") in at least one quadrant. There is no firm agreement on how
many quadrants must have ITC for angle closure to be present, but
current consensus appears to be that at least 180 degrees is required.
The amount of ITC is determined in a dark room using a one
mm beam on a bright setting while performing gonioscopy. Greater
amounts of illumination (a long wide beam, for example) will allow
light to enter the pupil which can artificially open the angle.
1. Primary Angle Closure Suspect (PACS): Some people are
completely normal except for the fact that the anterior chamber
angle has ITC on gonioscopy. There is no "disease" present, and no
evidence of harm to the patient. The clinician is concerned by the
appearance, but the IOP and the optic nerve are both normal, and
there are no peripheral anterior synechiae. How much angle closure
must be present to apply this categorization remains controversial,
but I typically use 180 degrees or more. Gonioscopy is performed as
above, having the patient look straight ahead and only modestly
tilting the lens if the view is difficult. Again, this is a somewhat
subjective evaluation, but there are no better approaches available.
There is ongoing debate about whether or not all these persons require
iridotomy to avoid the development of PACG or acute attacks.
2. Primary Angle Closure (PAC): This category includes people
Figure 3. Pigmentary glaucoma (Courtesy Daniel
Roberts, OD).
OOPPTTOOMMEETTRRIICC GGLLAAUUCCOOMMAA SSOOCCIIEETTYY//RREEVVIIEEWW OOFF OOPPTTOOMMEETTRRYY 2277
with ITC for 180 degrees or more as described above for PACS. Furthermore,
these people have some evidence that the angle appearance
is causing harm to the eye. More specifically, they have either
peripheral anterior synechiae (PAS) or elevated IOP, but they do not
have optic nerve damage and visual field loss. This condition is
considered pathologic (although there is almost no long-term data
on people with these findings), and most clinicians recommend
laser iridotomy for these people.
3. Primary Angle Closure Glaucoma (PACG): This category requires
the presence of ITC for 180 degrees or more, as described
above, along with glaucomatous optic neuropathy and visual field
loss. The glaucoma definition requires the same findings as one
would expect for open-angle glaucoma.
3. Primary Angle Closure Attack: This presents with classic
signs and symptoms. Patients have very elevated IOP, the angle is
closed, the conjunctiva is red, the cornea frequently is cloudy, and
the patient has eye pain and may have nausea and vomiting.
PACG occurs in about 0.5% of whites and blacks over the age of
40, and about 1.5% of Chinese and Indian individuals in this age
group, but is much more common in older populations. Recent
studies indicate that even in high prevalence countries such as China,
open angle glaucoma is more common than PACG. However,
even though PACG accounts for about a third of all glaucoma cases
in China, most of the 5.2 million people blind from glaucoma have
PACG. Similar findings were reported for Asian Indians where 41%
of those with PACG were blind in one or both eyes from PACG.
PACG is associated with relatively anterior lens position and a
proportionally thicker lens, both of which result in a relatively shallow
anterior chamber depth, one of the strongest risk factors for
PACG. Affected eyes are frequently hypermetropic (although not
uniformly so, and PACG frequently occurs in myopic individuals).
PACG is also associated with a short axial length and small corneal
diameters and radii of curvature. Interestingly, even though PACG is
more prevalent in China, one study found that Chinese, blacks and
whites had similar mean anterior chamber depths, indicating that
other factors (such as the response of the iris to various stimuli)
may contribute to higher rates of PACG among Chinese.
While the ocular biometric parameters described are associated
with the presence of PACG and acute attacks of angle closure, it is
not clear if any of them predicts which PAC suspects would have a
poor outcome if left untreated. Other important risk factors that are
associated with PACG and AAC attacks are female sex, age, and race.
In order to review the treatment of angle closure I will discuss
each of the four sub-categories separately.
1. PACS: As stated above, these individuals have no evidence of
disease but have ITC when examined on gonioscopy. There is debate
about how to manage such individuals, with some recommending
observation and others recommending laser iridotomy (LI)
even in cases of ITC for less than 180 degrees.
2. PAC: All those with PAC have evidence of ITC and the presence
of either PAS or elevated IOP. There is uniform consensus that LI is
indicated for these individuals to help relieve pupil block in order
to both prevent acute attacks and to reduce the risk of further progression
of angle closure.
3. PACG: Unless PAS are extensive and there is fear of causing a
substantial IOP spike while attempting LI, the first procedure for
diagnosed PACG is LI. PACG is then treated like any other form of
glaucoma with medications, surgery, or a combination of both. If
the angle opens after LI and it is possible to perform trabeculoplasty,
this is also a treatment option.
4. Acute Primary Angle Closure: The mainstay of treatment of
acute attacks remains medical therapy. This includes topical ocular
hypotensives as well as oral or intravenous carbonic anhydrase inhibitors
and in some cases hyperosmotic agents. Some have published
findings that acute paracentesis can lower IOP rapidly, but this
has the potential of causing damage to intraocular structures. Others
have reported that laser iridoplasty can lower IOP acutely, but longterm
data showing that this is more or less effective than medical
therapy are not yet published. Certainly, if the IOP remains elevated
after one to two hours, one can consider performing iridoplasty.
PACG is a leading cause of blindness worldwide. With current
technologies, most clinicians can only identify at risk individuals
with gonioscopy (Figure 1a and b, 2a and b). Gonioscopy is, therefore,
a fundamental part of the evaluation of patients seeking eyecare
and needs to be performed routinely. Management of PACG is
different from management of open angle glaucoma. For patients
to receive proper treatment, all clinicians must provide a complete
evaluation of the anterior chamber angle.
Dr. Friedman is an Associate Professor at the Wilmer Eye Institute, John
Hopkins University School of Medicine as well as an Associate Professor, Dept
of International Health, Johns Hopkins University Bloomberg School of Public
Health. He is an editorial board member of the Ophthalmology and Journal
of Glaucoma.
Suggested Readings
1. Congdon NG, Qi Y, Quigley HA, et al. Biometry and Primary Angle Closure Glaucoma among Chinese,
White, and Black populations. Ophthalmology 1997; 104:1489-1495.
2. Thomas George R, Parikh R, Muliyl J, et al. Five year risk of progression of angle closure to primary angle
closure glaucoma: a population based study. Acta Ophthalmol Scand 2003;81:480-485.
3. Gazzard G, Foster PJ, Devereux JG, Oen F, et al. Intraocular pressure and visual field loss in primary angle
closure and primary open angle glaucomas. Br J Ophthalmol 2003;87:720-725.
4. Aung T, Friedman DS, Chew PT, et al. Long-term outcomes in Asians after acute primary angle closure.
Ophthalmology 2004;111:1464-1469.
5. Friedman Ds, Chew PTK, Gazzard G, Ang LPK, et al. Long-term outcomes in fellow eyes after acute primary
angle closure glaucoma in the contralateral eye. Ophthalmology (submitted for publication).
6. Aung T, Ang LP, Chan SP, Chew PT. Acute primary angle-closure glaucoma: long-term intraocular pressure
outcome in Asian eyes. Am J Ophthalmol 2001;131:7-12.
Figure 1a & b. The gonioscopic (a) and anterior segment OCT (b) image of an open angle is seen.
Figure 2a & b. The gonioscopic (a) and anterior segment OCT(b) image of a closed angle,
undergoing an angle closure attack is seen.