16th Annual Glaucoma Report
What to Do When Topical Glaucoma Treatment Fails
Here we review four different types of glaucoma treatment failure and provide several tips on how you can intervene to save your patients’ vision.
Release Date: JULY 2010
Expiration Date: JULY 31, 2013
The determination of medical treatment failure in glaucoma can be a challenging process. In addition to individual clinical factors that must be assessed, the reliability and validity of the available data must be carefully considered. To address these wide-ranging issues, this article examines the relevant factors in determining whether medical treatment has failed, and it discusses specific intervention options for different forms of treatment failure.
Michael Sullivan-Mee, O.D., and Denise Pensyl, O.D.
This course is COPE approved for 2 hours of CE credit. COPE ID is 28593-GL. Check with your local state licensing board to see if this counts toward your CE requirement for relicensure.
This continuing education course is joint-sponsored by the Pennsylvania College of Optometry.
Drs. Sullivan-Mee and Pensyl have no relationships to disclose.
One could argue that the
most important aspect of
every glaucoma followup is the determination
of whether the current treatment
plan is a success or a failure.
Failing treatment plans require
clinical intervention because of
an unacceptably elevated risk for
progression. Conversely, successful
treatment plans generally remain
unaltered because the patient will
often maintain a reasonable level
of stability with continued adherence to the regimen.
Determination of medical treatment failure in glaucoma,
however, can be a challenging
process. In addition to individual
clinical factors that must also
be assessed and appropriately
weighed, the reliability and validity of the available data must be
carefully considered. Intraocular
pressure measurements, visual
field tests and clinical optic nerve
impressions each manifest variability and imprecision.
Additionally, optimization of
patient management ultimately
depends on the manner in which
medical treatment failure manifests
itself. For example, patients who
develop adverse reactions to
glaucoma medications are often
managed differently than those
with progressive visual field loss.
To address these wide-ranging
issues, this article examines the
relevant factors in determining
whether medical treatment has
failed, and it discusses specific
intervention options for different
forms of treatment failure.
Four Types of Treatment
Medical treatment failure in
glaucoma is characterized by a
diverse array of clinical findings
and events. Examples include progressive glaucomatous visual
field loss or glaucomatous optic
neuropathy, an unacceptable level
of measured intraocular pressure (IOP) and non-adherence to
treatment advice, as well as the
development of disc (Drance) hemorrhage, a retinal nerve fiber layer
defect and/or intolerable ocular
or systemic side effects caused by
IOP-lowering agents. Moreover,
non-glaucomatous events can
impact the determination of treatment failure (see “The Impact of
Secondary Conditions on Determining Success vs. Failure”).
The Impact of Secondary Conditions on Determining
Success vs. Failure
Development of secondary conditions that may or may not be related to glaucoma can also impact the determination of whether a specific treatment effect is acceptable. Examples include the development of retinal, optic nerve or visual pathway pathology, such as retinal vein occlusion; compressive optic neuropathy; or insults to the visual pathway within the brain. In these circumstances, additional vision compromise associated with the nonglaucomatous pathology frequently results in an upgrade of the patient’s risk status.
So, while conventional glaucoma care often follows a paradigm in which treatment intensity is increased once progressive disease has been identified, such an approach may not be appropriate for patients with additional forms of vision loss. Accordingly, target IOP is often recalculated to a lower level and treatment intensity is increased due to the reduced tolerance for any further vision loss in these patients. In other words, development of other forms of vision compromise can change what is considered treatment failure vs. treatment success in established glaucoma patients.
For this article, let’s consider
four general classifications of treatment failure: deterioration of visual function, deterioration of visual
ocular structure, unacceptable IOP
and adverse reaction from glaucoma medication.
Deterioration of Visual
A primary focus of glaucoma
monitoring is the determination
of whether a patient manifests
progressive glaucomatous damage.
Within that effort, both anatomic
structure (optic nerve/retinal nerve
fiber layer, peripapillary atrophy)
and visual function (field of vision)
must be regularly monitored; simultaneous development of glaucomatous nerve and field progression is
the exception rather than the rule.
While detection of substantial
deterioration in structure and function generally isn’t difficult, visual
outcomes are improved when accurate and reliable identification of
relatively small amounts of visual
field and optic nerve degeneration
are detected. This task, however,
can be rather challenging.
Fortunately, several high-tech
instruments are now available to
aid clinicians in this task, and these
tools continue to be enhanced and
improved. For instance, new statistical interpretation approaches
have shown greater sensitivity in
detecting progressive visual field
loss compared to expert clinician
review. Accordingly, these tools
are currently recommended for
routine clinical care.1
Standard achromatic automated
threshold perimetry remains the
reference standard for clinical
visual field testing of glaucoma
patients.2 To identify visual field
progression in a timely manner,
clinicians should establish a good
baseline (at least two valid, reliable
visual field tests within two weeks
of the onset of care) and then perform regular periodic testing.
One recent study established
guidelines for visual field testing
frequency and specifically quantified the amount of time needed
to identify different levels of
progression based on varied testing frequency.2 The authors also
studied the effect of test reliability.
Unsurprisingly, they noted that less
frequent testing and worse patient
reliability increased the amount of
time needed to identify progressive
visual field change.
The authors recommended six
visual field examinations in the
first two years of care.2 This
frequency, which generally exceeds
the customary rate of examination,
helps establish good baseline data
as well as indicates which patients
may be rapidly progressing.
• Intervention. Once progressive visual field loss is identified
and subsequently confirmed (with
one or two additional tests that
demonstrate repeatable field loss),
clinical intervention is usually indicated. Intervention options include
the institution of alternate or additional anti-glaucoma medications,
laser trabeculoplasty or invasive
surgical procedures, such as trabeculectomy.
Alternatively, some patients may
be best served by focused education
regarding the glaucomatous disease
process, which might foster better
compliance. And, other patients
may benefit from improved glaucoma medication instillation
techniques or medical schedule
modification to facilitate enhanced
adherence and persistence.
In many cases, a combination of
interventions may be best. Nonetheless, determination of the best
intervention must be made based
on individual case factors and
overall patient risk assessment (see
“Glaucoma Risk Assessment Calculations”).
Glaucoma Risk Assessment Calculations
Relevant factors for patient risk assessment include age, systemic health status, concurrent medications, life expectancy, current visual ability/disability,
central corneal thickness and overall
condition of ocular health (including
optic nerve and retinal status). Recently,
risk assessment calculators have been
developed for patients who match inclusion/exclusion criteria for the Ocular
Hypertension Treatment Study (OHTS)
and European Glaucoma Prevention
While these risk calculators are beneficial in many ways, several significant
drawbacks have been identified (e.g.,
life expectancy is not considered in
these prediction models). Additionally,
optimal utilization of the resultant risk
scores developed by these calculators
for treatment guidance is not universally
agreed upon. Moreover, because these
calculators apply to just a subgroup of
patients, risk assessment for diagnosed
glaucoma patients (and glaucoma suspects without primary ocular hypertension) must be achieved empirically via
the efforts of individual clinicians.
Nonetheless, these calculators offer
utility as validated risk assessment tools
for objective determination of glaucoma-related risk.
Deterioration of Ocular
Several aspects of optic nerve
structure have been associated with
progressive glaucomatous optic
neuropathy. These include optic
cup enlargement, neuroretinal rim
thinning, development of retinal
nerve fiber layer defect or disc
hemorrhage, and the appearance
or enlargement of beta-zone peripapillary atrophy.
Additionally, new research suggests that the substructures of
the optic nerve (not visible via
ophthalmoscopy) undergo the
earliest and most dramatic structural transformation in glaucoma.3 Currently, these changes are being
studied with deep-scanning spectral domain optical coherence
tomography (SD-OCT), which
holds promise for earlier detection
of glaucomatous optic neuropathy
compared to current capabilities.
Traditionally, serial clinical optic
(with or without
optic disc photography) has been
used as the primary clinical method
of detecting optic
nerve change over
time. Due to substantial variability in examiner
the difficulty in
however, the use
of serial clinical
on cup/disc ratio
been shown to be
a relatively poor
method for detecting glaucomatous
progression.4 Conversely, fundus photography—particularly stereo disc photography—remains a valid, useful,
widely available and generally
inexpensive method for documenting disc change.
Like clinical nerve evaluation,
however, subjective assessment
is still required for photography
interpretation. Newer imaging
instruments, which can quantify
optic nerve and retinal nerve fiber
layer parameters with high precision, are designed to overcome
this obstacle and, in some cases,
have consistently shown diagnostic
capability equal to or better than
However, evidence that these
instruments can detect subtle, progressive, anatomic change due to
glaucoma is still limited. In fact,
only the Heidelberg Retinal Tomograph (HRT, Heidelberg Engineering) has been broadly validated to
detect such glaucomatous
changes.6 Given the excellent intersession measurement reproducibility associated with SD-OCT,
however, it is likely that this technology will soon prove useful and
reliable for detection of progressive
glaucomatous structural change.7
Nevertheless, despite the
immense capabilities of the newer
imaging instruments, fundus photography remains the best method
to detect disc hemorrhage and
peripapillary atrophy expansion, as
well as to assess neuroretinal rim
• Intervention. One major
dilemma created by modern imaging equipment: How do we interpret structural change identified by
instruments that feature micronlevel precision? While these instruments may be capable of detecting
a change of a few microns in size,
the determination of whether the
change is clinically significant—or
due to artifact, related to normal
age-related deterioration, or attributed to true glaucomatous progression—must be better clarified.
Currently, the identification of
structural change by a high-tech
imaging instrument requires the
integration of all relevant case
factors to determine whether the
structural change is of clinical significance. When subtle structural
change is accompanied by other
factors that support progressive glaucoma, it is reasonable
to accept the detected change as
glaucomatous in nature. If subtle
change occurs without other supporting findings, however, the
clinician can reasonably decide to
monitor the case without additional therapeutic intervention.
In contrast to subtle change
identified on modern imaging
instruments, newly detected macroscopic structural changes, such
as glaucoma-related disc hemorrhage, retinal nerve fiber layer defect (detected by ophthalmoscopy or photography) or rim erosion, are almost always considered
signs of progressive disease. In
such cases, increased treatment
intensity (i.e., additional medical
or surgical IOP reduction) is indicated, given the poor prognosis
associated with these developments. Further, patients who demonstrate advanced
visual field loss virtually always require
aggressive IOP-lowering, because these
to a severe stage of
of treatment failure
due to an IOP level
that is considered
too high is a common occurrence in
of failure is highly
subjective and can be
influenced by many
whether IOP is too
high, the clinician’s
primary duty is to
the measured level
of IOP unequivocally increases risk
to an unacceptable
level for that specific
patient. While this
risk usually pertains
to progressive glaucoma, other risks,
such as corneal
endothelial decompensation or retinal
vascular compromise, also may be
of importance. Again, determination of an acceptable IOP level for a
particular patient is based on comprehensive risk factor assessment.
Additionally, clinicians must
consider the visit-to-visit reproducibility of the tonometry device
used to measure IOP. Reproducibility for Goldmann applanation
tonometry (GAT), the most commonly used and reigning reference
standard, approximates ±4mm Hg
under optimal conditions.9 So, IOP
measurements between visits generally must exceed ±4mm Hg to be
considered decidedly different from
The use of both systemic and
glaucoma medications is another
factor that must be considered
when determining whether a
patient’s IOP level is acceptable.
Systemic medications that affect
IOP include beta-blockers, diuretics and anti-cholinergic agents (if
angle closure potential is present).
Type and timing of glaucoma
medications are also important,
because these agents have varying
durations of action.
Consequently, when interpreting IOP measurements in patients
who use anti-glaucoma medications, you must determine whether
the last dose was taken recently
enough to have any effect on the
IOP measurement. Finally, medication adherence must also be considered, because compliance issues
are often responsible for unacceptably elevated IOP measurements in
patients on glaucoma therapy.
• Intervention. When discrepancies between measured and target
IOP arise, clinicians should not
automatically modify the treatment regimen. Instead, consider
other case factors, such as optic
nerve appearance and visual field
status, prior to regimen modification. Many patients are likely best
served by regimen maintenance
when the only indicator of risk is
an IOP that modestly exceeds the
clinician’s subjective target range.
The exception, of course, is when
IOP is particularly elevated despite
apparently good compliance.
When intervention is indicated,
however, results from several
recent glaucoma trials clearly show that aggressive IOP-lowering is
vital to treatment success.8,10-13
If the goal of glaucoma therapy
is to prevent the development or
worsening of symptomatic vision
loss, then the most important factors for making treatment decisions should involve the status and
stability of visual field and optic
nerve parameters. This is particularly important when considering
invasive surgical management procedures.
Adverse Reaction from
While some forms of treatment
failure are rather challenging
to identify and manage, others
are more straightforward. For
instance, identification of adverse
ocular reactions due to glaucoma
medications is usually an unambiguous process.
When new ocular surface
symptoms (i.e., itching, burning
and ocular discomfort) and signs
(i.e., periorbital erythema/edema,
conjunctival edema, conjunctival
injection and follicular or papillary
conjunctival response) develop in
a patient who is using glaucoma
drugs, consider the possibility of
a hypersensitive or toxic response
secondary to the medication. When
these signs and symptoms develop
in close proximity to the initiation of a glaucoma medication,
the diagnosis is usually clear-cut.
However, when ocular surface
inflammation develops after a
period of successful medication
use, the diagnosis can be more
from toxic response is clinically
important for optimizing management decisions. True hypersensitivity responses are most common
with alpha-2 agonists, such as
brimonidine, and sulfa-based carbonic anhydrase inhibitors, such
as dorzolamide, and occur much
less commonly with beta-blockers
and prostaglandin analogs. When
managing hypersensitivity reactions, permanent discontinuation
of the offending agent typically is
warranted, because hypersensitive
immune reaction to that agent can
be expected to persist indefinitely.
Notably, however, different
medication formulations with the
same primary base molecule may
have varying proclivities for inducing adverse immune response. For example, our research group
documented that most patients
who developed a hypersensitivity response to brimonidine 0.2%
preserved with BAK, after being
switched from brimonidine 0.15%
preserved with Purite, infrequently
experienced repeat hypersensitivity reactions when switched back
to brimonidine 0.15% with Purite
(only one in five patients developed
hypersensitivity to brimonidine
0.15% with Purite).14 So, reinitiation of brimonidine 0.15% with
Purite may be a reasonable treatment option for patients who later
exhibit hypersensitivity to brimonidine 0.2% with BAK.14
• Intervention. When toxicity
appears to be the primary inciting
factor for the adverse reaction,
the offending medication may still
be an option within the patient’s
long-term management plans.
Often, the tendency for toxicity
can be improved by ocular surface
rehabilitation. By addressing lid
disease and tear film abnormalities
with various treatments, including lid hygiene, lid massage, nonpreserved lubricant eye drops and
anti-inflammatory agents, the ocular surface can often be sufficiently
improved to permit re-initiation of
the offending agent.15
While management of adverse
reactions to topical glaucoma medications usually includes
permanent or temporary discontinuation of the offending agent in
conjunction with supportive therapy (i.e., lubricant eye drops and
cold compresses), clinicians also
must make decisions about how
to control IOP during this process.
For some patients, it may be reasonable to defer all glaucoma medications during recovery as long
as untreated IOP does not pose a
significant risk to the patient. If it
is determined that untreated IOP
will place the patient at undue
risk, however, the preferred IOP
control options include topical
pressure-lowering agents that are not preserved with BAK, including
Travatan Z (travoprost 0.004%,
Alcon), Alphagan P (brimonidine tartrate 0.1%, Allergan) and
Timoptic in Ocudose (timolol
maleate 0.25% or 0.5%, Aton
Pharma). Additionally or alternatively, consider an oral carbonic
anhydrase inhibitor in patients
with no sulfa allergy and normal
renal and hepatic function.
Identification of systemic side
effects from topical glaucoma medications can be challenging and
often requires clinician vigilance.
Cardiovascular, central nervous
system, respiratory and gastrointestinal side effects are common; a
patient’s risk for these complications varies based upon the medication used.
In-office blood pressure
and pulse assessment are easily achieved, and general patient
observation combined with
focused history gathering should
permit successful identification
of the majority of systemic side
effects from topical IOP-lowering
While management may include
discontinuation of the offending
agent, other techniques may be
appropriate, including reduced
dosing frequency, alternate formulations of the medicine, and/
or modified eye drop instillation
techniques (e.g., use of punctal
occlusion and post-instillation lid
Identification of medication
failure is a vital component of
glaucoma care. When failure
is identified, clinicians should
remember that the goal of glaucoma management is to prevent
new or progressive symptomatic
vision loss and ultimately preserve
the patient’s quality of life. Specific
interventions depend in part on
the type of failure that is present,
and may include medical regimen
modification, laser trabeculoplasty
or incisional surgery (e.g., trabeculectomy, glaucoma drainage tube).
In cases characterized by progressive vision loss, macroscopic
anatomic change or high-risk IOP
level, additional IOP-lowering
is usually indicated by whatever
means is necessary to achieve a
Conversely, monitoring without therapeutic change may be
appropriate for patients who
manifest an IOP level that is just
modestly above the optimal target
IOP range or in patients who only
exhibit subtle anatomic change on
advanced imaging devices. (In such
patients, however, close monitoring is indicated to detect developing evidence that corroborates
By using structured, individualized, comprehensive risk assessments, the best options for each
patient can be identified successfully. Subsequently, you can educate your patients about their best
therapeutic options, so they may
participate in their own decision decisionmaking process. Through this collaborative effort, optimal care can be achieved.
Dr. Sullivan-Mee is director of optometric education for the New Mexico VA Healthcare System at the Albuquerque VA Medical Center. Dr. Pensyl is an associate clinical instructor at the University of California Berkeley School of Optometry and a staff optometrist at the Albuquerque VA Medical Center.
- Casas-Llera P, Rebolleda G, Muñoz-Negrete FJ, et al. Visual
field index rate and event-based glaucoma progression analysis:
comparison in a glaucoma population. Br J Ophthalmol. 2009
- Chauhan BC, Garway-Heath DF, Goñi FJ, et al. Practical recommendations for measuring rates of visual field change in glaucoma.
Br J Ophthalmol. 2008 Apr;92(4):569-73.
- Downs JC, Yang H, Girkin C, et al. Three-dimensional histomorphometry of the normal and early glaucomatous monkey optic nerve
head: neural canal and subarachnoid space architecture. Invest
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- Tielsch JM, Katz J, Quigley HA, et al. Intraobserver and interobserver agreement in measurement of optic disc characteristics.
Ophthalmology. 1988 Mar;95(3):350-6.
- Vessani RM, Moritz R, Batis L, et al. Comparison of quantitative
imaging devices and subjective optic nerve head assessment by
general ophthalmologists to differentiate normal from glaucomatous
eyes. J Glaucoma. 2009 Mar;18(3):253-61.
- Bowd C, Balasubramanian M, Weinreb RN, et al. Performance of
confocal scanning laser tomograph Topographic Change Analysis
(TCA) for assessing glaucomatous progression. Invest Ophthalmol
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- Wolf-Schnurrbusch UE, Ceklic L, Brinkmann CK, et al. Macular
thickness measurements in healthy eyes using six different optical
coherence tomography instruments. Invest Ophthalmol Vis Sci.
- 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
- Sullivan-Mee M, Gerhardt G, Halverson KD, Qualls C. Repeatability and reproducibility for intraocular pressure measurement by
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- The effectiveness of intraocular pressure reduction in the treatment of normal-tension glaucoma. Collaborative Normal-Tension
Glaucoma Study Group. Am J Ophthalmol. 1998 Oct;126(4):498505.
- Lichter PR, Musch DC, Gillespie BW, et al. Interim clinical
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Ophthalmology. 2001 Nov;108(11):1943-53.
- Kass MA, Heuer DK, Higginbotham EJ, et al. The Ocular
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onset of primary open-angle glaucoma. Arch Ophthalmol. 2002
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- Passo MS, Palmer EA, Van Buskirk EM. Plasma timolol in glaucoma patients. Ophthalmology. 1984 Nov;91(11):1361-3.