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.
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 Failure
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
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 Function
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 Study (EGPS).7
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 Structure
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 nerve assessment (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 impressions and the difficulty in detecting subtle nerve changes, however, the use of serial clinical assessments (with particular reliance on cup/disc ratio estimates) has 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 glaucoma experts.5
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 color.
• 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 glaucomatous optic neuropathy and/or visual field loss virtually always require aggressive IOP-lowering, because these individuals have already progressed to a severe stage of the disease.8
A determination of treatment failure due to an IOP level that is considered too high is a common occurrence in clinical practice. This determination of failure is highly subjective and can be influenced by many diverse factors.
When deciding whether IOP is too high, the clinician’s primary duty is to ascertain whether 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 each another.
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 Glaucoma Medication
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 challenging.
Differentiating hypersensitive 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 medications.
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 closure).16
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 lower IOP.
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 progressive disease.)
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 Dec;93(12):1576-9.
- 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 Ophthalmol Vis Sci. 2007 Jul;48(7):3195-208.
- 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 Vis Sci. 2009 Feb;50(2):691-701.
- 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. 2009 Jul;50(7):3432-7.
- 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.
- Sullivan-Mee M, Gerhardt G, Halverson KD, Qualls C. Repeatability and reproducibility for intraocular pressure measurement by dynamic contour, ocular response analyzer, and Goldmann applanation tonometry. J Glaucoma. 2009 Dec;18(9):666-73.
- 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 outcomes in the Collaborative Initial Glaucoma Treatment Study comparing initial treatment randomized to medications or surgery. Ophthalmology. 2001 Nov;108(11):1943-53.
- Kass MA, Heuer DK, Higginbotham EJ, et al. 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; discussion 829-30.
- Leske MC, Heijl A, Hyman L, et al. Predictors of long-term progression in the Early Manifest Glaucoma Trial. Ophthalmology. 2007 Nov;114(11):1965-72.
- Sullivan-Mee M, Pensyl D, Alldredge BR, et al. Brimonidine hypersensitivity when switching between 0.2% and 0.15% formulations. J Ocul Pharmacol Ther. [Epub ahead of print]
- Deltry-Morel M. Side effects of glaucoma medications. Bull Soc Belge Ophtalmol. 2006;(299):27-40.
- Passo MS, Palmer EA, Van Buskirk EM. Plasma timolol in glaucoma patients. Ophthalmology. 1984 Nov;91(11):1361-3.