This year, we take a considerably deeper look at glaucomatous disease. While there have been no major new medicines or breakthroughs in the field of glaucoma over this past year, there is much to learn from a look at insights and perspectives from the worldwide body of glaucoma experts.

As members of the Optometric Glaucoma Society, we receive the journal International Glaucoma Review (IGR) every two months. The IGR is the most comprehensive update and review of the professional glaucoma literature around the globe. From this international journal, we have carefully selected articles and quotes (or in-context paraphrases) germane to medical therapy of the glaucomas, and offer them to you, along with our commentary (indicated in blue).

From The International Glaucoma Review (IGR),Vol. 6-3,March 2005:

CCT and measured IOP response in the Ocular Hypertension Treatment Study1

Purpose: To determine whether central corneal thickness (CCT) correlates with measured intraocular pressure (IOP) responses to topical hypotensive medication in the Ocular Hypertension Treatment Study (OHTS).

Conclusions: Individuals with thicker corneas had smaller measured IOP response to ocular hypotensive medication than those with normal or thin corneas.

Once-daily nonpreserved timolol vs. timolol maleate gel-forming solution²

Conclusion: This short-term study has demonstrated the equivalence of nonpreserved timolol to timolol maleate gel-forming solution in terms of IOP control.

This was demonstrated to be true a few years ago. There is no reason to prescribe more expensive gel solutions when less expensive, conventional solutions perform just as well.

Once-daily vs. once-weekly latanoprost³

We [S. Kurtz, G. Shemesh] evaluated the efficacy and safety of latanoprost eye drops once-weekly, compared to once-daily for improving patient compliance … The difference between post-treatment IOP was insignificant in both groups at each time point. The study group had fewer minor side effects than the control group (1/10 versus 6/10, respectively).

Conclusion: Latanoprost treatment once-weekly was as effective, and bore fewer minor side effects, as once-daily treatment after three months of follow-up.

While we all desire our patients to be consistent with their use of prostaglandins, perhaps we do not need to be overly concerned when they miss a drop or two from time to time. We know of some doctors who have patients using these meds Mondays, Wednesdays and Fridays only. In this economy, this may well be a rational approach, as long as target IOP is maintained.

IGR,Vol. 7-1, June 2005: Compliance and Persistency⁴

Recent Findings: The primary obstacles to medication compliance appear to be situational/environmental (e.g., being away from home or a change in routine) or related to the medication regimen (e.g., side effects or complexity). Persistency with ocular hypotensive therapies has been found to be poor. Retrospective cohort studies using survival analyses have reported that fewer than 25% of patients are persistent over 12 months.

Summary: Physicians may mistake either medication noncompliance or lack of persistency with poor efficacy. Such errors would likely increase health care costs if they result in unnecessary changes to a patient’s therapeutic regimen or in surgery.

IGR,Vol. 7-2, November 2005: Cooperation with Medical Therapy⁵

Olthoff, et al. reviewed many of the papers on cooperation with medical glaucoma therapy. They conclude that we know the following facts:

• Noncompliance with prescribed therapy is common;
• It may be a cause of worse visual outcomes;
• No patient characteristics accurately identify non-compliers;
• Patients underreport their noncompliance;
• Monitoring ideally should use mechanical devices;
• Pharmacy refill data are probably less accurate predictors of cooperation;
• Educational efforts may be useful in improving compliance;
• Compliance may be better with simpler regimens (fewer drops/day, less complex schedules of medications);
• Patients probably comply better if they make more doctor visits.

The main reason we see established glaucoma patients every three to four months is to urge them to comply and persist with their therapy. (We also check their IOP and examine their ONHs.) Unrelenting encouragement plays a powerful role in glaucoma patient care. Also, frequent “no-show” patients, in our experience, are commonly “noncompliant.” Be sure to have a system in place in your office to detect glaucoma patient “no-shows.” This enhances care and defends against malpractice.

Combining Prostaglandins⁶

In a well powered randomized clinical trial, the addition of topical bimatoprost to latanoprost significantly raises, rather than lowers, IOP. Despite [the trials] not having demonstrated a precise mechanism of why the co-administration of these two individually potent drugs should result in an elevated IOP, the message that latanoprost and bimatoprost should not be used together is still compelling.

It is probably reasonable to assume that none of the prostaglandins should be used together, and that no prostaglandin should be used more than once daily.

IGR,Vol. 8-1, June 2006: Glaucoma Worldwide⁷

A recent review of the data on prevalence of glaucoma for the coming four to 14 years indicates that the vast majority of angle-closure glaucoma (ACG) patients will be seen in Asia (87%), and half of the predicted blindness is due to ACG.

Results: Women will comprise 55% of OAG (open-angle glaucoma), 70% of ACG, and 59% of all glaucoma in 2010. Asians will represent 47% of those with glaucoma and 67% of those with ACG.

Conclusion: Glaucoma is the second leading cause of blindness, disproportionately affecting women and Asians.

We need to be very attentive to our Asian patients as they tend to be genetically predisposed to narrow angles. It may well be that all Asian patients should undergo gonioscopy (unless they have wide open Van Herick angles).

IOP and Glaucomatous Damage

In his editorial, “Ocular Hypertension and the Lost Suspect,” Erik Greve, M.D., Ph.D., states, “we are not so much interested in the absolute level of IOP (unless it is high) as in the relative raised IOP. It is the raised IOP (relative to the original) that is considered a risk factor for the development of glaucomatous damage.” He explains, “An original IOP of 12mm Hg may rise by as much as 50% to 18mm Hg and still be considered normal.” Thus, “a good percentage of socalled normal pressure glaucomas are ‘simply’ raised pressure glaucomas.” Greve concludes, ”we will have to rely on the detection of the earliest damage, or even better, the earliest change of damage,” to identify disease.

A very excellent point. This also emphasizes the value of getting prior patient records as these may provide an indication of IOP behavior over the past few years.

Correlating Structure and Function

Reported at the Glaucoma Society of India Meeting (December 2005):

“Measures of function and structure are synergistic in everyday clinical practice and should be used in combination whenever diagnostic uncertainty exists.”

Glaucoma Screening⁸

In The Nottingham Family Glaucoma Screening Study (Sung, et al.), “High frequencies of OAG/suspect OAG in siblings were confirmed.” This study found that, “About half of siblings initially diagnosed with OAG had visited optometrists in the previous year, indicating low sensitivity for OAG detection at those visits.”

This study indicates optometric care is equally as poor as ophthalmologic care, where roughly 50% of patients with glaucoma were missed or misdiagnosed, regardless of whether seen by an optometrist or ophthalmologist.

IGR,Vol. 8-2, September 2006: Gonioscopy

• Gonioscopy is indispensable to the diagnosis and management of all forms of glaucoma and is an integral part of the eye examination.
• An essential component of gonioscopy is the determination that iridotrabecular contact is either present or absent. If present, the contact should be judged to be appositional or synechial (permanent). The terms ‘iridotrabecular contact’ (and number of degrees) and ‘primary angle closure suspect’ should be substituted for ‘occludable’, as more accurate. The determination of synechial contact may require indentation of the cornea during gonioscopy, in which case a goniolens with a diameter smaller than the corneal diameter is preferred.
• It is desirable to record gonioscopic findings in clear text. Describing the anatomical structures seen, the angle width, the iris contour and the amount of pigmentation in the angle are all desirable.

While an ideal glaucoma workup includes attentive gonioscopy, studies of clinical practice patterns reveal that less than 50% of doctors perform gonioscopy, thus impeaching the term “indispensable” to characterize this procedure. As we have stated before, in our combined 56 years of caring for patients with glaucoma, gonioscopy has yielded the least valuable diagnostic information from the array of tests and procedures we routinely perform in our glaucoma workup. That being true, it is still wise to include gonioscopy in your glaucoma workup, as there are those uncommon patients for whom these findings can be helpful in managing their disease.

Laser and Medical Treatment of Primary Angle Closure Glaucoma

• Medical treatment should not be used as a substitute for laser peripheral iridotomy (LPI).
• Prostaglandin analogues appear to be the most effective medical agent in lowering IOP followingLPI, regardless of the extent of synechial closure.

This latter point is true, but it is important to recognize that beta-blockers and alpha adrenergic agonists, such as brimonidine, are “rapid onset” drugs and therefore are key pharmacotherapeutic players in the quick reduction of IOP. Certainly, the prostaglandins have the potential to ultimately achieve the greatest IOP reduction, but these drugs may take a day or two (at least) to achieve uveoscleral tissue remodeling via enhancement of matrix metalloproteinase activity. Moreover, LPI trumps medical therapy in an acute setting, and so prostaglandin use after LPI would be an excellent treatment choice (as would a once-daily topical betablocker).

Detection of Primary Angle Closure Glaucoma

• Angle closure case detection or opportunistic screening should be performed in all persons 40 years of age and older undergoing an eye examination.
• Given the low specificity of the flashlight test, it is not recommended for use in population-based screening or in the clinic.
• A shallow anterior chamber is strongly associated with angle closure.
• An acute attack of angle-closure is not glaucoma; if the optic nerve and visual field are normal, it is only an acute angle-closure.

We think any patient with Grade II or less Van Herick angles should undergo gonioscopy, particularly when that patient is over 40 years of age. The last bullet is right on the money; an angle-closure attack is just that – it is not glaucoma unless measurable damage occurs to the optic nerve. For instance, most patients with glaucomatocyclitic crisis do not develop glaucoma.

Genetically Regulated CCT and Glaucoma⁹

The recent finding that CCT is among the most heritable aspect of ocular structure, suggesting that CCT is genetically regulated, lends credence to the idea that CCT is linked somehow to glaucoma risk at a fundamental, biological level.

Conflicting findings and approaches as represented by these studies are typical of early work in any new field, as we begin to investigate potential biological links. The story of CCT and glaucoma is just starting to get interesting!

Interesting, indeed! Recently, a woman in her 40s presented in our office and requested a glaucoma evaluation because her father, who lived in another state, had been told he had glaucoma. Our examination found this lady to have CCTs of 640, IOPs of 23, and C/D ratios of 0.2. We’d be willing to bet her father also has thick corneas and actually does not have glaucoma, but rather, “corneal thicknessinduced” ocular hypertension. We hope to be able to render a second opinion to this patient’s father when he comes down for a visit. We believe many cases of ocular hypertension are errantly called “glaucoma.” Remember, it’s all about the optic nerve! Study the optic nerve. In glaucoma, all findings revolve around the optic nerve! (Repetition intended.)

Optic Nerve Health

The glaucomatous process is best recognized by the damage it causes to the optic nerve in so-called ‘characteristic’ ways. Valid determination of the health of the optic nerve is, then, one of the most important and direct methods of evaluating and managing patients with glaucoma.

Because physicians rely so heavily on the presence of ‘cupping,’ as a sign of a disc damaged by the glaucomatous process, critical consideration of the validity of this sign is appropriate and important. There are fatal flaws in the cup-to-disc ratio system, however, and indeed all systems that use the width of the cup as a measure of the presence of glaucoma damage. One of those fatal flaws, not recognized until recently, is that the size of the cup is strongly affected by the size of the optic disc.

Not evaluated by this study, but of equal importance, is the recognition that small discs tend to have small cups, and that systems that do not take this into account will also yield misleading results when considering small discs, indicating that discs are normal, when in fact they are acutely pathologic.

These comments are from Jost Jonas, M.D., of Germany, who is arguably the world’s foremost expert in the optic nerve. He stresses that optic disc size need not be exactly measured, but rather a, “crude assessment,” as to whether the disc is small, normal-sized, or large is all that is necessary. This is an excellent point that pushes us to become even more attentive to the optic nerve.

Ocular Drug Delivery for Glaucoma¹⁰

Human sclera is more permeable than the cornea to many hydrophilic and hydrophobic drugs. Furthermore, the rate of diffusion is determined by molecular mass and size. While drug diffusion through the cornea is not very efficient, the rate of drug diffusion through the sclera is significantly higher, roughly equal to the cornea denuded of epithelium. Further, the surface area of the sclera (approximately 17cm2) is a lot bigger than the cornea (approximately 1cm2). Thus, an effective case was made that perhaps the most compelling location from which to deliver sustained drugs to the eye (either anterior or posterior) may be the scleral surface.

The future for glaucoma therapies is very bright indeed. Opportunities are being developed that aim to deliver drugs in a sustained manner for prolonged periods of time that rely less on individual patient administration.

Provide Written Instructions¹¹

B. V. Kharod, et al. reported in the Journal of Glaucoma 2006 on their study of the effect of written instructions on accuracy of selfreporting medication regimen in glaucoma patients. At the end of their visits, patients were given a written chart describing their ophthalmic medications, frequency, and dosage.

Conclusion: The education level of the patient and the number of medications showed direct correlation with the patient’s ability to report medications accurately. Patients showed improvement in accuracy of reporting medications when given written instructions about their regimen, regardless of their level of education or number of medications.

IGR,Vol. 8-3, December 2006: Treating Ocular Hypertension to Reduce Glaucoma Risk: When to Treat?

When to treat the patient who presents with ocular hypertension has been a question that has ‘stumped’ the ophthalmic community for decades. The clinician should consider key factors such as age, thin corneal thickness measurements, large cup-to-disc ratio and mean IOP when determining who should be treated. However, the ultimate decision of when to treat will be determined by other issues such as life expectancy, the general health and the number of risk factors. Clearly, the treatment of only high-risk patients with ocular hypertension should be considered.

This one simple paragraph embodies the essence of clinical decision-making. “When to treat” is the ultimate decision, and can only be made by attentively evaluating each patient as an individual person.

Beta-blockers and Depression¹²

Conclusions: Use of topical betablockers by glaucoma patients does not appear to increase the risk of depression in this population. While the opposite has been taught as true for two decades, it has been clearly shown that there is no association.

Effects of previous argon laser trabeculoplasty on the ocular hypertensive action of latanoprost¹³

Results: Latanoprost induced a 17.5 ±16.6% decrease in the study group (ALT-treated eyes) and a 25.8 ±17.2% reduction in the control eyes.

Conclusions: Latanoprost is less effective in ALT-treated eyes than in eyes with POAG not treated with ALT.

Note the very wide-ranging responses in IOP reduction. We imagine these findings would hold true for any of the prostaglandins.

The cost-effectiveness of bimatoprost, latanoprost and timolol in treatment of primary open-angle glaucoma in five European countries¹⁴

Conclusion: First-line treatment of latanoprost is dominated in all countries. In four out of five countries, the timolol first-line therapy with add-on latanoprost is also dominated. Based on this pharmacoeconomic analysis, the most cost-effective strategy seems to be timolol first line with add-on latanoprost if target is not met after three months.

IGR: Vol. 9-1, June 2007: Target IOP

From the WGA Consensus Meeting on Intraocular Pressure, May 2007: The determination of a target IOP is based upon consideration of the amount of glaucoma damage, the IOP at which the damage has occurred, the life expectancy of the patient, and other factors including status of the fellow eye and family history of severe glaucoma. At present, the target IOP cannot be determined with any certainty in any patient.

Common Findings in Myopic Eyes¹⁵

Optic nerve head findings of tilted discs and peripapillary atrophy are common features found in myopic eyes. Corresponding visual field defects may or may not be present. As a result, establishment of glaucomatous damage and progression monitoring becomes more difficult bringing about uncertainties in glaucoma diagnosis and management. In one study of mostly myopes with optic disc cupping and visual field abnormalities suggestive of glaucoma, their condition was found to be stable during seven years follow-up. This is not surprising, considering the fact that the subjects on the average belong to the young and middle aged group. It is also worth mentioning that 56% of the subjects received treatment (IOP lowering medications). This opens the question whether the threshold for instituting treatment should be lowered or raised. For this particular group, withholding treatment is a good option.

We often encounter patients being treated for a disease they do not have. Remember, glaucoma is a progressive optic neuropathy. We might be wise to definitively determine progression prior to the institution of therapy!

Effects of Marijuana on IOP¹⁶

Marijuana lowers IOP for only two to three hours, making it highly impractical in most patients, and furthermore in the majority of patients the IOP lowering effect is lost in continued dosing.

IGR: Vol. 9-3, December 2007: Glaucoma Screening and Prevention

• With 90% of glaucoma undiagnosed worldwide, methods to bring more cases in for care may be considered theoretically worthwhile. Since patients, siblings, and children of OAG cases are five to ten times more likely to develop OAG, one approach is to bring in family members.
• High rates of undiagnosed glaucoma exceeding 50% are reported from various population studies in developed and developing countries, while current screening methods outside the clinical office have been proven to be non-cost effective.

We all need to more aggressively reach out to family members of glaucoma suspects to maximize prevention of glaucomatous vision compromise.

IGR,Vol. 9-4,March 2008: Angle Assessment: Gonioscopy and Illumination

• Sadly, ophthalmologists perform gonioscopy less frequently than they should. Moreover, when gonioscopy is performed the technique might not be ideal. Too often, gonioscopy is performed in a brightly lit room employing a diffuse bright beam of light. It has long been felt that excessive illumination could artificially open the iridocorneal angle, making the examiner miss people at risk for pupillary block angle-closure glaucoma.
• Ophthalmologists who perform gonioscopy in a bright room or with a slit lamp entering the pupil risk failing to identify occludable iridocorneal angles.

Obviously, these statements hold equal truth for optometrists.

CAIs and Corneal Effects

• Carbonic anhydrase (CA) isoenzymes II and IV play an important role in the pump function of the endothelium, keeping the cornea in a relatively steady state of dehydration.
• Dorzolamide is a potent inhibitor of CA II. In normal eyes, both original regulatory safety data and in subsequent studies, dorzolamide exhibited little in the way of corneal toxicity. There are, however, numerous anecdotal and published reports of irreversible corneal decompensation during dorzolamide therapy in some patients.
• Data suggests that patients with preexisting endothelial disease are more susceptible to the adverse corneal effects of topical carbonic anhydrase inhibitors (CAIs).
• The glaucoma clinician should pay more attention to the corneal endothelium, and in patients with compromised endothelia (i.e., Fuchs’ dystrophy, bullous keratopathy, penetrating keratoplasty), consider other drugs before topical CAIs.

IGR,Vol. 10-1 (and its supplement), July 2008: Diabetes and Glaucoma¹⁷

There is no clear evidence to support a relationship between diabetes and glaucoma … IOP level is usually slightly higher in diabetic patients … [however] this slight increase is currently thought to be caused by a higher central corneal thickness (CCT) in these patients. As reported in the OHTS, central corneal thickness (CCT) was higher in diabetic compared with non-diabetic subjects, and this increase in CCT may be responsible for an overestimation of IOP.

We stress that newer studies do NOT support a direct relationship between diabetes and glaucoma!

Sleep Apnea Syndrome and Circadian IOP¹⁸

Obstructive sleep apnea (OSA) is more prevalent in subjects with primary open-angle glaucoma (POAG) than in the general public and POAG is more prevalent in subjects with OSA than in the general public. OSA is often treated by nocturnal administration of continuous positive airway pressure (CPAP). CPAP is known to raise intraocular pressure (IOP).

In a study to determine the impact of CPAP on circadian IOP, it was noted that IOP dropped significantly within 30 minutes of stopping CPAP in the morning. By raising intra-thoracic pressure, thus venous pressure, thus episcleral venous pressure, CPAP likely raises IOP by reducing aqueous outflow. CPAP-induced IOP elevation may explain the increased prevalence of POAG in subjects with OSA, and these subjects may warrant ongoing glaucoma screening. When established glaucoma patients require CPAP therapy, the clinician should be aware that the resulting IOP changes may not be detectable during office hours, and that these patients may be at risk for disease progression despite apparently wellcontrolled IOP as measured in the diurnal period.

IGR,Vol. 10-2 (and its supplement), September 2008: Caffeine is Not a Risk Factor for Glaucoma¹⁹

In a rigorous cohort study with nearly thirty years of follow-up, the authors found no increased risk of glaucoma with increasing amounts of caffeine (even though) the large sample size of the study increases the risk of finding a statistically significant result that is not clinically significant. When our patients ask us about caffeine intake and glaucoma, we should tell them that caffeine was not found to be associated with glaucoma.

SWAP or Double?

A symposium on visual fields was held at the Second World Glaucoma Congress, where four timely questions were asked. These questions are set forth below, and then followed by expert consensus answers. We hope you will find the revelations pertinent to your clinical practice.

Q: Should SWAP and FDT be used to monitor glaucoma suspects with normal SAP?

A: The experts concluded that in the present state of understanding, there is no compelling evidence that either SWAP of FDT should be used, rather than SAP, to monitor glaucoma suspects having no known visual field defects.

Q: Should FDT be used for routine screening for glaucoma?

A: The panel agreed that although under well-controlled conditions FDT may be suitable of early detection of glaucomatous damage, in ‘real-world conditions’ it is likely to pick up functional defects due to other diseases as well. On the other hand, as screening campaigns are usually not designed to detect glaucoma alone but eye disease in general, FDT may have its place in mass screening, with other tests establishing the final diagnosis.

Q: Is FDT better than SWAP for the detection of early glaucoma?

A: The experts agreed that all evidence on this question is relatively thin and that the single study on which it was based, although carefully designed, needs to be complemented by further studies exploring the mechanisms underlying SWAP and FDT.

Q: Does selective testing with SWAP and FDT make them good for monitoring disease progression?

A: The panel agreed that there is no clear answer yet to this question, as there is no ‘Gold Standard’ to ascertain progression and as there are many uncharted areas that need to be explored by additional work before the ability of each method to detect change is established. With the evidence that is currently available, there seems to be no clear advantage to using either SWAP or FDT in place of standard automated perimetry to monitor glaucoma progression.

IGR,Vol. 10-3, December 2008: Imaging Technology in Glaucoma²⁰

Today we have several instruments that provide objective and quantitative measurements that are highly reproducible and show very good agreement with clinical estimates of optic disc and visual function. Yet, many clinicians continue to wonder how to use these in their clinical practice and clinical trials. Now, more than ever, it seems to be an appropriate time to assess the use of imaging in clinical practice.

Optic nerve head photography, particularly stereoscopic, provides a permanent record, but generally is not used because it is impractical and cameras generally are not available. Moreover, the differences among clinicians in their interpretation of photographs, either for diagnosis or progression, is remarkably large.

Given the substantial advances in glaucoma imaging, it is important to remind clinicians that current glaucoma diagnosis cannot be solely instrument-based. Rather, the imaging information should be considered as being complementary to other clinical measures. Nevertheless, given the variability of drawings and subjective photographic interpretation, imaging may elevate the assessment of the optic nerve by the general clinician, perhaps to the level of a fellowship-trained glaucoma specialist. Moreover, imaging enables the clinician to objectively evaluate the parapapillary RNFL [retina nerve fiber layer] that changes early in the course of the disease, which cannot be readily measured by clinical examination. Finally, imaging enables a practical comparison of a patient with a population of age-matched normals, facilitating the ability to identify abnormal structural features … Thus, clinicians should not make clinical decisions based solely on the results of one single test or technology.

This is wonderfully stated, and should be earnestly taken to heart by all clinicians!

You have just read a selection of information from glaucoma experts around the world. We hope the knowledge these experts provide enables you to offer enhanced, expert care to your patients with glaucoma.

We thank Murray Fingeret, O.D., for his precedent-setting vision in formally ushering our profession onto the world stage via the establishment of The Optometric Glaucoma Society, a member of the World Glaucoma Association.