EyeNet Magazine

Clinical Update: Glaucoma
Overlap Syndrome: The Multiple Factors of Multiple Glaucomas
By Miriam Karmel, Contributing Writer

Your glaucoma patient has long been stable on pressure-lowering therapy. So how do you now explain a sudden spike in pressure and new progression of visual field loss? Before changing the medication or blaming patient noncompliance, you might want to consider what Robert Ritch, MD, calls "overlap syndrome."

Overlap gives name to the situation in which the patient with glaucoma develops a new "and different" glaucoma risk factor that can speed glaucomatous damage. Overlap can also be used to describe the coexistence of two or more frank glaucomas in one eye, each of which may have a distinct etiology, time of onset, presentation and clinical course. Recognizing overlap conditions allows for new ways of treating patients, particularly those with secondary and normal-tension glaucomas.

Dr. Ritch, who is a professor of clinical ophthalmology and chief of the glaucoma service and surgery director at the New York Eye and Ear Infirmary, said, "Basically, if you have a patient with glaucoma who has been well-controlled and clicking along for some time, and then all of a sudden either the pressure goes up in one eye or a visual field destabilizes, that suggests the development of a second condition superimposed on the glaucoma."


Explaining Overlap

The overlap concept was first introduced in 1990, in a report of five middle-aged patients with increasingly uncontrollable IOP.1 All patients had exfoliation syndrome (XFS) and were then found to have had pigment dispersion syndrome (PDS) as well.

Following that report, Dr. Ritch and colleagues conducted a retrospective chart review of records at New York Eye and Ear Infirmary, and identified an additional 26 patients who had combined PDS/XFS. 2, 3 Those two glaucomas have no known etiologic relationship.

XFS is the most common identifiable disorder leading to the development of open-angle glaucoma worldwide, and it constitutes about 12 percent of glaucoma in the United States, where the combination could affect up to half a million individuals. In the context of PDS/ XFS, the overlap theory explains why patients with previous pigment dispersion syndrome who go on to develop exfoliation may be more susceptible to elevated IOP than patients with XFS who have not had PDS. The reason: preexisting damage to the trabecular meshwork.

Helpful model. While there can be other overlap combinations, PDS/XFS was chosen as a paradigm for the syndrome because of the ease of diagnosis and its prevalence. "It's easy and straightforward to look at patients who have clinical evidence of PDS and pseudoexfoliation," said Raghu Mudumbai, MD, a coauthor of the overlap studies and assistant professor of ophthalmology, at the University of Washington, Seattle.

Dr. Mudumbai reiterated Dr. Ritch's definition of overlap glaucomas. "In patients whose glaucoma is decompensating, and it's not an effect of the medication not working as well, or the patient not being compliant, perhaps it's a third possibility that a new comorbidity has been introduced that has exacerbated the underlying glaucoma."

Not necessarily obvious. Some overlap combinations, in fact, may not be readily apparent to the ophthalmologist, Dr. Mudumbai said. For example, after developing glaucoma, a patient may develop another risk factor that may not be as self-evident as pseudoexfoliation, but which may nevertheless contribute to the decompensation of the patient's glaucoma. "Overlap syndrome is a two-hit hypothesis," he continued. "One hit is your initial glaucoma process that causes some damage and some difficulty with pressure control, for example. You've been able to manage it fairly well with medication. But now, you introduce a second problem that overwhelms the system and as a result of that, decompensation takes place." The second hit could be the appearance of XFS in patients who previously had pigmentary dispersion syndrome, or it may be a pressure-independent process.

Pigment, pigment everywhere. "Overlap is a useful concept about which ophthalmologists need to be aware," said Donald S. Minckler, MD, professor of ophthalmology and pathology, University of California, Irvine. Dr. Minckler said that the PDS/XFS combination, as described by Drs. Ritch and Mudumbai, provides a very good basis for establishing the concept of overlap. "The important point is that patients with pigmentary dispersion with or without glaucoma have pseudoexfoliation-associated risks added to those of pigmentary dispersion - a double whammy - probably with a worse prognosis," he said. "Common sense dictates that the physician should watch for pseudoexfoliation to appear in pigmentary dispersion patients. Since we only see what we are looking for, being aware of the possibility is important for the small percentage of such patients whom we might encounter."

Take care in the OR (and the gym). Another example, Dr. Minckler said, is a patient with open-angle glaucoma who - for various reasons, sometimes ocular surgery - develops progressive angle closure with a significant change in symptoms. "I have also rarely encountered patients without typical pigment dispersion who developed remarkable IOP rise postcataract surgery, probably provoked by intraocular manipulations and resulting in iris pigment release, with obstruction of outflow channels. Such 'pigment storms' can be confused with uveitis and can also occur in rare cases after vigorous exercise in patients with pigmentary dispersion syndrome.?"


Borrowing From Beyond the Eye

There's precedent for looking beyond any single etiology for a particular pathology, said Dr. Mudumbai, noting that cardiovascular disease provides an example to support the overlap syndrome. "Who ever would have thought that tooth cavities or gum disease would be related to cardiovascular disease? But it's been shown that having poor dental health can lead to inflammatory factors that can lead to cardiovascular disease."

The cardiovascular example, which involves factors not typically related to heart disease, suggests that ophthalmologists who concentrate solely on IOP might not be able to control the glaucoma if they neglect to consider pressure-independent risk factors.

IOP not always revealing. When he elaborated the concept for Eye M.D.s at a 1999 meeting of the American Ophthalmological Society, Dr. Ritch told colleagues, "We are entering an era in which we are becoming more aware of the existence of an ever increasing list of nonpressure-dependent risk factors for glaucomatous damage." The risk factors he cited included: atrial fibrillation, vasospastic or autoregulatory disorders, nocturnal hypertension, abnormal platelet aggregation, hemorheologic abnormalities, sleep apnea and autoimmune phenomema. The development of one of those non-IOP-dependent risk factors may cause the sudden acceleration of glaucomatous damage.

"If somebody's been controlled for a long time and then goes out of control, don't just juggle the medications," Dr. Ritch said. "You have to look for a new kind of glaucoma starting up, or a non-IOP related risk factor. Look for something new that's developed."

Advice to clinicians. Dr. Mudumbai agreed. The sudden decompensation should be a red flag, he said. "You should at least go through the mental process of seeing whether another problem has been introduced that's feeding into the change that's occurred."

Don't doctors ordinarily do that? "They do," Dr. Mudumbai said. "But you should be more in tune for the possibility that another process may be going on that is affecting the patient's glaucoma. It's fairly easy to say, "Okay, the medications not working; I need to add another medication, as opposed to saying, "˜Maybe something else is happening. Maybe I should look again for pseudoexfoliation.'"

Dr. Ritch added that a better understanding of the etiology of new risk factors is required before appropriate treatments can be devised. In the meantime, he said that thinking in terms of overlap can form the basis for "understanding the sequential appearance of various risk factors over the course of the life of a patient with glaucoma."

In their 2000 Ophthalmology report, Drs. Ritch and Mudumbai expressed hope that awareness of newly arisen risk factors "will stimulate both a search for the specific causes in a particular patient workup and interdisciplinary investigations to identify these risk factors, with the goal of expanding our therapeutic armamentarium."


1 Layden, W. et al. Am J Ophthalmol 1990;109:530"“534.
2 Mudumbai, R. et al. Trans Am Ophthalmol Soc 1999;97:297"“321.
3 Ritch, R. et al. Ophthalmology 2000;107:1004"“1008.


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