FATAL SIGHT: Mooren's Ulcer

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	FATAL SIGHT: MOOREN'S ULCER by Linda Roach Monroe, Contributing Writer, EyeNet Magazine, Vol. 2, No. 4, April 1998 © 1998 American Academy of Ophthalmology, Reprinted with Permission Steven E. Wilson, MD, enjoys a good detective story. His bedside table usually features a novel by someone like Frederick Forsyth or John Grisham (only the early ones, please). "I almost always figure out 'whodunit' before the end of the book," says Dr. Wilson, medical director of refractive surgery at The Cleveland Clinic.* So perhaps it isn't so surprising that this same nose for detection was operating when he led a team that made a fundamental discovery about a cause for Mooren's ulcer, a rare corneal disease. His story provides a lesson in the role not only of intellectual curiosity, but also of serendipity, in pushing medicine outside the box of everyday thinking. "In 1991, when I was a fledgling assistant professor at the University of Texas Southwestern Medical Center at Dallas, I was 80 percent research and only 20 percent clinical," Dr. Wilson recalled in a recent interview with EyeNet. "So I didn't see a whole lot of patients. But I happened to see this one--we called her patient No. 1 in our later manuscript. "She had terrible Mooren's ulcer. It's the most horrible, painful, blinding disease that I ever have had to deal with in my career," he said. A chronic, relentlessly progressive, ulcerative keratitis, Mooren's starts in the periphery, but it can progress to involve the entire cornea. It is associated with autoimmune problems in some, but not all, patients. Rounding up the Usual Suspects In this case, the woman had advanced peripheral corneal ulcers in both eyes. Several areas had thinned to 90 percent of the corneal thickness. Treatment first with topical corticosteroids, and then with cyclosporine, didn't stop the disease from progressing to near-perforation. Conjunctival resection had to be performed on both eyes within two months of her first visit to Dr. Wilson. Near-perforation also had to be filled with acrylic glue. "The treatments up until that time were not really very effective," Dr. Wilson sums up. The patient's condition kept worsening. "But it was already appreciated at that time that in some patients if they became very severe you could treat them with cyclophosphamide systemically to do major immunosuppression," he said. A complete medical workup before Dr. Wilson tried cyclophosphamide showed only one abnormality, a slight elevation of some of her liver enzyme levels. This was attributed to the patient's obesity. But then came the first big clue that something else was going on. "Shortly after we put her on the cyclophosphamide, her liver enzymes just went into orbit," Dr. Wilson said. They went as high as 516 U/I for aspartate aminotransferase (normal, <35 U/I), 505 U/I for alanine aminotransferase (normal,<56 U/I) and 168 U/I for alkaline phosphatase (normal, <126 U/I). Meanwhile, after an initial improvement in her corneal ulcers, they began worsening again. Dr. Wilson thought the cyclophosphamide was causing toxic hepatitis, so he stopped it and referred the patient to a liver specialist, William M. Lee, MD. It was Dr. Lee who found the first big hint that the doctors had stumbled into a medical mystery: Although she was asymptomatic, the woman had positive serum antibodies to hepatitis C virus and liver biopsy showed severe chronic active hepatitis. Dr. Lee prescribed six months of treatment with interferon alfa for the hepatitis. However, the results served to thicken the plot further. The Plot Thickens "What happened was, not only did her liver enzymes go way back down but her Mooren's ulcer resolved," Dr. Wilson said. So the physicians began wondering if HCV could have been causing her eye condition. "I remember Dr. Lee calling me and saying, 'You know this is interesting. Maybe we should do liver studies on some of your other Mooren's ulcer patients.'" Dr. Wilson reminded his colleague that--as all the textbooks say--Mooren's is a very rare condition. "I laughed at him and told him I might go the rest of my life and never see another of these Mooren's ulcer patients." Which is the point at which serendipity played a role in the Mooren's saga. Unknown to him, another Mooren's ulcer patient had begun working his way through the UT Southwestern referral system within a couple of weeks of patient No. 1. Dr. Wilson was called into the case after nearly two years of failures of conventional treatments. Once again, there was the viral smoking gun: serum HCV antibodies in an asymptomatic patient. And interferon alfa resolved the corneal ulcers. Interestingly, the patient did not have hepatitis but HCV was detected in his blood using polymerase chain reaction. "It was when we got that second one that we really thought we had something," Dr. Wilson recalls. The doctors wrote it up as a letter to the New England Journal of Medicine (July 1, 1993), and later published their findings in Ophthalmology (April 1994). Smoking Guns Multiply But the story doesn't end there. Although Dr. Wilson has since learned anecdotally of at least 12 patients with Mooren's-like ulcers and HCV, it was left to John D. Gottsch, MD, and colleagues at Johns Hopkins University to write the real epilogue. "We've identified a protein in the cornea that appears to be acting as an antigen. There's an immune response that's responsible for the destruction that is seen in Mooren's ulcer," Dr. Gottsch explains. That antigen, it turns out, looks an awful lot like a protein on the surface of--yes--the hepatitis C virus, Dr. Gottsch said. So perhaps in some Mooren's patients who have hepatitis C their eye problem is caused by "molecular mimickry"--that is, the patient's immune system is primed by HCV and then attacks the similar-looking antigen in the cornea. (Extending the hypothesis further, other Mooren's cases not linked to HCV might somehow involve the same molecular pathway, disturbed by some other factor.) All this, of course, remains to be proven to a scientific certainty. But the smoking guns keep multiplying, and Dr. Wilson has been urging corneal specialists to look for occult HCV in the Mooren's patients--by liver biopsy if necessary. "Yes, that is somewhat controversial," Dr. Wilson acknowledges. "But my feeling is that liver biopsy has come to the point where it's relatively benign in the hands of an expert. Especially if a doctor is going to consider giving the patient cyclophosphamide, this is important. If the patient happens to have an occult active viral hepatitis, you could definitely kill them." Dr. Wilson has also been collaborating with Wilbur M.I. McElroy, MD, to try to determine whether Mooren's-like ulcers that are common in Africa are related to infection by HCV or another related virus. These studies are continuing. Meanwhile, Dr. Wilson has moved on to other mysteries--tracking down the molecular mechanisms of the cornea's healing response to PRK. It's fascinating research, but perhaps not quite enough for a medical detective's mind. One clue that this might be the case: Annoyed by how weak John Grisham's books have become, Dr. Wilson wrote a thriller that he's sending around to literary agents. "Over the last three years I wrote a novel about a surgeon who's accused, tried and convicted of murdering his wife based on faulty DNA evidence. It's called The Price of Privilege,"Dr. Wilson said. No word on how the story ends. *Dr. Wilson is presently Professor and Chair of the Department of Ophthalmology, University of Washington in Seattle, and Director of the Refractive Surgery Center at the University of Washington Eye Center.

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