• What Clinicians Need to Know About Prostaglandin-Associated Periorbitopathy

    By Marianne Doran, Contributing Writer
    Interviewing Stanley J. Berke, MD, and Louis R. Pasquale, MD

    This article is from March 2012 and may contain outdated material.

    The prostaglandin analogues used in glaucoma therapy are full of surprises. First, it was the unexpected—but often welcomed—lash-lengthening effects of bimatoprost (Lumigan), now marketed separately as Latisse for cosmetic purposes. More recently, however, a small group of glaucoma specialists has identified several less desirable ocular changes related to these widely used medications. Now these specialists are working to spread the word to other ophthalmologists.

    These potential side effects include ptosis, relative enophthalmos, inferior scleral show, periorbital fat atrophy and involution of dermatochalasis (see “Characteristics of PAP”). The changes are often quite obvious in patients receiving unilateral treatment, according to Stanley J. Berke, MD, associate clinical professor of ophthalmology at Hofstra North Shore–LIJ School of Medicine and chief of the glaucoma service at Nassau University Medical Center.

    First sight of unexplained changes. Dr. Berke first noticed these effects when a patient asked why one of his eyelids was drooping. The 62-year-old man had pseudoexfoliation glaucoma in his left eye and had been treated in that eye with travoprost (Travatan) for three and a half years, followed by bimatoprost for 18 months.

    “When I looked, the left eyelid was drooping only slightly, but there was noticeable facial asymmetry,” said Dr. Berke. “The most apparent finding was that the superior lid sulcus was recessed, and I also noticed a generalized fat atrophy (Fig. 1). When I measured him, I could see that the eye was actually sunken in by two millimeters (Fig. 2).”

    Nothing in product labeling. After finding no information about such effects in the product labeling of the three available prostaglandin analogues, Dr. Berke called the pharmaceutical companies. When company representatives told him that they knew nothing about these effects, he filed reports with each company to inform them of what he had seen.

    “Once I started looking for these changes, I couldn’t believe that they were so prevalent,” Dr. Berke said. “How could I—and everyone else—have missed them for all these years?”

    Emerging Picture of PAP

    Louis R. Pasquale, MD, director of the glaucoma service at the Massachusetts Eye and Ear Infirmary and associate professor of ophthalmology at Harvard Medical School, and his colleagues were the first U.S. ophthalmologists to publish a description of the periorbital changes that he and Dr. Berke had seen independently in some patients who were using prostaglandin analogues.1 (Earlier reports had been published in an optometry journal2 and a German ophthalmology journal.3) He has also been instrumental in naming the newly characterized syndrome. Dr. Pasquale noted that various terms have appeared in the literature, including deep superior sulcus syndrome and the acronym DUES, which stands for deepening of upper eyelid sulcus.

    “But these descriptions fail to acknowledge the full spectrum of the condition, which includes not only problems with the upper lid but also pathology below the lower lid,” said Dr. Pasquale. “Lid structural changes may also be occurring. That is why I prefer the term prostaglandin-associated periorbitopathy, or PAP.”

    Influence of eyedrop absorption. Dr. Pasquale noted that a clearer clinical picture of PAP is emerging. “When people think about glaucoma eyedrop application, they envision the drug penetrating into the eye and causing some kind of effect either on the ciliary body or on the outflow channels to reduce intraocular pressure,” he said. “But they fail to recognize that the drops are also absorbed by the periorbital tissue, maybe even more so than by the intraocular tissue.

    “This periorbital absorption extends into the fat cells in the anterior orbital compartment,” Dr. Pasquale continued, “and one of the things that is clearly occurring is an inhibition of the amount of fat accumulation per cell. Neuroradiological, histological and cell biological evidence now show that this is happening.” He added that one of the patients discussed in the literature had undergone an MRI that was weighted to highlight fat structures.4 “She was on treatment in one eye, and you could see a less intense signal coming from fat cells in the anterior orbital compartment.”

    How common is PAP? “At this point,” said Dr. Pasquale, “we don’t know how common PAP is, but it’s not rare. It seldom creates clinically significant ocular problems. However, I have some patients that I regard as Goldmann applanation challenges because the eye is sunken in so far that my technicians are unable to check their IOP. I have found that if I gently lift the lid with the wooden tip of a cotton applicator and carefully bring in the applanation tonometer, I can get a reliable reading.”

    One of the unanswered questions about PAP is whether the three available prostaglandin analogues have equal side effects. Dr. Berke suspects that bimatoprost has the most, followed by travoprost and then latanoprost (Xalatan), but this question is one of many that will need to be sorted out over time.

    Clues to the Mechanism of PAP

    In a recent study from Japan,5 researchers performed biopsies of periorbital fat in different groups of patients. Some of the patients were not on any glaucoma medications, whereas others were using one of the three prostaglandin analogues. “When the researchers looked at the fat biopsies, they found that cell density was highest in the patients on bimatoprost,” Dr. Pasquale said. Although this finding may seem paradoxical, he added that “cells in which fat production is reduced are going to look smaller and closer together than are cells that are happily making lots of fat per cell. The number of nuclei per cubic millimeter was higher in the bimatoprost-exposed cells because the volume of each fat cell was reduced compared to that of the control cells.”

    In another recent study, human fat cells were exposed in vitro to the different prostaglandin analogues.6 The results suggest that the transcription factors driving fat cell production per cell are downregulated in the presence of these drugs.

    He added, however, that other, as-yet-unidentified mechanisms could also be at work in PAP. “There may be biochemical reactions that result in disinsertion of Müller’s muscle from the superior tarsus, and a similar reaction may be occurring in the lower lid. Another possibility is that smooth muscle in the levator muscles contracts when exposed to the drugs, causing some tightening of the eyelids, which is another feature of this condition.”

    Patients and PAP

    Dr. Pasquale believes that mild versions of PAP are common. “That is actually good news in that this probably is not going to lead to severe problems,” he said. “But if I were a patient, I would want to know about it—that is what bothers me the most. It’s like the elephant in the room: It’s there, but no one is talking about it.”

    Monitoring the data for cases. “After systematically looking at 100 patients, we have not seen anything horrible,” Dr. Pasquale added. “But we will monitor our database in the coming months to determine whether we have any really florid cases. Our review will be ongoing, and we are engaging in a large cross-sectional study to identify the demographic features or diagnoses that might be associated with this condition.”

    How does PAP affect your patients? In the meantime, Dr. Berke urges all doctors treating glaucoma patients to discuss the possibility of PAP with their patients before initiating therapy; to look for signs of PAP and document any changes over time; and to consider establishing photo documentation before and after treatment.

    He also suggests taking individual patient characteristics into consideration when choosing a glaucoma medication. For example, patients who already have deep-set eyes at baseline or those who need only unilateral treatment may be good candidates for a class of eyedrops other than prostaglandin analogues. Finally, although PAP has recently been added to Latisse labeling, it does not yet appear on the labels of Lumigan, Travatan or Xalatan. Dr. Berke expects that these labeling changes will occur in the near future.


    Dr. Berke receives grant support and lecture fees from Alcon and Allergan; grant support from Merck; and lecture fees from Pfizer. Dr. Pasquale reports no financial interests but noted that his institution (Harvard) filed a patent to protect the intellectual property associated with prostaglandin analogues’ potential cosmetic and oculoplastic applications related to fat atrophy.


    1 Filippoupoulos T et al. Ophthal Plast Reconstr Surg. 2008;24(4)302-307.

    2 Peplinski LS, Albiani Smith K. Optom Vis Sci. 2004;81(8):574-577.

    3 Tappeiner C et al. Klin Monbl Augenheilkd. 2008;225(5):443-445.

    4 Jayaprakasam A et al. Orbit. 2010;29(6)357-359.

    5 Park J et al. Jpn J Ophthalmol. 2011;55(1): 22-27.

    6 Choi HY et al. J Ocul Pharmacol Ther. 2011;Nov. 22. [Epub ahead of print]

    Characteristics of PAP

    Dr. Berke listed a number of clinical findings associated with PAP:

    • Upper lid ptosis
    • Deepening of the upper lid sulcus
    • Involution of dermatochalasis
    • Periorbital fat atrophy
    • Mild enophthalmos
    • Inferior scleral show
    • Increased prominence of lid vessels
    • Tight eyelids