PROSTAGLANDIN ASSOCIATED ORBITOPATHY (PAP)

Introduction:

Prostaglandin Associated Periorbitopathy (PAP) is the constellation of eyelid and orbital changes that accompany the administration of topical prostaglandin analogue (PG-A) eye drops.

PAP is a common occurrence following PG-A treatment. It has been claimed that once the clinician is looking for it, it can be noticed nearly 100 percent of the time.

PAP has been reported with the use of most PG-As, including bimatoprost, travoprost, tafluprost, and latanoprost.

Older patients (>60 years) are at a greater risk of developing this condition. 

This entity was first described by Peplinski and Smith in 2004. However, the specific term Prostaglandin Associated Periorbitopathy (PAP) was coined by glaucoma specialists Dr. Louis Pasquale and Dr. Stanley Berke. Other terms previously used in the literature included Deep Superior Sulcus Syndrome and DUES (Deepening of Upper Eyelid Sulcus).

The clinical features of PAP are 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, and tight eyelids. 

Other known side effects of PG-As such as lengthening of lashes and increased pigmentation of the iris and periorbital skin, can possibly fit under the term PAP as well.

PAP can appear as early as a month after the use of bimatoprost and is caused by fat atrophy, inhibition of adipocyte production, and differentiation of orbital fat due to PGF receptor stimulation by PG analogs.

Severe orbital fat atrophy in a patient with prolonged bilateral PGA use. Very deep superior sulcus and "sunken" eye appearance.

Deep sulcus, loss of orbital crease and lengthening of eyelashes on the left side.

Histopathology:

In PAP, there is significantly reduced size of individual adipocytes, suggesting overall fat atrophy rather than adipocyte death. 

Some cases demonstrate a statistically significant increase in mean adipocyte density of treated eyes, suggesting that in a given area there was a higher total number of adipocytes and thus a smaller size of each individual adipocyte. Clumped nuclei suggesting adipocyte atrophy are also seen in some cases. 

Reports suggest that those treated with bimatoprost were most affected by PAP, followed by those treated with travoprost. Those treated with latanoprost showed an increased mean adipocyte density as well however this change was not found to be statistically significant.

Pathophysiology:

The proposed mechanisms for PAP include mitochondrial apoptosis pathway of adipocytes, inflammatory fibrotic changes to the eyelid or to Mueller's muscle, atrophy of existing adipocytes, and inhibition of adipogenesis. Currently, it is most widely thought that preaponeurotic and deep orbital fat atrophy are likely the main contributors responsible for the majority of PAP changes. 

Pharmacokinetic studies of a single topical administration of 0.1% bimatoprost in male cynomolgus monkeys indicate that eyelid specimens contain more than 2,000 times higher concentrations of bimatoprost compared with aqueous and more than 16 times higher concentrations compared with iris and ciliary body. Thus, there is significant periorbital absorption of PG-A  medication.

Diagnosis:

Some patients may complain of the onset of a droopy lid or their eyelid starting to get in the way of their vision when this was previously never an issue. Performing Goldman applanation becomes increasingly difficult on patients with PAP as their orbits seem increasingly sunken in. Rarely, patients may complain of diplopia. Most commonly, patients refer to such changes as "tired-appearing eyes".

On examination, MRD1 can be decreased as compared to measurements prior to the initiation of therapy. Hertel's exophthalmometry can reveal a mild degree of enophthalmos or at least a relative decrease in values as compared to baseline. MRD2 or a measurement of inferior scleral show may be increased as compared to baseline as well. Finally, prism alternate cover test or Maddox rod testing can reveal a relative muscle deficit, most commonly a slight limitation in abduction.

Imaging is not commonly done and is not usually indicated in patients suspected to have PAP.

Management:

Typically, discontinuation of the medication results in partial to complete reversal of PAP characteristics. This change has been noted to occur as quickly as 4-6 weeks.

Switching from bimatoprost to latanoprost has been somewhat effective in reversing signs of PAP. In a prospective study of 13 patients who experienced PAP on bimatoprost, 11 of them had either a decrease or disappearance of their symptoms after switching to latanoprost in only 2 months. This change was reported to have maintained over a 6 month follow up.