Prostaglandin F2α (PG) analogs are widely used to treat glaucoma and ocular hypertension because they offer a greater degree of intraocular pressure (IOP) reduction and fewer systemic side effects than β blockers do. Conjunctival hyperemia, trichiasis, and hyperpigmentation of the iris and eyelids are the common side effects of this therapy.1 A deepening of the upper eyelid sulcus or an appearance of a sunken eye is also a complication but it is not adequately recognized because of its low incidence and difficulty in identifying it when it occurs bilaterally. Peplinski et al.2 were the first to report this side effect in three patients on bimatoprost therapy in 2004. Each of their patients was receiving unilateral treatment, and the appearance was referred to a “sunken” eye, because the eye appeared sunken into the orbit compared with the contralateral eye. This report was followed by a number of similar reports on the side effects of bimatoprost.3,4 Yang et al.5 reported two cases of a sunken eye associated with travoprost therapy in 2009.
These reports have suggested that the this sign will resolve several months to several years after discontinuing the eye drops.2–5 However, stopping the therapy means that the IOP reduction may not be maintained, and there is a possibility of further deterioration of the visual fields.
The purpose of this study was to investigate whether the sunken eye appearance can be reduced by discontinuation of the offending prostaglandin analog or by switching to 0.005% latanoprost (Xalatan, Pfizer Inc., New York, NY).
Case 1 was a 78-year-old man with newly diagnosed normal tension glaucoma bilaterally. His untreated IOPs were 15 to 17 mmHg in the both eyes. There was no history of PG therapy. After 3 months of 0.004% travoprost (Travatan-ZTM, Alcon Japan Limited, Tokyo, Japan) therapy, the patient's family pointed out that his face had changed and that both his eyes appeared sunken in. Two months after discontinuing the drug, the patient's deepened upper eyelid sulcus recovered, and the patient's family agreed that his face had returned to normal. Photographs of the eyelids are presented in Fig. 1.
To treat the patient's severe visual field disturbance, latanoprost was started 5 months after discontinuing the travoprost, and after the sunken eye appearance was completely resolved. The sunken eyelid appearance did not occur in the 6 months that the patient was followed up after the medication change (Fig. 1c), and the patient's IOP on latanoprost was 11 to 12 mm Hg bilaterally. There was no darkening of the periorbital skin or changes in iris color noted during our observation period which extended for 6 months after the treatment was adjusted; however, the conjunctival hyperemia was slightly lessened after commencing the latanoprost therapy.
A 37-year-old woman was diagnosed with normal tension glaucoma in her right eye. Her untreated IOPs were 15 to 16 mm Hg in the right eye and 20 mm Hg in the left eye. She was prescribed latanoprost and timolol 0.5% and had good IOP control ranging from 11 to 13 mm Hg for 3 years. Unfortunately, a latanoprost-induced superficial punctate keratopathy and conjunctival hypermia developed, and the patient was switched to travoprost and carteolol hydrochloride 2% therapy.
After 6 months on this therapy, the patient complained that her right eye had gradually sunk into the orbit. We switched her to 0.005% latanoprost/0.5% timolol fixed combination therapy (Xalacom, Pfizer Inc., New York, NY), and the patient's eye returned to normal after 3 months (Fig. 2a to c). There were no iris color changes and darkening of the periorbital skin noted during the observation period that extended for 3 months after she was commenced on the latanoprost/timolol fixed combination therapy. The patient's IOP was 12 mm Hg in her right eye, and mild superficial punctate keratopathy and conjunctival hyperemia were observed at the final examination.
Case 3 was a 69-year-old woman with exfoliation glaucoma and exotropia in her left eye. She had been using topical 0.03% bimatoprost (Lumigan, Allergan Inc., Irvine, CA), 0.5% timolol, and 1.0% brinzolamide in the left eye for 6 months at the time of our examination. She had not used any other PG. Her IOP was 16 to 20 mm Hg in the left eye. The patient's family pointed out hyperpigmentation and a sunken left eye.
We switched to latanoprost/timolol fixed combination therapy. Photographs of the eyelids are presented in Fig. 3a to c. The sunken eye was almost completely resolved 2 months after switching to latanoprost. Conjunctival hyperemia and changes in the iris color were not noticed during our observation period; however, the darkening of periorbital skin was slightly lessened after switching to the latanoprost therapy. The patient's IOP was 15 to 17 mm Hg in the left after latanoprost/timolol fixed combination therapy.
Case 4 was a 62-year-old woman with normal tension glaucoma bilaterally. Her untreated IOPs were 14 to 16 mm Hg in the both eyes. She had not used any PG. Two months after beginning bimatoprost, the patient complained of pressure on both eyes causing pain and a feeling that both eyelids were sunk in. Her IOPs were 11 to 14 mm Hg in the right eye and 12 to 14 mm Hg in the left. We switched her to latanoprost therapy, and confirmed that the patient did not have any signs and symptoms after 3 months (Fig. 4a to c). Conjunctival hyperemia and changes in iris color were not noted during our observation period; however, the patient developed a slight darkening of the periorbital skin in her lower eyelids after she was placed on the latanoprost. Her IOP was then 12 mm Hg in both eyes at the final examination.
Our findings showed that switching from travoprost and bimatoprost to latanoprost for patients who had a deepening of the upper eyelid sulcus led to a resolution of the sunken appearance. Importantly, the IOP remained within the acceptable level after the latanoprost therapy. Thus, the switching not only improved the appearance of the eyes but also maintained the IOP in an acceptable range. The results of our study also showed that the sunken eye appearance may be a side effect of all PGs but the occurrence may be different for each PG.
In our hospital database, we found this “sunken” eye complication in two patients of 77 (2.6%) on travoprost and four patients (two other patients under observation) of 86 patients (4.7%) on bimatoprost. Therefore, although the absolute risk remains low, the relative risk of developing this side effect with bimatoprost compared with travoprost is significant.
There have been no reports of this sunken eye appearance in patients using latanoprost until 2010 or in tafluprost 0.0015%, which has only recently been put on the market in European and Asian countries. We suspect that there may be racial differences in the incidence of the sunken eye appearance. It is generally accepted that Asians have puffy eyelids, and the sunken eye appearance will be easier to detect than in Caucasians, who have deep set eyes and thin eyelids.
What causes this complication? One reason suggested by Yang et al.5 was that PGs decompose the collagen fibers around the eyelids. Originally, it was believed that PGs reduce the IOP by increasing the uveoscleral outflow by remodeling the extracellular matrix that consists of collagen types I, III, IV, fibronectin, laminin, and hyaluronan.6 Yang et al.5 hypothesized that another reason for this effect was that PGs cause fatty degeneration of the Mueller muscle and levator aponeurosis because this complication is also observed in eyes with blepharoptosis.
This hypothesis is not consistent with our findings because the degree of ptosis in our patients was little changed after resolution of the sunken eye appearance. We suggest that the major reason for this complication is the PG-induced lipolysis. Yang et al.5 also assumed that PGs cause fatty degeneration and fat absorption without providing clear evidence for this claim. In the report by Yang et al., however, one patient developed a “baggy lower eyelid” appearance suggesting a fat herniation into the lower eyelid after discontinuing travoprost. Filippopoulos et al.3 also reported that some patients had a lower eyelid baggy appearance after discontinuing bimatoprost. We believe that these phenomena support our hypothesis.
However, there are conflicting reports on whether PGs regulate lipolysis. As well as insulin and catecholamines, especially the prostaglandin E2 regulate lipolysis by decreasing c-AMP through EP-3 receptors.7 Jaworski et al.7 reported that adipose-specific phospholipase A2 plays a major role in modulating adipose tissue lipolysis by regulating PGE2 levels, as a result, ablation of adipose-specific phospholipase A2 in mice prevented obesity induced by feeding a high fat diet, or by leptin deficiency. The binding affinity for each of the PG receptors has been reported,8 but there have been no studies on the blocking activity for each of these PG receptors. If travoprost and bimatoprost block the activity of the EP-3 receptor, this could explain the side effects that are observed.
Recently Park et al.9 reported new pathological findings in the mechanism for this side effect. Suggestive fat atrophy, such as clumped nuclei of adipocytes, was observed in the PG-treated eyelids at biopsy. Furthermore, they investigated the cellular density of orbital fat tissue in patients taking bimatoprost, travoprost, and latanoprost who had developed sunken eyes. They concluded that there was a statistically significant difference between the cellular density of the bimatoprost and travoprost groups when compared to that of untreated groups (p < 0.001). However, the cellular density of the latanoprost group (p = 0.75) was not significantly different.
These results reinforce our suggestion that this side effect may be less common with latanoprost. The mechanism of fat atrophy remains somewhat unclear, but they speculated that this might be due to the effect of PGF2α, which prevents adipocyte differentiation.10
The reversal of the deepening of the upper eyelid sulcus after discontinuation of PGs, or changing to latanoprost may be due to the removal of, or decrease in, the aforementioned inhibitory effect; this allows adipogenesis to recommence. We speculate that these four different prostaglandins may have completely different occurrence rates of this side effects and time course may be different in it.
Further investigations are needed to reach a definite explanation for our observations.
Department of Ophthalmology
Saneikai Tsukazaki Hospital
68-1 Aboshi Waku, Himeji 671-1227, Japan
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