In Vivo Analysis of Prostaglandins-induced Ocular Surface and Periocular Adnexa Modifications in Patients with Glaucoma

Abstract

Background/aim: Prostaglandin analogues (PGAs) are a first-line medical treatment for glaucoma because of their powerful intraocular pressure (IOP) lowering effect, few systemic side-effects (SEs), and the once daily administration. Despite the high systemic safety profile, the chronic use of PGAs may induce periocular and ocular surface (OS)-related side effects, which affect a significant proportion of glaucomatous patients. In this review, we summarize the current knowledge about SEs of PGAs on periocular structures and OS, and their implications in clinical practice.

Materials and methods: A comprehensive literature search on the PubMed platform was performed. Two hundred fifty articles fulfilling key words were identified, of which 180 were excluded since they did not concern the effects of PGAs on the periocular tissues and OS, or because of their limited relevance. The following key words were used and combined, to narrow-down the literature: "prostaglandin" and "ocular surface," which identified 184 unique publications, of which 68 were selected; "prostaglandin" and "periocular" which identified 46 unique publications, of which 11 were selected. An additional search was conducted using "prostaglandin" and "Meibomian glands (MGs)", which identified twenty unique publications, of which 8 were selected. Thus, a total of 70 articles were chosen based on their relevance and were included in this review.

Results: Prostaglandin-associated peri-orbitopathy, skin pigmentation and hypertrichosis, eyelash growth, and MGs dysfunction are the most frequent modifications of periocular tissues. They are induced by the tissue accumulation of PGAs, and FP receptor stimulation. Without preservatives, PGAs act as stimulators of conjunctival goblet cells, which are the main source of ocular surface mucoproteins, and seem to increase conjunctival epithelium microcysts proposed as in vivo hallmark of the trans-scleral aqueous humour outflow. Additional PGA-induced modifications can be recognized in the cornea, corneo-scleral limbus, conjunctival stroma and, conjunctiva-associated lymphoid tissue, mainly appearing as inflammatory changes. OS epithelia desquamation, chemosis, apoptosis, dendritic cell activation, conjunctival or episcleral vasodilation, and sub-basal nerve plexus disruption were also described in patients receiving preserved PGAs.

Conclusion: PGAs induce several modifications of the OS structures and adnexa; nonetheless, none of them significantly reduces the local safety profile of this class of drugs. Moreover, the OS changes do not affect the IOP lowering efficacy of PGAs. On these bases, local SEs of PGAs should not discourage clinicians in using this class of medications because of their efficacy, the systemic safety profile, and the better adherence.

Keywords: Glaucoma; adverse events; benzalkonium chloride; in vivo confocal microscopy; medical therapy; prostaglandin analogues; review; side effects.

Figure 1. IVCM images of MGs in PF-PGAs (A) and preserved PGAs (B). Acinar unit density and area appeared reduced and meibomian glandsecretion was hyper-reflective in preserved PGAs compared to unpreserved PGAs.

Figure 2. Reduction of Goblet cells density in patient receiving preserved PGAs. Arrows indicate clusters of goblet cells dispersed within the epithelium.

Figure 3. Epithelial microcysts in patient treated with PF. PGAs appear as dark, round or oval-shaped structures (asterisk), sometimes clustered, below the conjunctival epithelium.

Figure 4. In vivo confocal microscopy of human conjunctiva-associated lymphoid tissue after a long-term therapy with PF-PGAs. Presumed follicles appear as roundish or oval-shaped structures composed of a network of collagen fibrils with an increased reflectivity because of core fibrosis (asterisk), hosting some hyper-reflective elements corresponding to immune cells (arrow).

Figure 5. Limbal transmission epithelium in PF-PGAs. The normal architecture of the LTE is preserved, even though the epithelium shows an increased reflectivity and some punctate reflective elements.

Figure 6. Dendritic cells at the limbus in preserved PGAs (arrow).Patients treated with preserved PGAs present an increase of DCs density.

Figure 7. Morphology of sub-basal plexus nerves in patient receiving preserved PGAs. Nerve tortuosity and bead-like formations are found.