Comment on “Insights into the pathogenesis of cystoid macular edema: leukostasis and related cytokines”

Dear Editor,

The review of Chung et al^[1] regarding the pathogenesis of cystoid macular edema (CME) raises valid postulates of shared pathogenesis which is based on inflammation and associated permeability. Albeit recognizing diverse etiological conditions, the definition of common pathways has the potential to improve interventionist strategies. One further mechanism for CME that is less appreciated, however, is the cascade of reactions induced or modulated by eicosanoids.

As an example, prostaglandin F2alpha (PGF2α) can have a pathological role in both acute and chronic inflammation^[2]. PGF2α can also serve as a biomarker of oxidative stress and inflammation^[3]. Following the discovery that the topical ocular application of several prostaglandins could reduce intraocular pressure in animal models, PGF2α was assessed in normotensive adults^[4]. PGF2α reduced intraocular pressure and did not seemingly produce aqueous flare or anterior chamber cellular responses, but was nevertheless deemed causative of lower eyelid reddening, symptomatic ocular irritation, conjunctival hyperemia, and headache^[4]. Shortly thereafter, it was hypothesized that prostaglandins were sentinel to the genesis of epinephrine maculopathy and aphakic CME^[5]. As a by-product of the latter research, the development of PGF2α analogues as a treatment for glaucoma was encouraged. Several such analogues (e.g., unoprostone, latanoprost, travaprost, bimatoprost) were clinically applied and represented a novel and very important arm in the therapeutics of increased intraocular pressure reduction. To this day, efficacy has been ascribed to an increase in the outflow of aqueous humor at the uveoscleral interface. PGF2α and its analogues were also found to induce the local release of various endogenous prostaglandins^[6].

Soon after clinical introduction, PGF2α analogues were being associated with iatrogenic CME induction, albeit for a minority of treated patients^[7]–^[8]. Whereas an interruption of the blood-retinal barrier was proposed as a mechanism for the latter toxicity, some contended that reagent preservative was causative^[7]–^[8]. Since then, a number of very convincing case reports have continued to raise concern with PGF2α analogues and CME causation^[9]. Several reviews also continued to draw attention to this phenomenon^[10]–^[11]. The large, although retrospective, case-control study of Wendel et al^[12] provides further support for a possible cause-and-effect relationship. Parallel to the above are studies which find that topical non-steroidal anti-inflammatory agents and corticosteroids, which have eicosanoid modulating effects, offer effective treatment of CME in some patients^[13]–^[14].

The availability of PGF2α analogues lends itself to the establishment of disease in experimental models. Such a reliable model of disease would then allow researchers to further explore not only the role of eicosanoids in disease, but also potentially further research into pathogenetic events that may be in common with other causations of CME. Throughout, however, one must be cautious with the assumption that all CME events have a common pathology or not^[15]. As well, co-factor events need consideration.