The causes of acute corneal edema can be divided into three large categories ¹⁰: triggered by epithelial or stromal noxas, such as trauma or viral infection ^11-13; triggered by endothelial dysfunction, as will be discussed throughout this article; and triggered by elevation of intraocular pressure (IOP) ².

Since the objective of this article is to make an exhaustive review of the causes of corneal edema without epithelial damage and with normal IOP numbers, only the causes that result in edema will be thoroughly reviewed since they affect, one way or another, the dehydrating function of the corneal endothelium.

Regarding other causes, on the one hand, direct trauma, inflammation of the epithelium or corneal stroma may induce endothelial damage, leukocyte migration or rupture ofthe epithelial barrier ^11,16, whereas IOP elevation can be caused when the ability of the endothelium to keep the cornea dehydrated is exceeded. This mechanism may be observed in scenarios such as acute angle-closure glaucoma, endotracheal intubation, and positive pressure ventilation ².

In other scenarios, this entity is secondary to some alterations in the function of the corneal endothelium, produced by one of the following causes:

The use of topical carbonic anhydrase inhibitors (CAI), especially in combination with other topical medications for chronic glaucoma such as latanoprost and timolol, has been reported as one ofthe causes of acute corneal edema with a degree of severity as in the case reported in this study ^17,18. Inhibiting carbonic anhydrase, which is involved in the expulsion ofbicarbonate on the corneal endothelium, may lead to water retention ¹⁷. The inability of the epithelial barrier caused by the use ofbenzalkonium chloride -preservative found in several formulations of ophthalmic eye drops- favors this effect ^19,20. Similarly, some association between the use of topical prostaglandin analogues, such as latanoprost and travoprost, and the development of anterior uveitis accompanied by corneal edema has been suggested ^21,22.

The development of acute corneal edema secondary to the use of topical mitomycin C in the management of postoperative corneal opacities has been reported as well ²³. This drug acts against cancer cells and normal cells during reproduction phases ²⁴, therefore, it may limit subepithelial fibrosis that manifests as corneal opacity ^25,26. In the case reported here, the development of the edema was attributed to the toxic effect of mitomycin C over the corneal endothelium, which was facilitated by continuous exposure to this drug in a cornea with denuded epithelium ²³.

Aside from topical medications, oral medications are also reported to cause acute corneal edema. This is the case of two NMDA receptor agonists (N-methyl-D-aspartate): amantadine and ketamine ^27-30.

Regarding amantadine, there is a relative risk (RR) of 1.7 (95%CI: 1.1-2.8) of developing corneal edema ³¹, whereas the use of ketamine alone has been clearly associated with only one case ²⁷. This seems to be influenced by the binding of these drugs to NMDA receptors in the corneal endothelium under normal conditions ³², which can lead to the loss of corneal endothelial cells and the subsequent development of edema. In these cases, edema is usually bilateral and decreases after stopping the medication ^27,30.

Other non-topical drugs have been considered as possible causes of acute corneal edema, including bacitracin, neomycin, polymyxin B, tetracaine, and phenothiazine ^2,33.

Some substances, when applied topically on the eye, can trigger endothelial dysfunction with consequent acute corneal edema. Such is the case of cardiac glycosides contained in species such as Digitalis purpurea or Asclepias curassavica, which may induce acute corneal edema as they inhibit Na+-K+-ATPase, which in turn participates in endothelial cell functions ^34,35.

In some cases, the development of corneal edema has been attributed to the presence of foreign bodies in the anterior chamber, this edema being the first manifestation of their presence. With this in mind, it is possible to say that, on the one hand, these bodies can produce corneal edema by inducing a local inflammatory response, which damages some endothelial cells. This was reported in the case related to nuclear fragments found in the anterior chamber, even years after phacoemulsification ^36,37. On the other, the object itself and its products can directly damage the corneal endothelium, favoring edema as in the case of worms trapped in the anterior chamber (filariasis) ³⁸. Other examples include the presence of cotton waste or other products in the anterior chamber following intraocular surgical interventions ³⁹.

Corneal endothelitis is an acute inflammatory process limited to the corneal endothelium that can be associated with acute corneal edema.

There are three viruses in the Herpesviridae family that can trigger this ophthalmic entity: varicella-zoster virus, HSV (herpes simplex virus) and cytomegalovirus ^40-42. In addition, cases of endothelitis caused by Mixovirus parotiditis have been reported ⁴³.

This entity manifests as one or multiple acute red eye crisis, with ciliary and pain predominance, and often accompanied by acute corneal edema and keratotic precipitates, with or without manifest uveitis ^40,42,44.

Acute corneal edema is a process that can be triggered by local inflammation in uveitis cases, which can damage the corneal endothelium affecting its function ⁴⁵.

Post-operative corneal edema is one of the most frequent causes of acute corneal edema ⁴⁶. This category groups all the cases in which various ocular surgical procedures generate damages that lead to endothelial decompensation ^47,48. Some of these procedures include cataract surgery with or without intraocular lens implantation, posterior vitrectomy, retinopexy, trabeculectomy, and other intraocular procedures. Minimally invasive procedures with different lasers such as iridotomy, trabeculoplasty and capsulotomy have also been reported ^46,47,49,50.

Corneal edema can appear immediately after phacoemulsification because of the direct effect of this procedure on the surrounding structures, with damage to the endothelial cells and even detachment of the Descemet's membrane ^51-54. This edema is mild and transient in most cases, and severe with associated endothelial cell damage in few cases.

Nine cases of corneal edema secondary to laser trabeculoplasty used to treat primary open-angle glaucoma have been reported ^49,55,57. In all cases, the edema appeared within the first days after the surgery and resolved in the following weeks or months. In most cases, patients experienced different degrees of corneal opacities as sequelae; thinning of the cornea posterior to the edema with hypermetropic changes was evidenced in 6 of them.

Although the cause is not clear, two possible mechanisms have been proposed: first, changes in endothelial cells documented after laser trabeculoplasty can lead to corneal edema in extreme cases ^58,59, and second, although highly unlikely, it may be secondary to the reactivation of HSV ⁵⁷ since these patients were using topical prostaglandin analogs, which have been associated with this effect ^60,61). This mechanism, added to inflammation induced by the surgical procedure, could cause an edema process.

The possibility of acute corneal edema due to the direct effect of the intraocular solutions used in surgery to maintain the anterior segment should be considered. Depending on their physico-chemical characteristics, these solutions can overcome the physiological resistance of the corneal endothelium, which tolerates changes in pH between 6.8 and 8.2, and osmolality variations of 200 to 450 mOsm ^48,62. Thus, substances that test these resistance limits, as reported with the accidental instillation of CAI dissolved in distilled water with 0 mOsm ⁶³, may cause acute corneal edema.

Similarly, depending on its components, some of these solutions may directly damage the endothelial barrier, as reported in components such as sodium bisulfate, thimerosal, chlorhexidine and even carbachol. These effects are favored by longer surgical interventions or by endothelium with preexisting damages ^64,65.

The development of corneal edema has been reported in some mitochondrial diseases such as Pearson's syndrome, Kearns-Sayre syndrome or chronic progressive external ophthalmoplegia ^66-69. These types of edemas are frequently chronic; however, some acute and even self-corrective cases have been reported, which can be attributed to acute decompensations of the patient's general condition, thus intensifying the failure of mitochondrial function ^66,70.

Some rheumatologic diseases have been recognized as a cause of acute corneal edema, for example polyarteritis nodosa or Reiter's syndrome ⁹. On rare occasions, other systemic diseases such as Werner's syndrome, Zellweger's syndrome, facomatosis, Refsum's disease and serum sickness (usually bilateral) may lead to acute corneal edema ⁹.

Corneal hypoxia can lead to edematization by causing endothelial dysfunction and alterations in corneal metabolism ⁷¹. Some examples include mild edema after using contact lenses or an oppressive occlusion ^71,72; for the latter case, edema is proposed as the product of a mixture between corneal hypoxia and IOP elevation ⁷³ . Furthermore, chronic endothelial diseases such as Fuchs endothelial dystrophy or iridocorneal endothelial syndrome usually begin with predominantly morning edemas secondary to nocturnal palpebral closure, which generates some degree of corneal hypoxia.

Moreover, acute corneal edema can be triggered by endothelial ischemia in a rather unusual scenario, as reported by Nielsen et al. ⁷⁴, who described the case of a patient with temporal arteritis and acute ischemia of the anterior segment of the eye who developed associated acute corneal edema and a decrease of 72% in the count of endothelial cells.

Based on case reports and biological plausibility, it has been proposed that cold may predispose to the development of acute corneal edema or trigger its onset in predisposed persons, particularly in high wind conditions. These conditions favor the evaporation of the tear film and inhibit the endothelial pump, which promotes the accumulation of water in the cornea ⁷⁵.

An acute corneal edema, known as acute corneal hydrops, has been reported on several occasions. It occurs in different corneal ectasias such as keratoconus, pellucid marginal degeneration, Terrien marginal degeneration, keratectasia after laser in situ keratomileusis (LASIK) and keratectasia after radial keratotomy ^76-79. This entity occurs due to the rupture of a decemet membrane weakened and deformed by corneal ectasia, usually after mechanical stress, which often corresponds to scraping of the eye ⁸⁰. This rupture leaves a space that allows the passage of fluids from the anterior chamber to the cornea, thus producing acute corneal edema ⁸¹.

To date, nine cases of unknown causes have been reported, which are characterized by sudden unilateral corneal edemas with multiple parallel lines in the endothelium, associated with visual loss without pain. These are known as self-limited corneal edemas with multiple parallel lines on the endothelium (SCEMPLE) ^82-84. Nevertheless, all these cases show a typical characteristic that was not found in the case reported here: the presence of parallel horizontal dotted lines along the corneal endothelium, visible by slit lamp, that correspond to detached endothelial cells grouped in aligned clusters ⁸². In addition, these symptoms resolved after a week without any kind of sequel.

A specific idiopathic entity was reported on a single occasion, which the authors called brush cell endotheliopathy ¹⁴. Such report presented the case of a woman with an acute crisis of corneal edema of 14 years accompanied by red eye and pain, with evidence of focal bullous keratopathy by slit lamp examination, and interdigitations in the margins of the endothelial cells, similar to a zipper, observed using confocal microscopy in vivo. The picture progressed over the years in terms of endothelial damage and the degree of corneal opacity, until a penetrating keratoplasty was necessary.

JAUD summarized the case and conducted the search of the scientific literature. JAUD and JSFO reviewed the content of the articles found and created a preliminary version of this article. GFE and GDS reviewed, completed and corrected this version.