A Review of Corneal Endotheliitis and Endotheliopathy: Differential Diagnosis, Evaluation, and Treatment

CMV-induced corneal endotheliitis can present with linear or circularly organized (often termed coin-shaped) KP in the presence or absence of local stromal edema (Fig. 1c) [11]. CMV-endotheliitis rarely results in diffuse distribution of KP. It is typically unilateral. One study by Koizumi et al. [16] reported that only 3 of 106 patients had bilateral involvement. Intraocular pressure (IOP) is often elevated at presentation. Co-existing anterior uveitis is not uncommon and may represent an alternate manifestation of the same disease [17]. This uveitis can progress to chronic anterior uveitis with either recurrent episodic iritis and raised IOP (resembling Posner–Schlossman syndrome) or the presence of anterior chamber cells and endothelial KP (resembling Fuchs’ heterochromic iridocyclitis) [11]. However CMV may also present atypically as bullous keratopathy without KPs or elevated IOP [18]. Contrary to other viral etiologies of endotheliitis and CMV infections in general, CMV-related endotheliitis is more common in immunocompetent individuals [17].

Herpetic endotheliitis typically presents with disciform KP but may also present with diffuse, linear, and sectoral KP (Fig. 1b) [10, 19]. Iritis and stromal edema are commonly seen, distinguishing this etiology from other causes of anterior uveitis. Elevated intraocular pressure is seen secondary to trabeculitis [20]. HSV endotheliitis is common in individuals who are immunocompromised and thorough history taking may elucidate prior or recurrent herpetic disease.

Mumps virus commonly involves glandular structures, with lacrimal gland involvement being the most common ocular manifestation [21, 22]. However, on rare occasions this virus can involve the endothelium and stroma [22, 23]. Patients with mumps endotheliitis typically present with unilateral central corneal edema that spares the epithelium, KP in the area of edema, elevated IOP, decreased visual acuity, and ocular discomfort. Importantly, mumps may be differentiated from other causes of endotheliitis by the relative absence of uveitis and iritis [23].

Other viruses, including those of the human herpes virus (HHV) family, have been reported as causing endotheliitis, albeit infrequently. Varicella zoster virus, of the herpes virus family, has been shown to cause disciform endotheliitis [24]. It has also been reported as a cause of endotheliitis after keratoplasty [25]. In addition Epstein–Barr Virus (EBV, Fig. 2), HHV-7, and HHV-8 have been implicated in endotheliitis [26, 27]. Coxsackie virus, while commonly known for its association with acute hemorrhagic conjunctivitis, may also cause endotheliitis [28]. Rhabdovirus has also been cited as a cause of unilateral endotheliitis [29].

CCL strengthens the inter-fibrillar covalent bonds within the stroma and prevents the progression of kerectasia [10]. One common method involves removal of the corneal epithelium and application of riboflavin solution which is later biochemically activated using ultraviolet A light.

Corneal endotheliitis presenting with hyperemia and photophobia has been reported after collagen cross-linking [59]. There may also be localized edema of the cornea containing coin-like KP [60]. However, the incidence of endotheliitis after CCL is relatively low. In a case study, Sharma et al. noted that only 10 of 350 patients (2.9%) presented with corneal endotheliitis after CCL with two patients eventually undergoing penetrating keratoplasty [61]. CCL was determined to be the cause due to lack of infectious or drug-induced etiologies. In the case presented by Gumus, treatment with topical steroids resulted in resolution of symptoms [60].

While the mechanism by which CCL causes endotheliitis remains undetermined, there are several likely contributing factors that should be considered [60]. An excessively thin cornea can allow the ultraviolet A (UV-A) treatment to penetrate to the endothelium and incite an inflammatory response. Yet, endotheliitis has been reported in corneas well above 400 µm of thickness, suggesting a host of other potential causes [62]. The use of riboflavin, which thins and dehydrates the cornea, may be a contributing factor. It has been theorized that riboflavin may incite inflammation but more investigation is needed to validate this claim [60, 63]. Another study assessing the long-term safety of CCL on the corneal endothelium found a significant decrease in endothelial cell density after CCL, which may contribute to the development of endotheliitis [64]. Pre-existing conditions such as Fuchs dystrophy, viral uveitis, and endotheliitis should also be considered prior to treatment of kerectasia with CCL.

Corneal edema may occur in patients after cataract surgery for a variety of reasons including retained lens fragments, Descemet’s membrane detachment, and Brown–McLean syndrome (BMS). The majority of postoperative corneal edema and endotheliopathy is associated with retained lens fragments. This typically presents 1–138 days postoperatively, but has been reported as late as 8.5 years postoperatively [65]. These complications can progress to corneal decompensation requiring Descemet stripping automated endothelial keratoplasty (DSAEK) or penetrating keratoplasty. BMS typically presents an average of 16 years after cataract surgery, with orange-brown pigment in the endothelium and peripheral corneal edema [10]. Confocal microscopy in some patients with BMS shows decreased endothelial cell density, while others show normal cell density, suggesting a multifactorial etiology [66‐68]. Intraocular surgery has also been reported to trigger CMV endotheliitis [69, 70]. Vitreous incarceration is an additional cause of endotheliopathy and corneal decompensation after cataract surgery. McDonnell et al. [71] performed electron microscopy on the endothelium of vitreous incarcerated patients postmortem and discovered migration of corneal endothelium onto the vitreous causing endotheliopathy. If presenting with corneal edema and endothelial dysfunction 12–48 h after anterior segment surgery, acute toxic anterior segment syndrome (TASS) should be considered. This is by definition a non-infectious inflammatory reaction with many potential causes including ointments, preservatives, retention of sterilization detergent, abnormal pH or salt concentration, trypan blue, trace metal deposits, and denatured viscoelastic material [72‐77]. These causes of corneal edema after posterior chamber intraocular lens implantation discussed above are not all true endotheliitis, yet should be considered in the differential of possible corneal endotheliitis.

Endotheliitis has been seen in allograft rejection following penetrating keratoplasty. Khodadoust and Attarzadeh discovered that the epithelium, stroma, and endothelium can illicit the host response against donor tissue [6]. Of these, endothelial rejection is the most common and is seen in up to 50% of graft rejections. More anterior procedures such as deep anterior lamellar keratoplasty (DALK) have led to the preservation of the host endothelium and subsequent decrease of endotheliitis caused by allograft rejection.

Dexamethasone implants are used for treatment of persistent macular edema refractory to anti-vascular endothelial growth factor (anti-VEGF) injections. These implants have been reported to occasionally migrate into the anterior chamber and cause temporary or even permanent endothelial damage even after removal of the implant [78‐80]. In strabismus-correcting surgeries, simultaneous resection of three rectus muscles, or even two in patients with compromised blood flow, may result in anterior segment ischemia [81]. These patients can present initially with anterior chamber cell and flare, Descemet’s folds, and mild uveitis, but may progress to severe corneal edema with or without striate keratopathy, hyphema, and posterior synechiae [82]. In retinal surgeries with silicone oil removal after a longer period (2–7 months), decreased corneal cell density and severe endothelial damage may occur, which does not improve even after removal of the oil [83]. Finally, patients may present with endothelial KPs, cells in the anterior chamber, and corneal edema after undergoing laser-assisted eyebrow epilation without proper eye protection [84].

Fungal infection is a well-documented cause of stromal and interstitial keratitis. In 2012, Garg [85] noted several fungal etiologies that infect the corneal epithelium which, if left untreated, have the potential to extend into the endothelium and cause decompensation and inflammation. In 2013, Zapata et al. [86] reported a case of infectious endotheliitis of suspected mycotic origin. Although no organisms were isolated, clinical improvement was seen after 5 days of antimycotic therapy. While rare, fungal origin should be considered in cases of infectious endotheliitis refractory to antiviral treatment.

Venom ophthalmia, a condition in which snake or frog venom has been excreted onto the eye, has been documented as causing marked corneal edema of the epithelium and endothelium [87]. Chu et al. [88] reviewed ten cases of venom ophthalmia in which corneal stromal edema with Descemet’s folds was a major sequela. The cases presented involved ten different species of venomous snakes. Another source of zoological caused corneal edema is arachnids. When threatened, tarantulas expel a cloud of barbed hairs that can contact the eye directly or be transferred from hand to eye. These barbs can then migrate through the cornea and lodge in the endothelium causing corneal edema and mutton-fat KP, and can eventually migrate further to the retina (Fig. 4) [89]. In addition, decreased endothelial cell density and persistent corneal edema have been reported 1 year after corneal bee sting [90]. There have also been reports of caterpillar hair and coral aquarium causing corneal edema and endothelial attenuation, respectively [91].

The use of contact lenses has historically been the cause of localized endothelial cell loss and corneal edema. The causes of this endothelial insult are attributed to acidification of corneal endothelium by a reduction in carbon dioxide efflux (hypercapnia) and also an accumulation of lactic acid due to oxygen deprivation [92]. The advancements in oxygen-permeable contact lenses have greatly reduced these endothelial changes but improper maintenance and use of contact lenses can induce hypoxia and endothelial insult.

Mustard gas keratopathy (MGK) is known to have diverse ocular manifestations including endothelial cell destruction. McNutt et al. studied MGK’s effect on the corneal endothelium of rabbits and found significant destruction in a pattern described as centripetal, concentrated centrally with diffuse peripheral destruction [93]. There are cases of delayed MGK in the literature where corneal symptoms present up to a decade later [94]. This delayed type of MGK makes it a relevant differential diagnosis for citizens of war-torn countries where bioterrorism is prevalent.

Exposure to certain plants such as Asclepias fruticosa (milkweed) and Calotropis procera (Sodom apple) can cause endothelial toxicity [95, 96]. With Asclepias fruticosa, treatment typically resolves the dysfunction in 2–3 days, while Calotropis procera often causes a permanent decrease in endothelial cell count with average resolution of edema in 3–6 months. There are also rare reports of cadmium in a woman’s eyeliner (khol) commonly used in the Middle East, Asia, and Africa causing severe corneal edema and endothelial dysfunction [97].

High-intensity exercise (e.g., ultramarathon runners) has also been associated with bilateral corneal edema. This is likely due to an increase in lactic acid levels in the aqueous humor and the oxidative stress that causes endothelial injury (ultramarathon-induced bilateral corneal edema) [98, 99].

Giant cell arteritis is an example where endothelial dysfunction is a sequela to the primary diagnosis [100]. A case study presented in June 2017 describes a woman who presented with unilateral corneal edema 1 day after uneventful cataract extraction. After 3 days, her presentation had progressed to bilateral corneal edema with ocular hypotony. Magnetic resonance angiography revealed stasis of the ophthalmic arteries and a tissue biopsy confirmed giant cell arteritis. A diagnosis of anterior segment ischemic syndrome was made and determined to be the cause of corneal decompensation [101].

Patients with sarcoidosis often present with pulmonary lymphadenopathy, elevated serum angiotensin converting enzyme (ACE), and granulomas in multiple organs. Ocular manifestations may include uveitis, macular edema, and endotheliitis. The endotheliitis is characterized by mutton-fat and granulomatous KP [102]. One case in the literature describes Crohn’s disease with leukocytoclastic vasculitis with an associated progressive cicatrizing endotheliitis. Mitochondrial diseases including chronic progressive external ophthalmoplegia, Kearns–Sayre syndrome, and Pearson’s syndrome cause acute corneal edema due to endothelial dysfunction [103‐105].

In 2016, Kelly et al. [106] reported a case of endotheliitis-like presentation in a 6-year-old diagnosed with retinoblastoma. The patient was unresponsive to corticosteroids and antivirals and aqueous humor was negative for any viral genomes.

Other cases of ocular hypotony inducing endothelial dysfunction have been reported including a case where the surgical correction of ocular hypotony cured the concomitant corneal edema [107].

As mentioned earlier, “multiple-parallel-line” endotheliitis has been reported as a steroid-responsive non-infectious idiopathic cause of endothelial dysfunction [12]. Some have postulated that this may be a subtle form of aqueous negative but serological positive viral endotheliitis; however, more data is needed to support this claim [13]. Another idiopathic entity termed “zipper cell endotheliopathy” has been described as focal denudation of endothelial cells surrounded by endothelial cells with zipper-like extensions and overlapping neighboring cells. Immunohistochemistry suggested that epithelial metaplasia could be a possible cause for this case [108].