Corneal endothelial cells are responsible for removing fluid from the cornea through sodium\/potassium-ATPase pumps, thus keeping the cornea relatively dehydrated and clear. Corneal edema occurs when excessive fluid is in the cornea, leading to a blue hue. Edema can occur focally from loss of the epithelial cell barrier or diffusely from pathology of the corneal endothelial cells.<\/p>\n
This article will discuss primary and secondary causes of corneal edema, including pathophysiology, diagnosis, and treatment. Proper management of the underlying disease can help prolong vision and comfort in affected eyes.<\/p>\n
Take-Home Points<\/strong><\/p>\n The cornea is the transparent outer fibrous tunic of the eye that protects the internal structures of the eye and transmits light to the retina to form an image. The canine cornea has 4 distinct \u201clayers\u201d from the outside in: multicellular epithelium, collagenous stroma, Descemet\u2019s membrane (a basement membrane of the endothelium), and single-layer endothelium.1<\/sup> The corneal epithelium and endothelium are important in preserving the clarity of the cornea. The epithelium provides an outer barrier that prevents fluid from the tears from infiltrating the stroma. The endothelium uses physiologic sodium\/potassium (Na+<\/sup>\/K+<\/sup>)-ATPase pumps to remove fluid (aqueous humor) from the stroma. Any disruption to the epithelium and\/or endothelium can result in fluid infiltrating the stroma, giving the eye a bluish, hazy appearance (<\/span>FIGURE 1<\/b><\/span>).1<\/sup> Any time a patient is presented with a \u201cblue eye,\u201d a thorough history, physical exam, and ophthalmic exam are essential for diagnosing the cause of the edema.<\/span><\/p>\n Figure 1. The diffuse bluish, lacy appearance to the cornea depicts deep corneal edema secondary to moderate corneal endothelial dystrophy.<\/p><\/div>\n A Schirmer tear test should be performed to quantify the aqueous portion of the tears prior to any drops being administered in the eye. Normal range for the test should be >15 mm\/minute.2<\/sup> Values lower than this may be indicative of dry eye, which can predispose the eye to ulcers and neovascularization that can lead to focal corneal edema.2<\/sup> Corneal ulceration<\/a> leads to secondary focal edema through influx of the aqueous portion of the tear film into the corneal stroma. Neovascularization leads to focal edema because new vessels leak serum into the cornea. On the other hand, significant corneal edema can result in secondary bullae (\u201cblister\u201d) formation, which can rupture and lead to ulceration. Thus, any eye with corneal edema should be stained with fluorescein to evaluate for corneal ulcers. Fluorescein will adhere to any exposed stroma, thus allowing for the evaluation of breaks in the corneal epithelium. <\/span><\/p>\n Intraocular pressure (IOP) measurement is the most important diagnostic tool for any eye with corneal edema as uveitis<\/a> and glaucoma<\/a> are both significant causes that can lead to blindness<\/a> if left untreated. The IOP can be obtained using rebound tonometry (e.g., TonoVet [iCare, <\/span>tonovet.com<\/span><\/a>], Tono-Vera Vet [Reichert, <\/span>reichert.com<\/span><\/a>]) or applanation tonometry (e.g., Tono-Pen AVIA [Reichert, <\/span>reichert.com<\/span><\/a>]). One study found that the measurements read by TonoVet versus Tono-Pen vary between these devices with elevated pressures; therefore, consistently using the same device is necessary when monitoring individual patients.3<\/sup> This study also compared diseased portions of the cornea (e.g., pigmentation, vascularization, edema) to normal areas on the same eye.3<\/sup> The diseased portion of the cornea varied on average 2.1 mm Hg (\u20136 to +16\u00a0mm Hg) with the TonoVet and 3.2 mm Hg (\u20137 to +20 mm Hg) with the Tono-Pen.3<\/sup> Therefore, IOP measurements should be attempted on the most normal portion of the cornea. <\/span><\/p>\n Normal canine IOP is in the range of 10 to 25 mm Hg.4<\/sup> Values above 25 mm Hg are consistent with glaucoma and should be taken seriously, as glaucoma can be devastating to intraocular structures and lead to blindness. Care should be taken to ensure that the values are not falsely elevated. Manual jugular pressure and eyelid manipulation can significantly increase IOP baseline values.5<\/sup> Skull shapes can also affect mean IOP, with brachycephalic breeds having a higher mean baseline (16.4 \u00b1 2.9 mm Hg) compared to mesaticephalic (11.8 \u00b1 3.7 mm Hg) and dolichocephalic (13.5 \u00b1 1 mm Hg) breeds. Stress can also falsely elevate IOPs.4<\/sup> With overly stressed patients, gabapentin and\/or trazodone can be used as they have not been shown to clinically affect the IOP.6<\/sup> <\/span><\/p>\n Low IOPs, especially in the single digits, may be indicative of uveitis. When low IOPs are seen concurrently with corneal edema, the eye should be examined closely for signs of inflammation (e.g., conjunctival hyperemia, miosis, hypopyon, hyphema, aqueous flare).7<\/sup> Corneal edema can make assessment of intraocular changes difficult. Working in a dark room and use of the focal slit beam on the ophthalmoscope can aid in visualizing these clinical signs. <\/span><\/p>\n Glaucoma<\/a> is an optic neuropathy associated with an increase in IOP leading to vision loss from irreversible damage to the retinal ganglion cells and optic nerve. Some breeds predisposed to primary glaucoma include cocker spaniels, Boston terriers, basset hounds, and wire-haired fox terriers, along with a long list of other breeds in which it has been described. Females are overrepresented, and the average age of presentation is between 4 and 10 years of age.4<\/sup> <\/span><\/p>\n Secondary glaucoma results from a variety of causes, including uveitis, lens luxations, hypermature cataracts, retinal detachments, progressive retinal atrophy, neoplasia, and intraocular surgery.4,8<\/sup> Signalment, presentation, and the ocular exam may lead clinicians to suspect secondary glaucoma.8<\/sup> For example, which part of the exam is worse? If the uveitis is worse than the pressure increase, or there are other changes in the eye as listed above, it is more likely to be secondary glaucoma. <\/span><\/p>\n Clinical signs of glaucoma depend on the severity of the pressures. Early stages may involve mild episcleral injection, mydriasis, and transient corneal edema. As the disease progresses and the pressures become higher, the corneal edema will be more severe and diffuse; additionally, significant mydriasis and episcleral injection, buphthalmia, and blindness can become apparent. Prolonged IOP >40 mm Hg is necessary to lead to corneal edema.4<\/sup> Diagnosis of glaucoma is based on an increased IOP, as described above. More advanced diagnostics, such as gonioscopy and ultrasound, may be used to evaluate the iridocorneal angle in the contralateral or \u201cnormal\u201d eye to assess the risk of that eye developing glaucoma.<\/span><\/p>\n The pathogenesis behind corneal edema associated with glaucoma is multifactorial. One study found that glaucomatous eyes had lower corneal endothelial cell counts as compared to healthy eyes, which could be due to direct damage from the elevated IOP, congenital alterations of the endothelium in patients that develop glaucoma, glaucoma medication toxicity, or a combination of these causes.9<\/sup> Another study found an increased cyclooxygenase 2 (COX-2) expression in corneal epithelial and endothelial cells of glaucomatous eyes, which may play a role in aqueous production\/removal or may be secondary to inflammation due to stretching of the tissues by the increased IOP.10<\/sup> Further studies are warranted to determine the significance of COX-2 in the pathogenesis of glaucoma and as a potential target for glaucoma therapy. Finally, during pressure elevations, the increased hydrostatic pressure in the anterior chamber decreases the normal flow of fluid from the cornea to the iridocorneal angle.4<\/sup> <\/span><\/p>\n Treatment for glaucoma is focused on lowering the IOP to safe levels (<20 mm Hg) to maintain the health of the optic nerve. Lowering the IOP also helps resolve or prevent further worsening of the corneal edema that has developed due to the aforementioned pathogenesis. If the pressure is controlled early enough, before the critical mass of endothelial cells is lost, the hydrostatic pressure is decreased and thus the endothelial cells can resume their normal function of removing fluid from the cornea. However, if too many endothelial cells are compromised, due to either chronic increased pressure or a severe pressure spike, corneal edema may be permanent despite proper pressure control.4,10<\/sup><\/span><\/p>\n Anterior lens luxation can be congenital, primary, or secondary:<\/span><\/p>\n When the lens luxates anteriorly, acute glaucoma can result from the lens blocking normal flow of aqueous fluid through the pupil.12<\/sup> Corneal edema can develop due to the direct trauma of the lens hitting the endothelium or secondary glaucoma (<\/span>FIGURE 2<\/b><\/span>). A slit beam on the direct ophthalmoscope will show a shallow anterior chamber and the equator of the lens anterior to the iris due to the luxation of the lens. Treatments for anterior lens luxations include transcorneal reduction of the lens or intracapsular lens extraction.12<\/sup><\/span><\/p>\n Figure 2. The bluish, lacy appearance of corneal edema secondary to an anterior lens luxation. Note the equator of the lens anterior to the iris, especially dorsally in this image.<\/p><\/div>\n Anterior uveitis<\/a> is inflammation of the iris and\/or ciliary body characterized by aqueous flare but can also encompass conjunctival hyperemia (<\/span>FIGURE 3<\/b><\/span>), miosis, hypopyon, or hyphema.7<\/sup> Uveitis can cause corneal edema due to an increase in endothelial permeability and a decrease in Na+<\/sup>\/K+<\/sup>-ATPase pump site density.7,13<\/sup> In these cases, there is normal endothelial cell density, but the cells are edematous with disrupted intercellular junctions.7<\/sup> The damage to the endothelium may be due to prostaglandins, oxygen-free radicals, and hydrolytic enzymes from leukocytes.7<\/sup> Uveitis is managed through treatment of the underlying cause as well as topical and systemic anti-inflammatories. The corneal edema should dissipate with resolution of the uveitis. However, if keratic precipitates form or the endothelial cells are irreversibly damaged from the inflammation, edema may not resolve.<\/span><\/p>\n Figure 3. Corneal edema secondary to anterior uveitis. Note the deep neovascularization and conjunctival hyperemia, both additional clinical signs of anterior uveitis.<\/p><\/div>\n Corneal endothelial dystrophy (CED) is a disease characterized by decreased endothelial cell density as well as abnormal morphology, including cell pleomorphism (variable size and shape of cells) and polymegathism (greater-than-normal variation in size), which results in increasing corneal edema.14<\/sup> It is a progressive and bilateral disease similar to a genetic disease in humans, Fuchs\u2019 dystrophy. <\/span><\/p>\n Boston terriers, Chihuahuas, and dachshunds are overrepresented in the diagnosis of CED.1,15<\/sup> In addition, a study from the University of California, Davis, found that of large breeds, German shorthaired and wirehaired pointers were overrepresented.16<\/sup> Females are also 3 times more likely to develop this disease, which is also seen in Fuchs\u2019 dystrophy. The median age of onset is between 10 and 12 years of age<\/a>,14,15<\/sup> with 92% of cases presenting over the age of 8\u00a0years.15<\/sup> These ages correlate with the average age of onset of Fuchs\u2019 dystrophy in humans at 50 to 60 years.14<\/sup> CED in Boston terriers is noted to typically start temporally then progress over 1\u00a0to 2\u00a0years to involvement of the entire cornea (<\/span>FIGURE 4<\/b><\/span>). <\/b>The German shorthaired and wirehaired pointers were noted to have a more diffuse edema on presentation.16<\/sup> <\/span><\/p>\n Figure 4. Diffuse corneal edema secondary to advanced endothelial dystrophy.<\/p><\/div>\n Although dogs are expected to be affected bilaterally, there can be an asymmetric onset and progression of the affected eyes.14 <\/sup>Conjunctival hyperemia can range from absent to reportedly 69% of eyes affected by CED.1,15<\/sup> The Schirmer tear test and IOPs are reported to be unaffected by CED.14<\/sup><\/span><\/p>\n The diffuse edema can result in formation of bullae that can rupture and lead to multiple tiny ulcerations, which then can progress to larger ulcers if the epithelium sloughs off. While CED itself is not painful, these ulcers are a source of pain and morbidity associated with this disease. At this time, treatment is mainly focused on preventing bullae and corneal ulcer formation to maintain comfort in these eyes. Palliative treatment includes topical 5% sodium chloride (NaCl) ointment, which helps reduce the development of bullae and subsequent ulcer formation. In normal corneas, treatment with 5% NaCl ointment was found to decrease central corneal thickness by 2% to 4%, but it is suspected that this percentage may be higher with diseased corneas.17<\/sup> However, significant corneal clearing should not be an expectation with topical 5% NaCl administration.1<\/sup> A new study found that a topical rho-associated kinase (ROCK) inhibitor, ripasudil, can show improvement or stabilization of the edema in up to 62% of dogs with endothelial dystrophy.18<\/sup> Further studies are warranted to better understand the efficacy, safety, and use of ROCK inhibitors in these cases. <\/span><\/p>\n Surgical options have also been used to help resolve some of the corneal edema. Thermokeratoplasty involves using thermal cautery to cause contraction of anterior stromal fibers multifocally, thus inducing scar tissue that physically prevents fluid from accumulating within the anterior stroma (<\/span>FIGURE 5<\/b><\/span>). This technique can only be performed over an ulcerated region but has been found to help resolve nonhealing corneal ulcers and reduce the incidence of developing recurrent ulcers.19<\/sup> <\/span><\/p>\n Figure 5A. Use of thermal cautery to create multifocal points of anterior stromal contraction.<\/p><\/div>\n Figure 5B. Eye post-thermokeratoplasty procedure. Stromal scarring acts as a barrier to fluid flow, hopefully decreasing overall corneal edema.<\/p><\/div>\n Another procedure is a superficial keratectomy and conjunctival advancement hood flap (SKCAHF) (<\/span>FIGURE 6<\/b><\/span>). In 1 recent study, this procedure allowed for improvement of corneal edema for at least 1 year postoperatively and reduction of the frequency of topical 5% NaCl administration. The owners also reported an improvement in vision and corneal clarity.20<\/sup> SKCAHF has also been shown to decrease corneal thickness and ocular pain by decreasing the risk\/rate of ulcer formation.21<\/sup> This procedure is thought to reduce edema because the conjunctiva provides an alternate route for fluid drainage.20<\/sup><\/span><\/p>\n Figure 6A. Severe corneal edema due to corneal endothelial degeneration with pigmentation and corneal neovascularization. This patient was blind due to the severity of the edema.<\/p><\/div>\n\n
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<\/a>Diagnostic Tests<\/h2>\n
Tear Production and Fluorescein Stain<\/h3>\n
Intraocular Pressure<\/h3>\n
Causes of Corneal Edema<\/h2>\n
Glaucoma<\/h3>\n
Anterior Lens Luxation<\/h3>\n
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<\/a>Uveitis<\/h3>\n
<\/a>Endothelial Dystrophy<\/h3>\n
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