Corneal Edema – Canine

Synonyms:
Bullous keratopathy
Corneal endothelial decompensation
Corneal endothelial degeneration
Corneal endothelial dystrophy
Corneal stromal edema

Disease Description:
Definition

Corneal edema refers to abnormal fluid accumulation in the corneal stroma. Stroma is the middle layer of the cornea. It comprises ~90% of corneal thickness, and is composed of primarily collagen fibers. Corneal stroma is normally in a dehydrated state (detergescence) to allow for transmittance of visible light, and blockage of nonvisible light in the ultraviolet and infrared spectra in order to protect intraocular structures.¹

Etiology and Pathophysiology

Corneal edema may result from disruption of both endothelium (i.e. deepest layer of the cornea adjacent to aqueous humor) and epithelium (i.e. most superficial layer adjacent to precorneal tear film). Disruption of epithelium causes a 200% increase in corneal thickness from edema.¹ Disruption of endothelium causes a 500% increase in corneal thickness from edema, making endothelium more important in maintaining  detergescence.¹ Corneal edema may also arise from corneal neoplasia, abscessation, vascularization, and various keratopathies, such as macular corneal dystrophy of the Labrador retriever and Florida keratopathy.^2,3 Corneal or limbal immune-mediated conditions that cause neovascularization and cellular infiltration may also be associated with stromal edema, such as episcleritis https://beta.vin.com/Members/Associate/Associate.plx?from=GetDzInfo&DiseaseId=153. This chapter discusses only corneal edema resulting from endothelial disease.

Corneal endothelium is a single cell layer that rests on Descemet’s membrane posterior to corneal stroma. It is composed of hexagonal cells that have almost no reproductive capacity.¹ Endothelial cells have an active pumping mechanism for moving water out of the cornea into the anterior chamber, and they provide a passive fluid barrier between aqueous humor and corneal stroma.¹ Endothelial cells are normally lost throughout life. During disease states endothelial cell loss is accelerated. When a critically-low density of cells is reached, the normal dehydrated state of corneal stroma is no longer maintained and corneal edema results. Factors that may result in loss of endothelial function or cell numbers include genetic/ inherited factors, developmental disorders, glaucoma, anterior lens luxation, trauma, inflammation, infection, and certain toxins.

Diagnosis

Physical Examination Findings/History: Corneal edema is characterized by a bluish-white discoloration of the cornea that appears to have a reticulated or cobble-stone pattern (Figure 1A). Edema is best visualized with magnification and slit lamp biomicroscopy. Depending on the underlying cause, onset can be sudden (e.g. acute glaucoma, uveitis, anterior lens luxation, Figure 2) or gradual (e.g. endothelial dystrophy/degeneration, chronic uveitis). Age of onset and clinical progression also vary based on the underlying cause.

Ocular Examination Findings: Endothelial decompensation and subsequent stromal edema can dramatically increase the thickness of the cornea. This thickness is more severe than edema caused by superficial corneal diseases, such as superficial ulcers. Thickening of the stroma can be appreciated by transillumination with a focal light source; transillumination using the slit beam on a direct ophthalmoscope; and with slit lamp biomicroscopy. In some cases, outward bowing of the corneal curvature (i.e. keratoconus) can occur (Figure 3).

Progressive or advanced stromal corneal edema can lead to overhydration of corneal epithelium and secondary epithelial erosion or ulceration (Figure 4A). Other secondary abnormalities include corneal vascularization (Figure 5A) and pigmentation with reduced vision; formation of corneal bullae (Figure 6); and conjunctival hyperemia (Figure 7). Corneal edema is not inherently painful; however, underlying causes (e.g. glaucoma, uveitis) and associated changes (e.g. corneal ulceration) may cause pain. 

Thorough ophthalmic examination is indicated to search for underlying causes, including measurement of intraocular pressure (IOP), fluorescein staining, Schirmer tear testing, and evaluation of intraocular structures. In some cases, edema is so dense that it precludes complete evaluation of intraocular structures. In this situation, imaging techniques may be pursued.

Ultrasonography: Ocular ultrasonography may be considered when intraocular structures cannot be visualized. Ultrasonography can identify anterior lens luxation, cataract changes, evidence of hyphema and/or vitreal hemorrhage, mass effects, and retinal detachment.

Advanced Imaging: Advanced imaging modalities have been developed to evaluate corneal stroma and endothelium, such as confocal microscopy, optical coherence tomography, pachymetry, and high-resolution ultrasound biomicroscopy.^4-8 Corneal imaging typically requires referral to a veterinary ophthalmologist and/or teaching institution.

Other Tests: Other testing depends on suspected underlying causes for the corneal edema.

Disease Description in this Species:

Etiology and Clinical Signs

Inherited Endothelial Dystrophy: Primary, inherited endothelial dystrophy results in premature loss of endothelial cells and subsequent corneal edema. Underlying genetic trait and inheritance pattern have not been determined.²⁰ Likewise, the pathophysiologic defect has not been defined but is believed to represent premature degeneration of endothelial cells.²⁰ Endothelial cell density is significantly lower in affected dogs than age-matched, normal dogs.²⁰ Edema may range from mild and slowly progressive to rapidly progressive and severe.²¹ An area of focal edema (usually in temporal quadrant) is noted initially (Figures 1A, 7), then the edema spreads centrally and becomes generalized (Figures 1B, 4B, 5A, 6). Although edema in one eye may precede edema in the other eye by months to a few years, eventually both eyes are usually affected.²¹ Vision loss may occur from progressive opacification of the cornea.

Primary endothelial dystrophy occurs most commonly in the Boston terrier, chihuahua, dachshund, and German shorthaired and wirehaired pointers.^20-22 It has also been observed in the basenji, boxer, chow chow, German shepherd dog, kuvasz, miniature bull terrier, miniature schnauzer, Nova Scotia duck tolling retriever, petit basset griffon vendeen, Polish lowland sheepdog, miniature poodle, shiba inu, Cavalier King Charles spaniel, basset hound, West Highland White terrier, and wirehaired fox terrier.^22,23

Most affected dogs are middle-aged when the edema is first noticed. In a study of affected Boston terriers, mean age was 10+2 years at the time of corneal imaging.⁶ In a long-term, retrospective study, dogs >11 years were over-represented.²⁰ Because of its late onset, endothelial dystrophy is sometimes described in the literature as corneal endothelial degeneration. No sex predisposition has been documented.²⁰

Glaucoma https://beta.vin.com/Members/Associate/Associate.plx?from=GetDzInfo&DiseaseId=1224 : Acute elevation of IOP >50 mmHg results in a pressure gradient that is too high for the normal endothelial pumping mechanism to overcome. Acute, diffuse corneal edema is a common sequela. Corneal edema from acute glaucoma disappears within hours if IOP is normalized. Chronic elevations in IOP can also cause endothelial cell death, with resultant edema at lower IOPs.

Anterior Lens Luxation https://beta.vin.com/Members/Associate/Associate.plx?from=GetDzInfo&DiseaseId=1303 : Corneal edema associated with anterior lens luxation may be diffuse if acute glaucoma develops. Focal corneal edema can occur adjacent to where the lens touches the cornea (Figure 8). Focal edema arises primarily from impairment of function of endothelium in that localized area. Focal corneal edema often persists despite normalization of IOP. Differentiating acute glaucoma from anterior lens luxation may be difficult when severe corneal edema does not allow visualization of lens location.  Both acute glaucoma and anterior lens luxations are considered ophthalmic emergencies and referral should be considered, even if the location of the lens cannot be definitively determined.

Trauma: Although glaucoma and anterior lens luxation can traumatize endothelium, other rarer causes include parasite (larval) and foreign body migration, penetrating injuries, and surgery. Parasitic and foreign body migration may cause diffuse corneal edema (Figure 9), while penetrating injuries https://beta.vin.com/Members/Associate/Associate.plx?from=GetDzInfo&DiseaseId=166 and surgical trauma often result in focal edema. Surgical trauma may be related to aggressive irrigation and manipulation during intraocular surgery. It may not become apparent for weeks to months after surgery. Advancements in phacoemulsification (cataract surgery) machines and use of viscoelastic solutions in the anterior chamber have significantly reduced the incidence of surgical trauma associated with cataract extraction and other intraocular surgeries. Addition of vitamin C to phacoemulsification fluids may also have a protective effect on endothelium.⁹

Inflammation/Infection: The most common inflammatory cause of corneal edema is anterior uveitis or panuveitis. Inflammatory mediators associated with uveitis https://beta.vin.com/Members/Associate/Associate.plx?from=GetDzInfo&DiseaseId=1196 , endophthalmitis, and panophthalmitis can adversely affect endothelial cells. Focal corneal edema is sometimes concentrated centrally and ventrally in areas adjacent to keratic precipitates (Figure 10). Severe uveitis, endophthalmitis, and panophthalmitis may result in diffuse corneal edema (Figure 2).

Endotheliitis is a presumed autoimmune disease of endothelium that may cause acute, focal stromal edema (Figure 11A). It occurs rarely in the dog, and usually requires slit lamp biomicroscopy or advanced imaging modalities to confirm the diagnosis. Endotheliitis typically resolves with therapy (Figure 11B); however, corneal edema can persist in some cases.¹⁰ Unlike retro-corneal pigmentation, endothelial pigmentation is not a feature of immune-mediated endotheliitis.¹¹

Vaccination against canine infectious hepatitis with canine adenovirus (CAV) -1 can cause an Arthus-type reaction within corneal endothelium. This reaction results in acute, severe corneal edema that is often unilateral and may be permanent. Current canine vaccines contain CAV-2 because it is less likely to induce this reaction. As a result, incidence of so-called blue eye has decreased substantially. 

Toxins: Administration of the oral anti-arrhythmic drug, tocainide, may cause corneal edema in dogs.²⁴ Edema is bilateral, progressive, and has limited the use of this drug in dogs.²⁴

Developmental Malformations: Focal corneal edema is sometimes associated with corneal fibrosis that occurs with iris-to-cornea persistent pupillary membranes https://beta.vin.com/Members/Associate/Associate.plx?from=GetDzInfo&DiseaseId=5542 .Anterior segment dysgenesis and more severe abnormalities may also cause diffuse corneal edema.

Breed/Sex/Age: no edits on my end except add Dalmation maybe because overrepresented in keratectomy study #13?

Clinical Findings: Conjunctival hyperemia/scleral injection

Blue-white discoloration to cornea, often with “cobblestone” appearance

Corneal pigmentation, ulceration or vascularization with diffuse corneal edema

Corneal edema

Glaucoma

Lens luxation or subluxation

Anterior uveitis

Keratic precipitates

Diagnostic Procedures/Results:

Ocular examination:

• Anterior chamber shallow or absent (lens endothelial touch)
• Aqueous flare
• Corneal penetration
• Elevated intraocular pressure
• Anterior uveitis
• Anterior segment dysgenesis
• Persistent pupillary membranes to cornea
• Keratic precipitates
• History of CAV-1 or CAV-2 vaccination

Images No misc. doc; 11 are Rachel’s images

Delete Figures 1, 2, 4, 5 already in the chapter.

Figure 1A: Endothelial dystrophy OD_schnauzer_day 1

Title: Endothelial dystrophy OD day 1

Caption: 12-yr-old miniature schnauzer with bilateral corneal edema. Courtesy Dr. Rachel Davis, 2022

Figure 1B: Endothelial dystrophy OD_schnauzer_6 months

Title: Endothelial dystrophy OD 6 months later

Caption: Corneal edema was progressive in both eyes. Courtesy Dr. Rachel Davis, 2022

Figure 3 already in the chapter becomes Figure 2.

Figure 6 already in the chapter becomes Figure 3.

Figure 4A: Corneal ulceration 4A_edema_GSD_preRx

Title: Superficial corneal erosion in an edematous cornea

Caption: 12-yr-old German shepherd dog. Not fluorescein retention in area of ring flash and perilimbal, superficial vascularization. Courtesy Dr. Rachel Davis, 2022

Figure 4B: Corneal ulceration 4B_edema_GSD_postRx

Title: Corneal ulceration post-treatment

Caption: The erosion was treated with diamond burr debridement and placement of a contact lens. Corneal edema was subsequently managed medically until the dog’s death. Courtesy Dr. Rachel Davis, 2022

Figure 5A: Endothelial dystrophy 4A_shih tzu_preop

Title: Advanced endothelial dystrophy OS preoperative photo

Caption: 13-yr-old shih tzu with history of marked corneal edema, recurrent corneal ulceration and vascularization. The eye was painful and keratoleptynsis was performed. Courtesy Dr. Rachel Davis, 2022

Figure 5B: Endothelial dystrophy 4B_shih tzu_postop

Title: OS 6 months following keratoleptynsis

Caption: The eye remained comfortable and visual for the duration of the dog’s life (another 2 years). Courtesy Dr. Rachel Davis, 2022

Figure 6 from MB Thread https://www.vin.com/members/boards/discussionviewer.aspx?DocumentId=8399268&SAId=1&FindSince=26280000 (post 1), id# 4613210, Dr. Murray Moffatt, 2018 (corneal bullae)

Figure 7 from MB Thread https://beta.vin.com/members/boards/discussionviewer.aspx?DocumentId=4865541&SAId=1&FindSince=26280000 (post 1), id# 1534125, Dr. Edward Berman, 2011 (focal edema, conjunctival hyeremia)

Figure 8: id# 539340. This image is Figure 1 in the Anterior Lens Luxation chapter: https://beta.vin.com/Members/Associate/Associate.plx?from=GetDzInfo&DiseaseId=1303&ShowA=1

Figure 9: Nematode in Eye > Shiller 4_092110-001

Title: Filarial nematode in anterior chamber with secondary corneal edema

Caption: Corneal edema progressed rapidly in this eye and resulted in permanent blindness. Courtesy Dr. Rhea Morgan 2010.

Figure 10: Endothelialitis_uveitis_poodle_preRx

Title: Corneal edema associated with uveitis/endothelial inflammation

Caption: 12-yr-old poodle. Courtesy Dr. Rachel Davis, 2022

Figure 11A: Endotheliitis_10A_CKCS_preRx

Title: Focal, acute endotheliitis

Caption: 1-yr-old Cavalier King Charles spaniel. Courtesy Dr. Rachel Davis, 2022

Figure 11B: Endotheliitis_10B_CKCS_preRx

Title: Focal endotheliitis resolved with medical therapy

Caption: Courtesy Dr. Rachel Davis, 2022

Figure 12: Keratoleptynsis_12_Boston terrier_post op

Title: Postoperative photo of keratoleptynsis

Caption: 8-yr-old Boston terrier with a history of progressive corneal edema and refractory corneal ulceration. Vision remained good and corneal ulcers did no recur over the following 2 years. Courtesy Dr. Rachel Davis, 2022

Figure 13: Keratoleptynsis_13_OS_Yorkie_postop

Title: 2-year postoperative photo of keratoleptynsis

Caption: 14-yr-old Yorkshire terrier underwent keratoleptynsis for progressive corneal edema (endothelial dystrophy) and recurrent ulceration. Although corneal ulceration resolved, corneal edema persisted and the graft sites became vascularized and pigmented. Courtesy Dr. Rachel Davis, 2022

Treatment/Management:

SPECIFIC THERAPY

No curative therapy is available for endothelial disease. Therapy is directed at treating the underlying condition; improving or stabilizing the corneal edema; and keeping the eye comfortable. See the Canine VINcyclopedia chapters on glaucoma, lens luxation and uveitis for further details.

Medical Therapy

Topical Sodium Chloride: Hyperosmotic sodium chloride (NaCl 5%) ointment or solution may be applied q 4-12 hrs. Typically, application q 8-12 hrs is tolerated but more frequent application may result in ocular irritation. Topical NaCl 5% can initially decrease corneal thickness but the effect is transient.¹¹ It has been postulated that NaCl 5% may help prevent subepithelial fluid bullae formation and secondary ulcer formation over time. Regardless of topical therapy, endothelial disease is typically progressive and corneal ulceration with discomfort may occur eventually.

Corneal Collagen Cross-Linking: Crossing-linking involves the application of a photosensitizer (riboflavin 0.1%) solution to the cornea, followed by exposure to UV-A light at a wavelength of 370 nm. Corneal cross-linking increases biomechanical and biochemical strength of the cornea and can transiently improve corneal edema by compaction of the stroma.¹⁷ Cross-linking is not an effective long-term treatment for corneal edema because its effects are transient.¹⁷  Collagen cross-linking may be beneficial for eyes with painful corneal erosions.

Surgical Therapy

Keratoleptynsis: Keratoleptynsis is a combination of superficial keratectomy and conjunctival hood grafting. Conjunctiva is grafted over the dorsal and ventral one-third of the cornea, leaving central, horizontal, visual axis uncovered. Grafted tissue remains in place permanently. Every effort is made to keep graft material as thin as possible to increase the chance it will transdifferentiate into corneal epithelium. Keratoleptynsis is recommended for eyes with progressive corneal edema and refractory ulcers.^13,14 Some eyes do very well following the procedure, with significant clearing of edema and resolution of corneal ulceration (Figure 12). However, vision may not improve if corneal edema progresses, and/or pigmentation of the graft occurs over time (Figure 13).  

Endothelial Keratoplasty: Endothelial transplantation, with or without Descemet’s stripping, has recently shown some promise for restoring vision and preventing corneal ulceration in dogs.^15,16 The procedure involves removal of diseased/degenerated endothelial cells and replacing them with a partial thickness graft of donor endothelium. Descemet’s stripping involves simultaneous removal of adjacent Descemet’s membrane and inclusion of donor Descemet’s in the graft. Donation of fresh, healthy corneal tissue is required, which can be challenging. Further studies are needed to evaluate long-term complications, graft longevity, and outcomes following endothelial keratoplasty.^15,16

Keratoprosthesis Insertion: Keratoprosthesis is an artificial cornea. With this surgery, diseased corneal is replaced by a prosthesis. Although retro-corneal fixation of keratoprosthesis has been reported in 20 canine eyes blinded by several types of corneal disease, outcomes were often poor.¹⁸

Salvage Procedures

Thermokeratoplasty: Thermokeratoplasty is pin-point cauterization of the cornea using a disposable, battery-powered cautery unit. Cauterization induces contracture of corneal stromal proteins, with the potential for transient improvement in corneal edema. It is ineffective as long-term therapy but may be beneficial in eyes with refractive corneal ulcers. Note that treated eyes may be more painful immediately after thermokeratoplasty. The technique has largely been replaced by the surgical options described above.

Enucleation: Enucleation may be considered for eyes that are chronically painful despite application of different therapies, particularly if referral is not an option or the patient has systemic health issues that preclude corneal surgery.

Potential Future Therapy

Endothelial Cell Replacement: Recently, successful culture of canine corneal endothelial cells has been reported.¹⁹ Implantation of culture-derived endothelial cells may be a potential future treatment option for canine endothelial disease.

SUPPORTIVE THERAPY

Stabilization of Tear Film: Topical lacrimomimetics (e.g. cyclosporine, tacrolimus) may be added to hyperosmotic saline therapy to help stabilize the tear film. They have been used as adjunctive therapy after keratoleptynsis surgery and in medical management of endothelial dystrophy/degeneration. The drugs are applied q 12-24 hrs and must be separated from NaCl 5% by 1 to 4 hrs for NaCl solution or ointment, respectively. When applied at the same time as NaCl, hypertonicity of NaCl is diluted.

Treatment of Corneal Erosions/Ulcers: Diamond burr debridement and contact lens placement are often beneficial for treating superficial corneal ulceration secondary to corneal edema, especially edema caused by endothelial dystrophy/degeneration. Superficial keratectomy can also be effective.¹² Because corneal edema is often a progressive disease, repeated ulcers and surgeries may be necessary over time. See the Canine VINcyclopedia chapter on Persistent Corneal Erosion https://beta.vin.com/Members/Associate/Associate.plx?from=GetDzInfo&DiseaseId=5525 for further details on medical and surgical options.  

MONITORING

Frequency of monitoring depends on the underlying cause of corneal edema. For eyes with endothelial dystrophy/degeneration that are pain free (i.e. not ulcerated), medical therapy may be instituted and the patient monitored q 3-6 months depending on severity. Instruct the owner to return if blepharospasm, tearing, or photophobia develop because they may indicate corneal erosion/ulceration. Regardless of topical therapy, progressive corneal edema can eventually lead to corneal ulceration. More frequent examinations (i.e. q 10-14 days) are indicated if corneal ulcers or erosions are present. Consider referral for further intervention when corneal ulcers do not heal after several weeks of medical therapy.

Following keratoleptynsis, recheck examinations are usually scheduled q 7-14 days until the grafts heal and sutures dissolve. Long-term monitoring q 3-6 months is indicated to assess progression of edema, as well as vascularization and pigmentation of the grafts. Repeated, frequent examinations (e.g. q 1-2 days, then q 7days, then q 1-3 months) are required for monitoring eyes following keratoplasty surgery.¹⁶

PROGNOSIS

Long-term prognosis is often guarded. Edema associated with acute elevation of IOP usually subsides if IOP is rapidly lowered. In most other cases; however, edema can be expected to persist. Although edema is usually progressive despite surgical intervention, surgery can often improve comfort and maintain some functional vision. Regardless of visual outcome, patient comfort must be prioritized when treating eyes with corneal edema.

Special Considerations

Other Resources
Recent VIN Message Board discussions on corneal edema
Recent VIN Message Board discussions on corneal endothelial dystrophy
VIN Message Board discussions on keratoleptynsis

Proceedings articles that discuss corneal edema
2014 VIN Rounds on corneal opacities

Ophthalmology Fun Case 181
Student Fun Case 26
For more images, see the Corneal Edema, Part 1 – Dog slideshow in the Image Library
For more images, see the Corneal Edema, Part 2 – Dog slideshow in the Image Library

Differential Diagnosis:

• Calcium keratopathy
• Corneal fibrosis/scarring
• Lipemic uveitis https://beta.vin.com/Members/Associate/Associate.plx?from=GetDzInfo&DiseaseId=1196
• Lipid keratopathy
• Superficial causes of corneal edema, e.g. thermal burns, chemical burns, ulcerative keratitis, persistent corneal erosions

1. Samuelson D. Ophthalmic Anatomy.  In Gelatt KN (ed): Veterinary Ophthalmology, 4^th ed. Blackwell Publishing, Ames IA. 2007. pp 49-60.
2. Phenotype of macular corneal dystrophy in Labrador Retrievers: A multicenter study.
   Source: Journals: Vet Ophthalmol. 2019 May; 22(3):294-304. Claudia Busse, Christiane Kafarnik, Rose Linn-Pearl et al
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3. A Carbohydrate Sulfotransferase-6 (CHST6) gene mutation is associated with Macular Corneal Dystrophy in Labrador Retrievers.
   Source: Journals: Vet Ophthalmol. 2016 November; 19(6):488-492. Roser Tetas Pont, Louise Downs, Louise Pettitt et al
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4.  In vivo evaluation of the cornea and conjunctiva of the normal laboratory beagle using time- and Fourier-domain optical coherence tomography and ultrasound pachymetry.
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   Source: Journals: Vet J. 2018 December; 242(0):59-66. A L Hoehn, S M Thomasy, P H Kass et al
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   Source: Journals: Vet Ophthalmol. 2016 January; 19(1):63-7. Ann R Strom, Dennis E Cortés, Sara M Thomasy et al
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7. Canine central corneal thickness measurements via Pentacam-HR® , optical coherence tomography (Optovue iVue® ), and high-resolution ultrasound biomicroscopy.
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9.  Effects of intracameral ascorbic acid on the corneal endothelium of dogs undergoing phacoemulsification.
   Source: Journals: Vet Ophthalmol. 2018 March; 21(2):151-159. Ivan R M Padua, Gisele P Valdetaro, Tiago B Lima et al
   Address: Document Linkcanine endotheliitis: clinical characteristics, advanced imaging features, and treatment
10. Canine endotheliitis: Clinical characteristics, advanced imaging features, and treatment.
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11. Progressive retrocorneal pigmentation in dogs: A clinical report of 34 cases.
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12. Superficial keratectomy as a treatment for non-healing corneal ulceration associated with primary corneal endothelial degeneration.
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15. Endothelial keratoplasty for corneal endothelial dystrophy in a dog.
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16. Early postoperative results of Descemet’s stripping endothelial keratoplasty in six dogs with corneal endothelial dystrophy.
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