Veterinary Ophthalmology (2014) 17, Supplement 1, 186–194
DOI:10.1111/vop.12152
CASE REPORT
Corneal dystrophy in Friesian horses may represent a variant of pellucid marginal degeneration Mary Lassaline-Utter,* Anne J. Gemensky-Metzler,† Nicole M. Scherrer,* Riccardo Stoppini,‡ Claire A. Latimer,§ Nicole E. MacLaren¶ and Kathern E. Myrna** *New Bolton Center, School of Veterinary Medicine, University of Pennsylvania, 382 West Street Road, Kennett Square, PA, 19348, USA; †College of Veterinary Medicine, The Ohio State University, 601 Vernon L, Tharp Street, Columbus, OH 43210, USA; ‡Clinica Veterinaria Equina Cascina Gufa, Strada Provinciale 201 Km 3, 26833 - Merlino (LO), Italy; §Rood and Riddle Equine Hospital, 2150 Georgetown Road, Lexington, KY 40511, USA; ¶Eye Care for Animals, 1021 E. 3300 S., Salt Lake City, UT 84106, USA; and **College of Veterinary Medicine, University of Georgia, 501 D. W. Brooks Dr, Athens, GA 30602, USA
Address communications to: M. Lassaline-Utter Tel.: (610) 925-6111 Fax: (610) 925-6800 e-mail: [email protected]
Abstract Objective To describe the clinical presentation, treatment, and outcome of a corneal dystrophy in Friesian horses and to analyze affected horses’ pedigrees to investigate its heritability. Animals Nine Friesians with bilateral disease were identified. Procedure Retrospective medical record review was used to identify Friesian horses exhibiting bilateral symmetric corneal lesions. Variables identified from medical records included patient sex and age at diagnosis; location, depth and size of corneal lesions; medical and surgical therapy instituted; and visual outcome. A four-generation pedigree for each included horse was used to construct a combined pedigree. Results The nine included horses had an average age at diagnosis of the first eye of 10.7 years, with males (8/9) significantly more frequently affected than females (1/9), P = 0.012. Lesions were inferior and averaged 5 mm in diameter. Depth ranged from superficial facets to perforations, which developed in nine of 18 eyes. Eight of nine perforations were surgically repaired, with seven of eight repaired eyes visual at last follow-up. All nine eyes that had not perforated remained visual. All affected horses shared a common ancestor within six generations. Conclusions This form of corneal dystrophy in Friesian horses, characterized by bilateral symmetric stromal loss, appears to be progressive but responds well to surgical repair, occurs more frequently in males, may have a genetic component in Friesian horses, and may be a variant of pellucid marginal degeneration. Key Words: cornea, dystrophy, Friesian, pellucid marginal degeneration, ulcer
INTRODUCTION
Friesian horses with bilateral symmetric corneal lesions have been independently identified at six different practices in the United States and Europe. The presence of three concurrent features suggested a diagnosis of corneal dystrophy in these patients: bilateral disease, symmetric location, and absence of accompanying uveitis.1–6 Corneal dystrophies, which are characterized by bilateral abnormal deposition of substances in the cornea, have historically been classified based on the layer of the cornea in which they occur and named eponymically as well as based
on their clinical appearance.1,2 More recently, a system was established by the International Committee for the Classification of Corneal Dystrophies based on the underlying genetic mechanism, which demonstrated that corneal dystrophies represent more of a spectrum of disease.7–10 Based on this classification system, corneal ectasias, or ‘thinning’ diseases, that had been classified as dystrophies may not, in fact, be dystrophies10,11 but more aptly be classified as degenerative. Bilateral stromal lesions noted in this series of Friesian horses with a presumptive diagnosis of corneal dystrophy made a breed-associated or inherited disease process © 2014 American College of Veterinary Ophthalmologists
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likely. Breed-related conditions reported in Friesians include retained placenta,12 dwarfism,13 hydrocephalus,14 and aortic rupture.15 It has been suggested that these disorders are collagen-related abnormalities associated with selection for a baroque-type phenotype with an upright neck and a hyper-reflexive locomotor pattern.16 An example of a collagen disorder with multisystem manifestations is Hereditary Equine Regional Dermal Asthenia, or HERDA, which is a connective tissue disorder seen in American Quarter Horses characterized by fragile skin that tears easily and has impaired healing.17 Horses with HERDA were found to have thinner corneas, increased tear production, and increased incidence of corneal ulcers than normal horses.17 A collagen disorder with multisystem manifestation may underlie breed-related conditions previously reported in Friesians. There are currently about 45 000 registered Friesians worldwide, with about 8000 in the United States. There are about 100 approved stallions, with about one quarter of those in the United States. Currently, the Dutch Friesian Studbook recognizes three different stallion lines, that of Age 168, Ritske 202, and Tetman 205. All three of these stallions’ sire lines trace to the stallion Nemo 51, whose line is the only unbroken stallion line still existing in the Friesian breed. The identification of a common ancestor among Friesians affected with bilateral stromal lesions would support the hypothesis that this corneal dystrophy has a genetic basis. The purpose of this report is twofold: first, to describe the clinical presentation, treatment, and outcome of this presumptive corneal dystrophy in Friesian horses; and second, to analyze affected horses’ pedigrees to investigate the heritability of this corneal dystrophy. MATERIALS AND METHOD
Case selection To provide a clinical description of corneal dystrophy in Friesians, using a retrospective record review, cases were identified at six hospitals. Inclusion criteria for this study were first, being of the Friesian breed, and second, exhibiting bilateral symmetric corneal lesions. Note that the inclusion criterion of having bilateral symmetric corneal lesions was intentionally liberal, not including lesion depth or location, to include as many potential cases as possible at this early stage of disease identification, as an independent means of diagnosis has not been established. Variables identified from medical records included patient sex and age at diagnosis; location, depth, and size of corneal lesions; medical and surgical therapy instituted; time to disease resolution; and visual outcome. Patients All patients underwent complete ophthalmic examination by one of the authors. The adnexa, anterior, and posterior ocular segments of both eyes were examined with a Finoff
transilluminator (Heine USA, Dover, NH, USA), slit-lamp biomicroscope (SL 15; Kowa, Tokyo, Japan), and with direct and indirect ophthalmoscopes (Heine USA).
Statistical analysis Descriptive statistics were computed for all recorded variables. Frequencies were calculated for the categorical variables patient sex (male or female), lesion location (axial, superior, inferior, temporal, or nasal), lesion depth (epithelialized facet, superficial ulcer, midstromal ulcer, deep stromal ulcer, or perforation), type of surgical therapy (diamond burr debridement, conjunctival graft, corneal graft, or amnion graft), and visual outcome (visual or nonvisual) using SAS FREQ (version 9.3; SAS Institute Inc, Cary, NC). Means and standard deviations were computed for the interval-scaled variables age at diagnosis (in years) and size of corneal lesion (in mm) using SAS UNIVARIATE (SAS Institute Inc). Because data were descriptive and no group comparisons were made, no inferential statistics were performed. RESULTS
Nine Friesians were identified with bilateral lesions. Four additional horses with unilateral disease were identified but not included further in this study. The nine included horses had an average age at diagnosis of the first eye of 10.7 years, with males significantly more frequently affected than females (8/9 males, P = 0.012). Lesions were characterized as inferior, with an average size of 5 mm in diameter. Depth ranged from barely perceptible facets to perforations, which developed in nine of 16 eyes. Eight of nine perforations were surgically repaired, and the ninth eye was enucleated. Seven of the eight eyes that were repaired were visual at last follow-up, and the eighth eye developed phthisis bulbi. Of the nine eyes that did not rupture, all remained visual. Individual case descriptions follow, in order of decreasing age.
Case descriptions First, a 19-year-old Friesian gelding was presented with iris prolapse inferotemporally OD. Enucleation was elected. Four years later, he was presented with an epithelialized descemetocele OS of 6 days duration in a location symmetric to the perforation OD. OS was comfortable at presentation, and there was no corneal vascularization nor reflex uveitis, and only very mild localized edema OD. The descemetocele was repaired with a conjunctival pedicle graft. Hyphema developed OD following recovery from general anesthesia but resolved. The conjunctival graft dehisced 10 days postoperatively, and the globe ruptured. The perforation was repaired with a corneoconjunctival transposition covered with a commercially available extracellular matrix membrane and remained visual. Second, a 17-year-old Friesian gelding was presented with a 90% depth stromal ulcer OS of unknown duration,
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which was notable for its lack of accompanying uveitis. At presentation, the gelding had an approximately 3 mm 90% depth corneal ulcer inferotemporally, with no other significant ocular abnormalities. The ulcer was deep enough, and the surrounding cornea clear enough, that it cast a well-defined shadow on the iris. The right eye appeared normal initially in the dark examination room, but in a stall with ambient light conditions, with sunlight casting shadows, a corneal facet was noted inferotemporally, with a similar shadow cast on the iris, corresponding in location but not depth to the ulcer OS (Fig. 1). Surgical repair of the deep ulcer OS (Fig. 2) was recommended but initially declined due to the patient’s apparent comfort and the presence of a lesion OD with unknown progression. Approximately 3 weeks after the initial exam, an iris prolapse was sustained OS, and the patient was readmitted for surgical repair. After perforation, the previously quiet comfortable eye developed a coating of fibrin extending from the pupil margin across the lens, and hyphema (Fig. 3). Surgical repair with a penetrating keratoplasty and conjunctival graft was routinely performed. Approximately 2 weeks postoperatively, the conjunctival graft OS dehisced and was excised understanding sedation. The underlying corneal graft remained intact and preserved the structural integrity of the globe, and thus, no further surgical intervention was warranted. While boarding in hospital, approximately 3 weeks following surgery OS, the facet OD was ulcerated and progressed in-depth to about 50%. Based on progression to iris prolapse OS, surgical intervention was elected OD. A lamellar keratectomy, corneal graft, and conjunctival graft were routinely performed OD. Within 3 weeks of the lamellar keratectomy OD, the conjunctival graft was noted to have depressed, or sunken in, to the keratectomy site and then
Figure 1. Inferotemporal corneal facet casting shadow on iris OD, corresponding in location but not depth to the ulcer OS in a 17year-old Friesian gelding.
subsequently dehisced. Due to perceived risk of subsequent perforation, a second surgical intervention was elected OD. Intra-operatively, the donor cornea previously transplanted was no longer present. A penetrating keratoplasty removing any remaining corneal stroma and Descemet’s membrane from the affected area of the cornea, again covered by a conjunctival graft, was performed OD. Surgery was routine. Postoperative medical therapy continued for approximately 6 weeks following the penetrating keratoplasty in each eye. At last follow-up, approximately 3 months postoperatively OD and 4 months postoperatively OS, both eyes were visual and comfortable (Figs 4 and 5).
Figure 2. Approximately 3 mm inferotemporal 90% depth stromal ulcer casting shadow on iris OS in a 17-year-old Friesian gelding pictured in Fig. 1.
Figure 3. Corneal perforation OS sustained approximately 3 weeks following initial presentation in a 17-year-old Friesian gelding pictured in Fig. 2, exhibiting fibrin extending from pupil margin across lens and hyphema.
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Third, a 14 YO gelding was presented with an epithelialized iris prolapse inferotemporally OD (Fig. 6) of long duration but an apparently normal OS (Fig. 7). The iris prolapse OD was repaired with a penetrating keratoplasty and amnion transplant, which healed with only mild scarring (Fig. 8). Approximately 1 month following presentation with the iris prolapse OD, a superficial ulcer was noted in a symmetric location OS. The superficial ulcer OS resolved following debridement.
Fourth, a 14-year-old stallion was presented with iris prolapse inferotemporally OS. The anterior chamber was shallow with broad posterior synechiae, fresh hyphema, and otherwise clear aqueous. In an otherwise quiet eye
Figure 6. Epithelialized iris prolapse OD at presentation in a 14year-old Friesian gelding.
Figure 4. Three-month postoperative lamellar keratectomy, corneal graft and conjunctival graft OD in a 17-year-old Friesian gelding pictured if Fig. 1.
Figure 7. Apparently normal OS that progressed to a superficial ulcer about 1 month later, which resolved following debridement in a 14-year-old Friesian gelding pictured in Fig. 6.
Figure 5. Four-month postoperative penetrating keratoplasty and conjunctival graft OS in a 17-year-old Friesian gelding pictured in Fig. 2.
Figure 8. Postoperative penetrating keratoplasty and amnion transplant in a 14-year-old Friesian gelding pictured in Fig. 6.
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OD, there was a 4 mm corneal facet with sloped sides and epithelialized Descemet’s membrane centrally in the same inferotemporal position as the lesion OS. Owners of this stallion conveyed that both eyes had this same appearance for years. The corneal defect OS was surgically repaired with a 6-mm frozen corneal button and pedicle conjunctival graft. Four days later, while hospitalized, a 2 mm iris prolapse, fibrin, and hyphema were noted OD. The cornea was closed primarily, and a conjunctival pedicle graft was placed. Seven days later, the surgical site OD dehisced. Surgical repair with extracellular matrix membrane and a conjunctival pedicle graft was performed. Two months after initial presentation, both surgical sites were healed and both eyes were quiet, comfortable, and visual. Fifth, a 12 YO gelding was presented with a fungal stromal abscess OD (Fig. 9) of approximately 2 weeks duration. OD had initially been described as having swollen lids but a clear cornea by the referring veterinarian. A corneal ulcer was diagnosed several days after lid swelling was detected. Corneal debridement was performed the day prior to referral. At presentation, there was moderate blepharospasm and mucoid discharge, and a superiotemporal white malacic corneal plaque with peripheral 40% stromal loss. Corneal cytology revealed fungal hyphae. Stromal loss progressed to approximately 80% depth within 2 weeks following presentation. A superficial ulcer was noted OS in a symmetric location approximately 2 weeks following presentation, while in hospital receiving medical treatment OD (Fig. 10). Medication was continued for approximately 1 week after diagnosis of the superficial ulcer OS, and for a total of approximately 8 weeks following presentation for the corneal abscess OD. Sixth, a 9 YO gelding was presented with iris prolapse OD. This was repaired with a penetrating keratoplasty
and conjunctival pedicle graft. Two years later, he represented with iris prolapse OS in a location symmetric to the prolapse OD. The iris prolapse OS was treated with a conjunctival pedicle graft. Visual outcomes resulted OU although both conjunctival grafts partially dehisced. Seventh, an 8 YO stallion was presented with an iris prolapse inferotemporally OS, but OD was apparently normal. The iris prolapse OS was treated with a penetrating keratoplasty and conjunctival graft but developed phthisis bulbi, presumably associated with severe uveitis and endophthalmitis. A facet was noted OD (Fig. 11) in a location symmetric to the iris prolapse OS 10 days following presentation for the iris prolapse OS (Fig. 12). The facet was ulcerated, treated routinely, and epithelialized.
Figure 9. Stromal abscess with history of ulceration OD in a 12year-old Friesian gelding.
Figure 11. Corneal facet OD that developed in previously normal cornea 10 days following hospitalization for treatment of iris prolapse OS in a 8-year-old Friesian stallion. The facet was ulcerated, treated routinely, and healed uneventfully.
Figure 10. Superficial ulcer OS symmetrical in location to stromal abscess OD that developed while hospitalized for treatment OD in a 12-year-old Friesian gelding pictured in Fig. 9.
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Eighth, a 2 YO colt was presented with a facet OD (Fig. 13) and an erosion OS (Fig. 14). Both lesions resolved with diamond burr debridement. Finally, ninth, a yearling filly was presented with epithelial defects inferonasally OU, which were presumed traumatic following a particularly windy day. Healing seemed prolonged relative to the severity of the lesions, both of which resolved with keratectomy and amnion transplant (Figs 15 and 16).
Pedigree analysis To investigate the heritability of this corneal dystrophy, a four-generation pedigree for each included horse was obtained from the Royal Society Friesian Horse Studbook if available, and a combined pedigree was constructed using the closest common ancestor (Fig. 17). Eight horses affected with bilateral corneal dystrophy in this study, and three with at least one affected eye, come from the Tetman line within six generations, and all but one of these
11 horses are offspring of Tetman’s son Mark within five generations. Pedigree information was not available for a 19-year-old gelding with bilateral disease or for an 8-yearold stallion with unilateral disease. DISCUSSION
The first objective of this study was to describe the clinical presentation, treatment, and outcome of this presumptive corneal dystrophy in Friesian horses. Nine horses with bilateral lesions and four with unilateral lesions were identified. Nine eyes sustained iris prolapse, which was repaired
Figure 14. Corneal erosion OS in location symmetric to corneal facet OD in a 2-year-old Friesian colt pictured in Fig. 13. The erosion resolved following diamond burr debridement.
Figure 12. Iris prolapse OS in a 8-year-old Friesian stallion pictured in Fig. 11.
Figure 13. Corneal facet OD in a 2-year-old Friesian colt.
Figure 15. Epithelial defect OD in Friesian yearling filly which healed following keratectomy and amnion transplant. Healing was prolonged.
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Figure 16. Symmetrical epithelial defect OS treated with keratectomy and amnion transplant in Friesian yearling filly pictured in Fig. 15.
Figure 17. Combined pedigree for nine Friesian horses with bilateral inferior corneal lesions as well as four horses with unilateral inferior corneal lesions. Males are represented as squares, and females as circles. A dashed line indicates direct lineage of more than one generation; a solid line indicates direct lineage of a single generation.
in eight eyes, seven of which had a visual outcome. All eyes that had not perforated had a visual outcomes. Of note was the absence of secondary uveitis in these cases prior to perforation, with blepharospasm, epiphora, conjunctival hyperemia, corneal edema, corneal vascularization, aqueous flare or miosis typically not reported, other than in chronic cases that progressed to perforation. The average included horse was a 10-year-old male with bilateral inferotemporal 5 mm diameter corneal lesions. Lesions ranged in size from 2 to 8 mm. Four of seven horses with bilateral disease for whom lesion location
could be confirmed photographically had inferotemporal lesions. One horse had inferonasal lesions, one had inferior lesions, and one had superiotemporal lesions. Location was not confirmed for two patients and was not recorded for horses with unilateral disease. Disease was detected at various corneal depths across the cases, from an epithelialized facet to a deep stromal ulcer, and in some cases progressed to ulceration and then perforation, which with surgical repair resulted in a visual comfortable eye in all but one case, which was so advanced at presentation that phthisis bulbi resulted. A striking feature of this disease was the apparently spontaneous development and progression of corneal disease in one eye that had appeared normal, or had only an epithelialized facet, during treatment of the contralateral eye. This occurred in four of nine patients. This spontaneous and progressive disease course suggests a degenerative process, although there were risk factors present that may have contributed to corneal ulcer development in the contralateral eye, such as hospitalization,18 general anesthesia,19 and an increase in proteases associated with presence of a corneal ulcer in the first eye affected.20 Additionally, five of nine eyes in three of five horses treated with a conjunctival graft, all performed by different surgeons, experienced some degree of dehiscence of the graft, although visual outcomes resulted. There may have been a progressive degenerative process even after surgical repair. While all included cases were followed to resolution of corneal ulceration and subsequent discontinuation of medication, further observation of these cases has not generally been available, so the likelihood of recurrence is unknown. One case, however, a stallion diagnosed at age 15 years with a unilateral deep epithelialized facet, was examined 5 years following identification of the corneal facet at age 20 years, and no abnormalities were noted at that time. The facet was no longer present, and no corneal lesions had been reported during numerous ocular examinations over the 5-year period, although the stallion was anecdotally reported to have occasional epiphora. This case represents the longest follow-up in the current case series and suggests that there may be a wide range of severity in this disease process, from spontaneous resolution to corneal rupture, if indeed all patients described in this series were affected with the same disease. Pellucid marginal degeneration, or PMD, may represent an underlying etiology for the corneal dystrophy seen in these patients. PMD is a corneal thinning disease that is traditionally classified as a dystrophy, although, adding to the confusion in the literature, is named degeneration. PMD is atypical among dystrophies based on the lack of corneal deposits seen with this disease.21 The name, derived from the Latin pellucere, which means ‘to shine through’,22 refers to the clinical appearance, which is a clear cornea despite the presence of corneal thinning,
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without vascularization or infiltrate. As reported in human patients, PMD typically occurs inferiorly in a peripheral crescent-shaped region.21 PMD is rare but more common in males and is typically progressive, with an average age of onset around 40 years in human patients.21,23,24 PMD is typically bilateral, although unilateral cases have been reported.25,26 The prevalence and etiology of PMD are unknown, although some authors have argued that it is a peripheral variant of keratoconus.27 There is no evidence that PMD is genetically inherited, although moderate to high astigmatism has been noted in asymptomatic family members of patients with PMD.28 Corneal topography, which evaluates the degree and distribution of surface irregularities in the cornea, captures the eccentric thinning seen in PMD. The hallmarks of PMD are a ‘crab claw’ appearance on corneal topography and ‘against the rule’ astigmatism, in which the horizontal corneal meridian has steeper curvature than the vertical corneal meridian (i.e., the corneal curvature is comparable with a football standing on its end). Both the ‘crab claw’ appearance and ‘against the rule’ astigmatism can be used to diagnose early corneal ectasia,29 although both may be present in keratoconus as well as PMD, with central thinning in the former and peripheral thinning in the latter. Advanced PMD may manifest with acute pain and sudden vision loss associated with corneal hydrops or even spontaneous corneal perforation.29 Histologically, PMD is associated with an increase in stromal mucopolysaccharides and irregularities or even breaks in Bowman’s layer.29 Mild PMD is most commonly managed using spectacles or contact lenses to correct astigmatism, whereas the more rare, severe cases are treated with various forms of keratoplasty, both penetrating and lamellar.23,24,30 Outcomes are generally good although astigmatism results if disease is severe enough to warrant surgical intervention.27,29 Based on the clinical presentation and outcomes of the cases in this report, PMD may represent an underlying etiology for this Friesian corneal dystrophy. PMD typically occurs inferiorly in a peripheral crescent-shaped region21; in these horses, lesions were peripheral but round, not crescent-shaped. PMD is more common in males and is typically progressive, with an average age of onset around 40 years in human patients21,23,24; in these horses, males were over-represented, disease was progressive, and the average age of onset of 10.5 years is consistent with adult onset observed in human patients. PMD is typically bilateral, although unilateral cases have been reported25,26; in these horses, bilateral disease was an inclusion criterion but unilateral cases were identified as well. However, without corneal topography and pachymetry, a definitive diagnosis is not possible. Additionally, it remains an open question whether all patients included in this report, both bilaterally and unilaterally affected, represent manifestations of the same underlying disease process. However, as an initial characterization and without further ultrastructural, topo-
graphical, or genetic data, PMD may offer the best clinical categorization. The second objective was to analyze affected horses’ pedigrees to investigate the heritability of this corneal dystrophy. Using pedigree information that was available for nine of 10 horses with bilateral disease and three of four horses with unilateral disease, all horses affected with corneal dystrophy in the present study, as well as horses with at least one affected eye, come from the Tetman stallion line, and all but one bilaterally affected horse are offspring of Tetman’s son Mark. While there is considerable inbreeding among Friesians, with an average ‘inbreeding’ coefficient of 0.157, comparable with mating between half siblings, and these particular horses are related in many cases through more than one line, the existence of a common ancestor is consistent with the hypothesis that this corneal dystrophy has a genetic basis. In conclusion, this form of corneal dystrophy in Friesian horses, characterized by bilateral symmetric stromal loss, appears to be progressive, but responds well to surgical repair; males may be at increased risk; and based on the symmetric location of the lesions, and initial pedigree analysis tracing affected horses back to a common sire, this syndrome may have a genetic basis in Friesian horses. A future goal will be to more specifically evaluate pellucid marginal degeneration as an underlying etiology of corneal dystrophy in Friesian horses. Further future efforts to support this goal will be directed at identifying additional affected horses, continuing to collect pedigree data to expand the pedigree analysis, performing corneal pachymetry and topography to identify potentially affected horses, performing ultrastructural analysis to better characterize the disease process, and performing a genome wide association study to identify single-nucleotide polymorphisms, or genetic variants, which are associated with this disease. REFERENCES 1. Waring GO, Rodrigues MM, Laibson PR. Corneal dystrophies. I. Dystrophies of the epithelium, Bowman’s layer and stroma. Survey of Ophthalmology 1978; 23: 71–122. 2. Waring GO, Rodrigues MM, Laibson PR. Corneal dystrophies. II. Endothelial dystrophies. Survey of Ophthalmology 1978; 23: 147–168. 3. Bistner SI, Aguirre G, Shively JN. Hereditary corneal dystrophy in the Manx cat: a preliminary report. Investigative Ophthalmology 1976; 15: 15–26. 4. Cooley PL, Dice PF 2nd. Corneal dystrophy in the dog and cat. The Veterinary Clinics of North America. Small Animal Practice 1990; 20: 681–692. 5. Crispin SM. Crystalline corneal dystrophy in the dog. Histochemical and ultrastructural study. Cornea 1988; 7: 149–161. 6. Vemuganti GK, Rathi VM, Murthy SI. Histological landmarks in corneal dystrophy: pathology of corneal dystrophies. Developments in Ophthalmology 2011; 48: 24–50. 7. Gupta SK, Hodge WG. A new clinical perspective of corneal dystrophies through molecular genetics. Current Opinion in Ophthalmology 1999; 10: 234–241.
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8. Weiss JS, Moller HU, Lisch W et al. The IC3D classification of the corneal dystrophies. Cornea 2008; 27(Suppl. 2): S1–S83. 9. Moller HU, Weiss JS. IC3D classification of corneal dystrophies. Developments in Ophthalmology 2011; 48: 1–8. 10. Vincent AL. Corneal dystrophies and genetics in the International Committee for Classification of Corneal Dystrophies era: a review. Clinical and Experimental Ophthalmology 2014; 42: 4–12. 11. Burdon KP, Vincent AL. Insights into keratoconus from a genetic perspective. Clinical and Experimental Optometry 2013; 96: 146–154. 12. Sevinga M, Barkema H, Stryhn H et al. Retained placenta in Friesian mares: incidence, and potential risk factors with special emphasis on gestational length. Theriogenology 2004; 61: 851–859. 13. Back W, Lugt J, Nikkels P et al. Phenotypic diagnosis of dwarfism in six Friesian horses. Equine Veterinary Journal 2008; 40: 282–287. 14. Sipma KD, Cornillie P, Saulez M et al. Phenotypic characteristics of hydrocephalus in stillborn Friesian foals. Veterinary Pathology Online 2013; 50: 1037–1042. 15. Ploeg M, Saey V, de Bruijn C et al. Aortic rupture and aorto-pulmonary fistulation in the Friesian horse: characterisation of the clinical and gross post mortem findings in 24 cases. Equine Veterinary Journal 2013; 45: 101–106. 16. Boerma S, Back W, Sloet van Oldruitenborgh-Oosterbaan M. The Friesian horse breed: a clinical challenge to the equine veterinarian? Equine Veterinary Education 2012; 24: 66–71. 17. Mochal CA, Miller WW, Cooley AJ et al. Ocular findings in quarter horses with hereditary equine regional dermal asthenia. Journal of the American Veterinary Medical Association 2010; 237: 304–310. 18. Chandler JA, Woerdt A, Prittie JE et al. Preliminary evaluation of tear production in dogs hospitalized in an intensive care unit. Journal of Veterinary Emergency and Critical Care 2013; 23: 274–279.
19. Brightman AH 2nd, Manning JP, Benson GJ et al. Decreased tear production associated with general anesthesia in the horse. Journal of the American Veterinary Medical Association 1983; 182: 243–244. 20. Ollivier F, Brooks D, Van Setten G et al. Profiles of matrix metalloproteinase activity in equine tear fluid during corneal healing in 10 horses with ulcerative keratitis. Veterinary Ophthalmology 2004; 7: 397–405. 21. Sridhar M, Mahesh S, Bansal A et al. Pellucid marginal corneal degeneration. Ophthalmology 2004; 111: 1102–1107. 22. Merriam-Webster I. Merriam-Webster’s Collegiate Dictionary. Merriam-Webster, Inc., Springfield, MA, 2005; pp 40a, 1623. 23. Kompella VB, Aasuri MK, Rao GN. Management of pellucid marginal corneal degeneration with rigid gas permeable contact lenses. Eye & Contact Lens 2002; 28: 140–145. 24. Tzelikis PF, Cohen EJ, Rapuano CJ et al. Management of pellucid marginal corneal degeneration. Cornea 2005; 24: 555–560. 25. Basak S, Hazra T, Bhattacharya D et al. Unilateral pellucid marginal degeneration. Indian Journal of Ophthalmology 2000; 48: 233. 26. Kaushik S, Jain A, Saini J. Unilateral pellucid marginal degeneration. Eye 2003; 17: 246–248. 27. Rodrigues MM, Newsome DA, Krachmer JH et al. Pellucid marginal corneal degeneration: a clinicopathologic study of two cases. Experimental Eye Research 1981; 33: 277–288. 28. Santo RM, Bechara SJ, Kara-Jose N. Corneal topography in asymptomatic family members of a patient with pellucid marginal degeneration. American Journal of Ophthalmology 1999; 127: 205– 207. 29. Jinabhai A, Radhakrishnan H, O’Donnell C. Pellucid corneal marginal degeneration: a review. Contact Lens and Anterior Eye 2011; 34: 56–63. 30. Biswas S, Brahma A, Tromans C et al. Management of pellucid marginal corneal degeneration. Eye 2000; 14: 629–634.
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DOI:10.1111/vop.12152
CASE REPORT
Corneal dystrophy in Friesian horses may represent a variant of pellucid marginal degeneration Mary Lassaline-Utter,* Anne J. Gemensky-Metzler,† Nicole M. Scherrer,* Riccardo Stoppini,‡ Claire A. Latimer,§ Nicole E. MacLaren¶ and Kathern E. Myrna** *New Bolton Center, School of Veterinary Medicine, University of Pennsylvania, 382 West Street Road, Kennett Square, PA, 19348, USA; †College of Veterinary Medicine, The Ohio State University, 601 Vernon L, Tharp Street, Columbus, OH 43210, USA; ‡Clinica Veterinaria Equina Cascina Gufa, Strada Provinciale 201 Km 3, 26833 - Merlino (LO), Italy; §Rood and Riddle Equine Hospital, 2150 Georgetown Road, Lexington, KY 40511, USA; ¶Eye Care for Animals, 1021 E. 3300 S., Salt Lake City, UT 84106, USA; and **College of Veterinary Medicine, University of Georgia, 501 D. W. Brooks Dr, Athens, GA 30602, USA
Address communications to: M. Lassaline-Utter Tel.: (610) 925-6111 Fax: (610) 925-6800 e-mail: [email protected]
Abstract Objective To describe the clinical presentation, treatment, and outcome of a corneal dystrophy in Friesian horses and to analyze affected horses’ pedigrees to investigate its heritability. Animals Nine Friesians with bilateral disease were identified. Procedure Retrospective medical record review was used to identify Friesian horses exhibiting bilateral symmetric corneal lesions. Variables identified from medical records included patient sex and age at diagnosis; location, depth and size of corneal lesions; medical and surgical therapy instituted; and visual outcome. A four-generation pedigree for each included horse was used to construct a combined pedigree. Results The nine included horses had an average age at diagnosis of the first eye of 10.7 years, with males (8/9) significantly more frequently affected than females (1/9), P = 0.012. Lesions were inferior and averaged 5 mm in diameter. Depth ranged from superficial facets to perforations, which developed in nine of 18 eyes. Eight of nine perforations were surgically repaired, with seven of eight repaired eyes visual at last follow-up. All nine eyes that had not perforated remained visual. All affected horses shared a common ancestor within six generations. Conclusions This form of corneal dystrophy in Friesian horses, characterized by bilateral symmetric stromal loss, appears to be progressive but responds well to surgical repair, occurs more frequently in males, may have a genetic component in Friesian horses, and may be a variant of pellucid marginal degeneration. Key Words: cornea, dystrophy, Friesian, pellucid marginal degeneration, ulcer
INTRODUCTION
Friesian horses with bilateral symmetric corneal lesions have been independently identified at six different practices in the United States and Europe. The presence of three concurrent features suggested a diagnosis of corneal dystrophy in these patients: bilateral disease, symmetric location, and absence of accompanying uveitis.1–6 Corneal dystrophies, which are characterized by bilateral abnormal deposition of substances in the cornea, have historically been classified based on the layer of the cornea in which they occur and named eponymically as well as based
on their clinical appearance.1,2 More recently, a system was established by the International Committee for the Classification of Corneal Dystrophies based on the underlying genetic mechanism, which demonstrated that corneal dystrophies represent more of a spectrum of disease.7–10 Based on this classification system, corneal ectasias, or ‘thinning’ diseases, that had been classified as dystrophies may not, in fact, be dystrophies10,11 but more aptly be classified as degenerative. Bilateral stromal lesions noted in this series of Friesian horses with a presumptive diagnosis of corneal dystrophy made a breed-associated or inherited disease process © 2014 American College of Veterinary Ophthalmologists
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likely. Breed-related conditions reported in Friesians include retained placenta,12 dwarfism,13 hydrocephalus,14 and aortic rupture.15 It has been suggested that these disorders are collagen-related abnormalities associated with selection for a baroque-type phenotype with an upright neck and a hyper-reflexive locomotor pattern.16 An example of a collagen disorder with multisystem manifestations is Hereditary Equine Regional Dermal Asthenia, or HERDA, which is a connective tissue disorder seen in American Quarter Horses characterized by fragile skin that tears easily and has impaired healing.17 Horses with HERDA were found to have thinner corneas, increased tear production, and increased incidence of corneal ulcers than normal horses.17 A collagen disorder with multisystem manifestation may underlie breed-related conditions previously reported in Friesians. There are currently about 45 000 registered Friesians worldwide, with about 8000 in the United States. There are about 100 approved stallions, with about one quarter of those in the United States. Currently, the Dutch Friesian Studbook recognizes three different stallion lines, that of Age 168, Ritske 202, and Tetman 205. All three of these stallions’ sire lines trace to the stallion Nemo 51, whose line is the only unbroken stallion line still existing in the Friesian breed. The identification of a common ancestor among Friesians affected with bilateral stromal lesions would support the hypothesis that this corneal dystrophy has a genetic basis. The purpose of this report is twofold: first, to describe the clinical presentation, treatment, and outcome of this presumptive corneal dystrophy in Friesian horses; and second, to analyze affected horses’ pedigrees to investigate the heritability of this corneal dystrophy. MATERIALS AND METHOD
Case selection To provide a clinical description of corneal dystrophy in Friesians, using a retrospective record review, cases were identified at six hospitals. Inclusion criteria for this study were first, being of the Friesian breed, and second, exhibiting bilateral symmetric corneal lesions. Note that the inclusion criterion of having bilateral symmetric corneal lesions was intentionally liberal, not including lesion depth or location, to include as many potential cases as possible at this early stage of disease identification, as an independent means of diagnosis has not been established. Variables identified from medical records included patient sex and age at diagnosis; location, depth, and size of corneal lesions; medical and surgical therapy instituted; time to disease resolution; and visual outcome. Patients All patients underwent complete ophthalmic examination by one of the authors. The adnexa, anterior, and posterior ocular segments of both eyes were examined with a Finoff
transilluminator (Heine USA, Dover, NH, USA), slit-lamp biomicroscope (SL 15; Kowa, Tokyo, Japan), and with direct and indirect ophthalmoscopes (Heine USA).
Statistical analysis Descriptive statistics were computed for all recorded variables. Frequencies were calculated for the categorical variables patient sex (male or female), lesion location (axial, superior, inferior, temporal, or nasal), lesion depth (epithelialized facet, superficial ulcer, midstromal ulcer, deep stromal ulcer, or perforation), type of surgical therapy (diamond burr debridement, conjunctival graft, corneal graft, or amnion graft), and visual outcome (visual or nonvisual) using SAS FREQ (version 9.3; SAS Institute Inc, Cary, NC). Means and standard deviations were computed for the interval-scaled variables age at diagnosis (in years) and size of corneal lesion (in mm) using SAS UNIVARIATE (SAS Institute Inc). Because data were descriptive and no group comparisons were made, no inferential statistics were performed. RESULTS
Nine Friesians were identified with bilateral lesions. Four additional horses with unilateral disease were identified but not included further in this study. The nine included horses had an average age at diagnosis of the first eye of 10.7 years, with males significantly more frequently affected than females (8/9 males, P = 0.012). Lesions were characterized as inferior, with an average size of 5 mm in diameter. Depth ranged from barely perceptible facets to perforations, which developed in nine of 16 eyes. Eight of nine perforations were surgically repaired, and the ninth eye was enucleated. Seven of the eight eyes that were repaired were visual at last follow-up, and the eighth eye developed phthisis bulbi. Of the nine eyes that did not rupture, all remained visual. Individual case descriptions follow, in order of decreasing age.
Case descriptions First, a 19-year-old Friesian gelding was presented with iris prolapse inferotemporally OD. Enucleation was elected. Four years later, he was presented with an epithelialized descemetocele OS of 6 days duration in a location symmetric to the perforation OD. OS was comfortable at presentation, and there was no corneal vascularization nor reflex uveitis, and only very mild localized edema OD. The descemetocele was repaired with a conjunctival pedicle graft. Hyphema developed OD following recovery from general anesthesia but resolved. The conjunctival graft dehisced 10 days postoperatively, and the globe ruptured. The perforation was repaired with a corneoconjunctival transposition covered with a commercially available extracellular matrix membrane and remained visual. Second, a 17-year-old Friesian gelding was presented with a 90% depth stromal ulcer OS of unknown duration,
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which was notable for its lack of accompanying uveitis. At presentation, the gelding had an approximately 3 mm 90% depth corneal ulcer inferotemporally, with no other significant ocular abnormalities. The ulcer was deep enough, and the surrounding cornea clear enough, that it cast a well-defined shadow on the iris. The right eye appeared normal initially in the dark examination room, but in a stall with ambient light conditions, with sunlight casting shadows, a corneal facet was noted inferotemporally, with a similar shadow cast on the iris, corresponding in location but not depth to the ulcer OS (Fig. 1). Surgical repair of the deep ulcer OS (Fig. 2) was recommended but initially declined due to the patient’s apparent comfort and the presence of a lesion OD with unknown progression. Approximately 3 weeks after the initial exam, an iris prolapse was sustained OS, and the patient was readmitted for surgical repair. After perforation, the previously quiet comfortable eye developed a coating of fibrin extending from the pupil margin across the lens, and hyphema (Fig. 3). Surgical repair with a penetrating keratoplasty and conjunctival graft was routinely performed. Approximately 2 weeks postoperatively, the conjunctival graft OS dehisced and was excised understanding sedation. The underlying corneal graft remained intact and preserved the structural integrity of the globe, and thus, no further surgical intervention was warranted. While boarding in hospital, approximately 3 weeks following surgery OS, the facet OD was ulcerated and progressed in-depth to about 50%. Based on progression to iris prolapse OS, surgical intervention was elected OD. A lamellar keratectomy, corneal graft, and conjunctival graft were routinely performed OD. Within 3 weeks of the lamellar keratectomy OD, the conjunctival graft was noted to have depressed, or sunken in, to the keratectomy site and then
Figure 1. Inferotemporal corneal facet casting shadow on iris OD, corresponding in location but not depth to the ulcer OS in a 17year-old Friesian gelding.
subsequently dehisced. Due to perceived risk of subsequent perforation, a second surgical intervention was elected OD. Intra-operatively, the donor cornea previously transplanted was no longer present. A penetrating keratoplasty removing any remaining corneal stroma and Descemet’s membrane from the affected area of the cornea, again covered by a conjunctival graft, was performed OD. Surgery was routine. Postoperative medical therapy continued for approximately 6 weeks following the penetrating keratoplasty in each eye. At last follow-up, approximately 3 months postoperatively OD and 4 months postoperatively OS, both eyes were visual and comfortable (Figs 4 and 5).
Figure 2. Approximately 3 mm inferotemporal 90% depth stromal ulcer casting shadow on iris OS in a 17-year-old Friesian gelding pictured in Fig. 1.
Figure 3. Corneal perforation OS sustained approximately 3 weeks following initial presentation in a 17-year-old Friesian gelding pictured in Fig. 2, exhibiting fibrin extending from pupil margin across lens and hyphema.
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Third, a 14 YO gelding was presented with an epithelialized iris prolapse inferotemporally OD (Fig. 6) of long duration but an apparently normal OS (Fig. 7). The iris prolapse OD was repaired with a penetrating keratoplasty and amnion transplant, which healed with only mild scarring (Fig. 8). Approximately 1 month following presentation with the iris prolapse OD, a superficial ulcer was noted in a symmetric location OS. The superficial ulcer OS resolved following debridement.
Fourth, a 14-year-old stallion was presented with iris prolapse inferotemporally OS. The anterior chamber was shallow with broad posterior synechiae, fresh hyphema, and otherwise clear aqueous. In an otherwise quiet eye
Figure 6. Epithelialized iris prolapse OD at presentation in a 14year-old Friesian gelding.
Figure 4. Three-month postoperative lamellar keratectomy, corneal graft and conjunctival graft OD in a 17-year-old Friesian gelding pictured if Fig. 1.
Figure 7. Apparently normal OS that progressed to a superficial ulcer about 1 month later, which resolved following debridement in a 14-year-old Friesian gelding pictured in Fig. 6.
Figure 5. Four-month postoperative penetrating keratoplasty and conjunctival graft OS in a 17-year-old Friesian gelding pictured in Fig. 2.
Figure 8. Postoperative penetrating keratoplasty and amnion transplant in a 14-year-old Friesian gelding pictured in Fig. 6.
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OD, there was a 4 mm corneal facet with sloped sides and epithelialized Descemet’s membrane centrally in the same inferotemporal position as the lesion OS. Owners of this stallion conveyed that both eyes had this same appearance for years. The corneal defect OS was surgically repaired with a 6-mm frozen corneal button and pedicle conjunctival graft. Four days later, while hospitalized, a 2 mm iris prolapse, fibrin, and hyphema were noted OD. The cornea was closed primarily, and a conjunctival pedicle graft was placed. Seven days later, the surgical site OD dehisced. Surgical repair with extracellular matrix membrane and a conjunctival pedicle graft was performed. Two months after initial presentation, both surgical sites were healed and both eyes were quiet, comfortable, and visual. Fifth, a 12 YO gelding was presented with a fungal stromal abscess OD (Fig. 9) of approximately 2 weeks duration. OD had initially been described as having swollen lids but a clear cornea by the referring veterinarian. A corneal ulcer was diagnosed several days after lid swelling was detected. Corneal debridement was performed the day prior to referral. At presentation, there was moderate blepharospasm and mucoid discharge, and a superiotemporal white malacic corneal plaque with peripheral 40% stromal loss. Corneal cytology revealed fungal hyphae. Stromal loss progressed to approximately 80% depth within 2 weeks following presentation. A superficial ulcer was noted OS in a symmetric location approximately 2 weeks following presentation, while in hospital receiving medical treatment OD (Fig. 10). Medication was continued for approximately 1 week after diagnosis of the superficial ulcer OS, and for a total of approximately 8 weeks following presentation for the corneal abscess OD. Sixth, a 9 YO gelding was presented with iris prolapse OD. This was repaired with a penetrating keratoplasty
and conjunctival pedicle graft. Two years later, he represented with iris prolapse OS in a location symmetric to the prolapse OD. The iris prolapse OS was treated with a conjunctival pedicle graft. Visual outcomes resulted OU although both conjunctival grafts partially dehisced. Seventh, an 8 YO stallion was presented with an iris prolapse inferotemporally OS, but OD was apparently normal. The iris prolapse OS was treated with a penetrating keratoplasty and conjunctival graft but developed phthisis bulbi, presumably associated with severe uveitis and endophthalmitis. A facet was noted OD (Fig. 11) in a location symmetric to the iris prolapse OS 10 days following presentation for the iris prolapse OS (Fig. 12). The facet was ulcerated, treated routinely, and epithelialized.
Figure 9. Stromal abscess with history of ulceration OD in a 12year-old Friesian gelding.
Figure 11. Corneal facet OD that developed in previously normal cornea 10 days following hospitalization for treatment of iris prolapse OS in a 8-year-old Friesian stallion. The facet was ulcerated, treated routinely, and healed uneventfully.
Figure 10. Superficial ulcer OS symmetrical in location to stromal abscess OD that developed while hospitalized for treatment OD in a 12-year-old Friesian gelding pictured in Fig. 9.
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Eighth, a 2 YO colt was presented with a facet OD (Fig. 13) and an erosion OS (Fig. 14). Both lesions resolved with diamond burr debridement. Finally, ninth, a yearling filly was presented with epithelial defects inferonasally OU, which were presumed traumatic following a particularly windy day. Healing seemed prolonged relative to the severity of the lesions, both of which resolved with keratectomy and amnion transplant (Figs 15 and 16).
Pedigree analysis To investigate the heritability of this corneal dystrophy, a four-generation pedigree for each included horse was obtained from the Royal Society Friesian Horse Studbook if available, and a combined pedigree was constructed using the closest common ancestor (Fig. 17). Eight horses affected with bilateral corneal dystrophy in this study, and three with at least one affected eye, come from the Tetman line within six generations, and all but one of these
11 horses are offspring of Tetman’s son Mark within five generations. Pedigree information was not available for a 19-year-old gelding with bilateral disease or for an 8-yearold stallion with unilateral disease. DISCUSSION
The first objective of this study was to describe the clinical presentation, treatment, and outcome of this presumptive corneal dystrophy in Friesian horses. Nine horses with bilateral lesions and four with unilateral lesions were identified. Nine eyes sustained iris prolapse, which was repaired
Figure 14. Corneal erosion OS in location symmetric to corneal facet OD in a 2-year-old Friesian colt pictured in Fig. 13. The erosion resolved following diamond burr debridement.
Figure 12. Iris prolapse OS in a 8-year-old Friesian stallion pictured in Fig. 11.
Figure 13. Corneal facet OD in a 2-year-old Friesian colt.
Figure 15. Epithelial defect OD in Friesian yearling filly which healed following keratectomy and amnion transplant. Healing was prolonged.
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Figure 16. Symmetrical epithelial defect OS treated with keratectomy and amnion transplant in Friesian yearling filly pictured in Fig. 15.
Figure 17. Combined pedigree for nine Friesian horses with bilateral inferior corneal lesions as well as four horses with unilateral inferior corneal lesions. Males are represented as squares, and females as circles. A dashed line indicates direct lineage of more than one generation; a solid line indicates direct lineage of a single generation.
in eight eyes, seven of which had a visual outcome. All eyes that had not perforated had a visual outcomes. Of note was the absence of secondary uveitis in these cases prior to perforation, with blepharospasm, epiphora, conjunctival hyperemia, corneal edema, corneal vascularization, aqueous flare or miosis typically not reported, other than in chronic cases that progressed to perforation. The average included horse was a 10-year-old male with bilateral inferotemporal 5 mm diameter corneal lesions. Lesions ranged in size from 2 to 8 mm. Four of seven horses with bilateral disease for whom lesion location
could be confirmed photographically had inferotemporal lesions. One horse had inferonasal lesions, one had inferior lesions, and one had superiotemporal lesions. Location was not confirmed for two patients and was not recorded for horses with unilateral disease. Disease was detected at various corneal depths across the cases, from an epithelialized facet to a deep stromal ulcer, and in some cases progressed to ulceration and then perforation, which with surgical repair resulted in a visual comfortable eye in all but one case, which was so advanced at presentation that phthisis bulbi resulted. A striking feature of this disease was the apparently spontaneous development and progression of corneal disease in one eye that had appeared normal, or had only an epithelialized facet, during treatment of the contralateral eye. This occurred in four of nine patients. This spontaneous and progressive disease course suggests a degenerative process, although there were risk factors present that may have contributed to corneal ulcer development in the contralateral eye, such as hospitalization,18 general anesthesia,19 and an increase in proteases associated with presence of a corneal ulcer in the first eye affected.20 Additionally, five of nine eyes in three of five horses treated with a conjunctival graft, all performed by different surgeons, experienced some degree of dehiscence of the graft, although visual outcomes resulted. There may have been a progressive degenerative process even after surgical repair. While all included cases were followed to resolution of corneal ulceration and subsequent discontinuation of medication, further observation of these cases has not generally been available, so the likelihood of recurrence is unknown. One case, however, a stallion diagnosed at age 15 years with a unilateral deep epithelialized facet, was examined 5 years following identification of the corneal facet at age 20 years, and no abnormalities were noted at that time. The facet was no longer present, and no corneal lesions had been reported during numerous ocular examinations over the 5-year period, although the stallion was anecdotally reported to have occasional epiphora. This case represents the longest follow-up in the current case series and suggests that there may be a wide range of severity in this disease process, from spontaneous resolution to corneal rupture, if indeed all patients described in this series were affected with the same disease. Pellucid marginal degeneration, or PMD, may represent an underlying etiology for the corneal dystrophy seen in these patients. PMD is a corneal thinning disease that is traditionally classified as a dystrophy, although, adding to the confusion in the literature, is named degeneration. PMD is atypical among dystrophies based on the lack of corneal deposits seen with this disease.21 The name, derived from the Latin pellucere, which means ‘to shine through’,22 refers to the clinical appearance, which is a clear cornea despite the presence of corneal thinning,
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without vascularization or infiltrate. As reported in human patients, PMD typically occurs inferiorly in a peripheral crescent-shaped region.21 PMD is rare but more common in males and is typically progressive, with an average age of onset around 40 years in human patients.21,23,24 PMD is typically bilateral, although unilateral cases have been reported.25,26 The prevalence and etiology of PMD are unknown, although some authors have argued that it is a peripheral variant of keratoconus.27 There is no evidence that PMD is genetically inherited, although moderate to high astigmatism has been noted in asymptomatic family members of patients with PMD.28 Corneal topography, which evaluates the degree and distribution of surface irregularities in the cornea, captures the eccentric thinning seen in PMD. The hallmarks of PMD are a ‘crab claw’ appearance on corneal topography and ‘against the rule’ astigmatism, in which the horizontal corneal meridian has steeper curvature than the vertical corneal meridian (i.e., the corneal curvature is comparable with a football standing on its end). Both the ‘crab claw’ appearance and ‘against the rule’ astigmatism can be used to diagnose early corneal ectasia,29 although both may be present in keratoconus as well as PMD, with central thinning in the former and peripheral thinning in the latter. Advanced PMD may manifest with acute pain and sudden vision loss associated with corneal hydrops or even spontaneous corneal perforation.29 Histologically, PMD is associated with an increase in stromal mucopolysaccharides and irregularities or even breaks in Bowman’s layer.29 Mild PMD is most commonly managed using spectacles or contact lenses to correct astigmatism, whereas the more rare, severe cases are treated with various forms of keratoplasty, both penetrating and lamellar.23,24,30 Outcomes are generally good although astigmatism results if disease is severe enough to warrant surgical intervention.27,29 Based on the clinical presentation and outcomes of the cases in this report, PMD may represent an underlying etiology for this Friesian corneal dystrophy. PMD typically occurs inferiorly in a peripheral crescent-shaped region21; in these horses, lesions were peripheral but round, not crescent-shaped. PMD is more common in males and is typically progressive, with an average age of onset around 40 years in human patients21,23,24; in these horses, males were over-represented, disease was progressive, and the average age of onset of 10.5 years is consistent with adult onset observed in human patients. PMD is typically bilateral, although unilateral cases have been reported25,26; in these horses, bilateral disease was an inclusion criterion but unilateral cases were identified as well. However, without corneal topography and pachymetry, a definitive diagnosis is not possible. Additionally, it remains an open question whether all patients included in this report, both bilaterally and unilaterally affected, represent manifestations of the same underlying disease process. However, as an initial characterization and without further ultrastructural, topo-
graphical, or genetic data, PMD may offer the best clinical categorization. The second objective was to analyze affected horses’ pedigrees to investigate the heritability of this corneal dystrophy. Using pedigree information that was available for nine of 10 horses with bilateral disease and three of four horses with unilateral disease, all horses affected with corneal dystrophy in the present study, as well as horses with at least one affected eye, come from the Tetman stallion line, and all but one bilaterally affected horse are offspring of Tetman’s son Mark. While there is considerable inbreeding among Friesians, with an average ‘inbreeding’ coefficient of 0.157, comparable with mating between half siblings, and these particular horses are related in many cases through more than one line, the existence of a common ancestor is consistent with the hypothesis that this corneal dystrophy has a genetic basis. In conclusion, this form of corneal dystrophy in Friesian horses, characterized by bilateral symmetric stromal loss, appears to be progressive, but responds well to surgical repair; males may be at increased risk; and based on the symmetric location of the lesions, and initial pedigree analysis tracing affected horses back to a common sire, this syndrome may have a genetic basis in Friesian horses. A future goal will be to more specifically evaluate pellucid marginal degeneration as an underlying etiology of corneal dystrophy in Friesian horses. Further future efforts to support this goal will be directed at identifying additional affected horses, continuing to collect pedigree data to expand the pedigree analysis, performing corneal pachymetry and topography to identify potentially affected horses, performing ultrastructural analysis to better characterize the disease process, and performing a genome wide association study to identify single-nucleotide polymorphisms, or genetic variants, which are associated with this disease. REFERENCES 1. Waring GO, Rodrigues MM, Laibson PR. Corneal dystrophies. I. Dystrophies of the epithelium, Bowman’s layer and stroma. Survey of Ophthalmology 1978; 23: 71–122. 2. Waring GO, Rodrigues MM, Laibson PR. Corneal dystrophies. II. Endothelial dystrophies. Survey of Ophthalmology 1978; 23: 147–168. 3. Bistner SI, Aguirre G, Shively JN. Hereditary corneal dystrophy in the Manx cat: a preliminary report. Investigative Ophthalmology 1976; 15: 15–26. 4. Cooley PL, Dice PF 2nd. Corneal dystrophy in the dog and cat. The Veterinary Clinics of North America. Small Animal Practice 1990; 20: 681–692. 5. Crispin SM. Crystalline corneal dystrophy in the dog. Histochemical and ultrastructural study. Cornea 1988; 7: 149–161. 6. Vemuganti GK, Rathi VM, Murthy SI. Histological landmarks in corneal dystrophy: pathology of corneal dystrophies. Developments in Ophthalmology 2011; 48: 24–50. 7. Gupta SK, Hodge WG. A new clinical perspective of corneal dystrophies through molecular genetics. Current Opinion in Ophthalmology 1999; 10: 234–241.
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