An association between systemic cyclosporine administration and development of.pdf

Veterinary Ophthalmology (2016) 19, Supplement 1, 77–85 DOI:10.1111/vop.12367 An association between systemic cyclosporine administration and development of acute bullous keratopathy in cats Kenneth E. Pierce Jr.,* David A. Wilkie,...

Veterinary Ophthalmology (2016) 19, Supplement 1, 77–85 DOI:10.1111/vop.12367 An association between systemic cyclosporine administration and development of acute bullous keratopathy in cats Kenneth E. Pierce Jr.,* David A. Wilkie,† Anne J. Gemensky-Metzler,† Paul G. Curran,‡ Wendy M. Townsend,§ Simon M. Petersen-Jones* and Joshua T. Bartoe* *Department of Small Animal Clinical Sciences, Michigan State University, East Lansing, MI,USA; †Department of Veterinary Clinical Sciences, The Ohio State University, Columbus, OH, USA; ‡Center for Statistical Training and Consulting, Michigan State University, East Lansing, MI, USA; and §Depart- ment of Veterinary Clinical Sciences, Purdue University, West Lafayette, IN, USA Address communications to: Abstract K. E. Pierce Objective To determine whether any association exists between the onset of feline Tel.: 732-922-0011 acute bullous keratopathy (ABK) and administration of systemic corticosteroid or Fax: 732-922-0991 immunosuppressive therapy. e-mail: [email protected] Animals studied Medical records of cats diagnosed with ABK between the years of 2000 and 2008 were retrospectively reviewed. Breed, age at diagnosis, weight, systemic disease status, eye affected, ophthalmic examination findings, systemic and topical therapy instituted, dosage and duration of therapy, visual outcome and histopathologi- cal analyses were recorded in cases meeting the inclusion criteria. Results A total of 12 cats of a surveyed population of 70 167 met the inclusion criteria with 17/24 eyes affected by ABK. Medical and/or surgical therapy was utilized for management of ABK with 13/17 eyes remaining sighted at the time of last follow-up. In a subset of cases corneal cytology, aerobic bacterial culture, FHV-1 PCR, virus iso- lation and/or histopathology were performed; no infectious organisms were identified. A rupture in Descemet’s membrane of the cornea was identified histologically in two globes. A total of 10 of 12 cats had been previously diagnosed with ongoing systemic disease. A total of 10 of 12 cats were receiving systemic therapy, and a significant asso- ciation (P < 0.001) was noted between systemic administration of corticosteroids and/ or cyclosporine A and the development of ABK. A total of 8 of 10 cats were adminis- tered oral prednisolone at doses between 1–2 mg/kg every 12–24 h. A total of 5 of 8 cats receiving oral prednisolone were concurrently administered oral cyclosporine at doses of 1.5–7 mg/kg every 12–24 h. Systemic cyclosporine therapy was found to be a significant risk factor (P < 0.001) for ABK development, while systemic prednisolone was not significant (P = 0.10). Conclusions Systemic cyclosporine administration appears to be a risk factor for devel- opment of ABK in the population of cats studied. Key Words: bullous keratopathy, cornea edema, cyclosporine, Descemet’s membrane rupture, feline, prednisolone Potential inciting infectious agents have been investi- INTRODUCTION gated including (i) bacteria – Chlamydophila felis (indirect Feline acute bullous keratopathy (ABK) arises from rapidly immunofluorescence assay [IFA]), Mycoplasma spp. (culture progressive imbibition of aqueous humor into the cornea and PCR),1 and other bacterial species (aerobic culture);1,2 causing disruption of the stromal collagen lamellar archi- (ii) protozoa – Toxoplasma gondii (serum antibody titers);1 tecture and marked deformation of corneal curvature.1 and (iii) viruses – feline herpesvirus Type 1 (conjunctival ABK has been reported in young cats between one and IFA, PCR and virus isolation), feline infectious peritonitis four years of age, with a single case report in a 14-year- virus (serum antibody titers), feline leukemia virus antigen old cat.1–4 (enzyme-linked immunosorbent assay [ELISA]) and feline © 2016 American College of Veterinary Ophthalmologists  14635224, 2016, S1, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/vop.12367 by Robin Stanley - National Health And Medical Research Council , Wiley Online Library on [04/09/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 78 pierce ET AL. immunodeficiency virus (ELISA).1,2 To date, an infecti- Somers, NY). Age, breed, gender and disease matched con- ous organism as a definitive causative agent remains trol cats within the hospital populations during the same speculative. time period were used for statistical comparisons. Chi- In 2005, Martin first reported the subjective clinical square analysis and Fisher’s exact test were used to compare observation of ABK developing in cats with a history of ABK-affected cats by breed, gender, with/without systemic receiving topical or systemic dexamethasone.5 Later, Evans disease, with/without receiving anti-inflammatory/immuno- et al.6 reported on two cats diagnosed with immune- suppressive agents to control cats. Independent sample mediated hemolytic anemia (IMHA), which developed t-tests were used to compare the duration of systemic ther- bilateral ABK while receiving cyclosporine (25 mg PO apy and the development of ABK. Data were considered q12 h) and prednisolone (3.5–4 mg/kg/day). We have also significant at P < 0.05. managed a number of cats that developed ABK while being treated for systemic diseases that required immuno- RESULTS suppressive therapy. However, there are no reports objectively evaluating administration of systemic immuno- Twelve of 70 167 (0.017%) cats included in the MSU and suppressive agents as a possible risk factor for develop- OSU hospital populations were confirmed to have a diag- ment of ABK. Here, we report the findings of a nosis of ABK, including seven spayed females, one intact retrospective study designed to determine whether any female and four neutered males (Table 1). All affected cats association exists between cats receiving anti-inflamma- were listed in the records as either mixed-breed or domes- tory/immunosuppressive agents for concurrent systemic tic short hair. The average body weight for ABK-affected disease and development of ABK. cats was 4.6  1.1 kg (range: 2.7–6.7 kg). Seventeen of twenty-four eyes of the twelve cats were diagnosed with ABK, including nine right eyes and seven MATERIALS AND METHODS left eyes (Table 2). One cat (#12) developed two separate Individual searches of all medical records maintained episodes of ABK in separate areas of the same cornea between the years 2000 and 2008 from both the Veteri- (OS); these lesions were recorded and analyzed separately. nary Teaching Hospital at Michigan State University Four cats (# 2, 5, 7 and 8) developed ABK bilaterally. The (MSU) and the Veterinary Medical Center at The Ohio average age of cats at the time of ABK diagnosis was State University (OSU) were performed to initially iden- 5.03  3.80 years (range 1.01–14.06 years). Eight of tify all feline patients with diagnoses/treatments including twelve (8/12) cats were diagnosed with ABK at < 5 years ABK, bullous keratopathy, keratopathy, corneal bullae, of age, three of twelve (3/12) cats between 5 and 10 years corneal edema, conjunctival graft and nictitans/third eyelid of age, and one cat (1/12) was > 10 years of age. The four flap. All records identified during the initial searches were cats with bilateral ABK (Table 2; cases 2, 5, 7 and 8) were reviewed separately by two investigators (KP & DW). all < 5 years of age at the time of diagnosis. Cats with ophthalmic examination findings consistent with Based on owner reported history, ABK onset time was: a diagnosis of ABK were further evaluated. Cases with a < 12 h in three of seventeen (3/17) eyes, between 12 and history of chronic ocular disease and/or previous topical 24 h in seven of seventeen (7/17) eyes, > 24 h in five of ocular medication application were excluded from analysis. seventeen (5/17) eyes and unrecorded for two of seventeen The following data: sex, spay/neuter status, breed, age at eyes (2/17). Complete ophthalmic examination findings diagnosis, body weight, affected eye, systemic disease sta- were not recorded for one eye (Cat # 1). Bullae size scor- tus, systemic and topical therapy instituted, dosage, and ing at the time of ABK diagnosis was as follows: 1 in three duration of therapy and visual outcome at follow-up were of seventeen (3/17) eyes, 2 in four of seventeen (4/17) collected from all ABK cases. eyes, 3 in two of seventeen (2/17) eyes, 4 in three of sev- Ophthalmic examination findings at the time of presen- enteen (3/17) eyes, 5 in three of seventeen (3/17) eyes and tation were recorded. The time to onset of ophthalmic size was not documented for two of seventeen (2/17) eyes. lesions was determined by the length of time passing Four of seventeen (4/17) eyes had corneal vascularization between the time the owner last remembered the affected present on initial examination. Anterior chamber depth eye as normal to the time of presentation. The size of bul- was considered to be within normal limits in eleven of lous lesions was given a number score based on the seventeen (11/17) eyes. Four of eleven (4/17) eyes were reported area of clinically affected cornea in comparison noted to have a shallow anterior chamber, and in one eye with the reported area of clinically unaffected cornea as (1/17) the anterior chamber could not be visualized due to described within the record. The bullae sizes were scored complete opacification of the cornea. Other concurrent as: pinpoint/focal = 1, 1/3 corneal surface area = 2, 1/2 ocular disease was absent at the time of ABK diagnosis in corneal surface area = 3, 2/3 corneal surface area = 4 and 13 eyes, with 4 eyes having superficial corneal ulcers and the entire corneal surface area affected = 5. 1 with an incipient cataract. All quantitative data were analyzed using Statistical Pack- In five of twelve (5/12) cats (Table 2; Cats #1, 2, 5, 6 & age for the Social Sciences version 19 (IBM Corporation, 11), additional diagnostic testing was performed including © 2016 American College of Veterinary Ophthalmologists, Veterinary Ophthalmology, 19, 77–85  Table 1. Systemic recorded data Signalment Systemic disease status Systemic therapy Age (at ABK Weight Systemic Diagnosis Age Dosage Duration Cat Breed diagnosis) Gender (kg) disease Diagnosis date (years) Drug Dose (mg/kg) (days) 1 Mixed 1 F 2.7 Yes FeLV positive 5/5/01 1 NA NA NA NA 2 Mixed 1.9 FS 4.4 Yes IMHA 12/16/08 1.5 Prednisolone 5 mg PO q 12 h 1 49 Cyclosporine 25 mg PO q 12–24 h 5.7 117 Prednisolone 10 mg PO q 24 h 2 113 Doxycycline 25 mg PO q 12 h 5.7 24 3 Mixed 3 MN 5.2 Yes Stomatitis 1/1/06 2 Methylprednisolone Injection q other month NA 365 acetate Prednisolone 10 mg PO 2 4 4 DSH 3.2 FS 5.36 Yes IBD 1/27/09 2.8 Prednisolone 5 mg PO q 12 h 1 171 Perianal dermatitis 1/2/09 2.8 Cyclosporine 25 mg PO q 24 h 4.7 NA Spinal hyperesthesia 1/2/09 2.8 Leukeran 2 mg PO q 48 h 1 Animax cream Apply to affected area q 12 h NA Neo-Predef Apply to affected area q 12 h NA w/tetracaine 5 Mixed 3.5 MN 4.92 Yes IMHA 9/10/07 2.8 Prednisolone 10 mg PO q 12 h 2 949 Cyclosporine 25 mg PO q 12 h 5 NA Doxycycline 50 mg PO q 12 h 10.16 NA 6 DSH 3.5 FS 5.1 Yes Asthma 6/29/03 0.3 Prednisolone 5 mg PO q 24 h 1 822 Methylprednisolone NA NA NA 7 Mixed 3.6 MN 6.7 Yes IMHA 1/9/07 2.4 Prednisolone 10 mg PO q 12 h 1.5 617 Chlorambucil 6 mg PO q 2 weeks 0.9 369 © 2016 American College of Veterinary Ophthalmologists, Veterinary Ophthalmology, 19, 77–85 Cyclosporine 10 mg PO q 12 h 1.5 176 Doxycycline 30 mg PO q 12 h 4.48 NA 8 Mixed 3.7 FS 3.4 Yes IBD 7/22/99 1.5 Prednisolone 5–7.5 mg PO q 12 h 1.5–1.7 1486 Demodex 3/16/04 6.1 Cyclosporine 25 mg PO q 24 h 7 12 Prednisolone 5 mg PO q 12 h 1.7 7 9 DSH 5 FS 4.6 Yes FeLV/FIV positive 9/26/05 5 Prednisolone 5 mg PO q 24 h 1 NA Doxycycline 20 mg PO q 12 h 4.3 NA 10 DSH 8 FS NA NA NA NA NA NA NA NA NA 11 Mixed 8.8 FS NA No 12 DSH 13.4 MN 3.8 Yes FHV-1 rhinitis NA NA NA NA NA FHV-1, feline herpes virus Type 1; FeLV/FIV, feline leukemia virus and feline immunodeficiency virus; IBD, inflammatory bowel disease; IMHA, immune-mediated hemolytic anemia; ABK, Acute bullous keratopathy. acute bullous keratopathy in cats 79 14635224, 2016, S1, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/vop.12367 by Robin Stanley - National Health And Medical Research Council , Wiley Online Library on [04/09/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License  14635224, 2016, S1, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/vop.12367 by Robin Stanley - National Health And Medical Research Council , Wiley Online Library on [04/09/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 80 pierce ET AL. Table 2. Acute bullous keratopathy recorded data Length of Onset clinical Visual Therapeutic follow-up Cat Eye signs Therapy Ophthalmic medications Surgery type outcome duration (days) (days) 1 OD NA M 5% NaCl o/s q 8 h NA 53 53 2 OD < 12 h B 5% NaCl o/s q hr E Blind 1 1 Terramycin o/o q 4 h OS < 12 h B 5% NaCl o/s q 4–6 h NF Sighted 44 46 Terramycin o/o q 4–6 h Optixcare o/s q 4–6 h 3 OS 24 h B 0.5% Levofloxacin o/s q 6 h K + CPG Sighted 14 1123 1% Atropine o/o q 24 h 4 OD < 12 h B 5% NaCl o/s q 4–6 h CPG Sighted 86 58 NPG o/s q 4–6 h 27 03% Ofloxacin o/s q 4–6 h 27 5 OS 24 h B Terramycin K + CPG Sighted NA 744 OD 12 h B Terramycin K + CPG Sighted NA 743 6 OS 50 h M 5% NaCl o/o q 4 h NA NA 0 7 OS 12 h M NPB o/o Sighted 4 160 OD 12 h B 5% NaCl o/o K + CPG Sighted NA Terramycin o/o 8 OS 48 h B 0.3% Ofloxacin o/s q 6 h PK -> NF Sighted 30 NA NPD o/s q 6 h 26 0.03% Flurbiprofen o/s q 6 h 26 NPG o/s q 8 h 42 1% Cyclosporine o/s q 12 h 641 Hylashield o/s q 6 h 346 OD 48 h B 0.3% Ofloxacin o/s q 6 h PK -> NF Sighted 45 NA NPD o/s q 6 h 25 0.03% Flurbiprofen o/s q 6 h 25 NPG o/s q 8 h 42 1% Cyclosporine o/s q 12 h 641 Hylashield o/s q 6 h 346 9 OD 12 h M 5% NaCl o/o q 6 h Sighted 70 70 10 OD NA B NPB o/o q 8 h NF Sighted 56 56 Terramycin o/o q 6 h 11 OD 24 h M Terramycin o/o q 6 h Sighted NA NA 1% Atropine o/o q 12 h NPB o/o q 6 h 12 OS > 2 weeks B 03% Tobramycin o/s q 4 h NF Sighted 42 OS 4 weeks M 0.3% Tobramycin o/o q 6 h NA NA 708 5% NaCl o/o q 8 h NPB, neomycin/polymyxin B sulfate/bacitracin zinc; PK, penetrating keratoplasty. corneal cytology (Cats #5 & 11), aerobic bacterial culture neomycin/polymyxin B sulfate/bacitracin zinc (NPB) oph- (Cats #6 & 11), feline herpes virus Type 1 (FHV-1) PCR thalmic ointment (3/6), oxytetracycline ophthalmic oint- (Cat #2), feline leukemia virus and feline immunodefi- ment (2/6), 0.3% tobramycin ophthalmic solution (1/6), ciency virus (FeLV/FIV) ELISA (Cat #2) and Toxoplasma 1% atropine ophthalmic ointment (1/6) and L-lysine gondii serum antibody titers (Cat #1). 500 mg per os q12 h (3/6). The average duration of ocular therapy for the seven- A combination of medical treatment and surgical man- teen ABK-affected eyes was 104.24  184.79 days (range agement was performed on eleven of seventeen (11/17) 1–641 days). Six of seventeen (6/17) eyes received medical eyes. The average duration of medical treatment following treatment alone. The average duration of medical treat- surgery was 313.88  189.02 days (range 1–641 days), ment alone was 42.3  34.27 days (range 4–70 days), which was calculated from eight of eleven (8/11) eyes for which was calculated from three of six (3/6) eyes for which which this information was available in the record. For this information was available in the record. For three of three of eleven eyes (3/11), duration of medical treatment six eyes (3/6), duration of medical treatment alone was not following surgery was not recorded. Selection of medica- recorded. Selection of medication for medically treated tion for surgically treated ABK-affected eyes included the ABK-affected eyes included the following: 5% sodium following: 5% sodium chloride (NaCl) ophthalmic oint- chloride (NaCl) ophthalmic ointment or solution (3/6), ment or solution (6/11), oxytetracycline ophthalmic oint- © 2016 American College of Veterinary Ophthalmologists, Veterinary Ophthalmology, 19, 77–85  14635224, 2016, S1, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/vop.12367 by Robin Stanley - National Health And Medical Research Council , Wiley Online Library on [04/09/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License acute bullous keratopathy in cats 81 ment (6/11), 0.3% ofloxacin ophthalmic solution (3/11), (a) neomycin/polymyxin B sulfate/gramicidin ophthalmic solution (2/11), neomycin/polymyxin B sulfate/dexametha- sone ophthalmic solution (2/11), 1% cyclosporine oph- thalmic solution (2/11), 0.03% flurbiprofen ophthalmic solution (2/11), neomycin/polymyxin B sulfate/bacitracin Zinc (NPB) ophthalmic ointment (1/11), 0.3% tobramycin ophthalmic solution (1/11), 0.5% levofloxacin ophthalmic solution (1/11), 1% atropine ophthalmic ointment (1/11) and L-lysine 500 mg per os q12 h (1/11). Thirteen surgi- cal procedures were performed on the 11 eyes including nictitans flap (5/13), keratectomy followed by a conjuncti- val pedicle graft (4/13), penetrating keratoplasty (PK; 2/13), conjunctival pedicle graft (1/13) and enucle- ation (1/13). The two eyes administered a combination of topical antibiotics, anti-inflammatories (NSAIDs and ster- oids) and an immunosuppressive were eyes that had a PK performed. Thirteen of 17 (76%) eyes were sighted at the time of last follow-up examination. Three of 6 medically treated eyes and 10/11 eyes managed with a combination of medical and (b) surgical therapy were sighted at the last follow-up examina- tion. One eye had diminished vision at presentation due to corneal perforation, and three eyes had an unknown visual status at follow-up. The eye with diminished vision was enucleated due to progression of the corneal lesion (Cat # 2; Fig. 1a and b). The length of follow-up ranged from 1 to 1123 days (mean 341.5  384.16 days). Two of the medi- cally treated cats were lost to follow-up after the initial diagnosis of ABK. Histopathology was performed on two globes (Cat #2) and two keratectomy specimens (Cat #5) (Fig. 1–3). Marked corneal stromal edema and degeneration were observed histopathologically in all submitted specimens and characterized as fibrillar and vacuolated with wide spacing between collagen fibers. The right eye of Cat #2 was enucleated as a result of corneal perforation (Fig. 1a and b), and the left eye was an immediate postmortem submission (Fig. 2a and b). In the perforated globe (OD Figure 1. (a) Image of Cat #2 OD at presentation prior to corneal of Cat #2), loss of the surface epithelium overlying the perforation. Note the bullous keratopathy lesion exhibiting marked corneal bullae, fibrin and few red blood cells within the focal corneal edema and deformation of the corneal curvature. Hair anterior chamber and an attenuated corneal endothelium artifact is observed on the surface of the deformed cornea. (b) Sub- with eosinophilic vacuolation was also observed. In the gross image of the perforated right eye of Cat #2 after enucleation and formalin fixation. Note the marked deformation of the axial postmortem globe (OS of Cat #2), which was managed cornea. with a nictitans flap and medical therapy, mucinous mate- rial within the cornea was identified superficial to a poste- rior focus of stromal fibrosis (Fig. 2b). Descemet’s had been previously diagnosed with systemic disease. membrane was ruptured and curled in vivo with endothe- These systemic diseases included the following: immune- lial migration between the curled segments and along its mediated hemolytic anemia (IMHA; 3/10), inflammatory external most aspect (Fig. 2 b and c). The presence of bowel disease (IBD; 2/10), FeLV infection based on posi- endothelial attenuation was not observed in the left globe. tive ELISA (2/10) and one of each: feline asthma, infec- A posterior focus of stromal fibrosis between a segment of tion with FIV based on positive ELISA, chronic FHV-1 ruptured Descemet’s membrane was observed in the two rhinitis and stomatitis. One IBD cat was diagnosed with keratectomy segments of Cat #5 (Fig. 3a and b). perianal dermatitis and spinal hyperesthesia (Cat #4), one At the time of ABK onset, two of twelve (2/12) cats FeLV-positive cat was also FIV positive (Cat # 9) and one were systemically healthy, while ten of twelve (10/12) cats IBD cat was infested with demodex mites (Cat # 8). © 2016 American College of Veterinary Ophthalmologists, Veterinary Ophthalmology, 19, 77–85  14635224, 2016, S1, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/vop.12367 by Robin Stanley - National Health And Medical Research Council , Wiley Online Library on [04/09/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 82 pierce ET AL. (a) (a) (b) (c) (b) Figure 2. (a) Image of the left eye of Cat #2 after removal of the nictitans flap. Axial to ventral paraxial corneal edema, stromal fibrosis and vascularization are depicted in this image. (b) Photomicrograph of an H&E stained section of Cat #2 OS that was immediately Figure 3. (a) Photomicrograph of an H&E stained section of cornea formalin fixed at postmortem evaluation. Note the mucinous material from Cat #5 who received a keratectomy and conjunctival graft within the cornea anterior to stromal fibrosis. The tip of the surgery. Illustrated is a focus of posterior stromal fibrosis spanning ruptured and curled Descemet’s membrane is observed within the the segment of Descemet’s membrane rupture. Note the curled edges bottom left of the image. (c) (figure 2b mag) Photomicrograph of an of Descemet’s membrane. (b) Higher magnification photomicrograph H&E stained section of Descemet’s membrane rupture in Cat #2 OS. of an H&E stained section of cornea from Cat #5. Note the rupture Note the presence of the curled membrane with endothelial in Descemet’s membrane and presence of posterior stromal fibrosis migration between the curled segments and along the internal and adjacent to the rupture. external aspect of Descemet’s membrane. Systemic disease was not a significant risk factor with Tetracaine powder both applied to affected skin (P = 0.72) for ABK development when compared to the twice daily (Cat #4); oral Chlorambucil at 0.9 mg/kg twice total number of cats diagnosed with IMHA, IBD and weekly (Cat #7); a methylprednisolone acetate injection FeLV within the hospital populations during the same every other month for 1 year’s duration (Cat #6); or a sin- time period. gle injection of methylprednisolone acetate (Cat #3). The Among the ten cats with previously diagnosed systemic dose and route of methylprednisolone injections adminis- disease, eight of ten (8/10) cats were receiving oral pred- tered in two cats were not recorded. One cat (Cat #4) also nisolone at dosages of 1–2 mg/kg every 12–24 h (Table 1) received a single 2-mg dose of Leukeran orally. Four cats as treatment for the systemic condition. Additionally, five were concurrently administered doxycycline orally at of the eight (5/8) cats administered oral prednisolone were dosages of 4.5–10 mg/kg twice daily. The duration of also receiving oral cyclosporine at dosages of 1.5–7 mg/kg administration for the eight cats treated with systemic every 12–24 h (Table 1) as treatment for the systemic medication ranged from 4 to 1493 days (mean condition. The remainder of the systemic therapies 438.08  452.54 days). Two of ten (2/10) cats diagnosed administered to the ABK cats included the following: topi- with systemic disease, a FeLV-positive cat and a cat with cal dermatologic nystatin–neomycin sulfate–thiostrepton– FHV-1 rhinitis, had no record of systemic medication triamcinolone acetonide (Animax) cream and Neo-Predef administration. © 2016 American College of Veterinary Ophthalmologists, Veterinary Ophthalmology, 19, 77–85  14635224, 2016, S1, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/vop.12367 by Robin Stanley - National Health And Medical Research Council , Wiley Online Library on [04/09/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License acute bullous keratopathy in cats 83 The risk for development of ABK in cats administered membrane can be associated with ABK lesions. ABK has systemic medication for treatment of systemic disease was been reported in numerous breeds of cats without familial significantly increased (P < 0.001) compared to cats not associations. Investigations into genetic markers or poten- receiving systemic medication. The mean duration of tial inheritance patterns for ABK development have yet to administration (438.08  452.54 days) of all systemic be performed. medication in ABK-affected cats was significantly longer Additional ophthalmoscopic lesions noted at presenta- (P = 0.04) compared to the mean duration of administra- tion in select cases of previously reported ABK-affected tion (166.58  289.95 days) of all systemic medication in cats include chronic keratitis with corneal vascularization an equal number of randomly selected control cats not and granulation tissue, corneal perforation, anterior uvei- diagnosed with ABK within the hospital populations. The tis, hyphema and anterior synechia in one cat; fibrinous duration of oral prednisolone administration (mean anterior uveitis in a cat with a positive serum corona virus 674.50  544.53 days; range: 4–1493 days) was calculated antibody titer; and anterior uveitis of unknown etiology in from information contained in the records of six of eight another cat.1,2 In the majority of these previously reported (6/8) ABK cats; the duration of oral prednisolone adminis- cases, diagnostic testing failed to determine an etiology tration was not recorded in two cats. The duration of for ABK development. Consistent with previous reports, prednisolone administration prior to the diagnosis of ABK some cats within our study were noted to have acute cor- was 144–822 days (mean 421.43  288.61 days) in 7/8 neal perforations, corneal vascularization, anterior uveitis cats. Systemic prednisolone administration in ABK cats and an incipient cataract. Diagnostic tests performed in (n = 8) was not statistically significant (P = 0.10) when select cases also failed to yield an etiology for ABK devel- compared to cats administered this medication in the opment. It is possible that an underlying, infectious or hospital population (n = 951). The duration of oral cyclos- inflammatory disease may potentiate ABK development in porine administration (mean 101.67  83.07 days; range: cats. However, in this study the systemic diseases of ABK- 12–176 days) was calculated from information contained affected cats were not a risk factor for ABK development in the records of three of five (3/5) cats; the duration of when compared to non-ABK-affected cats diagnosed with oral cyclosporine administration was not recorded in two the same systemic diseases in both hospital populations. It of five (2/5) cats. The duration of cyclosporine ther- is possible that the current methods of diagnostic investi- apy prior to diagnosis of ABK in these three cats was gations may be inadequate in ability to identify a potential 2–101 days (mean 39.67  53.58 days). The proportion of emerging etiology. Continued investigations into an ABK-affected cats receiving oral cyclosporine (n = 5) was underlying etiology for ABK development in cats are war- significantly higher (P < 0.001) than the proportion of ranted. unaffected cats in the hospital population receiving oral Unlike previous case reports of ABK cats lacking a his- cyclosporine (n = 45). There was no significant association tory of systemic therapy prior to ABK development, the between onset of ABK and any of the other systemic or majority of cats included in this investigation were receiv- dermatological medications administered. ing systemic therapy at either anti-inflammatory or immunosuppressive dosages. When compared to a random sample of non-ABK-affected cats diagnosed with the same DISCUSSION systemic disease during the same time frame, the mean Several etiological theories for ABK development in cats duration of therapy in ABK-affected cats was approxi- have been described and include an inherited corneal stro- mately 2.5 times longer than non-ABK-affected cats. Both mal dystrophy, enzymatic corneal stromal degradation systemic therapy and the duration of systemic therapy yielding collagen fiber breakdown, development secondary were significant risk factors for ABK development in cats. to an underlying disease process, and previous treatment Cyclosporine A, derived from the soil fungi Tolypocladium with topical or systemic corticosteroids.1,2 Inherited cor- inflatum, is an immunosuppressive drug first used to pre- neal dystrophy in the Manx cat has been described as an vent graft rejection and graft-vs.-host interactions in organ anterior stromal edema progressing to a marked epithelial transplant patients. It is primarily metabolized by the hep- edema and interepithelial bullae formation.7 Anterior stro- atic cytochrome P450 3A4 (CYP3A4) enzyme and excreted mal edema with collagen fibrillar separation and rounded in the bile.8 Intestinal CYP3A4 also contributes to cyclos- but present keratocyte nuclei were observed in Manx cats porine metabolism.8 Intra- and interspecies variations in with advanced dystrophic changes. Descemet’s membrane cyclosporine absorption, metabolism and excretion have and the corneal endothelium histopathologically appeared been reported in various species including humans, normal in Manx cats with corneal dystrophy. ABK- baboons, dogs, rabbits, rats and cats.8–10 Systemically affected cats differ in that surface epithelium over the bul- administered cyclosporine was a highly significant risk fac- lous lesions may exhibit subepithelial vesicles1 or may be tor for ABK development in cats in the present study. absent, marked stromal edema and collagen degeneration Inefficient cyclosporine metabolism or elevated serum can occur throughout all layers of stromal lamellae, kera- cyclosporine levels may account for idiosyncratic eruptive tocyte nuclei may be absent, and rupture of Descemet’s corneal lesions in select cats. However, pharmacokinetic © 2016 American College of Veterinary Ophthalmologists, Veterinary Ophthalmology, 19, 77–85  14635224, 2016, S1, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/vop.12367 by Robin Stanley - National Health And Medical Research Council , Wiley Online Library on [04/09/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 84 pierce ET AL. investigations of systemically administered cyclosporine in methods. Overall, aggressive medical and/or surgical inter- cats showed minimal side effects including diarrhea, vom- vention appears to result in stabilization of the decompen- iting, intermittent soft feces and one incidence of transient sating cornea, resolution of the bullous lesions and gingival hypertrophy.9,10 These reported side effects asso- retention of vision. ciated with cyclosporine administration were not docu- In Glover’s case series,1 three of four cats exhibited mented in the records of ABK-affected cats in this study. anterior uveitis at presentation. One cat with chronic Oral antifungal therapy, specifically ketoconazole and corneal perforation had a conjunctival pedicle graft other azoles, has been documented to increase serum placed, while the two remaining cats had enucleations cyclosporine concentrations by 1.8- and 2.2-fold, 12 and due to extensive corneal bullae formation. One of the 24 h, respectively after cyclosporine administration in latter two cats was diagnosed with feline infectious peri- cats.11 Ketoconazole has been shown to inhibit CYP3A4 tonitis and had lymphoplasmacytic panuveitis with retinal causing a rapid increase in serum cyclosporine concentra- detachment, while the other cat had a history of tions within 24 h of administration.12 Previous history and chronic, intermittent anterior uveitis and no abnormali- concurrent ketoconazole administrations were not docu- ties of Descemet’s membrane and corneal endothelium. mented within the record of ABK-affected cats. Other In this study, ophthalmoscopic evidence of uveitis at drugs, besides antifungals,11–16 reported to alter cyclospor- presentation was observed in seven eyes, one of which ine metabolism in other species include calcium channel was noted to have concurrent corneal perforation. The blockers,16,17 antibiotics (such as Doxycycline),16 antiemet- cause of the uveitis was undetermined in these eyes. It is ics,16,18 corticosteroids 10,16 and other agents.10,16,19–21 unknown if preexisting anterior uveitis predisposes ABK Doxycycline (n = 4), methylprednisolone (n = 2) and pred- or if the observed inflammation is secondary to the con- nisolone (n = 8) were the only drugs reported to affect current corneal changes. It is the author’s speculation cyclosporine absorption/metabolism and were adminis- that the latter may be true as the inclusion criteria was tered to ABK-affected cats in this study. In humans, doxy- set on the absence of historical ocular disease. However, cycline and methylprednisolone are reported to increase subclinical uveitis not recognized by the owner or refer- cyclosporine serum levels by inhibition of CYP3A4, while ring veterinarian cannot be ruled out as a contributing prednisolone induced CYP3A4 and intestinal P-glycopro- factor. tein resulting in a potential decreasing prednisolone clear- Histopathological samples from globes and keratectomy ance.10 The exact mechanisms of these corticosteroid specimens of previous reports1,2 all demonstrated marked interactions with cyclosporine are controversial within the corneal stromal edema and collagen fibrillar degeneration literature22 and may or may not account for the idiosyn- with no abnormalities in Descemet’s membrane and cor- cratic development of ABK in cats. The majority of cats neal endothelium. In contrast to previous reports, receiving systemic therapy in this study were administered endothelial attenuation was observed in a perforated globe prednisolone at a 6 times longer, mean duration than from Cat #2. Evidence of anterior uveitis at presentation cyclosporine. However, systemic prednisolone administra- was absent in this globe prior to perforation. It is unclear tion failed to achieve statistical significance when com- as to whether endothelial changes occurred in this globe pared to prednisolone receiving non-ABK cats within the prior to ABK development or after corneal perforation. hospital populations. Statistical significance may be Interestingly, while hospitalized the contralateral globe achieved with the presentation of more cases of ABK- developed ABK, was later histopathologically analyzed, affected cats administered prednisolone within the hospital and shown to have a spontaneous rupture of Descemet’s populations during this study period. Long-term, systemic membrane. This is the first report of a rupture in Desce- prednisolone or combined prednisolone and cyclosporine met’s membrane in an ABK-affected cat. Clinical observa- administration studies are necessary to elucidate the tions show some ABK lesions to be small, focal bullous potential for toxic drug effect on feline corneas and ABK lesions with an insidious progression in corneal involve- development. ment, while other lesions rapidly progress affecting a large Therapeutic strategies previously implemented to treat portion of the cornea within minutes to hours. A sponta- ABK lesions in cats include topical antibiotics, anti-inflam- neous rupture in Descemet’s membrane may account for matories, cycloplegics and tear supplements, and surgical the latter clinical presentation, however further procedures consisting of combined keratectomy and con- histopathological documentation of ruptures in Desce- junctival grafts, nictitans flaps and temporary tarsorrha- met’s membrane is necessary. The presence of a shallow phies.1,2,5 Therapies instituted in ABK cats in this study anterior chamber in several of the cases may support a are consistent with previous therapies and resulted in a spontaneous rupture in Descemet’s membrane with subse- good visual outcome. Corneal perforation in 1 of 4 cats quent leakage of aqueous into the corneal stroma. This was treated via enucleation. However, immediate surgical may also explain why a nictitans flap results in a favorable correction with a conjunctival graft or PK, in combination outcome, serving to tamponade the leaking aqueous, with topical therapies, was able to maintain a sighted eye allowing time for fibrous repair of the rent in Descemet’s at follow-up in the remaining three eyes treated by these membrane (Fig. 3a and b). © 2016 American College of Veterinary Ophthalmologists, Veterinary Ophthalmology, 19, 77–85  14635224, 2016, S1, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/vop.12367 by Robin Stanley - National Health And Medical Research Council , Wiley Online Library on [04/09/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License acute bullous keratopathy in cats 85 Several limitations have been noted during this retro- Proceedings of the American College of Veterinary spective analysis. The first is the low numbers of cats Ophthalmologists 2009. 7. Bistner SI, Aguirre G, Shively JN. Hereditary corneal dystrophy meeting the inclusion criteria. There is also potential for in the Manx cat: a preliminary report. Invest Ophthalmol 1976; 15: missing historical information, which may include or 15–26. exclude ABK cases during the study period. Based on the 8. Whalen RD, Tata PN, Burckart GJ et al. Species differences in relative rarity of ABK in cats, the strict inclusion criteria the hepatic and intestinal metabolism of cyclosporine. Xenobiotica used, and the consistency of our findings with those of 1999; 29: 3–9. previous investigations justifies our included cat popula- 9. Latimer KS, Rakich PM, Purswell BJ et al. Effects of cyclosporin tion as being representative of the occurrence of ABK in A administration in cats. Veterinary Immunology and Immunopathology 1986; 11: 161–173. cats. Select cases that were missing recorded systemic and 10. Robson D. Review of the pharmacokinetics, interactions and topical drug dosages, durations, frequency of administra- adverse reactions of cyclosporine in people, dogs and cats. Vet tion, ophthalmic examination findings and diagnostic test- Rec 2003; 152: 739–748. ing may skew true values for the duration of systemic and 11. McAnulty JF, Lensmeyer GL. The effects of ketoconazole on the topical therapy, length of follow-up, visual status and pharmacokinetics of cyclosporine A in cats. Veterinary Surgery identification of an etiologic agent. A number score was 1999; 28: 448–455. given for the subjective interpretation of bullae size based 12. Albengres E, Tillement JP. Cyclosporin and ketoconazole, drug interaction or therapeutic association? International Journal of on recorded information within the record. Objective Clinical Pharmacology, Therapy and Toxicology 1992; 30: 555–570. recorded measurements of bullae size may aid in further 13. Myre SA, Schoeder TJ, Grund VR et al. Critical ketoconazole characterization of ABK lesions in conjunction with dosage range for ciclosporin clearance inhibition in the dog. histopathological analyses. Future standardized, controlled Pharmacology 1991; 43: 233–241. prospective clinical analyses will facilitate elimination of 14. Omar G, Whiting PH, Hawksworth GM et al. Ketoconazole and bias. fluconazole inhibition of the metabolism of cyclosporin A by We report the association of ABK development with human liver in vitro. Therapeutic Drug Monitoring 1997; 19: 436– 445. systemic corticosteroid and cyclosporine therapy and with 15. Lo AC, Lui SL, Lo WK et al. The interaction of terbinafine and the duration of systemic therapy administered. Systemic cyclosporine A in renal transplant patients. British Journal of cyclosporine was found to be a significant risk factor for Clinical Pharmacology 1997; 43: 340–341. ABK development in cats. Aggressive medical and surgical 16. Dresser GK, Spence JD, Bailey DG. Pharmacokinetic- therapy resulted in a good visual outcome. A spontaneous pharmacodynamic consequences and clinical relevance of rupture of Descemet’s membrane was observed in two cytochrome P450 3A4 inhibition. Clinical Pharmacokinetics 2000; eyes. Therefore, careful monitoring for ABK development 38: 41–57. 17. Jacob LP, Malhotra D, Chan L et al. 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