Canine glaucoma constitutes a group of diseases characterized by increased intraocular pressure (IOP), disruption of axoplasmic flow in the optic nerve head, apoptosis of retinal ganglion cells and their axons, and cupping of the optic disc.1 Glaucoma is one of the leading causes of blindness in dogs, with a prevalence rate of approximately 1% to 2%.2–4 Even with extensive medical and surgical treatment, irreversible blindness and ocular pain are common sequelae in dogs.5 Treatment options for end-stage glaucomatous eyes include surgical procedures, such as enucleation and evisceration, and pharmacological ciliary body ablation (CBA). Pharmacological CBA may be preferred in dogs because it often does not require general anesthesia and may be economically favorable. Gentamicin and cidofovir are 2 intravitreal injections available for pharmacological CBA, and both drugs are known to be safe and effective in decreasing IOP by reducing aqueous humor production.6–9 However, when high-concentration gentamicin is unavailable, sedation may be necessary to inject a large volume of the drug.
Cidofovir is an antiviral drug that may have cytotoxic effects on the ciliary body, reduce aqueous humor formation, and decrease IOP when injected intravitreally.6 Cidofovir-induced ocular hypotony was first noted in humans as an adverse drug effect.10 Subsequently, studies determining the effects on IOP and toxicity of intravitreal cidofovir in guinea pig and rabbit models were established.11 A dose-dependent decrease in IOP was observed in guinea pigs, while a statistically insignificant drop in IOP was observed in rabbits 2 and 4 weeks after intravitreal cidofovir injection. Corneal epithelial edema, thickening, and vascularization; intraocular inflammation; destruction of the ciliary body and the outer retina; and retinal pigment epithelial changes were observed in guinea pigs histologically. Similar findings were observed in the rabbit eyes but at higher doses. More recently, intravitreal injection of cidofovir was reported to reduce IOP in canine patients with chronic glaucoma successfully.8
When drugs are injected intravitreally, various factors, including the volume and location of injection, pathophysiological condition of the vitreous body and lens, presence of inflammation and infection, and the molecular size of the drug, affect drug distribution.12 Studies on immediate efficacy and dose-dependent effect of intravitreal cidofovir injection in dogs are few,8,13 and studies on the long-term efficacy and the impact of the factors mentioned above on intravitreal cidofovir injection have not been conducted. Therefore, this retrospective cohort study aimed to evaluate the long-term efficacy, effects of different prognostic factors on outcomes, and complications of intravitreal cidofovir injection in end-stage glaucoma in dogs.
Methods
Patients
The medical records of client-owned dogs with ophthalmic diseases referred to the Seoul National University Veterinary Medical Teaching Hospital between 2016 and 2021 were retrospectively evaluated. Dogs that received intravitreal cidofovir injections after being diagnosed with chronic end-stage glaucoma were included in the study. Informed consent was obtained from the owners of all animals described in this work for the procedures and therapy undertaken and the use of data. All dogs underwent a complete ophthalmic examination, including neuro-ophthalmic examination, slit-lamp biomicroscopy (SL-D7; Topcon), indirect ophthalmoscopy (Vantage Indirect Ophthalmoscope; Keeler), and rebound tonometry (Tonovet; Icare). Chronic end-stage glaucoma was diagnosed based on an IOP of ≥ 25 mmHg, absence of menace response and dazzle reflexes, and clinical signs consistent with chronic glaucoma, including buphthalmos, episcleral injection, Haab striae, corneal edema, and lens dislocation. Optic nerve atrophy, tapetal hyperreflectivity, and retinal vessel attenuation were included as posterior changes observed in end-stage glaucoma. Eyes were excluded based on the following criteria: (1) follow-up period of < 6 months, (2) previous history of glaucoma surgery, or (3) suspected intraocular mass. Ocular ultrasonography was performed on all eyes suspected of intraocular mass before intravitreal cidofovir injection, especially when direct ophthalmic examination of the posterior segment was unavailable, to ensure no injected eyes had masses. Dogs that did not allow the injection with manual restraint were sedated for the procedure due to ethical concerns.
Glaucoma eye drops
The glaucoma eye drops included in this study were 0.005% latanoprost (Xalatan; Pfizer), 0.03% bimatoprost (Lumigan; Allergan), 2% dorzolamide (Trusopt; Merck), a combination of 2% dorzolamide hydrochloride with 0.5% timolol maleate (Cosopt; Merck), 1.0% brinzolamide (Azopt; Alcon Laboratories Inc), and 0.5% timolol (Timolol Maleate Ophthalmic Solution USP; Alcon). Different types of eye drop (range, 1 to 3 types of eye drop/dog) were prescribed according to the patient’s glaucoma status.
Intravitreal cidofovir injection
After application of 0.5% proparacaine hydrochloride ophthalmic solution (Alcaine; Alcon) on the site of aqueous humor paracentesis and intravitreal injection with a cotton swab for 1 minute, the eye was aseptically prepared with 0.5% povidone-iodine solution. None of the dogs were under sedation or anesthesia during the procedure. Aqueous humor paracentesis was performed through the peripheral cornea with a 30-g needle and a plunger-less syringe to ambient pressure. A volume of 0.12 mL (600 µg) of cidofovir was injected intravitreally with an insulin syringe 5 to 8 mm posterior to the dorsolateral limbus, in the area of pars plana, directed toward the optic nerve to avoid hemorrhage or damage of the lens. A combination of 4 mg of triamcinolone acetonide (Dongkwang) and 4 mg of gentamicin sulfate (Shinpoong) was injected with a 30-g needle underneath the dorsal subconjunctiva. All dogs were prescribed topical antibiotics and anti-inflammatory drugs to prevent infection and manage intraocular inflammation after injection. Prescribed postprocedure antibiotics and anti-inflammatory eye drops were 0.5% moxifloxacin (Vigamox; Alcon), 1% prednisolone acetate (Pred Forte; Allergan), neomycin/polymyxin B/dexamethasone (Maxitrol; Novartis), and 0.03% flurbiprofen sodium ophthalmic solution (Bausch & Lomb). Eye drops were chosen based on complete ophthalmic examination and clinical signs, and the frequency and period of application were decided accordingly. Glaucoma eye drops were continued for 4 days after injection and discontinued 10 days before the 2-week recheck.
Cidofovir reinjection, gentamicin (volume of 0.75 mL; 30 mg) injection, and enucleation were considered when IOP was ≥ 25 mm Hg and the patient showed clinical signs of high IOP, including episcleral and conjunctival injections, corneal edema, blepharospasm, third eyelid elevation, and changes in behavior. Glaucoma eye drops were represcribed when IOP was ≥ 25 mm Hg and when the owner did not want additional procedures.
Clinical data
A complete ophthalmic examination was performed during each reexamination. Clinical data at the time of injection and after injection (second week, sixth month, and final examination) were collected. Clinical data included signalment, injected eye (right or left), IOP, type of glaucoma, coexisting ocular diseases, number of different types of glaucoma eye drops applied before and after the procedure, and complications. Procedure success was defined as an IOP of ≤ 25 mm Hg after discontinuation of glaucoma eye drops at the 2-week recheck that remained to the 6-month recheck. Primary glaucoma was diagnosed when the glaucomatous eye showed no clinical signs of underlying ocular diseases that may trigger an increase in IOP at the onset of the disease. Breed predisposition and morphological findings of the iridocorneal angle and ciliary cleft via gonioscopy and ultrasound biomicroscopy of the contralateral eye were also considered. Secondary glaucoma was diagnosed when the eye had other concurrent ocular diseases that could have resulted in glaucoma. Coexisting ocular diseases that were recorded at the time of injection included intraocular hemorrhage, lens displacement, chronic uveitis, and vitreal degeneration. Previous intraocular surgery was also recorded.
Complications that were recorded included corneal ulceration, corneal degeneration, intraocular hemorrhage, progression of cataracts, development of ocular mass, endophthalmitis, and phthisis bulbi. Phthisis bulbi was diagnosed when IOP was below 5 mm Hg, and the eye showed clinical signs, including shrinkage and disorganization, characterized by a smaller globe size, folding of Descemet membrane, opaque and thickened cornea, neovascularization of the iris, and retinal detachment.14
Statistical analysis
Statistical analyses were performed with statistical software (SPSS for Mac, version 26; IBM). The intraclass correlation coefficient of the postinjection IOPs in eyes from the same dog was evaluated, and no statistically significant correlation was observed between the IOPs of the 2 eyes. Collected data were analyzed with a paired-sample t test. Multinomial logistic regression analysis and a stepwise variable selection method with the Bayesian information criterion were performed to evaluate the association between grouped postinjection IOPs and other variables. Multiple linear regression analysis was performed to evaluate the association between the time to phthisis bulbi and other variables. A χ2 test was conducted to statistically compare the single-injection success rates in different breeds. All data are presented as mean ± SD (SD). Statistical significance was set at P < .05.
Results
A total of 153 eyes from 130 dogs were included in this study (oculus dexter, 78 eyes; oculus sinister, 75 eyes). The mean ± SD (SD) follow-up duration was 19 ± 12 months (range, 6 to 67 months). The mean ± SD age was 10.8 ± 3.6 years (range, 1 to 18 years). Fifty-six dogs were spayed females, 50 were neutered males, 19 were intact females, and 5 were intact males. Fourteen breeds were included, and Shih Tzu (51/130 [39.2%]) was the predominant breed followed by the American Cocker Spaniel (30/130 [23.1%]), Maltese (16/130 [12.3%]), Poodle (10/130 [7.7%]), mixed breed (5/130 [3.8%]), and French Bulldog (4/130 [3%]). Other breeds included Bichon Frise, Jindo, Pekingese, Samoyed, Schnauzer, White Terrier, Boston Terrier, and Spitz (Table 1).
Breeds included in the study and the success rate of intravitreal cidofovir injection in each breed.
| Breeds | No. of dogs (%) | No. of eyes (%) | Success (%) | Single injection (%) |
|---|---|---|---|---|
| Shih Tzu | 51 (39.2) | 60 (39.2) | 51 (85.0) | 39 (65.0) |
| American Cocker Spaniel | 30 (23.1) | 36 (23.5) | 35 (97.2) | 22 (61.1) |
| Maltese | 16 (12.3) | 19 (12.4) | 19 (100.0) | 16 (84.2) |
| Poodle | 10 (7.7) | 12 (7.8) | 12 (100.0) | 11 (91.7) |
| Mixed | 5 (3.8) | 6 (3.9) | 6 (100.0) | 6 (100.0) |
| French Bulldog | 4 (3.0) | 4 (3.0) | 3 (75.0) | 4 (100.0) |
| Others | 14 (10.8) | 16 (10.5) | 14 (87.5) | 12 (75.0) |
One hundred eyes (100/153 [65.4%]) had primary glaucoma, and 44 (44/153 [28.8%]) had secondary glaucoma. Diagnoses of primary or secondary glaucoma in 9 eyes (9/130 [7.9%]) were limited because they were referred to the clinic in the late stages of the disease, and the cause could not be differentiated between the two. The preinjection IOPs prior to any injections were 47.6 ± 21.6 mm Hg (range, 5 to 99 mm Hg; median, 48 mm Hg), 48.3 ± 24.6 mm Hg (range, 5 to 96 mm Hg; median, 46.5 mm Hg), 45.3 ± 22.0 mm Hg (range, 11 to 90 mm Hg; median, 41 mm Hg), 54.0 ± 17.4 mm Hg (range, 34 to 76 mm Hg; median, 53 mm Hg), and 54.0 ± 18.4 mm Hg (range, 41 to 67 mm Hg; median, 54 mm Hg) in groups that received a single, second, third, fourth, and fifth injection, respectively (Table 2). In eyes with IOP lower than 25 mm Hg, cidofovir was injected because IOP spikes were observed once the glaucoma eye drops were discontinued, and the owners wanted to withdraw the eye drops. The coexisting conditions included chronic uveitis, cataracts, vitreal degeneration, lens dislocation, and intraocular hemorrhage. Chronic uveitis was observed in 108 eyes. Ninety eyes had cataracts, including 36 incipient cataracts, 9 immature cataracts, 15 mature cataracts, and 30 hypermature cataracts. The evaluation of cataract stages in 40 eyes was limited due to ocular surface diseases, including severe corneal edema and corneal pigmentation, severe miosis due to uveitis or drug, or posterior lens luxation. Aphakia was observed in 10 eyes due to previous intracapsular lens extraction or phacoemulsification. Vitreal degeneration was observed in 74 eyes, although ocular diseases of the anterior segment hindered diagnosis in some cases. Lens dislocation was diagnosed in 49 eyes, including 23 lens subluxation, 16 posterior lens luxation, 9 anterior lens luxation, and 1 subluxated intraocular lens after phacoemulsification with intraocular lens implantation. Intraocular hemorrhages, including hyphema, intravitreal hemorrhages, and blood clots in the anterior chamber and vitreous body, were observed in 19 eyes. Ten eyes had previous intraocular surgery; 7 eyes underwent phacoemulsification with or without intraocular lens implantation, and 3 eyes underwent intracapsular lens extraction (Table 3).
The number of intravitreal cidofovir injection and the success rate.
| No. of injections | No. of eyes (%) | Success (%) | Preinjection IOP (mm Hg) | Mean interval to the next injection (d) |
|---|---|---|---|---|
| 1 | 153 (100.0) | 106 (69.3) | 47.6 ± 21.6 | 59.0 ± 78.0 |
| 2 | 42 (27.5) | 25 (59.5) | 48.3 ± 24.6 | 79.0 ± 72.0 |
| 3 | 14 (9.2) | 6 (42.9) | 45.3 ± 22.0 | 28.0 ± 13.0 |
| 4 | 6 (3.1) | 2 (33.3) | 54.0 ± 17.4 | 39.5 ± 16.3 |
| 5 | 2 (1.5) | 1 (50.0) | 54.0 ± 18.4 | — |
IOP = Intraocular pressure.
Ocular conditions at the time of intravitreal cidofovir injection.
| Ocular conditions | Specific type | No. of eyes |
|---|---|---|
| Chronic uveitis | 108 | |
| Cataractsa | Hypermature | 30 |
| Mature | 15 | |
| Immature | 9 | |
| Incipient | 36 | |
| Vitreal degeneration | 74 | |
| Lens dislocation | Lens subluxation | 23 |
| Posterior lens luxation | 16 | |
| Anterior lens luxation | 9 | |
| IOL subluxation | 1 | |
| Intraocular hemorrhageb | 19 | |
| Previous intraocular surgeryc | 10 |
IOL = Intraocular lens.
aThe evaluation of cataract stages in 40 eyes was limited due to ocular surface diseases, including severe corneal edema and corneal pigmentation, severe miosis due to uveitis or drug, or posterior lens luxation. Aphakia was observed in 10 eyes due to previous intracapsular lens extraction or phacoemulsification.
bIntraocular hemorrhage included hyphema, intravitreal hemorrhages, and blood clots.
cSeven eyes underwent phacoemulsification with or without intraocular lens implantation, and 3 eyes underwent intracapsular lens extraction.
The overall success rate of intravitreal cidofovir injection was 91.5% (140/153). The success rate of a single injection was 69.3% (106/153). The second injection increased the success rate to 85.6% (131/153), the third to 89.5% (137/153), the fourth to 90.8% (139/153), and the fifth to 91.5% (140/153). Forty-two dogs received a second injection, and the success rate was 59.5% (25/42). Fourteen dogs received a third injection, and the success rate was 42.9% (6/14). Six dogs received a fourth injection, and the success rate was 33.3% (2/6). Two dogs received a fifth injection, and the success rate was 50.0% (1/2). The mean intervals between the first and second, second and third, third and fourth, and fourth and fifth injections were 59.0 ± 78.0 days (range, 14 to 371 days), 79.0 ± 72.0 days (range, 14 to 232 days), 28.0 ± 13.0 days (range, 14 to 42 days), and 39.5 ± 16.3 days (range, 28 to 51 days), respectively (Table 2). The single-injection success rates were lower in American Cocker Spaniels (61.1% [22/36]) and Shih Tzus (63.3% [38/60]) than in other breeds (P < .05; Table 1). The IOP 2 weeks after injection was 8.2 ± 5.9 mm Hg (range, 2 to 25 mm Hg) in the success group and 32.3 ± 13.7 mm Hg (range, 4 to 50 mm Hg) in the failure group. Out of the 23 eyes of the 13 dogs in which bilateral eyes were included, none of the dogs had both eyes failed. None of the dogs in the success group required continuation of glaucoma eye drops. Glaucoma eye drops were continued after injection in 9 dogs in the failure group. In 3 dogs, medication was continued until the final examination. The average time to discontinuation of medication in 6 dogs was 365.8 ± 250.7 days (range, 44 to 723 days). Anti-inflammatory eye drops were continued 3 months after injection in 5 dogs due to chronic uveitis that occurred after the injection in the success group. Postinjection uveitis was controlled with application of anti-inflammatory eye drops twice daily.
When prognostic variables (number of injections, number of glaucoma eye drops, cataract stages, age, sex, breed, preinjection IOP, previous intraocular surgery, intraocular hemorrhage, lens dislocation, and vitreal degeneration) were statistically evaluated, repetition of the procedure, the number of glaucoma eye drop types applied, and cataract stages were significantly correlated with IOPs 6 months after the injection. Dogs that received repeated injections, applied fewer glaucoma eye drop types before injection, and had more advanced cataract stages at the time of injection had significantly higher IOPs 6 months after the final injection (P < .05; Table 4). Other preinjection variables, including age, sex, breed, preinjection IOP, previous intraocular surgery, intraocular hemorrhage, lens dislocation, and vitreal degeneration, did not significantly correlate with postinjection IOP.
The association between prognostic variables and IOP (intraocular pressure) 6 months postinjection
| Prognostic variables | No. of eyes | IOP 6 months postinjection (mean ± SD; mm Hg) |
|---|---|---|
| No. of injection (n = 153) | ||
| 1 | 111 | 5.3 ± 4.2 |
| 2 | 28 | 8.7 ± 7.7 |
| 3 | 8 | 11.0 ± 6.0 |
| 4 | 4 | 14.8 ± 17.1 |
| 5 | 2 | 9.5 ± 7.8 |
| No. of glaucoma eye drops (n = 153)a | ||
| 0 | 2 | 16.0 ± 1.4 |
| 1 | 35 | 9.4 ± 9.3 |
| 2 | 100 | 5.7 ± 4.2 |
| 3 | 16 | 4.1 ± 2.5 |
| Cataract stages (n = 113)b | ||
| 0 | 23 | 4.7 ± 3.6 |
| 1 | 45 | 5.8 ± 3.8 |
| 2 | 45 | 8.2 ± 8.1 |
Cataract stages: 0 = no cataract, 1 = incipient and immature cataracts, 2 = mature and hypermature cataracts.
aNumber of glaucoma eye drops applied until the injection.
bCataract stages at the time of injection.
The most common complication was phthisis bulbi. Phthisis bulbi occurred within 6 months in 65 eyes (42.5%), and the time to phthisis bulbi was 234.2 ± 232.6 days (range, 18 to 1,068 days). The next most common complication was cataract progression (30.1%), followed by intraocular hemorrhage (16.3%), corneal ulceration (7.2%), corneal degeneration (6.5%), and corneal perforation (2.0%). A significant positive correlation was found between the time to phthisis bulbi and the number of injections, and negative correlations were found between the time to phthisis bulbi and age and the number of glaucoma eye drops administered before injection (P < .05; Table 5).
The association between prognostic variables, development of phthisis bulbi, and time to phthisis bulbi.
| Prognostic variables | No. of eyes | No. of eyes with phthisis bulbi (%) | Time to phthisis bulbi (mean ± SD days) |
|---|---|---|---|
| No. of injections (n = 153) | |||
| 1 | 111 | 88 (79.3) | 171.4 ± 166.7 |
| 2 | 28 | 17 (60.7) | 456.1 ± 298.6 |
| 3 | 8 | 3 (37.5) | 586.7 ± 330.1 |
| 4 | 4 | 1 (25.0) | 714.0 ± 0.0 |
| 5 | 2 | 1 (50.0) | 449.0 ± 0.0 |
| Age (y; n = 130)a | |||
| 0–5 | 9 | 5 (55.6) | 247.6 ± 326.6 |
| 6–10 | 48 | 34 (70.8) | 222.6 ± 222.4 |
| 11–15 | 66 | 53 (80.3) | 226.6 ± 208.9 |
| 16–20 | 7 | 6 (85.7) | 142.3 ± 71.5 |
| No. of glaucoma eye drops (n = 153)b | |||
| 0 | 2 | 0 (0.0) | — |
| 1 | 35 | 22 (62.9) | 253.8 ± 247.3 |
| 2 | 100 | 63 (80.8) | 237.3 ± 232.5 |
| 3 | 16 | 14 (87.5) | 186.9 ± 219.1 |
aAge at the time of injection.
bNumber of glaucoma eye drops applied until the injection.
A total of 6 globes were enucleated, and of these, 3 were enucleated due to a grossly enlarged globe and mass of the posterior segment on ocular ultrasonography, not found in the preinjection examination. In 1 eye, an ill-defined hypoechoic structure located behind the sclera was observed, and extraocular myositis, retrobulbar tumor, or retrobulbar abscess was suspected. In another dog, an isoechoic mass attached to the medial aspect of the lens and connected to the iris was observed. In the third dog, a hyperechoic mass in the vitreous chamber with moderate blood signal was observed. All 3 enucleated eyes underwent histopathological examination, and there was no evidence of neoplasia. Two eyes were enucleated after 1 year, and 1 eye was enucleated after 3 years. Histopathological evaluation revealed severe chronic-active diffuse suppurative endophthalmitis and fibrinosuppurative endophthalmitis. The eye diagnosed as having severe chronic-active suppurative endophthalmitis had ongoing endophthalmitis before the injection and had the contralateral eye enucleated due to endophthalmitis and glaucoma a year ago. The eye diagnosed as having fibrinosuppurative endophthalmitis had continuous chronic uveitis for about a year and showed sudden discomfort 2 weeks prior to enucleation. The remaining 3 eyes were enucleated due to corneal perforation. One eye was enucleated 2 days after cidofovir injection because of limbal perforation and suppurative inflammation at the site of aqueous humor paracentesis. The patient had a clinical history of severe exposure keratitis and keratoconjunctivitis sicca. The other eye perforated 4 days after the procedure because of deep corneal ulceration and endophthalmitis. The third eye was enucleated 5 months after experiencing recurrent deep corneal ulcerations. All the enucleated eyes received a single injection of cidofovir.
Twelve dogs displayed a transient but nondurable decrease in IOP. Three dogs had IOPs higher than 25 mm Hg at 6-month recheck after a transient decrease in IOP and were included in the failure group. In 5 dogs, IOPs decreased to below 25 mm Hg after repetition of cidofovir injection or addition of glaucoma eye drops. In 4 dogs, gradual decreases in IOP were observed postinjection after a transient but nondurable decrease without additional treatment or medication.
Discussion
Cidofovir is a cytidine nucleotide analog antiviral drug used to treat cytomegalovirus retinitis in humans.15 Dose-dependent iritis and ocular hypotony were noted in humans as ocular adverse effects of the drug.10,15 Consequently, studies evaluating the IOP and safety after intravitreal administration of the drug in normal guinea pigs and rabbits were conducted, and the results showed species-dependent and dose-dependent effects.11 With higher doses of the drug, decrease in IOP, intraocular inflammation, and damage of the ciliary body and retina were observed. In a study evaluating the dose-dependent effect of intravitreal cidofovir injection in 18 canine globes for 4 weeks, while there was no significant change in IOPs when 100 µg was injected, injection of 500 and 1,000 µg resulted in a permanent decrease in IOPs starting from 3 days after the injection.13 Both groups had the lowest IOP on day 10, and there was no difference between the groups that received 500 and 1,000 µg.
In a previous study8 evaluating the efficacy of 562.5 µg of cidofovir in canine patients with chronic glaucoma, the overall success rate was 97% with a minimum follow-up period of 2 weeks. The overall success rate of intravitreal gentamicin injection was 95% with a minimum follow-up period of 3 months.7 In the current study, the overall success rate was 91.5%, comparable to but lower than the success rates of the previous studies. However, the current study reflected the long-term outcome of the procedure because all eyes required a minimum follow-up period of 6 months from the time of injection. In the present study, the single-injection success rate was 69.3%, and when the injection was repeated up to 5 times, the success rate increased to 91.5%. Repetition of cidofovir injection rather than gentamicin injection or enucleation was chosen after a thorough discussion with the owners. Cidofovir injection was preferred mainly due to the lower volume of drug injected compared to gentamicin injection and better cosmetic outcomes compared to enucleation.
When prognostic variables were statistically evaluated, dogs that received multiple injections had significantly higher IOPs when evaluated 6 months after the injection. Dogs unresponsive to the initial intravitreal cidofovir injection might show a slow decrease in IOPs. Furthermore, dogs with more advanced cataract stages at the time of injection also had higher postprocedural IOPs. Lens-induced uveitis (LIU), or phacolytic uveitis, may be present in eyes with cataracts.16 In the presence of LIU, breakdown of the blood-ocular barrier occurs, and the rate of elimination of drugs from the vitreous may be greater than in normality.17,18 Lens-induced uveitis may also clog the trabecular meshwork with high-molecular-weight lens proteins, materials, or debris.16 Moreover, in chronic uveitis, tissue remodeling might occur and alter the anatomical structure of the aqueous humor drainage pathway.19–22 Although LIU may be present in all stages of cataracts, it is most often associated with advanced stages.23 In a previous study24 on vascular endothelial growth factor concentrations in the aqueous humor, dogs with clinically evident LIU had higher vascular endothelial growth factor concentrations than those with subclinical uveitis. Therefore, the higher elimination rate in advanced cataract stages may have altered the postprocedural IOPs, even when all dogs diagnosed with immature, mature, and hypermature cataracts were being treated with anti-inflammatory eye drops. However, further studies on the correlation between drug clearance rate and the effect of cidofovir between normal and inflammatory eyes should be conducted.
The most prevalent complication of intravitreal cidofovir injection in this study was phthisis bulbi (42.5%). In previous studies, phthisis bulbi occurred in 70% of patients 6 months after cidofovir injection and in 59.2% of patients 3 months after intravitreal gentamicin injection.7,8 Dogs with phthisis bulbi had smaller globe size and opaque cornea due to folding of Descemet membrane and thickened cornea. Entropion was observed in 13 eyes 1 to 3 years after the injection due to phthisis bulbi. Phthisis bulbi occurred within 6 months in 65 eyes, and the average time to phthisis bulbi was 234.2 days. The time to phthisis bulbi was significantly longer in dogs that received multiple injections and fewer preinjection glaucoma eye drops. Phthisis bulbi occurred within a shorter period in older dogs. Lower IOPs with aging have been observed in both humans and dogs.25,26 Decreased aqueous humor formation with aging has been observed in various human studies and presumably occurs due to the senile changes of nonpigmented ciliary body epithelium.27–30 Furthermore, with aging, an increase in particle diffusion due to vitreous liquefaction may occur when drugs are injected intravitreally.31 These senile changes in the canine eye may explain the faster occurrence of phthisis bulbi after cidofovir injections in older dogs.
Six eyes were enucleated, and none showed evidence of neoplasia. In a study32 by the Comparative Ocular Pathology Laboratory of Wisconsin, when 48 canine globes with a history of intravitreal gentamicin injection were submitted for histopathological evaluation, 19 globes were diagnosed with primary ocular tumors and showed malignancy and invasiveness. In another retrospective study of intravitreal cidofovir injection, 1 globe out of 167 globes was enucleated and revealed the development of uveal melanoma 4 months after the injection.8 These results may suggest that the occurrence of ocular tumors after cidofovir injection may be lower than after gentamicin injection. However, the possibility of development of neoplasia after intravitreal injection might not be totally excluded, and periodic monitoring would be recommended.
Although 3 eyes were enucleated due to corneal diseases, the development of corneal ulceration after injection in this study was low. In the current study, corneal ulceration occurred in 7.2% of patients. After intravitreal gentamicin injection, 22.3% of patients had ulcerative keratitis,7 and 2.4% developed superficial corneal ulceration after intravitreal cidofovir injection.8 Hence, intravitreal cidofovir injection did not increase the occurrence of corneal ulceration. In most cases, the coexisting corneal ulceration resolved after cidofovir injection following the resolution of cornea exposure resulting from buphthalmos.
Another factor to consider when evaluating the postinjection IOP is the condition of the ocular surface. Corneal fibrosis, observed in several cases in this study, might have resulted in the overestimation of IOPs due to altered corneal hysteresis and thickness. Several eyes in the current study had IOPs ≥ 25 mm Hg even after repeated injections, yet had no relevant clinical signs of elevated IOP, including episcleral and conjunctival injections, corneal edema, blepharospasm, third eyelid elevation, and changes in the dog’s behavior. In all cases, corneal fibrosis and thickening were examined via slit-lamp biomicroscopy. In humans and dogs, IOP measurements are affected by the biomechanical properties of the cornea.33,34 In dogs, central corneal thickness is reported to alter the measurement of IOPs with both rebound tonometry and applanation tonometry.33 In humans, 3 cases of false positive diagnosis of glaucoma due to corneal fibrosis have been reported.34
In a previous study35 evaluating the success of intravitreal gentamicin, the success rate decreased as the dog’s body weight increased. In the current study, each dog received the same volume of cidofovir, and no association between success rate and body weight was discovered. However, a prospective study should be conducted to evaluate the exact association between body weight and the use of dose. The dose-dependent effect of intravitreal injection of gentamicin and cidofovir has been confirmed.9,11 However, future studies on the precise evaluation of success rate and complications of each injected dose should also be conducted to establish the optimal dosage for successfully lowering IOP with minimal complications.
The limitations of this study include its retrospective nature. Not all variables were controlled for, and certain breeds were overrepresented. Furthermore, only dogs with a minimum follow-up period of 6 months were included in this study. The possibility of dogs experiencing IOP spikes after 6 months cannot be eliminated. Finally, there was a lack of histopathological assessment because only the globes in which enucleation was necessary were subjected to histopathological examination. Future studies on the precise evaluation of success rate and complications of each injected dose should also be conducted to establish the optimal dosage for successfully lowering IOP with minimal complications.
In this study, the long-term efficacy of intravitreal cidofovir injection for end-stage glaucoma was demonstrated in dogs. Postinjection IOPs were higher when the injection was repeated, more types of glaucoma eye drop were applied prior to the injection, and cataract stages were advanced at the time of injection. Phthisis bulbi was the most prevalent complication, but it did not require additional treatment.
Acknowledgments
None reported.
Disclosures
The authors have nothing to disclose. No AI-assisted technologies were used in the generation of this manuscript.
Funding
This study was supported by BK21 FOUR Future Veterinary Medicine Leading Education and Research Center and the Research Institute for Veterinary Science, College of Veterinary Medicine, Seoul National University, Seoul, Republic of Korea. In addition, this research was supported by the Basic Science Research Program through the National Research Foundation of Korea funded by the Ministry of Education (2021R1I1A1A01058695).
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