Long-lasting otic medications may be a rare cause of neurogenic keratoconjunctivitis sicca in dogs

Genia R. Bercovitz Department of Small Animal Medicine and Surgery, College of Veterinary Medicine, University of Georgia, Athens, GA

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Annora M. Gaerig Eye Care for Animals, Chicago, IL

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Emily D. Conway VCA Great Lakes Veterinary Specialists, Warrensville Heights, OH

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Jane Ashley Huey Memphis Veterinary Specialists & Emergency, Cordova, TN

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Mary R. Telle Department of Clinical Sciences, College of Veterinary Medicine, Mississippi State University, Mississippi State, MS

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Renata Stavinohova Lumbry Park Veterinary Specialists, Hampshire, UK

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Giunio Bruto Cherubini Dick White Referrals, Cambridgeshire, UK

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Angelo Capasso Lumbry Park Veterinary Specialists, Hampshire, UK

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Kathern E. Myrna Department of Small Animal Medicine and Surgery, College of Veterinary Medicine, University of Georgia, Athens, GA

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Abstract

OBJECTIVE

To characterize the clinical course and long-term prognosis of a suspected novel cause of neurogenic keratoconjunctivitis sicca (nKCS) secondary to florfenicol, terbinafine hydrochloride, mometasone furoate (Claro and Neptra) or florfenicol, terbinafine, betamethasone acetate (Osurnia).

ANIMALS

29 client-owned dogs.

PROCEDURES

Online survey and word-of-mouth recruitment were conducted to identify dogs that developed clinical signs of nKCS after application of otitis externa medication containing terbinafine and florfenicol. A retrospective analysis of medical records of dogs meeting inclusion criteria was then conducted. Included dogs had onset of clinical signs of nKCS within 1 day after application of otitis externa medications containing terbinafine and florfenicol and had documentation of low Schirmer tear test value (< 15 mm/min) of affected eyes.

RESULTS

29 dogs with medical records available for review met the inclusion criteria. Documented return of clinically normal tear production was identified in 24 of 29 dogs, with a median time from application of ear medication to documented return of clinically normal tear production of 86 days (range, 19 to 482 days). A corneal ulcer was diagnosed in 68% (20/29). Multivariable Cox regression analysis showed being referred to an ophthalmologist (P = .03) and having a deep ulcer (P = .02) were associated with a longer time to documentation of Schirmer tear test ≥ 15 mm/min.

CLINICAL RELEVANCE

Dogs that developed nKCS within 1 day after application of otitis externa medications containing terbinafine and florfenicol had a good prognosis for return of normal tear production within 1 year.

Abstract

OBJECTIVE

To characterize the clinical course and long-term prognosis of a suspected novel cause of neurogenic keratoconjunctivitis sicca (nKCS) secondary to florfenicol, terbinafine hydrochloride, mometasone furoate (Claro and Neptra) or florfenicol, terbinafine, betamethasone acetate (Osurnia).

ANIMALS

29 client-owned dogs.

PROCEDURES

Online survey and word-of-mouth recruitment were conducted to identify dogs that developed clinical signs of nKCS after application of otitis externa medication containing terbinafine and florfenicol. A retrospective analysis of medical records of dogs meeting inclusion criteria was then conducted. Included dogs had onset of clinical signs of nKCS within 1 day after application of otitis externa medications containing terbinafine and florfenicol and had documentation of low Schirmer tear test value (< 15 mm/min) of affected eyes.

RESULTS

29 dogs with medical records available for review met the inclusion criteria. Documented return of clinically normal tear production was identified in 24 of 29 dogs, with a median time from application of ear medication to documented return of clinically normal tear production of 86 days (range, 19 to 482 days). A corneal ulcer was diagnosed in 68% (20/29). Multivariable Cox regression analysis showed being referred to an ophthalmologist (P = .03) and having a deep ulcer (P = .02) were associated with a longer time to documentation of Schirmer tear test ≥ 15 mm/min.

CLINICAL RELEVANCE

Dogs that developed nKCS within 1 day after application of otitis externa medications containing terbinafine and florfenicol had a good prognosis for return of normal tear production within 1 year.

Introduction

Neurogenic keratoconjunctivitis sicca (nKCS) is a historically rare and uniquely presenting form of dry eye caused by the loss of efferent innervation to the lacrimal gland.1 This can lead to acute, complete loss of the aqueous portion of the tear film. These dogs typically present with unilateral, severe ocular discomfort and a Schirmer tear test (STT) value of close to zero. Concurrent ipsilateral xeromycteria and secondary corneal ulcerations are common. Efferent innervation begins in the rostral salivatory nucleus of the medulla oblongata, where the greater petrosal nerve, composed of preganglionic parasympathetic fibers, runs with postganglionic sympathetic fibers of the deep petrosal nerve.1 These fibers synapse on the pterygopalatine ganglion. Reported causes of preganglionic lesions resulting in nKCS include otitis media or interna1 and petrositis.2 Postganglionic fibers run with the trigeminal nerve to innervate the nasal glands and the lacrimal gland.1,2 Reported causes of postganglionic lesions include total ear canal ablation and bulla osteotomy, orbital trauma, myositis, abscesses, and dental disease.13 Causes of nKCS that could affect both the pre- and postganglionic pathways include idiopathic1,2,47 endocrinopathies such as hypothyroidism1,811 and diabetes mellitus,1,12,13 trauma,1 and intracranial neoplasia.1

Long-lasting otic medications containing terbinafine and florfenicol for treatment of canine otitis externa caused by susceptible strains of yeast (Malassezia pachydermatis) and bacteria (Staphylococcus pseudintermedius)1416 have been recently introduced in the veterinary market. These medications include formulations containing florfenicol, terbinafine hydrochloride, and mometasone furoate (Claro and Neptra) or florfenicol, terbinafine, betamethasone acetate (Osurnia). Claro is available in the US, and Neptra is available outside of the US. With each of these commercially available formulations, the product is deposited directly into the external ear canal and then absorbed over time, replacing the need for daily treatment. A perforated tympanic membrane is a contraindication for use.14,15

Due to the anatomic route of the facial nerve through the middle ear, otitis media is associated with development of nKCS.2 Components of the long-lasting otic medications have been shown to cause damage to the tympanic membrane or inner ear. For example, Osurnia has been shown to cause vesicle formation in the epithelium of canine tympanic membranes.17 These changes occurred in 2 dogs that received the medication at the recommended dose and in 4 dogs that received the medication at 5 times the recommended dose, both following 6 applications over 5 weeks. Aydın et al18 showed hearing loss in rats following intratympanic administration of terbinafine, demonstrated by increases in auditory brainstem response thresholds. The authors hypothesized that otic medications inadvertently administered intratympanically could result in damage to the facial nerve and, consequently, nKCS.

Recently, the authors recognized a pattern in which dogs were presented with nKCS within 1 day after administration of long-lasting otic medications. The purpose of the study reported here was to characterize the clinical course and long-term prognosis of a suspected novel cause of neurogenic keratoconjunctivitis sicca (nKCS) secondary to long-lasting ear medications in canines, define clinical characteristics and prognosis, and postulate a pathological location along the efferent pathway.

Materials and Methods

From September 2020 to February 2022, communication on the American College of Veterinary Ophthalmologists’ diplomate listserv and online surveys distributed to veterinarians were used to identify dogs that exhibited signs of nKCS following application of long-acting otic medications. Two surveys were created, one distributed to the University of Georgia Veterinary Teaching Hospital’s alumni network and another through the Veterinary Information Network (VIN) membership network. These surveys were used as a tool to identify dogs with signs of nKCS following application of otitis externa medications containing terbinafine and florfenicol. When dogs were reported via the surveys, the reporting veterinarian was contacted to request medical records for the reported dog for retrospective review. Not all veterinarians that reported dogs on the surveys permitted personal contact or responded to requests. Additionally, not all dogs met the inclusion criteria. Therefore, the number of reported dogs in the surveys was larger than the included dogs in this study. Any dog reported in the surveys that did not have medical records available for review or did not meet the inclusion criteria was not included in the statistical analysis.

The inclusion criteria were as follows: (1) ocular signs consistent with nKCS; (2) onset of these clinical signs within 1 day after application of florfenicol, terbinafine hydrochloride, mometasone furoate (Claro or Neptra) or florfenicol, terbinafine, betamethasone acetate (Osurnia); and (3) STT performed during the care of the dog that demonstrated a low value (< 15 mm/min). Clinical signs consistent with nKCS were severe and included acute onset of at least one of the following: conjunctival hyperemia, increased mucoid ocular discharge, blepharospasm, chemosis, or blepharitis. A low STT was not required at the onset of clinical signs but was required at some point during the care of the dog. Documentation of a dry nostril was not required. These leniencies were extended due to the novelty of this reaction and because an STT is often unsafe to perform in a fragile eye with a corneal ulcer. Data collected included geographic location, age at presentation, gender, breed, STT values, ocular and neurologic clinical signs at presentation, diagnostics to evaluate otitis externa or systemic health, concurrent systemic diseases, treatment, and progression. Time until return to normal tear production was defined as the number of days from application of the ear medication to documentation of an STT value ≥ 15 mm/min regardless of whether or not the dog remained on topical medications. Breeds were grouped by weight into small, medium, and large. To evaluate the relationship between referral to an ophthalmologist and ulcer type, the types of ulcers were regrouped for statistical analysis. Dogs with no corneal ulcer or a superficial corneal ulcer were grouped together as “no deep ulcer,” and dogs with stromal ulcers or descemetoceles were grouped together as “deep ulcers.”

Statistical analysis

All analyses were performed with standard software (SAS version 9.4; SAS Institute Inc). A significance threshold of 0.05 was used. A Kaplan-Meier curve was constructed for the return of tear production. Median time of documentation of return of normal tear production with 95% CI was computed. Log-rank tests were used to test for differences in normality times due to presence of ulcer, presence of a deep ulcer, use of pilocarpine, small- versus medium-sized breed, presence of neurologic clinical signs, type of ear medication, use of lacrimostimulants, and whether referred to an ophthalmologist. The P values were adjusted for multiplicity using the false discovery methods of Benjamini and Hochberg.19 A Cox proportional hazards model was used to test for a relationship of age with time until documentation of normal tear production, and a multivariable Cox proportional hazards model was used to test for associations of an ophthalmology referral and presence of a deep ulcer with time until normal tear production.

Results

Responses from both the VIN and University of Georgia surveys were obtained from veterinarians worldwide. Thirty-three veterinarians reported 40 dogs that developed clinical signs consistent with nKCS within 1 day after application of otitis externa medications containing terbinafine and florfenicol via the VIN survey. Six veterinarians reported 7 dogs that developed clinical signs consistent with nKCS within 1 day after application of the long-lasting otic medication through the University of Georgia alumni network survey. Ophthalmologists also reported cases via word-of-mouth recruitment on the American College of Veterinary Ophthalmologists’ diplomate listserv.

All veterinarians reporting adverse events through these 3 channels were then contacted for medical records. The records were reviewed, and only dogs that met the inclusion criteria were included for further analysis. Any dogs reported by veterinarians via the surveys or American College of Veterinary Ophthalmologist’s diplomate listserv that did not have medical records available for review or had medical records that indicated the dog did not meet the inclusion criteria were not included in the following summary statistics or analysis.

A total of 29 dogs and 37 affected eyes fulfilled the inclusion criteria. Twenty-four dogs were located in the US, and 5 dogs were located outside of the US (Supplementary Table S1). Small-breed dogs comprised 76% (22/29) of the included dogs, and 24% (7/29) were medium-sized breeds (Supplementary Table S2). Of the included dogs, 24 of 29 had documented return of normal tear production within the study follow-up period (by February 2022). For the 24 of 29 dogs that regained tear production, the median time from application of otitis externa medications containing terbinafine and florfenicol to documented return of tear production in dogs was 86 days (range, 19 to 482 days). Dogs with bilateral disease had return of normal tear production in both eyes at the same time. Of the 5 dogs that did not have documented return of normal tear production, 3 of 5 were lost to follow-up, and 2 of 5 dogs were initially diagnosed within 1 month of statistical evaluation. These 2 dogs were included in summary data reported regarding clinical signs but excluded from analysis regarding “time to documentation of return of normal tear production” due to the short follow-up period.

All dogs were initially presented (prior to application of the ear medication) for clinical signs consistent with otitis externa, and all dogs were diagnosed with otitis externa via cytology demonstrating bacteria, yeast, or both. Concurrent systemic pathology documented at the time of diagnosis of otitis externa included atopy (13/29 [45%]), cardiac murmur (4/29 [14%]), dental disease (2/29 [7%]), and an inflammatory enteropathy (1/29 [3.5%]). No ocular disease was documented prior to application of the ear medication in any dog.

An attempt to evaluate the tympanic membrane prior to medication application was documented in 45% (13/29) of dogs. An intact tympanic membrane was documented in 7 of 13 (54%) dogs, and the tympanic membrane could not be visualized in the remaining 6 of 13 (46%) dogs.

Claro was administered to 19 of 29 dogs, Osurnia to 5 of 29, and Neptra to 5 of 29. A long-lasting ear medication had been applied previously in 6 of 29 dogs in one or both ears without an adverse event. The median time until documented return to normal tear production that received Claro, Osurnia, and Neptra available for 24 of 29 dogs was 87 days, 102 days, and 134.5 days, respectively, though the difference was not significant (P = .92).

Initial clinical signs were documented within 24 hours of application of the ear medication in all dogs. The most common clinical signs noted by owners were ocular discharge (18/29 [62%]), blepharospasm (16/29 [55%]), a swollen appearance to the eye(s) (10/29 [34%]), pawing at the face or affected eye(s) (8/29 [28%]), hyporexia (6/29 [20%]), lethargy (5/29 [17%]), vomiting (4/29 [14%]), a red eye (4/29 [14%]), licking at nostrils (2/29 [7%]), and body shaking (2/29 [7%]). The median time from onset of clinical signs to documentation of a low STT was 13 days (range, 0 to 35 days; mean, 13 days). Initial STT values were 0 mm/min in 32 of 37 affected eyes, and the remaining 5 affected eyes had STTs of 2, 6, 7, 9, and 11 mm/min.

Ipsilateral xeromycteria was noted in 14 of 29 dogs, and the remaining dogs did not have records that commented on the lubrication of the ipsilateral nostril. In 34% (10/29) of dogs, concurrent neurologic abnormalities were reported. Eight of 10 dogs exhibited vestibular disease (vestibular ataxia in 6 of 8 dogs, head tilt in 1 of 8 dogs, and horizontal nystagmus in 1 of 8 dogs). Facial nerve paralysis ipsilateral to the affected eye was noted in 1 of 10 dogs and hearing loss in 2 of 10 dogs. Facial nerve paralysis and vestibular disease were reported to resolve in all dogs. Records of the precise timing of the resolution of the neurologic abnormalities in relation to regaining normal lacrimation were not available. The median time until normal tear production was documented in dogs that did or did not develop neurologic signs was 76.5 days (range, 19 to 212 days) or 102 days (range, 37 to 129 days), respectively, though this was not significant (P = .92).

The mean and median age at presentation was 7.9 years and 9 years, respectively (range, 0.9 to 13 years). Eighteen dogs were male (12/18 [67%] neutered), and 11 dogs were female (11/11 [100%] spayed). Shih Tzu or Shih Tzu–predominant mixed-breed dogs (6/29 [21%]) and Chihuahua or Chihuahua-predominant mixed-breed dogs (3/29 [7%]) were reported most commonly (Supplementary Table S2). There was no significant difference in median time to return of normal tear production based on age (P = .17) or weight (P = .92). The right eye was affected in 11 dogs, the left eye in 10 dogs, and both eyes in 8 dogs. Dogs for which an ear medication was applied to both ears did not necessarily demonstrate bilateral ocular disease (Table 1). Systemic evaluation was pursued in 15 of 29 dogs. Abnormal findings included high concentrations of ALP (3 dogs), ALT (2 dogs), and AST (1 dog); hypoglycemia (1 dog); otic bacterial culture consistent with Methicillin-resistant Staphylococcus aureus (1 dog); and head MRI that revealed bilateral moderate fluid accumulation in the tympanic bullae (1 dog).

Table 1

Summary of the laterality of ear or ears treated for otitis externa with a commercially available long-lasting topical otic product containing terbinafine and florfenicol and the eyes affected with neurogenic keratoconjunctivitis sicca within 1 day after otic treatment between September 2020 and February 2022 for 29 client-owned dogs.

Affected eyes Treated ears No. of dogs
AS AD AU
OD 0 6 5 11
OS 4 0 6 10
OU 0 0 8 8
Total 4 6 19 29

Note that when the ear medication was applied to both ears, it did not necessarily result in ocular abnormalities in both eyes.

AD = Right ear. AS = Left ear. AU = Both ears. OD = Right eye. OS = Left eye. OU = Both eyes.

A corneal ulcer was diagnosed on initial examination following application of the ear medication in 23 eyes of 20 dogs. Dogs that developed a corneal ulcer regained STT ≥ 15 mm/min in a median of 102 days (range, 51 to 141 days). Dogs that did not develop a corneal ulcer regained STT ≥ 15 mm/min in a median of 68 days (range, 37 to 129 days), though this was not significant (P = .82). Superficial ulcers were diagnosed in 14 of the 23 ulcerated eyes and healed (defined as a negative fluorescein stain) in a mean of 28 days (range, 8 to 64 days). Stromal ulcers were diagnosed in 4 eyes of 4 dogs and healed in a mean of 40 days (range, 11 to 92 days); however, 1 eye underwent a conjunctival graft and 1 eye was enucleated. Descemetoceles were diagnosed in 5 eyes of 4 dogs, and all were treated with corneo-conjunctival transposition grafts or conjunctival grafts. Healing occurred in a mean of 24 days (range, 17 to 30 days) from application of ear medication.

A total of 8 dogs (9 eyes) with deep corneal ulcers (4 eyes with stromal ulcers and 5 eyes with descemetoceles) had a median time until documentation of STT ≥ 15 mm/min of 212 days (range, 99 to 482 days), compared to 68 days (range, 37 to 87 days) for those (21/29) without a deep ulcer (P = .003; log rank). Dogs with a deep ulcer in one or both eyes had significantly (P = .001) longer median time to documentation of STT ≥ 15 mm/min.

Nineteen dogs were referred to an ophthalmologist. Of those, 9 eyes from 8 dogs demonstrated deep ulcers, 8 eyes from 8 dogs demonstrated superficial ulcers, and 8 eyes from 7 dogs did not develop an ulcer. Referral to an ophthalmologist was associated with significantly (P = .001) longer median time to documentation of return of normal STT (111 days) compared to the dogs that were not referred (37 days; Figure 1). Of the eyes that did not develop an deep corneal ulcer that were treated by an ophthalmologist, a significantly (P = .01) longer median time to return of normal STT was noted (median, 85 days; 95% CI, 51 to 141 days) compared to those eyes that were treated by primary care veterinarians (median, 37 days; 95% CI, 19 to 51 days).

Figure 1
Figure 1

Kaplan-Meier curve demonstrating the duration between the treatment of otitis externa with a commercially available long-lasting topical otic product containing terbinafine and florfenicol and the subsequent detection of return to clinically normal tear production (Schirmer tear test [STT] value ≥ 15 mm/min) for 29 client-owned dogs that were treated between September 2020 and February 2022, had onset of clinical signs of neurogenic keratoconjunctivitis sicca within 1 day after otic treatment, and grouped by whether they were not referred to an ophthalmologist and did not have a deep corneal ulcer (group 1; solid line; n = 10), were referred to an ophthalmologist but had no deep corneal ulcer (group 2; dashed line; 11), or were referred to an ophthalmologist and had a deep corneal ulcer (group 3; dashed and dotted line; 8) as reported in the medical records. Each step represents documentation of STT ≥ 15 mm/min for ≥ 1 dog; crosses represent censored dogs (dogs lost to follow-up). The number of dogs with low tear production (STT < 15 mm/min) for each group at each benchmark day is listed under the x-axis.

Citation: Journal of the American Veterinary Medical Association 261, 1; 10.2460/javma.22.07.0301

Multivariable Cox regression analysis showed that dogs having been referred to an ophthalmologist (hazard ratio [HR], 3.0; 95% CI, 3.0 [1.1 to 8.2]; P = .03) or with a deep ulcer (HR, 5.3; 95% CI, 1.4 to 20.1; P = .02) were each associated with a longer time to documentation of an STT value ≥ 15 mm/min. Since referral is a potential confounding factor, univariable analyses were performed. The time until dogs with or without a deep ulcer regained normal tear production was significantly (HR, 6.2; 95% CI, 1.6 to 23.8; P = .003) longer when referred to an ophthalmologist than when not referred. This analysis demonstrated a larger HR and smaller P value than the multivariate analysis. Dogs that had a nondeep ulcer had a significantly (HR, 3.6; 95% CI, 1.3 to 10.4; P = .02) longer time until return of normal tear production when referred to an ophthalmologist than when not referred. This indicated that dogs with a nondeep ulcer referred to an ophthalmologist had longer times until documentation of normal tear production than those with a nondeep ulcer and not referred. This analysis demonstrated a larger HR and the same P value than the multivariable analysis.

The median time from otic medication application to return of normal tear production for those that received or did not receive pilocarpine was 99 days (range, 51 to 118 days) or 68 days (range, 28 to 330 days), respectively, though this was not significant (P = .92). The median time from application of an ear medication to starting pilocarpine was 21 days (range, 7 to 36 days). The mean and median times from prescription of pilocarpine until documentation of return of normal tear production were 63 and 99 days (range, 5 to 456 days), respectively. Oral administration of pilocarpine was prescribed in 12 of 19 dogs and topical in 7 of 19 dogs. Of the dogs that were prescribed pilocarpine, 14 of 19 were weaned off pilocarpine in a median of 92 days (range, 39 to 490 days) and the remaining 5 of 19 dogs were lost to follow-up.

Dogs received a variety of combinations of ancillary medications including topical ophthalmic antimicrobials (24 dogs), oral antimicrobials (13 dogs), and topical immunomodulatory lacrimostimulants (14 dogs). Of the dogs prescribed immunomodulatory lacrimostimulants, 8 of 14 were prescribed cyclosporine and 6 of 14 were prescribed tacrolimus. The median time to normal tear production for those that received and did not receive immunomodulatory lacrimostimulants was 99 and 86 days, respectively, though this was not significant (P = .92).

Discussion

Our findings suggested that nKCS is a rare potential adverse effect of otitis externa medications containing terbinafine and florfenicol. The median time from application of ear medication to documented return of tear production was 86 days (range, 19 to 482 days) for the 24 dogs with long-term follow-up. The remaining 5 of the 29 included dogs were lost to follow-up or had insufficient follow-up.

The efferent lacrimal gland innervation pathway is complex. Pathology at any point along this pathway can result in nKCS. Toshida et al20 demonstrated that the transection of the superficial petrosal nerve in rabbits led to loss of tear production and a decrease in lacrimal gland size immediately and for at least 7 days, without development facial nerve paralysis. Jin et al21 demonstrated that denervation of postganglionic fibers in mice led to decreased basal tear secretion immediately and for at least 7 days.

Only a fraction of included dogs had reported clinical signs that aided in neurolocalization. Xeromycteria implied damage between the rostral salivatory nucleus and the pterygopalatine ganglion.2 Xeromycteria was noted in only 14 of 29 dogs. Damage may have been sustained along the ophthalmic division of the trigeminal nerve in dogs that did not develop xeromycteria.4 Alternatively, xeromycteria may have been present but not documented. Two dogs were presented with hearing loss, which suggested damage to the inner ear, though most dogs did not have documented clinically appreciable hearing loss. Further, facial nerve paralysis was noted in 1 dog, suggesting a preganglionic lesion. Ultimately, determining the pathological location along the pathway of innervation was difficult.

The presumed cause of nKCS in these dogs was penetration of the medication into the middle ear through a perforated tympanic membrane. Visualization of the tympanic membrane does not eliminate the risk of neurotoxicity, since small defects in the tympanic membrane could be present or otitis could progress to tympanic membrane compromise following administration. Nonetheless, the authors strongly recommend that veterinarians comply with label recommendations and perform an evaluation of the tympanic membrane prior to application of otitis externa medications containing terbinafine and florfenicol. Ototoxicity to aminoglycosides may be due to the A1555G mutation.22 It is possible the dogs that sustained hearing loss were more sensitive to these medications than others due to a common mutation.

An alternative etiology for the corneal ulcers was chemical injury from medication splatter if the dog shook its head immediately after application.23 No records of included dogs documented immediate head shaking after the application of the medication. The pH of Claro is acidic at 4.0 to 6.0. Acidic corneal contact irritants typically result in superficial, nonprogressive corneal ulcers because protein coagulation in the corneal epithelium limits further penetration of the acid.24 Discordantly, 8 dogs developed rapidly progressing deep ulcers. Due to the loss of the antimicrobial properties and proteinase inhibitors normally found in the aqueous portion of the tear film, dogs with KCS of any etiology are prone to developing corneal ulcers that can quickly progress in depth.25,26 In humans, KCS triggers an inflammatory response, which in turn activates transcription factors that result in expression of matrix metallic proteases, which play a pathological role in KCS.26 This can result in rapid stromal loss in the absence of infectious organisms. The loss of globulins and the flushing action of the tears place corneal ulcers in KCS dogs at risk for infection.2 Finally, given that nKCS developed in all dogs and corneal ulcers are a sequela of nKCS, the authors suspect the ulcers were secondary to nKCS rather than accidental and undocumented chemical corneal injury.

The median time until return of normal tear production in nonreferral dogs was less than referral dogs, even in those dogs that were referred without a corneal ulcer. Primary care veterinarians tended to recheck in shorter time frames (days to weeks) as compared to ophthalmologists (weeks to months). There also may have been factors related to severity other than ulceration confounding the relationship between time to return of normal tear production and referral to ophthalmologist that were not analyzed. The literature on nKCS reflects differing times until return of normal tear production. In the nKCS retrospective by Matheis et al,5 the median time until dogs discontinued medication for treatment of nKCS (available for 4 of 11 included dogs) was 125 days (range, 84 to 204 days). Similarly, Galley et al7 reported return of normal tear production in 11 of 23 dogs with nKCS in a mean of 115 days. Conversely, Wegg et al6 found that the mean time until return of normal tear production in dogs with nKCS was 24 ± 5.1 days, and 4 of 11 dogs had medications discontinued in a median of 72 days (range, 28 to 356 days). It is important to note that time to return to normal tear production while on pilocarpine (or other) treatment (equivalent time to resolution of clinical signs of nKCS while on treatment) is a different outcome variable than time to resolution of nKCS (defined as maintenance of normal tear production after discontinuation of all lacrimostimulant medical treatment, which implies return of normal nerve function). Sooner reevaluation for dogs that developed nKCS secondary to otitis externa medications containing terbinafine and florfenicol may be indicated compared to nKCS dogs not associated with long-acting otic medication administration.

The direct-acting parasympathomimetic drug pilocarpine is the traditional choice for treatment of nKCS. The mechanism of action and proposed benefit of this medication is to directly stimulate the lacrimal gland to produce tears during the period when the nerve is not functioning, thereby alleviating the clinical signs of nKCS that result in discomfort and corneal damage. Pilocarpine is not expected to have any therapeutic benefit in repairing nerve damage. Nineteen of the dogs in this study were prescribed pilocarpine. Most dogs in this study regained normal tear function, whether or not pilocarpine was prescribed, consistent with spontaneous resolution of nerve dysfunction. There was no significant (P = .92) difference in time from ear medication administration to documentation of normal tear production between those treated with pilocarpine and those not treated with pilocarpine. The authors caution, however, that these results do not indicate pilocarpine slowed down healing time and therefore is not recommended. Inherent in the limitations of a retrospective evaluation, tear production was not assessed daily, so the precise time until return of normal tear production was unknown. Further, time until dogs regained comfort was not assessed, as this is a subjective estimation and often not included in medical records. Further research is warranted to determine how soon comfort is restored with and without pilocarpine for nKCS treatment and its relation to STT values.

Limitations of this study were inherent in its retrospective design and small sample size. Ideally, complete systemic evaluations for other causes of nKCS, such as hypothyroidism or diabetes mellitus, would have been performed. In addition, nerve damage due to progression of otitis despite treatment rather than as a result of medication application cannot be excluded for all dogs, though the onset of signs of nKCS within 1 day after medication application in dogs with no previous ophthalmic signs suggests causal relationship. Small sample size and retrospective data limited power to detect differences in time to clinical improvement based on specific ear medication formulation, specific ophthalmic treatments, or time to starting treatments. Finally, STT values were not documented at the onset of the clinical signs in every patient, resulting in a delayed diagnosis.

The authors recommend advising clients to monitor for signs of nKCS following use of otitis externa medications containing terbinafine and florfenicol. Clinical signs include blepharospasm, ocular discharge, third eyelid elevation, conjunctivitis, or a dry naris, often with dry, crusted debris partially occluding the ipsilateral nostril. If observed, the authors recommend immediate reexamination with STT and fluorescein staining, as rapid progression to sight- and globe-threatening ulceration is possible. Osurnia has been shown to be absorbed through healthy canine skin in 1 day, and cerumen accumulation may act as a reservoir for further medication release.27 Therefore, cleaning of the medication from the ear canal is recommended to prevent further absorption of the medication if clinical signs of nKCS are noted. For further treatment recommendations for otitis media, readers are referred to dermatology texts.28 Initiation of treatment for nKCS with frequent topical lubrication and lacrimostimulant treatment is recommended. If a corneal ulcer is diagnosed, topical ophthalmic antimicrobials and systemic analgesics are recommended. Evaluation for concurrent neurologic abnormalities should be pursued. Clients should be advised that those that develop deep corneal ulcers may have longer healing times. Referral to an ophthalmologist for surgical stabilization of the cornea is recommended if deep corneal ulcers are noted.

In conclusion, the authors recommend advising clients of this rare occurrence prior to the application of otitis externa medications containing terbinafine and florfenicol. Based on these results, nKCS sustained within 24 hours of application of otitis externa medications containing terbinafine and florfenicol has a good prognosis for return of normal tear production within 1 year following application of the medication.

Supplementary Materials

Supplementary materials are posted online at the journal website: avmajournals.avma.org

Acknowledgments

The authors declare that there were no conflicts of interest, and no third-party funding or support was received in connection with this study or the writing or publication of the manuscript.

The authors thank Dr. Deborah Keys for her statistical evaluations, Dr. Mark Rishniw for his help developing the VIN.com survey, and Mrs. Katy Wilkins for her help developing the UGA alumni network survey.

This project was presented at the 2021 American College of Veterinary Ophthalmologists Conference.

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