Bercovitz Long-lasting otic medications may be a rare cause of neurogenic keratoconjunctivitis sicca in dogs ijavma-javma.22.07.0301.pdf

Long-lasting otic medications may be a rare cause of neurogenic keratoconjunctivitis sicca in dogs Genia R. Bercovitz, VMD1*; Annora M. Gaerig, DVM, MPH, DACVO2; Emily D. Conway, BVMS, MS, MRCVS, DACVO3; Jane Ashley Huey, DVM, MS, DACVO4; Mary R. Telle, DVM, MS, DACVO5; Renata Stavinohova, MVDr, PhD...

Long-lasting otic medications may be a rare cause of neurogenic keratoconjunctivitis sicca in dogs Genia R. Bercovitz, VMD1*; Annora M. Gaerig, DVM, MPH, DACVO2; Emily D. Conway, BVMS, MS, MRCVS, DACVO3; Jane Ashley Huey, DVM, MS, DACVO4; Mary R. Telle, DVM, MS, DACVO5; Renata Stavinohova, MVDr, PhD, PGCertSAOphthal, DipECVO, MRCVS6; Giunio Bruto Cherubini, DVM, DECVN, FRCVS7; Angelo Capasso, DVM, MSc, MRCVS6; Kathern E. Myrna, DVM, MS, DACVO1 1Department of Small Animal Medicine and Surgery, College of Veterinary Medicine, University of Georgia, Athens, GA 2Eye Care for Animals, Chicago, IL 3VCA Great Lakes Veterinary Specialists, Warrensville Heights, OH 4Memphis Veterinary Specialists & Emergency, Cordova, TN 5Department of Clinical Sciences, College of Veterinary Medicine, Mississippi State University, Mississippi State, MS 6Lumbry Park Veterinary Specialists, Hampshire, UK 7Dick White Referrals, Cambridgeshire, UK *Corresponding author: Dr. Bercovitz ([email protected]) doi.org/10.2460/javma.22.07.0301 OBJECTIVE To characterize the clinical course and long-term prognosis of a suspected novel cause of neurogenic keratoconjunc- tivitis 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 document- ed 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 hav- ing 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. N eurogenic keratoconjunctivitis sicca (nKCS) is a historically rare and uniquely presenting form of dry eye caused by the loss of efferent innervation to of the deep petrosal nerve.1 These fibers synapse on the pterygopalatine ganglion. Reported causes of preganglionic lesions resulting in nKCS include the lacrimal gland.1 This can lead to acute, complete otitis media or interna1 and petrositis.2 Postgangli- loss of the aqueous portion of the tear film. These onic fibers run with the trigeminal nerve to innervate dogs typically present with unilateral, severe ocular the nasal glands and the lacrimal gland.1,2 Reported discomfort and a Schirmer tear test (STT) value of causes of postganglionic lesions include total ear close to zero. Concurrent ipsilateral xeromycteria and canal ablation and bulla osteotomy, orbital trauma, secondary corneal ulcerations are common. Efferent myositis, abscesses, and dental disease.1–3 Causes of innervation begins in the rostral salivatory nucleus of nKCS that could affect both the pre- and postgangli- the medulla oblongata, where the greater petrosal onic pathways include idiopathic1,2,4–7 endocrinopa- nerve, composed of preganglionic parasympathetic thies such as hypothyroidism1,8–11 and diabetes mel- fibers, runs with postganglionic sympathetic fibers litus,1,12,13 trauma,1 and intracranial neoplasia.1 JAVMA | JANUARY 2023 | VOL 261 | NO. 1 97 Unauthenticated | Downloaded 06/01/24 01:34 AM UTC  Long-lasting otic medications containing terbi- view. Not all veterinarians that reported dogs on the nafine and florfenicol for treatment of canine otitis surveys permitted personal contact or responded to externa caused by susceptible strains of yeast (Mal- requests. Additionally, not all dogs met the inclusion assezia pachydermatis) and bacteria (Staphylococ- criteria. Therefore, the number of reported dogs in cus pseudintermedius)14–16 have been recently intro- the surveys was larger than the included dogs in this duced in the veterinary market. These medications study. Any dog reported in the surveys that did not include formulations containing florfenicol, terbin- have medical records available for review or did not afine hydrochloride, and mometasone furoate (Claro meet the inclusion criteria was not included in the and Neptra) or florfenicol, terbinafine, betametha- statistical analysis. sone acetate (Osurnia). Claro is available in the US, The inclusion criteria were as follows: (1) ocular and Neptra is available outside of the US. With each signs consistent with nKCS; (2) onset of these clinical of these commercially available formulations, the signs within 1 day after application of florfenicol, ter- product is deposited directly into the external ear ca- binafine hydrochloride, mometasone furoate (Claro nal and then absorbed over time, replacing the need or Neptra) or florfenicol, terbinafine, betamethasone for daily treatment. A perforated tympanic mem- acetate (Osurnia); and (3) STT performed during the brane is a contraindication for use.14,15 care of the dog that demonstrated a low value (< 15 Due to the anatomic route of the facial nerve mm/min). Clinical signs consistent with nKCS were through the middle ear, otitis media is associated severe and included acute onset of at least one of with development of nKCS.2 Components of the the following: conjunctival hyperemia, increased mu- long-lasting otic medications have been shown to coid ocular discharge, blepharospasm, chemosis, or cause damage to the tympanic membrane or inner blepharitis. A low STT was not required at the onset ear. For example, Osurnia has been shown to cause of clinical signs but was required at some point dur- vesicle formation in the epithelium of canine tympan- ing the care of the dog. Documentation of a dry nos- ic membranes.17 These changes occurred in 2 dogs tril was not required. These leniencies were extended that received the medication at the recommended due to the novelty of this reaction and because an dose and in 4 dogs that received the medication at 5 STT is often unsafe to perform in a fragile eye with times the recommended dose, both following 6 ap- a corneal ulcer. Data collected included geographic plications over 5 weeks. Aydın et al18 showed hearing location, age at presentation, gender, breed, STT loss in rats following intratympanic administration of values, ocular and neurologic clinical signs at pre- terbinafine, demonstrated by increases in auditory sentation, diagnostics to evaluate otitis externa or brainstem response thresholds. The authors hypoth- systemic health, concurrent systemic diseases, treat- esized that otic medications inadvertently adminis- ment, and progression. Time until return to normal tered intratympanically could result in damage to the tear production was defined as the number of days facial nerve and, consequently, nKCS. from application of the ear medication to documen- Recently, the authors recognized a pattern in tation of an STT value ≥ 15 mm/min regardless of which dogs were presented with nKCS within 1 day whether or not the dog remained on topical medi- after administration of long-lasting otic medications. cations. Breeds were grouped by weight into small, The purpose of the study reported here was to char- medium, and large. To evaluate the relationship be- acterize the clinical course and long-term prognosis tween referral to an ophthalmologist and ulcer type, of a suspected novel cause of neurogenic keratocon- the types of ulcers were regrouped for statistical junctivitis sicca (nKCS) secondary to long-lasting ear analysis. Dogs with no corneal ulcer or a superficial medications in canines, define clinical characteristics corneal ulcer were grouped together as “no deep ul- and prognosis, and postulate a pathological location cer,” and dogs with stromal ulcers or descemetoceles along the efferent pathway. were grouped together as “deep ulcers.” Materials and Methods Statistical analysis All analyses were performed with standard soft- From September 2020 to February 2022, com- ware (SAS version 9.4; SAS Institute Inc). A signifi- munication on the American College of Veterinary cance threshold of 0.05 was used. A Kaplan-Meier Ophthalmologists’ diplomate listserv and online curve was constructed for the return of tear pro- surveys distributed to veterinarians were used to duction. Median time of documentation of return of identify dogs that exhibited signs of nKCS follow- normal tear production with 95% CI was computed. ing application of long-acting otic medications. Two Log-rank tests were used to test for differences in surveys were created, one distributed to the Univer- normality times due to presence of ulcer, presence sity of Georgia Veterinary Teaching Hospital’s alumni of a deep ulcer, use of pilocarpine, small- versus network and another through the Veterinary Infor- medium-sized breed, presence of neurologic clinical mation Network (VIN) membership network. These signs, type of ear medication, use of lacrimostimu- surveys were used as a tool to identify dogs with lants, and whether referred to an ophthalmologist. signs of nKCS following application of otitis externa The P values were adjusted for multiplicity us- medications containing terbinafine and florfenicol. ing the false discovery methods of Benjamini and When dogs were reported via the surveys, the re- Hochberg.19 A Cox proportional hazards model was porting veterinarian was contacted to request medi- used to test for a relationship of age with time un- cal records for the reported dog for retrospective re- til documentation of normal tear production, and a 98 JAVMA | JANUARY 2023 | VOL 261 | NO. 1 Unauthenticated | Downloaded 06/01/24 01:34 AM UTC multivariable Cox proportional hazards model was mur (4/29 [14%]), dental disease (2/29 [7%]), and an used to test for associations of an ophthalmology inflammatory enteropathy (1/29 [3.5%]). No ocular referral and presence of a deep ulcer with time until disease was documented prior to application of the normal tear production. ear medication in any dog. An attempt to evaluate the tympanic membrane prior to medication application was documented in Results 45% (13/29) of dogs. An intact tympanic membrane Responses from both the VIN and University of was documented in 7 of 13 (54%) dogs, and the tym- Georgia surveys were obtained from veterinarians panic membrane could not be visualized in the re- worldwide. Thirty-three veterinarians reported 40 maining 6 of 13 (46%) dogs. dogs that developed clinical signs consistent with Claro was administered to 19 of 29 dogs, Osur- nKCS within 1 day after application of otitis externa nia to 5 of 29, and Neptra to 5 of 29. A long-lasting medications containing terbinafine and florfenicol ear medication had been applied previously in 6 via the VIN survey. Six veterinarians reported 7 dogs of 29 dogs in one or both ears without an adverse that developed clinical signs consistent with nKCS event. The median time until documented return to within 1 day after application of the long-lasting normal tear production that received Claro, Osurnia, otic medication through the University of Georgia and Neptra available for 24 of 29 dogs was 87 days, alumni network survey. Ophthalmologists also re- 102 days, and 134.5 days, respectively, though the ported cases via word-of-mouth recruitment on the difference was not significant (P =.92). American College of Veterinary Ophthalmologists’ Initial clinical signs were documented within diplomate listserv. 24 hours of application of the ear medication in all All veterinarians reporting adverse events dogs. The most common clinical signs noted by own- through these 3 channels were then contacted for ers were ocular discharge (18/29 [62%]), blepharo- medical records. The records were reviewed, and spasm (16/29 [55%]), a swollen appearance to the only dogs that met the inclusion criteria were in- eye(s) (10/29 [34%]), pawing at the face or affected cluded for further analysis. Any dogs reported by eye(s) (8/29 [28%]), hyporexia (6/29 [20%]), leth- veterinarians via the surveys or American College of argy (5/29 [17%]), vomiting (4/29 [14%]), a red eye Veterinary Ophthalmologist’s diplomate listserv that (4/29 [14%]), licking at nostrils (2/29 [7%]), and did not have medical records available for review or body shaking (2/29 [7%]). The median time from on- had medical records that indicated the dog did not set of clinical signs to documentation of a low STT meet the inclusion criteria were not included in the was 13 days (range, 0 to 35 days; mean, 13 days). following summary statistics or analysis. Initial STT values were 0 mm/min in 32 of 37 affected A total of 29 dogs and 37 affected eyes ful- eyes, and the remaining 5 affected eyes had STTs of filled the inclusion criteria. Twenty-four dogs were 2, 6, 7, 9, and 11 mm/min. located in the US, and 5 dogs were located out- Ipsilateral xeromycteria was noted in 14 of 29 side of the US (Supplementary Table S1). Small- dogs, and the remaining dogs did not have records breed dogs comprised 76% (22/29) of the included that commented on the lubrication of the ipsilateral dogs, and 24% (7/29) were medium-sized breeds nostril. In 34% (10/29) of dogs, concurrent neuro- (Supplementary Table S2). Of the included dogs, logic abnormalities were reported. Eight of 10 dogs 24 of 29 had documented return of normal tear exhibited vestibular disease (vestibular ataxia in 6 production within the study follow-up period (by of 8 dogs, head tilt in 1 of 8 dogs, and horizontal February 2022). For the 24 of 29 dogs that re- nystagmus in 1 of 8 dogs). Facial nerve paralysis gained tear production, the median time from ap- ipsilateral to the affected eye was noted in 1 of 10 plication of otitis externa medications containing dogs and hearing loss in 2 of 10 dogs. Facial nerve terbinafine and florfenicol to documented return of paralysis and vestibular disease were reported to re- tear production in dogs was 86 days (range, 19 to solve in all dogs. Records of the precise timing of the 482 days). Dogs with bilateral disease had return resolution of the neurologic abnormalities in relation of normal tear production in both eyes at the same to regaining normal lacrimation were not available. time. Of the 5 dogs that did not have documented The median time until normal tear production was return of normal tear production, 3 of 5 were lost to documented in dogs that did or did not develop neu- follow-up, and 2 of 5 dogs were initially diagnosed rologic signs was 76.5 days (range, 19 to 212 days) within 1 month of statistical evaluation. These 2 or 102 days (range, 37 to 129 days), respectively, dogs were included in summary data reported re- though this was not significant (P =.92). garding clinical signs but excluded from analysis re- The mean and median age at presentation was garding “time to documentation of return of normal 7.9 years and 9 years, respectively (range, 0.9 to tear production” due to the short follow-up period. 13 years). Eighteen dogs were male (12/18 [67%] All dogs were initially presented (prior to appli- neutered), and 11 dogs were female (11/11 [100%] cation of the ear medication) for clinical signs con- spayed). Shih Tzu or Shih Tzu–predominant mixed- sistent with otitis externa, and all dogs were diag- breed dogs (6/29 [21%]) and Chihuahua or Chihua- nosed with otitis externa via cytology demonstrating hua-predominant mixed-breed dogs (3/29 [7%]) bacteria, yeast, or both. Concurrent systemic pathol- were reported most commonly (Supplementary ogy documented at the time of diagnosis of otitis Table S2). There was no significant difference in me- externa included atopy (13/29 [45%]), cardiac mur- dian time to return of normal tear production based JAVMA | JANUARY 2023 | VOL 261 | NO. 1 99 Unauthenticated | Downloaded 06/01/24 01:34 AM UTC on age (P =.17) or weight (P =.92). The right eye ulcer. Referral to an ophthalmologist was associated was affected in 11 dogs, the left eye in 10 dogs, and with significantly (P =.001) longer median time to both eyes in 8 dogs. Dogs for which an ear medi- documentation of return of normal STT (111 days) cation was applied to both ears did not necessar- compared to the dogs that were not referred (37 ily demonstrate bilateral ocular disease (Table 1). days; Figure 1). Of the eyes that did not develop a Table 1—Summary of the laterality of ear or ears treat- ed for otitis externa with a commercially available long- lasting topical otic product containing terbinafine and florfenicol and the eyes affected with neurogenic kera- toconjunctivitis sicca within 1 day after otic treatment between September 2020 and February 2022 for 29 client-owned dogs. Treated ears Affected eyes AS AD AU No. of dogs 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 Figure 1—Kaplan-Meier curve demonstrating the dura- did not necessarily result in ocular abnormalities in both eyes. tion between the treatment of otitis externa with a com- AD = Right ear. AS = Left ear. AU = Both ears. OD = Right eye. mercially available long-lasting topical otic product con- OS = Left eye. OU = Both eyes. taining terbinafine and florfenicol and the subsequent detection of return to clinically normal tear production (Schirmer tear test [STT] value ≥ 15 mm/min) for 29 Systemic evaluation was pursued in 15 of 29 dogs. client-owned dogs that were treated between Septem- Abnormal findings included high concentrations of ber 2020 and February 2022, had onset of clinical signs ALP (3 dogs), ALT (2 dogs), and AST (1 dog); hy- of neurogenic keratoconjunctivitis sicca within 1 day af- poglycemia (1 dog); otic bacterial culture consistent ter otic treatment, and grouped by whether they were with Methicillin-resistant Staphylococcus aureus (1 not referred to an ophthalmologist and did not have a deep corneal ulcer (group 1; solid line; n = 10), were re- dog); and head MRI that revealed bilateral moderate ferred to an ophthalmologist but had no deep corneal fluid accumulation in the tympanic bullae (1 dog). ulcer (group 2; dashed line; 11), or were referred to an A corneal ulcer was diagnosed on initial exami- ophthalmologist and had a deep corneal ulcer (group 3; nation following application of the ear medication in dashed and dotted line; 8) as reported in the medical re- 23 eyes of 20 dogs. Dogs that developed a corneal cords. Each step represents documentation of STT ≥ 15 ulcer regained STT ≥ 15 mm/min in a median of 102 mm/min for ≥ 1 dog; crosses represent censored dogs (dogs lost to follow-up). The number of dogs with low days (range, 51 to 141 days). Dogs that did not de- tear production (STT < 15 mm/min) for each group at velop a corneal ulcer regained STT ≥ 15 mm/min in each benchmark day is listed under the x-axis. a median of 68 days (range, 37 to 129 days), though this was not significant (P =.82). Superficial ulcers deep corneal ulcer that were treated by an ophthal- were diagnosed in 14 of the 23 ulcerated eyes and mologist, a significantly (P =.01) longer median time healed (defined as a negative fluorescein stain) in a to return of normal STT was noted (median, 85 days; mean of 28 days (range, 8 to 64 days). Stromal ul- 95% CI, 51 to 141 days) compared to those eyes that cers were diagnosed in 4 eyes of 4 dogs and healed were treated by primary care veterinarians (median, in a mean of 40 days (range, 11 to 92 days); how- 37 days; 95% CI, 19 to 51 days). ever, 1 eye underwent a conjunctival graft and 1 eye Multivariable Cox regression analysis showed was enucleated. Descemetoceles were diagnosed in that dogs having been referred to an ophthalmolo- 5 eyes of 4 dogs, and all were treated with corneo- gist (hazard ratio [HR], 3.0; 95% CI, 3.0 [1.1 to 8.2]; conjunctival transposition grafts or conjunctival P =.03) or with a deep ulcer (HR, 5.3; 95% CI, 1.4 grafts. Healing occurred in a mean of 24 days (range, to 20.1; P =.02) were each associated with a longer 17 to 30 days) from application of ear medication. time to documentation of an STT value ≥ 15 mm/ A total of 8 dogs (9 eyes) with deep corneal min. Since referral is a potential confounding factor, ulcers (4 eyes with stromal ulcers and 5 eyes with univariable analyses were performed. The time until descemetoceles) had a median time until documen- dogs with or without a deep ulcer regained normal tation of STT ≥ 15 mm/min of 212 days (range, 99 tear production was significantly (HR, 6.2; 95% CI, 1.6 to 482 days), compared to 68 days (range, 37 to 87 to 23.8; P =.003) longer when referred to an ophthal- days) for those (21/29) without a deep ulcer (P = mologist than when not referred. This analysis dem-.003; log rank). Dogs with a deep ulcer in one or both onstrated a larger HR and smaller P value than the eyes had significantly (P =.001) longer median time multivariate analysis. Dogs that had a nondeep ulcer to documentation of STT ≥ 15 mm/min. had a significantly (HR, 3.6; 95% CI, 1.3 to 10.4; P = Nineteen dogs were referred to an ophthalmolo-.02) longer time until return of normal tear produc- gist. Of those, 9 eyes from 8 dogs demonstrated deep tion when referred to an ophthalmologist than when ulcers, 8 eyes from 8 dogs demonstrated superficial not referred. This indicated that dogs with a nond- ulcers, and 8 eyes from 7 dogs did not develop an eep ulcer referred to an ophthalmologist had longer 100 JAVMA | JANUARY 2023 | VOL 261 | NO. 1 Unauthenticated | Downloaded 06/01/24 01:34 AM UTC times until documentation of normal tear production damage to the inner ear, though most dogs did not than those with a nondeep ulcer and not referred. have documented clinically appreciable hearing loss. This analysis demonstrated a larger HR and the same Further, facial nerve paralysis was noted in 1 dog, P value than the multivariable analysis. suggesting a preganglionic lesion. Ultimately, deter- The median time from otic medication applica- mining the pathological location along the pathway tion to return of normal tear production for those of innervation was difficult. that received or did not receive pilocarpine was 99 The presumed cause of nKCS in these dogs was days (range, 51 to 118 days) or 68 days (range, 28 to penetration of the medication into the middle ear 330 days), respectively, though this was not signifi- through a perforated tympanic membrane. Visual- cant (P =.92). The median time from application of ization of the tympanic membrane does not elimi- an ear medication to starting pilocarpine was 21 days nate the risk of neurotoxicity, since small defects in (range, 7 to 36 days). The mean and median times the tympanic membrane could be present or otitis from prescription of pilocarpine until documentation could progress to tympanic membrane compromise of return of normal tear production were 63 and 99 following administration. Nonetheless, the authors days (range, 5 to 456 days), respectively. Oral ad- strongly recommend that veterinarians comply with ministration of pilocarpine was prescribed in 12 of label recommendations and perform an evaluation of 19 dogs and topical in 7 of 19 dogs. Of the dogs that the tympanic membrane prior to application of otitis were prescribed pilocarpine, 14 of 19 were weaned externa medications containing terbinafine and flor- off pilocarpine in a median of 92 days (range, 39 to fenicol. Ototoxicity to aminoglycosides may be due 490 days) and the remaining 5 of 19 dogs were lost to the A1555G mutation.22 It is possible the dogs that to follow-up. sustained hearing loss were more sensitive to these Dogs received a variety of combinations of ancil- medications than others due to a common mutation. lary medications including topical ophthalmic anti- An alternative etiology for the corneal ulcers microbials (24 dogs), oral antimicrobials (13 dogs), was chemical injury from medication splatter if the and topical immunomodulatory lacrimostimulants dog shook its head immediately after application.23 (14 dogs). Of the dogs prescribed immunomodula- No records of included dogs documented immediate tory lacrimostimulants, 8 of 14 were prescribed cy- head shaking after the application of the medication. closporine and 6 of 14 were prescribed tacrolimus. The pH of Claro is acidic at 4.0 to 6.0. Acidic corneal The median time to normal tear production for those contact irritants typically result in superficial, non- that received and did not receive immunomodula- progressive corneal ulcers because protein coagula- tory lacrimostimulants was 99 and 86 days, respec- tion in the corneal epithelium limits further penetra- tively, though this was not significant (P =.92). tion of the acid.24 Discordantly, 8 dogs developed rapidly progressing deep ulcers. Due to the loss of Discussion the antimicrobial properties and proteinase inhibi- tors normally found in the aqueous portion of the Our findings suggested that nKCS is a rare poten- tear film, dogs with KCS of any etiology are prone to tial adverse effect of otitis externa medications con- developing corneal ulcers that can quickly progress taining terbinafine and florfenicol. The median time in depth.25,26 In humans, KCS triggers an inflamma- from application of ear medication to documented tory response, which in turn activates transcription return of tear production was 86 days (range, 19 to factors that result in expression of matrix metallic 482 days) for the 24 dogs with long-term follow-up. proteases, which play a pathological role in KCS.26 The remaining 5 of the 29 included dogs were lost to This can result in rapid stromal loss in the absence follow-up or had insufficient follow-up. of infectious organisms. The loss of globulins and The efferent lacrimal gland innervation pathway the flushing action of the tears place corneal ulcers is complex. Pathology at any point along this path- in KCS dogs at risk for infection.2 Finally, given that way can result in nKCS. Toshida et al20 demonstrated nKCS developed in all dogs and corneal ulcers are a that the transection of the superficial petrosal nerve sequela of nKCS, the authors suspect the ulcers were in rabbits led to loss of tear production and a de- secondary to nKCS rather than accidental and un- crease in lacrimal gland size immediately and for at documented chemical corneal injury. least 7 days, without development facial nerve pa- The median time until return of normal tear pro- ralysis. Jin et al21 demonstrated that denervation of duction in nonreferral dogs was less than referral postganglionic fibers in mice led to decreased basal dogs, even in those dogs that were referred without tear secretion immediately and for at least 7 days. a corneal ulcer. Primary care veterinarians tended to Only a fraction of included dogs had reported recheck in shorter time frames (days to weeks) as clinical signs that aided in neurolocalization. Xero- compared to ophthalmologists (weeks to months). mycteria implied damage between the rostral saliva- There also may have been factors related to severity tory nucleus and the pterygopalatine ganglion.2 Xe- other than ulceration confounding the relationship romycteria was noted in only 14 of 29 dogs. Damage between time to return of normal tear production may have been sustained along the ophthalmic divi- and referral to ophthalmologist that were not ana- sion of the trigeminal nerve in dogs that did not de- lyzed. The literature on nKCS reflects differing times velop xeromycteria.4 Alternatively, xeromycteria may until return of normal tear production. In the nKCS have been present but not documented. Two dogs retrospective by Matheis et al,5 the median time until were presented with hearing loss, which suggested dogs discontinued medication for treatment of nKCS JAVMA | JANUARY 2023 | VOL 261 | NO. 1 101 Unauthenticated | Downloaded 06/01/24 01:34 AM UTC (available for 4 of 11 included dogs) was 125 days differences in time to clinical improvement based (range, 84 to 204 days). Similarly, Galley et al7 re- on specific ear medication formulation, specific ported return of normal tear production in 11 of 23 ophthalmic treatments, or time to starting treat- dogs with nKCS in a mean of 115 days. Conversely, ments. Finally, STT values were not documented at Wegg et al6 found that the mean time until return the onset of the clinical signs in every patient, re- of normal tear production in dogs with nKCS was 24 sulting in a delayed diagnosis. ± 5.1 days, and 4 of 11 dogs had medications dis- The authors recommend advising clients to mon- continued in a median of 72 days (range, 28 to 356 itor for signs of nKCS following use of otitis externa days). It is important to note that time to return to medications containing terbinafine and florfenicol. normal tear production while on pilocarpine (or oth- Clinical signs include blepharospasm, ocular dis- er) treatment (equivalent time to resolution of clini- charge, third eyelid elevation, conjunctivitis, or a dry cal signs of nKCS while on treatment) is a different naris, often with dry, crusted debris partially occlud- outcome variable than time to resolution of nKCS ing the ipsilateral nostril. If observed, the authors (defined as maintenance of normal tear production recommend immediate reexamination with STT and after discontinuation of all lacrimostimulant medi- fluorescein staining, as rapid progression to sight- cal treatment, which implies return of normal nerve and globe-threatening ulceration is possible. Osur- function). Sooner reevaluation for dogs that devel- nia has been shown to be absorbed through healthy oped nKCS secondary to otitis externa medications canine skin in 1 day, and cerumen accumulation may containing terbinafine and florfenicol may be indi- act as a reservoir for further medication release.27 cated compared to nKCS dogs not associated with Therefore, cleaning of the medication from the ear long-acting otic medication administration. canal is recommended to prevent further absorption The direct-acting parasympathomimetic drug of the medication if clinical signs of nKCS are noted. pilocarpine is the traditional choice for treatment of For further treatment recommendations for otitis nKCS. The mechanism of action and proposed ben- media, readers are referred to dermatology texts.28 efit of this medication is to directly stimulate the lac- Initiation of treatment for nKCS with frequent topical rimal gland to produce tears during the period when lubrication and lacrimostimulant treatment is recom- the nerve is not functioning, thereby alleviating the mended. If a corneal ulcer is diagnosed, topical oph- clinical signs of nKCS that result in discomfort and thalmic antimicrobials and systemic analgesics are corneal damage. Pilocarpine is not expected to have recommended. Evaluation for concurrent neurologic any therapeutic benefit in repairing nerve damage. abnormalities should be pursued. Clients should be Nineteen of the dogs in this study were prescribed advised that those that develop deep corneal ulcers pilocarpine. Most dogs in this study regained nor- may have longer healing times. Referral to an oph- mal tear function, whether or not pilocarpine was thalmologist for surgical stabilization of the cornea is prescribed, consistent with spontaneous resolution recommended if deep corneal ulcers are noted. of nerve dysfunction. There was no significant (P = In conclusion, the authors recommend advising.92) difference in time from ear medication admin- clients of this rare occurrence prior to the applica- istration to documentation of normal tear produc- tion of otitis externa medications containing terbi- tion between those treated with pilocarpine and nafine and florfenicol. Based on these results, nKCS those not treated with pilocarpine. The authors cau- sustained within 24 hours of application of otitis tion, however, that these results do not indicate pi- externa medications containing terbinafine and flo- locarpine slowed down healing time and therefore rfenicol has a good prognosis for return of normal is not recommended. Inherent in the limitations of tear production within 1 year following application a retrospective evaluation, tear production was not of the medication. assessed daily, so the precise time until return of normal tear production was unknown. Further, time until dogs regained comfort was not assessed, as Acknowledgments this is a subjective estimation and often not included The authors declare that there were no conflicts of inter- in medical records. Further research is warranted to est, and no third-party funding or support was received in determine how soon comfort is restored with and connection with this study or the writing or publication of the without pilocarpine for nKCS treatment and its rela- manuscript. The authors thank Dr. Deborah Keys for her statistical tion to STT values. evaluations, Dr. Mark Rishniw for his help developing the VIN. Limitations of this study were inherent in its com survey, and Mrs. Katy Wilkins for her help developing retrospective design and small sample size. Ideally, the UGA alumni network survey. complete systemic evaluations for other causes of This project was presented at the 2021 American Col- nKCS, such as hypothyroidism or diabetes melli- lege of Veterinary Ophthalmologists Conference. tus, would have been performed. In addition, nerve damage due to progression of otitis despite treat- References ment rather than as a result of medication applica- tion cannot be excluded for all dogs, though the on- 1. Webb AA, Cullen CL. Neuro-ophthalmology. In: Gelatt KN, Ben-Shlomo G, Gilger BC, Hendrix DVH, Kern TJ, Plummer set of signs of nKCS within 1 day after medication CE, eds. Veterinary Ophthalmology. 6th ed. Vol 2. Wiley application in dogs with no previous ophthalmic Blackwell; 2021:2285–2286. signs suggests causal relationship. Small sample 2. Garosi LS, Lowrie ML, Swinbourne NF. Neurological size and retrospective data limited power to detect manifestations of ear disease in dogs and cats. Vet Clin 102 JAVMA | JANUARY 2023 | VOL 261 | NO. 1 Unauthenticated | Downloaded 06/01/24 01:34 AM UTC  North Am Small Anim Pract. 2012;42(6):1143–1160. NADA 141–437. Regulations.gov. Accessed May 26, doi:10.1016/j.cvsm.2012.08.006 2022. https://www.regulations.gov/document/FDA- 3. Lorek A, Dennis R, van Dijk J, Bannoehr J. Occult oti- 2014-N-0002-0076 tis media in dogs with chronic otitis externa—magnetic 18. Aydın E, Taştan E, Aydoǧan F, Karaca G, Asım Şafak M. resonance imaging and association with otoscopic and Ototoxic effect of topical oxiconazole and terbinafine in cytological findings. Vet Dermatol. 2020;31(2):146–153. rats. J Otolaryngol Head Neck Surg. 2012;41(2):78–83. doi:10.1111/vde.12817 19. Benjamini Y, Hochberg Y. Controlling the false discovery 4. Klauss G, Constantinescu GM. Nonhypotensive autonomic rate: a practical and powerful approach to multiple test- agents in veterinary ophthalmology. Vet Clin North Am ing. J R Stat Soc Series B Stat Methodol. 1995;57(1): Small Anim Pract. 2004;34(3):777–800. doi:10.1016/ 289–300. doi:10.1111/j.2517-6161.1995.tb02031.x j.cvsm.2003.12.011 20. Toshida H, Nguyen DH, Beuerman RW, Murakami A. Eval- 5. Matheis FL, Walser-Reinhardt L, Spiess BM. Canine neu- uation of novel dry eye model: preganglionic parasympa- rogenic keratoconjunctivitis sicca: 11 cases (2006–2010). thetic denervation in rabbit. Invest Ophthalmol Vis Sci. Vet Ophthalmol. 2012;15(4):288–290. doi:10.1111/ 2007;48(10):4468–4475. doi:10.1167/iovs.06-1486 j.1463-5224.2011.00968.x 21. Jin K, Imada T, Hisamura R, et al. Identification of lacri- 6. Wegg ML. A retrospective evaluation of systemic and/ mal gland postganglionic innervation and its regulation or topical pilocarpine treatment for canine neurogenic of tear secretion. Am J Pathol. 2020;190(5):1068–1079. dry eye: 11 cases. Vet Ophthalmol. 2020;23(2):341–346. doi:10.1016/j.ajpath.2020.01.007 doi:10.1111/vop.12731 22. Lanvers-Kaminsky C, Zehnhoff-Dinnesen AA, Parfitt R, 7. Galley AP, Beltran E, Tetas Pont R. Neurogenic keratocon- Ciarimboli G. Drug-induced ototoxicity: mechanisms, junctivitis sicca in 34 dogs: a case series. Vet Ophthalmol. pharmacogenetics, and protective strategies. Clin Phar- 2022;25(2):140–152. doi:10.1111/vop.12949 macol Ther. 2017;101(4):491–500. doi:10.1002/cpt.603 8. Rushton JO, Leschnik M, Nell B. Suspected hypothyroid- 23. Animal Drug Safety-Related Labeling Changes. US associated neuropathy in a female Rottweiler dog. Can FDA. Accessed May 26, 2022. https://www.fda.gov/ Vet J. 2013;54(4):368–372. animal-veterinary/drug-labels/animal-drug-safety- 9. Williams DL, Pierce V, Mellor P, Heath MF. Reduced tear related-labeling-changes production in three canine endocrinopathies. J Small 24. Whitley RD, Hamor RE. Diseases and surgery of the ca- Anim Pract. 2007;48(5):252–256. nine cornea and sclera. In: Gelatt KN, Ben-Shlomo G, 10. Schwarz BC, Sallmutter T, Nell B. Keratoconjunctivitis Gilger BC, Hendrix DVH, Kern TJ, Plummer CE, eds. sicca attributable to parasympathetic facial nerve dys- Veterinary Ophthalmology. 6th ed. Vol 1. Wiley Blackwell; function associated with hypothyroidism in a horse. J Am 2021:1121. Vet Med Assoc. 2008;233(11):1761–1766. doi:10.2460/ 25. Giuliano EA. Diseases and surgery of the canine lacrimal javma.233.11.1761 secretory system. In: Gelatt KN, Ben-Shlomo G, Gilger 11. Singh S, Basu S. Unilateral dry eye due to possible iso- BC, Hendrix DVH, Kern TJ, Plummer CE, eds. Veterinary lated parasympathetic denervation of the lacrimal gland Ophthalmology. 6th ed. Vol 1. Wiley Blackwell; 2021:1010. in a woman with hypothyroidism. Cornea. 2022;41(5): 26. Caban M, Owczarek K, Lewandowska U. The role of me- 627–629. doi:10.1097/ICO.0000000000002867 talloproteinases and their tissue inhibitors on ocular dis- 12. Foote BC, Michau TM, Welihozkiy A, Stine JM. Retrospec- eases: focusing on potential mechanisms. Int J Mol Sci. tive analysis of ocular neuropathies in diabetic dogs fol- 2022;23(8):4256. doi:10.3390/ijms23084256 lowing cataract surgery. Vet Ophthalmol. 2019;22(3): 27. Ehling S, Baynes RE, Bäumer W. Impact of synthetic ca- 284–293. doi:10.1111/vop.12589 nine cerumen on in vitro penetration of auricular skin of 13. Gemensky-Metzler AJ, Sheahan JE, Rajala-Schultz PJ, dogs by florfenicol, terbinafine, and betamethasone ac- etate. Am J Vet Res. 2018;79(3):333–341. doi:10.2460/ Wilkie DA, Harrington J. Retrospective study of the prev- ajvr.79.3.333 alence of keratoconjunctivitis sicca in diabetic and non- 28. Miller WH, Griffin C, Campbell K. Diseases of eyelids, diabetic dogs after phacoemulsification. Vet Ophthalmol. claws, anal sacs, and ears. Muller and Kirk’s Small Animal 2015;18(6):472–480. Dermatology. 7th ed. Elsevier Mosby; 2013:757–767. 14. Claro. Package insert. Bayer HealthCare LLC; 2018. 15. Neptra. Package insert. Elanco; 2021. 16. Osurnia. Package insert. Dechra Veterinary Products; 2020. Supplementary Materials 17. Corrected Freedom of Information summary. Original Supplementary materials are posted online at the jour- new animal drug application. Osurnia otic gel for dogs. nal website: avmajournals.avma.org JAVMA | JANUARY 2023 | VOL 261 | NO. 1 103 Unauthenticated | Downloaded 06/01/24 01:34 AM UTC