Five domestic shorthair farm cats with a median age of 3 years (range, 2 to 6.5 years) and mean ± SD body weight of 4.3 ± 0.6 kg (9.5 ± 1.3 lb) were evaluated at the Kansas State University Veterinary Health Center because of a sudden onset of tremors, obtundation, blindness, and dilated pupils. Less than 12 hours earlier, the owner had attempted to treat the cats for a suspected ear mite (Otodectes cynotis) infestation by aural administration of a dose of an ivermectin pastea intended for oral administration to horses (approx 22 mg/cat; half of the dose was administered into each ear canal). Physical examination abnormalities were limited to moderate amounts of debris in both ear canals of all 5 cats. Neurologic examination revealed generalized body tremors, mild obtundation, and bilateral ear twitching. Mydriasis in ambient light, diminished (sluggish and incomplete) pupillary light reflexes, and lack of menace response were also detected. All other findings of neuro-ophthalmic and physical examinations were unremarkable for all cats.
Complete ophthalmic examination, including slit-lamp biomicroscopy and indirect binocular ophthalmoscopy, was performed in all cats by the same veterinarian (JMM). In 4 of 5 cats, no abnormalities were detected in the anterior and posterior segments of the eyes. In the left eye of the fifth cat, several abnormalities were evident. Those in the anterior segment of the eye were mild and consisted of an incipient anterior cortical cataract with focal pigmentation on the anterior lens capsule. Fundic examination of the same eye revealed a large retinal tear and detachment with degeneration of the corpus vitreum and suspension of pigmented cells in the vitreous humor. These pathological changes were considered chronic in nature and unrelated to ivermectin toxicosis. No abnormalities were evident in the anterior segment or fundus of the right eye of that cat.
Pupils of all cats were dilated with topically applied 1% tropicamide solution,b a 20-minute dark adaptation period was provided, and ERGc then was performed. None of the cats were sedated, and 1 cat was deemed too fractious to allow testing. Retinal responses for each eye of the other 4 cats were assessed individually by use of a series of 8 bright light flashes; the mean of 8 responses was calculated by the ERG device to provide a single result for each eye. Retinal responses were abnormal in all cats (Figure 1). Responses were diminished in 7 eyes and totally eliminated in 1 eye (the left eye of the cat with retinal detachment). Median response values were 57.9 μV (range, 37.1 to 93.6 μV) for right eyes and 59.3 μV (range, 0.0 to 154.7 μV) for left eyes. Values > 100 μV were used to indicate healthy retinal function, in accordance with information provided by the manufacturer of the ERG device.
Representative ERG recordings for the right eye (top row) and left eye (bottom row) of a cat with a sudden onset of tremors, obtundation, blindness, and dilated pupils after aural administration of a dose of ivermectin paste intended for oral administration to horses (approx 22 mg/cat; half of the dose was administered into each ear canal). Recordings were obtained 12 hours (A) and approximately 4 weeks (B) after ivermectin administration. The b-wave amplitudes (height of waveform measured from trough to peak; dashed lines and arrows) noticeably improved with time, which corresponded to resolution of clinical signs of vision loss.
Citation: Journal of the American Veterinary Medical Association 246, 11; 10.2460/javma.246.11.1238
Representative ERG recordings for the right eye (top row) and left eye (bottom row) of a cat with a sudden onset of tremors, obtundation, blindness, and dilated pupils after aural administration of a dose of ivermectin paste intended for oral administration to horses (approx 22 mg/cat; half of the dose was administered into each ear canal). Recordings were obtained 12 hours (A) and approximately 4 weeks (B) after ivermectin administration. The b-wave amplitudes (height of waveform measured from trough to peak; dashed lines and arrows) noticeably improved with time, which corresponded to resolution of clinical signs of vision loss.
Citation: Journal of the American Veterinary Medical Association 246, 11; 10.2460/javma.246.11.1238
Representative ERG recordings for the right eye (top row) and left eye (bottom row) of a cat with a sudden onset of tremors, obtundation, blindness, and dilated pupils after aural administration of a dose of ivermectin paste intended for oral administration to horses (approx 22 mg/cat; half of the dose was administered into each ear canal). Recordings were obtained 12 hours (A) and approximately 4 weeks (B) after ivermectin administration. The b-wave amplitudes (height of waveform measured from trough to peak; dashed lines and arrows) noticeably improved with time, which corresponded to resolution of clinical signs of vision loss.
Citation: Journal of the American Veterinary Medical Association 246, 11; 10.2460/javma.246.11.1238
Because of financial constraints, toxicological testing for ivermectin was performed for only 2 cats. Blood samples were collected, and serum was harvested and submitted for analysis at an external laboratory.d
All cats were hospitalized for approximately 8 hours for observation. No supportive care was provided, and the cats were deemed stable for release into the owner's care at the end of the observation period. Cats were discharged to the owner with instructions that the owner monitor them for progression of neurologic signs (seizures and coma). During a follow-up telephone conversation 5 days after initial evaluation, the owner reported that vision and pupillary dilation had noticeably improved in all 5 cats. Other general neurologic signs of tremors and obtundation had reportedly resolved within 3 days after hospital discharge.
Results for toxicological testing revealed that ivermectin (450 μg/L and 610 μg/L) was detected in both submitted serum samples; no reference was available to indicate whether such concentrations were toxic in cats. Test results were negative for the presence of abamectin, moxidectin, and selamectin in both samples.
Approximately 1 month after initial evaluation, 4 of 5 cats were reexamined. The cat in which ERG could not be performed previously because of a fractious temperament was not reexamined. The owner reported that all cats recovered their vision. Findings of physical and neurologic examination were unremarkable for 3 of 4 cats. The fourth cat had a bilateral ear infection, and large amounts of malodorous, purulent discharge were evident. The owner declined diagnostic testing, such as cytologic evaluation and bacteriologic culture, to identify the cause of the infection. Consequently, thorough lavage of the cat's ear canals was performed, cefovecin sodiume (8 mg/kg [3.6 mg/lb], SC) was administered, and an ear cleanser for daily use was dispensed.
Complete ophthalmic examination revealed appropriate pupil size, unremarkable direct and consensual pupillary light reflexes, and unremarkable menace response in 3 of 4 cats; the cat with retinal detachment of the left eye remained blind (no menace response) in that eye. Previously detected fundic abnormalities in the left eye were also unchanged. For the right eye of that cat and both eyes of the other cats, findings of fundic examinations remained unremarkable. Electroretinography was repeated, and b-wave amplitudes were noticeably improved in 7 of 8 eyes (median value for right eye, 212.2 μV [range, 148.9 to 251.7 μV]; left eye, 151.0 [range, 0.0 to 225.2 μV]; Figure 1). Responses in the left eye of the cat with retinal detachment remained totally extinguished.
Discussion
To the authors’ knowledge, the present report provided the first description of clinical signs and outcome, combined with serial ophthalmic examination and ERG findings, in a group of cats with ivermectin exposure via transdermal application. Reports of ivermectin toxicosis are common for dogs1–10 and less common for cats.6,11,12 This type of toxicosis has also been reported for equids (neonatal foal,13 adult horses,14,15 and miniature mule foal16). Clinical signs include blindness, mydriasis, ataxia, lethargy, tremors, and coma, and toxic exposure may result in death. Affected dogs may develop blindness without other clinical signs.
Previous reports of fundic examination and ERG findings in animals with suspected or confirmed ivermectin toxicosis are limited to 3 dogs7,8 and a mule foal.16 Funduscopic changes including multifocal retinal edema and folds with low-lying retinal separation were detected in 2 dogs with ivermectin toxicosis, with diminished ERG b-wave amplitudes evident in both dogs.7 Similar funduscopic and ERG findings have also been reported for a Jack Russell Terrier with ivermectin toxicosis that was treated by IV administration of a lipid solution.8 In all 3 dogs, fundic abnormalities combined with diminished ERG responses suggested blindness of retinal origin. In contrast, ophthalmoscopic and ERG findings were unremarkable in the aforementioned mule foal, which suggests that a central mechanism for the blindness was associated with ivermectin toxicosis in that animal.16
Ivermectin (22,23-dihydroavermectin B1a and 22,23-dihydroavermectin B1b) is a broad-spectrum antiparasitic drug in the avermectin family. The drug enhances release of GABA at presynaptic nerve terminals, and GABA then blocks postsynaptic stimulation of adjacent neurons by acting as an inhibitory neurotransmitter, which causes paralysis and eventual death of target parasites in which GABA acts as a peripheral-nerve neurotransmitter. Ivermectin generally has a wide safety margin in most species in which it is used, except for young animals such as foals and puppies, for which safety data are lacking. The drug must also be used with caution in certain dog breeds with ivermectin sensitivity caused by a deletion mutation in the multi-drug-resistance (mdr1) gene.5,17
Cats of the present report received the equivalent of approximately 22 mg of ivermectin/cat. Given the body weight of each cat, this dose was comparable to approximately 5.3 mg/kg (2.4 mg/lb). However, the recommended dosage for ivermectin to prevent heartworm disease in cats is 0.024 mg/kg (0.011 mg/lb), PO, every 30 to 45 days.18 Additionally, a commercially available ivermectin productf for topical (aural) treatment of ear mites (O cynotis) in cats contains 0.1 mg of ivermectin/mL, and the label instructions indicate a dose of 0.5 mL/ear canal (0.1 mg total dose/cat) for kittens as young as 4 weeks old. In comparison, cats of the present report received approximately 220 times the recommended ivermectin dose, via the transdermal route, of a formulation for oral administration to horses. Most existing reports1–4,7–9,11,12 of ivermectin toxicosis pertain to animals exposed, accidentally or intentionally, to a formulation not intended for that species. The opportunity for toxicosis development is particularly great when high-concentration ivermectin formulations for administration to large animals are used for small animal species. Investigators in 1 study19 evaluated the effects of a pour-on ivermectin product formulated for use on cattleg that was administered topically to cats at a dosage of 500 μg/kg (227.3 μg/lb), 2 or 4 times, 14 days apart. Although this treatment approach was found to be safe and effective for naturally acquired ectoparasite infestations and endoparasite infections, cats of the present report were exposed to a dose of ivermectin > 10 times as high as this individual experimental dose. Ivermectin (450 and 610 μg/L) was detected via toxicological assay of serum samples obtained from 2 cats, which confirmed systemic absorption and development of toxic effects after topical aural application; however, no reference was available to determine whether this concentration was indeed toxic in cats.
Mechanisms underlying blindness in animals with ivermectin toxicosis are unknown. Previous findings suggest the involvement of intracranial16 and retinal7,8 processes. γ-Amino butyric acid is considered the primary inhibitory neurotransmitter in the mammalian retina,20 and it plays an important role in processing visual information. If ivermectin were able to cross the blood-retinal barrier and increase the release of GABA, then retinal toxic effects could develop. In theory, visual impairment could result as the stimulation of retinal neurons (ie, photoreceptor cells, bipolar cells, and ganglion cells) is blocked and the biochemical process of phototransduction (in which light is converted to electrical signals within the photoreceptor cells of the retina) is disrupted. Abnormal ERG b-wave amplitudes detected in dogs7,8 and in the cats of the present report supported the hypothesis that blindness was of retinal origin in those animals. The cats lacked any funduscopic abnormalities; however, the small magnitude of retinal lesions in the dogs7,8 did not fully explain the severity of vision loss in those animals.
Differences likely exist among species in the degree of sensitivity to ivermectin, and those differences may be reflected in the various clinical signs reported. A mule foal16 was functionally blind with no evidence of retinal changes and unremarkable results of ERG, and 3 dogs7,8 had both retinal lesions and diminished ERG responses. Cats of the present report had no funduscopic abnormalities, but ERG responses were diminished. Serum ivermectin concentrations in 2 dogs with retinal changes were 1,040 μg/L7 and 1,500 μg/L.8 Serum ivermectin concentration in the mule foal was not measured.16 The dogs’ serum concentrations were approximately 2 to 3 times as high as in the 2 cats of the present study. The cats may have absorbed enough ivermectin to cause systemic effects and blindness due to retinal dysfunction without appreciable retinal lesions. Cats were examined soon after clinical signs of toxicosis were noticed and were not reexamined until 1 month after the initial evaluation. Retinal lesions may have developed and resolved between examinations, considering that clinical signs of vision impairment can precede funduscopic detection of lesions. The discrepancy between magnitude of retinal lesions and severity of vision impairment in these dogs and cats highlights the importance of electrodiagnostic testing for objective assessment of retinal function. Funduscopy and ERG should be considered complementary testing modalities for assessment of blind patients, particularly when ivermectin toxicosis is suspected. Electrodiagnostic testing may help to identify the neuroanatomic location of vision loss; blindness of retinal origin related to photoreceptor dysfunction should be detectable as an abnormally low ERG response,21 whereas blindness due to problems elsewhere within the visual pathway (ie, within the CNS) should not impact ERG results.
Findings in the present report suggested that in cats with blindness and suspected or known exposure to ivermectin, retinal lesions may not be detectable or development of retinal lesions may be time dependent. Electroretinography was an important diagnostic tool and, in addition to positive results of a serum toxicological assay, helped to confirm a diagnosis of ivermectin toxicosis. Complete recovery of vision and neurologic function was achieved in cats with time.
ABBREVIATIONS
| ERG | Electroretinography |
| GABA | γ-Amino butyric acid |
DuraMectin (1.87% ivermectin) paste, Durvet Inc, Blue Springs, Mo.
Tropicamide ophthalmic solution, Akorn Inc, Lake Forest, Ill.
RetinoGraphics BPM-100 system ERG/VEP, RetinoGraphics Inc, Norwalk, Conn.
California Animal Health and Food Safety Laboratory System, Davis, Calif.
Convenia, Zoetis Inc, Kalamazoo, Mich.
Acarexx (0.01% ivermectin) otic suspension, Boehringer Ingelheim Vetmedica Inc, St Joseph, Mo.
Ivomec (0.5% ivermectin) pour-on for cattle, Merial Ltd, Duluth, Ga.
References
1. Houston DM, Parent J, Matushek KJ. Ivermectin toxicosis in a dog. J Am Vet Med Assoc 1987; 191:78–80.
2. Hopkins KD, Marcella KL, Strecker AE. Ivermectin toxicosis in a dog. J Am Vet Med Assoc 1990; 197:93–94.
3. Hadrick MK, Bunch SE, Kornegay JN. Ivermectin toxicosis in two Australian Shepherds. J Am Vet Med Assoc 1995; 206:1147–1152.
4. Hopper K, Aldrich J, Haskins SC. Ivermectin toxicity in 17 Collies. J Vet Intern Med 2002; 16:89–94.
5. Nelson OL, Carsten E, Bentjen SA, et al. Ivermectin toxicity in an Australian Shepherd dog with the MDR1 mutation associated with ivermectin sensitivity in Collies. J Vet Intern Med 2003; 17:354–356.
6. Lovell RA. Ivermectin and piperazine toxicoses in dogs and cats. Vet Clin North Am Small Anim Pract 1990; 20:453–468.
7. Kenny PJ, Vernau KM, Puschner B, et al. Retinopathy associated with ivermectin toxicosis in two dogs. J Am Vet Med Assoc 2008; 233:279–284.
8. Epstein SE, Hollingsworth SR. Ivermectin-induced blindness treated with intravenous lipid therapy in a dog. J Vet Emerg Crit Care (San Antonio) 2013; 23:58–62.
9. Easby SM. Ivermectin in the dog. Vet Rec 1984; 115:45.
10. Paul AJ, Tranquilli WJ, Seward RL, et al. Clinical observations in Collies given ivermectin orally. Am J Vet Res 1987; 48:684–685.
11. Muhammad G, Abdul J, Khan MZ, et al. Use of neostigmine in massive ivermectin toxicity in cats. Vet Hum Toxicol 2004; 46:28–29.
12. Lewis DT, Merchant SR, Neer TM. Ivermectin toxicosis in a kitten. J Am Vet Med Assoc 1994; 205:584–586.
13. Godber LM, Derksen FJ, Williams JF, et al. Ivermectin toxicosis in a neonatal foal. Aust Vet J 1995; 72:191–192.
14. Swor TM, Whittenburg JL, Chaffin MK. Ivermectin toxicosis in three adult horses. J Am Vet Med Assoc 2009; 235:558–562.
15. Norman TE, Chaffin MK, Norton PL, et al. Concurrent ivermectin and Solanum spp. toxicosis in a herd of horses. J Vet Intern Med 2012; 26:1439–1442.
16. Plummer CE, Kallberg ME, Ollivier FJ, et al. Suspected ivermectin toxicosis in a miniature mule foal causing blindness. Vet Ophthalmol 2006; 9:29–32.
17. Mealey KL, Bentjen SA, Gay JM, et al. Ivermectin sensitivity in Collies is associated with a deletion mutation of the mdr1 gene. Pharmacogenetics 2001; 11:727–733.
18. Longhofer SL, Daurio CP, Plue RE, et al. Ivermectin for the prevention of feline heartworm disease, in Proceedings. Heartworm Symp 1995;177–182.
19. Pagé N, de Jaham C, Paradis M. Observations on topical ivermectin in the treatment of otoacariosis, cheyletiellosis, and toxocariosis in cats. Can Vet J 2000; 41:773–776.
20. Yang XL. Characterization of receptors for glutamate and GABA in retinal neurons. Prog Neurobiol 2004; 73:127–150.
21. Ekesten B. Ophthalmic examination and diagnostics part 4: electrodiagnostic evaluation of vision. In: Gelatt KN, Gilger BC, Kern TJ, eds. Veterinary ophthalmology. 5th ed. Ames, Iowa: Blackwell, 2013;684–702.
