Clinical features, outcomes, and long-term survival times of cats and dogs with central nervous system cryptococcosis in Australia: 50 cases (2000–2020)

Else Jacobson Department of Internal Medicine, Veterinary Specialist Services, Underwood, QLD, Australia

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John M. Morton Jemora Pty Ltd, East Geelong, VIC, Australia

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Dennis J. Woerde Department of Internal Medicine, Animal Referral Hospital, Homebush West, NSW, Australia

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Mary F. Thompson Department of Internal Medicine, The Animal Hospital, School of Veterinary Medicine, Murdoch University, Murdoch, WA, Australia

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Amanda M. Spillane Department of Internal Medicine, Queensland Veterinary Specialists, Stafford, QLD, Australia

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Anna Tebb Department of Internal Medicine, Western Australian Veterinary Emergency and Specialty, Success, WA, Australia

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Zoe della Valle Department of Internal Medicine, Melbourne Veterinary Specialist Centre, Glen Waverley, VIC, Australia

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Gemma Birnie Department of Internal Medicine, Brisbane Veterinary Specialist Centre, Albany Creek, QLD, Australia

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Richard Malik Centre for Veterinary Education, Veterinary Science Conference Centre, The University of Sydney, NSW, Australia

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Abstract

OBJECTIVE

To describe the clinical findings and outcomes of Australian cats and dogs with CNS cryptococcosis.

ANIMALS

19 cats and 31 dogs with CNS cryptococcosis diagnosed between 2000 and 2020.

PROCEDURES

A case series and cohort study were performed using the same 50 animals. Both studies were multi-institutional and both retrospective and prospective. Disease features were compared between cats and dogs, and associations between putative risk factors and survival time (ST) were assessed.

RESULTS

Dogs were younger at initial presentation than cats and had lower latex cryptococcal antigen agglutination titers. Extraneurologic signs were common and frequently involved sinonasal and contiguous tissues. Neuroanatomic localization was predominantly forebrain, central vestibular (including cerebellum), multifocal, or diffuse. CSF analysis predominantly showed pleocytosis, with eosinophilic inflammation common in dogs. Seventy-eight percent (39/50) of patients received antifungal treatment. Median STs (from presentation) in treated patients were 1,678 days for cats and 679 days for dogs. Abnormal mentation at presentation (in dogs) and CSF collection (in cats) were associated with shorter STs. In treated dogs, those that received glucocorticoids prior to diagnosis, or single rather than multiple antifungal agents, had shorter STs.

CLINICAL RELEVANCE

The prognosis for feline and canine CNS cryptococcosis is guarded, yet long STs are possible with appropriate treatment. Presence of subtle upper respiratory tract signs may suggest cryptococcosis in patients with neurologic signs, while the absence of neurologic signs does not preclude CNS involvement.

Abstract

OBJECTIVE

To describe the clinical findings and outcomes of Australian cats and dogs with CNS cryptococcosis.

ANIMALS

19 cats and 31 dogs with CNS cryptococcosis diagnosed between 2000 and 2020.

PROCEDURES

A case series and cohort study were performed using the same 50 animals. Both studies were multi-institutional and both retrospective and prospective. Disease features were compared between cats and dogs, and associations between putative risk factors and survival time (ST) were assessed.

RESULTS

Dogs were younger at initial presentation than cats and had lower latex cryptococcal antigen agglutination titers. Extraneurologic signs were common and frequently involved sinonasal and contiguous tissues. Neuroanatomic localization was predominantly forebrain, central vestibular (including cerebellum), multifocal, or diffuse. CSF analysis predominantly showed pleocytosis, with eosinophilic inflammation common in dogs. Seventy-eight percent (39/50) of patients received antifungal treatment. Median STs (from presentation) in treated patients were 1,678 days for cats and 679 days for dogs. Abnormal mentation at presentation (in dogs) and CSF collection (in cats) were associated with shorter STs. In treated dogs, those that received glucocorticoids prior to diagnosis, or single rather than multiple antifungal agents, had shorter STs.

CLINICAL RELEVANCE

The prognosis for feline and canine CNS cryptococcosis is guarded, yet long STs are possible with appropriate treatment. Presence of subtle upper respiratory tract signs may suggest cryptococcosis in patients with neurologic signs, while the absence of neurologic signs does not preclude CNS involvement.

Introduction

Cryptococcosis is a systemic mycosis of humans and animals caused by the Cryptococcus neoformans and Cryptococcus gattii species complexes. These environmental organisms can be primary or opportunistic pathogens, predominantly affecting the respiratory, ocular, and central nervous systems. Basidiospores or desiccated yeast cells usually gain entry to mammalian hosts via inhalation. The site of initial respiratory infection is host species specific. In cats and dogs, nasal colonization probably occurs first, which can progress to rhinosinusitis, with pulmonary involvement considered rare.1,2 Cats are up to 8 times as likely to develop cryptococcosis as dogs, and usually have protracted sinonasal infection, with late dissemination to other systems, including the CNS.1,35 In contrast, dogs often present with acute, severe, life-threatening signs,6 with increased chance of early CNS involvement.1,4,5,7 In both species, spread to the CNS may occur hematogenously or via osteolysis through the cribriform plate or sphenoidal sinus.8

In cats and dogs in Australia, C neoformans var grubii is the predominant cause of cryptococcosis,4 although C gattii accounts for approximately 50% of infections (5/9 cats; 11/22 dogs) in some areas.1 The molecular type of C gattii infections varies with geographic location, with VGI accounting for almost all small animal infections in eastern Australia,7 VGII predominating in Western Australia1 and the Pacific Northwest of America,9 and VGIII being more common in California, particularly in cats.5,8 In people, meningitis is the dominant presentation for C neoformans infections, typically in untreated HIV-infected patients.10 Recently, there has been increased recognition of C gattii infections, especially in Australia, California, and the northwest of the US and Canada.11 While initial reports suggested these infections occurred in immunocompetent people, recent evidence implies that subtle or as-yet-undetected immune defects (eg, granulocyte-macrophage colony-stimulating factor autoantibodies) may play a role.12

Limited literature has focused on CNS cryptococcosis in cats and dogs, comprising a single extensive case series from the US,8 with other reports limited to individual case reports1325 or small case series.26,27 Patient outcomes are poor, with published median survival times (MSTs) for both feline and canine CNS cryptococcosis of < 1 month.8 CNS involvement in cats and dogs with cryptococcosis is a negative prognostic indicator.28,29 An Australian study28 reported 50% (7/14) treatment successes (defined as long-term disease control or cure) in feline patients with CNS involvement, compared with 84% (38/45) for cats with non-CNS disease. In a Canadian study,29 initial presence or development of neurologic signs was associated with a 4.3 times increased risk of death. Despite the guarded prognosis, a subset of animals experience long-term robust disease control, with 32% (9/28) of treated cats and dogs described by Sykes et al8 having remission periods of ≥ 1 year.

This study’s objective was to describe the clinical and laboratory findings, treatments, and outcomes for cats and dogs in Australia with CNS cryptococcosis.

Materials and Methods

Study overview and animal selection

A case series and cohort study were performed using the same 50 animals. Both studies were multi-institutional and both retrospective and prospective. Referral centers in all Australian mainland states were invited to participate. Databases from cooperating veterinary referral centers were searched for cats and dogs diagnosed with cryptococcosis between 2000 and 2020. Data were collected and animals monitored for the prospective portion of the study between 2018 and 2020. Cats and dogs diagnosed with cryptococcosis were recruited if (i) the diagnosis was confirmed by culture, serology, or identification of characteristic organism morphology using cytologic or histologic techniques, and (ii) the animal had neurologic abnormalities recorded in the owner’s history, on neurologic examination, on clinicopathologic testing, or using diagnostic imaging.

Data collection

Information extracted from medical records included signalment, geographic location, history, physical and neurologic examination findings, latex cryptococcal antigen agglutination test (LCAT) results, CSF analysis, retroviral status (for cats), cytologic and histologic observations, mycology results including molecular typing (if performed), imaging findings, treatments, and outcomes. For animals with unknown outcome, further information was collected by contacting referring veterinarians and owners (when phone numbers were available).

Neurologic examination and neuroanatomic localization

Neurolocalization was based on abnormalities in the medical record for neurologic examinations performed at initial presentation at the referral center. Neurologic examinations were performed by internal medicine specialists or residents-in-training, and neurolocalization was performed retrospectively by the primary author. Due to limited access to specialist neurologists, as well as the infectious and typically multisystemic nature of cryptococcosis, these cases are commonly managed by internists in Australia. If neurologic abnormalities could not be localized to a single region, disease was classified as multifocal or diffuse. Regions for localization were forebrain, central vestibular or cerebellum, brain stem, and spinal cord. Pain responses or altered sensation were classified as hyperesthesia if there was increased sensitivity to stimulation or hyperpathia if there was an abnormally painful reaction to a stimulus (eg, spinal palpation)30 for animals for which the medical record was descriptive rather than specific.

Cerebrospinal fluid analyses

Animals with pleocytosis (elevated CSF total nucleated cell count [TNCC]) were classified according to the predominant cell type when differential cell counts were available. Pleocytosis was classified in the following order: (i) as eosinophilic (eosinophils > 10% of the nucleated cell population), (ii) according to the cell type that comprised > 70% of the nucleated cells, or (iii) as mixed, when each cell type comprised < 70% (usually < 50%) of the cells present.31

Outcomes

Medical records were examined at the time of identification of each eligible animal to ascertain whether the cat or dog had died, had been euthanized, was cured, or was under treatment. Animals were classified as cured if, at last recorded contact, they had no clinical signs of CNS cryptococcosis, had at least 1 negative reciprocal LCAT titer (defined as ≤ 2), and were no longer receiving antifungal treatment, or were classified as under treatment if, at last contact, they were receiving antifungal treatment and had a follow-up examination scheduled. For animals neither dead nor cured and with unknown treatment status, prospective follow-up with the referring veterinarian or owner was attempted and the animal’s status classified on the basis of any further information obtained. Deaths and euthanasias were classified as related to cryptococcosis if clinical signs present at diagnosis persisted or had progressed by the time of death or euthanasia and no other disease that could have contributed to death was evident.

Statistical analysis

Mann-Whitney U test exact P values were used to determine whether distributions of the continuous variables of age, duration of signs, reciprocal serum LCAT titer, CSF cell counts, and CSF protein concentrations (all at or soon after initial presentation) differed between cats and dogs. Fisher exact tests were used to determine whether categorical variables (historic signs and neurologic abnormalities) differed in frequency between cats and dogs. Clopper-Pearson binomial 95% CIs were calculated for proportions. For survival analyses, times from initial presentation to death or euthanasia were calculated in days (day of initial presentation = 1). For animals not known to have died at last follow-up, times were right-censored at date of last known examination or owner contact. Kaplan-Meier survival functions were constructed using deaths from all causes, and MST and 2- and 3-year ST percentages were estimated from these. STs were compared between cats and dogs, and, separately for cats and dogs, STs were compared between various subsets. Associations between ST and age at initial presentation and reciprocal serum LCAT titer (both categorized as above or not above median), abnormal mentation at presentation, history of seizures, whether general anesthesia was performed, and whether CSF was collected were determined by comparison of survival curves with the log-rank test, stratified by whether the animal had been treated with antifungal drugs (yes or no). For analyses of associations between ST and each of glucocorticoid treatment prior to diagnosis, glucocorticoids given after diagnosis, and whether single or multiple antifungal drugs were used for treatment, only animals treated with antifungal drugs were used. The variables chosen for survival analyses had been examined previously in feline and canine CNS cryptococcosis patients, and of these, abnormal mentation, presence of seizures, and high LCAT titers have been reported to be prognostically important in humans and animals.8 Analyses were performed using SPSS Statistics (version 28; IBM) and Stata (version 17; StataCorp). The P values are reported in the Results; our inference was informed by the actual P value magnitude along with prior evidence for the association, as recently recommended.32

Results

The database search identified 119 animals (63 cats; 56 dogs) with cryptococcosis. Of these, 53 (20 cats; 33 dogs) had neurologic abnormalities and were therefore enrolled. The following 3 were subsequently excluded: 2 dogs due to diagnostic uncertainty and 1 cat due to lack of evidence of intracranial cryptococcosis, leaving 50 enrolled animals (19 cats; 31 dogs; Figure 1).

Figure 1
Figure 1

Proportions and summary statistics for 19 cats and 31 dogs with CNS cryptococcosis diagnosed between 2000 and 2020 stratified by whether they received treatment with antifungal medication, then further subgrouped on the basis of outcome (known status [died, cured, or being treated] vs unknown status). Survival and follow-up times (medians and ranges in days) were calculated from the initial presentation (day 1) to the date of death, euthanasia, or last follow-up (last contact by veterinary examination or telephone contact [if the owner was contacted]).

Citation: Journal of the American Veterinary Medical Association 261, 2; 10.2460/javma.22.08.0342

Excluded dogs included a 5-year-old spayed female Siberian Husky with generalized seizures that had normal neurologic examination, head CT, and CSF analysis. Serum LCAT was positive (reciprocal titer 16). Fluconazole was started but discontinued 2 to 6 weeks later due to 2 negative follow-up LCAT titers. Antiseizure medications were not administered except for phenobarbitone for 2 days prior to referral. The dog had further seizures approximately 3 months after presentation and was euthanized 2 weeks later due to ongoing seizures. An alternate diagnosis of idiopathic epilepsy was likely. The second dog was a 12-year-old neutered male Staffordshire Bull Terrier with generalized and partial seizures. Neurologic examination was normal, head CT was performed but not reviewed by a boarded radiologist, and CSF analysis showed neutrophilic pleocytosis. CSF LCAT was borderline positive (reciprocal titer 2), and serum LCAT was not performed. No antifungal medications were administered, and the case was subsequently managed by the referring veterinarian with phenobarbitone and prednisolone. No further seizures occurred, and the dog was euthanized 684 days after diagnosis due to respiratory distress and abdominomegaly. An alternate cause of the seizures is likely, given the borderline positive CSF LCAT titer and prolonged ST without specific treatment. The cat without intracranial evidence of cryptococcosis was a 16-year-old male neutered domestic shorthair with sneezing and stertor at presentation. Head CT revealed a nasopharyngeal mass, which was confirmed histopathologically as cryptococcosis. Serum LCAT reciprocal titer was 4,096. Head CT also revealed 2 intracranial extra-axial masses, suspected to be meningiomas on the basis of imaging characteristics. Imaging did not reveal intracranial disease extension from sinonasal structures. Intracranial sampling was not performed.

Neurologic involvement was identified on the basis of clinical signs reported by the owner (17/19 cats; 24/31 dogs), on neurologic examination at initial presentation (15/17 cats; 24/27 dogs so tested), on CSF analysis (9/10 cats; 15/16 dogs so tested), on imaging studies (9/10 cats; 13/15 dogs that had head CT or MRI performed with boarded radiologist report available for review), or on gross and histologic examination at necropsy (1 dog). All cases with historic neurologic signs (ie, as reported by the owner) also had CNS abnormalities on neurologic examination at initial presentation, CSF analysis, or diagnostic imaging studies.

Geographic location and signalment

The 50 cats and dogs were contributed by referral centers on the east and west coasts and in northern Australia. Median age at initial presentation was 6.0 years (IQR, 4.2 to 8.5 years) for cats and 3.0 years (IQR, 1.9 to 4.0 years) for dogs. Age at presentation was lower in dogs than cats (P < .001). Males and females were approximately equally represented in both species. In dogs, 18 of 31 were female (14 spayed and 4 entire) and 13 of 31 were male (9 castrated and 4 entire). All 19 cats were neutered, with 10 of 19 male. Purebreds comprised 21% of cats and 61% of dogs. Cat breeds included domestic shorthair (n = 7), domestic medium hair (4), Ragdoll (3), domestic longhair (2), and 1 each of Birman, Himalayan cross, and Ragdoll cross. Dogs included Border Collie (n = 3), Doberman (2), Labrador Retriever (2), Maltese (2), Poodle cross (2), Staffordshire Bull Terrier (2), Staffordshire Bull Terrier cross (2), and 1 each of various other breeds.

Historic signs

Neurologic signs were present historically (ie, prior to initial presentation) in 89% (17/19) of cats and 77% (24/31) of dogs. Extraneurologic signs were evident in 84% (16/19) of cats and 65% (20/31) of dogs. Behavioral change and reduced appetite were more frequent in cats than dogs (P = .003 for both; Table 1). Median durations of historic neurologic signs were 7 days in both cats and dogs (ranges, 1 to 315 in cats and 1 to 112 in dogs). Median durations of extraneurologic signs were 15 days in cats (range, 1 to 462 days) and 21 days in dogs (range, 1 to 84 days).

Table 1

Historic neurologic and extraneurologic clinical signs noted in the medical record at initial presentation for 19 cats and 31 dogs with CNS cryptococcosis diagnosed between 2000 and 2020.

Clinical sign(s) No. of cats (n = 19) % of cats (95% CI) No. of dogs (n = 31) % of dogs (95% CI) P valuea
Any neurologic sign 17 89 (67–99) 24 77 (59–90) .452
 Gait abnormality 7 37 (16–62) 14 45 (27–64) .768
 Seizures 4 21 (6–46) 6 19 (7–38) > .99
 Blindness 4 21 (6–46) 5 16 (6–34) .715
 Behavioral change 7 37 (16–62) 1 3 (0–17) .003
 Apparent painb 1 5 (0–26) 7 23 (10–41) .134
 Abnormal mentation 3 16 (3–40) 3 10 (2–26) .661
 Vestibular signsc 3 16 (3–40) 2 6 (1–21) .355
 Collapse 2 11 (1–33) 3 10 (2–26) > .99
 Abnormal movementsd 1 5 (0–26) 4 13 (4–30) .637
 Mydriasis 3 16 (3–40) 1 3 (0–17) .147
 Anisocoria 1 5 (0–26) 0 0 (0–11) .380
Any nonspecific or extraneurologic sign 16 84 (60–97) 20 65 (45–81) .197
 Hyporexia or anorexia 14 74 (49–91) 9 29 (14–48) .003
 Lethargy 8 42 (20–67) 12 39 (22–58) > .99
 Upper respiratory tract signs 4 21 (6–46) 10 32 (17–51) .522
 Gastrointestinal tract signs 5 26 (9–51) 7 23 (10–41) > .99
 Weight loss 3 16 (3–40) 3 10 (2–26) .661
 Facial swelling or deformity 1 5 (0–26) 4 13 (4–30) .637
 Nictitating membrane prolapse 2 11 (1–33) 3 10 (2–26) > .99
 Lower respiratory tract signs 0 0 (0–18) 2 6 (1–21) .519
 Dermal lesions 2 11 (1–33) 0 0 (0–11) .140
 Lymphadenomegaly 1 5 (0–26) 1 3 (0–17) > .99
 Hypodipsia 0 0 (0–18) 2 6 (1–21) .519

aP values for null hypotheses that the frequency is the same in cats and dogs.bSigns of pain localized to the spine were observed in 1 cat and 4 dogs (2 dogs cervical, 1 dog lumbar, and 1 dog and 1 cat not further localized), with the remaining 3 dogs vocalizing randomly with poorly localizable signs of pain.c Vestibular signs included head tilt, spontaneous nystagmus, and vestibular ataxia.d Abnormal movements included tremors (2 dogs), fasciculations (2 dogs), and twitches (1 cat).

Neurologic examination

A systematic neurologic examination was performed at initial presentation in most animals (17/19 cats; 27/31 dogs), with abnormalities detected in 88% (15/17) of cats and 89% (24/27) of dogs. Abnormal mentation was more common in cats than dogs (P = .038; Table 2). The most common neurolocalization was forebrain (6 cats; 10 dogs), followed by multifocal or diffuse (3 cats; 5 dogs), central vestibular including the cerebellum (4 cats; 2 dogs), brain stem (2 cats; 2 dogs), and spinal cord (3 dogs). Five cats and 4 dogs had optic fundus abnormalities, viz chorioretinitis (4 cats; 3 dogs), optic disc changes consistent with optic neuritis (2 cats; 1 dog), and retinal hemorrhage (1 cat).

Table 2

Neurologic examination abnormalities at initial presentation noted in the medical record for 17 of the 19 cats and 27 of the 31 dogs described in Table 1 that had undergone a neurologic examination at that time.

Neurologic sign(s) No. of cats (n = 17) % of cats (95% CI) No. of dogs (n = 27) % of dogs (95% CI) P value
Cranial nerves 12 71 (44–90) 11 41 (22–61) .069
 Menace responses 8 47 (23–72) 6 22 (9–42) .107
 Pupillary light reflexes 6 35 (14–62) 6 22 (9–42) .489
 Blindness 4 24 (7–50) 5 19 (6–38) .716
 Mydriasis 2 12 (2–36) 6 22 (9–42) .455
 Spontaneous nystagmus 4 24 (7–50) 2 7 (1–24) .186
 Anisocoria 2 12 (2–36) 1 4 (0–19) .549
 Optic disc 2 12 (2–36) 1 4 (0–19) .549
 Head tilt 1 6 (0–29) 1 4 (0–19) > .99
 Strabismus 1 6 (0–29) 1 4 (0–19) > .99
 Dazzle reflex 0 0 (0–20) 2 7 (1–24) .515
 Oculocephalic reflex 1 6 (0–29) 1 4 (0–19) > .99
 Gag reflex 0 0 (0–20) 1 4 (0–19) > .99
 Nasal and facial sensation 0 0 (0–20) 1 4 (0–19) > .99
 Pupillary athetosis 1 6 (0–29) 0 0 (0–13) .386
 Corneal reflex 1 6 (0–29) 0 0 (0–13) .386
Gait 6 35 (14–62) 11 41 (22–61) .761
 Ataxia 3 18 (4–43) 10 37 (19–58) .198
 Paresis ambulatory 0 0 (0–20) 3 11 (2–29) .272
 Paresis nonambulatory 2 12 (2–36) 0 0 (0–13) .144
 Circling 1 6 (0–29) 0 0 (0–13) .386
Posture 4 24 (7–50) 3 11 (2–29) .402
 Abnormal movementsb 2 12 (2–36) 3 11 (2–29) > .99
 Decerebellate posture 1 6 (0–29) 0 0 (0–13) .386
 Pleurothotonus 1 6 (0–29) 0 0 (0–13) .386
Postural reactions 4 24 (7–50) 9 33 (17–54) .735
Mentation and behavior 8 47 (23–72) 4 15 (4–34) .035
 Altered mentation 8 47 (23–72) 4 15 (4–34) .035
 Pacing 1 6 (0–29) 0 0 (0–13) .386
Pain or altered sensationc 2 12 (2–36) 6 22 (9–42) .455
 Cervical hyperpathia 1 6 (0–29) 4 15 (4–34) .634
 Thoracic, lumbar, or sacral hyperpathia 2 12 (2–36) 1 4 (0–19) .549
 Hyperesthesia 0 0 (0–20) 2 7 (1–24) .515
 Photophobia 0 0 (0–20) 2 7 (1–24) .515
Segmental myotatic reflexes 1 6 (0–29) 5 19 (6–38) .380

aP values for null hypotheses that the frequency is the same in cats and dogs.b Abnormal movements: tremors (3 dogs), facial twitches (1 cat), and muscle fasciculations (1 cat).c Spinal hyperpathia was multifocal or diffuse in 1 cat and 1 dog.

Serology

Serum LCAT was positive in all (15/15) cats and most (24/25) dogs for which testing was performed. Positive serum reciprocal LCAT titers ranged from 64 to 16,389 (median, 1,280) in the 12 cats and 16 to 16,384 (median, 256) in the 22 dogs that had end point titers available. Titers were significantly (P = .031) higher in cats than in dogs (Figure 2). Animals without end point LCAT results available were a cat with a reciprocal titer > 1,048,576, 2 animals with reciprocal titers > 2,048 (1 cat; 1 dog), and 2 animals with no titer results available (1 cat; 1 dog). The dog with a negative serum LCAT (titer set to 0 for statistical analysis) had a nasal mass with extension into the olfactory lobe on CT, with cryptococcal organisms identified histologically. One cat and 3 dogs had CSF LCAT results available: positive in 1 cat and 2 dogs (reciprocal titer 256 in the cat; 1,024 in 1 dog, with no result available in the other positive dog) and negative in 1 dog. The dog with a negative CSF LCAT titer had central vestibular signs, serum reciprocal LCAT titer of 32, and marked eosinophilic pleocytosis (TNCC 1,503 X 109/L) with C neoformans identified on CSF culture.

Figure 2
Figure 2

Box-and-whisker plots of serum latex cryptococcal antigen agglutination test titers for 12 of the 19 cats and 23 of the 31 dogs described in Figure 1 that had end point titers available for analyses. The y-axis indicates the reciprocal titer at initial presentation. For each plot, the line in the box represents the median, the box represents the IQR (25th to 75th percentiles), the whiskers extend to the most extreme values that are ≤ 1.5 times the IQR below the 25th percentile (lower whisker) or above the 75th percentile (upper whisker), and circle and asterisks represent outlier results (ie, if more than 3 times the IQR above the upper whisker or below the lower whisker) for the cats and dogs, respectively. Latex cryptococcal antigen agglutination test titers were significantly (P = .031) lower in dogs than cats.

Citation: Journal of the American Veterinary Medical Association 261, 2; 10.2460/javma.22.08.0342

Mycology

Culture was performed in 4 of 19 cats and 17 of 31 dogs, either at or shortly after initial presentation, and was positive in 50% (2/4) of cats and 82% (14/17) of dogs. Samples cultured included CSF (2 cats; 8 dogs), fluid or tissue from the sinonasal cavity (nasal swab, nasal flush, biopsy of nasal mucosa, or sinonasal granuloma; 1 cat and 5 dogs), lymph node biopsy or aspirate (1 cat; 2 dogs), and 1 each of urine, intra-abdominal mass biopsy, ocular discharge, and facial subcutaneous mass biopsy. Two dogs had culture performed on tissues from multiple sites. Cryptococcal species isolated were C neoformans (2/2 cats; 12/14 dogs), C gattii (1/14 dogs), and species not further identified (1 dog). One C neoformans isolate from a cat was further identified as C neoformans var grubii. One C gattii isolate from a dog in southeast Queensland was genotyped as VGI.

Cerebrospinal fluid findings

CSF was collected and tested in approximately half the animals (10/19 cats; 16/31 dogs; Table 3). Site of collection was cisterna magna (6/10 cats; 7/16 dogs), lumbar cistern (1/10 cats), or unrecorded (3/10 cats; 9/16 dogs). CSF was abnormal in all but 1 cat and 1 dog. Inflammation was evident in most animals (8/10 cats; 15/16 dogs), with albuminocytologic dissociation present in 1 cat. Classification as inflammatory CSF was based on pleocytosis (6/10 cats; 14/16 dogs) or an abnormal differential cell count with either normal (1/10 cats) or insufficient sample (1/10 cats; 1/16 dogs) for TNCC. Animals with pleocytosis and differential cell count available for review (5 cats; 12 dogs) were classified according to the predominant cell type. Eosinophilic pleocytosis was most common in dogs (7/12 dogs) but not identified in cats. The remainder of animals had mononuclear pleocytosis (2/5 cats; 2/12 dogs), neutrophilic pleocytosis (1/5 cats; 2/12 dogs), or mixed pleocytosis (2/5 cats; 1/12 dogs). At presentation, the 2 animals with clinically normal results for CSF analysis had concurrent neurologic and upper respiratory tract signs, as follows: a cat had Cryptococcus sp DNA identified in CSF using multiplex qPCR and a serum reciprocal LCAT titer of 4,096, and a dog had rhinosinusitis with intracranial extension on MRI, with cryptococcus confirmed histologically and on culture of nasal mucosa, with a serum reciprocal LCAT titer of 128.

Table 3

Results of CSF analysis from a subset of the animals described in Table 1 that had undergone CSF collection and analysis.

Variable No. of animals tested No. of animals with high resultsa Median Rangeb Reference intervalc P value
RCC (X106/L) < 1 .361
  Dogs 14 13 163 0–7,396
  Cats 9 5 5 0–27,576
TNCC (X106/L) < 5 to < 8 .056
  Dogs 14 13 90 0–1,503
  Cats 9 6 10 1–712
Total protein (g/L) < 0.3 to < 0.5 .938
  Dogs 15 11 0.4 0.2–5.5
  Cats 8 5 0.8 0.2–6.2
Neutrophils (%) < 25 .774
  Dogs 9 4 30 2–86
  Cats 5 3 33 1–75
Mononuclear cells (%) NA .323
  Dogs 10 NA 42 8–98
  Cats 5 NA 66 22–96
Small mononuclear cells (%) NA .891
  Dogs 7 NA 15 2–40
  Cats 4 NA 23 5–33
Large mononuclear cells (%) NA .291
  Dogs 7 NA 15 5–57
  Cats 4 NA 33 17–84
Eosinophils (%) < 1 .178
  Dogs 8 8 45 2–95
  Cats 2 2 3 3–3

NA = Not applicable (no reference interval available). RCC = Red cell count. TNCC = Total nucleated cell count.

aMissing values were due to insufficient sample to determine nucleated cell count or protein concentration, cell type not being reported in the differential cell count, or missing data in the medical record.b Differential cell counts are summarized using only samples with elevated TNCCs.c Reference intervals varied with laboratory, year, species and site of CSF collection. Individual results were considered elevated if they fell outside the reference interval specific to that sample. Where there was discordance in reference intervals, the narrowest and widest reference intervals are both shown in the table.

Cryptococcal organisms were identified in the CSF in 70% (7/10) of cats and 50% (8/16) of dogs. Identification was via cytology (4/10 cats; 4/16 dogs), PCR assay (4/5 cats and 3/4 dogs that had PCR assays performed), or mycologic culture (0/2 cats and 5/8 dogs that had culture performed). Cryptococcal species isolated were C neoformans in 4 dogs and Cryptococcus sp not further identified in 1 dog.

MRI and CT imaging

MRI or CT imaging of the brain or head was performed, with boarded radiologist findings available in approximately half of the animals (10/19 cats; 15/31 dogs). Imaging was performed during initial diagnostic investigations in all patients except 1 dog (in which neurologic deterioration after trauma occurred while on long-term treatment for CNS cryptococcosis). In the majority, imaging was performed to investigate neurologic signs, although 2 cats and 5 dogs had MRI or CT performed to investigate sinonasal signs, facial swellings, or lymphadenomegaly. All 7 of these patients had intracranial abnormalities identified on imaging. MRI and CT findings for the animals in this study will be described in detail in a subsequent report.

Immunocompromise

Serologic testing for FIV and FeLV was performed at, or shortly prior to, initial presentation (9/19 and 8/19 cats, respectively); all results were negative. Glucocorticoids had been administered prior to diagnosis in approximately half the animals (10/19 cats; 14/31 dogs). Only 3 dogs and 1 cat received glucocorticoids prior to developing signs attributable to cryptococcosis; in the remainder they were administered empirically prior to obtaining a diagnosis. Animals received glucocorticoids on an outpatient basis (6/10 cats; 8/14 dogs), after diagnosis of meningitis on CSF analysis but while awaiting infectious disease testing (4/10 cats; 8/14 dogs), or both. All animals that received glucocorticoids had neurologic signs at presentation. Glucocorticoids given included dexamethasone (0.1 to 1.2 mg/kg, daily) and prednisolone (0.4 to 4.3 mg/kg, daily). No animals received other immunosuppressive medications.

Treatments

In total, 79% (15/19) of cats and 77% (24/31) of dogs were treated with antifungals. Most treated animals (11/15 cats; 16/24 dogs) received > 1 antifungal drug. In all of these except 1 dog, the treatment protocol consisted of amphotericin B and a triazole (fluconazole or itraconazole), administered sequentially or concurrently, with or without terbinafine. The remaining dog received itraconazole, then fluconazole.

Fluconazole was most frequently prescribed (14/15 cats; 21/24 dogs), followed by amphotericin B (11/15 cats; 15/24 dogs), itraconazole (2/15 cats; 6/24 dogs), and terbinafine (0/15 cats; 1/24 dogs). Amphotericin B formulations and route of administration included deoxycholate SC (5 cats; 14 dogs; 2 dogs received some doses IV or IP to avoid sterile abscesses), liposomal IV (5 cats), or unknown SC (1 dog; 1 cat). The median cumulative dose for amphotericin B deoxycholate was 4.0 mg/kg (IQR, 1.5 to 8.5 mg/kg) in cats and 11.6 mg/kg (IQR, 1.0 to 14.8 mg/kg) in dogs. The median cumulative dose of IV liposomal amphotericin B in cats was 11.5 mg/kg (IQR, 11.4 to 12.0 mg/kg). Reasons for discontinuation of amphotericin B at a cumulative dose < 10 mg/kg were death or euthanasia associated with cryptococcosis (3 cats; 3 dogs), azotemia (3 cats), owner decision (2 dogs), planned transition from induction to consolidation treatment with fluconazole (1 cat), or unknown (1 dog). Adverse effects associated with amphotericin B administration included azotemia (8/11 cats; 4/15 dogs), self-limiting sterile abscess formation (6 dogs), and sterile peritonitis (1 dog). Surgical debridement of non-neurologic lesions was performed in addition to antifungal treatment in 1 cat and 4 dogs. Corticosteroids were administered concurrently with antifungal medication in most treated animals (10/15 cats; 13/24 dogs). Median maximum dose was 0.2 mg/kg (range, 0.05 to 1 mg/kg) for dexamethasone, 0.5 mg/kg (range, 0.2 to 1.6 mg/kg) for prednisolone, and 1.0 mg/kg (range, 0.5 to 23 mg/kg) for methylprednisolone sodium succinate. Duration of treatment was relatively evenly split between single dose, short term (< 7 days), and long term (up to 20 weeks).

Outcomes

Patient outcomes stratified by treatment are shown (Figure 1). Regardless of treatment, reasons for death or euthanasia were related to cryptococcosis (7/11 cats; 16/16 dogs), unrelated to cryptococcosis (1/11 cats; drowned), or unknown (3/11 cats). These latter 3 cats were suspected of having progressive disease. They were presented with recurrence of neurologic signs (2/3 cats) or developed unilateral ocular abnormalities including exophthalmos (1/3 cats) between days 1,556 and 2,825, all while on long-term fluconazole with stable disease. In all 3 cats, owners elected euthanasia rather than pursuing further investigations or treatment. Reasons for euthanasia without pursuing treatment (n = 6 patients) were clinical deterioration, perceived poor prognosis, and financial limitations.

Of the treated animals not identified as having died, 63% (5/8) of cats and 77% (10/13) of dogs with > 1 year of follow-up from initial presentation had stable disease (3 cats; 8 dogs) or were considered cured (2 cats; 2 dogs) at last contact. These long-term treated or cured animals differed from the broader study population in that, at presentation, they had neurologic signs less frequently (3/5 cats; 5/10 dogs) and rarely had signs of abnormal mentation (1 cat only). In this subgroup, most animals (2/5 cats; 9/10 dogs) were treated with both amphotericin B and a triazole.

Overall estimated MST from initial presentation was 1,556 days (lower limit of the 95% CI, 10) for the 19 cats and 637 days (lower limit of the 95% CI, 9) for the 31 dogs (Figure 3). MST for patients treated with antifungals was 1,678 days (lower limit of the 95% CI, 60) for the 15 cats and 679 days (lower limit of the 95% CI, 16) for the 24 dogs. (Upper limits of these 95% CIs could not be calculated.) For cats and dogs, respectively, 2-year ST percentages were 69% (95% CI, 37% to 87%) and 49% (95% CI, 24% to 71%) and 3-year ST percentages were 52% (95% CI, 16% to 79%) and 49% (95% CI, 24% to 71%). In animals that survived beyond day 7 (14 cats; 21 dogs), MSTs were 1,678 days (lower limit of the 95% CI, 60) for cats and 2,012 days (lower limit of the 95% CI, 637) for dogs (antifungal treatment was initiated in all but 1 dog).

Figure 3
Figure 3

Kaplan-Meier survival curves for the 19 cats and 31 dogs described in Figure 1, grouped on the basis of whether dogs had signs of clinically normal versus abnormal mentation at presentation (A; P = .001), whether cats had versus did not have CSF collected (B; P = .015), whether dogs that received antifungal treatment were versus were not given glucocorticoids prior to diagnosis (C; P = .013) or were administered single versus multiple antifungal medications (D; P = .023), and by canines versus felines (E; P = .853). Log-rank test P values for comparison of survival time by subset are listed. Each step represents the death of ≥ 1 animal. Tick marks indicate right-censored intervals.

Citation: Journal of the American Veterinary Medical Association 261, 2; 10.2460/javma.22.08.0342

After adjustment for antifungal drug administration (“treatment”), abnormal mentation was associated with decreased ST in dogs (4/4 with abnormal mentation all died by day 13, and 12/27 with normal mentation died with a median of 679 days; P = .001). After adjustment for treatment, CSF collection was associated with decreased ST in cats (7/10 with CSF collected died by a median of 60 days and 4/9 without CSF collected died by a median of 1,678 days; P = .015). In treated dogs, variables associated with decreased ST were the administration of glucocorticoids before diagnosis (9/12 died by a median of 16 days, compared to 2/12 that did not receive glucocorticoids prior to diagnosis and died on days 2 and 31; P = .013) and the use of single rather than multiple antifungal medications (5/8 died by a median of 13 days, compared to 6/16 that received multiple antifungal medications and died by a median of 2,012 days; P = 0.023; Figure 3).

Discussion

To our knowledge, the present study represented the largest series of cats and dogs with cryptococcosis affecting the CNS ever assembled. It was the first study of cryptococcosis in companion animals in Australia to concentrate on the CNS. We evaluated clinical findings, treatments, and outcomes and had sufficient numbers to identify variables strongly associated with prognosis.

Neurologic signs present in this study were similar to those described previously.7,8,15,29,33 Cats showed behavioral change, altered mentation, and reduced appetite more frequently than dogs. Although not statistically significant, dogs more frequently displayed signs of pain than cats, both as a historic sign and on neurologic testing. These differences may reflect species-specific behavioral differences masking some signs, extent or location of cryptococcal lesions, or degree of CNS inflammation. In a Californian study,8 cats had reduced brain inflammation compared with dogs. The reason is unclear, but may be due to differences in cryptococcal isolates (which may be geographically dependent), anatomy, or host immune response. Extraneurologic signs mostly involved the sinonasal cavity and contiguous structures, with lower respiratory and alimentary involvement being rare. This is consistent with the upper respiratory tract being a common site of entry presumably due to differences in airflow or more efficient filtering of inhaled basidiospores by the elaborate turbinate architecture in cats and dogs compared to other species. When examined, retinal changes were detected frequently. As fundic examinations were recorded inconsistently, however, the frequency of ocular abnormalities was probably underestimated. In cats and dogs, cryptococcal entry to the brain appears to be commonly via neurocranial osteolysis secondary to sinonasal disease. This is supported by the frequent co-occurrence of upper respiratory tract and neurologic signs; the observation that extraneurologic signs commonly precede neurologic signs, particularly in cats; and imaging and necropsy findings in both species.1,4,5,8,25

Serologic testing is a vital diagnostic aid in feline and canine cryptococcosis. If conducted with technical proficiency, it is highly sensitive and specific.3335 Magnitude of reciprocal LCAT titers has been shown to correlate with disease severity but not with site of infection or presence of neurologic signs.29,36,37 In a large series of animals from California5 with disease affecting multiple body systems, cats had higher titers than dogs. Interestingly, when only CNS patients from this Californian cohort were examined,8 titer magnitude was similar in cats and dogs. In the present study, cats had higher LCAT titers than dogs. Differences between Australian and Californian data are likely attributable to the diverse range of cryptococcal molecular types (especially of C gattii) found in that part of the US. False-negative LCAT results have been reported with localized nasal, ocular, and CNS disease, particularly in dogs.5,8,33 This study found a false-negative titer in 1 dog.

Pleocytosis was the predominant finding on CSF analysis in the current and previous reports.8,21 Most dogs had eosinophilic pleocytosis, which in many instances was marked, while cats had mixed, mononuclear, or neutrophilic pleocytosis. Organisms were identified in CSF in 70% (7/10) of cats and 50% (8/16) of dogs. In a previous cohort from California,5,8 cryptococcal organisms were identified cytologically in CSF in 82% (9/11) of cats and 73% (11/15) of dogs. Failure to detect organisms in CSF, however, does not rule out cryptococcosis, as abundant organisms were identified at necropsy in several animals in which no organisms were detected in CSF.8 Importantly, 1 cat and 1 dog in the present study had normal CSF results, so CNS involvement should not be excluded on this basis. CSF analysis is invasive and can be associated with adverse effects and death. Some authors argue the risk of CSF collection outweighs the benefit given the utility of serology in obtaining a diagnosis and the accessibility of peripheral tissues should culture be deemed important.2 In this study, CSF collection in cats was associated with decreased ST, and in the Californian cohort,8 several patients failed to recover from anesthesia for CSF sampling. Risk of clinical deterioration or death with CSF collection in cryptococcal meningitis may be due to brain herniation associated with raised intracranial pressure or space-occupying lesions.2 When cryptococcosis is a differential diagnosis, CSF analysis should be reserved for the rare patient in which it is required to establish a diagnosis or to determine the infective biotype for animals in which this would alter treatment, ideally after cross-sectional imaging has evaluated herniation risk.

Interestingly, 2 cats and 5 dogs had CNS involvement identified during MRI or CT investigations of sinonasal disease or facial or cervical (lymph node) swellings, without any referable signs historically or on neurologic examination. It is possible that subtle evidence of neurologic involvement, such as mild optic neuritis or anosmia, went unnoticed in these animals, as only 1 dog from this group had results of fundic examination recorded (chorioretinitis). These animals (except for 1 dog euthanized when diagnosed 1 day after initial presentation) comprised approximately half the subset of patients considered cured or having stable disease on treatment with > 1 year follow-up. This suggests early identification of CNS involvement, with appropriate fungicidal treatment, may provide good long-term disease control. Although routine use of MRI or CT to investigate animals with suspected cryptococcosis is likely to identify this subset, the utility of blanket imaging is unclear. Cross-sectional imaging provides data about disease extent, although it is costly and may not change overall treatment recommendations or outcomes in animals with committed owners.

Overall, MSTs in this study were longer (1,556 days for cats; 637 days for dogs) than those previously reported for the Californian cohort8 (13 days for cats; 7 days for dogs). In the Californian study,8 dogs surviving ≥ 4 days from diagnosis had an MST of 190 days. A similar trend was noted in our study, with animals alive beyond day 7 commonly having long STs (MSTs, 1,678 days for cats and 2,012 days for dogs). This highlights that patients receiving antifungal treatment and not euthanized or dying in the first 7 days can have prolonged ST with stable disease during treatment and can even be cured. The apparently longer overall STs in our study compared with the Californian study8 may reflect differences in infective organism virulence (C neoformans predominated in our study versus more C gattii molecular type VGII and VGIII infections in California) or severity of disease at initial presentation (all but 1 cat had neurologic signs at presentation in the Californian study).

Despite apparently longer MSTs than previously reported,8 it is likely that many animals in our study were “undertreated.” Cumulative doses of amphotericin B were low, and flucytosine was not used in cats. Median cumulative doses of amphotericin B reported to achieve a cure in Australian cats and dogs with cryptococcosis involving any body system were 16 and 24 mg/kg, respectively.28 Flucytosine is standard care as a component of induction treatment in humans38 and cats.39 Its use in dogs is not recommended due to the high incidence of toxic epidermal necrolysis.40,41 Low cumulative doses of amphotericin B in animals that did not die during the early treatment phase were due to development of azotemia or owner decision. In many patients, nephrotoxicity is reversible with temporary cessation of administration,42 although amphotericin B was infrequently restarted in the present study. Over a third of dogs treated with subcutaneous infusions of amphotericin B experienced sterile abscess formation, which may have contributed to owner decision to cease treatment or reduce treatment frequency. Intraperitoneal administration may avoid this effect, although the 1 dog in our study that had amphotericin B administered IP developed self-limiting sterile peritonitis. Alternative formulations or dosing protocols may mitigate these effects. Oral amphotericin B is currently being developed, and studies in people43 and dogs44 have begun, while high single-dose or short-course liposomal amphotericin B has been shown to be noninferior for human cryptococcal meningitis.45,46 Further studies are needed to evaluate these approaches in cats and dogs.

Variables associated with reduced ST in dogs included abnormal mentation at diagnosis and, in treated dogs, use of glucocorticoid administration prior to diagnosis and treatment with single rather than multiple antifungals. Sykes et al8 reported that abnormal mentation at presentation negatively impacted outcome and hypothesized that abnormal mentation was due to raised intracranial pressure or overall high CNS fungal burden. In humans, raised intracranial pressure is negatively associated with outcome47 and therapeutic lumbar puncture is recommended during initial treatment.38 In the present study, glucocorticoids administered prior to commencing antifungal treatment had a negative effect on outcome in treated dogs. Glucocorticoid use may reduce host immune responses, thereby permitting the infection to intensify and more easily penetrate the CNS. Alternatively, it may be that patients that received glucocorticoids had more severe signs and therefore more advanced disease, although this would appear less likely as half of patients were treated in an outpatient setting. This highlights the importance of making a definitive diagnosis rather than using glucocorticoids symptomatically. The role of glucocorticoids in conjunction with antifungal treatment is unclear. Sykes et al8 found glucocorticoids improved early (< 10 days) ST, presumably by reducing inflammation associated with dying cryptococcal organisms and antigen release during early antifungal treatment. A large human study48 of 451 HIV-positive cryptococcal meningitis patients showed glucocorticoid use did not reduce mortality rate and was associated with higher risk of adverse effects or disability. As such, cautious use of glucocorticoids is advocated and then only during the initial treatment period in animals when neurologic deterioration is observed or anticipated and may prove life-threatening. The use of single rather than combination antifungal treatment was associated with poorer outcomes. In all but 1 dog, combination antifungal treatment constituted amphotericin B in addition to a triazole, either fluconazole or itraconazole. Treatment of CNS cryptococcosis with single-agent azole therapy is not ideal and is associated with persistence of clinical signs.8

This study had several limitations. Sourcing cats and dogs only from referral centers likely biased toward animals with more severe presentations and with more dedicated owners. Diagnostic investigations and treatments varied markedly between and within centers at the treating clinician’s discretion. Clinical data were limited to what was retrievable from records. Cryptococcal organisms were not identified in the brain or CSF in every animal, so the possibility of cryptococcosis in the nasal cavity with another neurologic disease cannot be completely excluded but is considered unlikely. Infecting cryptococcal species and molecular type were unknown in many patients, which hindered study of the epidemiology and impact of causal biotypes. LCAT was performed at multiple laboratories over a wide time frame, which may have introduced variability depending on operator technical proficiency, pronase pretreatment, and the assay kit used.49 Outcome was impacted by owner decision to euthanize, varied treatment protocols, and some patients with incomplete follow-up.

Although the prognosis for cats and dogs with CNS cryptococcosis is guarded, when owner commitment allows aggressive combination antifungal treatment, prolonged ST with stable disease or cure is often achievable. Altered mentation at first presentation in dogs and CSF collection in cats were negatively associated with outcome. Further studies are needed to determine optimal treatment protocols.

Acknowledgments

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

The authors thank David Collins, Kylie Long, and Kim Smith for their contribution of individual animals and Jennifer von Luckner and Wen-Jie Yang for initial records searches.

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  • Figure 1

    Proportions and summary statistics for 19 cats and 31 dogs with CNS cryptococcosis diagnosed between 2000 and 2020 stratified by whether they received treatment with antifungal medication, then further subgrouped on the basis of outcome (known status [died, cured, or being treated] vs unknown status). Survival and follow-up times (medians and ranges in days) were calculated from the initial presentation (day 1) to the date of death, euthanasia, or last follow-up (last contact by veterinary examination or telephone contact [if the owner was contacted]).

  • Figure 2

    Box-and-whisker plots of serum latex cryptococcal antigen agglutination test titers for 12 of the 19 cats and 23 of the 31 dogs described in Figure 1 that had end point titers available for analyses. The y-axis indicates the reciprocal titer at initial presentation. For each plot, the line in the box represents the median, the box represents the IQR (25th to 75th percentiles), the whiskers extend to the most extreme values that are ≤ 1.5 times the IQR below the 25th percentile (lower whisker) or above the 75th percentile (upper whisker), and circle and asterisks represent outlier results (ie, if more than 3 times the IQR above the upper whisker or below the lower whisker) for the cats and dogs, respectively. Latex cryptococcal antigen agglutination test titers were significantly (P = .031) lower in dogs than cats.

  • Figure 3

    Kaplan-Meier survival curves for the 19 cats and 31 dogs described in Figure 1, grouped on the basis of whether dogs had signs of clinically normal versus abnormal mentation at presentation (A; P = .001), whether cats had versus did not have CSF collected (B; P = .015), whether dogs that received antifungal treatment were versus were not given glucocorticoids prior to diagnosis (C; P = .013) or were administered single versus multiple antifungal medications (D; P = .023), and by canines versus felines (E; P = .853). Log-rank test P values for comparison of survival time by subset are listed. Each step represents the death of ≥ 1 animal. Tick marks indicate right-censored intervals.

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