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Central nervous system cryptococcosis in 3 cats in


Clinique Vétérinaire ADVETIA, 5 Rue Dubrunfaut, 75012, Paris, France


Cabinet Médicochirurgical d’Ophtalmologie Vétérinaire, 39 Rue Rouelle, 75015 Paris


*Corresponding author: stepapageorgiou@gmail.com


Three cats presenting a central nervous system cryptococcosis in France Cryptococcose du système nerveux central chez 3 chats en France
are reported. The first two cats presented with clinical signs attributed to
intracranial disease and the third to cervical myelopathy. Diagnostic imaging Une cryptococcose à localisation nerveuse centrale a été diagnostiquée chez
(magnetic resonance imaging or computed tomography) was either normal trois chats. Les deux premiers ont été présentés pour une symptomatologie
or revealed focal/ multifocal nodules within the central nervous system. évoquant une atteinte intracrânienne et le troisième, une myélopathie
Latex cryptococcal agglutination test on cerebrospinal fluid was positive cervicale. L’imagerie en coupe (imagerie par résonance magnétique
for all three cats. The first cat was successfully treated, although a relapse ou scanner) a mis en évidence des lésions isolées/ multifocales chez 2
was noted and treatment had to be maintained permanently. The second cat chats. Le test d’agglutination pour recherche des antigènes de la capsule
was euthanized before diagnosis was reached. Treatment failed to improve cryptococcique était positif sur les 3 cas à partir du LCR. Deux chats ont
neurological status of the third cat and euthanasia was elected. This case été traités par des antifongiques. Le premier a récupéré complètement,
series describes the clinical features, imaging characteristics and outcome malgré un épisode de rechute nécessitant la reprise du traitement de façon
of 3 cats with central nervous system cryptococcosis in France, where this permanente. Le deuxième a été euthanasié du fait de l’absence de réponse
affection is rarely reported. thérapeutique. Le dernier a été euthanasié avant l’obtention du diagnostic.
Cet article présente les signes cliniques, les caractéristiques d’imagerie et la
Keywords: cryptococcosis, cat, central nervous system, réponse thérapeutique de 3 chats atteints d’une cryptococcose du système
nerveux central en France, où cette affection semble très rare.
eye, France
Mots-clés : cryptococcose, chat, système nerveux
central, œil, France

Introduction normal. Cranial nerve testing revealed the absence of a

menace response in the left eye with normal direct and
Cryptococcosis, mainly caused by Cryptococcus consensual pupillary light reflexes. Vision was preserved for
neoformans and Cryptococcus gattii, is the most frequently both eyes. Behaviour and mentation appeared normal. These
reported feline systemic mycosis [4]. Cats are most likely neurological findings were consistent with a cerebellar lesion.
infected by inhaling dust containing the airborne fungal Ophthalmological examination revealed multiple, small,
yeast form [40]. Infection may result in upper respiratory, irregular pigmented foci, consistent with bilateral multifocal
cutaneous, ocular and central nervous system (CNS) granulomatous chorioretinitis (figure 1).
signs [40]. In the CNS, infection may lead to diffuse
meningoencephalitis or granulomatous lesions referred to as
« cryptococcomas » [40].

This case series describes the clinical features, imaging

findings, and outcome of 3 cats with CNS cryptococcosis.
To our knowledge it is the first report of cryptococcosis
with brain involvement in France. It is also the first report
of computed tomography (CT) findings of brain and spinal
cryptococcomas in companion animals.

Case description

A 4.5-year old female Norwegian cat was presented for

lethargy, anorexia, pyrexia and a left forelimb lameness
progressing to a 4-limb ataxia. The cat was mainly indoor, and
living in Paris. Physical examination revealed hyperthermia
(39.3°C). Upon neurological examination, postural reaction
deficits were detected in all 4 limbs. Spinal reflexes were Figure 1: Fundoscopic examination of left eye. Numerous multifocal cho-
rioretinal granulomas of variable size scattered across the fundus.
Revue Méd. Vét., 2016, 167, 9-10, 283-288

Routine blood count and chemistry was unremarkable. of iodinated contrast medium (2 mL/kg, Telebrix® 35;
Guerbet) these lesions presented a strong ring-enhancement
Feline leukaemia antigen (FeLV) and feline associated with diffuse and patchy meningeal enhancement
immunodeficiency virus (FIV) antibody assays were (figure 2). There was a mild mass effect in the frontal area. No
negative (Witness FeLV-FIV, Zoetis). abnormality involving the ethmoid sinuses or the cribriform
plate was noted. Infectious granulomas were suspected.
Magnetic resonance imaging (MRI) of the brain CSF was collected from the cerebellomedullary cistern,
was performed (MrV, Paramed, 0.22 T) under general and revealed a protein concentration of 0.4 g/l (reference
anaesthesia. Dorsal T1-weighted, T2-weighted and FLAIR value <0.35 g/l) and no pleocytosis. Toxoplasma gondii and
sequences were obtained. T1-weighted transverse images feline coronavirus serology assay from CSF was negative
were repeated after IV administration of gadolinium but qualitative LCAT (Crypto-LA II; Fumouze) was positive
diethylenetriaminepentaacetic acid (0.1 mmol/kg). MRI at a titer of 4. The cat was euthanized before diagnosis was
was normal. Cerebrospinal fluid (CSF) was collected from reached because of dramatic clinical deterioration. Necropsic
the cerebellomedullary cistern. The fluid had a total protein examination was not allowed.
concentration of 0.6 g/l (reference value <0.35 g/l) and no
pleocytosis. Numerous small (5 µm) yeast organisms that
were stripped of their capsules were identified on a Diff
Quick-stained CSF smear. Qualitative latex cryptococcal
antigen agglutination test (LCAT) (Crypto-LA II; Fumouze)
performed on CSF was positive at a titer of 8.

A diagnosis of CNS cryptococcosis was made. Itraconazole

(10 mg/kg q24h orally, Itrafungol®; Elanco) and prednisolone
(0.5 mg/kg q24h orally for 3 weeks, Mégasolone® 5 mg, Figure 2: CT-scan examination of the brain, soft tissue algorithm, after IV
Merial) were initiated. Clinical response to treatment was iodinated contrast medium injection. One lesion is visible in caudal
fossa (A) and two in rostral fossa (B). They are nodular and ring-en-
favourable and the cat was neurologically normal within hancing (arrowheads).
one month. Three months later the cat developed anorexia
and treatment was interrupted. Itraconazole was replaced by
Fluconazole (40 mg q12h orally, Triflucan®; Pfizer). Follow CASE 3
up CSF tap was performed every 2 months for protein, cell
count, LCAT and organism identification and was normal. An 11-year old male neutered domestic shorthair cat
After 11 months of treatment, fluconazole was discontinued was presented for an acute onset of right hemiparesis.
Three months later, clinical signs relapsed and treatment with The patient was an indoor cat, and lived in Paris. Physical
fluconazole was reinstituted at 16 mg per day. Two years and examination was normal. Neurological examination revealed
a half later the cat is alive and free of clinical signs. Treatment severe right sided ambulatory hemiparesis. There were right-
is maintained. sided postural deficits and spinal reflexes were normal.
Examination of cranial nerves was normal, as was the cat’s
CASE 2 behavior and mentation. These findings were compatible
with a C1-C5 myelopathy.
A 4-year old female neutered domestic shorthair
cat was presented with a history of head tilt, recurrent FeLV and FIV antibody assays were negative (Witness
episodes of fever and anorexia during the previous month. FeLV-FIV, Zoetis).
The cat was an outdoor Parisian cat. Physical examination
was unremarkable with the exception of obtundation. The cat was anaesthetised and a myelography was
Neurological examination revealed a head tilt to the left performed which revealed no spinal cord compression. A CT-
and an asymmetrical ataxia. Postural reaction deficits were scan (Aquilion, Toshiba, 4 slice) was performed. Pre-contrast
detected on the left side. Spinal reflexes were normal. There study of the cervicothoracic region was normal. After IV
was no evidence of an abnormal nystagmus or other cranial injection of iodinated contrast medium (2 mL/kg, Telebrix®
nerve deficits. The neurological examination was consistent 35; Guerbet), a single intramedullary area of enhancement,
with left central vestibular disease. lateralized to the right side, approximately 1cm long, was
visible at the level of C4-C5 vertebras (figure 3). The lesion
Routine blood count and chemistry was unremarkable. presented a strong, homogeneous contrast enhancement.
Differential diagnosis included intramedullary neoplasia and
The cat was anesthetised and CT- scan (Aquilion, infectious granuloma. Lumbar tap was performed but CSF
Toshiba, 4 slice) was performed. Multiple ill-defined intra- was heavily contaminated with blood. CSF was collected
axial nodules, hyperdense to the cerebral parenchyma, from the cerebellomedullary cistern, and revealed no
were identified in the left cerebello-pontine angle, in the pleocytosis and normal total protein. Toxoplasma gondii and
thalamus and in the cerebral hemispheres. After IV injection feline coronavirus serology assay from CSF were negative but

Revue Méd. Vét., 2016, 167, 9-10, 283-288


qualitative LCAT (Crypto-LA II; Fumouze) was positive at The criteria for an antemortem diagnosis of CNS
a titer of 4. The sample was insufficient to perform further cryptococcosis include one or more of the following: 1)
dilution. A diagnosis of cryptococcosis was made and identification of typical encapsulated yeast-like organisms
treatment was instituted with fluconazole (50 mg q12h orally, on CSF cytological examination, 2) a positive CSF fungal
Triflucan®; Pfizer) and prednisolone (1 mg/kg q24h orally, culture, 3) a positive measurement of cryptococcal antigens,
Dermipred® 5 mg; Sogeval). Clinical signs progressed to a 4) Isolation of C. neofomans outside the CNS and complete
non-ambulatory tetraparesis rapidly after treatment onset regression of the CNS signs with antifungal therapy [2].
and the cat was euthanized 1 week later due to continuous LCAT in serum and CSF is highly specific and sensitive and
worsening of his neurological status. Necropsic examination aids both in diagnosis and monitoring animals during and
was not allowed. after therapy [15,27,31].

Advanced imaging techniques may assist in the

diagnosis of cryptococcosis. Cerebral and spinal
cryptococcomas have been described in a few MRI studies
in cats [1,13,18,26,30,38,39]. CT-scan modifications in CNS
cryptococcosis had never been reported in cats in previous
reports. In humans, the most common CT findings included
normal studies, multiple nodules (both enhancing or non-
enhancing), diffuse cerebral atrophy or hydrocephalus [35].
In the second cat, CT-scan revealed similar lesions with
Figure 3: Transversal (A) and sagittal (B) reconstruction of myeloscanner
after IV iodinated contrast medium injection. A focal ovoid contrast- multiple ring-enhancing masses with a mild mass effect. In
enhancing lesion is visible in the right side of the cord at the level of the third cat, CT-scan revealed a single intramedullary lesion,
C4C5 (arrows). not visible on pre-contrast examination and presenting a
strong, homogeneous contrast enhancement after meglumine
Discussion ioxitalamate IV injection.

Cryptococcosis, principally caused by Cryptococcus CSF analysis may display mixed or neutrophilic
neoformans and Cryptococcus gattii, is the most frequently pleocytosis (ranging from 0 to 1440 cells/µL) and an elevated
reported feline systemic mycosis. Five serotypes of total protein concentration (ranging from 0.08-1.32 g/d)
Cryptococcus have been recognized: C. neoformans var grubii [39]. However normal CSF analysis is also reported in some
(serotype A), C neoformans var neoformans (serotype D), patients [39]. A mild increase in total protein concentration
a hybrid of these two varieties (serotype AD), and C. gattii was noted in cases 1 and 2 and CSF analysis was normal in the
(serotypes B and C) [40]. Recently, other varieties appeared 3rd case. However, due to blood contamination at the lumbar
to be pathogenic for the cat, namely Cryptococcus magnus tap, CSF collection in this case was performed rostral to the
and Cryptococcus albidus [21,22,36]. site of the lesion, possibly influencing the total nucleated cell
CNS cryptococcosis is an uncommon but potentially
fatal disease. Published case reports and studies of feline Differentiation of C neoformans from C gatii is possible
cryptococcosis are abundant in western Canada, western with a culture on L-canavanine-glycine-bromthymol blue
United States and Australia [7,8,12,17,23,27,31,34,39,43], agar [25]. Furthermore, the different strains can be typed
but very sporadic in Europe [1,5,9,10,11,14,19,24,30]. To the by molecular genotyping [33,42]. Culture and species
authors’ knowledge only one case of CNS cryptococcosis has differentiation was not attempted in any of the cases presented
been reported in France to date [1]. in this case series, as for clinical purposes a positive LCAT
titer in the CSF associated with signs of CNS disease were
In both animals and people, inhalation is the primary considered of diagnostic value. However, a positive culture
route of entry into the body. In contrast to humans where of the pathogen coupled with a drug susceptibility test would
cryptococcosis is often associated with immunodeficiency have enabled a better treatment option justification.
(acquired immunodeficiency syndrome), the disease in dogs
and cats occurs in immunocompetent hosts. Cats infected Many drugs have been reported for the treatment of
with FeLV or FIV are not considered to be at increased risk for cryptococcosis. Amphotericin appears to be an effective
infection but may experience more difficulty in clearing the agent to treat severe cases of cryptococcosis or cats that fail to
infection compared with cats not infected with retroviruses respond to azole therapy, especially the ones presenting with
[27,29,34,39]. Development of disease requires colonization neurological signs [34]. The drug’s most important side effect:
of the upper respiratory tract in dogs and cats [3]. CNS signs nephrotoxicity, and the exclusive parenteral administration
in cats have been reported secondary to respiratory infection limit its use [15,29]. For long-term therapy, imidazole
and not commonly as primary presenting signs [1,8,27]. compounds can be administrated orally, but 5-flucytosine
All three cats of the present study had CNS signs with no and ketoconazole (as single agents or in combination) have
reported history of respiratory signs. been unrewarding on CNS cryptococcosis [12,17]. These

Revue Méd. Vét., 2016, 167, 9-10, 283-288


agents have limited ability to reach effective therapeutic cats with intracranial diseases, even in regions were few cases
concentrations within the CNS without important side effects have been reported so far.
[15]. Triazole drugs have increased efficacy, better tissue
penetration and reduced toxicity compared to ketoconazole. References
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