CENTRAL NERVOUS SYSTEM CRYPTOCOCCOSIS IN 3 CATS IN FRANCE 283

Central nervous system cryptococcosis in 3 cats in

France
S. PAPAGEORGIOU1*, Y. RUEL1, J.-P. JÉGOU2, K. GNIRS1

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

1

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

2

*Corresponding author: stepapageorgiou@gmail.com

SUMMARY RÉSUMÉ

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

Introduction normal. Cranial nerve testing revealed the absence of a

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

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
CASE 1

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
284
Routine blood count and chemistry was unremarkable.
Feline leukaemia antigen (FeLV) and feline
immunodeficiency virus (FIV) antibody assays were
negative (Witness FeLV-FIV, Zoetis).
Magnetic resonance imaging (MRI) of the brain
was performed (MrV, Paramed, 0.22 T) under general
anaesthesia. Dorsal T1-weighted, T2-weighted and FLAIR
sequences were obtained. T1-weighted transverse images
were repeated after IV administration of gadolinium
diethylenetriaminepentaacetic acid (0.1 mmol/kg). MRI
was normal. Cerebrospinal fluid (CSF) was collected from
the cerebellomedullary cistern. The fluid had a total protein
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,
Merial) were initiated. Clinical response to treatment was
favourable and the cat was neurologically normal within
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
up CSF tap was performed every 2 months for protein, cell
count, LCAT and organism identification and was normal.
After 11 months of treatment, fluconazole was discontinued
Three months later, clinical signs relapsed and treatment with
fluconazole was reinstituted at 16 mg per day. Two years and
a half later the cat is alive and free of clinical signs. Treatment
is maintained.
CASE 2
A 4-year old female neutered domestic shorthair
cat was presented with a history of head tilt, recurrent
episodes of fever and anorexia during the previous month.
The cat was an outdoor Parisian cat. Physical examination
was unremarkable with the exception of obtundation.
Neurological examination revealed a head tilt to the left
and an asymmetrical ataxia. Postural reaction deficits were
detected on the left side. Spinal reflexes were normal. There
was no evidence of an abnormal nystagmus or other cranial
nerve deficits. The neurological examination was consistent
with left central vestibular disease.
Routine blood count and chemistry was unremarkable.
The cat was anesthetised and CT- scan (Aquilion,
Toshiba, 4 slice) was performed. Multiple ill-defined intra-
axial nodules, hyperdense to the cerebral parenchyma,
were identified in the left cerebello-pontine angle, in the
thalamus and in the cerebral hemispheres. After IV injection
PAPAGEORGIOU (S.) AND COLLABORATORS
of iodinated contrast medium (2 mL/kg, Telebrix® 35;
Guerbet) these lesions presented a strong ring-enhancement
associated with diffuse and patchy meningeal enhancement
(figure 2). There was a mild mass effect in the frontal area. No
abnormality involving the ethmoid sinuses or the cribriform
plate was noted. Infectious granulomas were suspected.
CSF was collected from the cerebellomedullary cistern,
and revealed a protein concentration of 0.4 g/l (reference
value <0.35 g/l) and no pleocytosis. Toxoplasma gondii and
feline coronavirus serology assay from CSF was negative
but qualitative LCAT (Crypto-LA II; Fumouze) was positive
at a titer of 4. The cat was euthanized before diagnosis was
reached because of dramatic clinical deterioration. Necropsic
examination was not allowed.
Figure 2: CT-scan examination of the brain, soft tissue algorithm, after IV
iodinated contrast medium injection. One lesion is visible in caudal
fossa (A) and two in rostral fossa (B). They are nodular and ring-en-
hancing (arrowheads).
CASE 3
An 11-year old male neutered domestic shorthair cat
was presented for an acute onset of right hemiparesis.
The patient was an indoor cat, and lived in Paris. Physical
examination was normal. Neurological examination revealed
severe right sided ambulatory hemiparesis. There were right-
sided postural deficits and spinal reflexes were normal.
Examination of cranial nerves was normal, as was the cat’s
behavior and mentation. These findings were compatible
with a C1-C5 myelopathy.
FeLV and FIV antibody assays were negative (Witness
FeLV-FIV, Zoetis).
The cat was anaesthetised and a myelography was
performed which revealed no spinal cord compression. A CT-
scan (Aquilion, Toshiba, 4 slice) was performed. Pre-contrast
study of the cervicothoracic region was normal. After IV
injection of iodinated contrast medium (2 mL/kg, Telebrix®
35; Guerbet), a single intramedullary area of enhancement,
lateralized to the right side, approximately 1cm long, was
visible at the level of C4-C5 vertebras (figure 3). The lesion
presented a strong, homogeneous contrast enhancement.
Differential diagnosis included intramedullary neoplasia and
infectious granuloma. Lumbar tap was performed but CSF
was heavily contaminated with blood. CSF was collected
from the cerebellomedullary cistern, and revealed no
pleocytosis and normal total protein. Toxoplasma gondii and
feline coronavirus serology assay from CSF were negative but
Revue Méd. Vét., 2016, 167, 9-10, 283-288
CENTRAL NERVOUS SYSTEM CRYPTOCOCCOSIS IN 3 CATS IN FRANCE
qualitative LCAT (Crypto-LA II; Fumouze) was positive at
a titer of 4. The sample was insufficient to perform further
dilution. A diagnosis of cryptococcosis was made and
treatment was instituted with fluconazole (50 mg q12h orally,
Triflucan®; Pfizer) and prednisolone (1 mg/kg q24h orally,
Dermipred® 5 mg; Sogeval). Clinical signs progressed to a
non-ambulatory tetraparesis rapidly after treatment onset
and the cat was euthanized 1 week later due to continuous
worsening of his neurological status. Necropsic examination
was not allowed.
Figure 3: Transversal (A) and sagittal (B) reconstruction of myeloscanner
after IV iodinated contrast medium injection. A focal ovoid contrast-
enhancing lesion is visible in the right side of the cord at the level of
C4C5 (arrows).
Discussion
Cryptococcosis, principally caused by Cryptococcus
neoformans and Cryptococcus gattii, is the most frequently
reported feline systemic mycosis. Five serotypes of
Cryptococcus have been recognized: C. neoformans var grubii
(serotype A), C neoformans var neoformans (serotype D),
a hybrid of these two varieties (serotype AD), and C. gattii
(serotypes B and C) [40]. Recently, other varieties appeared
to be pathogenic for the cat, namely Cryptococcus magnus
and Cryptococcus albidus [21,22,36].
CNS cryptococcosis is an uncommon but potentially
fatal disease. Published case reports and studies of feline
cryptococcosis are abundant in western Canada, western
United States and Australia [7,8,12,17,23,27,31,34,39,43],
but very sporadic in Europe [1,5,9,10,11,14,19,24,30]. To the
authors’ knowledge only one case of CNS cryptococcosis has
been reported in France to date [1].
In both animals and people, inhalation is the primary
route of entry into the body. In contrast to humans where
cryptococcosis is often associated with immunodeficiency
(acquired immunodeficiency syndrome), the disease in dogs
and cats occurs in immunocompetent hosts. Cats infected
with FeLV or FIV are not considered to be at increased risk for
infection but may experience more difficulty in clearing the
infection compared with cats not infected with retroviruses
[27,29,34,39]. Development of disease requires colonization
of the upper respiratory tract in dogs and cats [3]. CNS signs
in cats have been reported secondary to respiratory infection
and not commonly as primary presenting signs [1,8,27].
All three cats of the present study had CNS signs with no
reported history of respiratory signs.
Revue Méd. Vét., 2016, 167, 9-10, 283-288
285
The criteria for an antemortem diagnosis of CNS
cryptococcosis include one or more of the following: 1)
identification of typical encapsulated yeast-like organisms
on CSF cytological examination, 2) a positive CSF fungal
culture, 3) a positive measurement of cryptococcal antigens,
4) Isolation of C. neofomans outside the CNS and complete
regression of the CNS signs with antifungal therapy [2].
LCAT in serum and CSF is highly specific and sensitive and
aids both in diagnosis and monitoring animals during and
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
multiple ring-enhancing masses with a mild mass effect. In
the third cat, CT-scan revealed a single intramedullary lesion,
not visible on pre-contrast examination and presenting a
strong, homogeneous contrast enhancement after meglumine
ioxitalamate IV injection.
CSF analysis may display mixed or neutrophilic
pleocytosis (ranging from 0 to 1440 cells/µL) and an elevated
total protein concentration (ranging from 0.08-1.32 g/d)
[39]. However normal CSF analysis is also reported in some
patients [39]. A mild increase in total protein concentration
was noted in cases 1 and 2 and CSF analysis was normal in the
3rd case. However, due to blood contamination at the lumbar
tap, CSF collection in this case was performed rostral to the
site of the lesion, possibly influencing the total nucleated cell
count.
Differentiation of C neoformans from C gatii is possible
with a culture on L-canavanine-glycine-bromthymol blue
agar [25]. Furthermore, the different strains can be typed
by molecular genotyping [33,42]. Culture and species
differentiation was not attempted in any of the cases presented
in this case series, as for clinical purposes a positive LCAT
titer in the CSF associated with signs of CNS disease were
considered of diagnostic value. However, a positive culture
of the pathogen coupled with a drug susceptibility test would
have enabled a better treatment option justification.
Many drugs have been reported for the treatment of
cryptococcosis. Amphotericin appears to be an effective
agent to treat severe cases of cryptococcosis or cats that fail to
respond to azole therapy, especially the ones presenting with
neurological signs [34]. The drug’s most important side effect:
nephrotoxicity, and the exclusive parenteral administration
limit its use [15,29]. For long-term therapy, imidazole
compounds can be administrated orally, but 5-flucytosine
and ketoconazole (as single agents or in combination) have
been unrewarding on CNS cryptococcosis [12,17]. These
286
agents have limited ability to reach effective therapeutic
concentrations within the CNS without important side effects
[15]. Triazole drugs have increased efficacy, better tissue
penetration and reduced toxicity compared to ketoconazole.
Itraconazole improved or cured more than 50% of the reported
cats with CNS cryptococcosis, even though concentrations in
CSF appeared to be low [32]. In the first cat, the drug was
effective in resolving the neurological signs, but important
adverse effects were reported (weakness, anorexia). Even if
fluconazole was found to be less effective in vitro than were
ketoconazole and amphotericin B, it has been reported as
the treatment of choice for cats with CNS cryptococcosis
[27,29]. It has minimal side effects (gastrointestinal signs,
bone marrow suppression, hepatotoxicity) and excibits an
excellent penetration of the blood-brain barrier. In vitro
studies indicate differences in drug susceptibility between
different cryptococcal species and molecular types, as
well as between different geographical locations of one
moleculartype [6,16,20,28,37,41]. 
 4. -  BUERGELT C.D. : Cryptococcosis in cats, Vet. Med.,
Treatment is required for months to years, may be cost
prohibitive for many owners and even when continued for
long periods of time, does not preclude relapse [7,27,34].
Therapy should be continued until the test becomes negative
or ideally until at least two negative tests one month apart are
obtained. It has been recommended to periodically evaluate
CSF via LCAT, cytologic examinations or fungal cultures for
up to 1 year following resolution of clinical signs [15,26].
Unfortunately, animals may relapse, and a negative test does
not preclude a relapse or reinfection. The cat described in case
1 relapsed 3 months after treatment was interrupted based on
normal total protein, total nucleated cell count and negative
LCAT titre in CSF. To detect any early relapses, antigen titre
can be monitored every 3 to 6 months after treatment is
interrupted [40].
Animals treated early in the course of infection have a
fair chance of survival, with involvement of the CNS being
the only significant predictor of mortality [8,12,17,23,34].
However, in cases 2 and 3 the delay in diagnosis due to
unspecific clinical signs and geographic region unusual for
cryptococcosis may have contributed to poor outcome.
Cryptococcosis is a major opportunistic fungal infection
in immunocompromised humans [40]. Aerosol exposure of
people from organic material rich in bird excreta has been a
zoonotic concern [40]. Infected animals do not pose a public
health threat to owners and veterinarians as the organism
does not aerosolize from sites of infections and therefore
the disease cannot be directly contracted, even though
precautions should be taken when handling the yeast or
infected tissue to avoid inadvertent inoculation [40].
This paper documents the first report of feline cerebral
cryptococcosis in France and presents the first CT description
of cerebral and spinal cord cryptococcoma. It emphasizes the
importance of performing cryptococcal antigen testing in
PAPAGEORGIOU (S.) AND COLLABORATORS
cats with intracranial diseases, even in regions were few cases
have been reported so far.
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