Cerebral Phaeohyphomycosis Caused by Cladosporium spp. in Two Domestic Shorthair Cats

Case No. 1

A 3-year-old, spayed female, domestic shorthair cat was referred to the University of Florida, College of Veterinary Medicine (UF-CVM) for evaluation of seizures and inappropriate mentation. The cat had been moved from South Carolina to Florida 11 days prior to examination at UF-CVM. At that time, the owner had administered acepromazine^a (2 mg/kg body weight, per os [PO] once) for sedation during the trip. A generalized seizure occurred approximately 2 hours after receiving the acepromazine. The cat returned to a normal state that night, but 4 days later she became lethargic and inappetent. Ataxia was observed in all four limbs, and the cat had several more generalized seizures. The cat had been routinely vaccinated, had indoor and outdoor access, and there was one other healthy cat in the household.

A complete blood count (CBC) and serum biochemical evaluation performed by the referring veterinarian were unremarkable except for mild hyperglycemia (159.4 mg/dL; reference range, 76.0 to 145.0 mg/dL). Serum enzyme-linked immunosorbent assay (ELISA) tests for feline leukemia virus (FeLV) antigen and feline immunodeficiency virus (FIV) antibodies were negative. Therapy was initiated with crystalloid fluids (lactated Ringer’s solution,^b 30 mL/kg body weight, subcutaneously [SC] once), enrofloxacin^c (4.5 mg/kg body weight, PO q 12 hours), dexamethasone^d (0.6 mg/kg body weight, SC once), and phenobarbital^e (3 mg/kg body weight, PO q 12 hours). The cat’s condition deteriorated over the following 4 days, and referral was made to UF-CVM.

On initial examination at UF-CVM, the cat was obtunded, demented, and minimally responsive to external stimuli. Nonambulatory tetraparesis was noted, which was worse on the left side. There was curvature of the body to the right and a right head turn. Postural reactions and conscious proprioception were absent on the left side and decreased on the right side. The menace response was absent bilaterally, and anisocoria was noted, with the left pupil being slightly larger than the right. Pupillary light reflexes were within normal responses. Nystagmus, which varied from rotatory to vertical with changes in head position, was also observed. There was mild hyperesthesia noted on palpation of the cervical spine. Spinal reflexes and the remainder of the neurological examination were within normal limits. The reduced menace response with normal pupillary light reflexes and a head turn suggested a cerebral cortical lesion, while the nystagmus and anisocoria suggested involvement of the brain stem. Altered mentation, tetraparesis, and postural reaction deficits could have been caused by lesions in either area, and together with the hyperesthesia they suggested a multifocal central nervous system [CNS] lesion most consistent with an inflammatory etiology. The cat was estimated to be approximately 6% dehydrated, and the remainder of the physical examination, including a funduscopic examination, was unremarkable.

Complete blood count, serum biochemical evaluation, and urinalysis were within reference ranges. After rehydration (with lactated Ringer’s solution, 3 mL/kg per hour intravenously [IV]), a gallop rhythm was noted on cardiac auscultation. Thoracic radiography revealed mild generalized cardiomegaly, a mild generalized bronchial pattern within the pulmonary parenchyma, and a mild increase in the size of the caudal lobar arteries. Echocardiography revealed very mild left atrial enlargement (1.4 cm; reference range, 0.86 to 1.32 cm) with a left atrial to aortic root diameter ratio of 2:1 (reference range, <1.3:1). The electrocardiogram was unremarkable. A Dirofilaria immitis serum antibody titer was negative. Electroencephalography was performed using a combination bipolar and referential montage without sedation and revealed numerous spikes, spike and wave complexes, and paroxysms of rhythmic, high-amplitude, slow wave activity (30 to 60 μV; six per second), suspected to be seizure discharges [Figure 1]. Photic stimulation (one flash per second) elicited high-amplitude waveforms (30 to 100 μV; one per second) and an opisthotonic response from the cat. A brain-stem auditory-evoked potential (BAEP) showed increased latency of peaks I (2.51 milliseconds; reference range [mean ± two standard deviations], 1.51 to 2.35 milliseconds)¹ and II (3.23 milliseconds; reference range, 2.23 to 3.07 milliseconds) on the left side as compared with the right side (peak I, 1.99 milliseconds; peak II, 2.81 milliseconds). Peaks III and IV were not readily discernable on either side. Peak V was apparent on the left side with an increased latency (5.00 milliseconds; reference range, 3.59 to 4.39 milliseconds), but it was not visible on the right side [Figure 2]. The cat was anesthetized for cerebrospinal fluid (CSF) collection from the cerebellomedullary cistern. Cerebrospinal fluid analysis revealed a neutrophilic pleocytosis (1,280 red blood cells [RBC]/μL; 176 white blood cells [WBC]/μL; reference range, 0 to 5 WBC/μL; 74% neutrophils, 20% lymphocytes, 5% mononuclear phagocytes, 1% eosinophils) and elevated protein (91 mg/dL; reference range, 0 to 19 mg/dL). The neutrophils were nondegenerate, and the mononuclear phagocytes showed mild reactivity. Serum antibody titers for feline infectious peritonitis virus (FIPV) and Toxoplasma gondii (T. gondii) (immunoglobulin G [IgG] and immunoglobulin M [IgM]), and a serum antigen test for Cryptococcus neoformans (C. neoformans) were negative. Aerobic bacterial culture of the CSF was negative.

Therapy was initiated with methylprednisolone sodium succinate^f (15 mg/kg body weight, IV q 8 hours) and trimethoprim-sulfamethoxazole^g (15 mg/kg body weight, IV q 12 hours). Phenobarbital^h (3 mg/kg body weight, intramuscularly [IM], then PO q 12 hours) therapy was continued. The following morning, the neurological status was markedly improved. The cat was ambulating well, eating and drinking on her own, and was responsive to sound and other external stimuli. Tetraparesis and conscious proprioceptive deficits were still apparent, although improved. The cat was discharged with instructions for the owner to administer prednisoneⁱ (1 mg/kg body weight, PO q 12 hours), trimethoprim-sulfamethoxazole^j (15 mg/kg body weight, PO q 12 hours), and phenobarbital (3 mg/kg body weight, PO q 12 hours). Neurological status remained unchanged to slightly improved for 2 days. At this time, the cat had an episode of opisthotonus and lapsed into a stuporous, unresponsive state. Examination was similar to that at the time of admission to UF-CVM, and the owner elected euthanasia.

A necropsy was performed and revealed a locally extensive, 1.0 × 1.5 × 2.0-cm, dark green to dark brown, soft focus within the frontal cortex of the right hemisphere that extended into the adjacent left frontal lobe to a depth of 0.5 cm. The left hemisphere was submitted for immunofluorescence examination for the presence of rabies virus antigen, which was negative. Swabs of the right hemisphere were submitted for fungal culture. No other significant gross lesions were noted at necropsy.

Histopathological examination of the right frontal cortex was performed [Figures 3, 4] and revealed a large number of filamentous, septate, branching, dematiaceous (i.e., brown), fungal hyphae within a focally extensive area of the neuropil surrounding the lateral ventricle and extending into the lateral ventricle and associated choroid plexus. The fungal hyphae measured 5 to 7 μm in diameter and exhibited non-parallel sides. In addition to the filamentous hyphal forms, many fungal organisms were round to oval in shape and exhibited narrow-base budding. A moderate number of fungal bodies were present within the cytoplasm of multinucleate giant cells. Throughout the focus were perivascular infiltrates of a large number of lymphocytes, macrophages, and neutrophils and a lesser number of eosinophils. Many neurons within the focus were necrotic and surrounded by gemistocytic astrocytes and large amounts of eosinophilic cellular debris. The Virchow-Robin spaces surrounding blood vessels within these areas were moderately dilated (indicating perivascular edema), and axons within the surrounding white matter tracts were moderately distracted (indicative of cerebral edema). A small number of fungal hyphae and extensive perivascular infiltrates of lymphocytes, neutrophils, and macrophages were present within the meninges. There were no lesions detected on histopathological examination of the brain stem. Fungal culture of the mass lesion on Sabouraud Dextrose Agar^k at 25°C revealed growth of a Cladosporium spp. [Figure 5]. Routine histopathological examination of the heart, liver, lung, kidney, and spleen did not show any significant lesions.

Case No. 2

A 6-year-old, intact male, domestic shorthair cat was referred to the University of Georgia, College of Veterinary Medicine (UGA-CVM) for evaluation of chronic progressive dysequilibrium. The cat had been routinely vaccinated, had indoor and outdoor access, and lived in a household with five other healthy cats.

Sixteen days earlier, the cat was noted to have an acute onset of a right-sided head tilt with generalized ataxia accompanied by lethargy. The cat was examined by the referring veterinarian and was treated with IV fluids and an undocumented steroid preparation. A CBC and serum biochemical profile were within reference ranges. The cat improved for 2 days and then became anorexic and again demonstrated ataxia and depression. Clindamycin^l (5 mg/kg body weight, PO q 12 hours) and prednisone (1.5 mg/kg body weight, PO q 12 hours) therapy was initiated at this time. The cat’s neurological status continued to deteriorate over the next 10 days when it became recumbent and exhibited intermittent opisthotonus.

On examination at UGA-CVM, the cat was obtunded and demented, with dysequilbrium and a severe nonambulatory tetraparesis that was worse on the left side. Appendicular muscle tone was increased at rest. Ocular examination revealed an anisocoria with a dilated right pupil and a normal-sized left pupil. Bilateral chorioretinitis was identified on funduscopic examination. Pupillary light reflexes were within normal responses in both eyes, but the menace response was absent bilaterally. Physiological nystagmus was bilaterally decreased but worse on the left side, which accompanied a right-sided head tilt. A vertical nystagmus could be elicited after positioning the cat in dorsal recumbency. Postural reaction tests were difficult to assess because of the cat’s dysequilibrium, but responses were thought to be reduced in all four limbs and worse on the left side. Spinal reflexes were intact in all limbs. Mild hyperesthesia was detected on palpation of the cervical spine. Similar to case no. 1, the altered mentation, tetraparesis, and postural reaction deficits might have been explained by either cerebral or brain-stem lesions. However, the dysequilibrium, anisocoria, and nystagmus implicated brain-stem involvement, while the visual deficits suggested cerebral involvement. The chorioretinitis and hyperesthesia lent further evidence for a multifocal, and likely inflammatory, CNS lesion. No other abnormalities were noted on physical examination.

A CBC, serum biochemical profile, and urinalysis performed on the day of admission were within reference ranges. Serum antibody titers to T. gondii (IgG and IgM), FIV, and FIPV and antigen tests for FeLV and C. neoformans were considered negative for active infection. Propofol was used to anesthetize the cat for CSF collection from the cerebellomedullary cistern. The small amount of fluid obtained was very viscous and allowed only a cytological analysis, which revealed aggregates of neutrophils and macrophages with few erythrocytes. The appearance of the smear suggested a pyogranulomatous inflammation, and no organisms were observed. The cat failed to gain spontaneous respiration after the anesthesia and was subsequently euthanized with the consent of the owner.

At necropsy, abnormalities were confined to the CNS. The cerebellum was markedly swollen and rounded. The caudal lobe of the cerebellar vermis had herniated through the foramen magnum and was compressed. Hemorrhage was noted on the dorsal surface of the cerebellum. The medulla was also markedly swollen. On cut section, the cerebellum and medulla were diffusely gray and malacic. Similar gray, malacic foci were scattered throughout the cerebrum and hippocampus.

On histopathological examination, lymphocytic-plasmacytic infiltration of the leptomeninges was present from the frontal lobe to the cerebellum. The associated parenchyma had vessels with thick, perivascular cuffs of predominating lymphocytes and multiple foci of necrosis infiltrated with epithelioid macrophages and multinucleated giant cells, sometimes admixed with neutrophils, that contained narrow, septate, pigmented fungal hyphae. A Cladosporium spp. was identified on fungal culture of the brain.