Clinical and Imaging Findings in Five Dogs with Intracranial Blastomycosis (Blastomyces dermatiditis)

Introduction

A variety of fungal organisms have been reported to affect the central nervous system (CNS) in small animals including Cryptococcus neoformans, Coccidioides immitis, Cladophialophora spp., Blastomyces dermatiditis, Histoplasma capsulatum, Aspergillus spp., and Fusarium solani.¹ C. neoformans has a predilection for the CNS; however, other fungal diseases only rarely infect the CNS in dogs and cats.^1–7 With few exceptions, reports of intracranial fungal infection are limited to individual case reports. The purpose of this study was to report clinical and imaging findings in dogs with intracranial blastomycosis.

Materials and Methods

The radiology database of the College of Veterinary Medicine, University of Tennessee, was searched from Jan 1, 2000 to Dec 31, 2009 for dogs with a diagnosis of intracranial blastomycosis which had computed tomography (CT) performed as part of their diagnostic work-up. Signalment, history, clinical signs, laboratory data, diagnostic procedures, concurrent involvement of other organ systems, and outcome were recorded. CT examination of the head was performed using either a third^a or sixth^b generation CT scanner.Transverse images with a slice thickness between 3 mm and 5 mm were acquired before and after IV administration of an iodinated contrast material (800 mg I/kg of either Iohexol^c or Ioversol^d) using a standard algorithm. Multiplanar reconstruction was performed to generate sagittal and/or dorsal plane images. Imaging studies were reviewed by two board certified radiologists. CT features evaluated included location, size, margination, density, homogeneity, and presence and degree of contrast enhancement of intracranial lesions. Additional features evaluated included: evidence of meningeal contrast enhancement indicative of concurrent meningeal inflammation; bony lysis or periosteal reaction/hyperostosis; vasogenic edema characterized by mass effect and hypodensity associated with the white matter tracts; and presence and degree of hydrocephalus.

Results

Five dogs met the inclusion criteria (Table 1). Each of these five cases is described here.

TABLE 1 Summary of the Five Cases Diagnosed with Intracranial Blastomyces dermatiditis

CT, computed tomography; F, intact female; FS, spayed female; M, intact male; MC, castrated male; N/A, not applicable; PO, per os

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Case 1

A 2 yr old male neutered Yorkshire terrier presented with a 3 mo history of seizures. Physical examination and neurologic examination at time of presentation were within normal limits. Neurolocalization was in the forebrain. Differential diagnoses included idiopathic epilepsy, infectious or noninfectious meningoencephalitis (such as granulomatous meningoencephalitis [GME] or necrotizing meningoencephalitis [NME]) and, less likely, intracranial neoplasia. Thoracic radiographs revealed enlarged tracheobronchial lymph nodes and a generalized, unstructured interstitial pulmonary pattern. Abdominal radiographs were within normal limits. Abdominal ultrasound showed very mild mesenteric lymphadenopathy. A complete blood count (CBC) and serum biochemistry profile revealed a mild increase in total protein (8.0 g/dL; reference range, 5.6–7.6 g/dL), mild hypoalbuminemia (2.6 g/dL; reference range, 3.1–4.2 g/dL), and mild hyperglobulinemia (5.4 g/dL; reference range, 2.1–3.7 g/dL). Serum electrophoresis revealed a polyclonal gammopathy. Urinalysis was within normal limits. To further investigate the reason for the changes seen on thoracic radiographs (specifically, the tracheobronchial lymphadenopathy), a urine sample was submitted for a B. dermatitidis antigen enzyme immunoassay (EIA).^e CT examination demonstrated an irregularly marginated 1.8 cm × 1.6 cm × 1.6 cm intra-axial mass associated with the right frontal lobe, which extended across the midline and was associated with marked vasogenic edema. The mass was slightly hyperattenuating on precontrast images and showed strong and homogenous contrast enhancement. Meningeal enhancement was also noted (Figure 1).

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Differential diagnoses at this point included either an infectious process (fungal meningoencephalitis) or a disseminated neoplastic process (lymphoma). A primary brain tumor (e.g., glioma or astrocytoma) was considered less likely due to the dog's age, because of the concurrent meningeal enhancement noted on CT, and considering the radiographic diagnosis of tracheobronchial lymphadenopathy. Bacterial meningoencephalitis was considered unlikely based on findings of lymphadenopathy and strong homogenous enhancement of the intra-axial lesion. A cerebral spinal fluid tap was not performed due to concerns that the large intra-axial mass and vasogenic edema would increase the risk of cerebellar vermal herniation and exacerbation of clinical signs following the procedure.

A diagnosis of blastomycosis (B. dermatiditis) was made based on a high positive urine blastomycosis EIA test result (30.42 EIA units). The dog was treated with phenobarbital^f (5 mg/kg per os [PO] q 12 hr) and fluconazole^g (5 mg/kg PO q 12 hr). Repeat urine blastomycosis EIA 3 mo following initiation of treatment showed a decrease in antigenuria to 2.03 EIA units. Clinical signs resolved 6 mo after diagnosis. Seven months after initial presentation, urine EIA had decreased to 1.06 EIA units. Fluconazole was discontinued 10 mo after initial presentation, and the phenobarbital dose was tapered to 2.5 mg/kg PO q 12 hr. The dog remained clinically normal 13 mo following presentation.

Case 2

A 2 yr old female spayed Labrador retriever presented with a 3 mo history of a mucoserous nasal discharge and a 1 mo history of cluster seizures. On physical and neurologic examination, the dog appeared depressed. No other abnormalities were noted. Neurolocalization was in the forebrain. Differential diagnoses included infectious or noninfectious meningoencephalitis (GME, NME) and neoplasia. Idiopathic epilepsy was considered less likely. A CBC and serum biochemistry profile revealed a mild increase in total protein (8.0 g/dL) and hyperglobulinemia (4.9 g/dL). Urinalysis was not performed. Thoracic radiographs were within normal limits. CT demonstrated an approximately 6.0 cm × 3.0 cm × 2.5 cm irregularly marginated nasal mass with extensive bony lysis, mild periosteal reaction, frontal sinus and nasopharynx involvement, erosion of the cribriform plate, and extension into the olfactory bulb (Figure 2). The mass was heterogeneous on precontrast images, showed strong heterogeneous contrast enhancement, and was associated with mild vasogenic edema.

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Differential diagnoses at this point included nasal neoplasia and fungal infection. The owners elected euthanasia. Necropsy was performed and yielded a diagnosis of blastomycosis (B. dermatiditis) based on demonstration of the organism in hematoxylin and eosin stained sections of the nasal turbinates.

Case 3

A 4 yr old female spayed Labrador retriever presented with a 1 yr history of stertor and sneezing. Nasal discharge was only present during sneezing episodes and consisted of clear fluid. Physical examination findings included mild, symmetric swelling over the bridge of the nose, nasal stertor, and episodes of sneezing. Both nasal passages were patent. No neurologic abnormalities were noted. A CBC and serum biochemistry profile revealed mild leukocytosis (14.8×10³/μL; reference range, 5.1–14.0×10³/μL), a mild mature neutrophilia (10.9×10³/μL; reference range, 2.7–9.8×10³/μL), mild hypoalbuminemia (3.0 g/dL), and mild hyperglobulinemia (4.4 g/dL). Urinalysis was within normal limits. Differential diagnoses for chronic partial nasal obstruction included rhinitis, allergies, nasal foreign body, and nasal neoplasia.

CT examination revealed two separate nasal masses (Figures 3A, B). The first mass was an approximately 4.0 cm × 2.5 cm × 2.0 cm irregularly marginated, strongly contrast-enhancing mass associated with the caudal nasal cavity with destruction of nasal turbinates, erosion of the cribriform plate, and extension into the olfactory bulb. Additional features included hyperostosis of the adjacent portion of the frontal bone, irregular periosteal reaction, and vasogenic edema (Figure 3C). The second mass was an approximately 4.5 cm × 1.5 cm × 2.0 cm well-circumscribed and strongly contrast-enhancing mass present within the rostral aspect of the nasal cavity, centered on midline, causing abaxial deviation of both laminae of the vomer bone, and extending into both nasal cavities (Figure 3D). Differential diagnoses at this point included nasal neoplasia and granulomatous disease such as fungal rhinitis. Rhinoscopic biopsy of the rostral mass yielded a histologic diagnosis of blastomycosis (B. dermatiditis) Subsequent surgical biopsy of the caudal mass was also consistent with blastomycosis based on histopathology and fungal culture. Involvement of other organ systems was considered unlikely based on normal thoracic radiographs, absence of cutaneous and ophthalmologic abnormalities, lack of additional clinical signs, and lack of overt laboratory abnormalities. The dog was released into the referring veterinarian's care with the recommendation to start treatment with itraconazole and was lost to follow-up.

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Case 4

A 9 yr old male neutered Labrador retriever presented with a 2 wk history of sneezing and epistaxis. Physical examination revealed marked stertor, bilateral epistaxis, ocular discharge, and a dull hair coat. No other abnormalities were noted. A CBC and serum biochemistry profile showed leukocytosis (20.5×10³/μL), a mature neutrophilia (15.9×10³/μL), a normocytic, normochromic anemia (hematocrit was 36.2%; reference range, 41–60%), mild hypoalbuminemia (2.2 g/dL), and hyperglobulinemia (4.5 g/dL). The coagulation profile was normal. Urinalysis showed trace occult blood and proteinuria. Thoracic radiographs were within normal limits. Differential diagnoses included nasal neoplasia, rhinitis, and nasal foreign body.

CT examination demonstrated an approximately 4.0 cm × 4.0 cm × 2.5 cm irregularly shaped, heterogeneously contrast-enhancing mass associated with the caudal nasal cavity with erosion of the cribriform plate and extension into the olfactory bulb (Figure 4A). Additional features included hyperostosis and lysis of adjacent osseous boundaries of the nasal cavity, extensive turbinate lysis, extension into the nasopharynx, and vasogenic edema. Several smaller, ill-defined masses were noted associated with the nasal cavity with multifocal turbinate lysis, destruction of the vomer bone and hard palate, and extension into the oral cavity (Figure 4B). Differential diagnoses at this point included nasal neoplasia and granulomatous disease such as fungal rhinitis.

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Diagnosis of blastomycosis was made based on rhinoscopic biopsies demonstrating yeast consistent with B. dermatiditis within samples using routine stains. Involvement of other organ systems was considered unlikely based on the absence of cutaneous and ophthalmologic abnormalities, lack of additional clinical signs, normal thoracic radiographs, and lack of overt laboratory abnormalities. The dog was released into the referring veterinarian's care with the recommendation to start treatment with itraconazole and was lost to follow-up.

Case 5

A 4 yr old female Australian shepherd presented with a 5 mo history of right-sided exophthalmos and intermittent nasal discharge. A 3 mo history of cough was also reported. The dog had never been vaccinated or received prophylactic heartworm, flea, or tick prevention. On presentation, the dog was depressed. Right-sided exophthalmos, nasal discharge, and cough were noted on physical examination. The right eye did not retropulse but seemed to be visual based on positive menace and pupillary light reflexes (direct and consensual). Differential diagnoses for exophthalmos included orbital/retrobulbar neoplasia or, less likely, a retrobulbar abscess. Differential diagnoses for chronic cough were numerous and included parasitic or infectious diseases, respiratory foreign body, and pulmonary neoplasia. A CBC and serum biochemistry profile showed leukocytosis (21.0×10³/μL), neutrophilia (16.4×10³/μL) with a left shift (6% band neutrophils; reference range, 0–2%), a normocytic, normochromic anemia (hematocrit was 29.5%), mild hyperproteinemia (total protein was 7.7 g/dL), mild hypoalbuminemia (2.1 g/dL), and hyperglobulinemia (5.6 g/dL). Urinalysis was not performed. A heartworm test was negative and thoracic radiographs were within normal limits.

CT examination revealed a large, irregular, heterogeneous and moderately inhomogeneously contrast-enhancing mass extending from the calvarium into the nasal cavity, orbits, both frontal sinuses, the nasopharynx, and oral cavity (Figure 5). There was extensive bony lysis and mild periosteal reaction associated with the osseous structures bordering the mass. Vasogenic edema was present. Differential diagnoses at this point included nasal neoplasia and granulomatous disease such as fungal rhinitis. The owners elected euthanasia. Postmortem examination limited to the head was performed and yielded a diagnosis of B. dermatiditis based on demonstration of the organism on hematoxylin and eosin stained sections of the nasal mass. Examination of the remainder of the body was not performed and additional organ involvement could not be excluded.

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Discussion

Intracranial fungal diseases in small animals are uncommon, with the possible exception of cryptococcosis.^1–6,8 B. dermatiditis is endemic in the southern United States and commonly affects the respiratory tract, eyes, skin, and skeletal structures in dogs.^2,9,10 CNS involvement in systemic blastomycosis is rare as affected animals typically suffer from fulminant extraneural disease.^7,11–14 Interestingly, only two out of the five dogs in this study showed neurologic signs despite brain involvement, and only one dog had conclusive evidence of extraneural organ involvement. It is conceivable that CNS involvement may have been missed in some cases enrolled in earlier published studies when animals were neurologically asymptomatic and brain or nasal imaging were not performed as part of the diagnostic work-up. Asymptomatic CNS involvement in human patients with cutaneous and pulmonary blastomycosis has been reported with resultant treatment failure and development of clinically manifested CNS disease due to choice of antifungal medication with poor CNS penetration (such as ketoconazole).¹⁵ Based on that report, routine lumbar puncture and head CT have been advocated for all patients with blastomycosis, even without neurologic signs, to allow choice of the appropriate antifungal medication. Future studies are needed to evaluate the true prevalence of CNS involvement in canine blastomycosis.

Fungal diseases have been reported to predominantly affect young adult animals.^{2,3,8,9,12,16,17} In this study, four of the patients were between 2 yr and 4 yr of age, but a 9 yr old dog also met the inclusion criteria. Due to the low number of cases, no conclusions regarding sex predilection can be drawn. A breed predisposition of Labrador retrievers for blastomycosis has been reported in previous studies, and three patients in the current study were Labrador retrievers.^12,18 Future studies with larger case numbers are needed to investigate the true breed predisposition for intracranial infection.

Clinical laboratory findings in this patient population (normocytic, normochromic anemia, leukocytosis, and hyperproteinemia/hyperglobulinemia) were generally mild and consistent with inflammation/infection. This is in agreement with findings reported in the literature.⁹ Hypercalcemia of granulomatous disease was not encountered in patients enrolled in the current study.

In one dog included in this study (case 1), the diagnosis of blastomycosis was based on a positive urine antigen test rather than identification of the organism through cytologic or histologic examination, which represents a limitation of this study. According to the literature, a combination of compatible history, clinical signs, and suggestive radiographs in conjunction with positive serology tests may be substituted for identification of the organism in the diagnosis of blastomycosis.⁹ The antigen EIA used to test that dog reportedly has a very high sensitivity for the diagnosis of blastomycosis in dogs (93.5% for urine, 87.0% for serum).¹⁹ Specificity of this test in dogs has, to the authors' knowledge, not been investigated, but cross-reactivity with other fungal agents (especially Histoplasma spp.) and nonspecific false-positives have been reported.²⁰ The authors of the current study feel that a presumptive diagnosis of blastomycosis in the dog described in case 1 and inclusion in the study are supported by age, concurrent radiographic findings (tracheobronchial lymphadenopathy), high positive urine antigen test, and clinical improvement and decrease in antigenuria following initiation of treatment.

A variety of parameters may be used to characterize intracranial lesions on CT and MRI, including size, location, number, margination, contrast enhancement, and associated findings (e.g., meningeal/choroid plexus/ependymal contrast enhancement, bony lesions, hydrocephalus, vasogenic edema, mass effect, brain herniation, and hemorrhage). Brain lesions can be categorized as extra-axial (i.e., originating outside actual brain parenchyma) or intra-axial (originating from brain parenchyma).^21–23 Differential diagnoses for extra-axial lesions include certain neoplastic (e.g., meningioma, nasal tumor), inflammatory (e.g., meningitis, granuloma), and traumatic lesions (e.g., hematoma). Differential diagnoses for solitary intra-axial lesions include neoplasia, hematoma, cyst, abscess/granuloma, and infarct.²⁴ Although inflammatory brain diseases usually manifest as multifocal lesions, solitary masses may be encountered on occasion. Differential diagnoses for multifocal brain lesions include metabolic/toxic brain disease, inflammatory brain disease, infarcts, and certain intracranial neoplasms (e.g., lymphoma, disseminated histiocytic sarcoma, metastases, and occasionally meningiomas). Contrast enhancement after IV administration of contrast media indicates either maintained or newly acquired vascularization and lack of a functional blood-brain barrier.^25,26 Meningeal, choroid plexus, and ependymal contrast enhancement are consistent with meningitis, choroiditis, and ependymitis.^23,27 Alternatively, the contrast enhancement may be associated with diffuse infiltrative neoplastic processes such as lymphoma or disseminated histiocytic sarcoma.^28,29 Bony lysis or periosteal new bone formation may be observed secondary to either infection (osteomyelitis/ periostitis) or neoplasia.^30,31 Obstructive hydrocephalus may develop secondary to an intracranial space-occupying lesion or choroiditis/ependymitis.^23,24 Vasogenic brain edema can be found concurrently with a number of intracranial diseases, such as neoplasia or inflammation. Under normal circumstances, exchange of substances between the blood and the brain is limited by the blood-brain barrier. Damage to brain capillaries results in leakage of fluid into the extracellular space. The edema migrates along the white matter fiber tracts and may create a mass effect indicated by displacement of the falx cerebri or compression of the ventricular system. Vasogenic edema appears hypoattenuating on CT images and may be indistinguishable from the underlying intracranial lesion prior to contrast medium administration.^25,26 An increase in intracranial pressure (e.g., due to an intracranial mass) can lead to compression and displacement of brain parenchyma.^32–34 Foramen magnum herniation (herniation of the caudal portion of the cerebellum into and through the foramen magnum) and caudal transtentorial herniation (displacement of portions of the cerebral cortex ventral to the tentorium cerebelli) are most common and are best evaluated on sagittal (reconstructed) images. Finally, intracranial hemorrhage can occur secondary to a variety of intracranial disorders including vascular malformation, coagulopathy, neoplasia, or parasite migration; however, it is not a typical feature of granulomatous disease.³⁵ The CT appearance of hemorrhage depends on the time elapsed since the inciting event. Acute intracranial hemorrhage is strongly hyperattenuating to the surrounding brain parenchyma due to the high density of the globin component of hemoglobin.³⁶ Over time, density of the hematoma decreases due to the chemical breakdown of globin molecules. An acute hematoma does not show evidence of contrast enhancement whereas chronic hematomas might show ring-like enhancement due to neovascularization in the surrounding brain tissue.

Few reports of imaging findings in intracranial fungal infection in small animals can be found in the literature. CT and MRI findings are variable and include: solitary or multifocal intra-axial mass lesions with variable contrast enhancement; meningeal, ependymal, and choroid plexus enhancement; extension of fungal granulomas through the cribriform plate; ventriculomegaly; and mass effect in the cerebral white matter consistent with vasogenic edema.^{1,27,35,37–42} CT findings in a report of one dog with intracranial blastomycosis included marked periventricular contrast enhancement of the lateral ventricles, third ventricle, and mesencephalic aqueduct.⁴³ In another report of a dog with nasal and nasopharyngeal blastomycosis, erosion of the cribriform plate was noted.⁴⁴ CT examination in a cat with intracranial blastomycosis demonstrated a large, strongly contrast-enhancing intra-axial mass.⁴⁵ A large intra-axial mass with concurrent meningeal enhancement was found in one dog in the study reported herein; however, the majority of the dogs described in the current study had extra-axial masses that extended across the cribriform plate, with possible involvement of the frontal sinuses, orbit, nasopharynx, or oral cavity, and which were associated with a variable degree of osseous destruction and bony proliferation. Hydrocephalus was not noted in any of the five cases described herein. As the CT examinations were targeted to the nasal cavity and/or orbit in three of the five dogs, the entire brain was not included in the study, and cerebellar or subtentorial herniation was not evaluated. Sagittal reconstruction of the CT images of the two dogs that presented with seizures did not show evidence of brain herniation.

Imaging findings in dogs with blastomycosis, as seen in this study, may mimic other inflammatory and neoplastic diseases. Inflammatory brain diseases typically appear as multifocal intra-axial lesions and/or meningeal enhancement, whereas brain neoplasms are commonly single intra- or extra-axial masses.^46–48 Intracranial and extracranial extension of fungal granulomas with destruction of the cribriform plate, as seen in four dogs in this study, can be confused with nasal tumors.^{21,31,49–51} In a recent study, cribriform plate erosion was 92% specific for nasal neoplasia and was not seen in a single case of fungal rhinitis caused by A. fumigatus.⁵⁰ An imaging finding of a single intra-axial lesion as seen in one dog in this study may mimic a primary brain tumor, although those are more common in older dogs and are typically not associated with meningeal enhancement.^28,52 Finally, overlap exists between features of intracranial blastomycosis and diffuse infiltrative neoplastic disorders, such as lymphoma and disseminated histiocytic sarcoma, which are associated with very variable imaging findings.^28,29

CNS blastomycosis in humans is rare. Imaging findings are variable and include multifocal punctate contrast-enhancing lesions throughout the brain, single intra-axial, or extra-axial masses/abscesses, and meningitis.^53–56 Vasogenic edema in association with intra-axial masses has been reported.⁵⁷ Similar to findings in the present study, intracranial fungal lesions are easily mistaken for other more common inflammatory or neoplastic lesions due to the variable and nonspecific appearance.⁵⁸

Conclusion

Intracranial fungal diseases in dogs may be associated with a variety of imaging findings which may mimic other nonneoplastic or neoplastic brain disorders. Young age, concurrent meningeal and parenchymal involvement, and the presence of more than one lesion may raise suspicion of fungal disease, although overlap with neoplastic disorders exists.