History
A 3-year-old spayed female Basenji mix presented in September 2023 to the Veterinary Medical Center of Long Island for left-lateralized vestibular signs. The patient started head shaking in May 2023 and subsequently developed a left head tilt and vestibular tetra-ataxia. The vestibular signs waxed and waned with courses of marbofloxacin and amoxicillin–clavulanic acid. Acute onset of nystagmus prompted referral in September 2023. The patient was adopted from Arizona in 2021 into a New York home. Hyperglobulinemia (> 7.8 mg/dL) on serial serum biochemistries was initially documented in January of 2022, approximately 18 months prior to presentation.
Assessment
Anatomic diagnosis
Vestibular tetra-ataxia and left head tilt can be present with a lesion of the central vestibular system (brainstem and cerebellum) or of the left peripheral vestibular system (inner ear and vestibulocochlear nerve). While there was an absence of postural reaction deficits, mentation changes, or paresis that would indicate a central vestibular lesion, the resting nystagmus that changed directions of the fast phase was more indicative of a central vestibular lesion rather than a peripheral vestibular lesion.
Likely location of the lesion
Left central vestibular.
Etiologic diagnosis
Differential diagnoses for a 3-year-old dog with progressive central vestibular signs include meningoencephalitis of unknown etiology, infectious meningoencephalitis (eg, protozoal, fungal, bacterial, viral), and neoplasia (primary vs metastatic). Biochemistry and CBC were planned to evaluate for systemic disease. Magnetic resonance imaging, spinal fluid analysis, and serum neurologic PCR were recommended to evaluate for meningoencephalitis and neoplasia.
Diagnostic Test Findings
A serum chemistry revealed an elevated total protein (11.7 g/dL; reference range [RR], 5.5 to 7.6 g/dL) with a normal albumin (3 g/dL; RR, 2.5 to 4 g/dL). Due to machine error, an accurate globulin was unable to be obtained in-house. This error was presumptively due to hyperglobulinemia, given the patient’s clinical history. Aspartate aminotransferase was also elevated at 138 U/L (RR, 0 to 60 U/L). The remainder of the serum biochemistry and a CBC were unremarkable.
In the MRI study, the C7 and T1 vertebrae had marked cortical lysis, with T2-weighted (T2W) hyperintense and contrast-enhancing medullary cavities (Signa HDxt 1.5T; GE HealthCare). In the fourth ventricle there was a large, markedly T2W hypointense, T1-weighted isointense, smoothly marginated, bilobed, bilaterally symmetrical mass with marked homogeneous contrast enhancement (Figure 1). Centered on the mass, there was moderate focal meningeal contrast enhancement. The ventricular system rostral to the mass was moderately to markedly distended with periventricular FLAIR hyperintensities consistent with an acute obstructive hydrocephalus. Extending from the brainstem along the spinal cord to the level of C5, there were patchy regions of T2W hyperintense parenchyma, predominantly affecting the dorsal aspect of these structures.
The right side of the patient is to the left in transverse images. Transverse T2-weighted (panel A) and T1-weighted pre- (panel B) and postcontrast (panel C) MRI images of the brain at the level of the fourth ventricle of a 3-year-old spayed female Basenji mix presented for a 5-month history of waxing and waning left-lateralized vestibular signs that were unresponsive to antibiotics. In the fourth ventricle, a T2 hypointense, T1 isointense, strongly contrast-enhancing mass (panels A through C; white asterisks) causes a local mass effect. There is moderate focal meningeal contrast enhancement centered on the mass (panel C; white arrows).
Citation: Journal of the American Veterinary Medical Association 263, 3; 10.2460/javma.24.08.0544
A lateral cervical radiograph showed that the C7 vertebra, T1 vertebral body, and ventral aspect of the T1 spinous process had ill-defined lysis consistent with aggressive osseous lesions of C7 and T1.
In summary of the imaging, a mass was identified within the fourth ventricle with focal meningomyelitis, obstructive hydrocephalus, and suspected syringohydromyelia. The spinal cord and brainstem T2W hyperintensity were posited to be interstitial edema, gliosis, or other infiltrative process. Additionally, there were polyostotic aggressive osseous lesions involving C7 and T1.
A serum neurologic PCR was negative for Anaplasma spp, Ehrlichia spp, Rickettsia spp, Bartonella spp, Blastomyces dermatitidis, Coccidioides spp, Cryptococcus spp, Histoplasma capsulatum, canine distemper virus, West Nile virus, Borrelia burgdorferi, Neospora spp, and Toxoplasma gondii. Cerebrospinal fluid was not collected due to concern for intracranial hypertension on MRI. The patient was started on an anti-inflammatory tapering course of dexamethasone and meclizine and showed clinical improvement for about 3 weeks before declining neurologically as glucocorticoids were weaned. Despite reinstituting the initial dose of glucocorticoids, the patient began to show focal seizure activity and was intermittently tachypneic, which was suspected to be due to refractory cervical pain. Given the declining clinical status, the patient was euthanized and the brain, cervical spinal cord, and C7 and T1 vertebrae and paraspinal musculature were submitted for necropsy. Histopathology revealed severe, chronic multifocal to coalescing pyogranulomatous meningoencephalomyelitis, osteomyelitis, and myositis with intralesional fungal spherules 30 to 40 µm in diameter (Figure 2). Panfungal PCR on scrolls of formalin-fixed, paraffin-embedded affected tissue was negative presumptively due to the long formalin fixation times required for histopathology of brain tissue. The final diagnosis of meningoencephalitis, osteomyelitis, and myositis due to a Coccidioides sp was made on the basis of histopathologic appearance of the fungal spherules that were thick walled (2 to 3 µm) and approximately 30 to 40 µm in diameter.
Photomicrographs of histopathology of the brain at the level of the cerebellum and pons. A—A large focal mass at the margin of the pons and cerebellar white matter expands and compresses normal neuroparenchyma. Additionally, the lateral and ventral leptomeninges are expanded by a densely cellular granulomatous inflammatory infiltrate. B—Fungal spherules approximately 30 to 40 µm in diameter with a 2-µm-thick refractile wall are associated with large numbers of epithelioid macrophages, plasma cells, and lymphocytes with scattered multinucleated cells. Given the size and histologic appearance of the spherules, the main differential diagnosis is Coccidioides spp. Bar = 50 µm.
Citation: Journal of the American Veterinary Medical Association 263, 3; 10.2460/javma.24.08.0544
Comments
Given the discrete fourth ventricular mass, strong contrast enhancement throughout multiple structures (eg, bone, muscle, nervous tissue), and negative serum PCR (including Coccidioides spp), diagnosis of multifocal round cell neoplasia (eg, lymphoma) was prioritized following diagnostic imaging. Ultimately, histopathology confirmed the diagnosis of coccidioidomycosis.
The diagnostic imaging findings in this case were unusual and made antemortem diagnosis difficult. Prior studies1,2 have identified 2 distinct categories of lesions on MRI in presumptive cases of canine intracranial coccidioidomycosis: a granulomatous form and a diffuse form, with the granulomatous form being more common. The diffuse form results in bilaterally symmetric T2/FLAIR hyperintensities of the caudate nuclei and frontal lobes and has a breed predisposition for the Miniature Schnauzer.1
Coccidioidomycosis is a fungal infection that occurs in humans as well as in domestic and wild species. It is caused by 2 species: Coccidioides immitis and Coccidioides posadasii. Fungal spores are most commonly inhaled in endemic regions (eg, Southeastern US, Northern Mexico, and South America), typically causing chronic respiratory signs, and can also result in disseminated disease involving skin, bone, heart, ocular tissue, and nervous tissue. Disseminated disease in domestic animals most commonly presents as osteomyelitis causing lameness.3 Disseminated coccidioidomycosis affecting the nervous system typically results in seizures but can also cause paresis, ataxia, spinal pain, or cranial nerve deficits.1,2,4 A definitive diagnosis is made if the organism can be identified on cytology or histology, as imaging abnormalities can have overlapping features with neoplastic disease.4 Polymerase chain reaction and serological testing are available as well but may result in false negatives, as was the case before and after this patient was euthanized.1–4 Treatment typically includes long-term systemic antifungal therapy, including either amphotericin B or azoles, most commonly fluconazole.1–4 Prognosis is variable and dependent on severity and distribution of disease. Patients with exclusively pulmonary manifestation have the best prognosis for recovery compared to patients with disseminated disease.3
Nervous system coccidioidomycosis tends to cause supratentorial lesions inconsistent with this patient.1,4 This discrepancy may explain why the majority of dogs (25 of 45) in 1 study1 presented for generalized seizures as opposed to central vestibular signs (7 of 45), as was the case with our patient.
Another interesting feature noted in our patient was the marked T2W hypointensity of the fourth ventricular mass. T2-weighted hypointense masses have been described in cases of granulomas in both dogs and humans and could be related to the proteinaceous, fibrinous fungal capsule and high cellularity of the granuloma.1,4 In general, T2W hypointense lesions are uncommon and differentials for underlying causes of this particular change include hemorrhage and mineralization, which can be associated with neoplasia and, less commonly, chronic inflammation. This lesion was T1 isointense with no susceptibility artifact noted on T2*W imaging and was thus more suggestive of a fungal granuloma.
While some of the clinical features in this case fit well with coccidioidomycosis—such as the osteomyelitis and osteolysis noted on both imaging and histopathology—antemortem results of other diagnostics made diagnosis difficult. For example, while the historic marked hyperglobulinemia (a common biochemistry finding in cases of canine coccidioidomycosis) may have been related to latent infection, a false negative on serum PCR inhibited a timely diagnosis and initiation of systemic antifungal medications.1–3 While coccidioidomycosis has been reported in dogs with travel histories or systemic clinical signs up to 3 years prior to definitive diagnosis, the lack of a recent travel history to a Coccidioides-endemic area made suspicion of coccidioidomycosis much lower.1–3 Interestingly, the client also had a history of a Coccidioides pulmonary granuloma that was treated with 9 months of systemic antifungal medications; the disease was considered static at the time of this patient’s diagnosis.
In conclusion, this case highlights several important diagnostic considerations: first, negative infectious disease testing, especially serum PCR, does not fully rule out an infectious etiology of disease. Additionally, lack of a recent travel history to an endemic area does not preclude diagnosis of an infectious etiology.
Acknowledgments
The authors thank the owner of this patient for allowing them to report on this unique case, including personal health information. The authors also thank Dr. Jorge I. Alvarez for his help with preparation of the histologic images.
Disclosures
The authors have nothing to disclose. No AI-assisted technologies were used in the generation of this manuscript.
Funding
The authors have nothing to disclose.
References
- 1.↑
Kelley AJ, Stainback LB, Knowles KE, Moore TW, Plummer SB, Shoup OR. Clinical characteristics, magnetic resonance imaging features, treatment, and outcome for presumed intracranial coccidioidomycosis in 45 dogs (2009-2019). J Vet Intern Med. 2021;35(5):2222-2231. doi:10.1111/jvim.16243
- 2.↑
Spoor E, Stainback L, Plummer S, Knowles K. A novel form of intracranial coccidioidomycosis is present in dogs and exhibits characteristic clinical and magnetic resonance imaging findings. Vet Radiol Ultrasound. 2019;60(1):47-55. doi:10.1111/vru.12688
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Graupmann-Kuzma A, Valentine BA, Shubitz LF, Dial SM, Watrous B, Tornquist SJ. Coccidioidomycosis in dogs and cats: a review. J Am Anim Hosp Assoc. 2008;44(5):226-235. doi:10.5326/0440226
- 4.↑
Bentley RT, Heng HG, Thompson C, et al. Magnetic resonance imaging features and outcome for solitary central nervous system Coccidioides granulomas in 11 dogs and cats. Vet Radiol Ultrasound. 2015;56(5):520-530. doi:10.1111/vru.12258
