A 1 year old male neutered Yorkshire Terrier presented to the UGA Small Animal Emergency Service with a three week history of neck pain. The patient was initially treated by the referring veterinarian with an NSAID and methocarbamol, followed by an anti-inflammatory dose of prednisone, and finally an immune suppressive dose (2.6mg/kg) of prednisone and clindamycin 25mg BID. Despite temporary improvement, the patient’s neck pain persisted, so he was referred to UGA.
On presentation, the owner reported that the dog had been trembling, appeared disoriented, and had vision deficits. Forty-eight hours to presentation, the dog collapsed at home. This episode lasted less than 60 seconds, during which the owner observed nystagmus and defecation but no loss of consciousness. The dog had been previously healthy.
Mentation: Quiet to dull
Gait/posture: Intermittently circling to the right, low head carriage, guarding cervical region
Postural reactions: Normal hopping and placing
Spinal reflexes: Normal
Muscle mass/tone: Normal muscle tone of all four limbs, normal anal and tail tone
Cranial nerves: Absent menace OD, positional horizontal nystagmus with fast phase to the left, occasional vertical beats
Nociception: Not assessed, ambulatory
Paraspinal palpation: Painful on palpation of cervical region, decreased cervical range of motion
Neuroanatomic localization: Multifocal: left prosencephalon, C1-C5
– CBC: mild neutrophilic leukocytosis.
– Chemistry: no significant findings
The primary differential for the neurologic abnormalities was meningoencephalitis of unknown etiology (MUE) due to signalment and neurologic exam. Other differentials included congenital malformations, infection, or less likely metastatic or hematopoietic neoplasia. Alternately, the cranial nerve deficits and neck pain could be caused by two (unrelated) lesions.
Magnetic Resonance Imaging of the Brain
Transverse: T2W, T2-FLAIR, SWI, T1W-FLAIR, DWI, Phase, Trace, & ADC
Post-Contrast (Gadopentetate dimeglumine 1mmol/kg):
T1W-FLAIR in sagittal, transverse and dorsal planes. MPR reconstruction: T1-VIBE
Centered at the level of the left thalamus, a large complex space-occupying lesion is present. Centrally within this lesion there is an 8 x 11mm nodule characterized by a T2w hypointense, T1w hyperintense, strongly enhancing rim which contains punctate signal voids in SWI. At the center of this nodule is variably T2w hyperintense, T1w hypointense, non-enhancing fluid. This nodule displays restricted diffusion (hyperintense in Trace, hypointense in ADC map). Surrounding this nodule is extensive grey and white matter T2w-intermediate signal intensity which strongly enhances, and peripheral to these zones is severe T2w hyperintensity of the corona radiata, without enhancement or restricted diffusion (i.e. vasogenic edema). Signal changes extend on the left from the frontal lobe to the pons. The meninges are diffusely moderately thick and hyperenhancing, including the leptomeninges.
Severe mass effect is associated with the aforementioned space-occupying lesion, with severe cerebellar herniation, mild tentorial herniation, sulcar effacement on the left, and moderate rightward displacement of the falx. The lateral ventricles have rounded margins and bilaterally periventricular T2w-FLAIR hyperintensity is present.
The included portion of the cervical spinal cord is T2w hyperintense from the level of the mid-body of C2 to the edge of images (at C4) and contains centrally an interrupted, tubular T2W hyperintensity.
The left medial retropharyngeal lymph node is mildly larger compared to the right, of higher signal intensity in T2w and with peripheral enhancement. The remaining soft tissue structures are normal.
- Complex left thalamic mass with extensive meningoencephalitis and severely increased intracranial pressure
– Imaging characteristics of the central nodule are highly suggestive of an abscess (T2w hypointense rim, rim enhancement, restricted diffusion).
– Obstructive hydrocephalus appears present (rounding of the ventricular spaces, periventricular edema).
2. Cervical syringohydromyelia and myelopathy
– Both myelitis and syringohydromyelia related to CSF flow derangements secondary to 1. are considered.
3. Mild left medial retropharyngeal lymphadenopathy
– Reactive lymphadenopathy is prioritized.
Due to poor prognosis, the owners elected euthanasia.
Gross and formalin sections of the brain revealed multifocal to coalescing, variably well-demarcated, soft, tan to green, round foci (< 5 mm), predominantly within the left side of the brain, but with occasional malacic areas on the right side as well.
The final histopathologic diagnosis was chronic multifocal to coalescing severe pyogranulomatous encephalitis with intralesional pigmented fungal hyphae, and mild chronic lymphoplasmacytic meningitis. Fungal culture isolated a pigmented fungus, which was subsequently sequenced and identified as Cladophialophora bantiana. These findings are consistent with cerebral phaeohyphomycosis.
Based on human and animal model studies, brain abscessation can be divided into 4 stages: early cerebritis, late cerebritis, capsule formation and mature abscess. (Klopp, Hathcock et al. 2000) Based on the description of these stages, the lesion of this case would be classified as Stage 3 (early capsule formation).
The MRI appearance of brain abscesses in dogs and cats have been described. In a case series of seven intracranial bacterial abscesses in cats, MRI examination in all seven cats revealed predominantly intra-axial space-occupying lesions in the frontal or parietal region, diffusely hypointense on T1W, with a hyperintense core and hypointense peripheral ring on T2W, and strong ring enhancement. There were severe secondary effects on adjacent brain parenchyma such as perilesional white matter edema with variable subfalcine, subtentorial, and foramen magnum brain herniation. Based on MR findings, the authors stated that the primary differentials included infectious CNS disease or neoplasia (primary or metastatic). Ring enhancement is also often associated with gliomas.(Costanzo, Garosi et al. 2011)
In people, when a lesion demonstrates both ring enhancement and central restricted diffusion the differential is very narrowed. Although cerebral abscess is by far the most likely diagnosis, cerebral metastases, particularly necrotic adenocarcinoma are included on the differential. (du Plessis 2020)
A double rim sign is seen on MRI in approximately 75% of cerebral abscesses and is helpful in distinguishing an abscess from a glioblastoma. On both susceptibility weighted imaging (SWI) and T2W images, a double rim sign consists of two concentric rims surrounding the abscess cavity, the outer one which is hypointense, and the inner one which is relatively more hyperintense. (du Plessis 2020) This double rim sign was not present in the Yorkshire Terrier discussed here.
In people, SWI sequences are used to distinguish cerebral abscesses from glioblastomas. Abscesses tend to have smooth (90%) and complete (75%) low signal rims with a high-intensity line immediately internal to the low-intensity rim, thought to represent granulation tissue that lines the inner part of the fibrocollagenous abscess capsule. Glioblastomas, tend to have irregular (85%) and incomplete (85%) low signal rims thought to represent hemorrhagic products at the outer region of the necrotic core. (du Plessis 2020)
The location of the post-contrast ring enhancement can also differentiate abscesses and glioblastomas. The ring enhancement in an abscess corresponds to the T2 hypointense capsule, whereas for glioblastoma it occurs peripheral to the T2 hypointense rim in glioblastoma. (du Plessis 2020)
In human patients, additional MR sequences including MR spectroscopy, cerebral blood flow to the periphery of the lesion, and calculated ADC values of the central portion of the abscess have been reported to distinguish between abscesses and necrotic tumors. (Chiang, Hsieh et al. 2009) In particular, diffusion weighted imaging has been shown to help differentiate between abscess and necrotic tumors (Kim, Chang et al. 1998) and has been shown to be more expedient and accurate than proton MR spectroscopy. (Lai, Ho et al. 2002) Low ADC values in abscesses are attributable to the presence of pus. Pus is a highly viscous, thick, mucoid fluid consisting of inflammatory cells, bacteria, proteinaceous exudate and fibrinogen. Because of this high viscosity, diffusion water motion is severely curtailed. The high ADC values found in cystic or necrotic lesions are attributable to an intra-cavity fluid that is less viscous than that found in abscesses. It consists of necrotic tissue debris and contains fewer inflammatory cells than abscess fluid. (Desbarats, Herlidou et al. 2003) All brain abscesses have low ADC values indicative of restricted diffusion due to pus in the abscess cavity. Most cystic or necrotic tumors such as malignant glioma or metastases have high ADC values compared to normal brain. Intra-cavity fluid that is less viscous than fluid found in abscesses is responsible for high ADC values. (Kim, Yi et al. 2014) Increasing ADC values have been demonstrated during the resolution of intracranial abscesses in children (Fanning, 2006). Persistent low ADC values indicate treatment failure and pus accumulation. (Desbarats, Herlidou et al. 2003)
In people, low ADC in a ring-enhancing central nervous system lesion has also been reported in cerebral metastases. It has been suggested that early stage tumor necrosis with intracellular edema, but as yet no liquefaction, may give DWI findings similar to those for abscesses at the capsule stage. (Desbarats, Herlidou et al. 2003)
A veterinary case report has assessed ADC values in a cerebral abscess. Those authors compared two dogs (one with necrotizing leukoencephalitis and one with necrotic brain metastasis) and demonstrated low ADC values in the purulent NLE lesion and high ADC values in the metastatic lesions which corroborates reports in people. (Kim, Yi et al. 2014) In 2011, a retrospective study of the ADC characteristics of 37 histologically known cases concluded that singular quantitative ADC values are unlikely to be able to determine the histologic type of intracranial disease due to overlapping values between categories. This study was primarily comparing neoplastic intracranial disease (meningioma, glial cell tumors, choroid plexus tumors, pituitary tumors), against inflammatory brain disease, and infarcts (acute non-hemorrhagic infarcts, chronic non-hemorrhagic infarcts, and hemorrhagic infarcts). However, this study did not include intracranial abscesses. (Sutherland-Smith, King et al. 2011)
Cerebral phaeohyphomycosis is rarely reported in dogs ((Poutahidis, Angelopoulou et al. 2009, Elise B Russell 2016, Lana S. Rothenburga 2017)) and can cause disease localized to the CNS with or without systemic disease. Similar to our patient, Cladophialophora spp is the most common cause of intracranial phaeohyphomycosis in dogs (Bentley (2011) (Bentley, Faissler et al. 2011) C. bantiana (previously Cladosporium bantianum, Cladosporium trichoides, and Xylohypha bantiana) typically presents as brain granulomas without extraneural disease in dogs, cats, and humans. (Bentley, Taylor et al. 2018)
In a 2004 study of central nervous system phaeohyphomycosis in people, Cladophialophora bantiana accounted for 48% of 101 cases and was by far the most common species responsible for cerebral disease, which, in 87% of cases, consisted of brain abscess. In 52% of patients there was no underlying disease or risk factor. Overall mortality was 73% and was similar between immunosuppressed and immunocompetent. Almost all infections caused by C. bantiana in people have been confined to the CNS, indicating a highly neurotropic potential. The authors suggest that it may be reasonable to consider C. bantiana species a true pathogen, as opposed to an opportunist. (Revankar, Sutton et al. 2004)
In 2015, a review of Cladophialophora bantiana as an emerging veterinary pathogen was published. In addition to the equine case of that report, animal species affected by this fungus include cats, dogs, a snow leopard, and an alpaca. As in people, C. bantiana has a predeliction for the central nervous system in veterinary species. 58% of reported cases had lesions in the brain, and the clinical signs in these were similar to those of humans. Dissemination of the disease in animals is common, and 50% (12/24) of cases had concurrent lesions in various internal organs were observed with (n = 5) or without (n = 7) central nervous system involvement. As in humans, the outcome of cerebral or systemic phaeohyphomycosis is often fatal. Local infections may have a better prognosis, provided that surgery and long-term medical treatment are combined. (Rantala, Attia et al. 2015)
Eight dogs and seven cats with CNS phaeohyphomycosis have been described previously. The most common presentation is a single granuloma with associated meningitis, although multiple pyogranulomas with diffuse meningoencephalitis have also been described. In most reported cases (11/15), the infection was limited to the brain. Variable involvement of abdominal or thoracic organs (4/15) and vertebral column (1/15) have been reported. These cases have been uniformly fatal aside from a single case report (Bentley, Faissler et al. 2011) which was successfully treated using a combination of surgery and long-term antifungal treatment. Although most reports have included dogs with a normal immune system, intracranial phaeohyphomycosis has also been reported in association with distemper infection, ehrlichiosis, and leukopenia. (Bentley, Faissler et al. 2011)
An increased incidence of opportunistic fungal infections, including phaeohyphomycoses (ie. Cladophialophora) has been reported in immunosuppressed canine patients, with most cases being reported after the advent of cyclosporin within the veterinary community in 2003. These infections generally arise from cutaneous or respiratory inoculation, with sites of infection including skin, subcutaneous tissue, central nervous system, or disseminated disease.(Dedeaux, Grooters et al. 2018) In a recent retrospective study, 13% of immunosuppressed dogs were diagnosed with an opportunistic invasive cutaneous fungal infection. These fungal infections were 7.1 times more common in dogs treated with cyslosporin compared to other immunosuppressive therapies. (McAtee, Cummings et al. 2017)
Serology is not available for Cladophialophora. Because this organism most often causes intracranial infection without systemic disease, antemortem diagnosis may only be possible through surgical excisional biopsy or minimally invasive biopsy. In dogs, neurologic clinical signs (61%) predominate over ocular (45%) and nasal clinical signs (19%). Neurologic clinical signs depend on localization of the lesion(s). In CNS mycosis, common nonspecific signs including anorexia, lethargy, weight loss, and vomiting. Importantly, fever is frequently absent. Almost any organ can be affected. The respiratory tract is the major route of entry, but the organism may spread to hilar lymph nodes and hematogenously disseminate without clinical respiratory disease. Thoracic radiographs can be normal. Cerebrospinal fluid (CSF) nucleated cell count and protein levels are typically increased, often markedly. Mixed or neutrophilic pleocytosis are most common. CSF analysis does not usually reveal fungal organisms, unlike cases of cryptococcus. Fungal culture of the CSF is often negative. (Bentley, Taylor et al. 2018)
This is similar to a human study correlating results of microbiologic culture and histopathologic examination in which invasive septate mold infections suspected on histopathologic examination on autopsy, yielded a positive culture in only 52% of cases. The positive culture results were even lower for surgical biopsy (30%) and bronchoalveolar lavage (23%) samples. (Tarrand, Lichterfeld et al. 2003)
To date, most animals have been diagnosed at necropsy. Lesions can be a single unilateral cerebral or thalamic granuloma versus multifocal forebrain or disseminated lesions. In one case, the cerebral granuloma crossed the longitudinal fissure to the contralateral cortex. In another there were also smaller forebrain pyogranulomatous inflammatory foci. Bilateral pigmented lesions of the rostral cerebrum or multifocal gray or black pyogranulomas of the cerebrum or entire brain are also possible.(Bentley, Taylor et al. 2018)
Similar to people, in dogs, granulomas can be mistaken for glioma on MRI and both should be included in the differential diagnosis for intra-axial masses with peripheral contrast-enhancement. Other lesions with a neoplasm-like MRI appearance include cholesterol granuloma, granulomatous Acanthamoeba encephalitis, inflammatory pseudotumor, and the focal form of granulomatous meningoencephalomyelitis (GME). The recognition of certain findings atypical for glioma (mixed intra and extra-axial features, T2W-hypointensity without apparent hemorrhage, concomitant meningeal enhancement or minor contralateral lesions) can raise the suspicion of a granuloma. Signalment remains key in the interpretation of canine neuro-imaging. (Diangelo, Cohen-Gadol et al. 2019)
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