Robert J. Higgins

Magnetic resonance imaging and histological classification of intracranial meningiomas in 112 dogs.

BACKGROUND Intracranial meningiomas are the most common primary brain tumors in dogs. Classification of meningiomas by tumor grade and subtype has not been reported, and the value of magnetic resonance imaging (MRI) characteristics for predicting tumor subtype and grade has not been investigated. HYPOTHESIS Canine intracranial meningiomas are a heterogenous group of tumors with differing histological subtypes and grades. Prediction of histopathological classification is possible based on MRI characteristics. ANIMALS One hundred and twelve dogs with a histological diagnosis of intracranial meningioma. METHODS Retrospective observational study. RESULTS Meningiomas were overrepresented in the Golden Retriever and Boxer breeds with no sex predilection. The incidence of specific tumor grades was 56% benign (Grade I), 43% atypical (Grade II), and 1% malignant (Grade III). Grade I histological subtypes included meningothelial (43%), transitional (40%), microcystic (8%), psammomatous (6%), and angiomatous (3%). No statistically significant (P < .05) associations were found among tumor subtype or grade and any of the MRI features studied. CONCLUSIONS AND CLINICAL IMPORTANCE Meningiomas in dogs differ from their counterparts in humans mainly in their higher incidence of atypical (Grade II) tumors observed. MRI characteristics do not allow for prediction of meningioma subtype or grade, emphasizing the necessity of histopathology for antemortem diagnosis. The higher incidence of atypical tumors in dogs may contribute to the poorer therapeutic response in dogs with meningiomas as compared with the response in humans with meningiomas.

Description of Six New Capsular Types (29–34) of Streptococcus Suis

Streptococcus suis is probably the most important veterinary pathogen among streptococcal species belonging to the Lancefield group D. During the last 2 decades, it has been associated with a variety of infections in pigs and was recognized as an important zoonotic agent. Since its official recognition as a species in 1987, S. suis has been found in many other animal species, including cattle, small ruminants, horses, dogs, and cats . The number of capsular types has increased from 9 in 1983 to 29 in 1991. Among all S. suis capsular types, capsular type 2 is always the most prevalent type isolated from diseased pigs in most countries where the swine industry is important. This type also is practically the only one that causes human cases of septicemia, meningitis, and endocarditis. The majority of other isolates associated with pathologic processes belongs to capsular types 1/2, 3, 4, 6, 7, 8, and 9. Some capsular types such as 18, 19, and 21 are generally recovered from clinically healthy animals. 10 The number of untypeable S. suis isolates is now relatively low. Because some of these isolates are recovered in large numbers from several tissues of a diseased animal, they are considered potential pathogens for animals and they become candidates for new capsular types. In this article, we describe and propose 6 new capsular types of S. suis, designated as 29, 30, 31, 32, 33, and 34. Bacterial strains included in this study were reference strains of S. suis capsular types 1-28 and 1/2 and 6 other strains representing proposed capsular types 29-34. Strains representing capsular types 29, 30, 32, and 34 were recovered from diseased pigs, whereas strains representing capsular types 31 and 33 were isolated from a diseased calf and a diseased lamb, respectively. One of the diseased pigs had meningitis and 1 had septicemia, and the last 2 were aborted fetuses. The 2-month-old Holstein calf was affected with a cerebral edema and a generalized vasculitis, and S. suis was isolated in large numbers from the brain and lungs. The lamb had marked posterior paresis, and the right coxal femoral joint had marked thickening of the joint capsule with fibrin present in the joint space. Bacteriologic culturing of the synovial fluid resulted in the recovery of a large pure population of S. suis. Capsular types 29, 30, 31, and 34 reference strains originated from the Clinical Bacteriology Laboratory of the Faculty of Veterinary Medicine at the University of Montreal, and capsular types 32 and 33 reference strains were provided by S. A. Rawiuk, Bacteriology Section, Animal Health Laborato-

Glioblastoma Multiforme: Clinical Findings, Magnetic Resonance Imaging, and Pathology in Five Dogs:

Although glioblastoma multiforme (GBM), a World Health Organization grade IV astrocytoma, is the most common primary brain tumor in humans, in dogs GBM is relatively rare, accounting for only about 5% of all astrocytomas. This study presents combined clinical, neuroimaging, and neuropathologic findings in five dogs with GBM. The five dogs, aged from 5 to 12 years, were presented with progressive neurologic deficits that subsequent clinical neurologic examination and neuroimaging studies by magnetic resonance imaging (MRI), localized to space occupying lesions in the brain. MRI features of the tumors included consistent peritumoral edema (n = 5), sharp borders (n = 4), ring enhancement (n = 3), heterogenous T2-weighted signal intensity (n = 3), iso- to hypointense T1-weighted images (n = 5), necrosis (n = 5), and cyst formation (n = 2). Two tumors were diagnosed clinically using a computed tomography-guided stereotactic biopsy procedure. At necropsy all the tumors resulted in, on transverse sections, a prominent midline shift and had a variegated appearance due to intratumoral necrosis and hemorrhage. Histologically, they had serpentine necrosis with glial cell pseudopalisading and microvascular proliferation, features which distinguish human GBM from grade III astrocytomas. Immunoreactivity of tumor cells for glial fibrillary acidic protein was strongly positive in all cases, whereas 60% and 40% of the tumors also expressed epidermal growth factor receptor and vascular endothelial growth factor, respectively. These canine GBMs shared many diagnostic neuroimaging, gross, microcopic, and immunoreactivity features similar to those of human GBMs.

Divergent Astrovirus Associated with Neurologic Disease in Cattle

Using viral metagenomics of brain tissue from a young adult crossbreed steer with acute onset of neurologic disease, we sequenced the complete genome of a novel astrovirus (BoAstV-NeuroS1) that was phylogenetically related to an ovine astrovirus. In a retrospective analysis of 32 cases of bovine encephalitides of unknown etiology, 3 other infected animals were detected by using PCR and in situ hybridization for viral RNA. Viral RNA was restricted to the nervous system and detected in the cytoplasm of affected neurons within the spinal cord, brainstem, and cerebellum. Microscopically, the lesions were of widespread neuronal necrosis, microgliosis, and perivascular cuffing preferentially distributed in gray matter and most severe in the cerebellum and brainstem, with increasing intensity caudally down the spinal cord. These results suggest that infection with BoAstV-NeuroS1 is a potential cause of neurologic disease in cattle.

MAGNETIC RESONANCE IMAGING FEATURES OF CANINE INTRACRANIAL NEOPLASIA

Although histologic examination following stereotactic or surgical brain biopsy is required for definitive antemortem diagnosis of intracranial neoplasms, these tumors are often associated with magnetic resonance (MR) imaging features that warrant a presumptive or prioritized differential diagnosis. The MR imaging features of common canine central nervous system (CNS), adenohypophyseal, and metastatic intracranial neoplasms are reviewed. Characterization of neoplasms by histologic type and biological grade is based on the 2007 World Health Organization classification system for CNS tumors in humans.

Canine model of convection-enhanced delivery of liposomes containing CPT-11 monitored with real-time magnetic resonance imaging: Laboratory investigation

OBJECT Many factors relating to the safety and efficacy of convection-enhanced delivery (CED) into intracranial tumors are poorly understood. To investigate these factors further and establish a more clinically relevant large animal model, with the potential to investigate CED in large, spontaneous tumors, the authors developed a magnetic resonance (MR) imaging-compatible system for CED of liposomal nanoparticles into the canine brain, incorporating real-time MR imaging. Additionally any possible toxicity of liposomes containing Gd and the chemotherapeutic agent irinotecan (CPT-11) was assessed following direct intraparenchymal delivery. METHODS Four healthy laboratory dogs were infused with liposomes containing Gd, rhodamine, or CPT-11. Convection-enhanced delivery was monitored in real time by sequential MR imaging, and the volumes of distribution were calculated from MR images and histological sections. Assessment of any toxicity was based on clinical and histopathological evaluation. Convection-enhanced delivery resulted in robust volumes of distribution in both gray and white matter, and real-time MR imaging allowed accurate calculation of volumes and pathways of distribution. RESULTS Infusion variability was greatest in the gray matter, and was associated with leakage into ventricular or subarachnoid spaces. Complications were minimal and included mild transient proprioceptive deficits, focal hemorrhage in 1 dog, and focal, mild perivascular, nonsuppurative encephalitis in 1 dog. CONCLUSIONS Convection-enhanced delivery of liposomal Gd/CPT-11 is associated with minimal adverse effects in a large animal model, and further assessment for use in clinical patients is warranted. Future studies investigating real-time monitored CED in spontaneous gliomas in canines are feasible and will provide a unique, clinically relevant large animal translational model for testing this and other therapeutic strategies.

Spread and distribution of viral antigen in nervous canine distemper

SummaryCanine distemper virus (CDV) antigen was demonstrated immunocytochemically in the central nervous system (CNS) of 19 dogs killed from 16 to 170 days after infection. In the earliest lesions, infection of glial cells preceded demyelination, and the degree of myelin destruction correlated with the amount of viral antigen in the tissue. It was concluded that initial demyelination in distemper is directly viral-induced, but the nature of the infected glial cells remains uncertain. Ependymal infection and spread of virus in the subependymal white matter was often seen, suggesting invasion of CDV into the CNS along the CSF pathways. Inflammation during the latter stages of the infection appeared to be associated with viral clearance from the CNS in most dogs. In two dogs with chronic progressive neurologic distemper, viral antigen was still present in the brain suggesting that viral persistence and associated immunologic reactions may contribute to further myelin damage. With the exception of one dog that survived for 6 months after infection, viral antigen was no longer detected in the dogs that had reeovered.

Choroid Plexus Tumors in 56 Dogs (1985–2007)

BACKGROUND Choroid plexus tumors (CPTs) comprise approximately 10% of all primary brain tumors in dogs. The clinical utility of magnetic resonance imaging (MRI), cerebrospinal fluid (CSF) analysis, or both in the presumptive diagnosis of CPTs has not been determined. OBJECTIVES To report MRI and CSF findings in dogs with CPT and determine if there are distinguishing features that allow clinical discrimination between the tumor grades. ANIMALS Fifty-six client-owned dogs with naturally occurring CPT. METHODS Retrospective case series. The inclusion criterion was histologically confirmed CPT. Blinded review of cranial MRI and cisternal CSF analysis was performed. RESULTS Thirty-six of 56 dogs had a choroid plexus carcinoma (CPC) and 20 had a choroid plexus papilloma (CPP). Golden Retrievers were overrepresented compared with the hospital population (frequency 3.7 times that expected, confidence interval 95%= 2.0-6.7, P< .0002). Median CSF protein concentration in CPCs (108 mg/dL, range 27-380 mg/dL) was significantly higher than in CPPs (34 mg/dL, range 32-80 mg/dL) (P= .002). Only dogs with CPCs had a CSF protein concentration >80 mg/dL. Cytological evidence of malignancy in CSF was seen in 7 of 15 CPCs. Only CPCs had evidence of intraventricular or subarachnoid metastases on MRI. CONCLUSIONS AND CLINICAL IMPORTANCE MRI, CSF analysis or both can help to differentiate between CPPs and CPCs, and may provide valuable prognostic and pretreatment information.

Detection of infusate leakage in the brain using real-time imaging of convection-enhanced delivery: Laboratory investigation

OBJECT The authors have shown that convection-enhanced delivery (CED) of gadoteridol-loaded liposomes (GDLs) into different regions of normal monkey brain results in predictable, widespread distribution of this tracking agent as detected by real-time MR imaging. They also have found that this tracking technique allows monitoring of the distribution of similar nanosized agents such as therapeutic liposomes and viral vectors. A limitation of this procedure is the unexpected leakage of liposomes out of targeted parenchyma or malignancies into sulci and ventricles. The aim of the present study was to evaluate the efficacy of CED after the onset of these types of leakage. METHODS The authors documented this phenomenon in a study of 5 nonhuman primates and 7 canines, comprising 54 CED infusion sessions. Approximately 20% of these infusions resulted in leakage into cerebral ventricles or sulci. All of the infusions and leakage events were monitored with real-time MR imaging. The authors created volume-distributed versus volume-infused graphs for each infusion session. These graphs revealed the rate of distribution of GDL over the course of each infusion and allowed the authors to evaluate the progress of CED before and after leakage. RESULTS The distribution of therapeutics within the target structure ceased to increase or resulted in significant attenuation after the onset of leakage. CONCLUSIONS An analysis of the cases in this study revealed that leakage undermines the efficacy of CED. These findings reiterate the importance of real-time MR imaging visualization during CED to ensure an accurate, robust distribution of therapeutic agents.

‘Putting our heads together’: insights into genomic conservation between human and canine intracranial tumors

Numerous attributes render the domestic dog a highly pertinent model for cancer-associated gene discovery. We performed microarray-based comparative genomic hybridization analysis of 60 spontaneous canine intracranial tumors to examine the degree to which dog and human patients exhibit aberrations of ancestrally related chromosome regions, consistent with a shared pathogenesis. Canine gliomas and meningiomas both demonstrated chromosome copy number aberrations (CNAs) that share evolutionarily conserved synteny with those previously reported in their human counterpart. Interestingly, however, genomic imbalances orthologous to some of the hallmark aberrations of human intracranial tumors, including chromosome 22/NF2 deletions in meningiomas and chromosome 1p/19q deletions in oligodendrogliomas, were not major events in the dog. Furthermore, and perhaps most significantly, we identified highly recurrent CNAs in canine intracranial tumors for which the human orthologue has been reported previously at low frequency but which have not, thus far, been associated intimately with the pathogenesis of the tumor. The presence of orthologous CNAs in canine and human intracranial cancers is strongly suggestive of their biological significance in tumor development and/or progression. Moreover, the limited genetic heterogenity within purebred dog populations, coupled with the contrasting organization of the dog and human karyotypes, offers tremendous opportunities for refining evolutionarily conserved regions of tumor-associated genomic imbalance that may harbor novel candidate genes involved in their pathogenesis. A comparative approach to the study of canine and human intracranial tumors may therefore provide new insights into their genetic etiology, towards development of more sophisticated molecular subclassification and tailored therapies in both species.