Shannon P. Holmes

Magnetic resonance imaging for the differentiation of neoplastic, inflammatory, and cerebrovascular brain disease in dogs

BACKGROUND The reliability and validity of magnetic resonance imaging (MRI) for detecting neoplastic, inflammatory, and cerebrovascular brain lesions in dogs are unknown. OBJECTIVES To estimate sensitivity, specificity, and inter-rater agreement of MRI for classifying histologically confirmed neoplastic, inflammatory, and cerebrovascular brain disease in dogs. ANIMALS One hundred and twenty-one client-owned dogs diagnosed with brain disease (n = 77) or idiopathic epilepsy (n = 44). METHODS Retrospective, multi-institutional case series; 3 investigators analyzed MR images for the presence of a brain lesion with and without knowledge of case clinical data. Investigators recorded most likely etiologic category (neoplastic, inflammatory, cerebrovascular) and most likely specific disease for all brain lesions. Sensitivity, specificity, and inter-rater agreement were calculated to estimate diagnostic performance. RESULTS MRI was 94.4% sensitive (95% confidence interval [CI] = 88.7, 97.4) and 95.5% specific (95% CI = 89.9, 98.1) for detecting a brain lesion with similarly high performance for classifying neoplastic and inflammatory disease, but was only 38.9% sensitive for classifying cerebrovascular disease (95% CI = 16.1, 67.0). In general, high specificity but not sensitivity was retained for MR diagnosis of specific brain diseases. Inter-rater agreement was very good for overall detection of structural brain lesions (κ = 0.895, 95% CI = 0.792, 0.998, P < .001) and neoplastic lesions, but was only fair for cerebrovascular lesions (κ = 0.299, 95% CI = 0, 0.761, P = .21). CONCLUSIONS AND CLINICAL IMPORTANCE MRI is sensitive and specific for identifying brain lesions and classifying disease as inflammatory or neoplastic in dogs. Cerebrovascular disease in general and specific inflammatory, neoplastic, and cerebrovascular brain diseases were frequently misclassified.

Evaluation of standard magnetic resonance characteristics used to differentiate neoplastic, inflammatory, and vascular brain lesions in dogs.

Magnetic resonance (MR) imaging characteristics are commonly used to help predict intracranial disease categories in dogs, however, few large studies have objectively evaluated these characteristics. The purpose of this retrospective study was to evaluate MR characteristics that have been used to differentiate neoplastic, inflammatory, and vascular intracranial diseases in a large, multi-institutional population of dogs. Medical records from three veterinary teaching hospitals were searched over a 6-year period for dogs that had diagnostic quality brain MR scans and histologically confirmed intracranial disease. Three examiners who were unaware of histologic diagnosis independently evaluated 19 MR lesion characteristics totaling 57 possible responses. A total of 75 dogs with histologically confirmed intracranial disease were included in analyses: 51 with neoplasia, 18 with inflammatory disease, and six with cerebrovascular disease. Only strong contrast enhancement was more common in neoplasia than other disease categories. A multivariable statistical model suggested that extra-axial origin, T2-FLAIR mixed intensity, and defined lesion margins were also predictive of neoplasia. Meningeal enhancement, irregular lesion shape, and multifocal location distinguished inflammatory diseases from the other disease categories. No MR characteristics distinguished vascular lesions and these appeared most similar to neoplasia. These results differed from a previous report describing seven MR characteristics that were predictive of neoplasia in dogs and cats. Findings from the current study indicated that the high performance of MR for diagnosing canine intracranial diseases might be due to evaluator recognition of combinations of MR characteristics vs. relying on any one MR characteristic alone.

Superparamagnetic iron oxide nanoparticles as a means to track mesenchymal stem cells in a large animal model of tendon injury.

The goal of this study was to establish an SPIO-based cell-tracking method in an ovine model of tendonitis and to determine if this method may be useful for further study of cellular therapies in tendonitis in vivo. Functional assays were performed on labeled and unlabeled cells to ensure that no significant changes were induced by intracellular SPIOs. Following biosafety validation, tendon lesions were mechanically (n = 4) or chemically (n = 4) induced in four sheep and scanned ex vivo at 7 and 14 days to determine the presence and distribution of intralesional cells. Ovine MSCs labeled with 50 µg SPIOs/mL remained viable, proliferate, and undergo tri-lineage differentiation (p < 0.05). Labeled ovine MSCs remained detectable in vitro in concentrated cell numbers as low as 10 000 and in volumetric distributions as low as 100 000 cells/mL. Cells remained detectable by MRI at 7 days, as confirmed by correlative histology for dually labeled SPIO+/GFP+ cells. Histological evidence at 14 days suggested that SPIO particles remained embedded in tissue, providing MRI signal, although cells were no longer present. SPIO labeling has proven to be an effective method for cell tracking for a large animal model of tendon injury for up to 7 days post-injection. The data obtained in this study justify further investigation into the effects of MSC survival and migration on overall tendon healing and tissue regeneration.

Gait analysis in a pre- and post-ischemic stroke biomedical pig model

Severity of neural injury including stroke in human patients, as well as recovery from injury, can be assessed through changes in gait patterns of affected individuals. Similar quantification of motor function deficits has been measured in rodent animal models of such injuries. However, due to differences in fundamental structure of human and rodent brains, there is a need to develop a large animal model to facilitate treatment development for neurological conditions. Porcine brain structure is similar to that of humans, and therefore the pig may make a more clinically relevant animal model. The current study was undertaken to determine key gait characteristics in normal biomedical miniature pigs and dynamic changes that occur post-neural injury in a porcine middle cerebral artery (MCA) occlusion ischemic stroke model. Yucatan miniature pigs were trained to walk through a semi-circular track and were recorded with high speed cameras to detect changes in key gait parameters. Analysis of normal pigs showed overall symmetry in hindlimb swing and stance times, forelimb stance time, along with step length, step velocity, and maximum hoof height on both fore and hindlimbs. A subset of pigs were again recorded at 7, 5 and 3 days prior to MCA occlusion and then at 1, 3, 5, 7, 14 and 30 days following surgery. MRI analysis showed that MCA occlusion resulted in significant infarction. Gait analysis indicated that stroke resulted in notable asymmetries in both temporal and spatial variables. Pigs exhibited lower maximum front hoof height on the paretic side, as well as shorter swing time and longer stance time on the paretic hindlimb. These results support that gait analysis of stroke injury is a highly sensitive detection method for changes in gait parameters in pig.

Chiari-Like Malformation and Syringomyelia in American Brussels Griffon Dogs

Background Although Chiari‐like malformation (CM) and syringomyelia (SM) have been described in many small breed dogs, the prevalence and clinical manifestations of this complex have not been documented in a large cohort of American Brussels Griffon (ABG) dogs. Objectives To characterize the clinical and magnetic resonance imaging (MRI) features of CM and SM in the ABG breed. Animals Eighty‐four American Kennel Club registered ABG dogs were recruited. Methods Prospective study. Complete histories and neurologic examinations were obtained before MRI. Images were blindly reviewed and calculations were made by using OsiriX. All analyses were performed by Students t‐test, Spearmans correlation, ANOVA, and chi‐square test where appropriate. Results Chiari‐like malformation and SM were present in 65% and 52% of dogs, respectively. Twenty‐eight percent of dogs had neurologic deficits and 20% had neck pain. Mean central canal (CC) transverse height was 2.5 mm with a mean length of 3.6 cervical vertebrae. Neurologic deficits were significantly associated with a larger syrinx (P = .04, P = .08) and syrinx size increased with age (P = .027). SM was associated with a smaller craniocervical junction (CCJ) height (P = .04) and larger ventricles (P = .0001; P < .001). Conclusions and Clinical Importance Syringomyelia and CM are prevalent in American Brussels Griffon dogs. Syrinx size is associated with neurologic deficits, CM, larger ventricles, a smaller craniocervical junction height, neurologic deficits, and cerebellar herniation. Fifty‐two percent of dogs with a SM were clinically normal.

Magnetic resonance imaging findings in horses with septic arthritis.

Fourteen horses with septic arthritis underwent high-field (1.5 T) magnetic resonance imaging (MRI). Septic arthritis was diagnosed based on results from historical and clinical findings, synovial fluid analyses and culture, and radiographic, ultrasonographic, arthroscopic, and histopathologic findings. MR findings included diffuse hyperintensity within bone and extracapsular tissue on fat-suppressed images in 14/14 horses (100%), joint effusion, synovial proliferation, and capsular thickening in 13/14 horses (93%), bone sclerosis in 11/14 horses (79%), and evidence of cartilage and subchondral bone damage in 8/14 horses (57%). Intravenous gadolinium was administered to five of the 14 horses and fibrin deposition was noted in all horses. Other findings after gadolinium administration included synovial enhancement in 4/5 (80%) horses, and bone enhancement in 1/5 (20%) horses. The MR findings of septic arthritis in horses were consistent with those reported in people. MRI may allow earlier and more accurate diagnosis of septic arthritis in horses as compared with other imaging modalities, especially when the clinical diagnosis is challenging. It also provides additional information not afforded by other methods that may influence and enhance treatment.

Induced Pluripotent Stem Cell-Derived Neural Stem Cell Therapy Enhances Recovery in an Ischemic Stroke Pig Model.

Induced pluripotent stem cell-derived neural stem cells (iNSCs) have significant potential as an autologous, multifunctional cell therapy for stroke, which is the primary cause of long term disability in the United States and the second leading cause of death worldwide. Here we show that iNSC transplantation improves recovery through neuroprotective, regenerative, and cell replacement mechanisms in a novel ischemic pig stroke model. Longitudinal multiparametric magnetic resonance imaging (MRI) following iNSC therapy demonstrated reduced changes in white matter integrity, cerebral blood perfusion, and brain metabolism in the infarcted tissue. The observed tissue level recovery strongly correlated with decreased immune response, enhanced neuronal protection, and increased neurogenesis. iNSCs differentiated into neurons and oligodendrocytes with indication of long term integration. The robust recovery response to iNSC therapy in a translational pig stroke model with increased predictive potential strongly supports that iNSCs may be the critically needed therapeutic for human stroke patients.

Magnetic resonance imaging enhancement of intervertebral disc disease in 30 dogs following chemical fat saturation

OBJECTIVE To describe the patterns of enhancement of extradural intervertebral disc on chemically fat saturated gadolinium-enhanced magnetic resonance images and to investigate the clinical and pathological associations with enhancement. METHODS Medical records and magnetic resonance images were reviewed from 30 dogs with histopathologically confirmed disc disease and enhancement on a T1-weighted postcontrast fat saturated sequence. RESULTS Median duration of neurological signs was 4 days and the most common grade of severity was II, seen in 46·6% of dogs. Homogeneous, heterogeneous and peripheral patterns of disc enhancement were described, with peripheral enhancement most commonly identified (57% of dogs). There were no clinical or pathological differences between the dogs with each of the patterns. The mean signal intensity of a region of interest within the extruded disc material and contrast-to-noise ratio of the disc material were significantly higher on postcontrast T1-weighted fat saturated images (P=<0·0001 each). CLINICAL SIGNIFICANCE The use of fat saturated gadolinium-enhanced magnetic resonance imaging can detect enhancement of extradural disc material. Patterns of enhancement are not associated with the clinical presentation or pathological features.

Imaging diagnosis-CT myelography in a dog with intramedullary intervertebral disc herniation.

A 5-year-old Chihuahua was examined for peracute pain and paraparesis. Neuroanatomic localization was consistent with a symmetric T3-L3 myelopathy. Computed tomography (CT) of the T9-L5 vertebrae was normal. Myelography disclosed attenuation of the subarachnoid space from T11 to L1, consistent with spinal cord swelling. CT following the myelogram disclosed a focal area of intramedullary iodinated contrast medium at T13-L1. At surgery, intervertebral disc material was removed from the spinal cord. Based on the findings in this patient, intramedullary disc herniation should be considered a cause for focal intramedullary contrast medium accumulation.

MRI-Based Assessment of Intralesional Delivery of Bone Marrow-Derived Mesenchymal Stem Cells in a Model of Equine Tendonitis

Ultrasound-guided intralesional injection of mesenchymal stem cells (MSCs) is held as the benchmark for cell delivery in tendonitis. The primary objective of this study was to investigate the immediate cell distribution following intralesional injection of MSCs. Unilateral superficial digital flexor tendon (SDFT) lesions were created in the forelimb of six horses and injected with 10 × 106 MSCs labeled with superparamagnetic iron oxide nanoparticles (SPIOs) under ultrasound guidance. Assays were performed to confirm that there were no significant changes in cell viability, proliferation, migration, or trilineage differentiation due to the presence of SPIOs. Limbs were imaged on a 1.5-tesla clinical MRI scanner postmortem before and after injection to determine the extent of tendonitis and detect SPIO MSCs. Clusters of labeled cells were visible as signal voids in 6/6 subjects. Coalescing regions of signal void were diffusely present in the peritendinous tissues. Although previous reports have determined that local injury retains cells within a small radius of the site of injection, our study shows greater than expected delocalization and relatively few cells retained within collagenous tendon compared to surrounding fascia. Further work is needed if this is a reality in vivo and to determine if directed intralesional delivery of MSCs is as critical as presently thought.