Evaluation of neurofilament light chain as a biomarker in dogs with structural and idiopathic epilepsy.

BACKGROUND: Neurofilament light chain (NfL) is a frequently used biomarker in humans for both diagnostic and therapeutic monitoring purposes in various neurologic diseases. HYPOTHESIS/OBJECTIVES: It was hypothesized that dogs with diagnosed structural epilepsy (SE) would have a significantly higher serum NfL concentrations compared to dogs with idiopathic epilepsy (IE). The secondary hypothesis was that dogs would have a significantly higher serum NfL concentrations when measured within 7 days after a seizure compared to being seizure-free for at least 30 days. ANIMALS: Fifty client-owned dogs presented to the neurology service for evaluation of seizures were enrolled. Fourteen dogs had SE and 36 dogs had IE. METHODS: Prospective cohort study performed on 52 serum samples obtained for NfL concentration measurement using single molecule array technology. RESULTS: The median serum concentration of NfL in dogs with SE was significantly higher (109 pg/mL; range, 11.4-741.3 pg/mL) than in dogs with IE (17.7 pg/mL; range, 5.8-188 pg/mL; Wilcoxon rank sum test, P = .001). No significant relationship was found between serum NfL concentration and time of sampling in relation to the most recent seizure in dogs with IE. CONCLUSIONS AND CLINICAL IMPORTANCE: Serum NfL may serve as an adjunctive biomarker for the differentiation of SE and IE.

Comparison of stereotactic brain biopsy techniques in dogs: neuronavigation, 3D-printed guides, and neuronavigation with 3D-printed guides.

The objective of this research was to compare two previously described stereotactic brain biopsy (SBB) techniques, three-dimensional skull contoured guides (3D-SCGs) and neuronavigation with Brainsight, to a novel SBB technique using Brainsight combined with a 3D-printed headframe (BS3D-HF) to improve the workflow of SBB in dogs. This was a prospective methods comparison with five canine cadavers of different breeds and size. Initial helical CT was performed on cadavers with fiducial markers in place. Ten different target points were randomly selected for each method. The headframe for the BS3D-HF was designed and printed. Trajectories were planned for each method. Steinmann pins (SPs) were placed into the target points using the planned trajectories for each method, and CT was repeated (post CT). Accuracy was assessed by overlaying the initial CT onto the post CT and measuring the difference of the planned target point to the SP placement. For 3D-SCG, the median deviation was 2.48 mm (0.64-4.04). With neuronavigation, the median deviation was 3.28 mm (1.04-4.64). For BS3D-HF, the median deviation was 14.8 mm (8.87-22.1). There was no significant difference between 3D-SCG and neuronavigation for the median deviation (p = 0.42). When comparing BS3D-HF to 3D-SCG, there was a significant difference in the median deviation (p < 0.0001). Additionally, when comparing BS3D-HF to neuronavigation, there was a significant difference for the median deviation (p < 0.0001). Our findings concluded that both 3D-SCGs and neuronavigation were accurate for SBB, however BS3D-HF was not. Although feasible, the current BS3D-HF technique requires further refinement before it can be recommended for use for SBB in dogs.

Magnetic resonance and computed tomographic imaging characteristics and potential molecular mechanisms of feline meningioma associated calvarial hyperostosis.

Meningiomas are the most common feline primary brain tumours, and calvarial hyperostosis (CH) is frequently documented in association with this neoplastic entity. The clinical significance of and mechanisms driving the formation of CH in cats with meningiomas are poorly understood, although tumour invasion into the skull and tumour production of cytokines and enzymes have been implicated as causes of CH in humans. This retrospective study investigated relationships between signalment, MRI or CT imaging features, histopathologic tumour characteristics, alkaline phosphatase (ALP) isoenzyme concentrations, tumour expression of matrix metalloproteinases (MMP)-2, MMP-9, and interleukin-6 (IL-6), and progression free survival times (PFS) following surgical treatment in 27 cats with meningiomas with (n = 15) or without (n = 12) evidence of CH. No significant differences in breed, age, sex, body weight, tumour grade, tumour volume, peritumoral edema burden, ALP isoenzyme concentrations, tumour Ki-67 labelling indices or MMP-2 or MMP-9 expression and activity, or PFS were noted between cats with or without CH. There was a trend towards higher serum (p = .06) and intratumoral (p = .07) concentrations of IL-6 in cats with CH, but these comparisons were not statistically significant. Histologic evidence of tumour invasion into bone was observed in 5/12 (42%) with CH and in no (0/6) cats without CH, although this was not statistically significant (p = .07). Tumour invasion into bone and tumour production of IL-6 may contribute to the formation of meningioma associated CH in cats, although larger studies are required to further substantiate these findings and determine their clinical relevance.

Incidence, risk factors, and outcomes for early postoperative seizures in dogs with rostrotentorial brain tumors after intracranial surgery.

BACKGROUND: Seizures in the early postoperative period after intracranial surgery may affect outcome in dogs. OBJECTIVES: To determine the incidence of early postoperative seizures (EPS) in dogs with brain tumors, identify specific risk factors for EPS, and determine if EPS affects outcome. ANIMALS: Eighty-eight dogs that underwent 125 intracranial surgeries for diagnosis and treatment of rostrotentorial brain tumors. METHODS: Retrospective cohort study. All patients with a diagnosis of rostrotentorial brain tumor from 2006 to 2020 were included. Early postoperative seizures were diagnosed by observation of seizure activity within 14 days of neurosurgery. Previously diagnosed structural epilepsy, perioperative anticonvulsant drug (ACD) use, magnetic resonance imaging (MRI), and tumor characteristics were evaluated. Outcome measures included neurologic and nonneurologic complications, duration of hospitalization, and survival to discharge. RESULTS: Dogs with rostrotentorial brain tumors had EPS after 16/125 (12.8%) neurosurgical procedures (95% confidence interval [CI], 7%-19%). Presence of previous structural epilepsy was not associated with EPS risk (P = 1). Perioperative ACD use also was not associated with EPS (P = .06). Dogs with EPS had longer hospitalization (P < .001), were more likely to have neurologic complications postsurgery (P = .01), and were less likely to survive to discharge (P = .01). CONCLUSIONS AND CLINICAL IMPORTANCE: It is difficult to predict which dogs are at risk of EPS because the presence of previous structural epilepsy and the use of perioperative ACDs was not associated with EPS. However, seizures in the early postoperative period are clinically important because affected dogs had prolonged hospitalization, more neurologic complications, and decreased short-term survival.

Advancements in drug delivery methods for the treatment of brain disease.

The blood-brain barrier (BBB) presents a formidable obstacle to the effective delivery of systemically administered pharmacological agents to the brain, with ~5% of candidate drugs capable of effectively penetrating the BBB. A variety of biomaterials and therapeutic delivery devices have recently been developed that facilitate drug delivery to the brain. These technologies have addressed many of the limitations imposed by the BBB by: (1) designing or modifying the physiochemical properties of therapeutic compounds to allow for transport across the BBB; (2) bypassing the BBB by administration of drugs via alternative routes; and (3) transiently disrupting the BBB (BBBD) using biophysical therapies. Here we specifically review colloidal drug carrier delivery systems, intranasal, intrathecal, and direct interstitial drug delivery methods, focused ultrasound BBBD, and pulsed electrical field induced BBBD, as well as the key features of BBB structure and function that are the mechanistic targets of these approaches. Each of these drug delivery technologies are illustrated in the context of their potential clinical applications and limitations in companion animals with naturally occurring intracranial diseases.

Risk factors for adverse events occurring after recovery from stereotactic brain biopsy in dogs with primary intracranial neoplasia.

BACKGROUND: Stereotactic brain biopsy (SBB) allows for histopathologic diagnosis of brain tumors. Adverse events (AE) occur in 5 to 29% of dogs after SBB, but risk factors associated with developing AE are poorly described. OBJECTIVE: Identify clinicopathologic, diagnostic imaging, or procedural variables that are associated with AE in dogs after SBB. ANIMALS: Twenty-nine dogs with brain tumors. METHODS: Retrospective, case-control study. Dogs had laboratory investigations performed before SBB, as well as clinical examinations and diagnostic imaging of the brain before and after SBB. Cases experienced AE after SBB including transient exacerbation of preexisting neurologic deficits, transient new deficits, or permanent neurologic deficits. Controls had SBB performed without AE. Fisher's exact and Student's t tests were used to examine associations between the postulated risk factors and AE. RESULTS: Adverse events occurred in 8/29 (27%) dogs, and 7/8 AE (88%) were transient. Cases were significantly more likely to have T2W-heterogenous tumors (88 versus 38%; P = .04) and lower platelet counts (194.75 ± 108.32 versus 284.29 ± 68.54 ×103 /mm3 , P = .006). Dogs with gradient echo signal voids present on baseline imaging were significantly more likely to have hemorrhage present after biopsy, and 7/8 (88%) of cases had hemorrhage on imaging after SBB. CONCLUSION AND CLINICAL IMPORTANCE: Twenty-seven percent of dogs undergoing SBB experience AE, with the majority of AE resolving with 1 week. Platelet counts should be ≥185 000/mm3 to minimize risk of SBB-associated AE. Observation of intracranial hemorrhage after biopsy can have important clinical implications, as this was observed in 88% of dogs with AE.

Magnetization transfer and diffusion tensor imaging in dogs with intervertebral disk herniation.

BACKGROUND: Quantitative magnetic resonance imaging (QMRI) techniques of magnetization transfer ratio (MTR) and diffusion tensor imaging (DTI) provide microstructural information about the spinal cord. OBJECTIVE: Compare neurologic grades using the modified Frankel scale with MTR and DTI measurements in dogs with thoracolumbar intervertebral disk herniation (IVDH). ANIMALS: Fifty-one dogs with thoracolumbar IVDH. METHODS: Prospective cohort study. Quantitative MRI measurements of the spinal cord were obtained at the region of compression. A linear regression generalized estimating equations model was used to compare QMRI measurements between different neurological grades after adjusting for age, weight, duration of clinical signs, and lesion location. RESULTS: Grade 5 (.79 × 10-3 mm2 /s [median], .43-.91 [range]) and axial (1.47 × 10-3 mm2 /s, .58-1.8) diffusivity were lower compared to grades 2 (1.003, .68-1.36; P = .02 and 1.81 × 10-3 mm2 /s, 1.36-2.12; P < .001, respectively) and 3 (1.07 × 10-3 mm2 /s, .77-1.5; P = .04 and 1.92 × 10-3 mm2 /s, 1.83-2.37;P < .001, respectively). Compared to dogs with acute myelopathy, chronic myelopathy was associated with higher mean (1.02 × 10-3 mm2 /s, .77-1.36 vs. .83 × 10-3 mm2 /s, .64-1.5; P = .03) and radial diffusivity (.75 × 10-3 mm2 /s, .38-1.04 vs. .44 × 10-3 mm2 /s, .22-1.01; P = .008) and lower MTR (46.76, 31.8-56.43 vs. 54.4, 45.2-62.27; P = .004) and fractional anisotropy (.58, .4-0.75 vs. .7, .46-.85; P = .02). Fractional anisotropy was lower in dogs with a T2-weighted intramedullary hyperintensity compared to those without (.7, .45-.85 vs. .54, .4-.8; P = .01). CONCLUSION AND CLINICAL RELEVANCE: Mean diffusivity and AD could serve as surrogates of severity of spinal cord injury and are complementary to the clinical exam in dogs with thoracolumbar IVDH.

Canine Snake-Eye Myelopathy: Clinical, Magnetic Resonance Imaging, and Pathologic Findings in Four Cases.

Intramedullary signal change (ISC) is a non-specific finding that is frequently observed on magnetic resonance imaging (MRI) examinations of the canine spinal cord. ISC can represent a variety of primary pathological processes such as neoplasms or myelitides or secondary changes such as edema, cysts, gliosis, or myelomalacia. An unusual phenotype of ISC is the "snake-eye" myelopathy (SEM), which refers to bilaterally symmetric T2 hyperintensities preferentially affecting the ventral horn gray matter on transverse MR images, which resemble a pair of snake's eyes. The pathophysiology of SEM is poorly understood in humans, and this imaging finding may be associated with cervical spondylotic myelopathy, spinal cord ischemia, ossification of the posterior longitudinal ligament, amyotrophic lateral sclerosis, and Hirayama disease. Here we describe four dogs with cervical MRI examinations consistent with an SEM-like phenotype. All dogs initially presented with a central cord syndrome or tetraparesis referable to a C6-T2 neuroanatomic localization, which was attributed to disc-associated spinal cord compression in three cases, while one dog had the SEM-like phenotype with no identifiable etiology. Once the SEM-like phenotype was present on MRI examinations, dogs demonstrated insidious clinical deterioration despite therapeutic interventions. Deterioration was characterized by lower motor neuron weakness and neurogenic muscle atrophy progressing to paralysis in the thoracic limbs, while neurological functions caudal to the level of the SEM-like lesion remained largely preserved for months to years thereafter. Neuropathological features of the SEM-like phenotype include multisegmental cavitations and poliomyelomalacia of laminae VI-IX of the caudal cervical spinal cord, although the lesion evolved into pan-necrosis of gray matter with extension into the adjacent white matter in one case with an 8 years history of progressive disease. Although the pathophysiology of SEM remains unknown, the topographical distribution and appearance of lesions is suggestive of a vascular disorder. As the SEM-like phenotype was uniformly characterized by longitudinally and circumferentially extensive neuronal necrosis, results of this small case series indicate that dogs with clinical signs of central cord syndrome and the SEM-like phenotype involving the cervicothoracic intumescence on MR examinations have a poor prognosis for the preservation or recovery of thoracic limb motor function.