Blood‐brain barrier dysfunction in canine epileptic seizures detected by dynamic contrast‐enhanced magnetic resonance imaging

Abstract

Objective Dogs with spontaneous or acquired epilepsy exhibit resemblance in etiology and disease course to humans, potentially offering a translational model of the human disease. Blood‐brain barrier dysfunction (BBBD) has been shown to partake in epileptogenesis in experimental models of epilepsy. To test the hypothesis that BBBD can be detected in dogs with naturally occurring seizures, we developed a linear dynamic contrast‐enhanced magnetic resonance imaging (DCE‐MRI) analysis algorithm that was validated in clinical cases of seizing dogs and experimental epileptic rats. Methods Forty‐six dogs with naturally occurring seizures of different etiologies and 12 induced epilepsy rats were imaged using DCE‐MRI. Six healthy dogs and 12 naive rats served as control. DCE‐MRI was analyzed by linear‐dynamic method. BBBD scores were calculated in whole brain and in specific brain regions. Immunofluorescence analysis for transforming growth factor beta (TGF‐β) pathway proteins was performed on the piriform cortex of epileptic dogs. Results We found BBBD in 37% of dogs with seizures. A significantly higher cerebrospinal fluid to serum albumin ratio was found in dogs with BBBD relative to dogs with intact blood‐brain barrier (BBB). A significant difference was found between epileptic and control rats when BBBD scores were calculated for the piriform cortex at 48 hours and 1 month after status epilepticus. Mean BBBD score of the piriform lobe in idiopathic epilepsy (IE) dogs was significantly higher compared to control. Immunohistochemistry results suggested active TGF‐β signaling and neuroinflammation in the piriform cortex of dogs with IE, showing increased levels of serum albumin colocalized with glial acidic fibrillary protein and pSMAD2 in an area where BBBD had been detected by linear DCE‐MRI. Significance Detection of BBBD in dogs with naturally occurring epilepsy provides the ground for future studies for evaluation of novel treatment targeting the disrupted BBB. The involvement of the piriform lobe seen using our linear DCE‐MRI protocol and algorithm emphasizes the possibility of using dogs as a translational model for the human disease.

Advances regarding Neuroinflammation Biomarkers with Noninvasive Techniques in Epilepsy

“…Besides microglia and astrocytes, BBBD, as well as named BBB leakage, is also tightly coupled to neuroinflammation [ 66 ]. In the experimental epilepsy model of animals, BBBD can promote epileptogenesis [ 3 , 67 ]. Neuroinflammation may originate directly from the central nervous system or from the peripheral circulation due to the destruction of the BBB [ 68 ].…”

“…Neuroinflammation may originate directly from the central nervous system or from the peripheral circulation due to the destruction of the BBB [ 68 ]. The leakage of plasma constituents to the extracellular neuronal environment leads to progression of neuroinflammation and enhanced cortical excitability [ 66 , 67 ]. Noninvasive quantitative measures of BBBD are clinically required to reach a more accurate identification of neuroinflammation [ 69 ].…”

“…Therefore, BBBD may be used as a biomarker to monitor the efficacy of a potential therapeutic epilepsy treatment [ 73 ]. There is recent progress in the analysis of brain dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), in which the linear behavior of the contrast agents in the brain vasculature and parenchyma is used to evaluate BBB permeability [ 67 , 74 ]. It showed higher values of DCE-MRI index in predicting lesions with a higher propensity to cause seizure recurrence [ 75 ].…”

Increased resting state connectivity in the anterior default mode network of idiopathic epileptic dogs

“…Resting state networks (RSN) share similar features in humans and animals 9 but information regarding rs-fMRI in epilepsy in non-human species are spare and limited to rodent models so far 7 . Although the dog is an established large animal model for human epilepsy 10 , 11 , studies describing rs-fMRI of the canine brain in dogs affected by naturally-occurring epilepsy are currently lacking.…”

“…Naturally occurring canine idiopathic epilepsy has been proposed as a translational model for human epilepsy because the two species share similarities such as prevalence, clinical manifestation, electroencephalographic manifestation, and pharmacological response 10 , 11 , 20 – 23 . However, characterization of brain regions involved in canine epilepsy is lacking 11 , 21 , 23 , 24 .…”