Investigations on the pathophysiology of canine idiopathic epilepsy
AffiliationVeterinary Clinical Sciences
Document TypePhD thesis
Access StatusOpen Access
© 2018 Dr Marjorie Milne
The causes of canine epilepsy are poorly understood. The current aetiologic classification scheme for canine epilepsy includes the categories structural epilepsy, idiopathic epilepsy with genetic or suspected genetic cause, or idiopathic epilepsy of unknown cause. It is likely that dogs with idiopathic epilepsy of unknown cause have heterogeneous underlying pathologies, including subtle structural change that cannot be identified on conventional visual inspection of brain magnetic resonance images. This thesis examines the causes of epilepsy in a sample of Australian dogs presented to the University of Melbourne Veterinary Hospital. The general hypotheses explored by the studies described in this work are that some cases of canine idiopathic epilepsy have underlying structural brain pathologies similar to those identified in humans with epilepsy, and that canine idiopathic epilepsy is associated with increased cerebral levels of the excitatory neurotransmitter glutamate. The prevalence of epilepsy in dogs presented to the University of Melbourne Veterinary Hospital was 1.1%, and idiopathic epilepsy of unknown cause represented 75% of epilepsy diagnoses. Of the 25% of dogs with structural epilepsy, brain tumours were the most frequent cause (60%), followed by meningoencephalitis of unknown origin (11%). In dogs with idiopathic epilepsy, odds ratio analysis identified 21 breeds of dog with an increased risk of a diagnosis of epilepsy. The Hungarian viszla had a particularly strong association with this diagnosis, but in none of the dogs diagnosed with idiopathic epilepsy was a familial history of epilepsy reported. Based on retrospective, randomised and blinded, subjective review of brain magnetic resonance imaging scans of dogs with idiopathic epilepsy and controls, there was no convincing evidence of the magnetic resonance imaging findings of hippocampal sclerosis or focal cortical dysplasia. Brain MRIs were also evaluated using atlas-based segmentation and volumetry, based on a novel canine brain atlas developed for this research. Hippocampal atrophy was used as a biomarker for possible hippocampal sclerosis. Unilateral or bilateral hippocampal atrophy was identified in 15% of dogs with idiopathic epilepsy, based on identifying those dogs with a hippocampal formation volume below the lower 95% reference limit for hippocampal volume established in control dogs. Increased volume of the cerebral cortex was used as a biomarker for possible cortical dysplasia, and reduced volume of the cerebral cortex was a biomarker for cerebrocortical atrophy. Dogs with idiopathic epilepsy had statistically significant reductions in cerebrocortical volume in the left and right olfactory, temporal, occipital, and right parietal lobes. The second hypothesis was that dogs with idiopathic epilepsy had elevated cerebral glutamate, the major excitatory neurotransmitter in the brain. This was explored non-invasively in dogs with naturally occurring epilepsy, using proton magnetic resonance spectroscopy to measure in vivo brain glutamate. There was no significant difference in either glutamate or glutamate to creatine ratio between dogs with epilepsy and controls. Further work is required to establish whether hippocampal atrophy in dogs with epilepsy is due to hippocampal sclerosis. This work could use both volumetry, T2 relaxometry, and histopathologic evaluation of brain samples. Future investigation of the mechanisms of cerebrocortical atrophy in epilepsy may involve cortical thickness measures to allow targeted correlation of regions of localised cerebrocortical atrophy with brain histology, and fibre tracking to map epileptogenic networks, exploring the connections between EEG identified seizure focus and regions of cortical atrophy. The role of brain glutamate may be further investigated using multi-voxel magnetic resonance spectroscopy at 3 Tesla, and glutamate transporter proteins and receptors may be investigated through laboratory techniques.
Keywordscanine; epilepsy; magnetic resonance imaging; MRI; hippocampal sclerosis; glutamate; magnetic resonance spectroscopy; MRS
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