Structural and functional imaging of MRI-negative temporal lobe epilepsy and of the piriform cortex

© 2017 Dr David Noel VaughanTemporal lobe epilepsy (TLE) is the most common form of epilepsy in adults. Up to 40% have no clinically detectable abnormality on MRI, which makes accurate diagnosis and effective treatment a challenging problem. This thesis addresses two separate but related issues in this population. Firstly, we studied the pattern of white matter atrophy and abnormal functional connectivity in MRI-negative temporal lobe epilepsy (MRI-neg TLE), aiming to better understand the underlying pathophysiology and potential diagnostic features of this group. Secondly, we examined the involvement of the piriform cortex in TLE, and whether it might be a critical node in the development of focal seizures and therefore a potential target for therapeutic intervention. Medically refractory unilateral MRI-neg TLE was studied using diffusion weighted imaging, with comparison to TLE with hippocampal sclerosis (HS-TLE) and healthy controls. Fixel-based analysis revealed tract-specific white matter atrophy that was ipsilateral to the seizure focus but was also present in other tracts bilaterally. We propose a new conceptual model for white matter injury in MRI-neg TLE, where atrophy of the ipsilateral tapetum and uncinated fasciculus is a consequence of focal seizures, but that bilateral atrophy of the dorsal cingulum and corpus callosum fibres is common to many focal epilepsies and a consequence of global insults. Functional connectivity in MRI-neg TLE was assessed using a novel voxel-wise graph theory analysis. It revealed a lateralized decrease in connectivity of the lateral temporal neocortex, unlike HS-TLE where abnormal connectivity was detected at the hippocampus, thalamus and mesial prefrontal cortex. Together these data demonstrate that MRI-neg TLE should be considered a distinct syndrome from HS-TLE, as the key structural and functional abnormalities of MRI-neg TLE are related to neocortical rather than mesial temporal structures. The piriform cortex, part of primary olfactory cortex, is a key site for epileptogenesis in animal models, and is commonly involved in human epilepsy. Activation of the piriform cortex caused by interictal discharges was studied using simultaneous EEG-fMRI. In patients with focal epilepsy, a hemodynamic response at the ipsilateral piriform cortex was seen synchronously or just before the response at the presumed epileptic focus, indicating a probable role in discharge spread. In contrast, the contralateral piriform showed later or non-significant activation, and in generalized epilepsy there was bilateral activation with no special early role. Finally we investigated the impact of epilepsy on normal olfactory function in patients with TLE. These patients have a subtle impairment of odour discrimination and odour identification. Functional MRI using two novel olfactory tasks showed impaired activation of the ipsilateral piriform cortex in some individuals, which was correlated with the behavioural impairment.These olfactory fMRI paradigms have the potential to lateralize the epileptic side in HS-TLE, but are sensitive to several technical factors. Therefore, the disruption of normal ipsilateral piriform cortex function in epilepsy, and its early involvement in discharge propagation, highlights the importance of this brain region as a potential site of targeted intervention, both in MRI-neg TLE and in focal epilepsy more generally