Cortical Morphology and MRI Signal Intensity Analysis in Paediatric Epilepsy

Epilepsy encompasses a great variety of aetiologies, and as such is not a single disease but a group of diseases characterised by unprovoked seizures.The primary aim of the work presented in this thesis was to use multimodal structural imaging to improve understanding of epilepsy related brain pathology, both the epileptogenic lesions themselves and extralesional pathology, in order to improve pre-surgical planning in medicationresistant epilepsy and improve understanding of the underlying pathogenic mechanisms. The work focuses on 2 epilepsy aetiologies: focal cortical dysplasia (FCD) (chapters 2 and 3) and mesial temporal lobe epilepsy (chapters 4 & 5). Chapter 2 of this thesis develops surface-based, structural MRI post-processing techniques that can be applied to clinical T1 and FLAIR images to complement current MRI-based diagnosis of focal cortical dysplasias. Chapter 3 uses the features developed in Chapter 2 within a machine learning framework to automatically detect FCDs, obtaining 73% sensitivity using a neural network. Chapter 4 develops an in vivo method to explore neocortical gliosis in adults with TLE, while Chapter 5 applies this method to a paediatric cohort. Finally, the concluding chapter discusses contributions, main limitations and outlines options for future research

Cortical neuronal loss and hippocampal sclerosis are not detected by voxel-based morphometry in individual epilepsy surgery patients

Voxel-based morphometry (VBM) has detected differences between brains of groups of patients with epilepsy and controls, but the sensitivity for detecting subtle pathological changes in single subjects has not been established. The aim of the study was to test the sensitivity of VBM using statistical parametric mapping (SPM5) to detect hippocampal sclerosis (HS) and cortical neuronal loss in individual patients. T1-weighted volumetric 1.5 T MR images from 13 patients with HS and laminar cortical neuronal loss were segmented, normalised and smoothed using SPM5. Both modulated and non-modulated analyses were performed. Comparisons of one control subject against the rest (n ¼ 23) were first performed to ascertain the smoothing level with the lowest number of SPM changes in controls. Each patient was then compared against the whole control group. The lowest number of SPM changes in control subjects was found at a smoothing level of 10 mm full width half maximum for modulated and non-modulated data. In the patient group, no SPM abnormalities were found in the affected temporal lobe or hippocampus at this smoothing level. At lower smoothing levels there were numerous SPM findings in controls and patients. VBM did not detect any abnormalities associated with either laminar cortical neuronal loss or HS. This may be due to normalisation and smoothing of images and low statistical power in areas with larger interindividual differences. This suggests that the methodology may currently not be suitable to detect particular occult abnormalities possibly associated with seizure onset zone in individual epilepsy patients with unremarkable standard structural MRI

Neurobiological, cognitive, and psycho-social determinants of paediatric temporal lobe epilepsy surgery outcomes.

Aims We set out to identify neurobiological factors which may explain some of the observed individual variability in post-surgical cognitive outcomes in children who have undergone resective surgery to treat temporal lobe epilepsy. Method This retrospective study included 81 patients with medication-resistant temporal lobe epilepsy and 20 aged-matched healthy participants. Pre- and post-surgical hippocampal volumes and surgical resection volumes were obtained and studied for their association with neuropsychological variables. Results In our cohort of paediatric temporal lobe epilepsy patients, we observed a variable degree of pre-surgical hippocampal atrophy. Atrophy extent was associated with age at epilepsy onset. Following surgery, we showed a decline in verbal function and verbal memory, regardless of lesion laterality. Children with higher pre-operative scores were most vulnerable to post-operative decline in performance across all cognitive domains. In patients with left hemisphere lesions, extent of surgical resection was the only significant predictor of post-surgical verbal memory function. Conclusions Paediatric temporal lobe epilepsy is associated with impairments to general cognitive function and variable degree of hippocampal atrophy. Resective surgery can result in small cognitive declines at short follow up intervals (around 1 year). Our results are indicative that pre-operative verbal memory ability is supported by functional brain tissue in the ipsilesional hemisphere. Surgical methods which allow preservation of healthy hippocampal and cortical tissue are best employed if verbal memory outcomes are to be prioritised in paediatric epilepsy of left temporal lobe origin

Interictal Network Dynamics in Paediatric Epilepsy Surgery

Epilepsy is an archetypal brain network disorder. Despite two decades of research elucidating network mechanisms of disease and correlating these with outcomes, the clinical management of children with epilepsy does not readily integrate network concepts. For example, network measures are not used in presurgical evaluation to guide decision making or surgical management plans. The aim of this thesis was to investigate novel network frameworks from the perspective of a clinician, with the explicit aim of finding measures that may be clinically useful and translatable to directly benefit patient care. We examined networks at three different scales, namely macro (whole brain diffusion MRI), meso (subnetworks from SEEG recordings) and micro (single unit networks) scales, consistently finding network abnormalities in children being evaluated for or undergoing epilepsy surgery. This work also provides a path to clinical translation, using frameworks such as IDEAL to robustly assess the impact of these new technologies on management and outcomes. The thesis sets up a platform from which promising computational technology, that utilises brain network analyses, can be readily translated to benefit patient care

Magnetic resonance imaging protocols for paediatric neuroradiology

Increasingly, radiologists are encouraged to have protocols for all imaging studies and to include imaging guidelines in care pathways set up by the referring clinicians. This is particularly advantageous in MRI where magnet time is limited and a radiologist’s review of each patient’s images often results in additional sequences and longer scanning times without the advantage of improvement in diagnostic ability. The difficulties of imaging small children and the challenges presented to the radiologist as the brain develops are discussed. We present our protocols for imaging the brain and spine of children based on 20 years experience of paediatric neurological MRI. The protocols are adapted to suit children under the age of 2 years, small body parts and paediatric clinical scenarios

CPD – Education and Self-assessment: Functional imaging in epilepsy

AbstractFunctional imaging plays a growing role in the clinical assessment and research investigation of patients with epilepsy. This article reviews the literature on functional MRI (fMRI) investigation of EEG activity, fMRI evaluation of cognitive and motor functions, magnetic resonance spectroscopy (MRS), single photon emission computed tomography (SPECT) and positron emission tomography (PET) in epilepsy. The place of these techniques in clinical evaluation and their contribution to a better neurobiological understanding of epilepsy are discussed

Childhood status epilepticus: Structural consequences and assessment of a novel treatment

Status epilepticus (SE) is the commonest medical neurological emergency in childhood. In animal models of SE, the hippocampus is frequently damaged. The histological features resemble mesial temporal sclerosis (MTS), the commonest pathology in temporal lobe resections in adult humans. The commonest association with MTS is prolonged febrile convulsion (PFC). Hippocampal damage only occurs if seizures persist for at least 30 minutes. Early termination of seizures may decrease the incidence of MTS. Treatment with rectal diazepam is not always acceptable. An effective, convenient and acceptable method of treating SE would be advantageous. To address the question of whether MTS has different magnetic resonance (MR) characteristics dependent on antecedent, quantitative MR data from patients with histologically proven MTS was reviewed. Patients with a history of PFC have asymmetrical hippocampal volume (HCV) and T2 relaxation time (T2) when compared to patients with no history of PFC and controls. This may suggest that severity and extent of MTS may be, in part, determined by the cause. The assessment of whether SE results in acute brain abnormalities was carried out by prospectively investigating children using MR techniques. Within 48 hours of PFC there is an increase in HCV and T2 relaxation time when compared to controls. Patients with SE and no fever have an increased T2 relaxation time but normal hippocampal volume. PFC appears to result in acute hippocampal swelling, consistent with animal model data. The effect of non-febrile SE on limbic structures is less certain. Buccal midazolam was assessed as an effective, socially acceptable acute treatment for seizures. A pharmacokinetic/pharmacodynamic study confirmed rapid absorption into venous blood and brain. Buccal midazolam was shown to be an effective treatment for acute repetitive seizures and at least as effective as rectal diazepam in the treatment of seizures which have persisted for longer than 5 minutes

Neuroimaging for Epilepsy Diagnosis and Management

This chapter will cover the neuroimaging techniques and their application to the diagnostic work up and management of adults and children with new onset or chronic epilepsy. We will focus on the specific indications and requirements of different imaging techniques for the diagnosis and pre-surgical work up of pharmacoresistant focal epilepsies. We will discuss the sensitivity, specificity and prognostic value of imaging features, benign variants and artefacts, and the possible diagnostic significance of non-epileptogenic lesions. This chapter is intended to be relevant for day-to-day practice in average clinical circumstances, with emphasis on MRI and most commonly used functional neuroimaging techniques