Understanding haemodynamic changes surrounding epileptic events in children

The interrelationship between cerebral haemodynamics and epileptic activity has been the subject of study for over 100 years. The overall goal of this PhD is to use and develop multimodal imaging to better understand this relationship in a paediatric population. This has important implications for the localisation of epileptic activity that can aid pre-surgical evaluation and seizure detection. The benefit of interictal epileptiform discharge (IED) suppression in clinical treatment is under debate, considering little is known about their impact on cognitive function. By applying EEG-fMRI, it was found that transient effects of IEDs were responsible for connectivity differences between patients and controls, showing the widespread impact of IEDs on BOLD signal and suggesting the importance of IED suppression for normal functional connectivity. Haemodynamic changes may occur prior to epileptic event onset. Therefore we evaluated the response function (HRF) to IEDs in paediatric focal epilepsy patients, as an HRF was created from simultaneous EEG-fMRI data and found to be beneficial in the delineation of epileptic foci. However, the underlying neurovascular changes seen in this altered HRF still needed to be explored. Therefore EEG-NIRS was utilised to interpret the mechanistic changes found in BOLD during IEDs. NIRS provides the added information of concentration changes of both –oxy and –deoxy haemoglobin rather than relative changes in deoxyhaemoglobin. To perform these experiments a new optode holder applicable to the clinical environment had to be made and tested for efficacy. The best design was a flexible optode grid, as it required no interference with the standard clinical protocol. Once tested in patients, EEG-NIRS found pre-ictal/pre-IED increases in oxygen saturation and oxyhaemoglobin concentrations, thereby corroborating with prior haemodynamic changes seen in EEG-fMRI. Therefore, by utilizing both EEG-fMRI and EEG-NIRS a greater understanding of the haemodynamic changes surrounding epileptic events in children can be obtained

Thalamic volume reduction in drug-naive patients with new-onset genetic generalized epilepsy.

OBJECTIVE: Patients with genetic generalized epilepsy (GGE) have subtle morphologic abnormalities of the brain revealed with magnetic resonance imaging (MRI), particularly in the thalamus. However, it is unclear whether morphologic abnormalities of the brain in GGE are a consequence of repeated seizures over the duration of the disease, or are a consequence of treatment with antiepileptic drugs (AEDs), or are independent of these factors. Therefore, we measured brain morphometry in a cohort of AED-naive patients with GGE at disease onset. We hypothesize that drug-naive patients at disease onset have gray matter changes compared to age-matched healthy controls. METHODS: We performed quantitative measures of gray matter volume in the thalamus, putamen, caudate, pallidum, hippocampus, precuneus, prefrontal cortex, precentral cortex, and cingulate in 29 AED-naive patients with new-onset GGE and compared them to 32 age-matched healthy controls. We subsequently compared the shape of any brain structures found to differ in gray matter volume between the groups. RESULTS: The thalamus was the only structure to show reduced gray matter volume in AED-naive patients with new-onset GGE compared to healthy controls. Shape analysis revealed that the thalamus showed deflation, which was not uniformly distributed, but particularly affected a circumferential strip involving anterior, superior, posterior, and inferior regions with sparing of medial and lateral regions. SIGNIFICANCE: Structural abnormalities in the thalamus are present at the initial onset of GGE in AED-naive patients, suggesting that thalamic structural abnormality is an intrinsic feature of GGE and not a consequence of AEDs or disease duration

Thalamic volume reduction in drug-naive patients with new-onset genetic generalized epilepsy

OBJECTIVE: Patients with genetic generalized epilepsy (GGE) have subtle morphologic abnormalities of the brain revealed with magnetic resonance imaging (MRI), particularly in the thalamus. However, it is unclear whether morphologic abnormalities of the brain in GGE are a consequence of repeated seizures over the duration of the disease, or are a consequence of treatment with antiepileptic drugs (AEDs), or are independent of these factors. Therefore, we measured brain morphometry in a cohort of AED-naive patients with GGE at disease onset. We hypothesize that drug-naive patients at disease onset have gray matter changes compared to age-matched healthy controls. METHODS: We performed quantitative measures of gray matter volume in the thalamus, putamen, caudate, pallidum, hippocampus, precuneus, prefrontal cortex, precentral cortex, and cingulate in 29 AED-naive patients with new-onset GGE and compared them to 32 age-matched healthy controls. We subsequently compared the shape of any brain structures found to differ in gray matter volume between the groups. RESULTS: The thalamus was the only structure to show reduced gray matter volume in AED-naive patients with new-onset GGE compared to healthy controls. Shape analysis revealed that the thalamus showed deflation, which was not uniformly distributed, but particularly affected a circumferential strip involving anterior, superior, posterior, and inferior regions with sparing of medial and lateral regions. SIGNIFICANCE: Structural abnormalities in the thalamus are present at the initial onset of GGE in AED-naive patients, suggesting that thalamic structural abnormality is an intrinsic feature of GGE and not a consequence of AEDs or disease duration

Optimising EEG-fMRI for Localisation of Focal Epilepsy in Children

BACKGROUND: Early surgical intervention in children with drug resistant epilepsy has benefits but requires using tolerable and minimally invasive tests. EEG-fMRI studies have demonstrated good sensitivity for the localization of epileptic focus but a poor yield although the reasons for this have not been systematically addressed. While adults EEG-fMRI studies are performed in the "resting state"; children are commonly sedated however, this has associated risks and potential confounds. In this study, we assessed the impact of the following factors on the tolerability and results of EEG-fMRI in children: viewing a movie inside the scanner; movement; occurrence of interictal epileptiform discharges (IED); scan duration and design efficiency. This work's motivation is to optimize EEG-fMRI parameters to make this test widely available to paediatric population. METHODS: Forty-six children with focal epilepsy and 20 controls (6-18) underwent EEG-fMRI. For two 10 minutes sessions subjects were told to lie still with eyes closed, as it is classically performed in adult studies ("rest sessions"), for another two sessions, subjects watched a child friendly stimulation i.e. movie ("movie sessions"). IED were mapped with EEG-fMRI for each session and across sessions. The resulting maps were classified as concordant/discordant with the presumed epileptogenic focus for each subject. FINDINGS: Movement increased with scan duration, but the movie reduced movement by ~40% when played within the first 20 minutes. There was no effect of movie on the occurrence of IED, nor in the concordance of the test. Ability of EEG-fMRI to map the epileptogenic region was similar for the 20 and 40 minute scan durations. Design efficiency was predictive of concordance. CONCLUSIONS: A child friendly natural stimulus improves the tolerability of EEG-fMRI and reduces in-scanner movement without having an effect on IED occurrence and quality of EEG-fMRI maps. This allowed us to scan children as young as 6 and obtain localising information without sedation. Our data suggest that ~20 minutes is the optimal length of scanning for EEG-fMRI studies in children with frequent IED. The efficiency of the fMRI design derived from spontaneous IED generation is an important factor for producing concordant results

Combined EEG-fMRI and ESI improves localisation of paediatric focal epilepsy

OBJECTIVE: Surgical treatment in epilepsy is effective if the epileptogenic zone (EZ) can be correctly localized and characterized. Here we use simultaneous Electroencephalography-functional MRI (EEG-fMRI) data to derive EEG-fMRI and Electrical Source Imaging (ESI) maps. Their yield and their individual and combined ability to 1) localize the epileptogenic zone and 2) predict seizure outcome was then evaluated. METHODS: Fifty-three children with drug-resistant epilepsy underwent EEG-fMRI. Interictal discharges were mapped using both EEG-fMRI haemodynamic responses and Electrical Source Imaging (ESI). A single localization was derived from each individual test (EEG-fMRI global maxima (GM)/ESI maxima) and from the combination of both maps (EEG-fMRI/ESI spatial intersection). To determine the localisation accuracy and its predictive performance the individual and combined test localisations were compared to the presumed EZ and to the postsurgical outcome. RESULTS: Fifty-two/53 patients had significant maps; 47/53 for EEG-fMRI; 44/53 for ESI; 34/53 had both. The epileptogenic zone was well characterised in 29 patients; 26 had an EEG-fMRI GM localisation which was correct in 11; 22 patients had ESI localisation which was correct in 17; 12 patients had combined EEG-fMRI and ESI which was correct in 11. Seizure outcome following resection was correctly predicted by EEG-fMRI GM in 8/20 patients, by the ESI maxima in 13/16. The combined EEG-fMRI/ESI region entirely predicted outcome in 9/9 patients including 3 with no lesion visible on MRI. INTERPRETATION: EEG-fMRI combined with ESI provides a simple unbiased localisation that may predict surgery better than each individual test including in MRI-negative patients

Combined EEG-fMRI and ESI improves localisation of paediatric focal epilepsy

OBJECTIVE: Surgical treatment in epilepsy is effective if the epileptogenic zone (EZ) can be correctly localized and characterized. Here we use simultaneous Electroencephalography-functional MRI (EEG-fMRI) data to derive EEG-fMRI and Electrical Source Imaging (ESI) maps. Their yield and their individual and combined ability to 1) localize the epileptogenic zone and 2) predict seizure outcome was then evaluated. METHODS: Fifty-three children with drug-resistant epilepsy underwent EEG-fMRI. Interictal discharges were mapped using both EEG-fMRI haemodynamic responses and Electrical Source Imaging (ESI). A single localization was derived from each individual test (EEG-fMRI global maxima (GM)/ESI maxima) and from the combination of both maps (EEG-fMRI/ESI spatial intersection). To determine the localisation accuracy and its predictive performance the individual and combined test localisations were compared to the presumed EZ and to the postsurgical outcome. RESULTS: Fifty-two/53 patients had significant maps; 47/53 for EEG-fMRI; 44/53 for ESI; 34/53 had both. The epileptogenic zone was well characterised in 29 patients; 26 had an EEG-fMRI GM localisation which was correct in 11; 22 patients had ESI localisation which was correct in 17; 12 patients had combined EEG-fMRI and ESI which was correct in 11. Seizure outcome following resection was correctly predicted by EEG-fMRI GM in 8/20 patients, by the ESI maxima in 13/16. The combined EEG-fMRI/ESI region entirely predicted outcome in 9/9 patients including 3 with no lesion visible on MRI. INTERPRETATION: EEG-fMRI combined with ESI provides a simple unbiased localisation that may predict surgery better than each individual test including in MRI-negative patients