EEG correlated functional MRI and postoperative outcome in focal epilepsy

Background: The main challenge in assessing patients with epilepsy for resective surgery is localising seizure onset. Frequently, identification of the irritative and seizure onset zones requires invasive EEG. EEG correlated functional MRI (EEG-fMRI) is a novel imaging technique which may provide localising information with regard to these regions. In patients with focal epilepsy, interictal epileptiform discharge (IED) correlated blood oxygen dependent level (BOLD) signal changes were observed in approximately 50% of patients in whom IEDs are recorded. In 70%, these are concordant with expected seizure onset defined by non-invasive electroclinical information. Assessment of clinical validity requires post-surgical outcome studies which have, to date, been limited to case reports of correlation with intracranial EEG. The value of EEG-fMRI was assessed in patients with focal epilepsy who subsequently underwent epilepsy surgery, and IED correlated fMRI signal changes were related to the resection area and clinical outcome. Methods: Simultaneous EEG-fMRI was recorded in 76 patients undergoing presurgical evaluation and the locations of IED correlated preoperative BOLD signal change were compared with the resected area and postoperative outcome. Results: 21 patients had activations with epileptic activity on EEG-fMRI and 10 underwent surgical resection. Seven of 10 patients were seizure free following surgery and the area of maximal BOLD signal change was concordant with resection in six of seven patients. In the remaining three patients, with reduced seizure frequency post-surgically, areas of significant IED correlated BOLD signal change lay outside the resection. 42 of 55 patients who had no IED related activation underwent resection. Conclusion: These results show the potential value of EEG-fMRI in presurgical evaluation

Early lipofuscin accumulation in Frontal Lobe Epilepsy

OBJECTIVE: This study reports on a novel brain pathology in young patients with frontal lobe epilepsy (FLE) that is distinct from focal cortical dysplasia (FCD). METHODS: Surgical specimens from 20 young adults with FLE (mean age, 30 years) were investigated with histological/immunohistochemical markers for cortical laminar architecture, mammalian target of (mTOR) pathway activation and inhibition, cellular autophagy, and synaptic vesicle-mediated trafficking as well as proteomics analysis. Findings were correlated with pre-/postoperative clinical, imaging, and electrophysiological data. RESULTS: Excessive lipofuscin accumulation was observed in abnormal dysmorphic neurones in 6 cases, but not in seven FCD type IIB and 7 pathology-negative cases, despite similar age and seizure histories. Abnormal dysmorphic neurones on proteomics analysis were comparable to aged human brains. The mTOR pathway was activated, as in cases with dysplasia, but the immunoreactivities of nucleoporin p62, DEP-domain containing protein 5, clathrin, and dynamin-1 were different between groups, suggesting that enhanced autophagy flux and abnormal synaptic vesicle trafficking contribute to early lipofuscin aggregation in these cases, compared to suppression of autophagy in cases with typical dysplasia. Cases with abnormal neuronal lipofuscin showed subtle magnetic resonance imaging cortical abnormalities that localized with seizure onset zone and were more likely to have a family history. INTERPRETATION: We propose that excess neuronal lipofuscin accumulation in young patients with FLE represents a novel pathology underlying this epilepsy; the early accumulation of lipofuscin may be disease driven, secondary to as-yet unidentified drivers accelerating autophagic pathways, which may underpin the neuronal dysfunction in this condition

Narrative review of epilepsy: getting the most out of your neuroimaging

Neuroimaging represents an important step in the evaluation of pediatric epilepsy. The crucial role of brain imaging in the diagnosis, follow-up and presurgical assessment of patients with epilepsy is noted and has to be familiar to all neuroradiologists and trainees approaching pediatric brain imaging. Morphological qualitative imaging shows the majority of cerebral lesions/alterations underlying focal epilepsy and can highlight some features which are useful in the differential diagnosis of the different types of epilepsy. Recent advances in MRI acquisitions including diffusion-weighted imaging (DWI), post-acquisition image processing techniques, and quantification of imaging data are increasing the accuracy of lesion detection during the last decades. Functional MRI (fMRI) can be really useful and helps to identify cortical eloquent areas that are essential for language, motor function, and memory, and diffusion tensor imaging (DTI) can reveal white matter tracts that are vital for these functions, thus reducing the risk of epilepsy surgery causing new morbidities. Also positron emission tomography (PET), single photon emission computed tomography (SPECT), simultaneous electroencephalogram (EEG) and fMRI, and electrical and magnetic source imaging can be used to assess the exact localization of epileptic foci and help in the design of intracranial EEG recording strategies. The main role of these “hybrid” techniques is to obtain quantitative and qualitative informations, a necessary step to evaluate and demonstrate the complex relationship between abnormal structural and functional data and to manage a “patient-tailored” surgical approach in epileptic patients

The UK experience of stereoelectroencephalography in children: An analysis of factors predicting the identification of a seizure-onset zone and subsequent seizure freedom

OBJECTIVE: Stereoelectroencephalography (SEEG) is being used more frequently in the pre-surgical evaluation of children with focal epilepsy. It has been shown to be safe in children, but there are no multicenter studies assessing the rates and factors associated with the identification of a putative seizure-onset zone (SOZ) and subsequent seizure freedom following SEEG-guided epilepsy surgery. METHODS: Multicenter retrospective cohort study of all children undergoing SEEG at six of seven UK Children's Epilepsy Surgery Service centers from 2014 to 2019. Demographics, noninvasive evaluation, SEEG, and operative factors were analyzed to identify variables associated with the identification of a putative SOZ and subsequent seizure freedom following SEEG-guided epilepsy surgery. RESULTS: One hundred thirty-five patients underwent 139 SEEG explorations using a total of 1767 electrodes. A putative SOZ was identified in 117 patients (85.7%); odds of successfully finding an SOZ were 6.4 times greater for non-motor seizures compared to motor seizures (p = 0.02) and 3.6 times more if four or more seizures were recorded during SEEG (p = 0.03). Of 100 patients undergoing surgical treatment, 47 (47.0%) had an Engel class I outcome at a median follow-up of 1.3 years; the only factor associated with outcome was indication for SEEG (p = 0.03); an indication of “recurrence following surgery/treatment” had a 5.9 times lower odds of achieving seizure freedom (p = 0.002) compared to the “lesion negative” cohort, whereas other indications (“lesion positive, define extent,” “lesion positive, discordant noninvasive investigations” and “multiple lesions”) were not statistically significantly different. SIGNIFICANCE: This large nationally representative cohort illustrates that SEEG-guided surgery can still achieve high rates of seizure freedom. Seizure semiology and the number of seizures recorded during SEEG are important factors in the identification of a putative SOZ, and the indication for SEEG is an important factor in postoperative outcomes

On mapping epilepsy : magneto- and electroencephalographic characterizations of epileptic activities

Epilepsy is one of the most common neurological disorder, affecting up to 10 individuals per 1000 persons. The disorder have been known for several thousand years, with the first clinical descriptions dating back to ancient times. Nonetheless, characterization of the dynamics underlying epilepsy remains largely unknown. Understanding these patophysiological processes requires unifying both a neurobiological perspective, as well as a technically advanced neuroimaging perspective. The incomplete insight into epilepsy dynamics is reflected by the insufficient treatment options. Approximately 30% of all patients do not respond to anti-epileptic drugs (AEDs) and thus suffers from recurrent seizures despite adequate pharmacological treatments. These pharmacoresistant patients often undergo epilepsy surgery evaluations. Epilepsy surgery aims to resect the part of the brain that generates the epileptic seizure activity (seizure onset zone, SOZ). Nonetheless, up to 50% of all patients relapse after surgery. This can be due to incomplete mapping of both the SOZ and of other structures that might be involved in seizure initiation and propagation. Such cortical and subcortical structures are collectively referred to as the epileptic network. Historically, epilepsy was considered to be either a generalized disorder involving the entire brain, or a highly localized, focal, disorder. The modern technological development of both structural and functional neuroimaging has drastically altered this view. This development has made significant contributions to the now prevailing view that both generalized and focal epilepsies arise from more or less widespread pathological network pathways. Visualization of these pathways play an important role in the presurgical planning. Thus, both improved characterization and understanding of such pathways are pivotal in improvement of epilepsy diagnostics and treatments. It is evident that epilepsy research needs to stand on two legs: Both improved understanding of pathological, neurobiological and neurophysiological process, and improved neuroimaging instrumentation. Epilepsy research do not only span from visualization to understanding of neurophysiological processes, but also from cellular, neuronal, microscopic processes, to dynamical, large-scale network processes. It is well known that neurons involved in epileptic activities exhibit specific, pathological firing patterns. Genetic mutations resulting in neuronal ion channel defects can cause severe, and even lethal, epileptic syndromes in children, clearly illustrating a role for neuron membrane properties in epilepsy. However, cellular processes themselves cannot explain how epileptic seizures can involve, and propagate across, large cortical areas and generate seizure-specific symptomatologies. A strict cellular perspective can neither explain epilepsy-associated pathological interactions between larger distant regions in between seizures. Instead, the dynamical effects of cellular synchronization across both mesoscopic and macroscopic scales also need to be considered. Today, the only means to study such effects in human subjects are by combinations of neuroimaging modalities. However, as all measurement techniques, these exhibit individual limitations that affect the kind of information that can be inferred from these. Thus, once more we reach the conclusion that epilepsy research needs to rest upon both a neurophysiological/neurobiological leg, and a technical/instrumentational leg. In accordance with this necessity of a dual approach to epilepsy, this thesis covers both neurophysiological aspects of epileptic activity development, as well as functional neuroimaging instrumentation development with focus on epileptic activity detection and localization. Part 1 (neurophysiological part) is concerned with the neurophysiological dynamical changes that underlie development of so called interictal epileptiform discharges (IEDs) with special focus on the role of low-frequency oscillations. To this aim, both conventional magnetoencephalography (MEG) and intracranial electroencephalography (iEEG) with neurostimulation is analyzed. Part 2 (instrumentation part) is concerned with development of cutting-edge, novel on-scalp magnetoencephalography (osMEG) within clinical epilepsy evaluations and research with special focus on IEDs. The theses cover both modeling of osMEG characteristics, as well as the first-ever osMEG recording of a temporal lobe epilepsy patient

Variable Anisotropic Brain Electrical Conductivities in Epileptogenic Foci

Source localization models assume brain electrical conductivities are isotropic at about 0.33 S/m. These assumptions have not been confirmed ex vivo in humans. This study determined bidirectional electrical conductivities from pediatric epilepsy surgery patients. Electrical conductivities perpendicular and parallel to the pial surface of neocortex and subcortical white matter (n = 15) were measured using the 4-electrode technique and compared with clinical variables. Mean (±SD) electrical conductivities were 0.10 ± 0.01 S/m, and varied by 243% from patient to patient. Perpendicular and parallel conductivities differed by 45%, and the larger values were perpendicular to the pial surface in 47% and parallel in 40% of patients. A perpendicular principal axis was associated with normal, while isotropy and parallel principal axes were linked with epileptogenic lesions by MRI. Electrical conductivities were decreased in patients with cortical dysplasia compared with non-dysplasia etiologies. The electrical conductivity values of freshly excised human brain tissues were approximately 30% of assumed values, varied by over 200% from patient to patient, and had erratic anisotropic and isotropic shapes if the MRI showed a lesion. Understanding brain electrical conductivity and ways to non-invasively measure them are probably necessary to enhance the ability to localize EEG sources from epilepsy surgery patients

Surgical treatment of drug-resistant focal epilepsy: selection, economic considerations and long-term outcomes

Epilepsy surgery can be an effective treatment for drug-resistant focal epilepsy, but requires careful selection of appropriate candidates to achieve optimal results and minimise the chance of adverse outcomes, including seizure recurrence. Long-term data on multimodal outcomes and a better appreciation of various factors influencing surgical suitability will help facilitate informed discussions between clinicians and prospective surgical candidates. This thesis includes a comprehensive analysis of a cohort of individuals who had epilepsy surgery at a tertiary neurosciences centre over the last 30 years, supplemented by data on individuals who completed presurgical evaluation at the same centre but did not proceed to surgical resection. An inability to localise the epileptogenic zone (EZ), multifocal epilepsy, or an individual choice not to have either intracranial electroencephalography or surgery were the most common reasons why people referred for presurgical evaluation did not proceed to a definitive resection. A predictive model based on demographic, imaging and electroclinical data was constructed to assist early discussions about surgical suitability. Those with normal MRI, extratemporal epilepsy and evidence of bilateral seizure onsets on video telemetry had an estimated 2.9% chance of proceeding to surgery, and people with a normal MRI brain invariably required intracranial EEG. Frontal lobe epilepsy surgery was safe and effective, with a long-term (median seven years) seizure freedom rate of 27%, and another 11% having auras only. Psychiatric comorbidity frequently improved postoperatively and paralleled seizure freedom. Focal MRI abnormality and fewer anti-seizure medications at the time of surgery could help predict a good outcome. In contrast, the site of resection and intracranial monitoring were not independently significant. Localisation of the EZ should rely on clinical features and multimodal investigation, as in our cohort frontal lobe semiology alone could correctly lateralise the EZ in only 77% and localise to a sublobar level in 52%. For those who completed presurgical evaluation but did not have surgery, under 5% had >12 months of seizure-freedom following the decision not to proceed, although a quarter had substantial improvement with further anti-seizure medication (ASM) or neurostimulation. Evaluation for epilepsy surgery was lengthy for individuals and costly for the public health system. Both duration and cost depended on what investigations were required and varied according to different routes through the presurgical pathway, especially the need for intracranial EEG. The median duration of evaluation was 29.7 months (IQR 18.6-44.1 months), with a median cost per person of £9,138 (IQR £6,984-£14,868). Approximately £123,500 was spent per additional person seizure-free