Patrick W. Carney

The core network in absence epilepsy Differences in cortical and thalamic BOLD response

Objectives: We used EEG-fMRI to study epileptiform activity in a cohort of untreated children with typical absence seizures (AS). Our aim was to identify cortical and subcortical regions involved in spike and wave events and to explore the timing of activity in these regions. Methods: Eleven children with AS confirmed on video-EEG underwent EEG-fMRI. An event-related analysis of epileptiform activity was performed. Regions of interest (ROIs), identified in the event-related analysis, were used to study the time course of the blood oxygen level–dependent (BOLD) signal prior to and immediately following events of interest in these ROIs. Results: Group analysis confirmed positive BOLD in the thalamus and negative BOLD in the lateral and mesial parietal lobe, caudate nuclei, and additionally the brainstem reticular formation. The event-related time course differed between the thalamus, the parietal cortex, and the pons and caudate nuclei. In the subcortical structures, BOLD signal change occurred at, or immediately after, electrographic onset. Importantly, in the parietal cortex, but not in other cortical regions, there was a subtle BOLD signal increase for 10 seconds prior to the onset of epileptiform activity. Conclusions: In children with typical AS, we have confirmed a core network of structures involved in generalized epileptiform activity that includes the reticular structures of the brainstem. Furthermore, we have identified changes in parietal BOLD signal which precede the onset of epileptiform activity, suggesting the parietal cortex has a role in the initiation of epileptiform activity.

The frontal lobe in absence epilepsy: EEG-fMRI findings.

Objective: Studies of absence seizures (AS) using EEG with fMRI (EEG-fMRI) show a consistent network with prominent thalamic activation and a variety of cortical changes. Despite evidence suggesting a role of frontal cortex in seizure generation, group studies have not detected consistent AS-related changes in this region. We hypothesized that only a subgroup may show frontal cortical activation. Method: We studied 13 subjects with AS during EEG-fMRI to classify the different individual patterns of frontal cortical activation associated with AS. Results: Based upon visual inspection of surface-rendered activation maps we identified 2 subgroups that could be distinguished by the activation in the dorsolateral prefrontal cortex (DLPFC). One group of patients (n = 7) showed a primarily positive signal change (DLPFC-POS), whereas the other group (n = 6) showed a primarily negative signal change (DLFPC-NEG). When the DLPFC-POS group was compared to the DLPFC-NEG group, time-course analysis revealed a larger positive blood oxygenation level–dependent deflection following onset of the AS in cortical and subcortical areas beyond the DLPFC. This suggests a basic biological difference between these groups. Conclusion: These observations suggest that there may be at least 2 mechanisms underpinning AS in individuals with absence epilepsy. This may have phenotypic and genetic implications for understanding epilepsy syndromes.

Clinical genetic studies in benign childhood epilepsy with centrotemporal spikes.

Purpose:  To accurately determine the frequency and nature of the family history of seizures in patients with benign childhood epilepsy with centrotemporal spikes (BECTS).

A neurologist’s guide to genome-wide association studies

Genome-wide association studies are utilized for gene discovery in common diseases. Genotypes of large groups of unrelated patients are compared to controls. This has become feasible due to the recent technical advances in genomics and convincing positive results are now regularly being published. This review is an accessible introduction to the genetic and technical knowledge needed to interpret such studies. Genome-wide association studies are being applied to many neurologic diseases. Here we use idiopathic generalized epilepsy as an example to highlight the phenotyping, sample size, and statistical issues that must be addressed in such studies. These studies are likely to transform our understanding of complex neurologic diseases in the next few years. CAE = childhood absence epilepsy; CDCV = common disease-common variant; CDMRV = common disease-multiple rare variant; CNV = copy number variation; GTCS = generalized tonic-clonic seizures; GWAS = genome-wide association studies; IGE = idiopathic generalized epilepsy; JAE = juvenile absence epilepsy; JME = juvenile myoclonic epilepsy; LD = linkage disequilibrium; MS = multiple sclerosis; RLS = restless legs syndrome; RR = relative risk; SNP = single nucleotide polymorphism.

Insights into the Mechanisms of Absence Seizure Generation Provided by EEG with Functional MRI

Absence seizures (AS) are brief epileptic events characterized by loss of awareness with subtle motor features. They may be very frequent, and impact on attention, learning, and memory. A number of pathophysiological models have been developed to explain the mechanism of absence seizure generation, which relies heavily on observations from animal studies. Studying the structural and functional relationships between large-scale brain networks in humans is only practical with non-invasive whole brain techniques. EEG with functional MRI (EEG-fMRI) is one such technique that provides an opportunity to explore the interactions between brain structures involved in AS generation. A number of fMRI techniques including event-related analysis, time-course analysis, and functional connectivity (FC) have identified a common network of structures involved in AS. This network comprises the thalamus, midline, and lateral parietal cortex [the default mode network (DMN)], caudate nuclei, and the reticular structures of the pons. The main component displaying an increase in blood oxygen level dependent (BOLD) signal relative to the resting state, in group studies, is the thalamus while the most consistent cortical change is reduced BOLD signal in the DMN. Time-course analysis shows that, rather than some structures being activated or inactivated during AS, there appears to be increase in activity across components of the network preceding or following the electro-clinical onset of the seizure. The earliest change in BOLD signal occurs in the DMN, prior to the onset of epileptiform events. This region also shows altered FC in patients with AS. Hence, it appears that engagement of this network is central to AS. In this review, we will explore the insights of EEG-fMRI studies into the mechanisms of AS and consider how the DMN is likely to be the major large-scale brain network central to both seizure generation and seizure manifestations.

Seizures initially diagnosed as panic attacks: case series

Panic attacks and partial epileptic seizures are both brief paroxysmal episodes that may present with similar clinical features. We present three patients with varying intracranial pathology, in whom the presenting seizures were initially diagnosed as panic attacks, delaying definitive treatment. The relationship between seizures and anxiety or panic is complex and the two conditions can co-exist. Thus, any patient with panic attacks should have a careful history and examination. Atypical features, or failure to respond to treatment, warrant further investigation with imaging or specialist epilepsy referral for video-EEG

Siblings with refractory occipital epilepsy showing localized network activity on EEG-fMRI.

The benign occipital epilepsies of childhood include Panayiotopoulos and Gastaut syndromes; a third syndrome, idiopathic photosensitive occipital epilepsy may also begin in childhood or adolescence. We describe siblings with occipital epilepsy characterized by refractory, frequent, brief visual seizures and normal magnetic resonance imaging (MRI). Electroencephalography (EEG) with functional MRI (fMRI) supports localization of interictal epileptiform activity to the occipital lobes. Our hypothesis is that the siblings share a genetic focal epilepsy arising from a localized occipital network. Although they share many features of Gastaut syndrome, their refractory ongoing seizures in adolescence is unusual and likely due to underlying genetic determinants.

EEG–fMRI in Idiopathic Generalised Epilepsy (Adults)

At the highest level, epilepsy syndromes are classified as being either focal or generalised (Commission on Classification and Terminology of the International League Against Epilepsy 1981, 1989). Focal epilepsies appear to arise from a localised part of the brain and then spread (Commission on Classification and Terminology of the International League Against Epilepsy 1989). They are usually identified by pinpointing the onset of seizures from a specific location, and there will often be a focal structural abnormality. A more challenging problem for imaging is understanding the structures involved in idiopathic generalised epilepsy (IGE), which does not have identifiable lesions and appears to arise bilaterally and symmetrically throughout the brain (Blumenfeld 2005; Commission on Classification and Terminology of the International League Against Epilepsy 1989).