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The neural underpinnings of impaired consciousness and of the variable severity of behavioural deficits from one absence seizure to the next are not well understood. We aimed to measure functional MRI (fMRI) and electroencephalography (EEG) changes in absence seizures with impaired task performance compared with seizures in which performance was spared. In this cross-sectional study done at the Yale School of Medicine, CT, USA, we recruited patients from 59 paediatric neurology practices in the USA. We did simultaneous EEG, fMRI, and behavioural testing in patients aged 6–19 years with childhood or juvenile absence epilepsy, and with an EEG with typical 3–4 Hz bilateral spike-wave discharges and normal background. The main outcomes were fMRI and EEG amplitudes in seizures with impaired versus spared behavioural responses analysed by t test. We also examined the timing of fMRI and EEG changes in seizures with impaired behavioural responses compared with seizures with spared responses. 93 patients were enrolled between Jan 1, 2005, and Sept 1, 2013; we recorded 1032 seizures in 39 patients. fMRI changes during seizures occurred sequentially in three functional brain networks. In the default mode network, fMRI amplitude was 0·57% (SD 0·26) for seizures with impaired and 0·40% (0·16) for seizures with spared behavioural responses (mean difference 0·17%, 95% CI 0·11–0·23; p<0·0001). In the task-positive network, fMRI amplitude was 0·53% (SD 0·29) for seizures with impaired and 0·39% (0·15) for seizures with spared behavioral responses (mean difference 0·14%, 95% CI 0·08–0·21; p<0·0001). In the sensorimotor-thalamic network, fMRI amplitude was 0·41% (0·25) for seizures with impaired and 0·34% (0·14) for seizures with spared behavioural responses (mean difference 0·07%, 95% CI 0·01–0·13; p=0·02). Mean fractional EEG power in the frontal leads was 50·4 (SD 15·2) for seizures with impaired and 24·8 (6·5) for seizures with spared behavioural responses (mean difference 25·6, 95% CI 21·0–30·3); middle leads 35·4 (6·5) for seizures with impaired, 13·3 (3·4) for seizures with spared behavioural responses (mean difference 22·1, 95% CI 20·0–24·1); posterior leads 41·6 (5·3) for seizures with impaired, 24·6 (8·6) for seizures with spared behavioural responses (mean difference 17·0, 95% CI 14·4–19·7); p<0·0001 for all comparisons. Mean seizure duration was longer for seizures with impaired behaviour at 7·9 s (SD 6·6), compared with 3·8 s (3·0) for seizures with spared behaviour (mean difference 4·1 s, 95% CI 3·0–5·3; p<0·0001). However, larger amplitude fMRI and EEG signals occurred at the outset or even preceding seizures with behavioural impairment. Impaired consciousness in absence seizures is related to the intensity of physiological changes in established networks affecting widespread regions of the brain. Increased EEG and fMRI amplitude occurs at the onset of seizures associated with behavioural impairment. These finding suggest that a vulnerable state might exist at the initiation of some absence seizures leading them to have more severe physiological changes and altered consciousness than other absence seizures. National Institutes of Health, National Institute of Neurological Disorders and Stroke, National Center for Advancing Translational Science, the Loughridge Williams Foundation, and the Betsy and Jonathan Blattmachr Family.

The ultimate goal of epileptology is the complete abolishment of epileptic seizures. This might be achieved by a system that predicts seizure onset combined with a system that interferes with the process that leads to the onset of a seizure. Seizure prediction remains, as of yet, unresolved in absence-epilepsy, due to the sudden onset of seizures. We have developed a real-time absence seizure prediction algorithm, evaluated it and implemented it in an on-line, closed-loop brain stimulation system designed to prevent the spike-wave-discharges (SWDs), typical for absence epilepsy, in a genetic rat model. The algorithm corretly predicted 88% of the SWDs while the remaining were quickly detected. A high number of false-positive detections occurred mainly during light slow-wave-sleep. Inclusion of criteria to prevent false-positives greatly reduced the false alarm rate but decreased the sensitivity of the algoritm. Implementation of the latter version into a closed-loop brain-stimulation-system resulted in a 72% decrease in seizure activity. In contrast to long standing beliefs that SWDs are unpredictable, these results demonstrate that they can be predicted and that the development of closed-loop seizure prediction and prevention systems is a feasable step towards interventions to attain control and freedom from epileptic seizures.

Childhood absence epilepsy (CAE), involves 3 Hz generalized spikes and waves discharges (GSWDs) on the electroencephalogram (EEG), associated with ictal discharges (seizures) with clinical symptoms and impairment of consciousness and subclinical discharges without any objective clinical symptoms or impairment of consciousness. This study aims to comparatively characterize neuronal networks underlying absence seizures and subclinical discharges, using source localization and functional connectivity (FC), to better understand the pathophysiological mechanism of these discharges. Routine EEG data from 12 CAE patients, consisting of 45 ictal and 42 subclinical discharges were selected. Source localization was performed using the exact low-resolution electromagnetic tomography (eLORETA) algorithm, followed by FC based on the imaginary part of coherency. FC based on the thalamus as the seed of interest showed significant differences between ictal and subclinical GSWDs ( p  < 0.05). For delta (1–3 Hz) and alpha bands (8–12 Hz), the thalamus displayed stronger connectivity towards other brain regions for ictal GSWDs as compared to subclinical GSWDs. For delta band, the thalamus was strongly connected to the posterior cingulate cortex (PCC), precuneus, angular gyrus, supramarginal gyrus, parietal superior, and occipital mid-region for ictal GSWDs. The strong connections of the thalamus with other brain regions that are important for consciousness, and with components of the default mode network (DMN) suggest the severe impairment of consciousness in ictal GSWDs. However, for subclinical discharges, weaker connectivity between the thalamus and these brain regions may suggest the prevention of impairment of consciousness. This may benefit future therapeutic targets and improve the management of CAE patients.

Using multi-frequency magnetoencephalography (MEG) data, we investigated whether the effective connectivity (EC) network of patients with childhood absence epilepsy (CAE) is altered during the inter-ictal period in comparison with healthy controls. MEG data from 13 untreated CAE patients and 10 healthy controls were recorded. Correlation analysis and Granger causality analysis were used to construct an EC network at the source level in eight frequency bands. Alterations in the spatial pattern and topology of the network in CAE were investigated by comparing the patients with the controls. The network pattern was altered mainly in 1–4 Hz, showing strong connections within the frontal cortex and weak connections in the anterior–posterior pathways. The EC involving the precuneus/posterior cingulate cortex (PC/PCC) significantly decreased in low-frequency bands. In addition, the parameters of graph theory were significantly altered in several low- and high-frequency bands. CAE patients display frequency-specific abnormalities in the network pattern even during the inter-ictal period, and the frontal cortex and PC/PCC might play crucial roles in the pathophysiology of CAE. The EC network of CAE patients was over-connective and random during the inter-ictal period. This study is the first to reveal the frequency-specific alteration in the EC network during the inter-ictal period in CAE patients. Multiple-frequency MEG data are useful in investigating the pathophysiology of CAE, which can serve as new biomarkers of this disorder.

Cerebrovascular blood flow in absence seizures and flow patterns during the ictal period have not been thoroughly investigated. We aimed to evaluate cerebral blood flow changes in typical juvenile absence seizures during the ictal and postictal phases. Seizures were recorded in three patients (mean age: 21 ± 1 years) with multiple daily typical absence seizures. Simultaneous video electroencephalography and bilateral middle cerebral artery transcranial Doppler ultrasonography recordings were conducted during seizures. Basal, ictal, and postictal blood flow velocities were recorded bilaterally, and offline analyses were performed in relation with generalized spike and wave discharges. Total of 43 seizures were recorded. Ictal increase and postictal decrease of cerebral blood flow velocities were significant for both sides ( P  < 0.001). The interhemispheric asymmetry in the ictal velocity increase was significant ( P  < 0.05). The interhemispheric asymmetry in the postictal velocity decrease was not significant ( P  > 0.05). The blood flow velocity increase after seizure onset indicates a vascular coupling mechanism. A sudden and then a gradual decrease in blood flow velocity, which lasted even after the seizure ceased, might suggest a preventive mechanism to avoid excessive seizure duration or even an absence status epilepticus. Significant asymmetries in increase and a symmetrical decrease may support the cortical focus theory.

The neuroanatomical and pathophysiological basis of primary generalised absences is uncertain. Administration of endogenous opioids has been shown to result in absence-like seizures in animal models. Positron emission tomography scans were performed in eight patients with primary generalised epilepsy and eight control subjects. Regional cerebral blood flow was measured interictally with C15O2, after which a 90 minute dynamic study with the opioid-receptor ligand 11C-diprenorphine was performed. Serial absences were precipitated by hyperventilation for 10 minutes, starting 30-40 minutes after injection of diprenorphine. Absences, with generalised spike-wave discharges on the EEG, occurred for between 10% and 51% of the provocation period. No individual (normal or patient) had any interictal focal abnormalities of cerebral blood flow. After provocation of serial absence seizures, there was increased diprenorphine elimination from the association cortex, but not from the thalamus, basal ganglia, or cerebellum, compared with control subjects and patients scanned without provocation of absences. It was possible to simulate the observed increased diprenorphine elimination following seizures in cerebral cortex using a two tissue compartment model, with an estimated 15-41% decrease in the specific tracer uptake rate constant (k3). These results suggest that endogenous opioids are released in the association cortex at the time of serial absences, lead to increased receptor occupancy, and may have an important role in the pathophysiology of generalised absences.

A prospective study of 32 children with epileptic encephalopathies 12 years or younger revealed a high incidence of focal cortical metabolic defects on 18-fluorodeoxyglucose positron emission tomography (PET) not suspected from clinical, EEG, or magnetic resonance imaging findings. PET scans were normal in all five children with typical de novo Lennox-Gastaut syndrome but showed cortical metabolic abnormalities in three out of four with atypical de novo Lennox-Gastaut syndrome, five out of six with Lennox-Gastaut syndrome following infantile spasms, six out of eight with severe myoclonic epilepsy in infancy, one out of two with epilepsy with myoclonic-astatic seizures, and four out of six with an unclassified epileptic encephalopathy. This suggests that some children with epileptic encephalopathies previously thought to have primary generalised seizures or seizures due to multifocal pathology may have unifocal cortical origin for their seizures. Such an origin may be amenable to surgery.

Radiographs of the lumbar vertebral column and sacral region obtained for 182 epileptic patients after spina bifida occulta were studied. Spina bifida occulta was twice as common in patients with idiopathic epilepsy as in those with symptomatic epilepsy and twice as common as in the normal population. A relationship between spina bifida occulta and idiopathic epilepsy is discussed.

Idiopathic generalized epilepsy (IGE) is a complex epilepsy syndrome with various subtypes that appear normal on conventional magnetic resonance imaging (MRI). However, advanced quantitative MRI techniques have revealed subtle structural abnormalities. This study aims to identify specific cerebral regions with structural and volumetric alterations in IGE patients. A retrospective study was conducted on 38 IGE patients and 38 age and sex-matched healthy control subjects. MRI images were processed and segmented semi-automatically to extract volumes of cortical and subcortical brain regions. Statistical analysis was performed to compare volumes between IGE patients and controls. IGE patients exhibited significantly increased volumes in the precuneus ( p  = 0.002), and the pallidum ( p  < 0.001) compared to control subjects. No significant differences were observed in other regions, such as the precentral gyrus and frontal gyri. This study highlights conflicting results in the literature regarding radiologic volumetric data in IGE. While our findings imply the potential utility of incorporating volumetric analysis in the radiologic diagnosis of IGE patients to enhance targeted treatment approaches, it is important to exercise caution in interpreting these results, especially since these are primarily based on group-wise comparison. The increased volumes of the precuneus and pallidum in IGE patients suggest possible diagnostic implications. However, the extent of their clinical significance necessitates further investigation. Further research should investigate the clinical significance of these volumetric alterations and their potential role in guiding personalized treatment strategies for IGE patients.

In patients suffering absence epilepsy, recurring seizures can significantly decrease their quality of life and lead to yet untreatable comorbidities. Absence seizures are characterized by spike-and-wave discharges on the electroencephalogram associated with a transient alteration of consciousness. However, it is still unknown how the brain responds to external stimuli during and outside of seizures. This study aimed to investigate responsiveness to visual and somatosensory stimulation in Genetic Absence Epilepsy Rats from Strasbourg (GAERS), a well-established rat model for absence epilepsy. Animals were imaged under non-curarized awake state using a quiet, zero echo time, functional magnetic resonance imaging (fMRI) sequence. Sensory stimulations were applied during interictal and ictal periods. Whole-brain hemodynamic responses were compared between these two states. Additionally, a mean-field simulation model was used to explain the changes of neural responsiveness to visual stimulation between states. During a seizure, whole-brain responses to both sensory stimulations were suppressed and spatially hindered. In the cortex, hemodynamic responses were negatively polarized during seizures, despite the application of a stimulus. The mean-field simulation revealed restricted propagation of activity due to stimulation and agreed well with fMRI findings. Results suggest that sensory processing is hindered or even suppressed by the occurrence of an absence seizure, potentially contributing to decreased responsiveness during this absence epileptic process.