Interictal Epileptic Activity Research Articles

Utilization of magnetoencephalography results to obtain favourable outcomes in epilepsy surgery

Magnetoencephalography (MEG) is a well-known technique in the presurgical evaluation of epilepsy patients. Like EEG, it can detect and localize epileptic activity. Epilepsy surgery can be used to evaluate MEG source localizations. Resection volumes were determined in 33 epilepsy surgery patients. The resection volume, taken together with the post-operative outcome, was used to evaluate MEG results. The scattering MEG localizations of interictal epileptic activity were represented by an ellipsoidal volume. Using this MEG results ellipsoid, it was demonstrated that a high coverage by the resection volume and a small distance to the resection volume are both correlated to a favourable outcome; in addition, a homogeneous distribution of MEG localizations is correlated to a favourable outcome. This study shows that MEG source localization can help to delineate epileptic activity and, along with other techniques, should be taken into account for epilepsy surgery.

Infraslow oscillations modulate excitability and interictal epileptic activity in the human cortex during sleep

Human cortical activity has been intensively examined at frequencies ranging from 0.5 Hz to several hundred Hz. Recent studies have, however, reported also infraslow fluctuations in neuronal population activity, magnitude of electroencephalographic oscillations, discrete sleep events, as well as in the occurrence of interictal events. Here we use direct current electroencephalography to demonstrate large-scale infraslow oscillations in the human cortex at frequencies ranging from 0.02 to 0.2 Hz. These oscillations, which are not detectable in conventional electroencephalography because of its limited recording bandwidth (typical lower limit 0.5 Hz), were observed in widespread cortical regions. Notably, the infraslow oscillations were strongly synchronized with faster activities, as well as with the interictal epileptic events and K complexes. Our findings suggest that the infraslow oscillations represent a slow, cyclic modulation of cortical gross excitability, providing also a putative mechanism for the as yet enigmatic aggravation of epileptic activity during sleep.

Vagus nerve stimulation in patients with catastrophic childhood epilepsy, a 2-year follow-up study

Purpose: To establish the long-term efficacy and tolerability of vagus nerve stimulation (VNS) in children with a Lennox-like syndrome. Method: This study was a longitudinal observational prospective cohort analysis. Baseline: 6 months. Follow-up: 24 months. Screening (baseline and every 6 months): MRI (baseline only), EEG, neuropsychological evaluation, ECG and blood sampling for antiepileptic drug levels. Nineteen children are included. Results: A seizure frequency reduction of 20.6% was found at the end of the follow-up period. No relationship was detected between the length of the stimulation period and the reduction in the seizure frequency. 21% of the patients showed a reduction in seizure frequency of 50% or more. The seizure severity showed improvement in the first 12 months of treatment. The largest seizure reduction was found in the patients with highest frequency of background activity at the baseline EEG. Neuropsychological findings: no negative impact on behaviour, moderate improvement in function, behaviour and mood. Largest seizure reduction was found in the group with the highest baseline mental function. The scores for mental age improved independently of the seizure control. Twelve patients (63%) experienced minor side effects, which subsided after 1 month. Conclusion: (1) There was a significant reduction in seizure frequency and severity. (2) No serious side effects were recorded. (3) No negative effects on cognition or quality of life were apparent. (4) Patients with highest baseline mental functioning showed the highest seizure reduction. (5) Those patients with less disturbed EEG (high background activity and less interictal epileptic activity) showed the highest seizure reduction.

Effects of epileptiform EEG discharges on cognitive function: Is the concept of “transient cognitive impairment” still valid?

In this article we review the existing evidence on the cognitive impact of interictal epileptiform EEG discharges. Such cognitive impairment occurs exclusively in direct relation to episodes of epileptiform EEG discharges and must be distinguished from (post) ictal seizure effects and from the nonperiodic long-term “stable” interictal effects caused by the clinical syndrome or the underlying etiology. Especially in patients with short nonconvulsive seizures, characterized often by difficult-to-detect symptoms, the ictal or postictal effects may be overlooked and the resulting cognitive effects may be erroneously related to the epileptiform EEG discharges. The existing epidemiological data show that the prevalence of cognitive impairment during epileptiform EEG discharges is low. In one study 2.2% of the patients referred to a specialized epilepsy center for EEG recording showed a definite relationship between epileptiform EEG discharges and cognitive impairments (“transient cognitive impairment”). Several studies have sought to analyze to what extent cognitive impairment can be attributed to epileptiform EEG discharges among the other epilepsy factors (such as the effect of the clinical syndrome). These studies show that epileptiform EEG discharges have an additional and independent effect, but this effect is mild and limited to transient mechanistic cognitive processes (alertness, mental speed). This finding concurs with clinical studies that also reported only mild effects. In only exceptional cases are epileptiform EEG discharges the dominant factor explaining cognitive impairment. In addition, some studies have indicated that such mild effects may accumulate over time (when frequent epileptiform EEG discharges persist over years) and consequently result in effects on stable aspects of cognitive function such as educational achievement and intelligence. Hence, the clinical relevance is that early detection of cognitive effects of epileptiform EEG discharges and subsequent treatment may prevent a definite impact on cognitive and educational development. The disruptive effects of epileptiform EEG discharges on long-term potentiation, as established in animal experiments, may be one of the neurophysiological mechanisms underlying this accumulation. In conclusion the concept of “transient cognitive impairment” is still valid, but refinement of methodology has shown that a large proportion of presumed transient cognitive impairment can be attributed to subtle seizures, while interictal epileptic activity accounts for a much smaller part of the cognitive effects than previously thought. In particular cryptogenic partial epilepsies are associated with the risk of cognitive impairment. We hope that increased clinical awareness of this need for early detection will stimulate longitudinal and prospective research that eventually also will provide an answer to the questions of when and how epileptiform discharges that are not part of a seizure need to be treated.

Resting functional MRI with temporal clustering analysis for localization of epileptic activity without EEG

We report on the methods and initial findings of a novel noninvasive technique, resting functional magnetic resonance imaging (fMRI) with temporal clustering analysis (TCA), for localizing interictal epileptic activity. Nine subjects were studied including six temporal lobe epilepsy (TLE) patients with confirmed localization indicated by successful seizure control after resection. The remaining three subjects had standard presurgical evaluations with inconsistent results or suspected extratemporal lobe foci. Peaks of activity, presumably epileptic, were detected in all nine subjects, using the resting functional MRI with temporal clustering analysis. In all six patients who underwent resective surgery, the fMRI with temporal clustering analysis accurately determined the epileptogenic hippocampal hemisphere ( P = 0.005). In the three subjects without confirmed localization, the technique determined regions of activity consistent with those determined by the presurgical assessments. Though more studies are required to validate this technique, the results demonstrate the potential of the resting fMRI with temporal clustering technique to detect and localize epileptic activity without the need for simultaneous electroencephalography (EEG). The greatest potential benefit of this technique will be in the evaluation of patients with suspected extratemporal lobe epilepsy and patients whose standard assessments are discordant.

Systemic overexpression of the alpha 1B-adrenergic receptor in mice: an animal model of epilepsy.

A lack of selective alpha1-adrenergic receptor (alpha1-ARs) agonists and antagonists has made it difficult to clarify the precise function of these receptors in the CNS. We recently generated transgenic mice that overexpress either wild-type or a constitutively active mutant alpha 1B-AR in tissues that normally express the receptor. Both wild-type and mutant mice showed an age-progressive neurodegeneration with locomotor impairment and probable stress-induced motor events, which can be partially reversed by alpha 1-AR antagonists. We hypothesized that the wild-type and mutant mice may exhibit spontaneous epileptogenicity as compared with normal (nontransgenic) mice. Normal, wild-type, and mutant mice were studied. Twenty mice (1 year old) underwent prolonged video-EEG monitoring over a 4-week period. Raw EEG data were blindly analyzed by visual inspection for the presence of interictal and ictal epileptic activities. During the acute postoperative period (< or = 3 days), both wild-type (26.1 +/- 8.07 spikes/day) and mutant mice (116.87 +/- 55.13) exhibited more frequent interictal spikes than did normal mice (2.17 +/- 0.75; p value, <0.05), but all three groups showed EEG and clinical seizures. During the later monitoring periods (>3 days), wild-type and mutant mice showed more frequent interictal spikes (15.44 +/- 4.07; p < 0.01; and 6.05 +/- 2.46; p < 0.05, respectively) as compared with normal mice (0.41 +/- 0.41), but only mutant mice had spontaneous clinical seizures (means +/- SEM). The selective overexpression of the alpha 1B-AR is associated with increased in vivo spontaneous interictal epileptogenicity and EEG/behavioral seizures. These results suggest a possible role (direct or indirect) for the alpha 1B-ARs in the development and expression of epileptogenicity.

Localization of interictal epileptic activity with 128-channel EEG

Localization of interictal epileptic activity with 128-channel EEG

Suppression of Interictal Epileptic Activity by AEDs

Rates of full suppression of interictal epileptiform activity were compared for phenobarbital (PHB), carbamazepine (CBZ), and valproate (VPA), in a study at Tufts University School of Medicine, Boston, MA.

Local Lyapunov exponents detect epileptic zones in spike-less interictal MEG recordings

Objective: In terms of dynamical system theory the rapid alteration of electromagnetic brain signal properties observed with transition from interictal into ictal epileptic activity implies an alteration between at least two dynamical states (attractors). We explored whether such a multistability is reflected also in the dynamical characteristics of the interictal signal. Methods: A combined method consisting of structural MRI, multichannel magnetoencephalography (MEG) and the non-linear dynamics was applied for the detection of subthreshold interictal activity in temporal lobe epilepsy. Employing multichannel MEG we calculated local Lyapunov exponents (ILE) as a measure of the probability of state transitions in patients with mesiotemporal and extra-mesiotemporal focal epilepsy. Results: The spatial distribution of the variability of ILE was found to be correlated to the side of the epileptic focus, thus, providing a reliable estimate of its localization. Conclusion: Our results demonstrate that interictal epileptic activity is characterized by an increase of the number of transitions between different attractors.

Dipole-source analysis in a realistic head model in patients with focal epilepsy.

By the use of three different head models in EEG dipole analysis, we tried to model the origin of interictal and ictal epileptic activity as precisely as possible. Further, as a control, a second evaluation was made by an independent group to control for interindividual reliability of the dipole source analysis. With the realistic head model (CURRY) considering cortex, skull, and skin segmentation, the spike source was located. In five patients with mesial temporal epileptogenesis, confirmed by successful epilepsy surgery, the spike source was close to the hippocampus, with a mean distance of the dipole source from the hippocampus of 13.6 mm (range, 9-17.2 mm). In one case the ictal EEG also could be analyzed and resulted in a dipole-source localization comparable to the interictal source. In both head models using either pure cortex segmentation only or a concentric three-shell model, the dipole source was systematically dislocated in a more superior position. Data analysis by a second group with independently chosen EEG samples and identical individual head model resulted in deviations of <5.3 mm. Data analysis using independently selected spikes and independently segmented head models resulted in deviations < or =16.7 mm. In four cases of extratemporal epileptogenesis, the origin of interictal epileptiform discharges was localized to the suspected primary epileptogenic zone.

Sleep and sleep deprivation as EEG activating methods

Objectives: We examined retrospectively 19 patients with a history of clinical seizures, but normal activity or unclear epileptiform abnormalities in wake EEG recordings and obtained preliminary data for a controlled cohort study to evaluate the effects of sleep deprivation (SD) on interictal epileptic activity. Methods: Nineteen patients referred to our EEG department for diagnostic or follow-up purposes were divided in two groups on the basis of the different EEG protocols applied. The first group ( n=5) underwent two laboratory polysomnographies during afternoon naps, after SD, but the patients failed to fall asleep in one of the two occasions. The second group ( n=14) was submitted to two polysomnographies, the first without SD and the second after SD. Results: The first group of patients demonstrated focal epileptic discharges in 4 patients in which wake after SD appeared to be less activated that sleep after SD. In the second group the results obtained from the waking part of the recordings suggest a lack of activating effect due to SD. Conclusions: SD does not seem to offer greater activation than sleep alone. However, a mild SD may be a convenient activating method for inducing sleep and drowsiness without using any drug.

Source Localization and Possible Causes of Interictal Epileptic Activity in Tumor-Associated Epilepsy

Electrophysiological studies in gliomas have demonstrated action potentials in neoplastic cells. These “spiking tumor cells” are, however, an enigma. In attempt to find evidences for spikes within tumoral borders, 21 patients with different intracerebral tumors were preoperatively screened for the occurrence of epileptogenic discharges using multichannel MEG and EEG. A correlation between histopathology and the distance between dipole and tumor border could be found. Glioma patients showed epileptic activities closer to the border than those with mixed glioneuronal neoplasms and metastases. Four glioma patients demonstrated epileptic activity within the tumor boundary, however, not in the deep center of the tumor. Patch-clamping of cells from acute glioma slices did not yield a correlation between the presence of voltage-gated sodium channels in tumor cells and the MEG/EEG data. Our results demonstrate that the zone with the highest epileptogenic potential is different in gliomas and other brain tumors. However, our data do not strongly suggest that glioma cells are directly involved in the generation of tumor-associated epilepsy in vivo via their capability to generate action potentials.

Chronic epileptogenesis requires development of a network of pathologically interconnected neuron clusters: a hypothesis.

The "silent period" is a characteristic of human localization-related symptomatic epilepsy. In mesial temporal lobe epilepsy (MTLE), it follows an initial precipitating injury, and in animal models of MTLE in which brain damage is artificially created, there is also a prolonged interval between injury and the onset of spontaneous seizures. The neuronal reorganization responsible for epileptogenesis presumably takes place during this silent interval; however, the functional correlates of this process are poorly understood. We have previously described high-frequency (250 to 500 Hz) oscillations, called fast ripples (FR), in the hippocampus and entorhinal cortex (EC) of intrahippocampal kainic acid (KA)-injected rats and patients with MTLE that are confined to the region of spontaneous seizure generation. We have proposed, therefore, that FR reflect the mechanisms responsible for epileptogenesis. If this is the case, they should appear during the process of epileptogenesis, before the appearance of spontaneous seizures. The purpose of the present study was to record continuously from rats after KA injection to compare the temporal development of FR with spontaneous seizures. Additional goals were to determine in these rats after spontaneous seizures begin (a) the volume of tissue in which FR can be recorded in hippocampus and EC, (b) the multiple-unit and field potential correlates of FR oscillations, and (c) whether there is an association of FR with mossy fiber sprouting. After unilateral KA injection in the posterior hippocampus, interictal field epileptic activity and single-unit activity were recorded from freely moving animals using multiple-contact microelectrodes in dentate gyrus (DG) and EC. One group of animals underwent continuous recording to determine the time of onset of both FR oscillations and spontaneous seizures. A second group was implanted after behavioral seizures began to measure the area within which FR could be recorded as well as their unit and field potential correlates. The neo-Timm method was used to reveal mossy fiber sprouting, and gray value analysis was used to measure the intensity of sprouting in the inner molecular layer of DG. In KA-injected rats, FR were observed in hippocampal areas adjacent to the lesion and in the ipsilateral EC 11 to 14 days after injection, whereas spontaneous behavioral seizures occurred 2 to 4 months after injection. Analysis of depth profiles of interictal FR in the DG and EC showed that they were generated in local areas with a volume of about 1.0 mm3, and unit recordings indicated that they reflected fields of hypersynchronous action potentials. FR were found in areas of DG with more intensive mossy fiber sprouting. However, the correspondence was not absolute. The electrophysiological and anatomical data are consistent with the participation of FR oscillations, within small neuronal assemblies, in the development of chronic epileptogenesis. It is hypothesized that small clusters of pathologically interconnected neurons develop after focal hippocampal injury and that these clusters are capable of generating powerful hypersynchronous bursts of action potentials, which initiate epileptogenesis via a kindling effect. As the silent period progresses, a network of such clusters is formed that allows the development of discharges that spread throughout the limbic system. When this network engages brain areas that control motor activity, clinical seizures occur and the silent period ends.

Uncoupling of blood flow and metabolism in focal epilepsy.

Interictal measurements of cerebral blood flow are less helpful in localizing epileptic foci than are measurements of brain metabolism. This may be related to an uncoupling of blood flow and metabolism. In this study, brain metabolism and blood flow were compared in an acute experimental model of focal interictal epilepsy. Interictal epileptic foci were induced by an epicortical application of penicillin in rats. After 1 h, stereotyped interictal activity was initiated, lasting until the end of the experiment. Brain metabolism was determined with [14C]deoxyglucose, and cerebral blood flow with [14C]iodoan-tipyrine autoradiography. In control experiments, metabolism and blood flow were coupled. In animals with focal interictal epileptic activity, the metabolism was strongly increased in the focus and reduced in areas lateral to the focus. In contralateral brain areas, blood flow and metabolism varied in a parallel fashion. Ipsilateral to the focus, however, blood flow and metabolism were altered disproportionately. In the focus, the increase of blood flow was less marked than the increase of metabolism, and the area with increased blood flow was larger than the area with increased metabolism. Lateral to the focus, in the area with a hypometabolism, blood flow was not concomitantly reduced. The experiments show that blood flow and metabolism in focal epilepsy may be uncoupled in widespread regions. This is due neither to structural abnormalities nor to the duration or discharge pattern of epileptic activity. The results explain why interictal metabolic investigations have a higher predictive value in presurgical epilepsy evaluation than do interictal measurements of blood flow.

Interhemispheric EEG coherence after corpus callosotomy

Interhemispheric coherence analysis of scalp electroencephalograms (EEGs) in three intractable epileptic patients before and after surgical section of the anterior part of the corpus callosum was performed. Equidistant EEG periods recorded under resting conditions free of interictal epileptic activity and periods with generalized spike‐and‐wave discharges were investigated. Mean coherence values for five frequency EEG bands (delta, theta, alpha, beta 1 and beta 2) before and after corpus callosotomy were compared with each other and statistically evaluated. Anterior callosotomy led, in all cases, to a decrease of interhemispheric EEG coherence in most localizations, with the most profound decreases in the region corresponding to the section. These results support the hypothesis that the corpus callosum plays an important role in resting interhemispheric integration and EEG synchronization, similar to its central role in propagation of specific epileptic activity.

Suppression of background brain activity influence in localizing epileptic spike sources from biomagnetic measurements.

The origin of inter-ictal epileptic activity can be localized from the magnetoencephalogram (MEG) using the Equivalent Current Dipole (ECD) as a source model. One problem with such localizations is that in many patients, the localization of an epileptic spike source becomes inaccurate because the epileptic spikes are superimposed by pathologic brain rhythmic activities. This paper proposes to use the spatial coherence of the measured magnetic field caused by the measured magnetic field to suppress its influence in the ECD localization. In the method proposed here, the covariance matrix, which expresses the spatial coherence of the rhythmic magnetic field, is first calculated using a data portion where no spikes exist and rhythmic slow waves are evident. Then, ECD localization is performed by minimizing the least-squares cost function modified by the covariance matrix. Experiments using a computer generated ECD field and rhythmic slow waves measured from a patient suffering from complex partial epilepsy prove the basic effectiveness of the method proposed. Localizations of actual spike sources in the same clinical data are performed, and results indicating the effectiveness of the proposed method are obtained.

Magnetic field tomography of cortical and deep processes: examples of “real-time mapping” of averaged and single trial MEG signals

Magnetic field tomography (MFT) provides 3-dimensional estimates of brain activity, from non-contact, non-invasive measurements of the magnetic field generated by coherent electrical activity in the brain. MFT analysis of averaged auditory “odd-ball” data show cortical and deep activation, presumably from the amygdala and hippocampus. These results are compared with MFT estimates obtained from a patient who had undergone lobectomy which removed these structures. The variability from subject to subject is confounded by variability between trials for the same subject; the relationship between the averaged and single trials is probed by bi-hemispheric simultaneous measurements performed under the same odd-ball paradigm and by MFT analysis of auditory evoked data and interictal epileptic activity.

Potential contribution of bilateral magnetic source imaging to the evaluation of epilepsy surgery candidates.

The current procedures that are used to evaluate candidates for epilepsy surgery are time-consuming, costly, and often invasive. Magnetic source imaging (MSI), the combination of magnetoencephalography and anatomic imaging modalities, has shown promise as an efficient noninvasive means of localizing and characterizing seizure sources for possible resection. However, MSI has been limited by the inability to conduct simultaneous bilateral monitoring. In this study, a newly developed dual-magnetometer system was employed to record bilaterally the interictal activity in 30 candidates for epilepsy surgery. A standard monitoring protocol that included concurrent electroencephalographic recording and required a 2- to 3-hour examination period for each patient was developed. As a first step in a series of studies, the resultant MSI indications were compared with the information available from standard magnetic resonance imaging and concurrent electroencephalographic results. In 83% of the cases, this MSI protocol provided new information about the location of interictal epileptic activity that could be directive for subsequent patient care. Based on these results, it seems that MSI may become a cost-effective early step in epilepsy surgery evaluation. To continue the development on this basis, a study intended to validate the accuracy of MSI indicated by comparison with invasive electroencephalography has been initiated.

3D location of interictal epileptic activity by neuromagnetic method

3D location of interictal epileptic activity by neuromagnetic method

Intrinsic epileptogenicity of human dysplastic cortex as suggested by corticography and surgical results.

Cortical dysplastic lesions (CDyLs) are often associated with severe partial epilepsies. We describe the electrographic counterpart of this high degree of epileptogenicity, manifested by continuous or frequent rhythmic epileptogenic discharges recorded directly from CDyLs during intraoperative electrocorticography (ECoG). These ictal or continuous epileptogenic discharges (I/CEDs) assumed one of the following three patterns: (1) repetitive electrographic seizures, (2) repetitive bursting discharges, or (3) continuous or quasicontinuous rhythmic spiking. One or more of these patterns were present in 23 of 34 patients (67%) with intractable partial epilepsy associated with CDyLs, and in only 1 of 40 patients (2.5%) with intractable partial epilepsy associated with other types of structural lesions. I/CEDs were usually spatially restricted, thus contrasting with the more widespread interictal ECoG epileptic activity, and tended to colocalize with the magnetic resonance imaging-defined lesion. Completeness of excision of cortical tissue displaying I/CEDs correlated positively with surgical outcome in patients with medically intractable seizures; i.e., three-fourths of the patients in whom it was entirely excised had favorable surgical outcome; in contrast, uniformly poor outcome was observed in those patients in whom areas containing I/CEDs remained in situ. We conclude that CDyLs are highly and intrinsically epileptogenic, and that intraoperative ECoG identification of this intrinsically epileptogenic dysplastic cortical tissue is crucial to decide the extent of excision for best seizure control.