fNIRS-EEG study of focal interictal epileptiform discharges

Functional near-infrared spectroscopy (fNIRS) acquired with electroencephalography (EEG) is a relatively new non-invasive neuroimaging technique with potential for long term monitoring of the epileptic brain. Simultaneous EEG-fNIRS recording allows the spatio-temporal reconstruction of the hemodynamic response in terms of the concentration changes in oxy-hemoglobin (HbO) and deoxy-hemoglobin (HbR) associated with recorded epileptic events such as interictal epileptic discharges (IEDs) or seizures. While most previous studies investigating fNIRS in epilepsy had limitations due to restricted spatial coverage and small sample sizes, this work includes a sufficiently large number of channels to provide an extensive bilateral coverage of the surface of the brain for a sample size of 40 patients with focal epilepsies. Topographic maps of significant activations due to each IED type were generated in four different views (dorsal, frontal, left and right) and were compared with the epileptic focus previously identified by an epileptologist. After excluding 5 patients due to the absence of IEDs and 6 more with mesial temporal foci too deep for fNIRS, we report that significant HbR (respectively HbO) concentration changes corresponding to IEDs were observed in 62% (resp. 38%) of patients with neocortical epilepsies. This HbR/HbO response was most significant in the epileptic focus region among all the activations in 28%/21% of patients.

Optical imaging and two-photon microscopy study of hemodynamic changes contralateral to ictal focus during epileptiform discharges

Il est relativement bien établi que les crises focales entraînent une augmentation régionale du flot sanguin dans le but de soutenir la demande énergétique en hémoglobine oxygénée des neurones épileptiques. Des changements hémodynamiques précoces ont également été rapportés dans la région homologue controlatérale, bien que ceci ait été moins bien caractérisé. Dans cette étude, notre objectif est de mieux caractériser, lors de crises focales, la nature des changements hémodynamiques précoces dans la région homologue controlatérale au foyer épileptique. L'imagerie optique intrinsèque (IOI) et la microscopie deux-photons sont utilisées pour étudier les changements hémodynamiques dans la région homologue controlatérale au site de crises focales induites par l’injection de 4-aminopyridine (4-AP) dans le cortex somatosensitif ipsilatéral de souris. Dans l'étude d'IOI, des changements de l’oxyhémoglobine (HbO), de la désoxyhémoglobine (HbR) et du débit sanguin cérébral ont été observées dans la région homologue controlatérale au site de crises focales lors de toutes les crises. Toutefois, ces changements étaient hétérogènes, sans patron cohérent et reproduisible. Nos expériences avec la microscopie deux-photons n’ont pas révélé de changements hémodynamiques significatifs dans la région homotopique controlatérale lors de trains de pointes épileptiques. Nos résultats doivent être interprétés avec prudence compte tenu de plusieurs limitations: d’une part absence de mesures électrophysiologiques dans la région d’intérêt controlatérale au foyer simultanément à l’imagerie deux-photons et à l'IOI; d’autre part, lors des expériences avec le deux-photons, incapacité à générer de longues décharges ictales mais plutôt des trains de pointes, couverture spatiale limitée de la région d’intérêt controlatérale, et faible puissance suite au décès prématuré de plusieurs souris pour diverses raisons techniques. Nous terminons en discutant de divers moyens pour améliorer les expériences futures.

Widespread grey matter changes and hemodynamic correlates to interictal epileptiform discharges in pharmacoresistant mesial temporal epilepsy

Focal onset epilepsies most often occur in the temporal lobes. To improve diagnosis and therapy of patients suffering from pharmacoresistant temporal lobe epilepsy it is highly important to better understand the underlying functional and structural networks. In mesial temporal lobe epilepsy (MTLE) widespread functional networks are involved in seizure generation and propagation. In this study we have analyzed the spatial distribution of hemodynamic correlates (HC) to interictal epileptiform discharges on simultaneous EEG/fMRI recordings and relative grey matter volume (rGMV) reductions in 10 patients with MTLE. HC occurred beyond the seizure onset zone in the hippocampus, in the ipsilateral insular/operculum, temporo-polar and lateral neocortex, cerebellum, along the central sulcus and bilaterally in the cingulate gyrus. rGMV reductions were detected in the middle temporal gyrus, inferior temporal gyrus and uncus to the hippocampus, the insula, the posterior cingulate and the anterior lobe of the cerebellum. Overlaps between HC and decreased rGMV were detected along the mesolimbic network ipsilateral to the seizure onset zone. We conclude that interictal epileptic activity in MTLE induces widespread metabolic changes in functional networks involved in MTLE seizure activity. These functional networks are spatially overlapping with areas that show a reduction in relative grey matter volumes.

Prolonged activation of the N-methyl-d-aspartate receptor–Ca2+ transduction pathway causes spontaneous recurrent epileptiform discharges in hippocampal neurons in culture

The molecular basis for developing symptomatic epilepsy (epileptogenesis) remains ill defined. We show here in a well characterized hippocampal culture model of epilepsy that the induction of epileptogenesis is Ca2+-dependent. The concentration of intracellular free Ca2+ ([Ca2+]i) was monitored during the induction of epileptogenesis by prolonged electrographic seizure activity induced through low-Mg2+ treatment by confocal laser-scanning fluorescent microscopy to directly correlate changes in [Ca2+]i with alterations in membrane excitability measured by intracellular recording using whole-cell current–clamp techniques. The induction of long-lasting spontaneous recurrent epileptiform discharges, but not the Mg2+-induced spike discharges, was prevented in low-Ca2+ solutions and was dependent on activation of the N-methyl-d-aspartate (NMDA) receptor. The results provide direct evidence that prolonged activation of the NMDA–Ca2+ transduction pathway causes a long-lasting plasticity change in hippocampal neurons causing increased excitability leading to the occurrence of spontaneous, recurrent epileptiform discharges.

Clustering epileptiform discharges in the interictal electroencephalogram with topography preserving maps

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In vitro modulation of epileptiform activity in the hippocampal formation of immature rodents by GABAergic antagonists, dopamine and methylxanthines

Während des frühen Lebens stellen epileptische Anfälle schwere neurologische Zustände dar, weil sie ein großer Risikofaktor für die Manifestation der Epilepsie sind und eine hohe pharmakologische Resistenz zeigen. In meiner Doktorarbeit konzentrierte ich mich auf die Frage, wie verschiedene Neurotransmitter-Systeme und klinisch verwendete Medikamente epileptiforme Entladungen im perinatalen Hippocampus beeinflussen. rnIm ersten Teil meines Projektes untersuchte ich die Wirkung von GABA-Antagonisten und Modulatoren, die zwischen phasischen und tonischen GABAergen Strömen differenzieren, auf Feldpotentialaktivität in Hippocampusschnitten. Diese Experimente zeigten, dass im unreifen Hippocampus synaptische GABAerge Aktivität benötigt wird, um die Erregbarkeit zu begrenzen, während tonische GABAerge Ströme die Erregbarkeit verstärken können. Dies könnte darauf hinweisen, dass Antiepileptika mit einer höheren Spezifität für synaptische GABAA-Rezeptoren wirksamer zur Behandlung von epileptischen Anfällen bei Neugeborenen sein können. rnUm den Einfluss von Dopamin auf die Erregbarkeit des unreifen Hippocampus herauszufinden, untersuchte ich im zweiten Teil meiner Arbeit die Wirkung von verschiedenen Dopaminkonzentrationen und spezifische Agonisten und Antagonisten der Dopamin-Rezeptor-Subtypen auf epileptiforme Entladungen. Diese Experimente zeigten, dass niedrige Dopamin Konzentrationen eine antikonvulsive Wirkung haben, welche vom D2-ähnliche-Rezeptor-Agonisten Quinpirol nachgeahmt werden kann, während höhere Dopamin-Konzentrationen eine prokonvulsive Wirkung über Aktivierung von D1-ähnlichen Rezeptoren hervorrufen. Obwohl unsere Untersuchungen eine mögliche Verwendung von D2-ähnlichen Rezeptor-Agonisten zur Kontrolle epileptischer Anfälle in Neugeborenen nahelegen, müssen mögliche negative Auswirkungen von DAergen Agonisten und Antagonisten auf die neuronale Entwicklung berücksichtigt werden.rnIm dritten Teil meiner Arbeit untersuchte ich welche Konzentrationen von Methylxanthinen epileptische Anfälle in Hippocampuspreparationen auslösen die synaptische Übertragungen verändern können. Diese Experimente zeigten, dass sowohl Theophyllin als auch Koffein in höheren Konzentrationen die basale synaptische Übertragungen in der CA1-Region des Hippocampus modifizieren und epileptiforme Entladungen provozieren. Die Auswirkungen auf die postsynaptischen Antworten und spontanen epileptiformen Entladungen durch Koffein waren weniger ausgeprägt, was darauf hindeutet, dass diese Substanz potentiell vorteilhafter für therapeutische Anwendungen bei Frühgeborenen sein kann. rnZusammenfassend bereichern die Ergebnisse meiner Studie erheblich unser Wissen über die zugrunde liegenden Mechanismen epileptiformer Aktivität im unreifen Hippocampus und den therapeutischen Einsatz von Methylxanthinen und Pharmaka, die auf das GABAerge und DArge System einwirken.rnrn

Inhibition of calcium/calmodulin kinase II alpha subunit expression results in epileptiform activity in cultured hippocampal neurons

Several models that develop epileptiform discharges and epilepsy have been associated with a decrease in the activity of calmodulin-dependent kinase II. However, none of these studies has demonstrated a causal relationship between a decrease in calcium/calmodulin kinase II activity and the development of seizure activity. The present study was conducted to determine the effect of directly reducing calcium/calmodulin-dependent kinase activity on the development of epileptiform discharges in hippocampal neurons in culture. Complimentary oligonucleotides specific for the α subunit of the calcium/calmodulin kinase were used to decrease the expression of the enzyme. Reduction in kinase expression was confirmed by Western analysis, immunocytochemistry, and exogenous substrate phosphorylation. Increased neuronal excitability and frank epileptiform discharges were observed after a significant reduction in calmodulin kinase II expression. The epileptiform activity was a synchronous event and was not caused by random neuronal firing. Furthermore, the magnitude of decreased kinase expression correlated with the increased neuronal excitability. The data suggest that decreased calmodulin kinase II activity may play a role in epileptogenesis and the long-term plasticity changes associated with the development of pathological seizure activity and epilepsy.

A role for Src kinase in spontaneous epileptiform activity in the CA3 region of the hippocampus

Members of the Src family of nonreceptor protein tyrosine kinases (PTKs) have been implicated in the regulation of cellular excitability and synaptic plasticity. We have investigated the role of these PTKs in in vitro models of epileptiform activity. Spontaneous epileptiform discharges were induced in vitro in the CA3 region of rat hippocampal slices by superfusion with the potassium channel blocker 4-aminopyridine in Mg2+-free medium. In hippocampal slices treated in this fashion, Src kinase activity was increased and the frequency of epileptiform discharges could be greatly reduced by inhibitor of the Src family of PTKs, 4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine (PP2), but not by the inactive structural analog 4-amino-7-phenylpyrazol[3,4-d]pyrimidine (PP3). 4-Amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine also reduced epileptiform activity induced by either 4-aminopyridine or Mg2+-free medium alone. These observations demonstrate a role for Src family PTKs in the pathophysiology of epilepsy and suggest potential therapeutic targets for antiepileptic therapy.

Epileptic networks are strongly connected with and without the effects of interictal discharges

OBJECTIVE Epilepsy is increasingly considered as the dysfunction of a pathologic neuronal network (epileptic network) rather than a single focal source. We aimed to assess the interactions between the regions that comprise the epileptic network and to investigate their dependence on the occurrence of interictal epileptiform discharges (IEDs). METHODS We analyzed resting state simultaneous electroencephalography-functional magnetic resonance imaging (EEG-fMRI) recordings in 10 patients with drug-resistant focal epilepsy with multifocal IED-related blood oxygen level-dependent (BOLD) responses and a maximum t-value in the IED field. We computed functional connectivity (FC) maps of the epileptic network using two types of seed: (1) a 10-mm diameter sphere centered in the global maximum of IED-related BOLD map, and (2) the independent component with highest correlation to the IED-related BOLD map, named epileptic component. For both approaches, we compared FC maps before and after regressing out the effect of IEDs in terms of maximum and mean t-values and percentage of map overlap. RESULTS Maximum and mean FC maps t-values were significantly lower after regressing out IEDs at the group level (p < 0.01). Overlap extent was 85% ± 12% and 87% ± 12% when the seed was the 10-mm diameter sphere and the epileptic component, respectively. SIGNIFICANCE Regions involved in a specific epileptic network show coherent BOLD fluctuations independent of scalp EEG IEDs. FC topography and strength is largely preserved by removing the IED effect. This could represent a signature of a sustained pathologic network with contribution from epileptic activity invisible to the scalp EEG.

From EEG to BOLD: Brain mapping and estimating transfer functions in simultaneous EEG-fMRI acquisitions

Simultaneous acquisition of electroencephalography (EEG) and functional magnetic resonance imaging (fMRI) aims to disentangle the description of brain processes by exploiting the advantages of each technique. Most studies in this field focus on exploring the relationships between fMRI signals and the power spectrum at some specific frequency bands (alpha, beta, etc.). On the other hand, brain mapping of EEG signals (e.g., interictal spikes in epileptic patients) usually assumes an haemodynamic response function for a parametric analysis applying the GLM, as a rough approximation. The integration of the information provided by the high spatial resolution of MR images and the high temporal resolution of EEG may be improved by referencing them by transfer functions, which allows the identification of neural driven areas without strong assumptions about haemodynamic response shapes or brain haemodynamic`s homogeneity. The difference on sampling rate is the first obstacle for a full integration of EEG and fMRI information. Moreover, a parametric specification of a function representing the commonalities of both signals is not established. In this study, we introduce a new data-driven method for estimating the transfer function from EEG signal to fMRI signal at EEG sampling rate. This approach avoids EEG subsampling to fMRI time resolution and naturally provides a test for EEG predictive power over BOLD signal fluctuations, in a well-established statistical framework. We illustrate this concept in resting state (eyes closed) and visual simultaneous fMRI-EEG experiments. The results point out that it is possible to predict the BOLD fluctuations in occipital cortex by using EEG measurements. (C) 2010 Elsevier Inc. All rights reserved.

Diagnostic yield of short-term video-EEG monitoring for epilepsy and PNESs: a European assessment.

INTRODUCTION: Although long-term video-EEG monitoring (LVEM) is routinely used to investigate paroxysmal events, short-term video-EEG monitoring (SVEM) lasting <24 h is increasingly recognized as a cost-effective tool. Since, however, relatively few studies addressed the yield of SVEM among different diagnostic groups, we undertook the present study to investigate this aspect. METHODS: We retrospectively analyzed 226 consecutive SVEM recordings over 6 years. All patients were referred because routine EEGs were inconclusive. Patients were classified into 3 suspected diagnostic groups: (1) group with epileptic seizures, (2) group with psychogenic nonepileptic seizures (PNESs), and (3) group with other or undetermined diagnoses. We assessed recording lengths, interictal epileptiform discharges, epileptic seizures, PNESs, and the definitive diagnoses obtained after SVEM. RESULTS: The mean age was 34 (±18.7) years, and the median recording length was 18.6 h. Among the 226 patients, 127 referred for suspected epilepsy - 73 had a diagnosis of epilepsy, none had a diagnosis of PNESs, and 54 had other or undetermined diagnoses post-SVEM. Of the 24 patients with pre-SVEM suspected PNESs, 1 had epilepsy, 12 had PNESs, and 11 had other or undetermined diagnoses. Of the 75 patients with other diagnoses pre-SVEM, 17 had epilepsy, 11 had PNESs, and 47 had other or undetermined diagnoses. After SVEM, 15 patients had definite diagnoses other than epilepsy or PNESs, while in 96 patients, diagnosis remained unclear. Overall, a definitive diagnosis could be reached in 129/226 (57%) patients. CONCLUSIONS: This study demonstrates that in nearly 3/5 patients without a definitive diagnosis after routine EEG, SVEM allowed us to reach a diagnosis. This procedure should be encouraged in this setting, given its time-effectiveness compared with LVEM.

Acquired auditory agnosia in childhood and normal sleep electroencephalography subsequently diagnosed as Landau-Kleffner syndrome: a report of three cases.

Aim  We report three cases of Landau-Kleffner syndrome (LKS) in children (two females, one male) in whom diagnosis was delayed because the sleep electroencephalography (EEG) was initially normal. Method  Case histories including EEG, positron emission tomography findings, and long-term outcome were reviewed. Results  Auditory agnosia occurred between the age of 2 years and 3 years 6 months, after a period of normal language development. Initial awake and sleep EEG, recorded weeks to months after the onset of language regression, during a nap period in two cases and during a full night of sleep in the third case, was normal. Repeat EEG between 2 months and 2 years later showed epileptiform discharges during wakefulness and strongly activated by sleep, with a pattern of continuous spike-waves during slow-wave sleep in two patients. Patients were diagnosed with LKS and treated with various antiepileptic regimens, including corticosteroids. One patient in whom EEG became normal on hydrocortisone is making significant recovery. The other two patients did not exhibit a sustained response to treatment and remained severely impaired. Interpretation  Sleep EEG may be normal in the early phase of acquired auditory agnosia. EEG should be repeated frequently in individuals in whom a firm clinical diagnosis is made to facilitate early treatment.

Clinical neurophysiological assessment of sepsis-associated brain dysfunction: a systematic review.

IntroductionSeveral studies have reported the presence of electroencephalography (EEG) abnormalities or altered evoked potentials (EPs) during sepsis. However, the role of these tests in the diagnosis and prognostic assessment of sepsis-associated encephalopathy remains unclear.MethodsWe performed a systematic search for studies evaluating EEG and/or EPs in adult (¿18 years) patients with sepsis-associated encephalopathy. The following outcomes were extracted: a) incidence of EEG/EP abnormalities; b) diagnosis of sepsis-associated delirium or encephalopathy with EEG/EP; c) outcome.ResultsAmong 1976 citations, 17 articles met the inclusion criteria. The incidence of EEG abnormalities during sepsis ranged from 12% to 100% for background abnormality and 6% to 12% for presence of triphasic waves. Two studies found that epileptiform discharges and electrographic seizures were more common in critically ill patients with than without sepsis. In one study, EEG background abnormalities were related to the presence and the severity of encephalopathy. Background slowing or suppression and the presence of triphasic waves were also associated with higher mortality. A few studies demonstrated that quantitative EEG analysis and EP could show significant differences in patients with sepsis compared to controls but their association with encephalopathy and outcome was not evaluated.ConclusionsAbnormalities in EEG and EPs are present in the majority of septic patients. There is some evidence to support EEG use in the detection and prognostication of sepsis-associated encephalopathy, but further clinical investigation is needed to confirm this suggestion.

Continuous electroencephalography in the medical intensive care unit.

OBJECTIVES: To examine predictors and the prognostic value of electrographic seizures (ESZs) and periodic epileptiform discharges (PEDs) in medical intensive care unit (MICU) patients without a primary acute neurologic condition. DESIGN: Retrospective study. SETTING: MICU in a university hospital. PATIENTS: A total of 201 consecutive patients admitted to the MICU between July 2004 and January 2007 without known acute neurologic injury and who underwent continuous electroencephalography monitoring (cEEG) for investigation of possible seizures or changes in mental status. INTERVENTION: None. MEASUREMENTS AND MAIN RESULTS: Median time from intensive care unit (ICU) admission to cEEG was 1 day (interquartile range 1-4). The majority of patients (60%) had sepsis as the primary admission diagnosis and 48% were comatose at the time of cEEG. Ten percent (n = 21) of patients had ESZs, 17% (n = 34) had PEDs, 5% (n = 10) had both, and 22% (n = 45) had either ESZs or PEDs. Seizures during cEEG were purely electrographic (no detectable clinical correlate) in the majority (67%) of patients. Patients with sepsis had a higher rate of ESZs or PEDs than those without sepsis (32% vs. 9%, p < 0.001). On multivariable analysis, sepsis at ICU admission was the only significant predictor of ESZs or PEDs (odds ratio 4.6, 95% confidence interval 1.9-12.7, p = 0.002). After controlling for age, coma, and organ dysfunction, the presence of ESZs or PEDs was associated with death or severe disability at hospital discharge (89% with ESZs or PEDs, vs. 39% if not; odds ratio 19.1, 95% confidence interval 6.3-74.6, p < 0.001). CONCLUSION: In this retrospective study of MICU patients monitored with cEEG, ESZs and PEDs were frequent, predominantly in patients with sepsis. Seizures were mainly nonconvulsive. Both seizures and periodic discharges were associated with poor outcome. Prospective studies are warranted to determine more precisely the frequency and clinical impact of nonconvulsive seizures and periodic discharges, particularly in septic patients.

Prognostic value of continuous eeg monitoring during therapeutic hypothermia in patients with coma after cardiac arrest

INTRODUCTION: Continuous EEG (cEEG) is increasingly used to monitor brain function in neuro-ICU patients. However, its value in patients with coma after cardiac arrest (CA), particularly in the setting of therapeutic hypothermia (TH), is only beginning to be elucidated. The aim of this study was to examine whether cEEG performed during TH may predict outcome. METHODS: From April 2009 to April 2010, we prospectively studied 34 consecutive comatose patients treated with TH after CA who were monitored with cEEG, initiated during hypothermia and maintained after rewarming. EEG background reactivity to painful stimulation was tested. We analyzed the association between cEEG findings and neurologic outcome, assessed at 2 months with the Glasgow-Pittsburgh Cerebral Performance Categories (CPC). RESULTS: Continuous EEG recording was started 12 ± 6 hours after CA and lasted 30 ± 11 hours. Nonreactive cEEG background (12 of 15 (75%) among nonsurvivors versus none of 19 (0) survivors; P < 0.001) and prolonged discontinuous "burst-suppression" activity (11 of 15 (73%) versus none of 19; P < 0.001) were significantly associated with mortality. EEG seizures with absent background reactivity also differed significantly (seven of 15 (47%) versus none of 12 (0); P = 0.001). In patients with nonreactive background or seizures/epileptiform discharges on cEEG, no improvement was seen after TH. Nonreactive cEEG background during TH had a positive predictive value of 100% (95% confidence interval (CI), 74 to 100%) and a false-positive rate of 0 (95% CI, 0 to 18%) for mortality. All survivors had cEEG background reactivity, and the majority of them (14 (74%) of 19) had a favorable outcome (CPC 1 or 2). CONCLUSIONS: Continuous EEG monitoring showing a nonreactive or discontinuous background during TH is strongly associated with unfavorable outcome in patients with coma after CA. These data warrant larger studies to confirm the value of continuous EEG monitoring in predicting prognosis after CA and TH.