Prognostic value of early electrographic biomarkers of epileptogenesis in high-risk ischaemic stroke patients.

BACKGROUND AND PURPOSE: Post-stroke epilepsy (PSE) is frequent. Better prediction of PSE would enable individualized management and improve trial design for epilepsy prevention. The aim was to assess the complementary value of continuous electroencephalography (EEG) data during the acute phase compared with clinical risk factors currently used to predict PSE. METHODS: A prospective cohort of 81 patients with ischaemic stroke who received early continuous EEG monitoring was studied to assess the association of early EEG seizures, other highly epileptogenic rhythmic and periodic patterns, and regional attenuation without delta (RAWOD, an EEG pattern of stroke severity) with PSE. Clinical risk factors were investigated using the SeLECT (stroke severity; large-artery atherosclerosis; early clinical seizures; cortical involvement; territory of middle cerebral artery) scores. RESULTS: Twelve (15%) patients developed PSE. The presence of any of the investigated patterns was associated with a risk of epilepsy of 46%, with a sensitivity and specificity of 83% and 78%. The association remained significant after adjusting for the SeLECT score (odds ratio 18.8, interquartile range 3.8-72.7). CONCLUSIONS: It was found that highly epileptogenic rhythmic and periodic patterns and RAWOD were associated with the development of PSE and complemented clinical risk factors. These findings indicate that continuous EEG provides useful information to determine patients at higher risk of developing PSE and could help individualize care.

Diagnostic and therapeutic approaches in refractory insular epilepsy.

Due to heterogenous seizure semiology and poor contribution of scalp electroencephalography (EEG) signals, insular epilepsy requires use of the appropriate diagnostic tools for its diagnosis and characterization. The deep location of the insula also presents surgical challenges. The aim of this article is to review the current diagnostic and therapeutic tools and their contribution to the management of insular epilepsy. Magnetic resonance imaging (MRI), isotopic imaging, neurophysiological imaging, and genetic testing should be used and interpretated with caution. Isotopic imaging and scalp EEG have demonstrated a lower value in epilepsy from insular compared to temporal origin, which increases the interest of functional MRI and magnetoencephalography. Intracranial recording with stereo-electroencephalography (SEEG) is often required. The insular cortex, being highly connected and deeply located under highly functional areas, is difficult to reach, and its ablative surgery raises functional issues. Tailored resection based on SEEG or alternative curative treatments, such as radiofrequency thermocoagulation, laser interstitial thermal therapy, or stereotactic radiosurgery, have produced encouraging results. The management of insular epilepsy has benefited from major advances in the last years. Perspectives for diagnostic and therapeutic procedures will contribute to better management of this complex form of epilepsy.

Duration of nonconvulsive seizures in critically ill patients.

INTRODUCTION: Non-convulsive seizures (NCSz) and non-convulsive status epilepticus (NCSE) are frequent in critically ill patients. Specific temporal thresholds to define both are lacking and may be needed to guide appropriate treatment. METHOD: Retrospective review of 995 NCSz captured during continuous EEG monitoring of 111 consecutive critically ill patients. Seizures were classified according to their type and underlying etiology (acute or progressive brain injury, seizure-related disorders and acute medical illness). Median and interquartile ranges [IQR] were calculated. Suggested temporal threshold for NCSE was defined as the 95 percentile of seizure duration. RESULTS: Most (69%) patients had an underlying acute or progressive brain injury. The 95 percentile of seizure duration was 518 s, overall, with variation according to underlying etiology (median 86 [47-137] s for brain injury, 73 [45-115] s for seizure-related disorders, and 92 [58-223] s for acute medical illness, respectively; p = 0.0025; 95 percentile 424, 304, and 1725 s, respectively). Forty-one (37%) patients were comatose and had significantly longer seizures than non-comatose patients (median 99 [49-167] vs. 73 [46-123] s; p < 0.001; 95 percentile: 600 vs 444 s). CONCLUSION: To define NCSE, a temporal threshold of 10 min in critically ill patients with a primary neurological diagnosis can be applied, while a temporal threshold of 30 min might be suitable for patients with an underlying acute medical illness.

Respective Contribution of Ictal and Inter-ictal Electrical Source Imaging to Epileptogenic Zone Localization.

Interictal electrical source imaging (ESI) encompasses a risk of false localization due to complex relationships between irritative and epileptogenic networks. This study aimed to compare the localizing value of ESI derived from ictal and inter-ictal EEG discharges and to evaluate the localizing value of ESI according to three different subgroups: MRI lesion, presumed etiology and morphology of ictal EEG pattern. We prospectively analyzed 54 of 78 enrolled patients undergoing pre-surgical investigation for refractory epilepsy. Ictal and inter-ictal ESI results were interpreted blinded to- and subsequently compared with stereoelectroencephalography as a reference method. Anatomical concordance was assessed at a sub-lobar level. Sensitivity and specificity of ictal, inter-ictal and ictal plus inter-ictal ESI were calculated and compared according to the different subgroups. Inter-ictal and ictal ESI sensitivity (84% and 75% respectively) and specificity (38% and 50% respectively) were not statistically different. Regarding the sensitivity, ictal ESI was never higher than inter-ictal ESI. Regarding the specificity, ictal ESI was higher than inter-ictal ESI in malformations of cortical development (MCD) (60% vs. 43%) and in MRI positive patients (49% vs. 30%). Within the ictal ESI analysis, we showed a higher specificity for ictal spikes (59%) and rhythmic discharges > 13 Hz (50%) than rhythmic discharges < 13 Hz (37%) and (ii) for MCD (60%) than in other etiologies (29%). This prospective study demonstrates the relevance of a combined interpretation of distinct inter-ictal and ictal analysis. Inter-ictal analysis gave the highest sensitivity. Ictal analysis gave the highest specificity especially in patients with MCD or a lesion on MRI.

Electrical source imaging in cortical malformation-related epilepsy: a prospective EEG-SEEG concordance study.

OBJECTIVE: Delineation of the epileptogenic zone (EZ) in refractory epilepsy related to malformations of cortical development (MCDs) often requires intracranial electroencephalography (EEG) recordings, especially in cases of negative magnetic resonance imaging (MRI) or discordant MRI and video-EEG findings. It is therefore crucial to promote the development of noninvasive methods such as electrical source imaging (ESI). We aimed to (1) analyze the localization concordance of ESI derived from interictal discharges and EZ estimated by stereo-EEG (SEEG); (2) compare the concordance of ESI, MRI, and electroclinical correlations (ECCs) with SEEG-EZ; and (3) assess ESI added value in the EZ localization. METHODS: We prospectively analyzed 28 consecutive patients undergoing presurgical investigation for MCD-related refractory epilepsy in 2009-2012. ESI derived from 64-channel scalp EEG was interpreted with blinding to, and subsequently compared with, SEEG-estimated EZ. Anatomic concordance of ESI with SEEG-EZ was compared with that of video-EEG and MRI. We further assessed ESI added value to ECC and MRI. RESULTS: Twelve patients (43%) had temporal and 16 (57%) had extratemporal epilepsy. MRI was negative in 11 (39%) and revealed a cortical malformation in 17 (61%). ESI was fully concordant with the EZ in 10 (36%) and partly concordant in 15 (53%). ECC presented a full and partial concordance with EZ in 11% and 82% of cases, respectively, and MRI in 11% and 46%, respectively. Of 11 patients with negative MRI, ESI was fully concordant with the EZ in 7 (64%) and partly concordant in 4 (36%). ESI correctly confirmed restricted or added localizations to ECC and MRI in 12 (43%) of 28 patients and in 8 (73%) of 11 patients with negative MRI. SIGNIFICANCE: ESI contributes to estimating the EZ in MCD-related epilepsy. The added value of ESI to ECC is particularly high in patients with MCD and negative MRI, who represent the most challenging cases for epilepsy surgery. A PowerPoint slide summarizing this article is available for download in the Supporting Information section here.

Delayed effective connectivity characterizes the epileptogenic zone during stereo-EEG.

OBJECTIVE: Single-pulse electrical stimulations (SPES) can elicit normal and abnormal responses that might characterize the epileptogenic zone, including spikes, high-frequency oscillations and cortico-cortical evoked potentials (CCEPs). In this study, we investigate their association with the epileptogenic zone during stereoelectroencephalography (SEEG) in 28 patients with refractory focal epilepsy. METHODS: Characteristics of CCEPs (distance-corrected or -uncorrected latency, amplitude and the connectivity index) and the occurrence of spikes and ripples were assessed. Responses within the epileptogenic zone and within the non-involved zone were compared using receiver operating characteristics curves and analysis of variance (ANOVA) either in all patients, patients with well-delineated epileptogenic zone, and patients older than 15 years old. RESULTS: We found an increase in distance-corrected CCEPs latency after stimulation within the epileptogenic zone (area under the curve = 0.71, 0.72, 0.70, ANOVA significant after false discovery rate correction). CONCLUSIONS: The increased distance-corrected CCEPs latency suggests that neuronal propagation velocity is altered within the epileptogenic network. This association might reflect effective connectivity changes at cortico-cortical or cortico-subcortico-cortical levels. Other responses were not associated with the epileptogenic zone, including the CCEPs amplitude, the connectivity index, the occurrences of induced ripples and spikes. The discrepancy with previous descriptions may be explained by different spatial brain sampling between subdural and depth electrodes. SIGNIFICANCE: Increased distance-corrected CCEPs latency, indicating delayed effective connectivity, characterizes the epileptogenic zone. This marker could be used to help tailor surgical resection limits after SEEG.

Direct evidence of nonadherence to antiepileptic medication in refractory focal epilepsy.

The adherence to medication in drug-resistant focal epilepsy (RFE) remains largely unknown. The present work aimed to assess the frequency of recent adherence to antiepileptic drugs (AEDs) in patients with RFE. This prospective observational study screened all patients with RFE, admitted to the Nancy University Hospital between April 2006 and September 2008, for a 5-day hospitalization without AED tapering. The adherence to AEDs was assessed by measuring serum drug levels on day 1 (reflecting the recent "at home" adherence) and day 5 (reflecting the individual reference concentration when drug ingestion was supervised). A patient was considered nonadherent if at least one of their serum drug levels was different between days 1 and 5. The day-1 value was considered different from day 5 when it was at least 30% lower (underdosed) or 30% higher (overdosed). Nonadherent patients were classified as under-consumers in the case of one or more underdosed day-1 values, over-consumers in the case of one or more overdosed day-1 values, or undefined if they exhibited both underdosed and overdosed day-1 values. Forty-four of the 48 screened patients were included. Eighteen (40.9%) of 44 patients were nonadherent. Among them, 12 (66.7%) were over-consumers, 4 (22.2%) were under-consumers, and 2 (11.1%) were undefined nonadherents. The study indicates that recent adherence to antiepileptic medication in this group of patients with RFE is poor. Overconsumption is the most frequent form of nonadherence in this population and should be specifically assessed to prevent its possible consequences in terms of AEDs dose-dependent adverse events.

Functional neuroimaging of the reciprocal influences between sleep and wakefulness.

The activity patterns adopted by brain neuronal populations differ dramatically between wakefulness and sleep. However, these vigilance states are not independent and they reciprocally interact. Here, we provide evidence that in humans, regional brain activity during wakefulness is influenced by sleep regulation, namely by the interaction between sleep homeostasis and circadian signals. We also show that, by contrast, regional brain activity during sleep is influenced by the experience acquired during the preceding waking period. These data reveal the dynamic interactions by which the succession of vigilance states support normal brain function and human cognition.

Assessment of a standardized EEG reactivity protocol after cardiac arrest.

OBJECTIVE: Reactivity assessment during EEG might provide important prognostic information in post-anoxic coma. It is still unclear how best to perform reactivity testing and how it might be affected by hypothermia. Our primary aim was to determine and compare the effectiveness, inter-rater reliability and prognostic value of different types of stimulus for EEG reactivity testing, using a standardized stimulation protocol and standardized definitions. Our secondary aims were to assess the effect of hypothermia on these measures, and to determine the prognostic value of a simplified sequence with the three most efficient stimuli. METHODS: Prospective single-center cohort of post-anoxic comatose patients admitted to the intensive care unit of an academic medical center between January 1, 2016 and December 31, 2018 and receiving continuous EEG monitoring (CEEG). Reactivity was assessed using standardized definitions and standardized sequence of stimuli: auditory (mild noise and loud noise), tactile (shaking), nociceptive (nostril tickling, trapezius muscle squeezing, endotracheal tube suctioning), and visual (passive eye opening). Gwet's AC1 and percent agreement (PA) were used to measure inter-rater agreement (IRA). Ability to predict favorable neurological outcome (defined as a Cerebral Performance Category of 1 to 2: no disability to moderate disability) was measured with sensitivity (Se), specificity (Sp), accuracy, and odds ratio [OR]. These were calculated for each stimulus type and at the level of the entire sequence comprising all the stimuli. RESULTS: One-hundred and fifteen patients were included and 242 EEG epochs were analyzed. Loud noise, shaking and trapezius muscle squeezing most frequently elicited EEG reactivity (42%, 38% and 38%, respectively) but were all inferior to the entire sequence, which elicited reactivity in 58% cases. The IRA for reactivity to individual stimuli varied from moderate to good (AC1:58-69%; PA:56-68%) and was the highest for loud noise (AC1:69%; PA:68%), trapezius muscle squeezing (AC1:67%; PA:65%) and passive eye opening (AC1:68%; PA:64%). Mild (odds ratio [OR]:11.0; Se:70% and Sp:86%) and loud noises (OR:27.0; Se:73% and Sp:75%), and trapezius muscle squeezing (OR:15.3; Se:76% and Sp:83%) during hypothermia had the best predictive value for favorable neurological outcome, although each was inferior to the whole sequence (OR:60.2; Se:91% and Sp:73%). A simplified sequence of loud noise, shaking and trapezius muscle squeezing had the same performance for predicting neurological outcome as the entire sequence. Hypothermia did not significantly affect the effectiveness of stimulation, but IRA was slightly better during hypothermia, for all stimuli. Similarly, the predictive value was higher during hypothermia than during normothermia. CONCLUSIONS: Despite a standardized stimulation protocol and standardized definitions, the IRA of EEG reactivity testing in post-anoxic comatose patients was only good at best (AC1 < 70%), and its predictive value for neurological outcome remained imperfect, in particular with Sp values < 90%. While no single stimulus appeared superior to others, a full sequence using all stimuli or a simplified sequence comprising loud noise, shaking and trapezius muscle squeezing had the best combination of IRA and predictive value. SIGNIFICANCE: This study stresses the necessity to use multiple stimulus types to improve the predictive value of reactivity testing in post-anoxic coma and confirms that it is not affected by hypothermia.

Localizing value of electrical source imaging: Frontal lobe, malformations of cortical development and negative MRI related epilepsies are the best candidates.

OBJECTIVE: We aimed to prospectively assess the anatomical concordance of electric source localizations of interictal discharges with the epileptogenic zone (EZ) estimated by stereo-electroencephalography (SEEG) according to different subgroups: the type of epilepsy, the presence of a structural MRI lesion, the aetiology and the depth of the EZ. METHODS: In a prospective multicentric observational study, we enrolled 85 consecutive patients undergoing pre-surgical SEEG investigation for focal drug-resistant epilepsy. Electric source imaging (ESI) was performed before SEEG. Source localizations were obtained from dipolar and distributed source methods. Anatomical concordance between ESI and EZ was defined according to 36 predefined sublobar regions. ESI was interpreted blinded to- and subsequently compared with SEEG estimated EZ. RESULTS: 74 patients were finally analyzed. 38 patients had temporal and 36 extra-temporal lobe epilepsy. MRI was positive in 52. 41 patients had malformation of cortical development (MCD), 33 had another or an unknown aetiology. EZ was medial in 27, lateral in 13, and medio-lateral in 34. In the overall cohort, ESI completely or partly localized the EZ in 85%: full concordance in 13 cases and partial concordance in 50 cases. The rate of ESI full concordance with EZ was significantly higher in (i) frontal lobe epilepsy (46%; p = 0.05), (ii) cases of negative MRI (36%; p = 0.01) and (iii) MCD (27%; p = 0.03). The rate of ESI full concordance with EZ was not statistically different according to the depth of the EZ. SIGNIFICANCE: We prospectively demonstrated that ESI more accurately estimated the EZ in subgroups of patients who are often the most difficult cases in epilepsy surgery: frontal lobe epilepsy, negative MRI and the presence of MCD.

Guillain-Barré syndrome following hepatitis E.

Guillain-Barré syndrome (GBS) is often triggered by a preceding bacterial or viral infection. Occasionally, it has been observed in association with acute hepatitis A, B and C, and three cases have been previously described in India in which GBS was associated with acute hepatitis E. A molecular mimicry mechanism is supposed to be involved in the pathogenesis of GBS triggered by infectious agents, although the nature of the shared epitopes has not been characterized in most instances, including that in the case of hepatotropic viruses. We report a case of GBS following acute hepatitis E in a European individual. The presence of antiganglioside GM2 antibodies in this patient suggested molecular mimicry involving ganglioside GM2 in the pathogenesis of GBS associated with hepatitis E.