Mesial temporal lobe spiking reveals distinct patterns of blood oxygen level-dependent functional magnetic resonance imaging activation using simultaneous intracranial electroencephalography-functional magnetic resonance imaging.

OBJECTIVE: Temporal lobe epilepsy (TLE) has a high probability of becoming drug resistant and is frequently considered for surgical intervention. However, 30% of TLE cases have nonlesional magnetic resonance imaging (MRI) scans, which is associated with worse surgical outcomes. Characterizing interactions between temporal and extratemporal structures in these patients may help understand these poor outcomes. Simultaneous intracranial electroencephalography-functional MRI (iEEG-fMRI) can measure the hemodynamic changes associated with interictal epileptiform discharges (IEDs) recorded directly from the brain. This study was designed to characterize the whole brain patterns of IED-associated fMRI activation recorded exclusively from the mesial temporal lobes of patients with nonlesional TLE. METHODS: Eighteen patients with nonlesional TLE undergoing iEEG monitoring with mesial temporal IEDs underwent simultaneous iEEG-fMRI at 3 T. IEDs were marked, and statistically significant clusters of fMRI activation were identified. The locations of IED-associated fMRI activation for each patient were determined, and patients were grouped based on the location and pattern of fMRI activation. RESULTS: Two patterns of IED-associated fMRI activation emerged: primarily localized (n = 7), where activation was primarily located within the ipsilateral temporal lobe, and primarily diffuse (n = 11), where widespread bilateral extratemporal activation was detected. The primarily diffuse group reported significantly fewer focal to bilateral tonic-clonic seizures and had better postsurgical outcomes. SIGNIFICANCE: Simultaneous iEEG-fMRI can measure the hemodynamic changes associated with focal IEDs not visible on scalp EEG, such as those arising from the mesial temporal lobe. Significant fMRI activation associated with these IEDs was observed in all patients. Two distinct patterns of IED-associated activation were seen: primarily localized to the ipsilateral temporal lobe and more widespread, bilateral activation. Patients with widespread IED associated-activation had fewer focal to bilateral tonic-clonic seizures and better postsurgical outcome, which may suggest a neuroprotective mechanism limiting the spread of ictal events.

Interictal discharges in the human brain are travelling waves arising from an epileptogenic source.

While seizure activity may be electrographically widespread, increasing evidence has suggested that ictal discharges may in fact represent travelling waves propagated from a focal seizure source. Interictal epileptiform discharges (IEDs) are an electrographic manifestation of excessive hypersynchronization of cortical activity that occur between seizures and are considered a marker of potentially epileptogenic tissue. The precise relationship between brain regions demonstrating IEDs and those involved in seizure onset, however, remains poorly understood. Here, we hypothesize that IEDs likewise reflect the receipt of travelling waves propagated from the same regions which give rise to seizures. Forty patients from our institution who underwent invasive monitoring for epilepsy, proceeded to surgery and had at least one year of follow-up were included in our study. Interictal epileptiform discharges were detected using custom software, validated by a clinical epileptologist. We show that IEDs reach electrodes in sequences with a consistent temporal ordering, and this ordering matches the timing of receipt of ictal discharges, suggesting that both types of discharges spread as travelling waves. We use a novel approach for localization of ictal discharges, in which time differences of discharge receipt at nearby electrodes are used to compute source location; similar algorithms have been used in acoustics and geophysics. We find that interictal discharges co-localize with ictal discharges. Moreover, interictal discharges tend to localize to the resection territory in patients with good surgical outcome and outside of the resection territory in patients with poor outcome. The seizure source may originate at, and also travel to, spatially distinct IED foci. Our data provide evidence that interictal discharges may represent travelling waves of pathological activity that are similar to their ictal counterparts, and that both ictal and interictal discharges emerge from common epileptogenic brain regions. Our findings have important clinical implications, as they suggest that seizure source localizations may be derived from interictal discharges, which are much more frequent than seizures.

Slow wave sleep is associated with forgetting in patients with temporal lobe epilepsy.

While time spent in slow wave sleep (SWS) after learning promotes memory consolidation in the healthy brain, it is unclear if the same benefit is obtained in patients with temporal lobe epilepsy (TLE). Interictal epileptiform discharges (IEDs) are potentiated during SWS and thus may disrupt memory consolidation processes thought to depend on hippocampal-neocortical interactions. Here, we explored the relationship between SWS, IEDs, and overnight forgetting in patients with TLE. Nineteen patients with TLE studied object-scene pairs and memory was tested across a day of wakefulness (6 hrs) and across a night of sleep (16 hrs) while undergoing continuous scalp EEG monitoring. We found that time spent in SWS after learning was related to greater forgetting overnight. Longer duration in SWS and number of IEDs were each associated with greater forgetting, although the number of IEDs did not mediate the relationship between SWS and memory. Further research, particularly with intracranial recordings, is required to identify the mechanisms by which SWS and IEDs can be pathological to sleep-dependent memory consolidation in patients with TLE.

Identification and classification of pathology and artifacts for human intracranial cognitive research.

Intracranial electroencephalography (iEEG) presents a unique opportunity to extend human neuroscientific understanding. However, typically iEEG is collected from patients diagnosed with focal drug-resistant epilepsy (DRE) and contains transient bursts of pathological activity. This activity disrupts performances on cognitive tasks and can distort findings from human neurophysiology studies. In addition to manual marking by a trained expert, numerous IED detectors have been developed to identify these pathological events. Even so, the versatility and usefulness of these detectors is limited by training on small datasets, incomplete performance metrics, and lack of generalizability to iEEG. Here, we employed a large annotated public iEEG dataset from two institutions to train a random forest classifier (RFC) to distinguish data segments as either 'non-cerebral artifact' (n = 73,902), 'pathological activity' (n = 67,797), or 'physiological activity' (n = 151,290). We found our model performed with an accuracy of 0.941, specificity of 0.950, sensitivity of 0.908, precision of 0.911, and F1 score of 0.910, averaged across all three event types. We extended the generalizability of our model to continuous bipolar data collected in a task-state at a different institution with a lower sampling rate and found our model performed with an accuracy of 0.789, specificity of 0.806, and sensitivity of 0.742, averaged across all three event types. Additionally, we created a custom graphical user interface to implement our classifier and enhance usability.

Latencies to the first interictal epileptiform discharges recorded by the electroencephalography in different epileptic patients.

PURPOSE: Interictal epileptiform discharges (IEDs) captured in electroencephalography (EEG) have a high diagnostic value for epileptic patients. Extending the recording time may increase the possibility of obtaining IEDs. The purpose of our research was to determine how long it took for various epileptic individuals to receive their first IEDs. METHODS: We retrospectively analyzed patients who were diagnosed with epilepsy and had no anti-seizure medications (ASMs) between September 2018 and March 2019 in the neurology department of the First Affiliated Hospital of Xi'an Jiaotong University. Each individual underwent a 24-h long-term video electroencephalographic monitoring (VEM) procedure. Clinical information including age, gender, age of seizure onset, frequency of seizures, the interval between last seizure and VEM, and results of neuroimaging were gathered. We also calculated the times from the start of the VEM to the first definite IEDs. RESULTS: A total of 241 patients were examined, including 191 with focal-onset epilepsy and 50 with generalized epilepsy. In individuals with focal-onset epilepsy, the median latency to the first IED was 63.0 min (IQR 19.0-299.0 min), as compared to 30.0 min (IQR 12.5-62.0 min) in patients with generalized epilepsy (p < 0.001). The latency to the first IED is significantly related to the age of seizure onset (HR = 0.988, p = 0.049), the interval between last seizure and VEM (HR = 0.998, p = 0.013). But it is not correlated with seizure frequency, gender and age. CONCLUSIONS: IEDs were discovered during 24-h EEG monitoring in 222/241(92.1%) of the epilepsy patients that were included. Compared to focal-onset epilepsy, generalized epilepsy demonstrated a much shorter latency to IED. Patients with late-onset epilepsy or those without recent episodes may require longer EEG monitoring periods.

Association between subclinical epileptiform discharge and the behavioral and psychological symptoms in patients with Alzheimer's dementia.

OBJECTIVES: Behavioral and psychological symptoms of dementia (BPSD) are highly prevalent in patients with Alzheimer's disease (AD), causing burdens on caregivers. Behavioral and psychological symptoms of dementia and subclinical epileptiform discharge (SED) increased with the disease course of AD. However, the interaction between them was still unknown. The present study aimed to evaluate the associations between SED and BPSD. METHODS/DESIGN: Patients with AD from Kaohsiung Municipal Ta-tung Hospital were included in this study. International 10-20 system scalp electroencephalography (EEG) for 13 min was performed to detect SED. Behavioral and psychological symptoms of dementia was assessed by neuropsychiatric inventory (NPI) questionnaires. The occurrence of BPSD subsyndromes was compared between patients with and without SED. RESULTS: Two hundred sixty-three adult patients qualified for the inclusion criteria and were enrolled in this study. The mean age of patients was 80.2 years, and approximately 62% were women. 17.1% of patients showed SED on EEG. Apathy was the most commonly reported BPSD subsyndrome in this cohort. There was no significant difference in the prevalence of BPSD between patients with and without SED. (75.6% vs. 67.4%, p = 0.2806). However, the NPI score of irritability subsyndrome was significantly higher in the SED (+) group (2.6 ± 3.7 vs. 1.2 ± 2.7, p = 0.0028). In addition, subclinical epileptiform discharge in the frontal lobe was associated with a considerably higher occurrence of hyperactivity subsyndrome, including irritability. CONCLUSIONS: SED may not be a direct cause of BPSD, but the presence of SED may affect the manifestation of BPSD.

Delta oscillation coupled propagating fast ripples precede epileptiform discharges in patients with focal epilepsy.

Epileptiform spikes are used to localize epileptogenic brain tissue. The mechanisms that spontaneously trigger epileptiform discharges are not yet elucidated. Pathological fast ripple (FR, 200-600 Hz) are biomarkers of epileptogenic brain, and we postulated that FR network interactions are involved in generating epileptiform spikes. Using macroelectrode stereo intracranial EEG (iEEG) recordings from a cohort of 46 patients we found that, in the seizure onset zone (SOZ), propagating FR were more often followed by an epileptiform spike, as compared with non-propagating FR (p < 0.05). Propagating FR had a distinct frequency and larger power (p < 1e-10) and were more strongly phase coupled to the peak of iEEG delta oscillation, which likely correspond with the DOWN states during non-REM sleep (p < 1e-8), than non-propagating FR. While FR propagation was rare, all FR occurred with the highest probability within +/- 400 msec of epileptiform spikes with superimposed high-frequency oscillations (p < 0.05). Thus, a sub-population of epileptiform spikes in the SOZ, are preceded by propagating FR that are coordinated by the DOWN state during non-REM sleep.

miR-139-5p upregulation alleviated spontaneous recurrent epileptiform discharge-induced oxidative stress and apoptosis in rat hippocampal neurons via regulating the Notch pathway.

Epilepsy was characterized by the occurrence of spontaneous recurrent epileptiform discharges (SREDs) in neurons. Previous studies suggested that microRNA (miR)-139-5p and the Notch pathway were implicated in epilepsy; however, their interaction remained vague. Rat primary hippocampal neurons were isolated and identified by immunofluorescence staining. The cells were then used for SREDs model construction and further subjected to flow cytometry for apoptosis detection. Contents of lactate dehydrogenase (LDH), malondialdehyde (MDA), super oxidase dismutase (SOD) contents, and reactive oxygen species (ROS), and the level of mitochondrial membrane potential (MMP) were determined using commercial kits. Target gene and potential binding sites of miR-139-5p were predicted with TargetScan and confirmed by dual-luciferase reporter assay. Expressions of miR-139-5p, Notch pathway-related proteins and apoptosis-related proteins were measured by quantitative real-time polymerase chain reaction and western blot as needed. The results showed that the hippocampal neurons were microtubule-associated protein 2 (MAP2)-positive. miR-139-5p was downregulated in SREDs model cells. SREDs promoted apoptosis and increased the contents of LDH, MDA, and ROS and the level of MMP while reducing miR-139-5p expression and SOD content in cells, which was reversed by miR-139-5p overexpression. Notch-1 was recognized as the target gene of miR-139-5p, and its expression was negatively regulated by miR-139-5p. Besides, Notch-1 overexpression reversed the effects of miR-139-5p upregulation on the expressions of Notch pathway-related proteins and apoptosis-related proteins, cell apoptosis, oxidative stress and MMP in SREDs-treated cells. Our results indicated that miR-139-5p upregulation alleviated SREDs-induced oxidative stress and cell apoptosis via regulating the Notch pathway, which provides new insights into the role of miRNA in the occurrence and development of epilepsy.

The role of interictal discharges in ictogenesis - A dynamical perspective.

Interictal epileptiform discharge (IED) is a traditional hallmark of epileptic tissue that is generated by the synchronous activity of a population of neurons. Interictal epileptiform discharges represent a heterogeneous group of pathological activities that differ in shape, duration, spatiotemporal distribution, underlying cellular and network mechanisms, and their relationship to seizure genesis. The exact role of IEDs in epilepsy is still not well understood, and there remains a persistent dichotomy about the impact on IEDs on seizures. Proseizure, antiseizure, and no impact on ictogenesis have all been described in previous studies. In this article, we review the existing knowledge on the role of interictal discharges in seizure genesis, and we discuss how dynamical approaches to ictogenesis can explain the existing dichotomy about the multifaceted role of IEDs in ictogenesis. This article is part of the Special Issue "NEWroscience 2018".

Interictal epileptiform discharges shape large-scale intercortical communication.

Dynamic interactions between remote but functionally specialized brain regions enable complex information processing. This intercortical communication is disrupted in the neural networks of patients with focal epilepsy, and epileptic activity can exert widespread effects within the brain. Using large-scale human intracranial electroencephalography recordings, we show that interictal epileptiform discharges (IEDs) are significantly coupled with spindles in discrete, individualized brain regions outside of the epileptic network. We found that a substantial proportion of these localized spindles travel across the cortical surface. Brain regions that participate in this IED-driven oscillatory coupling express spindles that have a broader spatial extent and higher tendency to propagate than spindles occurring in uncoupled regions. These altered spatiotemporal oscillatory properties identify areas that are shaped by epileptic activity independent of IED or seizure detection. Our findings suggest that IED-spindle coupling may be an important mechanism of interictal global network dysfunction that could be targeted to prevent disruption of normal neural activity.

Diagnostic yield of seizure recordings and neuroimaging in patients with focal epilepsy without interictal epileptiform discharges.

OBJECTIVE: Repeated routine electroencephalography (EEG) or even long-term video-EEG monitoring (VEM) does not always record interictal epileptiform discharges (IEDs) in some patients with epilepsy. The present study investigated whether focal seizures detected by VEM and focal abnormalities on neuroimaging are useful for the diagnosis of patients with focal epilepsy without IEDs. METHODS: We retrospectively reviewed 409 consecutive patients with focal epilepsy (207 men, aged 9 to 76 years) who underwent 4- or 5-day VEM, magnetic resonance imaging (MRI), and fluorine-18-fluorodeoxyglucose positron emission tomography (FDG-PET) for diagnosis to identify patients without IEDs. The occurrence of focal seizures during VEM and the presence of focal abnormalities on neuroimaging were investigated in those patients. The occurrence rate of seizures during VEM was investigated in patients with daily, weekly, monthly, and yearly seizure frequency based on history-taking. RESULTS: Ninety-five (23.2%) of 409 patients with focal epilepsy did not have IEDs. Fifty-five (57.9%) of the 95 patients had focal seizures during VEM. Fifty-four patients (56.8%) showed focal abnormalities compatible with seizure semiology on neuroimaging investigations. Neither seizure recordings nor neuroimaging abnormalities were seen in 16 (16.8%) of the 95 patients. The occurrence rate of seizures during VEM depended on the seizure frequency at history-taking. However, 28 (45.9%) of 61 patients with monthly and yearly seizure frequency had focal seizures during 4- or 5-day VEM with seizure induction. CONCLUSIONS: Video-EEG monitoring can detect focal seizures in patients with focal epilepsy but no IEDs. Comprehensive assessment including VEM and neuroimaging study is important for the diagnosis.

Anti-epileptic drugs improved serial 7s scores on the Mini-Mental State Examination in elderly with cognitive impairment and epileptiform discharge on electroencephalography.

AIM: As the population ages, epilepsy among elderly people is increasing. Epileptic seizures in the elderly are mostly complex partial seizures without convulsions, so more caution is needed in the diagnosis of epilepsy. If epileptic seizures in the context of memory impairment are overlooked, epilepsy may be misdiagnosed as dementia. However, in older patients with epilepsy, there is a possibility that cognitive function may be impaired in the interictal phase. This study aims to investigate the efficacy of anti-epileptic drug (AED) treatment for patients with cognitive impairment and interictal epileptiform discharge (IED) on electroencephalography. METHODS: The outcome of AED administration in 50 patients who exhibited IED was retrospectively investigated. Their cognitive functions were assessed by the Mini-Mental State Examination (MMSE) at both baseline and after AED administration. RESULTS: In all patients who underwent electroencephalography, IED were temporal spikes, and re-examination of the 50 patients revealed that the frequency of temporal spikes had decreased or else disappeared in 41 patients (82%) after AED administration. In these 41 patients, the mean MMSE score significantly increased from 23.4 ± 3.7 at baseline to 24.7 ± 4.8 after AED treatment (P <0.01). Similarly, the mean serial 7s score (MMSE subscale) also improved significantly from 2.5 ± 1.8 to 3.6 ± 1.6 (P <0.01). The MMSE score was significantly improved only in the 41 patients with recovery of IED. CONCLUSION: AED treatment for elderly amnestic patients with temporal spikes was effective in improving cognitive decline and related electroencephalographic abnormalities. A more thorough search of IED is necessary in elderly amnesic patients because there is a possibility that IED modifies cognitive function.

Ripple oscillations in the left temporal neocortex are associated with impaired verbal episodic memory encoding.

BACKGROUND: We sought to determine if ripple oscillations (80-120 Hz), detected in intracranial electroencephalogram (iEEG) recordings of patients with epilepsy, correlate with an enhancement or disruption of verbal episodic memory encoding. METHODS: We defined ripple and spike events in depth iEEG recordings during list learning in 107 patients with focal epilepsy. We used logistic regression models (LRMs) to investigate the relationship between the occurrence of ripple and spike events during word presentation and the odds of successful word recall following a distractor epoch and included the seizure onset zone (SOZ) as a covariate in the LRMs. RESULTS: We detected events during 58,312 word presentation trials from 7630 unique electrode sites. The probability of ripple on spike (RonS) events was increased in the SOZ (p < 0.04). In the left temporal neocortex, RonS events during word presentation corresponded with a decrease in the odds ratio (OR) of successful recall, however, this effect only met significance in the SOZ (OR of word recall: 0.71, 95% confidence interval (CI): 0.59-0.85, n = 158 events, adaptive Hochberg, p < 0.01). Ripple on oscillation (RonO) events that occurred in the left temporal neocortex non-SOZ also correlated with decreased odds of successful recall (OR: 0.52, 95% CI: 0.34-0.80, n = 140, adaptive Hochberg, p < 0.01). Spikes and RonS that occurred during word presentation in the left middle temporal gyrus (MTG) correlated with the most significant decrease in the odds of successful recall, irrespective of the location of the SOZ (adaptive Hochberg, p < 0.01). CONCLUSION: Ripples and spikes generated in the left temporal neocortex are associated with impaired verbal episodic memory encoding. Although physiological and pathological ripple oscillations were not distinguished during cognitive tasks, our results show an association of undifferentiated ripples with impaired encoding. The effect was sometimes specific to regions outside the SOZ, suggesting that widespread effects of epilepsy outside the SOZ may contribute to cognitive impairment.

Cortical spreading depolarizations in the postresuscitation period in a cardiac arrest male rat model.

Neurological injury develops over days following cardiac arrest (CA); however, the exact mechanisms remain unknown. After stroke or trauma, the progression of neurological injury is associated with cortical-spreading depolarizations (CSDs). The objective was to investigate whether CA and subsequent resuscitation in rats are associated with 1) the development of spontaneous negative direct current (DC) shifts indicative of CSDs, and 2) changes in artificially induced CSDs in the postresuscitation period. Male Sprague-Dawley rats were randomized into four groups: 1) CA 90, 2) Control 90, 3) CA 360, and 4) Control 360. Following 8 min of asphyxial CA, animals were resuscitated using adrenaline, ventilation, and chest compressions. Animals were observed for 90 or 360 min, respectively, before a 210-min data collection period. Cortical potentials were recorded through burr holes over the right hemisphere. Animals were intubated and monitored with invasive blood pressure, ECG, and arterial blood gas samples throughout the study. Spontaneous DC shifts occurred in only 1 of the 14 CA animals. In control animals, DC shifts were easy to induce, and their shape was highly uniform, consistent with that of classical CSDs. In CA animals, significantly fewer DC shifts could be induced, and their shape was profoundly altered compared with controls. We observed frequent epileptiform discharges and temporal clusters of activity. Spontaneous CSDs were not a consistent finding in CA animals. Instead, spontaneous epileptiform discharges and temporal cluster of activity were observed, while the shapes of induced DC shifts were profoundly altered compared with controls. © 2017 Wiley Periodicals, Inc.

Ripples on spikes show increased phase-amplitude coupling in mesial temporal lobe epilepsy seizure-onset zones.

OBJECTIVE: Ripples (80-150 Hz) recorded from clinical macroelectrodes have been shown to be an accurate biomarker of epileptogenic brain tissue. We investigated coupling between epileptiform spike phase and ripple amplitude to better understand the mechanisms that generate this type of pathologic ripple (pRipple) event. METHODS: We quantified phase amplitude coupling (PAC) between epileptiform electroencephalography (EEG) spike phase and ripple amplitude recorded from intracranial depth macroelectrodes during episodes of sleep in 12 patients with mesial temporal lobe epilepsy. PAC was determined by (1) a phasor transform that corresponds to the strength and rate of ripples coupled with spikes, and a (2) ripple-triggered average to measure the strength, morphology, and spectral frequency of the modulating and modulated signals. Coupling strength was evaluated in relation to recording sites within and outside the seizure-onset zone (SOZ). RESULTS: Both the phasor transform and ripple-triggered averaging methods showed that ripple amplitude was often robustly coupled with epileptiform EEG spike phase. Coupling was found more regularly inside than outside the SOZ, and coupling strength correlated with the likelihood a macroelectrode's location was within the SOZ (p < 0.01). The ratio of the rate of ripples coupled with EEG spikes inside the SOZ to rates of coupled ripples in non-SOZ was greater than the ratio of rates of ripples on spikes detected irrespective of coupling (p < 0.05). Coupling strength correlated with an increase in mean normalized ripple amplitude (p < 0.01), and a decrease in mean ripple spectral frequency (p < 0.05). SIGNIFICANCE: Generation of low-frequency (80-150 Hz) pRipples in the SOZ involves coupling between epileptiform spike phase and ripple amplitude. The changes in excitability reflected as epileptiform spikes may also cause clusters of pathologically interconnected bursting neurons to grow and synchronize into aberrantly large neuronal assemblies.

Is it time for individualized testing in the electroencephalogram (EEG) laboratory?

BACKGROUND AND PURPOSE: The interictal electroencephalogram (EEG) has an important role in the classification and treatment of epilepsy. In busy EEG laboratories, valuable resources are used in order to comply with current recommendations regarding the length of EEG recordings. Our aim was to examine the time to first interictal epileptiform discharge (IED) in standard and sleep-deprived EEGs. METHODS: Standard and sleep-deprived EEG recordings with IEDs were retrospectively reviewed during a 2-year period. Bedside EEGs and long-term video-EEGs were excluded. IED latency according to EEG type, age group and inpatient/outpatient status was analyzed with the Kaplan-Meier estimator. RESULTS: The study group included 684 patients, 372 (54%) males, aged 0.2-89 years. Standard (n = 316) and sleep-deprived (n = 368) EEGs were performed in 245 inpatients and 439 outpatients. The EEG was requested in 96% of the inpatients following a seizure. Most IEDs were recorded whilst the patients were awake (43%) or drowsy (34%). Ninety percent of the IEDs were recorded within 18.5 min, earlier in standard (14.6 vs. 21.3 min) (P = 0.024) EEGs and in inpatients (14 vs. 21.3 min) (P = 0.002). IED latency was unaffected by age. CONCLUSIONS: Electroencephalogram type and admission status may be used for individual determination of the duration of EEG recording. Reducing the duration of standard and sleep-deprived EEGs may be considered especially in inpatients.

Epilepsy beyond seizures: Predicting enduring cognitive dysfunction in genetic generalized epilepsies.

Reduced cognitive functioning has been documented in the genetic generalized epilepsies (GGE). Among a number of hypothesized causal mechanisms, some evidence from other epilepsy syndromes suggests the impact of epileptiform discharges. This study investigates the relationship between cognitive function in GGE and burden of epileptiform discharges within a 24-hour EEG recording, controlling for variables relevant to cognitive function in epilepsy. As part of a larger prospective cohort study, 69 patients with EEG-confirmed GGE (11-58years) underwent 24-hour EEG and detailed neuropsychological assessment using the Woodcock Johnson III Tests. Ten-second pages of the EEG were marked manually page-by-page on longitudinal bipolar montage with 0.5 to 70Hz bandwidth by an experienced EEG reader. Multiple regression analyses were conducted. Epileptiform discharges were detected in 90% of patients. Less than 0.01% of electrophysiological events of two or more seconds were recognized by patients. Regression analysis demonstrated that the cumulative duration of epileptiform discharges over a 24-hour period predicted overall cognitive ability and memory function, accounting for 9.6% and 11.8% of adjusted variance, respectively. None of the epilepsy covariates included in multiple regression analysis added significantly to the model. Duration of epileptiform discharges negatively predicts overall cognitive ability and memory function, even after accounting for other known determinants of cognition. Prolonged epileptiform discharges are common and remain unreported by patients, raising important questions regarding the management of GGE syndromes and their associated comorbidities. Further research is required to investigate causal mechanisms if we are to improve cognitive outcomes in this common group of epilepsies.

Patient specific hemodynamic response functions associated with interictal discharges recorded via simultaneous intracranial EEG-fMRI.

Simultaneous collection of scalp EEG and fMRI has become an important tool for studying the hemodynamic changes associated with interictal epileptiform discharges (IEDs) in persons with epilepsy, and has become a standard presurgical assessment tool in some centres. We previously demonstrated that performing EEG-fMRI using intracranial electrodes (iEEG-fMRI) is of low risk to patients in our research centre, and offers unique insight into BOLD signal changes associated with IEDs recorded from very discrete sources. However, it is unknown whether the BOLD response corresponding to IEDs recorded by iEEG-fMRI follows the canonical hemodynamic response. We therefore scanned 11 presurgical epilepsy patients using iEEG-fMRI, and assessed the hemodynamic response associated with individual IEDs using two methods: assessment of BOLD signal changes associated with isolated IEDs at the location of the active intracranial electrode, and by estimating subject-specific impulse response functions to isolated IEDs. We found that the hemodynamic response associated with the intracranially recorded discharges varied by patient and by spike location. The observed shape and timing differences also deviated from the canonical hemodynamic response function traditionally used in many fMRI experiments. It is recommended that future iEEG-fMRI studies of IEDs use a flexible hemodynamic response model when performing parametric tests to accurately characterize these data.

Recurrent nonconvulsive status epilepticus in a patient with progressive left hemispheric leukoencephalopathy after a remote viral meningoencephalitis.

Nonconvulsive status epilepticus (NCSE), defined as changes in behavior and/or mental processes from baseline with continuous epileptiform discharges, remains a diagnostic and treatment challenge. Here, we present a 68-year-old female who developed 3 episodes of NCSE 10 years after a viral meningoencephalitis which gradually progressed to left hemispheric leukoencephalopathy. In this case, we hypothesize that immune-mediated mechanisms and perhaps genetic predisposition played a role in epileptogenesis, and these will be discussed. This article is part of a Special Issue entitled "Status Epilepticus".

Epileptogenesis after traumatic brain injury in Plau-deficient mice.

Several components of the urokinase-type plasminogen activator receptor (uPAR)-interactome, including uPAR and its ligand sushi-repeat protein 2, X-linked (SRPX2), are linked to susceptibility to epileptogenesis in animal models and/or humans. Recent evidence indicates that urokinase-type plasminogen activator (uPA), a uPAR ligand with focal proteinase activity in the extracellular matrix, contributes to recovery-enhancing brain plasticity after various epileptogenic insults such as traumatic brain injury (TBI) and status epilepticus. Here, we examined whether deficiency of the uPA-encoding gene Plau augments epileptogenesis after TBI. Traumatic brain injury was induced by controlled cortical impact in the somatosensory cortex of adult male wild-type and Plau-deficient mice. Development of epilepsy and seizure susceptibility were assessed with a 3-week continuous video-electroencephalography monitoring and a pentylenetetrazol test, respectively. Traumatic brain injury-induced cortical or hippocampal pathology did not differ between genotypes. The pentylenetetrazol test revealed increased seizure susceptibility after TBI (p<0.05) in injured mice. Epileptogenesis was not exacerbated, however, in Plau-deficient mice. Taken together, Plau deficiency did not worsen controlled cortical impact-induced brain pathology or epileptogenesis caused by TBI when assessed at chronic timepoints. These data expand previous observations on Plau deficiency in models of status epilepticus and suggest that inhibition of focal extracellular proteinase activity resulting from uPA-uPAR interactions does not modify epileptogenesis after TBI.