Auditory aura in frontal opercular epilepsy: sounds from afar.

Auditory auras are typically considered to localize to the temporal neocortex. Herein, we present two cases of frontal operculum/perisylvian epilepsy with auditory auras. Following a non-invasive evaluation, including ictal SPECT and magnetoencephalography, implicating the frontal operculum, these cases were evaluated with invasive monitoring, using stereoelectroencephalography and subdural (plus depth) electrodes, respectively. Spontaneous and electrically-induced seizures showed an ictal onset involving the frontal operculum in both cases. A typical auditory aura was triggered by stimulation of the frontal operculum in one. Resection of the frontal operculum and subjacent insula rendered one case seizure- (and aura-) free. From a hodological (network) perspective, we discuss these findings with consideration of the perisylvian and insular network(s) interconnecting the frontal and temporal lobes, and revisit the non-invasive data, specifically that of ictal SPECT.

Ictal single photon emission computed tomography in epileptic auras.

OBJECTIVES: Little is known about whether ictal single photon emission computed tomography (SPECT) during an isolated aura can localize the epileptogenic zone (EZ). This study seeks to evaluate the yield of ictal SPECT injection in isolated epileptic auras. METHODS: We identified 20 patients with focal epilepsy studied during 26 isolated auras by ictal interictal subtraction SPECT coregistered to magnetic resonance imaging (SISCOM). Studies were rated by two readers who blindly scored the images for presence or absence of an area of dominant hyperperfusion and the lateralization and localization of ictal hyperperfusion; kappa statistics were calculated. Results are correlated with the localization or lateralization of the EZ, time of injection, and electroencephalography (EEG) findings during aura. RESULTS: Fourteen (53%) of 26 injections in 13 patients were rated by both readers as having an area of dominant hyperperfusion with poor interobserver agreement (k = 0.128). Nine of 26 injections in eight patients were correctly lateralized to the side of the EZ (κ = 0.46), but only one of 21 injections in one patient was correctly localized (κ = 0.146). No difference was found when comparing temporal and extratemporal cases. Studies obtained in auras with ictal EEG change were no more likely to be correctly localized than in ones without (p = 0.19). The timing of injection was not a predictor of success. SIGNIFICANCE: Ictal SPECT injection during an isolated aura has a low yield of correct localization of the EZ and cannot be relied on alone during presurgical evaluation. A repeat injection during a seizure with clinical signs and ictal EEG accompaniment is recommended.

Ripple classification helps to localize the seizure-onset zone in neocortical epilepsy.

PURPOSE: Fast ripples are reported to be highly localizing to the epileptogenic or seizure-onset zone (SOZ) but may not be readily found in neocortical epilepsy, whereas ripples are insufficiently localizing. Herein we classified interictal neocortical ripples by associated characteristics to identify a subtype that may help to localize the SOZ in neocortical epilepsy. We hypothesize that ripples associated with an interictal epileptiform discharge (IED) are more pathologic, since the IED is not a normal physiologic event. METHODS: We studied 35 patients with epilepsy with neocortical epilepsy who underwent invasive electroencephalography (EEG) evaluation by stereotactic EEG (SEEG) or subdural grid electrodes. Interictal fast ripples and ripples were visually marked during slow-wave sleep lasting 10-30 min. Neocortical ripples were classified as type I when superimposed on epileptiform discharges such as paroxysmal fast, spike, or sharp wave, and as type II when independent of epileptiform discharges. KEY FINDINGS: In 21 patients with a defined SOZ, neocortical fast ripples were detected in the SOZ of only four patients. Type I ripples were detected in 14 cases almost exclusively in the SOZ or primary propagation area (PP) and marked the SOZ with higher specificity than interictal spikes. In contrast, type II ripples were not correlated with the SOZ. In 14 patients with two or more presumed SOZs or nonlocalizable onset pattern, type I but not type II ripples also occurred in the SOZs. We found the areas with only type II ripples outside of the SOZ (type II-O ripples) in SEEG that localized to the primary motor cortex and primary visual cortex. SIGNIFICANCE: Neocortical fast ripples and type I ripples are specific markers of the SOZ, whereas type II ripples are not. Type I ripples are found more readily than fast ripples in human neocortical epilepsy. Type II-O ripples may represent spontaneous physiologic ripples in the human neocortex.

Intractable focal epilepsy contralateral to the side of facial atrophy in Parry-Romberg syndrome.

We report an unusual case of Parry-Romberg syndrome in which medically refractory focal epilepsy with ongoing epilepsia partialis continua (EPC) arose from the hemisphere contralateral to the side of facial atrophy. Unilateral cerebral involvement was confirmed by multi-modal brain imaging, as well as by electroencephalography (EEG) and magnetoencephalography (MEG). While in many cases of Parry-Romberg syndrome, the side of cerebral involvement is ipsilateral to that of the cutaneous lesion, these "discordant" exceptions imply that other yet undefined mechanisms may be responsible for the distribution of the cutaneous and cerebral pathologies.

Ictal biting injuries in the epilepsy monitoring unit, a cohort study of incidence and semiological significance.

PURPOSE: Oral biting injuries are widely recognized complications of seizures. Value in differentiating epileptic vs paroxysmal non-epileptic seizures is well demonstrated, but frequency and semiological value are poorly described. We aimed to evaluate frequency in an epilepsy monitoring unit setting as well as semiological value. MATERIAL AND METHODS: Systematic evaluation of ictal oral injuries was provided by the nursing staff on the Epilepsy Monitoring Unit. Cases were identified by chart review. Demographic, diagnostic and seizure-related data were collected from medical records and video-EEG recording, and correlated with location of tongue laceration. Lateralized oral lacerations while recumbent were further analyzed to eliminate contribution of body position. RESULTS: 89 events were reported in 52 individuals (5.6% of all admissions or 8.3% of patients with epileptic seizures). Lacerations occurred in 88 epileptic seizures (80 generalized, three focal, five undetermined) and one non-epileptic seizure. 87/88 had a tonic component and 86/88 had a clonic component. Lateralized tongue laceration occurred in 30 patients. This correlated with body position during the event but not with handedness or seizure characteristics. CONCLUSIONS: Oral biting is a common complication in the epilepsy monitoring unit. Its presence suggests a tonic or clonic component but is of no help in localizing seizure onset.

Bim regulation may determine hippocampal vulnerability after injurious seizures and in temporal lobe epilepsy.

Programmed cell death pathways have been implicated in the mechanism by which neurons die following brief and prolonged seizures, but the significance of proapoptotic Bcl-2 family proteins in the process remains poorly defined. Expression of the death agonist Bcl-2-interacting mediator of cell death (Bim) is under the control of the forkhead in rhabdomyosarcoma (FKHR) transcription factors. This prompted us to examine the response of this pathway to experimental seizures and in hippocampi from patients with intractable temporal lobe epilepsy. A short period of status epilepticus in rats that damaged the hippocampus activated FKHR/FKHRL-1 and induced a significant increase in expression of Bim. Blocking of FKHR/FKHRL-1 dephosphorylation after seizures improved hippocampal neuronal survival in vivo, and Bim antisense oligonucleotides were neuroprotective against seizures in vitro. Inhibition of Akt increased the FKHR/Bim response and DNA fragmentation within the normally resistant cortex. Analysis of hippocampi from patients with intractable epilepsy revealed that Bim levels were significantly lower than in controls and FKHR was inhibited; we were able to reproduce these results experimentally in rats by evoking multiple brief, noninjurious electroshock seizures. We conclude that Bim expression may be a critical determinant of whether seizures damage the brain, and that its control may be neuroprotective in status epilepticus and epilepsy.

Interictal ripples nested in epileptiform discharge help to identify the epileptogenic zone in neocortical epilepsy.

OBJECTIVE: This study aimed to identify the subtype of interictal ripples that help delineate the epileptogenic zone in neocortical epilepsy. METHODS: Totally 25 patients with focal neocortical epilepsy who had invasive electroencephalography (EEG) evaluation and subsequent surgery were included. They were followed up for at least 2years. Interictal ripples (80-250Hz) and fast ripples (250-500Hz) during slow-wave sleep were identified. Neocortical ripples were defined as type I ripples when they were superimposed on epileptiform discharges, and as type II ripples when they occurred independently. Resection ratio was calculated to present the extent to which the cortical area showing an interictal event or the seizure onset zone (SOZ) was completely removed. RESULTS: Fast ripples and types I and II ripples were found in 8, 19, and 21 patients, respectively. Only the higher resection ratio of interictal fast or type I ripples was correlated to the Engel 1a surgical outcome. CONCLUSIONS: Type I ripples could assist in localizing the epileptogenic zone in neocortical epilepsy. SIGNIFICANCE: Type I and fast ripples both may be pathological high-frequency oscillations.

Endoplasmic reticulum stress and apoptosis signaling in human temporal lobe epilepsy.

Apoptosis signaling pathways are implicated in the pathogenesis of temporal lobe epilepsy (TLE), but the role of endoplasmic reticulum (ER) stress and ER-localized apoptosis signaling components remains largely unexplored. Presently, we investigated ER stress and ER localization of proapoptotic Bcl-2 family members and initiator and effector caspases in resected hippocampus from patients with intractable TLE and compared findings with autopsy controls. Hippocampal immunoreactivity for KDEL (Lys-Asp-Glu-Leu), a motif in ER stress chaperones glucose-regulated proteins 78 and 94, and calnexin, was significantly higher in TLE hippocampus compared with controls. The ER-containing microsomal fraction in control brain contained Bid, Bim, and caspase 3, whereas Bad and caspases 6, 7, and 9 were very low or absent. In contrast, caspases 6, 7, and 9 were present within the microsomal fraction of TLE brain. Furthermore, cleaved caspases 7 and 9 were detected in TLE samples but not controls, and KDEL-expressing neurons coexpressed cleaved caspase 9. Potentially adaptive changes were also detected, including lowered Bim levels in this fraction, and binding of caspase 7 to the X-linked inhibitor of apoptosis protein. These data suggest seizures may induce ER stress and trigger proapoptotic signaling pathways in the ER that are counteracted by antiapoptotic signals in chronic human TLE.

Caspase-3 cleavage and nuclear localization of caspase-activated DNase in human temporal lobe epilepsy.

Programmed cell death (apoptosis) signaling pathways have been implicated in seizure-induced neuronal death and the pathogenesis of human temporal lobe epilepsy (TLE). End-stage DNA fragmentation during cell death may be mediated by nucleases including caspase-activated DNase (CAD), apoptosis-inducing factor (AIF) and endonuclease G. In the present study, we investigated the subcellular localization of these nucleases in resected hippocampus from TLE patients and autopsy controls. Subcellular fractionation determined levels of CAD were significantly higher in the nuclear fraction of TLE samples compared with controls, and semiquantitative immunohistochemistry revealed cleaved caspase-3 positive cells in TLE sections but not controls. While mitochondrial levels of AIF and endonuclease G were higher in TLE samples than controls, nuclear localization of AIF was limited and restricted to cells that were negative for cleaved caspase-3. Nuclear accumulation of endonuclease G was not found in TLE samples. These data support ongoing caspase-dependent apoptosis signaling in human TLE and suggest that interventions targeting such pathways may have potential as adjunctive neuroprotective therapy in epilepsy.

Advances of Intracranial Electroencephalography in Localizing the Epileptogenic Zone.

Intracranial electroencephalography (iEEG) provides the best precision in estimating the location and boundary of an epileptogenic zone. Analysis of iEEG in the routine EEG frequency range (0.5-70 Hz) remains the basis in clinical practice. Low-voltage fast activity is the most commonly reported ictal onset pattern in neocortical epilepsy, and low-frequency high-amplitude repetitive spiking is the most commonly reported ictal onset pattern in mesial temporal lobe epilepsy. Recent studies using wideband EEG recording have demonstrated that examining higher (80-1000 Hz) and lower (0.016-0.5 Hz) EEG frequencies can provide additional diagnostic information and help to improve the surgical outcome. In addition, novel computational techniques of iEEG signal analysis have provided new insights into the epileptic network. Here, we review some of these recent advances. Although these sophisticated and advanced techniques of iEEG analysis show promise in localizing the epileptogenic zone, their utility needs to be further validated in larger studies.

A decrease of ripples precedes seizure onset in mesial temporal lobe epilepsy.

High-frequency oscillations (HFOs) are promising biomarkers for epileptic foci; however, their characteristic changes during the preictal period remain unclear. Here, the preictal HFOs were recorded and detected by an automated HFOs detection method in the mouse pilocarpine model as well as in patients with mesial temporal lobe epilepsy (mTLE) and neocortical epilepsy. A total of sixteen low-voltage fast (LVF) and fifty-three hypersynchronous-onset (HYP) seizures were recorded in ten mice. The rate of ripples (80-250Hz) decreased during 1min before the onset of LVF and HYP seizures, which was primarily due to the reduction of type II (independent of epileptiform discharges) rather than type I ripples (superimposed on epileptiform activities). The ripple rate decreased until 30s before HYP seizure, whereas it increased with a peak at 40s during the 1min preictal period of LVF seizures. Furthermore, the "ripple reduction" phenomenon was also observed in all twelve seizures from nine patients with mTLE but not in neocortical epilepsy. These results indicate that ripples may potentially be helpful for understanding the mechanisms of ictogenesis in mTLE, and the different modes of ripple changes during the minute before LVF and HYP seizures might also be beneficial for the diagnosis of seizure types.

Epileptic auras: phenomenology and neurophysiology.

This review discusses the phenomenology, neurophysiology, and localization of epileptic auras with particular emphasis on how auras can manifest as part of an epileptic network. Epileptic auras, as the first clinical symptom of a seizure, may lead us to infer the site of seizure onset. At the same time, auras can also be a result of activation or alteration in an epileptic network. They can be highly specific or ill-defined in symptomatology. They occur as a result of limited seizure activation, allowing access of the neural signal to the conscious brain. An understanding of epileptic auras offers a window into understanding fundamental brain functions, and helps the clinician at the bedside to make appropriate diagnostic and therapeutic choices.

Combining stereo-electroencephalography and subdural electrodes in the diagnosis and treatment of medically intractable epilepsy.

Stereo-electroencephalography (SEEG) has advantages for exploring deeper epileptic foci. Nevertheless, SEEG can only sample isolated cortical areas and its spatial limitation, with the inability to record contiguous cortical regions, may cause difficulties in interpretation. In light of these limitations, the authors describe the hybrid technique of SEEG and subdural strip electrode placement. The hybrid technique was used for a presurgical evaluation in four patients with intractable epilepsy. Initially, the depth electrodes were inserted with a robotic stereotactic system. Thereafter, a skin incision and a small craniectomy were performed at the entry point of the strip electrode trajectory. The dura was opened and, under live fluoroscopic guidance, strip electrodes were slid into the subdural space. In these patients, the additional subdural strip electrodes provided (1) information regarding the precise description of seizure spread in the cortical surface adjacent to the subdural space, (2) identification of epileptogenic zones located near the crown, (3) more precise definition of functional cortex and (4) a better delineation of the interface between epileptogenic zones and functional cortex. This hybrid technique provides additional data compared to either technique alone, offering superior understanding of the dynamics of the epileptic activity and its interaction with functional cortical areas.

Pseudotemporal ictal patterns compared with mesial and neocortical temporal ictal patterns.

PURPOSE: This study analyzes falsely localizing pseudotemporal ictal EEG patterns, to test if it is possible to differentiate them from those in "true" temporal lobe epilepsy. METHODS: We retrospectively studied 33 patients who had epilepsy surgery and a favorable outcome (Engel I), belonging to three groups: 10 patients (37 seizures) with pseudotemporal ictal patterns (PT), 12 patients (45 seizures) with mesial temporal epilepsy because of hippocampal sclerosis (HS), and 11 patients (41 seizures) with neocortical temporal epilepsy (NT). Ictal EEGs were analyzed visually according to predetermined criteria and by using a source localization program (BESA5.1). The topographies of interictal discharges were compared among the three groups. RESULTS: Ictal patterns and locations overlapped across all the groups. The initial onset patterns in NT were less likely to localize to one temporal region as compared with the other groups (P < 0.008). Rhythmic temporal theta as later pattern was seen significantly more frequently in HS than in NT (P < 0.001). All seizures in PT spread to the contralateral side compared with 73 of 86 (85%) of "true temporal" seizures (P < 0.05). Source analysis of the ictal discharge and topographic distribution of interictal discharges were not able to separate the three groups. CONCLUSIONS: Pseudotemporal ictal patterns are morphologically indistinguishable from true temporal ictal patterns. Although statistically more common in hippocampal sclerosis, rhythmic theta pattern can be seen as a result of propagation from extratemporal sites.

Cingulate epilepsy: report of 3 electroclinical subtypes with surgical outcomes.

IMPORTANCE: The literature on cingulate gyrus epilepsy in the magnetic resonance imaging era is limited to case reports and small case series. To our knowledge, this is the largest study of surgically confirmed epilepsy arising from the anterior or posterior cingulate region. OBJECTIVE: To characterize the clinical and electrophysiological findings of epilepsies arising from the anterior and posterior cingulate gyrus. DESIGN, SETTING, AND PARTICIPANTS: We studied consecutive cingulate gyrus epilepsy cases identified retrospectively from the Cleveland Clinic and University of Texas Southwestern Medical Center epilepsy databases from 1992 to 2009. Participants included 14 consecutive cases of cingulate gyrus epilepsies confirmed by restricted magnetic resonance image lesions and seizure freedom or marked improvement following lesionectomy. MAIN OUTCOMES AND MEASURES: The main outcome measure was improvement in seizure frequency following surgery. The clinical, video electroencephalography, neuroimaging, pathology, and surgical outcome data were reviewed. RESULTS: All 14 patients had cingulate epilepsy confirmed by restricted magnetic resonance image lesions and seizure freedom or marked improvement following lesionectomy. They were divided into 3 groups based on anatomical location of the lesion and corresponding seizure semiology. In the posterior cingulate group, all 4 patients had electroclinical findings suggestive of temporal origin of the epilepsy. The anterior cingulate cases were divided into a typical (Bancaud) group (6 cases with hypermotor seizures and infrequent generalization with the presence of fear, laughter, or severe interictal personality changes) and an atypical group (4 cases presenting with simple motor seizures and a tendency for more frequent generalization and less-favorable long-term surgical outcome). All atypical cases were associated with an underlying infiltrative astrocytoma. CONCLUSIONS AND RELEVANCE: Posterior cingulate gyrus epilepsy may present with electroclinical findings that are suggestive of temporal lobe epilepsy and can be considered as another example of pseudotemporal epilepsies. The electroclinical presentation and surgical outcome of lesional anterior cingulate epilepsy is possibly influenced by the underlying pathology. This study highlights the difficulty in localizing seizures arising from the cingulate gyrus in the absence of a magnetic resonance image lesion.

Functional connectivity estimated from intracranial EEG predicts surgical outcome in intractable temporal lobe epilepsy.

This project aimed to determine if a correlation-based measure of functional connectivity can identify epileptogenic zones from intracranial EEG signals, as well as to investigate the prognostic significance of such a measure on seizure outcome following temporal lobe lobectomy. To this end, we retrospectively analyzed 23 adult patients with intractable temporal lobe epilepsy (TLE) who underwent an invasive stereo-EEG (SEEG) evaluation between January 2009 year and January 2012. A follow-up of at least one year was required. The primary outcome measure was complete seizure-freedom at last follow-up. Functional connectivity between two areas in the temporal lobe that were sampled by two SEEG electrode contacts was defined as Pearson's correlation coefficient of interictal activity between those areas. SEEG signals were filtered between 5 and 50 Hz prior to computing this correlation. The mean and standard deviation of the off diagonal elements in the connectivity matrix were also calculated. Analysis of the mean and standard deviation of the functional connections for each patient reveals that 90% of the patients who had weak and homogenous connections were seizure free one year after temporal lobectomy, whereas 85% of the patients who had stronger and more heterogeneous connections within the temporal lobe had recurrence of seizures. This suggests that temporal lobectomy is ineffective in preventing seizure recurrence for patients in whom the temporal lobe is characterized by weakly connected, homogenous networks. This pilot study shows promising potential of a simple measure of functional brain connectivity to identify epileptogenicity and predict the outcome of epilepsy surgery.