Pharmacoresistant Focal Epilepsy Research Articles

Stereoelectroencephalography-Guided Laser Ablations in Patients With Neocortical Pharmacoresistant Focal Epilepsy: Concept and Operative Technique.

Laser ablation surgery has had encouraging results in the treatment of multiple intracranial diseases including primary and metastatic brain tumors, radiation necrosis, and epilepsy. The use of the stereoelectroencephalography (SEEG) method in combination with laser thermocoagulation therapy with the goal of modulating epileptic networks in patients with neocortical nonlesional phamacoresistant epilepsy has not been previously described. To describe the novel methodological and conceptual aspects related to SEEG-guided laser ablations in patients with magnetic resonance imaging (MRI)-negative pharmacoresistant neocortical focal epilepsy. Guided by previous SEEG intracranial data, a laser ablation probe was inserted by using a robotic guidance device in a 17-yr-old medically refractory epilepsy patient with difficult to localize seizures and nonlesional MRI. The laser applicator position was confirmed by MRI, targeting the left mesial rostral superior frontal gyrus. The ablation was performed under multiplanar digital imaging views and real-time thermal imaging and treatment estimates in each plane. A postablation MRI (contrasted T1 sequence) confirmed the ablation's location and size. The entire procedure was achieved in approximately 100 min. The actual ablation was performed in less than 3 min. Approximately, additional 30 min preoperatively were used for positioning and robot registration. Precise placement of laser application (in comparison with preplanned trajectories) was achieved using the robotic guidance and confirmed by the intraoperative magnetic resonance images. No complications were reported. The patient has been seizure-free since surgery. The follow-up period is 20 mo. Two additional patients, treated with similar methodology, are also described. The preliminary experience with the described method shows the feasibility of a unique combination of the SEEG methodology with laser thermocoagulation in patients with neocortical MRI-negative pharmacoresistant focal epilepsy.

Probabilistic functional tractography of the human cortex revisited

In patients with pharmaco-resistant focal epilepsies investigated with intracranial electroencephalography (iEEG), direct electrical stimulations of a cortical region induce cortico-cortical evoked potentials (CCEP) in distant cerebral cortex, which properties can be used to infer large scale brain connectivity. In 2013, we proposed a new probabilistic functional tractography methodology to study human brain connectivity. We have now been revisiting this method in the F-TRACT project (f-tract.eu) by developing a large multicenter CCEP database of several thousand stimulation runs performed in several hundred patients, and associated processing tools to create a probabilistic atlas of human cortico-cortical connections. Here, we wish to present a snapshot of the methods and data of F-TRACT using a pool of 213 epilepsy patients, all studied by stereo-encephalography with intracerebral depth electrodes. The CCEPs were processed using an automated pipeline with the following consecutive steps: detection of each stimulation run from stimulation artifacts in raw intracranial EEG (iEEG) files, bad channels detection with a machine learning approach, model-based stimulation artifact correction, robust averaging over stimulation pulses. Effective connectivity between the stimulated and recording areas is then inferred from the properties of the first CCEP component, i.e. onset and peak latency, amplitude, duration and integral of the significant part. Finally, group statistics of CCEP features are implemented for each brain parcel explored by iEEG electrodes. The localization (coordinates, white/gray matter relative positioning) of electrode contacts were obtained from imaging data (anatomical MRI or CT scans before and after electrodes implantation). The iEEG contacts were repositioned in different brain parcellations from the segmentation of patients' anatomical MRI or from templates in the MNI coordinate system. The F-TRACT database using the first pool of 213 patients provided connectivity probability values for 95% of possible intrahemispheric and 56% of interhemispheric connections and CCEP features for 78% of intrahemisheric and 14% of interhemispheric connections. In this report, we show some examples of anatomo-functional connectivity matrices, and associated directional maps. We also indicate how CCEP features, especially latencies, are related to spatial distances, and allow estimating the velocity distribution of neuronal signals at a large scale. Finally, we describe the impact on the estimated connectivity of the stimulation charge and of the contact localization according to the white or gray matter. The most relevant maps for the scientific community are available for download on f-tract. eu (David et al., 2017) and will be regularly updated during the following months with the addition of more data in the F-TRACT database. This will provide an unprecedented knowledge on the dynamical properties of large fiber tracts in human.

PB14. Fully automated segmentation of intracerebral depth electrode contacts with subsequent separation into distinct electrodes in patients with pharmacoresistant epilepsy

Introduction The localization of the seizure onset zone, being mandatory prior to epilepsy surgery, frequently requires the use of invasive depth electrodes. The interpretation of the electrophysiological recordings then critically depends on the visualization of the electrode positions in 3D MRI scans of these patients. We developed a fully automated software pipeline to segment the depth electrode contacts and to achieve a separation into distinct electrodes. The pipeline uses pre- and post-implantation cranial computerized tomography as well as post-implantation 3D MRI. It consists of standard pre-processing routines for co-registering and masking of images and a custom-made image analysis procedure. Prior spatial information about the implanted electrodes is not required. Methods In a first step, both the pre-implantation CT (preOP-CT) and the post-implantation CT (OP-CT) were co-registered to a post-implantation 3D MRI. Then masks of brain and skull bone were extracted from the preOP-CT, and an automated search for intensity clusters was performed in the brain masked OP-CT. The detected clusters were finally separated into electrode contacts. The only requirements for this method were a voxel size of 1 × 1 × 1 mm or better for the OP-CT and an equidistant spacing of the contacts of all implanted electrodes. Results The method was tested in 28 patients with pharmacoresistant focal epilepsy (161 electrodes and 1608 contacts altogether). A comparison between automatic segmentation and visual identification of the electrode contacts showed that 1597 contacts (99.3%) were correctly detected. Only 9 contacts, which were all located within or outside the skull bone, remained undetected. In 2 patients, one single contact was falsely detected and had to be corrected manually. The pre-processing routines (co-registration and masking) took about 30 min per patient. The image analysis procedure (cluster search and electrode separation) took less than 30 s per patient. Conclusions The implemented method is, to the best of our knowledge, the first fully automated procedure for the segmentation of intracerebral depth electrode contacts with subsequent separation of the detected contacts into distinct electrodes, which can be directly superimposed on 3D MRI. The method does not require any a priori information about the implanted electrodes and is able to identify the loci of depth electrode contacts in a fast and reliable manner.

Anticonvulsant effect of dipropofol by enhancing native GABA currents in cortical neurons in mice.

Temporal lobe epilepsy (TLE), the most common pharmacoresistant focal epilepsy disorder, remains a major unmet medical need. Propofol is used as a short-acting medication for general anesthesia and refractory status epilepticus with issues of decreased consciousness and memory loss. Dipropofol, a derivative of propofol, has been reported to exert antioxidative and antibacterial activities. Here we report that dipropofol exerted anticonvulsant activity in a mouse model of kainic acid-induced seizures. Whole cell patch-clamp recordings of brain slices from the medial entorhinal cortex (mEC) revealed that dipropofol hyperpolarized the resting membrane potential and reduced the number of action potential firings, resulting in suppression of cortical neuronal excitability. Furthermore, dipropofol activated native tonic GABAA currents of mEC layer II stellate neurons in a dose-dependent manner with an EC50 value of 9.3 ± 1.6 μM (mean ± SE). Taken together, our findings show that dipropofol activated GABAA currents and exerted anticonvulsant activities in mice, thus possessing developmental potential for new anticonvulsant therapy. NEW & NOTEWORTHY The anticonvulsant effect of dipropofol was shown in a mouse model of kainic acid-induced seizures. Whole cell patch-clamp recordings of brain slices showed suppression of cortical neuronal excitability by dipropofol. Dipropofol activated the native tonic GABAA currents in a dose-dependent manner.

P2-3-6. Simultaneous recording of SDE and SEEG for pharmacoresistant focal epilepsy

Based on the concept of epilepsy surgery, subdural electrode (SDE) implantation is performed to identify the epileptic focus and to decide the range of resection. One of the major limitations of SDE is their inability to evaluate electric signals from the depth of the brain. On the other hands, stereotactic electroencephalography (SEEG) can appropriately cover target areas even though they reside in deep structures, and enable us to observe epileptic network. Hereby we report a patient with the pharmacoresistant left parietal lobe epilepsy, presenting with hyperkinetic seizures, which needs differentiation from the frontal lobe epilepsy. Sensory language area had to be identified by functional mapping. In this patient, we have performed simultaneous implantation of both SDE and SEEG covering the left frontal and the left parietal lobes. As a result, both sensory language area and epileptogenic zone were identified in the parietal lobe, not in the frontal lobe. The current case demonstrated that simultaneous implantation of SDE and SEEG is a feasible technique for identifying the epileptogenic zone and the functional areas in preoperative evaluation of epilepsy surgery.

ATPase N-ethylmaleimide-sensitive Fusion Protein: A Novel Key Player for Causing Spontaneous Network Excitation in Human Temporal Lobe Epilepsy

The molecular basis for onset, maintenance and propagation of excitation along neuronal networks in epilepsy is still poorly understood. Besides different neurotransmitter receptors that control signal transfer at the synapse, one key regulator involved in all of these processes is the ATPase N-ethylmaleimide-sensitive fusion protein (NSF). Therefore, we analyzed receptor subunits and NSF levels in tissues from the medial temporal gyrus (MTG) of patients with pharmaco-resistant focal temporal lobe epilepsy resected during epilepsy surgery and autopsy controls. The resected tissues were further characterized by field potential recordings into tissues with and without spontaneous sharp wave activity. We detected increased levels of NSF, NMDA 1.1, 2A and GABAAγ2 receptor subunits associated with spontaneous sharp wave spiking activity. We further identified correlations between NSF, AMPA receptor subunit, metabotropic glutamate receptor and adenosine 1 receptor levels in the spontaneous sharp wave spiking tissues. Our findings suggest that NSF plays a key role in controlling spontaneous network excitation in epilepsy by two mechanisms of action: (1) directly via controlling transmitter release at the presynaptic side, and (2) indirectly via altering the function of possible receptor crosstalk and directing/integrating specific receptor compounds through/into the postsynaptic membrane.

Brain regions and epileptogenicity influence epileptic interictal spike production and propagation during NREM sleep in comparison with wakefulness.

Non-rapid eye movement (NREM) sleep is known to be a brain state associated with an activation of interictal epileptic activity. The goal of this work was to quantify topographic changes occurring during NREM sleep in comparison with wakefulness. We studied intracerebral recordings of 20 patients who underwent stereo-electroencephalography (SEEG) during presurgical evaluation for pharmacoresistant focal epilepsy. We measured the number of interictal spikes (IS) and quantified the co-occurrence of IS between brain regions during 1hour of NREM sleep and 1hour of wakefulness. Co-occurrence is a method to estimate IS networks based on a temporal concordance between IS of different brain regions. Each studied region was labeled as "seizure-onset zone" (SOZ), "propagation zone" (PZ), or "not involved region" (NIR). During NREM sleep, the number of interictal spikes significantly increased in all regions (mean of 68%). This increase was higher in medial temporal regions than in other regions, whether involved in the SOZ. Spike co-occurrence increased significantly in all regions during NREM sleep in comparison with wakefulness but was greater in neocortical regions. Spike co-occurrence in medial temporal regions was not higher than in other regions, suggesting that the increase of the number of spikes in this region was in great part a local effect. This study demonstrated that medial temporal regions show a greater propensity to spike production or propagation during NREM sleep compared to other brain regions, even when the medial temporal lobe is not involved in the SOZ.

Classification of Focal and Non Focal Epileptic Seizures Using Multi-Features and SVM Classifier.

Identifying epileptogenic zones prior to surgery is an essential and crucial step in treating patients having pharmacoresistant focal epilepsy. Electroencephalogram (EEG) is a significant measurement benchmark to assess patients suffering from epilepsy. This paper investigates the application of multi-features derived from different domains to recognize the focal and non focal epileptic seizures obtained from pharmacoresistant focal epilepsy patients from Bern Barcelona database. From the dataset, five different classification tasks were formed. Total 26 features were extracted from focal and non focal EEG. Significant features were selected using Wilcoxon rank sum test by setting p-value (p < 0.05) and z-score (-1.96 > z > 1.96) at 95% significance interval. Hypothesis was made that the effect of removing outliers improves the classification accuracy. Turkey's range test was adopted for pruning outliers from feature set. Finally, 21 features were classified using optimized support vector machine (SVM) classifier with 10-fold cross validation. Bayesian optimization technique was adopted to minimize the cross-validation loss. From the simulation results, it was inferred that the highest sensitivity, specificity, and classification accuracy of 94.56%, 89.74%, and 92.15% achieved respectively and found to be better than the state-of-the-art approaches. Further, it was observed that the classification accuracy improved from 80.2% with outliers to 92.15% without outliers. The classifier performance metrics ensures the suitability of the proposed multi-features with optimized SVM classifier. It can be concluded that the proposed approach can be applied for recognition of focal EEG signals to localize epileptogenic zones.

Automated Online Quantification Method for 18F-FDG Positron Emission Tomography/CT Improves Detection of the Epileptogenic Zone in Patients with Pharmacoresistant Epilepsy.

To assess the validity of an online method to quantitatively evaluate cerebral hypometabolism in patients with pharmacoresistant focal epilepsy as a complement to the visual analysis of the 18F-FDG positron emission tomography (PET)/CT exam. A total of 39 patients with pharmacoresistant epilepsy and probable focal cortical dysplasia [22 patients with frontal lobe epilepsy (FLE) and 17 with temporal lobe epilepsy (TLE)] underwent a presurgical evaluation including EEG, video-EEG, MRI, and 18F-FDG PET/CT. We conducted the automated quantification of their 18F-FDG PET/CT data and compared the results with those of the visual-PET analysis conducted by experienced nuclear medicine physicians. For each patient group, we calculated Cohen's Kappa coefficient for the visual and quantitative analyses, as well as each method's sensitivity, specificity, and positive and negative predictive values. For the TLE group, both the visual and quantitative analyses showed high agreement. Thus, although the quantitative analysis could be used as a complement, the visual analysis on its own was consistent and precise. For the FLE group, on the other hand, the visual analysis categorized almost half of the cases as normal, revealing very low agreement. For those patients, the quantitative analysis proved critical to identify the focal hypometabolism characteristic of the epileptogenic zone. Our results suggest that the quantitative analysis of 18F-FDG PET/CT data is critical for patients with extratemporal epilepsies, and especially those with subtle MRI findings. Furthermore, it can easily be used during the routine clinical evaluation of 18F-FDG PET/CT exams. Our results show that quantification of 18F-FDG PET is an informative complementary method that can be added to the routine visual evaluation of patients with subtle lesions, particularly those in the frontal lobes.

Impact of focal cortical dysplasia Type IIIa on seizure outcome following anterior mesial temporal lobe resection for the treatment of epilepsy.

OBJECTIVE Temporal lobe epilepsy (TLE) is the most common type of pharmacoresistant focal epilepsy, for which anterior mesial temporal lobe resection (AMTLR) is a treatment option. Focal cortical dysplasia Type IIIa (FCD IIIa), a developmental lesion resulting from defects in neuronal formation and migration into the temporal pole (FCD I) combined with hippocampal sclerosis (HS), can be a neuropathological finding. In this study, the authors investigate the impact of FCD IIIa on seizure outcome in patients with TLE who underwent AMTLR. METHODS The authors performed a retrospective analysis of all patients with TLE who underwent AMTLR at their institution between June 2011 and April 2014. Histopathological analysis was used to determine whether patients had HS together with FCD I (FCD IIIa) or HS alone. The groups were compared with regard to age, sex, years of epilepsy, and seizure outcome using the Engel classification. RESULTS A total of 51 patients with TLE underwent AMTLR at the authors' institution. FCD IIIa was diagnosed in 13 cases. The patients experienced seizures for a mean duration of 31.1 years. The mean length of follow-up after the procedure was 18 months. All patients with FCD IIIa had a favorable seizure outcome (Engel Class I or II) compared with 71% of the patients with no pathological findings in the temporal pole (p < 0.01). CONCLUSIONS Patients with histopathologically proven FCD IIIa had a significantly better seizure outcome after AMTLR than patients with HS alone. Further effort should be made during presurgical evaluation to detect FCD IIIa so that the most suitable resection technique can be chosen and postoperative seizure outcome can be predicted for patient counseling.

Upregulation of Neuronal Adenosine A1 Receptor in Human Rasmussen Encephalitis.

Rasmussen encephalitis (RE) is a rare neurological disorder characterized by unilateral inflammation of cerebral cortex and other structures, most notably the hippocampus, progressive cognitive deterioration, and pharmacoresistant focal epilepsy. The pathogenesis of RE with unilateral cortical atrophy and focal seizures is still enigmatic. Activation of adenosine A1 receptors (A1R) has been proven to prevent the spatial spread of seizures. We hypothesized that the epileptogenic mechanisms underlying RE are related to changes in neuronal A1R expression. Immunnohistochemistry was used to examine the expression of A1R and adenosine kinase (ADK) in cortical specimens from RE (n = 12), and compared with control cortical tissue. The quantification of A1R and ADK expression was evaluated by Western blot. A1R was predominantly localized in perinuclear of neurons and not in astrocytes or microglia. Upregulation of neuronal A1R was observed in the lesions of RE. Reactive astrocytes and subpopulation of remaining neurons demonstrated over-expression of the ADK within the lesions of RE. Significant increase of A1R and ADK expression in RE compared with controls was confirmed by Western blot. These results suggest that over-expression of ADK is a common pathologic hallmark of RE, and that upregulation of neuronal A1R in RE is crucial in preventing the spread of seizures.

Anterior Thalamic High Frequency Band Activity Is Coupled with Theta Oscillations at Rest.

Cross-frequency coupling (CFC) between slow and fast brain rhythms, in the form of phase–amplitude coupling (PAC), is proposed to enable the coordination of neural oscillatory activity required for cognitive processing. PAC has been identified in the neocortex and mesial temporal regions, varying according to the cognitive task being performed and also at rest. PAC has also been observed in the anterior thalamic nucleus (ATN) during memory processing. The thalamus is active during the resting state and has been proposed to be involved in switching between task-free cognitive states such as rest, in which attention is internally-focused, and externally-focused cognitive states, in which an individual engages with environmental stimuli. It is unknown whether PAC is an ongoing phenomenon during the resting state in the ATN, which is modulated during different cognitive states, or whether it only arises during the performance of specific tasks. We analyzed electrophysiological recordings of ATN activity during rest from seven patients who received thalamic electrodes implanted for treatment of pharmacoresistant focal epilepsy. PAC was identified between theta (4–6 Hz) phase and high frequency band (80–150 Hz) amplitude during rest in all seven patients, which diminished during engagement in tasks involving an external focus of attention. The findings are consistent with the proposal that theta–gamma coupling in the ATN is an ongoing phenomenon, which is modulated by task performance.

Brain molecular imaging in pharmacoresistant focal epilepsy: Current practice and perspectives

This review aims to synthesize all the available data on brain molecular imaging, such as single-photon emission computed tomography (SPECT) and interictal fluorodeoxyglucose positron emission tomography (FDG-PET), in focal epilepsies. SPECT imaging is able to measure regional cerebral blood flow and its major innovation remains its ictal imaging value. On the other hand, FDG-PET, which has higher spatial resolution and lower background activity than SPECT, enables glycolytic metabolism to be identified in interictal states. Therefore, interictal FDG-PET has greater sensitivity than interictal SPECT, especially in temporal lobe epilepsies (TLEs). Thus, 18F-FDG-PET is a necessary step in the presurgical evaluation of TLEs, but also of extratemporal epilepsies (ETEs), contributing to >30% of the decision to undertake surgery. In addition, FDG-PET has particular diagnostic value in focal epilepsies showing normal magnetic resonance imaging (MRI). PET also has good prognostic value for post-surgical outcomes as well as cognitive impairment, especially in cases where the hypometabolism extent is limited. Moreover, the notion of an epileptic network is well highlighted by functional PET imaging, allowing better understanding of the pathological substrates of these disorders. Future development of quantitative analysis software and of novel radiotracers and cameras will certainly enhance its clinical usefulness.

Characterization of focal cortical dysplasia with balloon cells by layer‐specific markers: Evidence for differential vulnerability of interneurons

Focal cortical dysplasia (FCD) is a major cause of pharmacoresistant focal epilepsy. Little is known about the pathomechanisms underlying the characteristic cytoarchitectural abnormalities associated with FCD. In the present study, a broad panel of markers identifying layer-specific neuron subpopulations was applied to characterize dyslamination and structural alterations in FCD with balloon cells (FCD 2b). Pan-neuronal neuronal nuclei (NeuN) and layer-specific protein expression (Reelin, Calbindin, Calretinin, SMI32 (nonphosphorylated neurofilament H), Parvalbumin, transducin-like enhancer protein 4 (TLE4), and Vimentin) was studied by immunohistochemistry on paraffin sections of FCD2b cases (n = 22) and was compared to two control groups with (n = 7) or without epilepsy (n = 4 postmortem cases). Total and layer-specific neuron densities were systematically quantified by cell counting considering age at surgery and brain region. We show that in FCD2b total neuron densities across all six cortical layers were not significantly different from controls. In addition, we present evidence that a basic laminar arrangement of layer-specific neuron subtypes was preserved despite the severe disturbance of cortical structure. SMI32-positive pyramidal neurons showed no significant difference in total numbers, but a reduction in layers III and V. The densities of supragranular Calbindin- and Calretinin-positive interneurons in layers II and III were not different from controls, whereas Parvalbumin-expressing interneurons, primarily located in layer IV, were significantly reduced in numbers when compared to control cases without epilepsy. In layer VI, the density of TLE4-positive projection neurons was significantly increased. Altogether, these data show that changes in cellular composition mainly affect deep cortical layers in FCD2b. The application of a broad panel of markers defining layer-specific neuronal subpopulations revealed that in FCD2b neuronal diversity and a basic laminar arrangement are maintained despite the severe disturbance of cytoarchitecture. Moreover, it showed that Parvalbumin-positive, inhibitory interneurons are highly vulnerable in contrast to other interneuron subtypes, possibly related to the epileptic condition.

Physiological and pathological high-frequency oscillations have distinct sleep-homeostatic properties.

ObjectiveThe stage of sleep is a known modulator of high-frequency oscillations (HFOs). For instance, high amplitude slow waves during NREM sleep and the subtypes of REM sleep were shown to contribute to a better separation between physiological and pathological HFOs. This study investigated rates and spatial spread of the different HFO types (physiological and pathological ripples in the 80–250 Hz frequency band, and fast ripples above 250 Hz) depending on time spent in sleep across the different sleep cycles.MethodsFifteen patients with focal pharmaco-resistant epilepsy underwent one night of video-polysomnography during chronic intracranial EEG recording for presurgical epilepsy evaluation. The HFO rate and spread across the different sleep cycles were determined with an automatic HFO detector. We built models to explain the observed rate and spread based on time in sleep and other variables i.e. sleep stage, delta band and sigma band activity, and slow wave amplitude. Statistical significance of the different variables was determined by a model comparison using the Akaike information criterion.ResultsThe rate of HFOs depends significantly on the accumulated time of sleep. As the night advanced, the rate of pathological ripples and fast ripples decreased during NREM sleep (up to 15% per hour spent in the respective sleep stages), while the rate of physiological ripples increased during REM sleep (8% per hour spent in REM sleep). Interestingly, the stage of sleep but not the sleep cycle determined the extent of spread of HFOs, showing a larger field during NREM sleep and a more restricted field during REM sleep.ConclusionThe different dependence with sleep time for physiological and pathological ripples is in keeping with their distinct underlying generating mechanisms. From a practical point of view, the first sleep cycle seems to be best suitable for studying HFOs in epilepsy, given that the contrast between physiological and pathological ripple rates is largest during this time.

The promise of subtraction ictal SPECT co-registered to MRI for improved seizure localization in pediatric epilepsies: Affecting factors and relationship to the surgical outcome

ObjectiveIctal SPECT is promising for accurate non-invasive localization of the epileptogenic brain tissue in focal epilepsies. However, high quality ictal scans require meticulous attention to the seizure onset. In a relatively large cohort of pediatric patients, this study investigated the impact of the timing of radiotracer injection, MRI findings and seizure characteristics on ictal SPECT localizations, and the relationship between concordance of ictal SPECT, scalp EEG and resected area with seizure freedom following epilepsy surgery. MethodsScalp EEG and ictal SPECT studies from 95 patients (48 males and 47 females, median age=11years, (25th, 75th) quartiles=(6.0, 14.75) years) with pharmacoresistant focal epilepsy and no prior epilepsy surgery were reviewed. The ictal SPECT result was examined as a function of the radiotracer injection delay, seizure duration, epilepsy etiology, cerebral lobe of seizure onset identified by EEG and MRI findings. Thirty two patients who later underwent epilepsy surgery had postoperative seizure freedom data at <1, 6 and 12 months. ResultsSixty patients (63.2%) had positive SPECT localizations − 51 with a hyperperfused region that was concordant with the cerebral lobe of seizure origin identified by EEG and 9 with discordant localizations. Of these, 35 patients (58.3%) had temporal and 25 (41.7%) had extratemporal seizures. The ictal SPECT result was significantly correlated with the injection delay (p<0.01) and cerebral lobe of seizure onset (specifically frontal versus temporal; p=0.02) but not MRI findings (p=0.33), epilepsy etiology (p≥0.27) or seizure duration (p=0.20). Concordance of SPECT, scalp EEG and resected area was significantly correlated with seizure freedom at 6 months after surgery (p=0.04). SignificanceIctal SPECT holds promise as a powerful source imaging tool for presurgical planning in pediatric epilepsies. To optimize the SPECT result the radiotracer injection delay should be minimized to≤25s, although the origin of seizure onset (specifically temporal versus frontal) also significantly impacts the localization.

An automatic detection of focal EEG signals using new class of time–frequency localized orthogonal wavelet filter banks

It is difficult to detect subtle and vital differences in electroencephalogram (EEG) signals simply by visual inspection. Further, the non-stationary nature of EEG signals makes the task more difficult. Determination of epileptic focus is essential for the treatment of pharmacoresistant focal epilepsy. This requires accurate separation of focal and non-focal groups of EEG signals. Hence, an intelligent system that can detect and discriminate focal–class (FC) and non–focal–class (NFC) of EEG signals automatically can aid the clinicians in their diagnosis. In order to facilitate accurate analysis of non-stationary signals, joint time–frequency localized bases are highly desirable. The performance of wavelet bases is found to be effective in analyzing transient and abrupt behavior of EEG signals. Hence, we employ a novel class of orthogonal wavelet filter banks which are localized in time–frequency domain to detect FC and NFC EEG signals automatically. We classify EEG signals as FC and NFC using the proposed wavelet based system. We compute various entropies from the wavelet coefficients of the signals. These entropies are used as discriminating features for the classification of FC and NFC of EEG signals. The features are ranked using Student’s t-test ranking algorithm and then fed to Least Squares-Support Vector Machine (LS–SVM) to classify the signals. Our proposed method achieved the highest classification accuracy of 94.25%. We have obtained 91.95% sensitivity and 96.56% specificity, respectively, using this method.The classification of FC and NFC of EEG signals helps in localization of the affected brain area which needs to undergo surgery.

Increased subcortical oligodendroglia‐like cells in pharmacoresistant focal epilepsy in children correlate with extensive epileptogenic zones

Cortical resections in epilepsy surgery tend to involve multiple lobes in children, compared to adults, partly due to underlying pathology. Oligodendroglia-like cells (OLCs) have been observed in surgical specimens from children with pharmacoresistant epilepsy. We hypothesize that OLCs recruit multiple-lobe epileptogenic zones in pediatric pharmacoresistant focal epilepsy. We examined the surgical specimens from 30 children who underwent epilepsy surgery (1.8- to 16.9-years-old; mean age 9.7 years). Immunohistochemical assays of OLCs were performed using Olig2, which is a marker of OLC. OLC populations in three sites (gray matter, gray-white matter junction, and white matter) were counted. We also performed immunohistochemical staining with neuronal nuclear antigen (NeuN) and glial fibrillary acidic protein (GFAP) for neuronal and astroglial markers, respectively. NeuN- and GFAP-positive cells were distinguished from OLCs. OLC results were compared with seizure types, scalp and intracranial video-electroencephalography (EEG), magnetic resonance imaging (MRI), surgical resection area, histopathologic diagnosis, and seizure outcome. Histopathologic diagnosis consisted of 14 cases of focal cortical dysplasia (FCD; type I; 4, type II; 9, type III; one); 6 cases of oligodendrogliosis; 6 cases of astrocytic gliosis; 2 cases of hyaline protoplasmic astrocytopathy; and 2 cases of tuberous sclerosis. Fifteen children (50%) underwent multiple-lobe resections after intracranial video-EEG. There was a positive correlation between the number of resected electrodes and the OLC population in the white matter (correlation coefficient 0.581, p = 0.001) and at the gray-white matter junction- (correlation coefficient 0.426, p = 0.027). OLC populations in both areas were increased significantly in nine children with epileptic spasms (ES) (gray-white matter junction [p = 0.021] and white matter [p = 0.025]), and nine nonfocal ictal scalp EEG findings (gray-white matter junction [p = 0.04] and white matter [p = 0.042]). The OLC population in white matter was significantly increased in children with 11 nonfocal interictal scalp EEG findings (p = 0.01), with 15 multiple-lobe resections (p = 0.028). Pharmacoresistant epilepsy in children with increased OLCs presented with nonfocal epileptiform discharges on scalp EEG and ES, and they required multiple-lobe resections. We found increased populations of subcortical OLCs in the extensive epileptogenic zone.

Thalamic interictal epileptiform discharges in deep brainstimulated epilepsy patients.

The relationships between interictal epileptiform discharges (IEDs) in the anterior (ANT) and dorsomedial nuclei (DMNT) of the thalamus and electro-clinical parameters in pharmacoresistant focal epilepsy patients receiving intrathalamic electrodes for deep brain stimulation (DBS) were investigated. Thalamus-localized IEDs (LIEDs) and surface EEG (sEEG)-IEDs were evaluated in eight patients who underwent ANT-DBS. Occurrence and frequency of ANT- and DMNT-LIEDs and pre-operative sEEG-IEDs were examined with respect to seizure onset location and seizure outcome following ANT-DBS. LIEDs were identified in all eight patients, in the ANT, DMNT, or both. ANT-LIEDs were observed in all patients with an unequivocal temporal seizure onset zone. The ANT-LIED frequency correlated with pre-surgical sEEG-IED frequency (ρ=0.76, p=0.033) and predicted ANT-DBS responsiveness (T=-2.6; p=0.0428). Of the five patients with bilateral sEEG-IEDs, all had ANT-LIEDs, but only one patient had DMNT-LIEDs. All patients with no or unilateral sEEG-IEDs had DMNT-LIEDs. Observation of LIEDS in the ANT and DMNT supports the hypothesis that these nuclei are involved in propagation of focal epileptic activity. Their correspondence with differing electro-clinical features suggests that these nuclei are functionally distinguishable nodes within the epileptic networks of individual patients.

Low-dose radiosurgery or hypofractionated stereotactic radiotherapy as treatment option in refractory epilepsy due to epileptogenic lesions in eloquent areas – Preliminary report of feasibility and safety

PurposeThe eradication of epileptogenic lesions (e.g. focal cortical dysplasia) can be used for treatment of drug-resistant focal epilepsy, but in highly eloquent cortex areas it can also lead to a permanent neurological deficit. In such cases the neuromodulation effect of low-dose high-precision irradiation of circumscribed lesions may represent an alternative therapy. MethodA total of 10 patients with eloquent localized lesions causing pharmacoresistant focal epilepsy were prospectively identified. After informed consent, six patients agreed and were treated with risk adapted low-dose radiosurgery (SRS) or hypofractionated stereotactic radiotherapy (hfSRT). Comprehensive data concerning treatment modalities and outcome after short-term follow up (mean=16.3 months) were prospectively collected and evaluated. ResultsFrom the six patients, two patients were treated with hfSRT (marginal dose 36Gy) and four with SRS (marginal dose 13Gy). Clinical target volume (CTV) ranged from 0.70ccm to 4.32ccm. The short-term follow-up ranged from 6 to 27 months. There were no side effects or neurological deficits after treatment. At last available follow-up two patients were seizure-free, one of them being off antiepileptic drugs. The seizure frequency improved in one and remained unchanged in three patients. ConclusionTreatment of eloquent localized epileptogenic lesions by SRS and hfSRT showed no adverse events and an acceptable seizure outcome in this small prospective patient series. The relatively short-term follow-up comprises one of the study's drawbacks and therefore a longer follow-up should be awaited in order to evaluate the neuromodulation effect of the treatment. These preliminary results may however justify the initiation of a larger prospective trial investigating whether focused low-dose stereotactic irradiation could be an option for lesions in eloquent brain areas.