Are auras a reliable clinical indicator in medial temporal lobe epilepsy with hippocampal sclerosis?

BACKGROUND AND PURPOSE: Medial temporal lobe epilepsy with unilateral hippocampal sclerosis (MTLE-HS) is the most frequent form of surgical temporal lobe epilepsy. In this study, it was aimed to determine whether different types of aura represent a cardinal and characteristic feature of MTLE-HS and might provide a diagnostic complement to help identify patients who will be seizure-free after surgery. METHODS: All types of auras and associations of auras reported by 400 MTLE-HS patients referred for surgery were retrospectively collected and their statistical correlation with the postoperative outcome was examined in a subgroup of 305 patients who underwent surgery. RESULTS: A total of 876 auras were collected, classified into 12 categories. Globally, MTLE-HS patients reported widely variable auras and groupings of auras. Most common were autonomic and abdominal visceral auras, followed by psychoaffective and experiential auras; less common, but seen in 10%-15% of patients, were non-specific auras, somatosensory auras and visual auras, and least common, reported by less than 10% of patients, were auditory, gustatory, vestibular, olfactory and intellectual auras. No auras were reported in 10% of patients. 65% of patients experienced more than one type of aura (two to seven). No specific groupings of aura type were apparent. No evidence was found for correlation between postoperative outcome and (i) any category of aura, (ii) the number of categories of aura per patient and (iii) any association of categories of auras. CONCLUSION: Auras and association of auras vary widely in MTLE-HS and provide no useful insight into surgical outcome.

Surgical treatment for mesial temporal lobe epilepsy associated with hippocampal sclerosis.

INTRODUCTION: Hippocampal sclerosis is the most common cause of pharmacoresistant epilepsy amenable for surgical treatment and seizure control. The aim of this article is to review and evaluate the published literature related to the outcome of the surgical treatment of mesial temporal lobe epilepsy (MTLE) associated with hippocampal sclerosis (HS) and to describe the future prospects in this field. STATE OF ART: Surgery of MTLE associated with HS achieves long-term seizure freedom in about 70% (62-83%) of cases. Seizure outcome is similar in the pediatric population. Mortality following temporal resection is very rare (<1%) and the rate of definitive neurological complication is low (1%). Gamma knife stereotactic radiosurgery used as a treatment for MTLE would have a slightly worse outcome to that of surgical resection, but would provide neuropsychological advantage. However, the average latency before reducing or stopping seizures is at least 9 months with radiosurgery. Regarding palliative surgery, amygdalohippocampal stimulation has been demonstrated to improve the control of epilepsy in carefully selected patients with intractable MTLE who are not candidates for resective surgery. PERSPECTIVES: Recent progress in the field of imaging and image-guidance should allow to elaborate tailored surgical strategies for each patient in order to achieve seizure freedom. Concerning therapeutics, closed-loop stimulation strategies allow early seizure detection and responsive stimulation. It may be less toxic and more effective than intermittent and continuous neurostimulation. Moreover, stereotactic radiofrequency amygdalohippocampectomy is a recent approach leading to hopeful results. Closed-loop stimulation and stereotactic radiofrequency amygdalohippocampectomy may provide a new treatment option for patients with pharmacoresistant MTLE. CONCLUSIONS: Mesial temporal lobe surgery has been widely evaluated and has become the standard treatment for MTLE associated with HS. Alternative surgical procedures like gamma knife stereotactic radiosurgery and amygdalohippocampal stimulation are currently under assessment, with promising results.

[Evolution of ideas and techniques, and future prospects in epilepsy surgery]. / Évolution des idées et des techniques, et perspectives d'avenir en chirurgie de l'épilepsie.

INTRODUCTION: The aim of this article was to review and evaluate the published literature related to the outcome of epilepsy surgery, while placing it in an historical perspective, and to describe the future prospects in this field. STATE OF ART: Temporal lobe surgery achieves seizure freedom in about 70% of cases. Seizure outcome is similar in the pediatric population. Extratemporal resections impart good results to 40% to 60% of patients, with a better prognosis in the case of frontal lobe surgery. Pediatric hemispherotomy leads to seizure control in about 80% of children. Radiosurgery used as a treatment for temporal mesial epilepsy has an outcome quite similar to that obtained with surgical resection, but provides a neuropsychological advantage. Radiosurgery is also effective in 60% of children treated for seizures related to hypothalamic hamartoma. Regarding palliative surgery, callosotomy and multiple subpial transections show satisfactory outcomes in over 60% of cases. Neuromodulation techniques (vagus nerve stimulation and bilateral stimulation of the anterior nucleus of the thalamus) allow a 50% reduction of seizures in half of patients. PERSPECTIVES: Transcranial magnetic stimulation combined with electroencephalography seems a promising technique because of its diagnostic, prognostic and therapeutic applications. Transcranial ultrasound stimulation, which can reversibly control neuronal activity, is also under consideration. Concerning neuromodulation, trigeminal nerve stimulation may become an alternative to vagus nerve stimulation; while other targets of deep brain stimulation are being evaluated. Also, the possibility of coupling SEEG seizure focus detection with concomitant laser or radiofrequency focus destruction is under development. CONCLUSIONS: Constant evolution of epilepsy surgery has improved patient outcomes over time. Current research and development axes suggest the continuation of this trend and a reduction of the invasiveness of surgical procedures.

[Paraganglioma of the cauda equina region: Report of six cases and review of the literature]. / Paragangliomes de la queue de cheval : à propos de six cas et revue de la littérature.

BACKGROUND AND PURPOSE: Paragangliomas of the cauda equina are rare tumors. The standard treatment is surgical resection. Our study aims to compare our clinical, radiological, prognostic data to the literature and to offer management and follow-up recommendations. METHODS: In this retrospective study, six patients with paraganglioma of the cauda equina region were treated. Symptoms included radicular nerve pain and low back pain with occasional sphincter dysfunction and motor deficit. MRI showed well-circumscribed lesions with homogeneous enhancement following gadolinium injection. Treatment involved complete surgical resection of the tumor under electrophysiological control. In addition to the characteristics of the tumor, we assessed operating results as well as postoperative morbidity and follow-up. RESULTS: All patients had complete removal of the tumor, which required in most cases the resection of the carrying root. The intervention allowed a regression of the initial symptoms, with possible postoperative regressive sphincter disorders. Clinical and radiological follow-up (19 months on average), showed no tumor recurrence. CONCLUSIONS: The reference treatment of these tumors is complete surgical resection, usually requiring the sacrifice of the carrying nerve root. Intra-operative nerve roots stimulation is recommended to reduce the risk of motor deficit linked to this radical treatment. A long-term clinical and radiological follow-up is recommended.

[Seizure prediction: from myth to reality]. / Prédiction des crises d'épilepsie: du mythe à la réalité.

INTRODUCTION: Clinical, metabolic and electrophysiologic studies suggest the existence of a preictal state, a transition between the interictal state and seizure. STATE OF THE ART: Analysis of the intracranial EEG by mathematical methods shows changes of the brain dynamics several minutes before the occurrence of partial seizures. These modifications can be widespread and not restricted to the epileptogenic focus, which would explain why they can also be detected from scalp EEG. Several scenarios could underlie the preictal state: a progressive recruitment of neurons or a facilitating state with a high probability of seizure occurrence. Because of the high rate of false predictions, no satisfactory method for seizure prediction has been currently proposed. PERSPECTIVES: A European multicenter study (Evolving platform for improving living expectation of patients suffering from IctAl events [EPILEPSIAE]) is currently evaluating a combination of 44 methods applied for EEG and ECG analysis on long-term recordings obtained from a large multicenter database (www.epilepsiae.eu). CONCLUSION: Combining analyses of multi-level signals including intracranial EEG and microelectrodes, scalp EEG and in vitro electrophysiological studies of post-operative tissues should help clarify brain dynamics during the pre-ictal state.

[Epileptiform activities generated in vitro by human temporal lobe tissue]. / Activités épileptiques produites in vitro par le tissu temporal humain.

Drug-resistant partial epilepsies, including temporal lobe epilepsies with hippocampal sclerosis and cortical dysplasias, offer the opportunity to study human epileptic activity in vitro since the preferred therapy often consists of the surgical removal of the epileptogenic zone. Slices of this tissue retain functional neuronal networks and may generate epileptic activity. The properties of cells in this tissue do not seem to be significantly changed, but excitatory synaptic characteristics are enhanced and GABAergic inhibition is preserved. Typically, epileptic activity is not generated spontaneously by the neocortex, whether dysplastic or not, but can be induced by convulsants. The initiation of ictal discharges in neocortex depends on both GABAergic signaling and increased extracellular potassium. In contrast, a spontaneous interictal-like activity is generated by tissues from patients with temporal lobe epilepsies associated with hippocampal sclerosis. This activity is initiated not in the hippocampus but in the subiculum, an output region that projects to the entorhinal cortex. Interictal events seem to be triggered by GABAergic cells, which paradoxically excite approximately 20% of subicular pyramidal cells, while simultaneously inhibiting the majority. Interictal discharges are therefore sustained by both GABAergic and glutamatergic signaling. The atypical depolarizing effects of GABA depend on a pathological elevation in the basal levels of chloride in some subicular cells, similar to those of developmentally immature cells. This defect is caused by the perturbation of the expression of the cotransporters regulating the intracellular chloride concentration, the importer NKCC1, and the extruder KCC2. Blockade of excessive NKCC1 by the diuretic bumetanide restores intracellular chloride and thus hyperpolarizing GABAergic actions, suppressing interictal activity.

Autonoetic consciousness in autobiographical memories after medial temporal lobe resection.

This study aims to investigate autonoetic consciousness associated with episodic autobiographical memory in patients who had undergone unilateral medial temporal lobe resection for intractable epilepsy. Autonoetic consciousness, defined as the conscious feeling of mentally travelling back in time to relive a specific event, was assessed using the Remember/Know (R/K) paradigm across different time periods as proposed in the autobiographical memory task developed by Piolino et al. (TEMPau task). Results revealed that the two patient groups (left and right temporal resection) gave reduced sense of reliving (R) responses and more familiarity (K) responses than healthy controls. This poor autonoetic consciousness was highlighted when patients were asked to justify their Remember responses by recalling sensory-perceptive, affective or spatiotemporal specific details across all life periods. These results support the bilateral MTL contribution to episodic autobiographical memory covering the entire lifespan, which is consistent with the multiple trace theory of MTL function. This study also demonstrates the bilateral involvement of MTL structures in recalling specific details of personal events characterized by autonoetic consciousness.

Autobiographical memory after temporal lobe resection: neuropsychological and MRI volumetric findings.

This study examined the contribution of medial temporal lobe (MTL) structures in autobiographical memory. While some investigators have reported a temporal gradient in memory performance, characterized by retrieval difficulties limited to recent periods of life [Squire and Alvarez (Retrograde amnesia and memory consolidation: a neurobiological perspective. Curr Opin Neurobiol 1995; 5: 169-77)], others have suggested that this impairment involves all life-time periods [Nadel and Moscovitch (Memory consolidation, retrograde amnesia and the hippocampal complex. Curr Opin Neurobiol 1997; 7: 217-27)]. In this study, autobiographical memory was assessed in 22 patients who had undergone a left (n = 12) or a right (n = 10) MTL resection for the relief of epileptic seizures and in 22 normal control participants. For this purpose, we used an autobiographical memory task (TEMPau, Piolino et al., 2003) across four time periods covering the subjects' entire lifespan. For each period, an overall autobiographical memory score (AM score) was obtained, from which a strictly episodic score (SE score), characterized by specificity and richness of details, was computed. For all events recalled, Remember responses justified by specificity of factual, spatial and temporal contents (jR responses) were measured using the Remember/Know paradigm. MRI volumetric analyses performed on the medial (i.e. hippocampus, temporopolar, entorhinal, perirhinal and parahippocampal cortices) and lateral temporal (i.e. superior, middle and inferior temporal gyri) lobe structures stated that the resection mainly included MTL structures. AM and SE scores were impaired in patients with right and left MTL resections as compared to normal controls across all time periods, reflecting the patients' particular difficulty in producing specific and detailed memories across all periods. This impairment was associated with poor autonoetic consciousness, revealed by the small number of jR responses across all periods. Results of correlation analysis between MRI volume measures of temporal lobe structures and autobiographical memory scores suggest that the right MTL structures are particularly responsive in reliving the encoding context regardless of remoteness. Our results support the bilateral MTL contribution to episodic autobiographical memory covering the entire lifespan, which is consistent with the multiple trace theory of MTL function [Moscovitch et al. (Functional neuroanatomy of remote episodic, semantic and spatial memory: a unified account based on multiple trace theory. J Anat 2005; 207: 35-66.)].

A volumetric MRI study of the hippocampus and the parahippocampal region after unilateral medial temporal lobe resection.

Segmentation guidelines on high-resolution MRI designed to assess remaining volumes of the hippocampus and the parahippocampal cortices after medial temporal lobe (MTL) surgery could provide a useful tool to investigate the involvement of these anatomical regions in surgical outcomes and in human memory. For this purpose, we implemented an MRI volumetric analysis, already applied to healthy population or epileptic patient before surgery, to quantify the volume of the hippocampus, the temporopolar cortex and the regions of the parahippocampal gyrus (perirhinal, entorhinal and parahippocampal cortices) spared after unilateral MTL resection carried out to treat medically uncontrolled temporal lobe epilepsy (TLE). Based on the locations of remaining anatomical landmarks, we quantified the volume of these regions in 24 patients after MTL resection and in 16 control participants. Our results show that (1) mean volumes of these regions contralateral to the epileptic focus were similar to those of normal subjects, (2) volumetric measures obtained from the resected side were much smaller than those from the non-resected side or from normal values and (3) the extent of MTL resection was comparable in right or left MTL surgery. Individual analysis of patients showed that the parahippocampal cortex, as opposed to the other regions, was not systematically removed across patients. As a post-operative MRI-based method, it therefore proves valuable to assess group data as well as to explore differences between individual patients.

Intracranial extra-axial cavernous (HEM) angiomas: tumors or vascular malformations?

INTRODUCTION: Extra-axial cavernous hemangiomas or angiomas [(hem)angiomas] are relatively rare lesions. They usually arise in relation to the dura mater intracranially or at the spinal level. Most of these lesions have been described in the middle cranial fossa at level of the cavernous sinus. Controversy still exists regarding the exact nature of these extra-axial cavernous angiomas: vascular tumor versus vascular malformation similar to intra-axial cavernomas. It has been suggested that they could represent an adult form of the hemangioma of infancy. Extra-axial cavernous (hem)angiomas often mimic meningiomas and their clinical behavior and imaging appearance are quite different than those of intra-axial cavernous angiomas. SUBJECTS AND METHODS: Five patients ranging in age from 24 to 63 years with a histologically proven dural cavernous angioma were retrospectively included. The lesions were located at level of the cavernous sinus (4 cases) and falx. CT and MR scans were performed in all cases and angiography in three patients. Four patients underwent surgery and a biopsy was performed in one case. One lesion was embolized before biopsy. Histology was available in all patients. RESULTS: In the operated patients, the lesion was totally resected in 2 cases and partially in the other 2. No postsurgical complication was noted. Histology revealed a vascular malformation composed of large vascular channels lined by flat endothelium and separated by fibroconnective tissue stroma. The pathological diagnosis was cavernous angioma. CONCLUSION: On the basis of the analysis of the literature and of our cases, intra-cranial extra-cerebral so-called cavernous (hem)angiomas present findings suggesting that they are vascular malformative lesions, analogous to the intra-axial cavernous angioma. A relationship with the hemangiomas of infancy seems unlikely. Correct terms for extra-cerebral cavernous (hem)angiomas are cavernoma, cavernous angioma, or venous vascular malformation of cavernous type . The term hemangioma should be avoided and reserved for the common vascular tumor of infancy.

[Heschl's gyrus identification using functional MRI: neurosurgical issue]. / Identification du gyrus de heschl en IRM fonctionnelle.

AIM: Localizing Heschl's gyrus with functional MRI (fMRI) is a particularly difficult challenge due to the noise of the echo planar sequences and the frequent activation of language areas during auditory paradigms. The goal of this study was to search for a paradigm capable of assessing only pure primary auditory cortex activation with fMRI. MATERIAL AND METHOD: Ten healthy adults were studied. Subjects were asked to continuously perform a visual decisional task while passively listening to an ON-OFF randomized paradigm of tones and rhythmic stimuli. Data were analyzed with SPM. RESULTS: Auditory cortex activation was assessed by observing activated pixels in functional images. Due to the distraction effect of the visual decisional task, functional images of pure primary auditory cortex were obtained in all subjects, with strong and selective activation in the Heschl's gyrus. CONCLUSION: This technique, coupled with fMRI data of language areas can be used as a preoperative tool for surgical preplanning in the left superior temporal region. It shows a clear distinction between resectable areas (primary auditory cortex) and not resectable essential areas (language areas).

Pituitary carcinoma: report of an exceptional case and review of the literature.

Pituitary carcinomas are exceptional tumors and constitute 0.1 to 0.2% of pituitary tumors. Their definition includes well-established criteria but distant metastasis is the hallmark required for diagnosis. We report the fourth case of gonadotropic pituitary carcinoma described in the literature. This case illustrates the dramatic outcome of these tumors. The most interesting feature of our case was the loss of differentiation with time, established by retrospective analysis of the primary tumor surgically treated 15 years earlier. Most of the previously reported cases exhibited a majority of adrenocoticotropin and non-functioning pituitary tumors. However, the frequency of non-functioning tumors seems smaller than previously believed. In the discussion, we stress the need to detect these very aggressive tumors as early as possible and identify treatments to improve the dramatic course of these carcinomas.

Role of the supplementary motor area in motor deficit following medial frontal lobe surgery.

OBJECTIVE: Patients undergoing surgical resection of medial frontal lesions may present a transient postoperative deficit that remains largely unpredictable. The authors studied the role of the supplementary motor area (SMA) in the occurrence of this deficit using fMRI. METHODS: Twenty-three patients underwent a preoperative fMRI before resection of medial frontal lesions. Tasks included self-paced flexion/extension of the left and right hand, successively. Preoperative fMRI data were compared with postoperative MRI data and with neurologic outcome. RESULTS: Following surgery, 11 patients had a motor deficit from which all patients recovered within a few weeks or months. The deficit was similar across patients, consisting of a global reduction in spontaneous movements contralateral to the operated side with variable severity. SMA activation was observed in all patients. The deficit was observed when the area activated in the posterior part of the SMA (SMA proper) was resected. CONCLUSIONS: fMRI is able to identify the area at risk in the SMA proper whose resection is highly related to the occurrence of the motor deficit. The clinical characteristics of this deficit support the role of the SMA proper in the initiation and execution of the movement.

Obstruction of Magendie's and Luschka's foramina. Cine-MRI, aetiology and pathogenesis.

BACKGROUND: Obstruction of the foramina of Magendie and Luschka represents one possible aetiology for a progressive tetra-ventricular hydrocephalus. METHOD: Our case report is a 58-year-old woman initially presenting with a pseudo-vertebrobasilar insufficiency clinical syndrome. A ventriculo-cisternostomy of the third ventricle was performed by an endoscopic procedure with a clinical and radiological success (three year follow-up). FINDINGS: Comparative studies of cerebrospinal fluid (CSF) flow measurements by cine magnetic resonance imaging (cine-MRI) showed that Magendie's and Luschka's foramina permeabilities were restored after the ventriculo-cisternostomy. INRTERPRETATION: This case shows that endoscopic ventriculo-cisternostomy of the third ventricle can provide an effective treatment for specific tetra-ventricular hydrocephalus. Cine-MRI findings open the discussion on possible aetiologies and pathophysiologies.

[Intramedullary tumors]. / Tumeurs intramédullaires.

Intramedullary tumours represent 2-4% of all central nervous system tumours. Clinical presentation can adopt any aspect of slow medullar compression. Often benign, these tumours are mostly of glial origin: ependymomas or astrocytomas. Diagnosis has been revolutionised by magnetic resonance imaging, which allows a precise analysis of the tumour with differentiation between the consistent portion and its satellite cysts. Surgery remains the treatment of choice. Total removal can often be achieved and no further complementary treatment is justified, except in proven malignancy. If resection has been partial, radiotherapy remains controversial as non-deprived of untoward effects, when delivered at efficient dose. Long term follow-up is mandatory, as there are late recurrences or secondary aggravations, evolving on their own. As post-therapeutic clinical state is highly correlated with the pretherapeutic state, intramedullary tumours are to be considered as medical emergencies.

Is amygdalohippocampectomy really selective in medial temporal lobe epilepsy? A study using positron emission tomography with (18)fluorodeoxyglucose.

PURPOSE: Selective amygdalohippocampectomy (SAH) is a surgical technique effective for the treatment of medial temporal lobe epilepsy, which selectively removes the epileptogenic hippocampus and amygdala but spares the temporal neocortex. However, the benefit of SAH in terms of functional outcome is debated. In this study, we aimed to assess the metabolic consequences of SAH. METHODS: Volumetric magnetic resonance imaging (MRI) and fluorodeoxyglucose positron emission tomography (PET) studies were performed in nine patients with medial temporal lobe epilepsy associated with hippocampal sclerosis before and after SAH. Regions of interest were delineated on MRIs and then replaced on PET images using an automatic 3D image registration. We calculated absolute metabolic rates of glucose and normalized metabolic values in each region of interest. RESULTS: The comparison between preoperative and postoperative metabolic values showed a statistically significant worsening of the hypometabolism on the ipsilateral temporal pole on the superior and the hippocampal levels (p < 0.05 and 0.0045, respectively). A postoperative increase of the metabolic activity also was noted in the contralateral anterior hippocampus (p < 0.05) and the orbitofrontal cortex bilaterally (p < 0.002 and 0.001, respectively) CONCLUSIONS: SAH functional benefit is controversial. SAH worsened significantly the hypometabolism of a temporal structure that was not surgically removed (i.e., the temporal pole), and it improved postoperatively the metabolic activity in the contralateral hippocampus and the orbitofrontal cortex. Whether this postoperative improvement is linked to the selectivity of the surgical procedure must be further clarified.

Lesions affecting the parahippocampal cortex yield spatial memory deficits in humans.

Anatomical studies in monkeys, and functional imaging and lesion studies in humans, suggest that, within the primate medial temporal neocortex, the parahippocampal cortex (PHC) is particularly involved in spatial tasks. However, evidence for a functional specialization of the PHC regarding its spatial memory functions has so far been lacking. Here, we investigated spatial memory functions of the human perirhinal cortex (PRC) and PHC. Patients with lesions affecting the PRC but sparing the PHC, and patients with lesions affecting both PRC and PHC, performed an oculomotor delayed response task with unpredictably varied memory delays of up to 30 s. Compared to controls, patients with PRC+PHC lesions showed a significant delay-dependent inaccuracy of memory-guided eye movements contralateral to the lesion side, whereas patients with PRC lesions showed no significant inaccuracy. Our results show that the PHC is a critical component for spatial memory in humans and suggest that (i) extrahippocampal spatial memory functions of the medial temporal lobe may not be equally distributed in the medial temporal neocortex, but may be largely confined to the PHC, and (ii) damage to connections between cortices involved in spatial cognition and rostral regions of the temporal lobe is unlikely to account for the observed spatial memory deficits with PHC lesions.

Accurate prediction of postoperative outcome in mesial temporal lobe epilepsy: a study using positron emission tomography with 18fluorodeoxyglucose.

BACKGROUND: Recent studies suggest that positron emission tomography may be a reliable predictive indicator of clinical outcome following surgical treatment for epilepsy. OBJECTIVE: We evaluated 30 patients with documented medial temporal lobe epilepsy to determine if prediction of postoperative outcome is improved with the use of positron emission tomography with (18)fluorodeoxyglucose. PATIENTS AND METHODS: We performed a discriminant analysis to determine the combination of metabolic asymmetry indexes in temporal and extratemporal regions defined by magnetic resonance imaging that best predicted the postoperative outcome. Seizure outcome was assessed at least 2 years after surgery: patients were classified as seizure free (n = 14, group A), mostly improved (n = 10, group B), or as having persistent seizures (n = 6, group C). RESULTS: Discriminant analysis was first performed in groups A and C. The temporal pole seemed to be the only temporal region for which metabolism was a significant predictor of the postoperative outcome (F(1,18) = 10.19; P =.005). The predictive value of positron emission tomography with (18)fluorodeoxyglucose was considerably improved by the multivariate analysis (F(4,15) = 7.21; P =.002), which correctly predicted the 2 -year prognosis in 100% of the patients using 4 regions: the temporal pole, the medial temporal region, the anterior part of the lateral temporal neocortex, and the basofrontal region. As a validation, we performed this 4-region analysis in the patients in group B. The difference among the 3 groups was highly significant (F = 15.5, P<.001). CONCLUSION: These findings suggest that the interictal metabolic pattern reliably predicts the 2-year prognosis after surgery in patients with medial temporal lobe epilepsy.