The Virtual Epileptic Patient: Individualized whole-brain models of epilepsy spread.

Individual variability has clear effects upon the outcome of therapies and treatment approaches. The customization of healthcare options to the individual patient should accordingly improve treatment results. We propose a novel approach to brain interventions based on personalized brain network models derived from non-invasive structural data of individual patients. Along the example of a patient with bitemporal epilepsy, we show step by step how to develop a Virtual Epileptic Patient (VEP) brain model and integrate patient-specific information such as brain connectivity, epileptogenic zone and MRI lesions. Using high-performance computing, we systematically carry out parameter space explorations, fit and validate the brain model against the patient's empirical stereotactic EEG (SEEG) data and demonstrate how to develop novel personalized strategies towards therapy and intervention.

Contextual modulation of hippocampal activity during picture naming.

Picture naming is a standard task used to probe language processes in healthy and impaired speakers. It recruits a broad neural network of language related areas, among which the hippocampus is rarely included. However, the hippocampus could play a role during picture naming, subtending, for example, implicit learning of the links between pictured objects and their names. To test this hypothesis, we recorded hippocampal activity during plain picture naming, without memorization requirement; we further assessed whether this activity was modulated by contextual factors such as repetition priming and semantic interference. Local field potentials recorded from intracerebral electrodes implanted in the healthy hippocampi of epileptic patients revealed a specific and reliable pattern of activity, markedly modulated by repetition priming and semantic context. These results indicate that the hippocampus is recruited during picture naming, presumably in relation to implicit learning, with contextual factors promoting differential hippocampal processes, possibly subtended by different sub-circuitries.

Comparison of Brain Networks During Interictal Oscillations and Spikes on Magnetoencephalography and Intracerebral EEG.

Electromagnetic source localization in electroencephalography (EEG) and magnetoencephalography (MEG) allows finding the generators of transient interictal epileptiform discharges ('interictal spikes'). In intracerebral EEG (iEEG), oscillatory activity (above 30 Hz) has also been shown to be a marker of neuronal dysfunction. Still, the difference between networks involved in transient and oscillatory activities remains largely unknown. Our goal was thus to extract and compare the networks involved in interictal oscillations and spikes, and to compare the non-invasive results to those obtained directly within the brain. In five patients with both MEG and iEEG recordings, we computed correlation graphs across regions, for (1) interictal spikes and (2) epileptic oscillations around 30 Hz. We show that the corresponding networks can involve a widespread set of regions (average of 10 per patient), with only partial overlap (38 % of the total number of regions in MEG, 50 % in iEEG). The non-invasive results were concordant with intracerebral recordings (79 % for the spikes and 50 % for the oscillations). We compared our interictal results to iEEG ictal data. The regions labeled as seizure onset zone (SOZ) belonged to interictal networks in a large proportion of cases: 75 % (resp. 58 %) for spikes and 58 % (resp. 33 %) for oscillations in iEEG (resp. MEG). A subset of SOZ regions were detected by one type of discharges but not the other (25 % for spikes and 8 % for oscillations). Our study suggests that spike and oscillatory activities involve overlapping but distinct networks, and are complementary for presurgical mapping.

Recording of fast activity at the onset of partial seizures: depth EEG vs. scalp EEG.

Rapid discharges (25-80 Hz), a characteristic EEG pattern often recorded at seizure onset in partial epilepsies, are often considered as electrophysiological signatures of the epileptogenic zone. While the recording of rapid discharges from intracranial electrodes has long been established, their observation from the scalp is challenging. The prevailing view is that rapid discharges cannot be seen clearly (or at all) in scalp EEG because they have low signal-to-noise ratio. To date, however, no studies have investigated the 'observability' of rapid discharges, i.e. under what conditions and to what extent they can be visible in recorded EEG signals. Here, we used a model-based approach to examine the impact of several factors (distance to sources, skull conductivity, source area, source synchrony, and background activity) on the observability of rapid discharges in simultaneously simulated depth EEG and scalp EEG signals. In our simulations, the rapid discharge was clearly present in depth EEG signals but mostly almost not visible in scalp EEG signals. We identified some of the factors that may limit the observability of the rapid discharge on the scalp. Notably, surrounding background activity was found to be the most critical factor. The findings are discussed in relation to the presurgical evaluation of epilepsy.

Performance in recognition memory is correlated with entorhinal/perirhinal interictal metabolism in temporal lobe epilepsy.

In addition to the hippocampus, the entorhinal/perirhinal cortices are often involved in temporal lobe epilepsy (TLE). It has been proposed that these anterior parahippocampal structures play a key role in recognition memory. We studied the voxel-based PET correlation between number of correctly recognized targets in a new recognition memory paradigm and interictal cerebral metabolic rate for glucose, in 15 patients with TLE with hippocampal sclerosis. In comparison to healthy subjects, patients had decreased recognition of targets (P<0.001) and ipsilateral hypometabolism (relative to side of hippocampal sclerosis) of the hippocampus, entorhinal/perirhinal cortices, medial temporal pole, and middle temporal gyrus (P<0.05, corrected by false discovery rate method). Performance correlated with interictal metabolism of ipsilateral entorhinal/perirhinal cortices (P<0.005, Spearman's rank test), but this relationship was not significant in the hippocampus itself (P>0.18, Spearman's rank test). These findings highlight the preferential involvement of entorhinal/perirhinal cortices in recognition memory in patients with TLE, and suggest that recognition memory paradigms may be useful in assessing anterior parahippocampal functional status in TLE.

Imaging haemodynamic changes related to seizures: comparison of EEG-based general linear model, independent component analysis of fMRI and intracranial EEG.

BACKGROUND: Simultaneous EEG-fMRI can reveal haemodynamic changes associated with epileptic activity which may contribute to understanding seizure onset and propagation. METHODS: Nine of 83 patients with focal epilepsy undergoing pre-surgical evaluation had seizures during EEG-fMRI and analysed using three approaches, two based on the general linear model (GLM) and one using independent component analysis (ICA): The results were compared with intracranial EEG. RESULTS: The canonical GLM analysis revealed significant BOLD signal changes associated with seizures on EEG in 7/9 patients, concordant with the seizure onset zone in 4/7. The Fourier GLM analysis revealed changes in BOLD signal corresponding with the results of the canonical analysis in two patients. ICA revealed components spatially concordant with the seizure onset zone in all patients (8/9 confirmed by intracranial EEG). CONCLUSION: Ictal EEG-fMRI visualises plausible seizure related haemodynamic changes. The GLM approach to analysing EEG-fMRI data reveals localised BOLD changes concordant with the ictal onset zone when scalp EEG reflects seizure onset. ICA provides additional information when scalp EEG does not accurately reflect seizures and may give insight into ictal haemodynamics.

[Surgery and additional protontherapy for treatment of invasive and recurrent squamous cell carcinomas: technique and preliminary results]. / Association chirurgie-protonthérapie dans le traitement des carcinomes invasifs et récidivants de la conjonctive: technique et résultats préliminaires.

INTRODUCTION: Invasive squamous cell carcinomas are uncommon neoplasias with high recurrence and mortality rates. The improvement of tumoral control requires additional treatments such as cryotherapy, topical chemotherapy, and radiotherapy. We present the technique and preliminary results of associating treatment with surgery and proton beam therapy for recurrent and invasive squamous cell carcinomas. MATERIALS AND METHODS: From June 2001 to September 2008, 15 patients were treated in our ocular oncologic center for squamous cell carcinomas either with recurrences or with invaded resection margins. The treatment combined new surgical resection with protontherapy. Specific improvements in proton beam therapy have been made at the Nice Cyclotron to adapt the treatment to conjunctival tumors. Proton beam carving consists in using a specific device to treat the thickness of the whole lesion site and the adjacent conjunctiva and to spare the surrounding healthy structures. RESULTS: Patients were staged according to the TNM classification of malignant tumors in T2: 3; T3: 5; T4: 7. Mean follow-up was 39.1 months (range, 6-90 months). Our 15 patients included 12 males and three females. Left eyes were involved in eight cases. The mean age at first consultation was 63.7 years (range, 46-80 years). In 13 cases (86.8%), the bulbar and limbic conjunctiva was involved, in five of these cases the cornea was invaded, and the anterior chamber was involved in one case. In one case, the tumor was located on bulbar conjunctiva near the caruncle (6.6%) and in one case in the fornix (6.6%). One patient died of another cancer after 48 months of follow-up. We obtained local tumor control for 13 patients (86.8%) and recurrences for two patients (13.2%). One of them has presented with cervical node metastases. These two patients who presented recurring and extensive tumors had had previous repeated surgeries in other centers. Moreover, proton beam therapy was performed more than 6 months after the initial treatment. Exenteration and enucleation had to be performed to treat these recurrences 6 and 24 months after proton beam therapy. The exentered patient has been lost to follow-up. No patients developed recurrences with additional proton beam therapy performed within 6 months after initial surgical resection. As for side effects, seven patients suffered from sicca syndrome, six needed cataract surgeries, three unesthetic dilatations of episclera vessels, two conjunctival postradiation dysplasias, two experienced eyelash loss, one stenosis of the lacrimal duct, and one glaucoma controlled by monotherapy. Conjunctiva and amniotic grafts had to be performed on one of the patients presenting with dysplasia. Due to the rarity and diversity of these cases, it is nearly impossible to carry out prospective and comparative studies. CONCLUSION: Traditional adjuvant treatments often failed to control recurring and invasive squamous cell carcinomas. We often ended up performing exenteration to control local recurrences. The preliminary results of the present study suggest that proton beam therapy may be considered as a good alternative to traditional treatments with acceptable side effects.

Neural networks underlying hyperkinetic seizures of "temporal lobe" origin.

PURPOSE: Hyperkinetic seizures are most often considered to originate from prefrontal cortex. Recently however, it has been suggested that hyperkinetic seizures can be found in patients with temporal lobe seizures. The objective of this study was to determine the features of temporal epilepsy with hyperkinetic seizures and the functional anatomy of involved brain networks. METHODS: We retrospectively identified patients investigated by depth electrodes (SEEG) in whom hyperkinetic manifestations were proved to be linked to initial temporal lobe involvement. Seizure organisation was determined according to the "Epileptogenicity Index" (EI), a new way to quantify rapid discharges at seizure onset. RESULTS: We found 7 patients among 130 SEEG investigations that fulfilled the inclusion criteria. Most of the patients presented with hyperkinetic occurring (or predominating) during sleep. SEEG signal analysis demonstrated a common temporo-frontal network in which the temporal pole played a central role. Major involvement of the orbito-frontal cortex and to a lesser extent the cingulate gyrus was also a particular feature of these seizures. DISCUSSION: Seizures originating in the temporal lobe must be recognized as an important cause of hyperkinetic seizures. The temporal pole and its connexions with medio-basal prefrontal cortex represent the main structures involved in epileptogenic networks.

The neuronal sources of EEG: modeling of simultaneous scalp and intracerebral recordings in epilepsy.

In many applications which make use of EEG to investigate brain functions, a central question is often to relate the recorded signals to the spatio-temporal organization of the underlying neuronal sources of activity. A modeling attempt to quantitatively investigate this imperfectly known relationship is reported. The proposed plausible model of EEG generation relies on an accurate representation of the neuronal sources of activity. It combines both an anatomically realistic description of the spatial features of the sources (convoluted dipole layer) and a physiologically relevant description of their temporal activities (coupled neuronal populations). The model was used in the particular context of epileptiform activity (interictal spikes) to interpret simultaneously generated scalp and intracerebral EEG. Its integrative properties allowed for the bridging between source-related parameters (spatial extent, location, synchronization) and the properties of resulting EEG signals (amplitude of spikes, amplitude gradient along intracerebral electrodes, topography over scalp electrodes). The sensitivity of both recording modalities to source-related parameters was also studied. The model confirmed that the cortical area involved in interictal spikes is rather large. Its relative location with respect to recording electrodes was found to strongly influence the properties of EEG signals as the source geometry is a critical parameter. The influence, on simulated signals, of the synchronization degree between neuronal populations within the epileptic source was also investigated. The model revealed that intracerebral EEG can reflect epileptic activities corresponding to weak synchronization between neuronal populations of the epileptic patch. These results, as well as the limitations of the model, are discussed.

Long-term efficacy of gamma knife radiosurgery in mesial temporal lobe epilepsy.

BACKGROUND: Gamma knife (GK) radiosurgery has been proposed as an alternative to classic microsurgery in mesial temporal lobe epilepsy (MTLE). Short-term follow-up studies have reported encouraging results, but long-term efficacy is not known. OBJECTIVE: To report the efficacy and tolerance of GK radiosurgery in MTLE after a follow-up > 5 years. METHODS: Patients with a follow-up > 5 years presenting with MTLE and treated with a marginal dose of 24 Gy were included in the study. RESULTS: Fifteen patients were included. Eight were treated on the left side, and 7 were treated on the right. The mean follow-up was 8 years (range 6-10 years). At the last follow-up, 9 of 16 patients (60%) were considered seizure free (Engel Class I) (4/16 in Class IA, 5/16 in Class IB). Seizure cessation occurred with a mean delay of 12 months (+/- 3) after GK radiosurgery, often preceded by a period of increasing aura or seizure occurrence (6/15 patients). The mean delay of appearance of the first neuroradiologic changes was 12 months (+/- 4). Nine patients (60%) experienced mild headache and were placed on corticosteroid treatment for a short period. All patients who were initially seizure free experienced a relapse of isolated aura (10/15, 66%) or complex partial seizures (10/15, 66%) during antiepileptic drug tapering. Restoration of treatment resulted in good control of seizures. CONCLUSION: Gamma knife radiosurgery is an effective and safe treatment for mesial temporal lobe epilepsy. Results are maintained over time with no additional side effects. Long-term results compare well with those of conventional surgery.

[The concept of an epileptogenic network in human partial epilepsies]. / Le concept de réseau épileptogène dans les épilepsies partielles humaines.

An anatomical and functional model of drug-resistant partial seizures is presented and discussed based on research conducted by our team over the last decade. This research is based on the study of intracerebral stereoelectroencephalography (SEEG) recordings in an attempt to identify the neural networks involved in generating paroxystic activities so as to understand their dynamics in space and time, and to propose targeted therapies that could "control" these networks. Today, the classical notion of epileptic focus should be replaced by a more complex model that takes into account the potential interactions within the neuronal networks involved in seizures. During partial epileptic seizures, the cerebral structures involved are the seat of characteristic oscillations that may be synchronized or, on the contrary, that can desynchronize in a transitory manner. These epileptic rhythms disturb the physiological rhythms that underlie the cognitive and emotional processes, which can thus be altered in partial epilepsy, even if located far from the original discharge site. We suggest that seizures originate in a group of structures that are highly epileptogenic (epileptogenic zone network, [EZN]) whose activity is synchronized before the appearance of fast oscillations that are transitorily desynchronized. Later, other cortical and subcortical structures are the seat of slower, synchronized rhythmic modifications (propagation network, [PN]). The emergence of clinical signs in the seizure depend on these phenomena, which in some cases can mimic a normal cognitive process or, on the contrary, lead to a deep rupture in normal cerebral functioning.

[High-resolution EEG (HR-EEG) and magnetoencephalography (MEG)]. / EEG haute résolution (EEG-HR) et magnétoencéphalographie (MEG).

HR-EEG (high resolution EEG) and MEG (magnetoencephalography) allow the recording of cerebral electromagnetic activities with excellent temporal resolution. These tools have also considerably progressed in spatial resolution and now constitute real methods of Electric and Magnetic Source Imaging. Their limits and the precision of the results obtained are discussed in distinct types of partial epilepsy. HR-EEG and MEG allow localization of scalp-EEG interictal spikes and more rarely ictal activities. They now contribute to the presurgical evaluation of pharmacoresistant partial epilepsies. These investigations appear to be of particular importance in presurgical assessment of MRI-negative epilepsy.

[Radiosurgery for drug-resistant epilepsies: state of the art, results and perspectives]. / Rôle de la radiochirugie Gamma Knife dans le traitement des épilepsies pharmacorésistantes: situation actuelle, résultats et perspectives.

BACKGROUND: There is growing interest in the use of radiosurgery in epilepsy. We analyzed our experience in this field in an attempt to define the potential of radiosurgery in epileptology. MATERIAL AND METHODS: [corrected] Our local clinical experience (134 patients), accumulated over the last 15 years, mainly includes treatment of temporal lobe epilepsy without space-occupying lesions (59 patients), including 53 with pure MTLE, 61 cases of hypothalamic hamartoma, two cases of callosotomy, and 12 other types of epilepsy. RESULTS: The analysis of our material, as well as other clinical and experimental data, suggest that the use of radiosurgery is beneficial only to patients in whom a strict preoperative definition of the extent of the epileptogenic zone (or network) has been achieved and strict rules of dose planning have been applied. As soon as these principles are not observed, the risk of treatment failure and/or side effects increases dramatically. Long-term outcome data are now available and published for MTLE but not yet for other types of epilepsy. Long-term safety and efficacy in MTLE are comparable to surgical resection but radiosurgery has the advantage of sparing verbal memory in patients operated by Gamma Knife (GK) on the dominant side. In small hamartomas, the efficacy is comparable to microsurgery but with a dramatic reduction in risk. CONCLUSION: The vast amount of clinical materiel and long-term evaluation now support the use of GK surgery in small hypothalamic hamartomas and MTLE when the patient is at risk of verbal memory loss.

[Natural development over 4 years of a macular small choroidal melanoma in a single-eyed patient]. / Evolution naturelle sur cinq ans d'un mélanome choroïdien de petite taille chez un patient monophtalme.

We report the case of a single-eyed patient with a small (2.2 mm thick with largest tumor diameter 7.6 mm) choroidal melanoma involving the entire macular surface with few functional signs. Visual acuity was 20/63. The patient was informed of the side effects and so was followed regularly at the oncology unit over 4 years. During this period, the tumor volume increased fourfold (the thickness reached 4.3 mm and the LTD 10.4 mm), with visual acuity decreasing to 20/250: proton beam therapy was therefore performed. The patient showed no metastasis more than 2 years after the treatment. This unusual case raises the question of small choroidal melanoma management, especially if the patient is single-eyed, in good general health, middle-aged and if the tumor is retrofoveal with just a few functional signs: when, why and who should be treated?

Modeling and interpretation of scalp-EEG and depth-EEG signals during interictal activity.

In epileptic patients candidate to surgery, the interpretation of electrophysiological signals recorded invasively (depth-EEG) and non-invasively (scalp-EEG) is a crucial issue to determine epileptogenic network and to define subsequent therapeutic strategy. This issue is addressed in this work through realistic modeling of both scalp-EEG and depth-EEG signals. The model allows for studying the influence, on signals, of source-related parameters leading to the generation of epileptic transient activity (interictal spikes). This parametric study is based on a variety of scenarios in which either spatial or temporal features of the sources of activity are modified. Statistical quantities measured on simulated signals allow for better understanding of the influence of source-related parameters on the information conveyed by these signals, collected from scalp or depth electrodes.

Spread-out Bragg peak and monitor units calculation with the Monte Carlo code MCNPX.

The aim of this work was to study the dosimetric potential of the Monte Carlo code MCNPX applied to the protontherapy field. For series of clinical configurations a comparison between simulated and experimental data was carried out, using the proton beam line of the MEDICYC isochronous cyclotron installed in the Centre Antoine Lacassagne in Nice. The dosimetric quantities tested were depth-dose distributions, output factors, and monitor units. For each parameter, the simulation reproduced accurately the experiment, which attests the quality of the choices made both in the geometrical description and in the physics parameters for beam definition. These encouraging results enable us today to consider a simplification of quality control measurements in the future. Monitor Units calculation is planned to be carried out with preestablished Monte Carlo simulation data. The measurement, which was until now our main patient dose calibration system, will be progressively replaced by computation based on the MCNPX code. This determination of Monitor Units will be controlled by an independent semi-empirical calculation.

What is the significance of interictal water diffusion changes in frontal lobe epilepsies?

The aim of this study was to better understand the significance of interictal changes in water molecule diffusivity defined by diffusion-weighted imaging (DWI) in frontal lobe epilepsy (FLE), as well as to test the accuracy of interictal DWI in the definition of the epileptogenic zone (EZ). DWI was carried out in 14 patients with refractory FLE (9 negative-MRI) as well as in 25 controls. Statistical mapping analysis (SPM2) of diffusivity maps was used to detect, for each subject, significant diffusivity alterations. We then studied the relationships between diffusion and depth recorded electrical abnormalities. Clinical correlates of the extent of diffusivity changes were also tested. We found areas of significantly increased diffusivity (SID) in 13 patients. Eight had SID in the EZ, 9 within the irritative zone (IZ) and 12 outside, mainly in connected areas. We found a correlation between the extent of SID and the duration of epilepsy (p corrected=0.026, R=0.621). In addition, SID was significantly less widespread in negative-MRI patients (p=0.028). However, we found no significant differences concerning either seizure frequency (p=0.302), seizure generalization (p=0.841), history of status (p=0.396), or surgical outcome (p=0.606). We suggest that SID in normal appearing areas is not a specific signature of epileptogenicity in FLE, and is more likely to reflect multifactorial and potentially evolving neuro-glial injuries.

[Analysis of ocular surface alterations following proton beam radiation in eyes with conjunctival malignant melanoma]. / Analyse der okulären Oberfläche nach Protonenbestrahlung bei malignem Melanom der Bindehaut.

BACKGROUND: In cases of large, diffuse or multilocular growth pattern of conjunctival melanoma, proton beam irradiation can serve as an alternative therapy to exenteration. In extended tumours, ocular surface problems can result after therapy. In this study we examined ocular surface integrity of ten patients who underwent proton beam radiation between 1996 and 2002. METHODS: The patients were examined during their follow-up. Eight of the ten cases who underwent proton radiotherapy were recurrent tumours, which were previously treated with other adjuvant therapies. We performed a standard ophthalmological examination and detailed tear film diagnostics. RESULTS: The follow-up was 17-87 months (mean: 40.9+/-20.1). In six cases more than 50% of the upper and lower eyelids were included in the radiation field. All of these cases showed moderate to severe sicca symptoms. The impression cytology revealed squamous metaplasia of conjunctival cells in nine of ten cases. CONCLUSIONS: Squamous metaplasia of conjunctival epithelia indicates a radiogenic, persisting disturbance of differentiation of the conjunctival epithelial cells. The tear film instability correlates with the loss of mucin-secreting goblet cells and meibomian gland dysfunction.