Pathways to epilepsy surgery in children with tuberous sclerosis complex-associated epilepsy.

BACKGROUND: Previous studies showed the efficacy of epilepsy surgery in carefully selected children with epilepsy associated with tuberous sclerosis complex. However, how this selection is conducted, and the characteristics of the patients brought to surgery are still poorly described. By conducting a multicentric retrospective cohort study covering the practice of the last twenty years, we describe the paths leading to epilepsy surgery in children with epilepsy associated with tuberous sclerosis complex. METHODS: We identified 84 children diagnosed with tuberous sclerosis complex and epilepsy by matching two exhaustive registries of genetic diseases and subsequent medical records reviews within two French neuropediatric and epilepsy centers. Demographic, clinical, longitudinal, and diagnostic and surgical procedures data were collected. RESULTS: Forty-six percent of the children were initially drug-resistant and 19% underwent resective surgery, most often before the age of four. Stereotactic electroencephalography was performed prior to surgery in 44% of cases. Fifty-seven and 43% of patients remained seizure-free one and ten years after surgery, respectively. In addition, 52% of initially drug-resistant patients who did not undergo surgery were seizure-free at the last follow-up. The number of anti-seizure medications required decreased in 50% of cases after surgery. Infantile spasms, intellectual disability, autism spectrum disorder or severe behavioral disorders were not contraindications to surgery but were associated with a higher rate of complications and a lower rate of seizure freedom after surgery. CONCLUSION: Despite the assumption of complex multifocal epilepsy and practical difficulties in young children with tuberous sclerosis complex, successful surgery results are comparable with other populations of patients with drug-resistant epilepsy, and a spontaneous evolution to drug-sensitive epilepsy may occur in non-operated patients.

Long-term Effect of Multichannel tDCS Protocol in Patients with Central Cortex Epilepsies Associated with Epilepsia Partialis Continua.

Epilepsia partialis continua (EPC) is a rare type of focal motor status epilepticus that causes continuous muscle jerking in a specific part of the body. Experiencing this type of seizure, along with other seizure types, such as focal motor seizures and focal to bilateral tonic-clonic seizures, can result in a disabling situation. Non-invasive brain stimulation methods like transcranial direct current stimulation (tDCS) show promise in reducing seizure frequency (SF) when medications are ineffective. However, research on tDCS for EPC and related seizures is limited. We evaluated personalized multichannel tDCS in drug-resistant EPC of diverse etiologies for long-term clinical efficacy We report three EPC patients undergoing a long-term protocol of multichannel tDCS. The patients received several cycles (11, 9, and 3) of five consecutive days of stimulation at 2 mA for 2 × 20 min, targeting the epileptogenic zone (EZ), including the central motor cortex with cathodal electrodes. The primary measurement was SF changes. In three cases, EPC was due to Rasmussen's Encephalitis (case 1), focal cortical dysplasia (case 2), or remained unknown (case 3). tDCS cycles were administered over 6 to 22 months. The outcomes comprised a reduction of at least 75% in seizure frequency for two patients, and in one case, a complete cessation of severe motor seizures. However, tDCS had no substantial impact on the continuous myoclonus characterizing EPC. No serious side effects were reported. Long-term application of tDCS cycles is well tolerated and can lead to a considerable reduction in disabling seizures in patients with various forms of epilepsy with EPC.

Neurofeedback and epilepsy: Renaissance of an old self-regulation method?

Neurofeedback is a brain-computer interface tool enabling the user to self-regulate their neuronal activity, and ultimately, induce long-term brain plasticity, making it an interesting instrument to cure brain disorders. Although this method has been used successfully in the past as an adjunctive therapy in drug-resistant epilepsy, this approach remains under-explored and deserves more rigorous scientific inquiry. In this review, we present early neurofeedback protocols employed in epilepsy and provide a critical overview of the main clinical studies. We also describe the potential neurophysiological mechanisms through which neurofeedback may produce its therapeutic effects. Finally, we discuss how to innovate and standardize future neurofeedback clinical trials in epilepsy based on evidence from recent research studies.

High-purified cannabidiol efficacy and safety in a cohort of adult patients with various types of drug-resistant epilepsies.

About 30% of patients with epilepsy are drug resistant. Lennox-Gastaut syndrome (LGS), Dravet syndrome (DS) and tuberous sclerosis complex (TSC) are diseases for which high-purified-cannabidiol (CBD) known as Epidiolex® (GW pharma) can be prescribed in add-on of other medications in case of drug-resistance. Currently, there are only a few recent data in the literature about the efficacy and safety of CBD in other forms of refractory epilepsies especially focal epilepsies in adults. We report retrospectively the experience of high-purified-CBD use in two French reference medical centers for epilepsy in various forms of drug-resistant epilepsy. We distinguished two groups of patients: group A with epileptic encephalopathies and group B with focal or multifocal epilepsy. Safety and efficacy (% of responder patients) were evaluated. Finally, 73 patients (51 in group A and 22 in group B) used high-purified CBD as an add-on treatment for their drug-resistant epilepsy. Patients in group A were significantly younger (P=0.0155), with a longer exposition of treatment (P=0.0497) than group B and with higher doses (P=0.0300). Respectively, 15 patients (29.4%) and five patients (22.7%) were responders during the follow-up period (P=0.552). The association with clobazam was more frequent in responders than in non-responder patients (16 patients [80%] versus four [20%]). The most frequent side effect was somnolence. At the end of follow-up, 15 patients in group A (29.4%) and nine patients in group B (40.1%) had stopped the high-purified-CBD treatment due to aggravation of seizure, absence of positive effects, or adverse events. This study showed no significant difference regarding the type of drug-resistant epilepsy and suggests that this treatment may be of interest for all types of drug-resistant epilepsy.

Sleep and epilepsy: A clinical and pathophysiological overview.

The interaction between sleep and epilepsy is complex. A better understanding of the mechanisms linking sleep and epilepsy appears increasingly important as it may improve diagnosis and therapeutic strategies in patients with epilepsy. In this narrative review, we aim to (i) provide an overview of the physiological and pathophysiological processes linking sleep and epilepsy; (ii) present common sleep disorders in patients with epilepsy; (iii) discuss how sleep and sleep disorders should be considered in new therapeutic approaches to epilepsy such as neurostimulation; and (iv) present the overall nocturnal manifestations and differential diagnosis between epileptic seizures and parasomnia.

Basal temporal lobe epilepsy: SEEG electroclinical characteristics.

OBJECTIVE: Temporal lobe epilepsy is the most common type of focal drug-resistant epilepsy. Seizures with predominant involvement of basal temporal regions (BTR) are not well characterized. In this stereo electroencephalography (SEEG) study, we aimed at describing the ictal networks involving BTR and the associated clinical features. METHODS: We studied 24 patients explored with SEEG in our center with BTR sampling. We analyzed their seizures using a quantitative method: the "epileptogenicity index". Then we reported the features of the patients with maximal epileptogenicity within BTR, especially ictal network involved, ictal semiology and post-surgical outcome. RESULTS: We found that rhinal cortex, parahippocampal cortex and posterior fusiform gyrus were the most epileptogenic structures within the BTR (mean EI: 0.57, 0.55, 0.54 respectively). Three main groups of epileptogenic zone organization were found: anterior (23% of total seizures) posterior (30%) and global (47%, both anterior and posterior). Contralateral spread was found in 35% of left seizures and 20% of right seizures. Naming deficit was more prevalent in left BTR (71% vs 29% in right seizures; p = 0.01) whereas automatic speech production was preferentially represented in right seizures (11% vs 54%; p = 0.001). Surgery was proposed for 11 patients (45.8%), leading to seizure freedom in 72% (Engel Class I). One patient presented post-operative permanent functional deficit. CONCLUSION: Basal-temporal lobe epilepsy seems to be a specific entity among the temporal epilepsy spectrum with specific clinical characteristics. Resective surgery can be proposed with good outcomes in a significant proportion of patients and is safe provided that adequate language assessment has been preoperatively made.

Medical treatment of Rasmussen's Encephalitis: A systematic review.

Rasmussen's encephalitis (RE) is a severe, rare, chronic inflammatory brain disease resulting in drug-resistant epilepsy and progressive destruction of one hemisphere with loss of neurological function. RE is associated with a deterioration of background electroencephalography (EEG) activity, a progressive atrophy on magnetic resonance imaging (MRI) imaging and an extensive positron emission tomography hypometabolism over the affected hemisphere. RE is an immune-mediated disease, with a predominant role of CD8+ T cytotoxic cells, microglial cells, and activation of inflammasome pathway. The diagnosis of RE is based on clinical (intractable epilepsy and neurological deterioration), electrophysiological (unilateral EEG slowing) and MRI (hemiatrophy) criteria. Antiseizure medications are generally unable to stop seizures. The most effective procedure is hemispherotomy (surgical disconnection of one cerebral hemisphere), but this is associated with permanent motor and neurological deficits. Treatments targeting the immune system are recommended especially in the early stages of the disease or in patients with slow disease progression and mild deficits and/or not eligible for surgery. Based on the pathophysiology, several immunotherapies have been tried in RE (none exhaustively: corticosteroid, intravenous immunoglobulins, tacrolimus, azathioprine, adalimumab, mycophenolate mofetil, natalizumab). However, only small cohorts have been reported without comparative study. In this review, we will summarise some pathophysiological mechanisms of RE, before reporting the literature data concerning immunotherapies. We then discuss the limitations of these studies and the prospects for further research.

Psychogenic non-epileptic seizures: Chronology of multidisciplinary team approach to diagnosis and management.

While the diagnosis and management of psychogenic non-epileptic seizures (PNES) remain challenging, certain evidence-based guidelines exist, which can help to optimize patient care. A multidisciplinary team approach appears to have many benefits. Current recommendations exist for some aspects of diagnosis and management of PNES, including levels of diagnostic certainty as proposed by the International League Against Epilepsy's expert Task Force on PNES. Other aspects of clinical still care lack clear consensus, including use of suggestion techniques for recording PNES and optimal terminology, since the term "functional seizures" has recently been proposed as a possible term to replace "PNES". The present article aims to (1) review current recommendations and (2) discuss our own team's experience in managing patients with PNES. This is organized chronologically in terms of the roles of the neurologist, psychiatrist and psychologist, and discusses diagnostic issues, psychiatric assessment and treatment, and psychotherapeutic approaches.

Predictive factors of postoperative outcome in the elderly after resective epilepsy surgery.

OBJECTIVE: To evaluate the efficiency of resective epilepsy surgery (RES) in patients over 50 years and determine prognostic factors. RESULTS: Over the 147 patients over 50 years (54.9±3.8 years [50-69]) coming from 8 specialized French centres for epilepsy surgery, 72.1%, patients were seizure-free and 91.2% had a good outcome 12 months after RES. Seizure freedom was not associated with the age at surgery or duration of epilepsy. In multivariate analysis, seizure freedom was associated with MRI and neuropathological hippocampal sclerosis (HS) (P=0.009 and P=0.028 respectively), PET hypometabolism (P=0.013), temporal epilepsy (P=0.01). On the contrary, the need for intracranial exploration was associated with a poorer prognosis (P=0.001). Postoperative number of antiepileptic drugs was significantly lower in the seizure-free group (P=0.001). Neurological adverse event rate after surgery was 21.1% and 11.7% of patients had neuropsychological adverse effects overall transient. CONCLUSIONS: RES is effective procedure in the elderly. Even safe it remains at higher risk of complication and population should be carefully selected. Nevertheless, age should not be considered as a limiting factor, especially when good prognostic factors are identified.

The Bayesian Virtual Epileptic Patient: A probabilistic framework designed to infer the spatial map of epileptogenicity in a personalized large-scale brain model of epilepsy spread.

Despite the importance and frequent use of Bayesian frameworks in brain network modeling for parameter inference and model prediction, the advanced sampling algorithms implemented in probabilistic programming languages to overcome the inference difficulties have received relatively little attention in this context. In this technical note, we propose a probabilistic framework, namely the Bayesian Virtual Epileptic Patient (BVEP), which relies on the fusion of structural data of individuals to infer the spatial map of epileptogenicity in a personalized large-scale brain model of epilepsy spread. To invert the individualized whole-brain model employed in this study, we use the recently developed algorithms known as No-U-Turn Sampler (NUTS) as well as Automatic Differentiation Variational Inference (ADVI). Our results indicate that NUTS and ADVI accurately estimate the degree of epileptogenicity of brain regions, therefore, the hypothetical brain areas responsible for the seizure initiation and propagation, while the convergence diagnostics and posterior behavior analysis validate the reliability of the estimations. Moreover, we illustrate the efficiency of the transformed non-centered parameters in comparison to centered form of parameterization. The Bayesian framework used in this work proposes an appropriate patient-specific strategy for estimating the epileptogenicity of the brain regions to improve outcome after epilepsy surgery.

The role of the dorsal anterior insula in ecstatic sensation revealed by direct electrical brain stimulation.

BACKGROUND: An ecstatic phenomenon is an altered state of consciousness with a sense of "hyper-reality", and a complete present-moment awareness with a feeling of union with the Universe. A better understanding of the network mechanisms underlying this fascinating subjective experience may help to unravel some mysteries of human consciousness. Insula has been recently proposed to be a key region to elicit these symptoms. OBJECTIVE/HYPOTHESIS: We studied functional connectivity changes in several brain areas during the induction of ecstatic auras by direct electrical stimulation of the dorsal anterior insular cortex in patients with refractory focal epilepsy implanted with intracerebral electrodes (stereotactic-EEG, SEEG) in the context of their pre-surgical evaluation. METHODS: Three patients were selected on the basis of the occurrence of ecstatic symptoms triggered by direct intracerebral electrical stimulation (ES) of the antero-dorsal part of the insula. ES was performed (50 Hz, 1.5-2.1 mA, in a bipolar fashion to each contact in the gray matter during a 3 s period) to map functional cortices and trigger habitual seizures. One stimulation inducing ecstatic changes in each patient was analyzed. Functional connectivity analysis was performed by measuring interdependencies (nonlinear regression analysis based on the h2 coefficient) between SEEG signals before and after stimulations. RESULTS: In all patients, only the stimulation of dorsal anterior insula was able to reproduce an ecstatic aura. We observed a significant increase of functional connectivity values between several brain regions in the immediate period following stimulations. The most commonly implicated region was the dorsal anterior insula. Out-degrees (a measure intended to identify leading structures in a network) identified the dorsal anterior insula as the most common leading region in the induced networks. CONCLUSION(S): Our findings bring additional support in favor of a major role played by the dorsal anterior insula in ecstatic experiences.

Deep brain activities can be detected with magnetoencephalography.

The hippocampus and amygdala are key brain structures of the medial temporal lobe, involved in cognitive and emotional processes as well as pathological states such as epilepsy. Despite their importance, it is still unclear whether their  neural activity can be recorded non-invasively. Here, using simultaneous intracerebral and magnetoencephalography (MEG) recordings in patients with focal drug-resistant epilepsy, we demonstrate a direct contribution of amygdala and hippocampal activity to surface MEG recordings. In particular, a method of blind source separation, independent component analysis, enabled activity arising from large neocortical networks to be disentangled from that of deeper structures, whose amplitude at the surface was small but significant. This finding is highly relevant for our understanding of hippocampal and amygdala brain activity as it implies that their activity could potentially be measured non-invasively.

Malformations of cortical development: The role of 7-Tesla magnetic resonance imaging in diagnosis.

Comparison studies between 7T and 1.5 or 3T magnetic resonance imaging (MRI) have demonstrated the added value of ultra-high field (UHF) MRI to better identify, delineate and characterize malformations of cortical development (MCD), and to disambiguate doubtful findings observed at lower field strengths. High resolution structural sequences such as magnetization prepared two rapid acquisition gradient echoes (MP2RAGE), fluid and white matter suppression MP2RAGE (FLAWS), and susceptibility-weighted imaging (SWI) appear to be key to the improvement of MCD diagnosis in clinical practice. 7T MRI offers not only images of high resolution and contrast but also provides many quantitative approaches capable of acting as more efficient probes of microstructure and ameliorating the categorization of MCDs. Post-processing of multiparametric ultra-high resolution and quantitative data may also be used to improve automated detection of MCD via machine learning. Therefore, 7T MRI can be considered as a useful tool in the presurgical evaluation of drug-resistant partial epilepsies, particularly, but not exclusively, in cases of normal appearing conventional MRI. It also opens many perspectives in the fields of in vivo histology and computational anatomy.

EpiTools, A software suite for presurgical brain mapping in epilepsy: Intracerebral EEG.

BACKGROUND: In pharmacoresistant epilepsy, exploration with depth electrodes can be needed to precisely define the epileptogenic zone. Accurate location of these electrodes is thus essential for the interpretation of Stereotaxic EEG (SEEG) signals. As SEEG analysis increasingly relies on signal processing, it is crucial to make a link between these results and patient's anatomy. Our aims were thus to develop a suite of software tools, called "EpiTools", able to i) precisely and automatically localize the position of each SEEG contact and ii) display the results of signal analysis in each patient's anatomy. NEW METHOD: The first tool, GARDEL (GUI for Automatic Registration and Depth Electrode Localization), is able to automatically localize SEEG contacts and to label each contact according to a pre-specified nomenclature (for instance that of FreeSurfer or MarsAtlas). The second tool, 3Dviewer, enables to visualize in the 3D anatomy of the patient the origin of signal processing results such as rate of biomarkers, connectivity graphs or Epileptogenicity Index. RESULTS: GARDEL was validated in 30 patients by clinicians and proved to be highly reliable to determine within the patient's individual anatomy the actual location of contacts. COMPARISON WITH EXISTING METHODS: GARDEL is a fully automatic electrode localization tool needing limited user interaction (only for electrode naming or contact correction). The 3Dviewer is able to read signal processing results and to display them in link with patient's anatomy. CONCLUSION: EpiTools can help speeding up the interpretation of SEEG data and improving its precision.

Time rescaling reproduces EEG behavior during transition from propofol anesthesia-induced unconsciousness to consciousness.

General anesthesia (GA) is a reversible manipulation of consciousness whose mechanism is mysterious at the level of neural networks leaving space for several competing hypotheses. We recorded electrocorticography (ECoG) signals in patients who underwent intracranial monitoring during awake surgery for the treatment of cerebral tumors in functional areas of the brain. Therefore, we recorded the transition from unconsciousness to consciousness directly on the brain surface. Using frequency resolved interferometry; we studied the intermediate ECoG frequencies (4-40 Hz). In the theoretical study, we used a computational Jansen and Rit neuron model to simulate recovery of consciousness (ROC). During ROC, we found that f increased by a factor equal to 1.62 ± 0.09, and δf varied by the same factor (1.61 ± 0.09) suggesting the existence of a scaling factor. We accelerated the time course of an unconscious EEG trace by an approximate factor 1.6 and we showed that the resulting EEG trace match the conscious state. Using the theoretical model, we successfully reproduced this behavior. We show that the recovery of consciousness corresponds to a transition in the frequency (f, δf) space, which is exactly reproduced by a simple time rescaling. These findings may perhaps be applied to other altered consciousness states.

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.

Technical solutions for simultaneous MEG and SEEG recordings: towards routine clinical use.

OBJECTIVE: The simultaneous recording of intracerebral EEG (stereotaxic EEG, SEEG) and magnetoencephalography (MEG) is a promising strategy that provides both local and global views on brain pathological activity. Yet, acquiring simultaneous signals poses difficult technical issues that hamper their use in clinical routine. Our objective was thus to develop a set of solutions for recording a high number of SEEG channels while preserving signal quality. APPROACH: We recorded data in a patient with drug resistant epilepsy during presurgical evaluation. We used dedicated insertion screws and optically insulated amplifiers. We recorded 137 SEEG contacts on 10 depth electrodes (5-15 contacts each) and 248 MEG channels (magnetometers). Signal quality was assessed by comparing the distribution of RMS values in different frequency bands to a reference set of MEG acquisitions. MAIN RESULTS: The quality of signals was excellent for both MEG and SEEG; for MEG, it was comparable to that of MEG signals without concurrent SEEG. Discharges involving several structures on SEEG were visible on MEG, whereas discharges limited in space were not seen at the surface. SIGNIFICANCE: SEEG can now be recorded simultaneously with whole-head MEG in routine. This opens new avenues, both methodologically for understanding signals and improving signal processing methods, and clinically for future combined analyses.