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.

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.

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.

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.

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.

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.

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.

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.

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.

Long-term memory deficits in temporal lobe epilepsy.

Memory complaints and deficits are common in patients with epilepsy, especially temporal lobe epilepsy (TLE), where memory-related brain structures are directly involved in the epileptic process. In recent years, substantial progress has been made in delineating memory impairment in TLE, challenging the traditional neuropsychological approach of the disorder. In particular, several lines of evidence have suggested that, beyond the apparent deficit demonstrable by standardized neuropsychological evaluations, TLE may also negatively interact with long-term memory, producing considerable loss of information of the patient's autobiographical history and an inability to maintain newly acquired information over a period of time. These observations have led to the development of innovative assessment techniques, and prompted a new domain of investigation focused on the relationships between interictal epileptiform activities and the integrity of anatomo-functional systems. The present paper reviews the available evidence for long-term memory deficits in TLE with respect to remote and very long-term memory, and discusses their putative pathophysiological mechanisms and the developing potential strategies to improve memory functioning.

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.

Resting cortical PET metabolic changes in psychogenic non-epileptic seizures (PNES).

BACKGROUND: The pathophysiology of psychogenic non-epileptic seizures (PNES) is poorly understood. Functional neuroimaging data in various functional neurological disorders increasingly support specific neurobiological dysfunction. However, to date, no studies have been reported of positron emission tomography (PET) in patients presenting with PNES. METHODS: Sixteen patients being evaluated in a specialist epilepsy centre underwent PET with 2-deoxy-2-[fluorine-18]fluoro-d-glucose ((18)FDG-PET) because of suspected intractable epileptic seizures. However, in all patients, the diagnosis was subsequently confirmed to be PNES with no coexisting epilepsy. (18)FDG-PET was also performed in 16 healthy controls. A voxel by voxel intergroup analysis was performed to look for significant differences in interictal (resting state) cerebral metabolism. In addition, metabolic connectivity was studied using voxel-wise inter-regional correlation analysis. RESULTS: In comparison to group analysis of healthy participants, the group analysis of patients with PNES exhibited significant PET hypometabolism within the right inferior parietal and central region, and within the bilateral anterior cingulate cortex. A significant increase in metabolic correlation was found in patients with PNES, in comparison to healthy participants, between the right inferior parietal/central region and the bilateral cerebellum, and between the bilateral anterior cingulate cortex and the left parahippocampal gyrus. CONCLUSIONS: To the best of our knowledge, this is the first study describing FDG-PET alterations in patients with PNES. Although we cannot exclude that our data reflect changes due to comorbidities, they may indicate a dysfunction of neural systems in patients with PNES. Hypometabolism regions might relate to two of the pathophysiological mechanisms that may be involved in PNES, that is, emotional dysregulation (anterior cingulate hypometabolism) and dysfunctional processes underlying the consciousness of the self and the environment (right parietal hypometabolism). TRIAL REGISTRATION NUMBER: NCT00484523.

Transient epileptic amnesia: Update on a slowly emerging epileptic syndrome.

Transient epileptic amnesia (TEA) is a recently individualized, late-onset, pharmaco-sensitive form of mesial temporal lobe epilepsy with recurrent episodes of acute memory loss, but also interictal memory disturbances characterized by autobiographical and topographical memory impairment and a long-term consolidation deficit. In this article, we review the main clinical and electrophysiological characteristics of TEA, discuss its putative neuroanatomical substrate and mechanisms, common features and how it differs from related concepts, with the overall aim to defend the idea that TEA deserves to be recognized as a distinct epilepsy syndrome. While the pathophysiological basis remains largely unknown, emotional and/or dysimmune factors may have a potential influence. Most importantly, the concept of TEA is highly relevant to tertiary epilepsy and memory clinics, but also to routine neurology practice, leading to an adequate diagnosis and management of epilepsy-related, acute and long-standing memory deficits.

[Biofeedback and drug-resistant epilepsy: back to an earlier treatment?]. / Biofeedback et épilepsie pharmacorésistante : le retour d'une thérapeutique ancienne ?

Biofeedback is a complementary non-pharmacological and non-surgical therapeutic developed over the last thirty years in the management of drug-resistant epilepsy. Biofeedback allows learning cognitive and behavioral strategies via a psychophysiological feedback loop. Firstly, this paper describes the different types of biofeedback protocols used for the treatment of drug-refractory epilepsy and their physiological justifications. Secondly, this paper analyzes the evidence of effectiveness, from a medical point of view, on reducing the numbers of seizures, and from a neurophysiological point of view, on the changing brain activity. Electroencephalography (EEG) biofeedback (neurofeedback) protocol on sensorimotor rhythms (SMR) has been investigated in many studies, the main limitation being small sample sizes and lack of control groups. The newer neurofeedback protocol on slow cortical potential (SCP) and galvanic skin response (GSR) biofeedback protocols have been used in a smaller number of studies. But, these studies are more rigorous with larger sized samples, matched control groups, and attempts to control the placebo effect. These protocols also open the way for innovative neurophysiological researches and may predict a renewal of biofeedback techniques. Biofeedback would have legitimacy in the field of clinical drug-resistant epilepsy at the interface between therapeutic and clinical neurophysiology.

NeoCoMM: A neocortical neuroinspired computational model for the reconstruction and simulation of epileptiform events.

BACKGROUND: Understanding the pathophysiological dynamics that underline Interictal Epileptiform Events (IEEs) such as epileptic spikes, spike-and-waves or High-Frequency Oscillations (HFOs) is of major importance in the context of neocortical refractory epilepsy, as it paves the way for the development of novel therapies. Typically, these events are detected in Local Field Potential (LFP) recordings obtained through depth electrodes during pre-surgical investigations. Although essential, the underlying pathophysiological mechanisms for the generation of these epileptic neuromarkers remain unclear. The aim of this paper is to propose a novel neurophysiologically relevant reconstruction of the neocortical microcircuitry in the context of epilepsy. This reconstruction intends to facilitate the analysis of a comprehensive set of parameters encompassing physiological, morphological, and biophysical aspects that directly impact the generation and recording of different IEEs. METHOD: a novel microscale computational model of an epileptic neocortical column was introduced. This model incorporates the intricate multilayered structure of the cortex and allows for the simulation of realistic interictal epileptic signals. The proposed model was validated through comparisons with real IEEs recorded using intracranial stereo-electroencephalography (SEEG) signals from both humans and animals. Using the model, the user can recreate epileptiform patterns observed in different species (human, rodent, and mouse) and study the intracellular activity associated with these patterns. RESULTS: Our model allowed us to unravel the relationship between glutamatergic and GABAergic synaptic transmission of the epileptic neural network and the type of generated IEE. Moreover, sensitivity analyses allowed for the exploration of the pathophysiological parameters responsible for the transitions between these events. Finally, the presented modeling framework also provides an Electrode Tissue Model (ETI) that adds realism to the simulated signals and offers the possibility of studying their sensitivity to the electrode characteristics. CONCLUSION: The model (NeoCoMM) presented in this work can be of great use in different applications since it offers an in silico framework for sensitivity analysis and hypothesis testing. It can also be used as a starting point for more complex studies.

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.