The Interconnected Mechanisms of Oxidative Stress and Neuroinflammation in Epilepsy

One of the most important characteristics of the brain compared to other organs is its elevated metabolic demand. Consequently, neurons consume high quantities of oxygen, generating significant amounts of reactive oxygen species (ROS) as a by-product. These potentially toxic molecules cause oxidative stress (OS) and are associated with many disorders of the nervous system, where pathological processes such as aberrant protein oxidation can ultimately lead to cellular dysfunction and death. Epilepsy, characterized by a long-term predisposition to epileptic seizures, is one of the most common of the neurological disorders associated with OS. Evidence shows that increased neuronal excitability—the hallmark of epilepsy—is accompanied by neuroinflammation and an excessive production of ROS; together, these factors are likely key features of seizure initiation and propagation. This review discusses the role of OS in epilepsy, its connection to neuroinflammation and the impact on synaptic function. Considering that the pharmacological treatment options for epilepsy are limited by the heterogeneity of these disorders, we also introduce the latest advances in anti-epileptic drugs (AEDs) and how they interact with OS. We conclude that OS is intertwined with numerous physiological and molecular mechanisms in epilepsy, although a causal relationship is yet to be established.

Management of Epileptic Seizures in Disorders of Consciousness: An International Survey

Epileptic seizures/post-traumatic epilepsy (ES/PTE) are frequent in persons with brain injuries, particularly for patients with more severe injuries including ones that result in disorders of consciousness (DoC). Surprisingly, there are currently no best practice guidelines for assessment or management of ES in persons with DoC. This study aimed to identify clinician attitudes toward epilepsy prophylaxis, diagnosis and treatment in patients with DoC as well as current practice in regards to the use of amantadine in these individuals. A cross-sectional online survey was sent to members of the International Brain Injury Association (IBIA). Fifty physician responses were included in the final analysis. Withdrawal of antiepileptic drug/anti-seizure medications (AED/ASM) therapy was guided by the absence of evidence of clinical seizure whether or not the AED/ASM was given prophylactically or for actual seizure/epilepsy treatment. Standard EEG was the most frequent diagnostic method utilized. The majority of respondents ordered an EEG if there were concerns regarding lack of neurological progress. AED/ASM prescription was reported to be triggered by the first clinically evident seizure with levetiracetam being the AED/ASM of choice. Amantadine was frequently prescribed although less so in patients with epilepsy and/or EEG based epileptic abnormalities. A minority of respondents reported an association between amantadine and seizure. Longitudinal studies on epilepsy management, epilepsy impact on neurologic prognosis, as well as potential drug effects on seizure risk in persons with DoC appear warranted with the goal of pushing guideline development forward and improving clinical assessment and management of seizures in this unique, albeit challenging, population.

Permutation Entropy-Based Interpretability of Convolutional Neural Network Models for Interictal EEG Discrimination of Subjects with Epileptic Seizures vs. Psychogenic Non-Epileptic Seizures

The differential diagnosis of epileptic seizures (ES) and psychogenic non-epileptic seizures (PNES) may be difficult, due to the lack of distinctive clinical features. The interictal electroencephalographic (EEG) signal may also be normal in patients with ES. Innovative diagnostic tools that exploit non-linear EEG analysis and deep learning (DL) could provide important support to physicians for clinical diagnosis. In this work, 18 patients with new-onset ES (12 males, 6 females) and 18 patients with video-recorded PNES (2 males, 16 females) with normal interictal EEG at visual inspection were enrolled. None of them was taking psychotropic drugs. A convolutional neural network (CNN) scheme using DL classification was designed to classify the two categories of subjects (ES vs. PNES). The proposed architecture performs an EEG time-frequency transformation and a classification step with a CNN. The CNN was able to classify the EEG recordings of subjects with ES vs. subjects with PNES with 94.4% accuracy. CNN provided high performance in the assigned binary classification when compared to standard learning algorithms (multi-layer perceptron, support vector machine, linear discriminant analysis and quadratic discriminant analysis). In order to interpret how the CNN achieved this performance, information theoretical analysis was carried out. Specifically, the permutation entropy (PE) of the feature maps was evaluated and compared in the two classes. The achieved results, although preliminary, encourage the use of these innovative techniques to support neurologists in early diagnoses.

The Anti-Epileptic Effects of Carbenoxolone In Vitro and In Vivo

Gap junctions (GJs) are intercellular junctions that allow the direct transfer of ions and small molecules between neighboring cells, and GJs between astrocytes play an important role in the development of various pathologies of the brain, including regulation of the pathological neuronal synchronization underlying epileptic seizures. Recently, we found that a pathological change is observed in astrocytes during the ictal and interictal phases of 4-aminopyridin (4-AP)-elicited epileptic activity in vitro, which was correlated with neuronal synchronization and extracellular epileptic electrical activity. This finding raises the question: Does this signal depend on GJs between astrocytes? In this study we investigated the effect of the GJ blocker, carbenoxolone (CBX), on epileptic activity in vitro and in vivo. Based on the results obtained, we came to the conclusion that the astrocytic syncytium formed by GJ-associated astrocytes, which is responsible for the regulation of potassium, affects the formation of epileptic activity in astrocytes in vitro and epileptic seizure onset. This effect is probably an important, but not the only, mechanism by which CBX suppresses epileptic activity. It is likely that the mechanisms of selective inhibition of GJs between astrocytes will show important translational benefits in anti-epileptic therapies.

Functional MRI-based study of emotional experience in patients with psychogenic non-epileptic seizures: Protocol for an observational case-control study–EMOCRISES study

Background Psychogenic non epileptic seizures (PNES) are a frequent, disabling and costly disorder for which there is no consensual caring. They are considered as a dissociative disorder and they share many common characteristics with post-traumatic stress disorder (PTSD). Nevertheless, their pathophysiology is still unclear. In this study, we plan to obtain new data comparing functional brain activity of participants suffering from PNES, from PTSD and healthy controls via functional brain MRI during resting state and under emotional visual stimulation. The protocol presented hereunder describes an observational study with no direct treatment implication. Nevertheless, it could lead to a better understanding of PNES and to identifying targets for specialised cares of post-traumatic or dissociative disorders, like repetitive transcranial magnetic stimulation. Methods & analysis This is a prospective, single-centre, interventional, non-randomized, open, controlled and exploratory clinical study. It will involve 75 adult French, right-handed women in 3 groups, either suffering from PNES or PTSD, or healthy controls. An informed consent will be signed by each participant. All of them will be given psychiatric tests to assess dissociation and alexithymia, psychopathological profile and history, and emotional recognition. Each participant will undergo a functional brain MRI. We will record anatomical images and five functional imaging sequences including emotional periodic oscillatory stimulation, standard emotional stimulation, Go / No Go task under emotional stimulation, and resting state. Analysis will include a descriptive analysis of all participants and the treatment for functional magnetic resonance imaging images of each sequence. Registration, ethics & dissemination This study was approved the regional Protection of Persons Committee under the reference 16.10.01 and by the French National Medical Security Agency under the reference 2016-A01295-46. The protocol and results will be published in peer-reviewed academic medical journals and disseminated to research teams, databases, specialised media and concerned patients’ organisations.

Case Report: Primary Pulmonary Angiosarcoma With Brain Metastasis

Primary pulmonary angiosarcoma (PPA) is a rare malignant vascular tumor, of which early diagnosis is challenging due to lack of specific clinical manifestations and a low level of suspicion. Here, we report a case of PPA presented with advanced brain metastasis. A 21-year-old patient with 1 week history of headache and mild cough was hospitalized for a head injury. Head MRI showed multiple intracranial lesions with brain edema. Chest CT displayed bilateral pulmonary infiltrates with mediastinal lymph node enlargement. After 2 months of anti-tuberculosis treatment, the patient was readmitted for persistent headache and cough with occasional hemosputum along with worsening pulmonary and intracranial lesions. Despite seizure prophylaxis and control of intracranial pressure and brain edema, his symptoms progressively aggravated, accompanied by cough with bloody sputum, frequent epileptic seizures, and hypotension. He eventually developed coma and died within 3 months of onset of symptoms. An autopsy confirmed PPA with brain metastasis.

A Versatile Clustered Regularly Interspaced Palindromic Repeats Toolbox to Study Neurological CaV3.2 Channelopathies by Promoter-Mediated Transcription Control

Precise genome editing in combination with viral delivery systems provides a valuable tool for neuroscience research. Traditionally, the role of genes in neuronal circuits has been addressed by overexpression or knock-out/knock-down systems. However, those techniques do not manipulate the endogenous loci and therefore have limitations. Those constraints include that many genes exhibit extensive alternative splicing, which can be regulated by neuronal activity. This complexity cannot be easily reproduced by overexpression of one protein variant. The CRISPR activation and interference/inhibition systems (CRISPRa/i) directed to promoter sequences can modulate the expression of selected target genes in a highly specific manner. This strategy could be particularly useful for the overexpression of large proteins and for alternatively spliced genes, e.g., for studying large ion channels known to be affected in ion channelopathies in a variety of neurological diseases. Here, we demonstrate the feasibility of a newly developed CRISPRa/i toolbox to manipulate the promoter activity of the Cacna1h gene. Impaired, function of the low-voltage-activated T-Type calcium channel CaV3.2 is involved in genetic/mutational as well as acquired/transcriptional channelopathies that emerge with epileptic seizures. We show CRISPR-induced activation and inhibition of the Cacna1h locus in NS20Y cells and primary cortical neurons, as well as activation in mouse organotypic slice cultures. In future applications, the system offers the intriguing perspective to study functional effects of gain-of-function or loss-of-function variations in the Cacna1h gene in more detail. A better understanding of CaV3.2 channelopathies might result in a major advancement in the pharmacotherapy of CaV3.2 channelopathy diseases.