Remote effects of temporal lobe epilepsy surgery: Long‐term morphological changes after surgical resection

Tipologia: ORIGINAL ARTICLE

2023-04-25

Abstract

Objective

Epilepsy surgery is an effective treatment for drug-resistant patients. However, how different surgical approaches affect long-term brain structure remains poorly characterized. Here, we present a semiautomated method for quantifying structural changes after epilepsy surgery and compare the remote structural effects of two approaches, anterior temporal lobectomy (ATL), and selective amygdalohippocampectomy (SAH).

Methods

We studied 36 temporal lobe epilepsy patients who underwent resective surgery (ATL = 22, SAH = 14). All patients received same-scanner MR imaging preoperatively and postoperatively (mean 2 years). To analyze postoperative structural changes, we segmented the resection zone and modified the Advanced Normalization Tools (ANTs) longitudinal cortical pipeline to account for resections. We compared global and regional annualized cortical thinning between surgical treatments.

Results

Across procedures, there was significant cortical thinning in the ipsilateral insula, fusiform, pericalcarine, and several temporal lobe regions outside the resection zone as well as the contralateral hippocampus. Additionally, increased postoperative cortical thickness was seen in the supramarginal gyrus. Patients treated with ATL exhibited greater annualized cortical thinning compared with SAH cases (ATL: −0.08 ± 0.11 mm per year, SAH: −0.01 ± 0.02 mm per year, t = 2.99, P = 0.006). There were focal postoperative differences between the two treatment groups in the ipsilateral insula (P = 0.039, corrected). Annualized cortical thinning rates correlated with preoperative cortical thickness (r = 0.60, P < 0.001) and had weaker associations with age at surgery (r = −0.33, P = 0.051) and disease duration (r = −0.42, P = 0.058).

Significance

Our evidence suggests that selective procedures are associated with less cortical thinning and that earlier surgical intervention may reduce long-term impacts on brain structure.

Fonte: Epilepsia Open, T. Campbell Arnold, Lohith G. Kini, John M. Bernabei, Andrew Y. Revell, Sandhitsu R. Das, Joel M. Stein, Timothy H. Lucas, Dario J. Englot, Victoria L. Morgan, Brian Litt, Kathryn A. Davis

The epilepsy phenotype of ST3GAL3‐related developmental and epileptic encephalopathy

Tipologia: ORIGINAL ARTICLE

2023-04-24

Abstract

Objective

ST3GAL3-related developmental and epileptic encephalopathy (DEE-15) is an autosomal recessive condition characterized by intellectual disability, language and motor impairments, behavioral difficulties, stereotypies, and epilepsy. Only a few cases have been reported, and the epilepsy phenotype is not fully elucidated.

Methods

A retrospective chart review of two siblings with ST3GAL3-related DEE was completed. In addition, we reviewed all published cases of ST3GAL3-related congenital disorder of glycosylation.

Results

Two brothers presented with global developmental delay, motor and language impairment, hypotonia, and childhood-onset seizures. Seizures started between 2.5 and 5 years and had tonic components. Both siblings had prolonged periods of seizure freedom on carbamazepine. Tremor was present in the younger sibling. Whole exome sequencing revealed two novel pathogenic variants in ST3GAL3, (a) c.302del, p.Phe102Serfs*34 and (b) c.781C>T, p.Arg261*, which were inherited in trans. Magnetic resonance imaging showed T2 hyperintensities and restricted diffusion in the brainstem and middle cerebellar peduncle in the older sibling, also described in two reported cases. A review of the literature revealed 24 cases of ST3GAL3-related CDG. Twelve cases had information about seizures, and epilepsy was diagnosed in 8 (67%). The median age of seizure onset was 5.5 months. Epileptic spasms were most common (67%). Four children were diagnosed with Infantile Epileptic Spasms syndrome and Lennox Gastaut syndrome (57%). Most children (n = 6, 75%) had seizures despite anti-seizure medication treatment.

Significance

Seizures related to ST3GAL3-related DEE often occur in infancy and may present as epileptic spasms. However, seizure onset may also occur outside of infancy with mixed seizure types and show good response to treatment with prolonged seizure freedom. Tremor may also be uniquely observed in this condition.

Fonte: Epilepsia Open, Robyn Whitney, Puneet Jain, Rajesh RamachandranNair, Kevin C. Jones, Hassan Kiani, Mark Tarnopolsky, Brandon Meaney

Assessment of tau phosphorylation and β‐amyloid pathology in human drug‐resistant epilepsy

Tipologia: ORIGINAL ARTICLE

2023-04-24

Abstract

Objective

Epilepsy can be comorbid with cognitive impairments. Recent evidence suggests the possibility that cognitive decline in epilepsy may be associated with mechanisms typical of Alzheimer's disease (AD). Neuropathological hallmarks of AD have been found in brain biopsies surgically resected from patients with drug-resistant epilepsies. These include hyperphosphorylation of the tau protein (p-tau) that aggregates into neuropil threads (NT) or neurofibrillary tangles (NFT), as well as the presence of β-amyloid (Aβ) deposits. While recent studies agree on these AD neuropathological findings in epilepsy, some contrast in their correlation to cognitive decline. Thus, to further address this question we determined the abundance of p-tau and Aβ proteins along with their association with cognitive function in 12 cases of refractory epilepsy.

Methods

Cortical biopsies surgically extracted from the temporal lobes of patients with refractory epilepsy were processed for immunohistology and enzyme-linked immunoassays to assess distribution and levels, respectively, of p-tau (Antibodies: Ser202/Thr205; Thr205; Thr181) and Aβ proteins. In parallel, we measured the activation of mechanistic target of rapamycin (mTOR) via p-S6 (Antibodies: Ser240/244; Ser235/236). Pearson correlation coefficient analysis determined associations between these proteins and neurophysiological scores for full-scale intelligence quotient (FSIQ).

Results

We found a robust presence of p-tau (Ser202/Thr205)-related NT and NFT pathology, as well as Aβ deposits, and p-S6 (Ser240/244; Ser235/236) in the epilepsy biopsies. We found no significant correlations between p-tau (Thr205; Thr181), Aβ, or mTOR markers with FSIQ scores, although some correlation coefficients were modest to strong.

Significance

These findings strongly support the existence of hyperphosphorylated tau protein and Aβ deposits in patients with human refractory epilepsy. However, their relation to cognitive decline is still unclear and requires further investigation.

Fonte: Epilepsia Open, Alisha Aroor, Phuoc Nguyen, Yibo Li, Rohit Das, Joaquin N. Lugo, Amy L. Brewster

Cannabidiol in the acute phase of febrile infection‐related epilepsy syndrome (FIRES)

Tipologia: SHORT RESEARCH ARTICLE

2023-04-24

Abstract

Febrile infection-related epilepsy syndrome (FIRES) is a prolonged refractory status epilepticus (SE) that develops among healthy individuals after a febrile infection. FIRES treatment is challenging due to its poor response to antiseizure medications (ASMs) and anesthetic drugs. The use of cannabidiol (CBD) as an adjunctive treatment has been suggested, albeit data about its role in the acute phase is lacking. This report describes the use of purified CBD in the acute phase of two pediatric cases of FIRES and their long-term outcome. Both children were treated with several ASMs, immunomodulators, anesthetics, and nonpharmacological treatment (ketogenic diet). CBD was administered, as an adjunctive treatment, through nasogastric tube about 30 days after onset. SE resolved within 3 days of reaching the target dose and both were seizure-free for 1 year after. Although it is difficult to define the extent to which each previous therapy contributed to recovery, in both cases CBD therapy was a turning point, reinforcing its potential role as add-on treatment in the acute phase of FIRES.

Fonte: Epilepsia Open, Anna Fetta, Elisa Crotti, Elena Campostrini, Luca Bergonzini, Carlo Alberto Cesaroni, Francesca Conti, Veronica Di Pisa, Valentina Gentile, Maria Cristina Mondardini, Cesare Vezzoli, Lucio Giordano, Duccio Maria Cordelli

Treatment of status epilepticus: Physiology, pharmacology, and future directions

Tipologia: INVITED ARTICLE

2023-04-21

Abstract

The review presents retrospective, present views and future perspectives on the treatment of status epilepticus (SE). First, presynaptic, postsynaptic, and extrasynaptic mechanisms underlying sustaining ongoing seizure activity are highlighted. Next, mechanism-based choices of antiseizure medications capable of promptly arresting SE are introduced. Finally, challenges associated with translating the advances in laboratory research in clinical practice are discussed.

Fonte: Epilepsia Open, Raman Sankar

Epilepsy in Niger: An overview of the current situation

Tipologia: CRITICAL REVIEW

2023-04-21

Abstract

A major public health concern in the world, particularly in sub-Saharan African countries, epilepsy is poorly studied in Niger, and its prevalence in the general population is unknown. Only two hospital-based studies have been published in Niger, reporting an estimated mean hospital prevalence of epilepsy of 24.2% (95% CI: 23.2–25.2), mainly affecting patients younger than 18 years (54.6%, 95% CI: 52.2–57.0), and males (59.8%, 95% CI: 57.4–62.2). To date in Niger, people living with epilepsy (PWE) are usually cared for by non-physician healthcare workers (mainly nurse technicians in mental health), general medical doctors (non-specialist physician), and non-neurologist physicians. In routine practice, these health workers make the diagnosis of epilepsy essentially based on the clinic, i.e., the repetition of epileptic seizures over time (mainly generalized tonic–clonic seizures) because most of them practiced in health centers or district hospitals or regional hospital centers in which electroencephalogram and neuroradiological explorations are of limited access or unavailable as well as a referral neurologist. Only 10 neurologists are currently practicing in Niger for a total population estimated at 21466800 inhabitants by the World Health Organization in 2018. In 41.8% (95% CI: 39.4–43.2) of the cases, the etiology was unknown with neuroradiological explorations and laboratory tests not performed in most cases. Genetic etiologies are the most frequent etiologies (40.8; 95% CI: 38.4–43.2), followed by Structural etiologies (11.7; 95% CI: 10.1–13.3) particularly hypoxic–ischemic brain injury, and infectious etiologies (6.8%; 95% CI: 5.6–8.0), especially cerebral malaria. PWEs are the target of social stigma and discrimination due to erroneous cultural and religious beliefs about epilepsy of the people from Niger. The present review is an update on the different aspects of epilepsy in Niger.

Fonte: Epilepsia Open, Moussa Toudou‐Daouda

Introduction to the special issue on status epilepticus: neuronal injury, plasticity, and therapies; Celebrating the legacy of Dr. Claude G. Wasterlain

Tipologia: SUPPLEMENT ARTICLE

2023-04-21
Epilepsia Open, EarlyView.

Fonte: Epilepsia Open, Jerome Engel Jr, Solomon L. Moshé, Astrid Nehlig, Denson G. Fujikawa, Raman Sankar, David E. Naylor, Andrey M. Mazarati, Claude G. Wasterlain

The potential role of astroglial GABAA receptors in autoimmune encephalitis associated with GABAA receptor antibodies and seizures

Tipologia: CONCEPTS AND HYPOTHESES

2023-04-20

Abstract

The γ-aminobutyric acid (GABA) is the main inhibitory transmitter in the central nervous system and GABA receptors mediate the inhibitory synaptic transmission. GABA binding to neuronal GABA_AR leads to a rapid hyperpolarization and a higher excitation threshold due to increase in membrane Cl^- permeability. The synaptic GABA_AR is mostly composed of two α(1-3), two β and one γ subunit with the most abundant configuration α1β2γ2. Recently, antibodies (Abs) against α1, β3 and γ2 subunits of GABA_AR were detected in a severe form of autoimmune encephalitis with refractory seizures, status epilepticus and multifocal brain lesions, affecting gray and white matter. Experimental studies confirmed multiple mechanisms and direct functional effects of GABA_AR Abs on neurons with decreased GABAergic synaptic transmission and increased neuronal excitability. The expression of GABA_AR on astrocytes is well established. However, extensive studies about effects of autoimmune GABA_AR Abs on astrocytic GABA_AR are missing. We hypothesize that GABA_AR Abs may lead additionally to blocking astrocytic GABA_ARs with impaired Ca²⁺ homeostasis/spreading, astrocytic Cl^- imbalance, dysfunction of astrocyte-mediated gliotransmission (e.g., decreased adenosine levels) and accumulation of excitatory neurotransmission, all this contributing to seizures, variable clinical/MRI presentations and severity. The most abundant expressed GABA_AR subunits in rodent astrocytes are α1, α2, β1, β3 and γ1 localized in both white and gray matter. Data about GABA_AR subunits in human astrocytes are even more limited, comprising α2, β1 and γ1. Overlapping binding of GABA_AR Abs to neuronal and astroglial receptors is still possible. In vitro and in vivo animal models can be helpful to test effects of GABA_AR Abs on glia. This is from epileptological point of view relevant because of the increasing evidence, confirming the glial involvement in the pathogenesis of epilepsy. Taken together, autoimmune disorders are complex and multiple mechanisms including glia could contribute to the pathogenesis of GABA_AR encephalitis with seizures.

Fonte: Epilepsia Open, Fatme Seval Ismail, Pedro M. Faustmann

FKBP5 blockade may provide a new horizon for the treatment of stress‐associated disorders; an in‐silico study

Tipologia: ORIGINAL ARTICLE

2023-04-20

Abstract

Objective

We searched for, from the FDA (Food and Drug Administration-USA)-approved drugs, inhibitors of FKBP5 with tolerable adverse effect profiles (e.g., mild headache, sedation, etc.) and with the ability to cross the blood brain barrier (BBB), using bio-informatics tools (in-silico). This may pave the road for designing clinical trials of such drugs in patients with functional seizures (FS) and other stress-associated disorders.

Methods

Several databases were used to find all the approved drugs that potentially have interactions with FKBP51 protein [i.e., CTD gene-chemical interaction section of FKBP51 protein of Harmonizome of Mayaanlab, DrugCenteral database, PDID (Protein Drug Interaction Database), DGIdb (the Drug Gene Interaction database)]. Other databases were also searched [e.g., clinicaltrials.gov; DRUGBANK (the FASTA format of the FKBP51 protein was imported to the target sequencing section of the database to find the associated drugs), and the STITCH database (to find the related chemical interaction molecules)].

Results

After a comprehensive search of the designated databases, 28 unique and approved drugs were identified. Fluticasone propionate and Mifepristone and Ponatinib, Mirtazapine, Clozapine, Enzalutamide, Sertraline, Prednisolone, Fluoxetine, Dexamethasone, Clomipramine, Duloxetine, Citalopram, Chlorpromazine, Nefazodone, and Escitalopram are inhibitors of FKBP5 and have BBB permeability.

Significance

While the current in-silico repurposing study could identify potential drugs (that are already approved and are widely available) for designing clinical trials in patients with stress-associated disorders (e.g., FS), any future clinical trial should consider the pharmacological profile of the desired drug and also the characteristics and comorbidities of the patients in order to foster a success.

Fonte: Epilepsia Open, Ali A. Asadi‐Pooya, Mahdi Malekpour, Bardia Zamiri, Mohammad Kashkooli, Negar Firouzabadi

The goal of explaining black boxes in EEG seizure prediction is not to explain models’ decisions

Tipologia: CRITICAL REVIEW

2023-04-19

Abstract

Many state-of-the-art methods for seizure prediction, using the electroencephalogram, are based on machine learning models that are black boxes, weakening the trust of clinicians in them for high-risk decisions. Seizure prediction concerns a multidimensional time-series problem that performs continuous sliding window analysis and classification. In this work, we make a critical review of which explanations increase trust in models' decisions for predicting seizures. We developed three machine learning methodologies to explore their explainability potential. These contain different levels of model transparency: a logistic regression, an ensemble of fifteen Support Vector Machines, and an ensemble of three Convolutional Neural Networks. For each methodology, we evaluated quasi-prospectively the performance in 40 patients (testing data comprised 2055 hours and 104 seizures). We selected patients with good and poor performance to explain the models' decisions. Then, with Grounded Theory, we evaluated how these explanations helped specialists (data scientists and clinicians working in epilepsy) to understand the obtained model dynamics. We obtained four lessons for better communication between data scientists and clinicians. We found that the goal of explainability is not to explain the system's decisions but to improve the system itself. Model transparency is not the most significant factor in explaining a model decision for seizure prediction. Even when using intuitive and state-of-the-art features, it is hard to understand brain dynamics and their relationship with the developed models. We achieve an increase in understanding by developing, in parallel, several systems that explicitly deal with signal dynamics changes that help develop a complete problem formulation.

Fonte: Epilepsia Open, Mauro. F. Pinto, Joana Batista, Adriana Leal, Fábio Lopes, Ana Oliveira, António Dourado, Sulaiman I. Abuhaiba, Francisco Sales, Pedro Martins, César A. Teixeira