Drug-refractory Epilepsy Patients Research Articles

Biophysical modeling of the electric field magnitude and distribution induced by electrical stimulation with intracerebral electrodes

Intracranial electrodes are used clinically for diagnostic or therapeutic purposes, notably in drug-refractory epilepsy (DRE) among others. Visualization and quantification of the energy delivered through such electrodes is key to understanding how the resulting electric fields modulate neuronal excitability, i.e. the ratio between excitation and inhibition. Quantifying the electric field induced by electrical stimulation in a patient-specific manner is challenging, because these electric fields depend on a number of factors: electrode trajectory with respect to folded brain anatomy, biophysical (electrical conductivity / permittivity) properties of brain tissue and stimulation parameters such as electrode contacts position and intensity. Here, we aimed to evaluate various biophysical models for characterizing the electric fields induced by electrical stimulation in DRE patients undergoing stereoelectroencephalography (SEEG) recordings in the context of pre-surgical evaluation. This stimulation was performed with multiple-contact intracranial electrodes used in routine clinical practice. We introduced realistic 3D models of electrode geometry and trajectory in the neocortex. For the electrodes, we compared point (0D) and line (1D) sources approximations. For brain tissue, we considered three configurations of increasing complexity: a 6-layer spherical model, a toy model with a sulcus representation, replicating results from previous approaches; and went beyond the state-of-the-art by using a realistic head model geometry. Electrode geometry influenced the electric field distribution at close distances (∼3 mm) from the electrode axis. For larger distances, the volume conductor geometry and electrical conductivity dominated electric field distribution. These results are the first step towards accurate and computationally tractable patient-specific models of electric fields induced by neuromodulation and neurostimulation procedures.

Difficulties in the implementation of the ketogenic diet in adult patients with refractory epilepsy

BackgroundKetogenic diet therapies (KDT) are appropriate therapeutic options for pediatric and adult patients with intractable epilepsy. The application of KDT among adult patients with refractory epilepsy is limited compared to children for several reasons, including poor compliance. We present the significant reasons for the lack of adherence to KDT in our adult patients with intractable epilepsy. MethodsThis study was conducted retrospectively in adult patients with drug-resistant epilepsy who wereofferedand accepted toimplementKDT between 2014 and 2021. Demographic and clinical data were collected via electronic health records. The eventual outcome of KDT results was obtained from the consultant dietitian. The prevalence and reasons for the failure to implement KDT were investigated. We also obtained detailed information about patients who successfully applied the KDT. ResultsA total of 33 patients (18F; median age 28) who wereoffered and accepted to implement KDT were included. Baseline seizure frequency was >4 per week in 49%, and more than half of the patients used >3 anti-seizure medications (ASM). Epilepsy types were temporal in 10 (30%), extratemporal in 10 (30%), generalized in 6 (18%), and unclassified in 7 (22%) patients.Only 3 patients (9%) were able to maintain KDT in the long term. One of them (33%) benefited from this therapy.In the remaining 30 patients, the reasons for failure were inability to contact the dietitian in 5, failure to apply KDT for a particular reason in 7, inappropriate blood test results or any medical/surgical comorbidities in 6, improvement in seizure burden due to change in ASM in 5, still insufficient knowledge of KDT in 3, unresponsiveness to diet due to incorrect implementation in 1 and unidentified reasons in 3 patients. ConclusionsA significant percentage of adult patients with refractory seizures failed to use KDTin our study(91%).Strategies to improve compliance and minimize the side effects might increase the number of drug-refractory epilepsy patients who could benefit from this therapy.

Energy-Efficient Neural Network for Epileptic Seizure Prediction.

Seizure prediction for drug-refractory epilepsy patients can improve their quality of life, reduce their anxiety, and help them take the necessary precautions. Nowadays, numerous deep learning algorithms have been proposed to predict seizure onset and obtain better performance than traditional machine learning methods. However, these methods require a large set of parameters and large hardware resources; they also have high energy consumption. Therefore, these methods cannot be implemented on compact, low-power wearable, or implantable medical devices. The devices should operate on a real-time basis to continually inform the epileptic patients. In this paper, we describe energy-efficient and hardware-friendly methods to predict the epileptic seizures. A model of only 45 kB was obtained by the neural architecture search and was evaluated across three datasets. The overall sensitivity, false prediction rate, and area under receiver operating characteristic curve were 99.81%, 0.005/h, 1 and 93.48%, 0.063/h, 0.977 and 85.19%, 0.116/h, 0.933, respectively, for three public datasets. This model was further reduced with several methods for model compression. The performances for the model sizes less than 50 kB for scalp EEG data and less than 10 kB for intracranial EEG data outperformed all the other models of similar model sizes. In particular, the energy consumption estimation was less than 10 mJ per inference for scalp EEG signal and less than 0.5 mJ per inference for intracranial EEG signal, which meet the requirements for low-power wearable and implantable devices, respectively.

Practical Drug Treatment Recommendations on the Drug Refractory Epilepsy Patients: 2021 Clinical Guideline Subcommittee for Epilepsy in the Korean Neurological Association

One third of the overall epilepsy population are estimated to be a drug refractory epilepsy (DRE), defined as the patients who failed to control seizure reduction, even tried two or more appropriate antiepileptic drugs (AEDs) trials. Those people need additional AEDs trials or other treatment options (resective surgery, neuromoulation, etc.). Here, we, clinical guideline committee of the Korean Neurological Association (KNA) introduce the recommendations of AEDs treatments including not only old and new AEDs currently available in Korea but also AEDs planned to be launched in the new future for DRE patients with literature review to help efficient decision of the clinician. The authors reviewed literatures and assessed efficacy and tolerability on 12 currently available and four newly introduced/or planned AEDs applied to DRE patients, published from November 2015 to July 2021. Brivaracetam, eslicarbazepine, canabidiol and cenobamate are the four AEDs that are newly introduced or planned to be launched soon. The reviewed articles are publications after November 2015, 2018 American Association of Neurology guideline, new AEDs which were introduced or planned to be launched as of 2021. All AEDs are classified based on the therapeutic rating scheme, generating recommendations. Overall 173 papers have been reviewed and analyzed for recommendation rationales. KNA introduce additional add-on treatment or conversional monotherapy guidelines on the drug refractory focal and generalized epilepsy. We hope these guidelines or recommendations to help clinical decision for the treatment of drug refractory epilepsy patients

ATP and adenosine-Two players in the control of seizures and epilepsy development.

Despite continuous advances in understanding the underlying pathogenesis of hyperexcitable networks and lowered seizure thresholds, the treatment of epilepsy remains a clinical challenge. Over one third of patients remain resistant to current pharmacological interventions. Moreover, even when effective in suppressing seizures, current medications are merely symptomatic without significantly altering the course of the disease. Much effort is therefore invested in identifying new treatments with novel mechanisms of action, effective in drug-refractory epilepsy patients, and with the potential to modify disease progression. Compelling evidence has demonstrated that the purines, ATP and adenosine, are key mediators of the epileptogenic process. Extracellular ATP concentrations increase dramatically under pathological conditions, where it functions as a ligand at a host of purinergic receptors. ATP, however, also forms a substrate pool for the production of adenosine, via the action of an array of extracellular ATP degrading enzymes. ATP and adenosine have assumed largely opposite roles in coupling neuronal excitability to energy homeostasis in the brain. This review integrates and critically discusses novel findings regarding how ATP and adenosine control seizures and the development of epilepsy. This includes purine receptor P1 and P2-dependent mechanisms, release and reuptake mechanisms, extracellular and intracellular purine metabolism, and emerging receptor-independent effects of purines. Finally, possible purine-based therapeutic strategies for seizure suppression and disease modification are discussed.

Decreased Cerebrospinal Fluid and Serum Concentrations of Pigment Epithelium-Derived Factor in Drug-Refractory Epilepsy Patients

Dan Chen1, Zheng Xiao2, Liang Wang2, Fei Xiao2, Zhi Qin Xi2, Xue Feng Wang2 and Qiao Cheng3* Author Affiliations 1Department of Neurosurgery, China 2Department of Neurology, China 3Department of Endocrine and Breast Surgery, China Received: May 15, 2019 | Published: June 06, 2019 Corresponding author: Qiao Cheng, Department of Endocrine and Breast Surgery, China DOI: 10.26717/BJSTR.2019.18.003184 Also View In:

Quality of Life and Its Determinants in Adult Drug Refractory Epilepsy Patients Who Were Not Candidates for Epilepsy Surgery: A Correlational Study.

Background and PurposeThis study was performed to elucidate quality of life (QOL) and its determinants in adult drug refractory epilepsy (DRE) patients who were not candidates for epilepsy surgery.MethodsA correlational study was performed at the center of excellence, epilepsy between July 2014 to June 2016. All consecutive DRE patients who were not candidates for epilepsy surgery were enrolled. The outcomes were QOL, assessed using the quality of life inventory in epilepsy-31 items (QOLIE-31) inventory and the correlation of QOL with epilepsy-related variables like seizure severity and frequency. We also compared current QOL with QOL during the pre-surgical evaluation to strengthen our study outcome.ResultsA total of 129 adult patients were enrolled over two years. The mean age was 26.5 ± 6.7 years and male: female ratio was 3: 1. The mean age at epilepsy onset was 9.6 ± 6.6 years and mean duration of epilepsy was 14.9 ± 7.5 years. There was lower seizure frequency than during pre-surgical evaluation in 37.2% of patients, while in 62.8% the seizure frequency remained the same or was higher. Nine (6.98%) patients became seizure free. In comparison to QOL status during the pre-surgical evaluation, there was statistically significant worsening of QOL in all domains (p < 0.01). Seizure severity significantly correlated with almost all QOL domains (p ≤ 0.01), while seizure frequency significantly correlated with only the single domain of overall QOL (p = 0.03).ConclusionsThe QOL of DRE patients who were not candidates for epilepsy surgery worsened relative to the QOL during the pre-surgical evaluation period. Seizure severity significantly correlated with QOL, but seizure frequency did not.

Investigation of altered microstructure in patients with drug refractory epilepsy using diffusion tensor imaging.

The risk of refractory epilepsy can be more dangerous than the adverse effect caused by medical treatment. In this study, we employed voxel-wise analysis (VWA) and tract-based spatial statistics (TBSS) methods to measure microstructural changes using diffusion tensor imaging (DTI) in patients of drug refractory epilepsy (DRE) who had been epileptic for more than 10years. To examine the specific microstructural abnormalities in DRE patients and its difference from medically controlled epilepsy (MCE), we acquired DTI data of 7 DRE patients, 37 MCE patients, and 31 healthy controls (HCs) using a 3T MRI scanner. Comparisons between epileptic patients and HCs between MCE and DRE patients were performed based on calculated diffusion anisotropic indices data using VWA and TBSS. Compared to HCs, epileptic patients (including MCE and DRE) showed significant DTI changes in the common affected regions based on VWA, whereas TBSS found that widespread DTI changes in parts of microstructures of bilateral hemispheres were more obvious in the DRE patients than that in the MCE patients when compared with HCs. In contrast, significant reduction of fractional anisotropy values of thalamo-cortical fibers, including left superior temporal gyrus, insular cortex, pre-/post-central gyri, and thalamus, were further found in DRE patients compared with MCE. The results of multiple diffusion anisotropic indices data provide complementary information to understand the dysfunction of thalamo-cortical pathway in DRE patients, which may be contributors to disorder of language and motor functions. Our current study may shed light on the pathophysiology of DRE.

Clinical features and genetic analysis of intellectual disability in children with epilepsy of unknown causes

Objective To explore the clinical features, genetic causes and prognosis of intellectual disability with epilepsy(ID-E) in children. Methods The data of unknown causes of ID-E children(n=40) who were identified in Department of Pediatrics, Xiangya Hospital of Central South University from March 2015 to March 2016 were respectively analyzed, and follow-up studies were performed to investigate the epilepsy control and intellectual deve-lopment. Results Forty unexplained ID-E included 25(62.5%) male, and 34(85.0%) cases were severe intellectual disability patients.The onset age of epilepsy was 0.16 to 8.00 years old, median age was 1.5 years old.Twenty cases (50.0%) had slow electroencephalogram background, and 22 cases(55.0%) had focal spikes.Ten cases(25.0%) had abnormal cranial images, with brain dysplasia or atrophy.Follow-up lasted from 0.58 to 1.58 years, and 19 cases (47.5%) had seizure control.Twenty-five cases (62.5%) had used at least 2 anti-epilepsy drugs during follow-up, and 19 cases (47.5%) had drug refractory epilepsy.Improvement of mental or motor development in epilepsy controlled group and the uncontrolled group were 12 cases (63.2%) and 2 cases (9.5%). There were separately 8 cases(8/40 cases, 20.0%) and 3 cases(3/16 cases, 18.8%) diagnosed respectively by whole genome-wide analysis of copy number variants(CNVs) and gene-panel whose CNVs test findings were negative. Conclusions ID-E patients of unknown causes have the following clinical features: they were mostly found in male patients with severe intellectual disability, and drug refractory epilepsy patients have rather high percentage; well controlling of epilepsy is useful for improvement of mental and motor development.Genetic analysis is significant for control and prognosis of ID-E patients, and genome-wide CNVs have high positive rates which can be used as first-tier test to detect genetic etiology of ID-E of unknown cause. Key words: Intellectual disability; Epilepsy; Genetic test

Comparative Study of Voxel-Based Epileptic Foci Localization Accuracy between Statistical Parametric Mapping and Three-dimensional Stereotactic Surface Projection.

Fluorine-18-fluorodeoxyglucose positron-emission tomography (18F-FDG-PET) is widely used to help localize the hypometabolic epileptogenic focus for presurgical evaluation of drug-refractory epilepsy patients. Two voxel-based brain mapping methods to interpret 18F-FDG-PET, statistical parametric mapping (SPM) and three-dimensional stereotactic surface projection (3D-SSP), improve the detection rate of seizure foci. This study aimed to compare the consistency of epileptic focus detection between SPM and 3D-SSP for 18F-FDG-PET brain mapping analysis. We retrospectively reviewed the clinical, electroecephalographic, and brain imaging results of 35 patients with refractory epilepsy. 18F-FDG-PET studies were revaluated by SPM, 3D-SSP, and visual assessment, and the results were compared to the magnetic resonance imaging (MRI) lesion location and to the presumed epileptogenic zone (PEZ) defined by video-electroencephalogram and other clinical data. A second consistency study compared PET analyses to histopathology and surgical outcomes in the 19 patients who underwent lesion resection surgery. Of the 35 patients, consistency with the PEZ was 29/35 for SPM, 25/35 for 3D-SSP, 14/35 for visual assessment, and 10/35 for MRI. Concordance rates with the PEZ were significantly higher for SPM and 3D-SSP than for MRI (P < 0.05) and visual assessment (P < 0.05). Differences between SPM and 3D-SSP and between visual assessment and MRI were not significant. In the 19 surgical patients, concordance with histopathology/clinical outcome was 14/19 for SPM, 15/19 for 3D-SSP, 14/19 for visual assessment, and 9/19 for MRI (P > 0.05). A favorable Engel outcome (class I/II) was found in 16 of 19 cases (84%), and failure of seizure control was found in 3 of 19 patients (class III/IV). Voxel-based 18F-FDG-PET brain mapping analysis using SPM or 3D-SSP can improve the detection rate of the epileptic focus compared to visual assessment and MRI. Consistency with PEZ was similar between SPM and 3D-SSP; according to their own characteristics, 3D-SSP is recommended for primary evaluation due to greater efficiency and operability of the software, while SPM is recommended for high-accuracy localization of complex lesions. Therefore, joint application of both software packages may be the best solution for FDG-PET analysis of epileptic focus localization.

DNA Methylation Profiling Reveals Correlation of Differential Methylation Patterns with Gene Expression in Human Epilepsy.

DNA methylation plays important roles in regulating gene expression and has been reported to be related with epilepsy. This study aimed to define differential DNA methylation patterns in drug-refractory epilepsy patients and to investigate the role of DNA methylation in human epilepsy. We performed DNA methylation profiling in brain tissues from epileptic and control patients via methylated-cytosine DNA immunoprecipitation microarray chip. Differentially methylated loci were validated by bisulfite sequencing PCR, and the messenger RNA (mRNA) levels of candidate genes were evaluated by reverse transcriptase PCR. We found 224 genes that showed differential DNA methylation between epileptic patients and controls. Among the seven candidate genes, three genes (TUBB2B, ATPGD1, and HTR6) showed relative transcriptional regulation by DNA methylation. TUBB2B and ATPGD1 exhibited hypermethylation and decreased mRNA levels, whereas HTR6 displayed hypomethylation and increased mRNA levels in the epileptic samples. Our findings suggest that certain genes become differentially regulated by DNA methylation in human epilepsy.

Perfusion SPECT, SISCOM and PET 18F-FDG in the assessment of drug-refractory epilepsy patients candidates for epilepsy surgery

AimsBrain perfusion SPECT (ictal–interictal), SPECT images and subtraction ictal SPECT coregistered to MRI (SISCOM) and 18F-FDG-PET (interictal) play an important role in the pre-surgical diagnosis of patients with medically refractory epilepsy.This study aimed to establish the reproducibility of visual ictal–interictal SPECT and SISCOM analysis altogether with the capacity of SPECT, SISCOM and PET to determine the epileptogenic zone. Material and methods99mTc-HMPAO SPECT ictal–interictal and SISCOM (Analyze 7.0) were performed on 47 refractory epilepsy patients (24 F, 19–60 yrs). In 13 patients, SISCOM was also performed using a new programme (Focus DET). Ictal–interictal SPECT and SISCOM images were analyzed independently by two nuclear medicine physicians (observers 1 and 2). Kappa concordance coefficient was used to evaluate the reproducibility. In sixteen patients, SPECT, SISCOM and PET findings were compared with the resected area during the surgery, and surgical outcome using Engel scale or with the stereo EEG-(SEEG). ResultsThe ictal–interictal SPECT interobserver agreement was 91%, Kappa index 0.86, SISCOM (Analyze 7.0) interobserver agreement percentage was 82%, Kappa index 0.80, Analyze 7.0 showed a higher inconclusive results than visual SPECT analysis. SISCOM FocusDET interobserver agreement was 92%, Kappa index 0.87, with lower inconclusive results than Analyze 7.0. SPECT, SISCOM and PET combined findings identified 87% seizure onset zone: 79% temporal, 26% parieto-temporal and 7% frontal. ConclusionsIctal–interictal SPECT and SISCOM showed a high reproducibility in this sample of patients with drug-refractory epilepsy. SPECT, SISCOM and PET combined findings improved detection of epileptogenic zone in comparison with the individual assessment.

Focal cortical dysplasia type IIIc associates with multiple cerebral cavernomas

The distinction of isolated malformations and combined lesions constitutes a major novelty in the 2011 consensus classification of the International League against Epilepsy (ILAE) for focal cortical dysplasias (FCD). Cortical lamination abnormalities together with vascular lesions are subsumed as FCD IIIc. Little is known regarding frequency and etiology of this entity. Here, we systematically evaluated biopsy specimens from 72 drug-refractory epilepsy patients with cerebral cavernous malformations (CCM) regarding presence of associated FCD. Due to a non-perpendicular orientation of the cortical structures or absence of sufficient cortical tissue adjacent to the vascular lesion 25 samples were not classifiable. In the remaining 47 cases FCD IIIc was rare (4.3%), but significantly increased in patients with multiple CCM (28.6%; p<0.05 vs. single CCM). Association of FCD IIIc with multiple CCM may argue against FCD IIIc as an acquired lesion.

Cliniconeuropathologic correlations show astroglial albumin storage as a common factor in epileptogenic vascular lesions

Intracerebral vascular malformations including cavernous angiomas (CAs) and arteriovenous malformations (AVMs) are an important cause of chronic pharmacoresistant epilepsies. Little is known about the pathogenetic basis of epilepsy in patients with vascular malformations. Intracerebral deposits of iron-containing blood products have been generally regarded as responsible for the strong epileptogenic potential of CAs. Here, we have analyzed whether blood-brain barrier (BBB) dysfunction and subsequent astrocytic albumin uptake, recently described as critical trigger of focal epilepsy, represent pathogenetic factors in vascular lesion-associated epileptogenesis. We examined the correlation between hemosiderin deposits, albumin accumulation, and several clinical characteristics in a series of 80 drug-refractory epilepsy patients with CAs or AVMs who underwent surgical resection. Analysis of clinical parameters included gender, age of seizure onset, epilepsy frequency, duration of epilepsy before surgery, and postoperative seizure outcome classification according to Engel class scale. Hemosiderin deposits in the adjacent brain tissue of the vascular lesion were semiquantitatively analyzed. Fluorescent double-immunohistochemistry using GFAP/albumin costaining was performed to study albumin extravasation. Our results suggest that a shorter duration of preoperative epilepsy is correlated with significantly better postsurgical outcome (p < 0.05), whereas no additional clinical or neuropathologic parameter correlated significantly with the postsurgical seizure situation. Intriguingly, we observed strong albumin immunoreactivity within the vascular lesion and in perilesional astrocytes (57.65 ± 4.05%), but not in different control groups. Our present data on albumin uptake in brain tissue adjacent to AVMs and CAs suggests BBB dysfunction and accumulation of albumin within astrocytes as a new pathologic feature potentially associated with the epileptogenic mechanism for vascular lesions and provides novel therapy perspectives for antiepileptogenesis in affected patients.

Up-regulation of serum- and glucocorticoid-induced protein kinase 1 in the brain tissue of human and experimental epilepsy

Several studies have shown that serum- and glucocorticoid-induced protein kinase 1(SGK1) can regulate both glutamate receptors and glutamate transporters and may participate in the regulation of neuroexcitability in neuronal diseases. In our previous study, we analyzed differential gene expression in the anterior temporal neocortex of drug-refractory epilepsy patients relative to control patients using a complementary DNA microarray and found that the SGK1 gene was up-regulated more than twofold in the brain tissues of epileptic patients. In the current study, we measured SGK1 expression in the brain tissues of humans and in an experimental model of rat epilepsy in order to explore the relationship between SGK1 expression and epilepsy. The SGK1 expression was detected in thirty human brain tissues derived from patients undergoing operation for drug-refractory epilepsy and was also detected in eight samples from autopsies. Meanwhile, we investigated SGK1 expression during the epileptic process in rats using immunofluorescence, RT-PCR and western blot analysis. SGK1 expression was enhanced in the temporal neocortex of patients with drug-refractory epilepsy and was also highly expressed in the rat brain during different phases of the epileptic process. SGK1 expression was also related with the elevation of EAAT3, which expression reduced after knockdown SGK1. These results provide new insight into the potential role of SGK1 in the pathophysiology of epilepsy.