Search results for: epilepsy

Authors: Tomáš Nejedlý, Dominika Mrázková, Jitka Viktorová

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The blood-brain barrier (BBB) serves as a protective shield, preventing the entry of harmful substances into the central nervous system. On the other hand, it also restricts the transport of neuroactive drugs, such as antiepileptics, which mitigate epileptic seizures. Drug-resistant epilepsy is often associated with the overexpression of efflux transporters, including P-glycoprotein (P-gp) or multidrug resistance protein 1 (MRP1), on the BBB. The aim of this work is to find P-gp and MRP1 inhibitors derived from phytocannabinoids and terpenes. The work evaluates whether these compounds interact directly with P-gp or MRP1 by rhodamine 123 or fluorescein efflux assay. The effect of phytocannabinoids on the gene expression of these transporters is also studied using qPCR and Western blot. These transporters are found in BBB cells; however, we decided to use the human ovarian cancer cell line (A2780ADR) due to its overproduction of P-gp and malignant glioma cell line (U87) due to its overproduction of MRP1. The results showed that while terpenes suppressed the activity of efflux transporters, phytocannabinoids tended to decrease their expression. Terpenes demonstrated an average inhibition of 65%, surpassing phytocannabinoids, which exhibited an average inhibition of approximately 30%. Particularly noteworthy was the modulating effect of (-)-α-bisabolol with the highest activity among the compounds tested. Based on these findings, phytocannabinoids and terpenes emerge as promising natural candidates for addressing drug resistance linked to efflux transporters. Acknowledgment: The project was funded by the Grant No 22-20860S of The Czech Science Foundation.

Keywords: drug-resistant epilepsy, efflux transporters, multidrug resistance protein 1, P-glycoprotein, phytocannabinoids, terpens

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Authors: Emílie Kučerová, Tereza Veverková, Marina Morozovová, Eva Kudová, Jitka Viktorová

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The blood-brain barrier (BBB) is a key element regulating the transport of substances between the blood and the central nervous system (CNS). The BBB protects the CNS from potentially harmful substances and maintains a suitable environment for nervous activity in the CNS, but at the same time, it represents a significant obstacle to the entry of drugs into the CNS. Pharmacoresistant epilepsy is a form of epilepsy that cannot be suppressed using two (or more) appropriately chosen antiepileptic drugs. In many cases, pharmacoresistant epilepsy is characterized by an increased concentration of efflux pumps on the luminal sides of the endothelial cells that form the BBB and an increased number of drug-metabolizing enzymes in the BBB cells, thereby preventing the effective transport of antiepileptic drugs into the CNS. Currently, a number of scientific groups are focusing on the preparation and improvement of BBB models in vitro in order to study cell interactions or transport mechanisms. However, in pathological conditions such as pharmacoresistant epilepsy, there are changes in BBB structure, and current BBB models are insufficient for related research. Our goal is to develop a suitable BBB model for pharmacoresistant epilepsy in vitro and use it to test the transfer of potential antiepileptic drugs. This model is created by co-culturing immortalized human cerebral microvascular endothelial cells, human vascular pericytes and immortalized human astrocytes. The BBB in vitro is cultivated in the form of a 2D transwell model and the integrity of the barrier is verified by measuring transendothelial electrical resistance (TEER). From the current results, a contact cell arrangement with the cultivation of endothelial cells on the upper side of the insert and the co-cultivation of astrocytes and pericytes on the lower side of the insert is selected as the most promising for BBB model cultivation. The pharmacoresistance of the BBB model is achieved by long-term cultivation of endothelial cells in an increasing concentration of selected antiepileptic drugs, which should lead to increased production of efflux pumps and drug-metabolizing enzymes. The pharmacoresistant BBB model in vitro will be further used for the screening of substances that could act both as antiepileptics and at the same time as inhibitors of efflux pumps in endothelial cells. This project was supported by the Technology Agency of the Czech Republic (TACR), Personalized Medicine: Translational research towards biomedical applications, No. TN02000109 and by the Academy of Sciences of the Czech Republic (AS CR) – grant RVO 61388963.

Keywords: antiepileptic drugs, blood-brain barrier, efflux transporters, pharmacoresistance

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Authors: Sarah K. Amer, Walaa Alaa

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Epilepsy is an important cause of mortality and morbidity, according to WHO statistics. It is characterized by the presence of frequent seizures occurring more than 24 hours apart. Carbamazepine (CBZ) is considered first-line treatment for epilepsy. However, reports have shown that CBZ oral formulations failed to achieve optimum systemic delivery, minimize side effects, and enhance patient compliance. Besides, the literature has signified the lack of therapeutically efficient CBZ transdermal formulation and the urge for its existence owing to its ease and convenient method of application and highlighted capability to attain higher bioavailability and more extended-release profiles compared to conventional oral CBZ tablets. This work aims to prepare CBZ microspheres (MS) that are embedded in a transdermal gel containing Vitamin B to be co-delivered. MS were prepared by emulsion-solvent diffusion method using Eudragit S as core forming polymer and hydroxypropyl methylcellulose (HPMC) polymer. The MS appeared to be spherical and porous in nature, offering a large surface area and high entrapment efficiency of CBZ. The transdermal gel was prepared by solvent-evaporation technique using HPMC that, offered high entrapment efficiency and Eudragit S that provided an extended-release profile. Polyethylene glycol, Span 80 and Pyridoxine were also added. Data indicated that combinations of CBZ with pyridoxine can reduce epileptic seizures without affecting motor coordination. Extended-release profiles were evident for this system. The patches were furthermore tested for thickness, moisture content, folding endurance, spreadability and viscosity measurements. This novel pharmaceutical formulation would be of great influence on seizure control, offering better therapeutic effects.

Keywords: epilepsy, carbamazepine, pyridoxine, transdermal

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Authors: Kyosuke Kamada, Christoph Kapeller, Michael Jordan, Mostafa Mohammadpour, Christy Li, Christoph Guger

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Cortico-cortical evoked potentials (CCEP) refer to responses generated by cortical electrical stimulation at distant brain sites. These responses provide insights into the functional networks associated with language or motor functions, and in the context of epilepsy, they can reveal pathological networks. Locating the origin and spread of seizures within the cortex is crucial for pre-surgical planning. This process can be enhanced by employing cortical stimulation at the seizure onset zone (SOZ), leading to the generation of CCEPs in remote brain regions that may be targeted for disconnection. In the case of a 24-year-old male patient suffering from intractable epilepsy, corpus callosotomy was performed as part of the treatment. DTI-MRI imaging, conducted using a 3T MRI scanner for fiber tracking, along with CCEP, is used as part of an assessment for surgical planning. Stimulation of the SOZ, with alternating monophasic pulses of 300µs duration and 15mA current intensity, resulted in CCEPs on the contralateral frontal cortex, reaching a peak amplitude of 206µV with a latency of 31ms, specifically in the left pars triangularis. The related fiber tracts were identified with a two-tensor unscented Kalman filter (UKF) technique, showing transversal fibers through the corpus callosum. The CCEPs were monitored through the progress of the surgery. Notably, the SOZ-associated CCEPs exhibited a reduction following the resection of the anterior portion of the corpus callosum, reaching the identified connecting fibers. This intervention demonstrated a potential strategy for mitigating the impact of intractable epilepsy through targeted disconnection of identified cortical regions.

Keywords: CCEP, SOZ, Corpus callosotomy, DTI

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Authors: Maurice Ntahobari, Levin Kuhlmann, Mario Boley, Zhinoos Razavi Hesabi

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For machine learning based epileptic seizure prediction, it is important for the model to be implemented in small implantable or wearable devices that can be used to monitor epilepsy patients; however, current state-of-the-art methods are complex and computationally intensive. We use Shapley Additive Explanation (SHAP) to find relevant intracranial electroencephalogram (iEEG) features and improve the computational efficiency of a state-of-the-art seizure prediction method based on the extra trees classifier while maintaining prediction performance. Results for a small contest dataset and a much larger dataset with continuous recordings of up to 3 years per patient from 15 patients yield better than chance prediction performance (p < 0.004). Moreover, while the performance of the SHAP-based model is comparable to that of the benchmark, the overall training and prediction time of the model has been reduced by a factor of 1.83. It can also be noted that the feature called zero crossing value is the best EEG feature for seizure prediction. These results suggest state-of-the-art seizure prediction performance can be achieved using efficient methods based on optimal feature selection.

Keywords: machine learning, seizure prediction, extra tree classifier, SHAP, epilepsy

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Authors: Hind O. Osman, Tilal Elsaman, Bashir A. Yousef, Esraa Elhadi, Aimun A. E. Ahmed, Eyman Mohamed Eltayib, Malik Suliman Mohamed, Magdi Awadalla Mohamed

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Epilepsy is the most common neurological condition and cause of substantial morbidity and mortality. In the present study, the molecular hybridization tool was adopted to obtain six Schiff bases of isatin and adamantane-1-carbohydrazide (18–23). Then, their anticonvulsant activity was evaluated using a pentylenetetrazole- (PTZ-) induced seizure model using phenobarbitone as a positive control. Our findings showed that compounds 18–23 provided significant protection against PTZ-induced seizure, and maximum activities were associated with compound 23. Moreover, all investigated compounds increased the latency of induced convulsion and reduced the duration of epilepsy, with compound 23 being the best. Interestingly, most of the synthesized molecules showed a reduction in neurological symptoms and severity of the seizure. Molecular docking studies suggest GABA-A receptor as a potential target, and in silico ADME screening revealed that the pharmaceutical properties of compound 23 are within the specified limit. Thus, compound 23 was identified as a promising candidate that warrants further drug discovery processes.

Keywords: isatin and adamantane, anticonvulsant activity, PTZ-induced seizure, molecular docking

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Authors: Bliss Singhal

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Epilepsy is a prevalent neurological disorder affecting approximately 50 million individuals worldwide and 1.2 million Americans. There exist millions of pediatric patients with intractable epilepsy, a condition in which seizures fail to come under control. The occurrence of seizures can result in physical injury, disorientation, unconsciousness, and additional symptoms that could impede children's ability to participate in everyday tasks. Predicting seizures can help parents and healthcare providers take precautions, prevent risky situations, and mentally prepare children to minimize anxiety and nervousness associated with the uncertainty of a seizure. This research proposes a comprehensive framework to predict seizures in pediatric patients by evaluating machine learning algorithms on unimodal neuroimaging data consisting of electroencephalogram signals. The bandpass filtering and independent component analysis proved to be effective in reducing the noise and artifacts from the dataset. Various machine learning algorithms’ performance is evaluated on important metrics such as accuracy, precision, specificity, sensitivity, F1 score and MCC. The results show that the deep learning algorithms are more successful in predicting seizures than logistic Regression, and k nearest neighbors. The recurrent neural network (RNN) gave the highest precision and F1 Score, long short-term memory (LSTM) outperformed RNN in accuracy and convolutional neural network (CNN) resulted in the highest Specificity. This research has significant implications for healthcare providers in proactively managing seizure occurrence in pediatric patients, potentially transforming clinical practices, and improving pediatric care.

Keywords: intractable epilepsy, seizure, deep learning, prediction, electroencephalogram channels

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Authors: Eyad Talal Attar

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Epilepsy is a prevalent neurological condition that impacts a considerable population of around 50 million individuals globally, rendering it one of the most widespread neurological disorders. The condition is distinguished by recurring seizures, which are abrupt and transient disruptions in a cerebral activity that can induce alterations in perception, conduct, and awareness. Seizures can be classified as focal or generalized, based on the specific site and scope of the atypical brain activity. Focal seizures are identified by confinement to a particular brain area and can elicit localized manifestations. Generalized seizures are identified by extensive electrical activity throughout the brain, and they can appear in various symptoms such as convulsions, muscle rigidity, and loss of consciousness. This study represents seven individuals chosen according to the number of seizures in the range of three to five seizure and investigates the ability to detect brain seizure activity. The EEG recording Siena Scalp Database was used from PhysioNet databases. EEGLAB is a robust tool utilized for processing and analyzing electroencephalogram (EEG) data and is used to analyze the raw data. The efficacy of Independent Component Analysis ICA algorithms has been demonstrated in the separation of arterial EEG sources and neuronal-generated EEG sources.

Keywords: EEG, MATLAB software, power spectral density, PSD, signal analysis, attention, alpha, beta, gamma

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Authors: Barbosa M. L. S., von Ancken A. C. B., Coelho C. P.

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In order to improve the treatment of epileptic dogs, this case report aims toobjective todescribe the use of the homeopathic medicine Cicuta virosa for the treatmentof seizuresin dogs that already use allopathy to control them. Howeach patient presents symptoms individually, the choice of medicationhomeopathic treatment must also be individualized. He was treated in the municipality of RibeirãoPires, São Paulo - Brazil, an animal of the canine species, female, 7 years old, SRD, with a history of seizuregeneralized tonic-clonic for two years, with a variable frequency of 1-2 seizures perday. With no identifiable etiology, the patient used phenobarbital daily, and the dose ofmedication was increased according to the frequency of seizures. The serum concentration of phenobarbital within 12 hours of itsadministration via blood sample was within the range ofreference. The patient experienced weight gain and intermittent sedation. the choice ofhomeopathic medicine Cicuta virosa 6 cH, prepared according to the PharmacopoeiaBrazilian Homeopathic Medicine, occurred due to its characteristic action on the nervous system, especially in epileptic animals that present with seizures, spasmodic contractions of the muscles of the whole body starting from the head, mouth, extremely violent, with rigidity and opisthotonos, extreme agitation, contortionsmultiple. The animal was submitted to treatment with 2 globules orally twicea day for 30 days. The treatment resulted in a clinical cure as there was no moreseizures, being effective to control this symptom.

Keywords: homeopathy, cicuta virosa, epilepsy, veterinary medicine

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Authors: Gaetano Zazzaro, Angelo Martone, Roberto V. Montaquila, Luigi Pavone

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Seizure is the main factor that affects the quality of life of epileptic patients. The diagnosis of epilepsy, and hence the identification of epileptogenic zone, is commonly made by using continuous Electroencephalogram (EEG) signal monitoring. Seizure identification on EEG signals is made manually by epileptologists and this process is usually very long and error prone. The aim of this paper is to describe an automated method able to detect seizures in EEG signals, using knowledge discovery in database process and data mining methods and algorithms, which can support physicians during the seizure detection process. Our detection method is based on Artificial Neural Network classifier, trained by applying the multilayer perceptron algorithm, and by using a software application, called Training Builder that has been developed for the massive extraction of features from EEG signals. This tool is able to cover all the data preparation steps ranging from signal processing to data analysis techniques, including the sliding window paradigm, the dimensionality reduction algorithms, information theory, and feature selection measures. The final model shows excellent performances, reaching an accuracy of over 99% during tests on data of a single patient retrieved from a publicly available EEG dataset.

Keywords: artificial neural network, data mining, electroencephalogram, epilepsy, feature extraction, seizure detection, signal processing

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Authors: Christine F. Boos, Fernando M. Azevedo

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Electroencephalogram (EEG) is a record of the electrical activity of the brain that has many applications, such as monitoring alertness, coma and brain death; locating damaged areas of the brain after head injury, stroke and tumor; monitoring anesthesia depth; researching physiology and sleep disorders; researching epilepsy and localizing the seizure focus. Epilepsy is a chronic condition, or a group of diseases of high prevalence, still poorly explained by science and whose diagnosis is still predominantly clinical. The EEG recording is considered an important test for epilepsy investigation and its visual analysis is very often applied for clinical confirmation of epilepsy diagnosis. Moreover, this EEG analysis can also be used to help define the types of epileptic syndrome, determine epileptiform zone, assist in the planning of drug treatment and provide additional information about the feasibility of surgical intervention. In the context of diagnosis confirmation the analysis is made using long term EEG recordings with at least 24 hours long and acquired by a minimum of 24 electrodes in which the neurophysiologists perform a thorough visual evaluation of EEG screens in search of specific electrographic patterns called epileptiform discharges. Considering that the EEG screens usually display 10 seconds of the recording, the neurophysiologist has to evaluate 360 screens per hour of EEG or a minimum of 8,640 screens per long term EEG recording. Analyzing thousands of EEG screens in search patterns that have a maximum duration of 200 ms is a very time consuming, complex and exhaustive task. Because of this, over the years several studies have proposed automated methodologies that could facilitate the neurophysiologists’ task of identifying epileptiform discharges and a large number of methodologies used neural networks for the pattern classification. One of the differences between all of these methodologies is the type of input stimuli presented to the networks, i.e., how the EEG signal is introduced in the network. Five types of input stimuli have been commonly found in literature: raw EEG signal, morphological descriptors (i.e. parameters related to the signal’s morphology), Fast Fourier Transform (FFT) spectrum, Short-Time Fourier Transform (STFT) spectrograms and Wavelet Transform features. This study evaluates the application of these five types of input stimuli and compares the classification results of neural networks that were implemented using each of these inputs. The performance of using raw signal varied between 43 and 84% efficiency. The results of FFT spectrum and STFT spectrograms were quite similar with average efficiency being 73 and 77%, respectively. The efficiency of Wavelet Transform features varied between 57 and 81% while the descriptors presented efficiency values between 62 and 93%. After simulations we could observe that the best results were achieved when either morphological descriptors or Wavelet features were used as input stimuli.

Keywords: Artificial neural network, electroencephalogram signal, pattern recognition, signal processing

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Authors: Seolah Lee, Yoohyk Jang, Soyoung Lee, Kon Chu, Sang Kun Lee

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Objective: The International League Against Epilepsy (ILAE) currently suggests a topiramate serum level range of 5-20 mg/L. However, numerous institutions have observed substantial drug response at lower levels. This study aims to investigate the correlation between topiramate serum levels, drug responsiveness, and adverse events to establish a more accurate and tailored therapeutic range. Methods: We retrospectively analyzed topiramate serum samples collected between January 2017 and January 2022 at Seoul National University Hospital. Clinical data, including serum levels, antiseizure regimens, seizure frequency, and adverse events, were collected. Patient responses were categorized as "insufficient" (reduction in seizure frequency <50%) or "sufficient" (reduction ≥ 50%). Within the "sufficient" group, further subdivisions included seizure-free and tolerable seizure subgroups. A population pharmacokinetic model estimated serum levels from spot measurements. ROC curve analysis determined the optimal serum level cut-off. Results: A total of 389 epilepsy patients, with 555 samples, were reviewed, having a mean dose of 178.4±117.9 mg/day and a serum level of 3.9±2.8 mg/L. Out of the samples, only 5.6% (n=31) exhibited insufficient response, with a mean serum level of 3.6±2.5 mg/L. In contrast, 94.4% (n=524) of samples demonstrated sufficient response, with a mean serum level of 4.0±2.8 mg/L. This difference was not statistically significant (p = 0.45). Among the 78 reported adverse events, logistic regression analysis identified a significant association between ataxia and serum concentration (p = 0.04), with an optimal cut-off value of 6.5 mg/L. In the subgroup of patients receiving monotherapy, those in the tolerable seizure group exhibited a significantly higher serum level compared to the seizure-free group (4.8±2.0 mg/L vs 3.4±2.3 mg/L, p < 0.01). Notably, patients in the tolerable seizure group displayed a higher likelihood of progressing into drug-resistant epilepsy during follow-up visits compared to the seizure-free group. Significance: This study proposed an optimal therapeutic concentration for topiramate based on the patient's responsiveness to the drug and the incidence of adverse effects. We employed a population pharmacokinetic model and analyzed topiramate serum levels to recommend a serum level below 6.5 mg/L to mitigate the risk of ataxia-related side effects. Our findings also indicated that topiramate dose elevation is unnecessary for suboptimal responders, as the drug's effectiveness plateaus at minimal doses.

Keywords: topiramate, therapeutic range, low dos, antiseizure effect

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Authors: Jia H. Wong, Jingli Zhang, Habsah Mohamad, Iswatun H. Abdullah Ripain, Muhammad Bilal, Amelia J. Lloyd, Abdul A. Mohamed Yusoff, Jafri M. Abdullah

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Epilepsy is one of the most common neurological diseases affecting more than 50 million of people worldwide. Epilepsy is a state of recurrent, spontaneous seizures with multiple syndromes and symptoms of different causes of brain dysfunction, prognosis, and treatments; characterized by transient, occasional and stereotyped interruptions of behavior whereby the excitatory-inhibitory activities within the central nervous system (CNS) are thrown out of balance due to various kinds of interferences. The goal of antiepileptic treatment is to enable patients to be free from seizures or to achieve control of seizures through surgical treatment and/or pharmacotherapy. Pharmacotherapy through AED plays an important role especially in countries with epilepsy treatment gap due to costs and availability of health facilities, skills and resources, yet there are about one-third of the people with epilepsy have drug-resistant seizures. Hence, this poses considerable challenges to the healthcare system and the effort in providing cost-effective treatment as well as the search for alternatives to treatment and management of epilepsy. Enhancement of γ-aminobutyric acid (GABA)-mediated inhibitory neurotransmission is one of the key mechanisms of actions of antiepileptic drugs. GABA type > a receptors (GABAAR) are ligand-gated ion channels that mediate rapid inhibitory neurotransmission upon the binding of GABA with a heteropentameric structure forming a central pore that is permeable to the influx of chloride ions in its activated state. The major isoform of GABAA receptors consists of two α1, two β2, and one γ2 subunit. It is the most abundantly expressed combinations in the brain and the most commonly researched through Xenopus laevis oocytes. With the advancing studies on ethnomedicine and traditional treatments using medicinal plants, increasing evidence reveal that spice and herb plants with medicinal properties play an important role in the treatment of ailments within communities across different cultures. Capsaicin is the primary natural capsaicinoid in hot peppers of plant genus Capsicum, consist of an aromatic ring, an amide linkage and a hydrophobic side chain. The study showed that capsaicins conferred neuroprotection in status epilepticus mouse models through anti-ictogenic, hypothermic, antioxidative, anti-inflammatory, and anti-apoptotic actions in a dose-dependent manner. In this study, five capsaicin derivatives were tested for their ability to increase the GABA-induced chloride current on α1β2γ2S of GABAAR expressed on Xenopus laevis oocytes using the method of two-microelectrode voltage clamp. Two of the capsaicin derivatives, IS5 (N-(4-hydroxy-3-methoxybenzyl)-3-methylbutyramide) and IS10 (N-(4-hydroxy-3-methoxybenzyl)-decanamide) at a concentration of 30µM were able to significantly increase the GABA-induced chloride current with p=0.002 and p=0.026 respectively. This study were able to show the enhancement effect of two capsaicin derivatives with moderate length of hydrocarbon chain on this receptor subtype, revealing the promising inhibitory activity of capsaicin derivatives through enhancement of GABA-induced chloride current and further investigations should be carried out to verify its antiepileptic effects in animal models.

Keywords: α1β2γ2 GABAA receptors, α1β2γ2S, antiepileptic, capsaicin derivatives, two-microelectrode voltage clamp, Xenopus laevis oocytes

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Authors: Asher John Mohan, Krishna K. L.

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Objectives: (1) To assess the extent of memory impairment induced by Phenytoin (PHT) at normal and reduced dose on temporal lobe epileptic mice. (2) To evaluate the protective effect of Levetiracetam (LEV) on aggravation of memory impairment in temporal lobe epileptic mice by PHT. Materials and Methods: Albino mice of either sex (n=36) were used for the study for a period of 64 days. Convulsions were induced by intraperitoneal administration of pilocarpine 280 mg/kg on every 6th day. Radial arm maze (RAM) was employed to evaluate the memory impairment activity on every 7th day. The anticonvulsant and memory impairment activity were assessed in PHT normal and reduced doses both alone and in combination with LEV. RAM error scores and convulsive scores were the parameters considered for this study. Brain acetylcholine esterase and glutamate were determined along with histopathological studies of frontal cortex. Results: Administration of PHT for 64 days on mice has shown aggravation of memory impairment activity on temporal lobe epileptic mice. Although the reduction in PHT dose was found to decrease the degree of memory impairment the same decreased the anticonvulsant potency. The combination with LEV not only brought about the correction of impaired memory but also replaced the loss of potency due to the reduction of the dose of the antiepileptic drug employed. These findings were confirmed with enzyme and neurotransmitter levels in addition to histopathological studies. Conclusion: This study thus builds a foundation in combining a nootropic anticonvulsant with an antiepileptic drug to curb the adverse effect of memory impairment associated with temporal lobe epilepsy. However further extensive research is a must for the practical incorporation of this approach into disease therapy.

Keywords: anti-epileptic drug, Phenytoin, memory impairment, Pilocarpine

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Authors: Roya Vakili, Lekaa Elhajjmoussa, Barzin Omidi-Shal, Kim Blake

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Objective: The purpose of this case report is to highlight the successful treatment of a patient with Coloboma, Heart defect, Atresia choanae, Retarded growth and development, Genital hypoplasia, Ear anomalies/deafness, (CHARGE syndrome) using a vagal nerve stimulator (VNS). Background: This is the first documented case report, to the authors' best knowledge, for a patient with CHARGE syndrome, epilepsy, autism, and postural orthostatic tachycardia syndrome (POTS) that was successfully treated with an implanted VNS therapeutic device. Methodology: The study is a case report. Results: This is the case of a 24-year-old female patient with CHARGE syndrome (non-random association of anomalies Coloboma, Heart defect, Atresia choanae, Retarded growth and development, Genital hypoplasia, Ear anomalies/deafness) and several other comorbidities including refractory epilepsy, Patent Ductus Arteriosus (PDA) and POTS who had significant improvement of her symptoms after VNS implantation. She was a VNS candidate given her longstanding history of drug-resistant epilepsy and current disposition secondary to CHARGE syndrome. Prior to VNS implantation, she experienced three generalized seizures a year and daily POTS-related symptoms. She was having frequent lightheadedness and syncope spells due to a rapid heart rate and low blood pressure. The VNS device was set to detect a rapid heart rate and send appropriate stimulation anytime the heart rate exceeded 20% of the patient’s normal baseline. The VNS device demonstrated frequent elevated heart rates and concurrent VNS release every 8 minutes in addition to the programmed events. Following VNS installation, the patient became more active, alert, and communicative and was able to verbally communicate with words she was unable to say prior. Her GI symptoms also improved, as she was able to tolerate food better orally in addition to her G and J tube, likely another result of the vagal nerve stimulation. Additionally, the patient’s seizures and POTS-related cardiac events appeared to be well controlled. She had prolonged electroencephalogram (EEG) testing, showing no significant change in epileptiform activity. Improvements in the patient’s disposition are believed to be secondary to parasympathetic stimulation, adequate heart rate control, and GI stimulation, in addition to behavioral changes and other benefits via her implanted VNS. Conclusion: VNS showed promising results in improving the patient's quality of life and managing her diverse symptoms, including dysautonomia, POTs, gastrointestinal mobility, cognitive functioning as well seizure control.

Keywords: autism, POTs, CHARGE, VNS

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Authors: Giancarlo La Marca, Engy Shokry, Fabio Villanelli

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Epilepsy is one of the most common neurological disorders, with an estimated prevalence of 50 million people worldwide. Twenty five percent of the epilepsy population is represented in children under the age of 15 years. For antiepileptic drugs (AED), there is a poor correlation between plasma concentration and dose especially in children. This was attributed to greater pharmacokinetic variability than adults. Hence, therapeutic drug monitoring (TDM) is recommended in controlling toxicity while drug exposure is maintained. Carbamazepine (CBZ) is a first-line AED and the drug of first choice in trigeminal neuralgia. CBZ is metabolised in the liver into carbamazepine-10,11-epoxide (CBZE), its major metabolite which is equipotent. This develops the need for an assay able to monitor the levels of both CBZ and CBZE. The aim of the present study was to develop and validate a LC-MS/MS method for simultaneous quantification of CBZ and CBZE in dried blood spots (DBS). DBS technique overcomes many logistical problems, ethical issues and technical challenges faced by classical plasma sampling. LC-MS/MS has been regarded as superior technique over immunoassays and HPLC/UV methods owing to its better specificity and sensitivity, lack of interference or matrix effects. Our method combines advantages of DBS technique and LC-MS/MS in clinical practice. The extraction process was done using methanol-water-formic acid (80:20:0.1, v/v/v). The chromatographic elution was achieved by using a linear gradient with a mobile phase consisting of acetonitrile-water-0.1% formic acid at a flow rate of 0.50 mL/min. The method was linear over the range 1-40 mg/L and 0.25-20 mg/L for CBZ and CBZE respectively. The limit of quantification was 1.00 mg/L and 0.25 mg/L for CBZ and CBZE, respectively. Intra-day and inter-day assay precisions were found to be less than 6.5% and 11.8%. An evaluation of DBS technique was performed, including effect of extraction solvent, spot homogeneity and stability in DBS. Results from a comparison with the plasma assay are also presented. The novelty of the present work lies in being the first to quantify CBZ and its metabolite from only one 3.2 mm DBS disc finger-prick sample (3.3-3.4 µl blood) by LC-MS/MS in a 10 min. chromatographic run.

Keywords: carbamazepine, carbamazepine-10, 11-epoxide, dried blood spots, LC-MS/MS, therapeutic drug monitoring

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Authors: Mohammad Zavid Parvez, Manoranjan Paul

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A seizure prediction method is proposed by extracting global features using phase correlation between adjacent epochs for detecting relative changes and local features using fluctuation/deviation within an epoch for determining fine changes of different EEG signals. A classifier and a regularization technique are applied for the reduction of false alarms and improvement of the overall prediction accuracy. The experiments show that the proposed method outperforms the state-of-the-art methods and provides high prediction accuracy (i.e., 97.70%) with low false alarm using EEG signals in different brain locations from a benchmark data set.

Keywords: Epilepsy, seizure, phase correlation, fluctuation, deviation.

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Authors: Merve Colak, Gizem Donmez Yalcin

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Glutamate has many neurological functions in the central nervous system and is found at high concentrations in the brain. Increased levels of glutamate in the neuronal space are toxic, causing neuron damage and death. This is called glutamate-induced excitotoxicity. Excitotoxicity is among the causes of many neurological diseases such as trauma, cerebral ischemia, epilepsy, Parkinson's Disease, Alzheimer's Disease. Since neuroblastoma cells are known to be excitotoxic, we propose that excitotoxicity can be studied in neuroblastoma cells. Excitotoxicity can be induced using kainic acid in neuroblastoma cells. Measuring the secretion of glutamate, excitotoxicity can be analyzed in neuroblastoma cells.

Keywords: glutamate, excitotoxicity, kainic acid, Sirt4

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Authors: Anisa Suraya Ab Razak, Izza Hayat

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Introduction: The diagnosis and management of severe hyponatremia in neuropsychiatric patients present a significant challenge to physicians. Several factors contribute, including diagnostic shadowing and attributing abnormal behavior to intellectual disability or psychiatric conditions. Hyponatraemia is the commonest electrolyte abnormality in the inpatient population, ranging from mild/asymptomatic, moderate to severe levels with life-threatening symptoms such as seizures, coma and death. There are several documented fatal case reports in the literature of severe hyponatremia secondary to psychogenic polydipsia, often diagnosed only in autopsy. This paper presents a case study of acute severe hyponatremia in a neuropsychiatric patient with early diagnosis and admission to intensive care. Case study: A 21-year old Caucasian male with known epilepsy and learning disability was admitted from residential living with generalized tonic-clonic self-terminating seizures after refusing medications for several weeks. Evidence of superficial head injury was detected on physical examination. His laboratory data demonstrated mild hyponatremia (125 mmol/L). Computed tomography imaging of his brain demonstrated no acute bleed or space-occupying lesion. He exhibited abnormal behavior - restlessness, drinking water from bathroom taps, inability to engage, paranoia, and hypersexuality. No collateral history was available to establish his baseline behavior. He was loaded with intravenous sodium valproate and leveritircaetam. Three hours later, he developed vomiting and a generalized tonic-clonic seizure lasting forty seconds. He remained drowsy for several hours and regained minimal recovery of consciousness. A repeat set of blood tests demonstrated profound hyponatremia (117 mmol/L). Outcomes: He was referred to intensive care for peripheral intravenous infusion of 2.7% sodium chloride solution with two-hourly laboratory monitoring of sodium concentration. Laboratory monitoring identified dangerously rapid correction of serum sodium concentration, and hypertonic saline was switched to a 5% dextrose solution to reduce the risk of acute large-volume fluid shifts from the cerebral intracellular compartment to the extracellular compartment. He underwent urethral catheterization and produced 8 liters of urine over 24 hours. Serum sodium concentration remained stable after 24 hours of correction fluids. His GCS recovered to baseline after 48 hours with improvement in behavior -he engaged with healthcare professionals, understood the importance of taking medications, admitted to illicit drug use and drinking massive amounts of water. He was transferred from high-dependency care to ward level and was initiated on multiple trials of anti-epileptics before achieving seizure-free days two weeks after resolution of acute hyponatremia. Conclusion: Psychogenic polydipsia is often found in young patients with intellectual disability or psychiatric disorders. Patients drink large volumes of water daily ranging from ten to forty liters, resulting in acute severe hyponatremia with mortality rates as high as 20%. Poor outcomes are due to challenges faced by physicians in making an early diagnosis and treating acute hyponatremia safely. A low index of suspicion of water intoxication is required in this population, including patients with known epilepsy. Monitoring urine output proved to be clinically effective in aiding diagnosis. Early referral and admission to intensive care should be considered for safe correction of sodium concentration while minimizing risk of fatal complications e.g. central pontine myelinolysis.

Keywords: epilepsy, psychogenic polydipsia, seizure, severe hyponatremia

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Authors: D. K. Sreekantha, T. M. Girish, R. H. Fattepur

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In this article, we have given an overview of medical expert systems, which can be used for the developed of physicians in making decisions such as appropriate, prognostic, and therapeutic decisions which help to organize, store, and gives appropriate medical knowledge needed by physicians and practitioners during medical operations or further treatment. If they support the studies by using these systems, advanced tools in medicine will be developed in the future. New trends in the methodology of development of medical expert systems have also been discussed in this paper. So Authors would like to develop an innovative IT based solution to help doctors in rural areas to gain expertise in Medical Science for treating patients. This paper aims to survey the Soft Computing techniques in treating patient’s problems used throughout the world.

Keywords: expert system, fuzzy logic, knowledge base, soft computing, epilepsy

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Authors: Ardiansyah I. Ryan, Ashsholih K. R., Fathurrohman G. R., Kurniadi M. R., Huda P. A

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The burden of brain-related disease is very high. There are a lot of brain-related diseases with limited treatment result and thus raise the burden more. The Parkinson Disease (PD), Mental Health Problem, or Paralysis of extremities treatments had risen concern, as the patients for those diseases usually had a low quality of life and low chance to recover fully. There are also many other brain or related neural diseases with the similar condition, mainly the treatments for those conditions are still limited as our understanding of the brain function is insufficient. Brain Implant Technology had given hope to help in treating this condition. In this paper, we examine the current update of the brain implant technology. Neurotechnology is growing very rapidly worldwide. The United States Food and Drug Administration (FDA) has approved the use of Deep Brain Stimulation (DBS) as a brain implant in humans. As for neural implant both the cochlear implant and retinal implant are approved by FDA too. All of them had shown a promising result. DBS worked by stimulating a specific region in the brain with electricity. This device is planted surgically into a very specific region of the brain. This device consists of 3 main parts: Lead (thin wire inserted into the brain), neurostimulator (pacemaker-like device, planted surgically in the chest) and an external controller (to turn on/off the device by patient/programmer). FDA had approved DBS for the treatment of PD, Pain Management, Epilepsy and Obsessive Compulsive Disorder (OCD). The target treatment of DBS in PD is to reduce the tremor and dystonia symptoms. DBS has been showing the promising result in animal and limited human trial for other conditions such as Alzheimer, Mental Health Problem (Major Depression, Tourette Syndrome), etc. Every surgery has risks of complications, although in DBS the chance is very low. DBS itself had a very satisfying result as long as the subject criteria to be implanted this device based on indication and strictly selection. Other than DBS, there are several brain implant devices that still under development. It was included (not limited to) implant to treat paralysis (In Spinal Cord Injury/Amyotrophic Lateral Sclerosis), enhance brain memory, reduce obesity, treat mental health problem and treat epilepsy. The potential of neurotechnology is unlimited. When brain function and brain implant were fully developed, it may be one of the major breakthroughs in human history like when human find ‘fire’ for the first time. Support from every sector for further research is very needed to develop and unveil the true potential of this technology.

Keywords: brain implant, deep brain stimulation (DBS), deep brain stimulation, Parkinson

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Authors: Tetyana Kendzerska, David T. Zhu, Michael Pugliese, Douglas Manuel, Mohsen Sadatsafavi, Marcus Povitz, Therese A. Stukel, Teresa To, Shawn D. Aaron, Sunita Mulpuru, Melanie Chin, Claire E. Kendall, Kednapa Thavorn, Rebecca Robillard, Andrea S. Gershon

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The impact of the COVID-19 pandemic on the management of ambulatory care sensitive conditions (ACSCs) remains unknown. To compare observed and expected (projected based on previous years) trends in all-cause mortality and healthcare use for ACSCs in the first year of the pandemic (March 2020 - March 2021). A population-based study using provincial health administrative data.General adult population (Ontario, Canada). Monthly all-cause mortality, and hospitalizations, emergency department (ED) and outpatient visit rates (per 100,000 people at-risk) for seven combined ACSCs (asthma, COPD, angina, congestive heart failure, hypertension, diabetes, and epilepsy) during the first year were compared with similar periods in previous years (2016-2019) by fitting monthly time series auto-regressive integrated moving-average models. Compared to previous years, all-cause mortality rates increased at the beginning of the pandemic (observed rate in March-May 2020 of 79.98 vs. projected of 71.24 [66.35-76.50]) and then returned to expected in June 2020—except among immigrants and people with mental health conditions where they remained elevated. Hospitalization and ED visit rates for ACSCs remained lower than projected throughout the first year: observed hospitalization rate of 37.29 vs. projected of 52.07 (47.84-56.68); observed ED visit rate of 92.55 vs. projected of 134.72 (124.89-145.33). ACSC outpatient visit rates decreased initially (observed rate of 4,299.57 vs. projected of 5,060.23 [4,712.64-5,433.46]) and then returned to expected in June 2020. Reductions in outpatient visits for ACSCs at the beginning of the pandemic combined with reduced hospital admissions may have been associated with temporally increased mortality—disproportionately experienced by immigrants and those with mental health conditions. The Ottawa Hospital Academic Medical Organization

Keywords: COVID-19, chronic disease, all-cause mortality, hospitalizations, emergency department visits, outpatient visits, modelling, population-based study, asthma, COPD, angina, heart failure, hypertension, diabetes, epilepsy

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Authors: Mrinalini Ranjan, Sudheesh Chethil

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Epilepsy is a common neurological disorder characterised by the recurrence of seizures. Electroencephalogram (EEG) signals are complex biomedical signals which exhibit nonlinear and nonstationary behavior. We use two methods 1) Detrended Fluctuation Analysis (DFA) and 2) Recurrence Plots (RP) to capture this complex behavior of EEG signals. DFA considers fluctuation from local linear trends. Scale invariance of these signals is well captured in the multifractal characterisation using detrended fluctuation analysis (DFA). Analysis of long-range correlations is vital for understanding the dynamics of EEG signals. Correlation properties in the EEG signal are quantified by the calculation of a scaling exponent. We report the existence of two scaling behaviours in the epileptic EEG signals which quantify short and long-range correlations. To illustrate this, we perform DFA on extant ictal (seizure) and interictal (seizure free) datasets of different patients in different channels. We compute the short term and long scaling exponents and report a decrease in short range scaling exponent during seizure as compared to pre-seizure and a subsequent increase during post-seizure period, while the long-term scaling exponent shows an increase during seizure activity. Our calculation of long-term scaling exponent yields a value between 0.5 and 1, thus pointing to power law behaviour of long-range temporal correlations (LRTC). We perform this analysis for multiple channels and report similar behaviour. We find an increase in the long-term scaling exponent during seizure in all channels, which we attribute to an increase in persistent LRTC during seizure. The magnitude of the scaling exponent and its distribution in different channels can help in better identification of areas in brain most affected during seizure activity. The nature of epileptic seizures varies from patient-to-patient. To illustrate this, we report an increase in long-term scaling exponent for some patients which is also complemented by the recurrence plots (RP). RP is a graph that shows the time index of recurrence of a dynamical state. We perform Recurrence Quantitative analysis (RQA) and calculate RQA parameters like diagonal length, entropy, recurrence, determinism, etc. for ictal and interictal datasets. We find that the RQA parameters increase during seizure activity, indicating a transition. We observe that RQA parameters are higher during seizure period as compared to post seizure values, whereas for some patients post seizure values exceeded those during seizure. We attribute this to varying nature of seizure in different patients indicating a different route or mechanism during the transition. Our results can help in better understanding of the characterisation of epileptic EEG signals from a nonlinear analysis.

Keywords: detrended fluctuation, epilepsy, long range correlations, recurrence plots

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Authors: Boukari Nassim

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This paper describes the use of odd pair autoregressive coefficients (Yule _Walker and Burg) for the feature extraction of electroencephalogram (EEG) signals. In the classification: the radial basis function neural network neural network (RBFNN) is employed. The RBFNN is described by his architecture and his characteristics: as the RBF is defined by the spread which is modified for improving the results of the classification. Five types of EEG signals are defined for this work: Set A, Set B for normal signals, Set C, Set D for interictal signals, set E for ictal signal (we can found that in Bonn university). In outputs, two classes are given (AC, AD, AE, BC, BD, BE, CE, DE), the best accuracy is calculated at 99% for the combined odd pair autoregressive coefficients. Our method is very effective for the diagnosis of epileptic EEG signals.

Keywords: epilepsy, EEG signals classification, combined odd pair autoregressive coefficients, radial basis function neural network

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Authors: Piyush Swami, Bijaya Ketan Panigrahi, Sneh Anand, Manvir Bhatia, Tapan Gandhi

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Visual inspection of electroencephalogram (EEG) signals to detect epileptic signals is very challenging and time-consuming task even for any expert neurophysiologist. This problem is most challenging in under-developed and developing countries due to shortage of skilled neurophysiologists. In the past, notable research efforts have gone in trying to automate the seizure detection process. However, due to high false alarm detections and complexity of the models developed so far, have vastly delimited their practical implementation. In this paper, we present a novel scheme for epileptic seizure detection using empirical mode decomposition technique. The intrinsic mode functions obtained were then used to calculate the standard deviations. This was followed by probability density based classifier to discriminate between non-ictal and ictal patterns in EEG signals. The model presented here demonstrated very high classification rates ( > 97%) without compromising the statistical performance. The computation timings for each testing phase were also very low ( < 0.029 s) which makes this model ideal for practical applications.

Keywords: electroencephalogram (EEG), epilepsy, ictal patterns, empirical mode decomposition

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Authors: Dauda G., Bila Ha Sani Y. M., Magaji M. G., Musa A. M., Hassan H. S.

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Introduction: Globimetula oreophila is a parasitic plant with a known therapeutic value that is widely used in the treatment of various ailments, including malaria, hypertension, cancer, diabetes, epilepsy and as a diuretic agent. Objectives: The present study is aimed at analyzing and documenting the level of trace and toxic metals in the crude ethanol leaf extract of G. oreophila. Methods: After collection and authentication, the leaves were air-dried, mashed into powder, weighed and extracted using aqueous ethanol (70%). The crude extract (0.5g) was digested with HNO₃: HCl (3:1); then heated to 2000C and analyzed for its metal content by atomic absorption spectroscopy (AAS). Results: Fe had the highest concentration (32.73mg/kg), while Pb was not detected. The concentrations of Co, Cu, Ni, Zn and Cd detected were 5.97, 10.8, 8.01 and 0.9mg/kg, respectively. The concentration of Cd, Fe and Ni were above the permissible limit of FAO/WHO. Conclusion: The results also show that the analyzed plant is a beneficial source of appropriate and essential trace metals. However, the leaf of G. oreophila in the present study was probably unsafe for long-term use because of the level of Fe, Ni, and Cd concentration.

Keywords: Globimetula oreophila, minerals, trace element, crude extract

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Authors: Harim Mohsin, Afshan Channa, Beena Saad

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The Kocher Debre Semelaigne Syndrome (KDSS) is known as cretinism muscular hypertrophy. It is an unusual presentation in intellectually deficit children, commonly associated with congenital or iatrogenic hypothyroidism. The creatinine phosphokinase (CPK) is usually elevated and it’s commonly found in males, consanguineous marriage and ages 18 months to 10 years. It might be misdiagnosed without the classical features of hypothyroidism at first presentation. We present a case of 15 year old intellectually deficit female with epilepsy managed on phenytoin. She had rigidity, myxedema, calf muscle hypertrophy and agitation. The patient was managed as Neuroleptic Malignant Syndrome due to raised CPK of 40,680 IU/L and mixed presentation. Nevertheless, no improvement was noticed and thyroid profile was done to exclude alternative resources. Thyroid stimulating hormone (TSH) was 74.5 IU, Free T3 1.22 ng/dl, and Free T4 0.43 ng/dl. Thyroxine was started along with change in antiepileptic leading to recovery. This case report highlights the inconsistent finding of KDSS. The female gender, non-consanguineous marriage, delayed onset with primarily neuromuscular symptoms, and raised CPK is a rare demonstration in KDSS. Additionally, thyroid profile is not routinely done, which can lead to misdiagnosis and mismanagement.

Keywords: cretinism, hypothyroidism, intellectual deficit, KDSS

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Authors: Marwa Qaraqe, Muhammad Ismail, Erchin Serpedin

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This paper presents a novel architecture for a patient-specific epileptic seizure onset detector using scalp electroencephalography (EEG). The proposed architecture is based on the decision fusion calculated from energy and neural synchronization related features. Specifically, one level of the detector calculates the condition number (CN) of an EEG matrix to evaluate the amount of neural synchronization present within the EEG channels. On a parallel level, the detector evaluates the energy contained in four EEG frequency subbands. The information is then fed into two independent (parallel) classification units based on support vector machines to determine the onset of a seizure event. The decisions from the two classifiers are then combined together according to two fusion techniques to determine a global decision. Experimental results demonstrate that the detector based on the AND fusion technique outperforms existing detectors with a sensitivity of 100%, detection latency of 3 seconds, while it achieves a 2:76 false alarm rate per hour. The OR fusion technique achieves a sensitivity of 100%, and significantly improves delay latency (0:17 seconds), yet it achieves 12 false alarms per hour.

Keywords: epilepsy, EEG, seizure onset, electroencephalography, neuron, detection

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Authors: Anat Achiron

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Background: Multiple sclerosis (MS) is a chronic autoimmune disease that affects the central nervous system in young adults. It involves the immune system attacking the protective covering of nerve fibers (myelin), leading to inflammation and damage. MS can result in various neurological symptoms, such as muscle weakness, coordination problems, and sensory disturbances. Seizures are not common in MS, and the frequency is estimated between 0.4 to 6.4% over the disease course. Objective: Investigate the frequency of seizures in individuals with multiple sclerosis and to identify associated risk factors. Methods: We evaluated the frequency of seizures in a large cohort of 5686 MS patients followed at the Sheba Multiple Sclerosis Center and studied associated risk factors and comorbidities. Our research was based on data collection using a cohort study design. We applied logistic regression analysis to assess the strength of associations. Results: We found that younger age at onset, longer disease duration, and prolonged time to immunomodulatory treatment initiation were associated with increased risk for seizures. Conclusions: Our findings suggest that seizures in people with MS are directly related to the demyelination process and not associated with other factors like medication side effects or comorbid conditions. Therefore, initiating immunomodulatory treatment early in the disease course could reduce not only disease activity but also decrease seizure risk.

Keywords: epilepsy, seizures, multiple sclerosis, white matter, age

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Authors: Ali Misaghi, Afshin Akhondzadeh Basti, Ehsan Sadeghi

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Staphylococcus aureus is a pathogen of major concern for clinical infection and food borne illness. Humans and most domesticated animals harbor S. aureus, and so we may expect staphylococci to be present in food products of animal origin or in those handled directly by humans, unless heat processing is applied to destroy them. Cuminum cyminum L. has been allocated the topic of some recent studies in addition to its well-documented traditional usage for treatment of toothache, dyspepsia, diarrhea, epilepsy and jaundice. The air-dried seed of the plant was completely immersed in water and subjected to hydro distillation for 3 h, using a clevenger-type apparatus. In this study, the effect of Cuminum cyminum L. essential oil (EO) on growth of Staphylococcus aureus in white brined cheese was evaluated. The experiment included different levels of EO (0, 7.5, 15 and 30 mL/ 100 mL milk) to assess their effects on S. aureus count during the manufacture, ripening and storage of Iranian white brined cheese for up to 75 days. The significant (P < 0.05) inhibitory effects of EO (even at its lowest concentration) on this organism were observed. The significant (P < 0.05) inhibitory effect of the EO on S. aureus shown in this study may improve the scope of the EO function in the food industry.

Keywords: cuminum cyminum L. essential oil, staphylococcus aureus, white brined cheese

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