Search Results (124)

The radiological finding of Dark White Matter (DWM)—characteristic diffuse subcortical white matter hypointensity on T2/FLAIR sequences—is underrecognized, but has important clinical implications. Recent systematic evidence shows that over 60% of previously published cases showed seizures in association with DWM findings—it is also particularly predictive of the underlying etiology, particularly non-ketotic hyperglycemic hyperosmolar state (NKH). Based on our previous work, we reinterpret the data, focusing only on patients with seizures and DWM, to summarize the most essential and distinguishing features of these patients. Both cortical and subcortical abnormalities in DWM are more frequently associated with anti-MOG encephalitis. DWM with or without cortical involvement is more commonly found in NKH among patients with seizures. This updated systematic review will describe the proposed pathophysiological mechanisms, clinical associations, and implications for DWM in patients with seizures, and highlight how early recognition of DWM may allow for targeted diagnostic strategies and treatment options. We expanded our previous search with details regarding seizure features, our results show that DWM is associated with repetitive seizures and Status Epilepticus (both convulsive and non), in line with other peri-ictal MRI abnormalities associated with prolonged seizure activity. DWM-associated seizures are mostly focal, rather than generalized. Moreover, the high percentage of clinical recovery at follow-up suggests that DWM may be predictive of a good outcome, especially in NKH cases, although this needs to be confirmed in future studies. Full article

Status epilepticus (SE) is a neurological emergency. Current evidence dictates a step-by-step approach with a first line of therapy consisting of benzodiazepines (BDZs). In many situations, the currently approved approach does not terminate a BDZ-resistant SE. This happens in Stage 1 Plus, a framework designed by the author to recognize cases of probable benzodiazepine-resistant status epilepticus even before treatment initiation. These cases include Prolonged SE (SE lasting > 10 min), the absence of prominent motor phenomena, and acute etiology (primary central nervous system etiologies most of all). BDZ-refractory SE cases (Stage 1 Plus) might require a different approach, one targeting the unresponsive GABA signaling state mediated by NMDA/AMPA receptors, such as combined polytherapy with Ketamine from the start. These considerations stem from the receptor trafficking hypotheses: in prolonged seizure activity and primary central nervous system etiologies, GABA receptors get internalized and move away from synapses, and therefore, SE becomes resistant to BDZ. A rational polytherapy that might restore the unresponsiveness to BDZ in SE should include NMDA antagonists, such as Ketamine. Ketamine has proven effective in many experimental models of status epilepticus, and much evidence is gathering supporting its use in humans, especially in refractory and super-refractory SE. We lack studies evaluating combined polytherapy in SE, especially in the early phases. The author suggests here that Ketamine should be used along with first-line BDZ in the early SE stage falling in the category of Stage 1 Plus and as a first-line anesthetic infusion drug in refractory SE, especially in cases progressing from Stage 1 Plus, eventually adding continuous midazolam/propofol infusion in later phases. This systematic review’s objective is to summarize the presently available evidence of the early use of combined polytherapy that includes Ketamine, along with the currently available evidence of Ketamine use in early, established, and refractory SE. Nine studies were included. Boluses of Ketamine and Midazolam are effective in pediatric convulsive Stage 1 Plus SE. The results show that earlier Ketamine administration (especially within 12 h of SE onset) was significantly associated with improved seizure control, with a more favorable safety profile than Midazolam in refractory SE. Notably, a dosage of less than 0.9 mg/kg/h proves ineffective in terminating SE. Ketamine has the advantage of preventing intubation, possibly shortening the length of stay in the intensive care unit. Full article

Background/Objectives: Approximately 1% of people worldwide suffer from epilepsy. The development of safer and more effective antiepileptic medications (AEDs) is still urgently needed because all AEDs have some unwanted side effects and roughly 30% of epileptic patients cannot stop having seizures when taking current AEDs. It should be noted that the derivatives of pyrazolo[3,4-b]pyridine are important core structures in many drug substances. The aim of this study is to synthesize new derivatives of piperazino-substituted pyrazolo[3,4-c]-2,7-naphthyridines and 9,11-dimethylpyrimido[1′,2′:1,5]pyrazolo[3,4-c]-2,7-naphthyridines for the evaluation of their neurotropic activity. Methods: The synthesis of the target compounds was performed starting from 1-amino-3-chloro-2,7-naphthyridines and using well-known methods. The structures of all the synthesized compounds were confirmed by spectroscopic data. Compounds were studied for their potential neurotropic activities (anticonvulsant, sedative, anti-anxiety, and antidepressive), as well as side effects, in 450 white mice of both sexes and 50 male Wistar rats. The anticonvulsant effect of the newly synthesized compounds was investigated by using the following tests: pentylenetetrazole, thiosemicarbazide-induced convulsions, and maximal electroshock. The psychotropic properties of the selected compounds were evaluated by using the following tests: the Open Field test, the Elevated Plus Maze (EPM), the Forced Swimming test, and Rotating Rod Test to study muscle relaxation. For the docking studies, AutoDock 4 (version 4.2.6) was used, as well as the structures of the GABA_A receptor (PDB ID: 4COF), the SERT transporter (PDB ID: 3F3A), and the 5-HT_1A receptor (PDB ID: 3NYA) obtained from the Protein Data Bank. Results: A series of piperazino-substituted pyrazolo[3,4-c]-2,7-naphthyridines (3a–j) and 9,11-dimethylpyrimido[1′,2′:1,5]pyrazolo[3,4-c]-2,7-naphthyridines (4a–j), as well as new heterocyclic systems, i.e., isoxazolo[5,4-c]-2,7-naphthyridines 6a–d, were synthesized and evaluated for their neurotropic activity. The investigation showed that some of these compounds (3a,b,d,f–i and 4a,d,f,i) display high anticonvulsant activity, especially in the test of antagonism with pentylenetetrazol, surpassing the well-known antiepileptic drug ethosuximide. Thus, the most active compounds in the pentylenpotetrazole test are 3h, 3i, and 4i; the ED50 of compound 4i is 23.8, and the therapeutic index is more than 33.6, which is the highest among these three active compounds. On the other hand, they simultaneously exhibit psychotropic (anxiolytic, antidepressant, or sedative) or behavioral depressant) effects. The effective compounds do not cause myorelaxation at the tested doses and have high therapeutic indices. Docking on the most active compounds, i.e., 3h, 3i, and 4i, is in agreement with the experimental results. Conclusions: The studies reveled that some of these compounds (3i, 4a, and 4i) display high anticonvulsant and psychotropic activities. The most active compounds contained methyl and diphenylmethyl groups in the piperazine ring. The docking studies identified compounds 3i, 4i, and 4a as the most potent anticonvulsants, showing strong affinity for GABA_A, 5-HT_1A receptors, and the SERT transporter. Notably, compound 4i formed two hydrogen bonds with Thr176 and Arg180 on GABA_A and exhibited a binding energy (−8.81 kcal/mol) comparable to that of diazepam (−8.90 kcal/mol). It also showed the strongest binding to SERT (−7.28 kcal/mol), stabilized by interactions with Gly439, Ile441, and Arg11. Furthermore, 4i displayed the best docking score with 5-HT_1A (−9.10 kcal/mol) due to multiple hydrogen bonds and hydrophobic interactions, supporting its potential as a dual-acting agent targeting both SERT and 5-HT_1A. Full article

Epilepsy is a neurological disorder characterized by repeated convulsions. Antiepileptic drugs (AEDs) are the main course of therapy for epilepsy. These medications are given according to each patient’s personal medical history and the types of seizures they suffer. They have been employed for decades to manage epilepsy, thus delivering relief from seizures through numerous mechanisms of action. Aside from their anticonvulsant attributes, current evidence suggests that certain AEDs may display potential inhibitory effects against cancer invasion and metastasis. This review explored the complicated interactions between the modes of action of AEDs and the pathways causing cancer, and the potential impact of AEDs on the invasion and metastasis of various forms of cancer, while addressing their associated side effects. For example, valproic acid inhibits histone deacetylase, causing hyperacetylation of genes, especially those regulating cell cycle, culminating in cell cycle arrest. Topiramate inhibits carbonic anhydrase, thus disrupting the acidic microenvironment needed for cancer cells to thrive. Lacosamide increases the slow inactivation of the voltage gated Na⁺ channel, thus inhibiting the growth, proliferation, and metastasis of many cancers. Although drug development is a complex task due to regulatory, intellectual property, and economic challenges, researchers are exploring drug repurposing tactics to overcome these challenges and to find new therapeutic alternatives for diseases like cancer. Thus, drug repurposing is considered among the most effective ways to develop drug candidates using novel properties and therapeutic characteristics, and this review also discusses these issues. Full article

Background: Absence epilepsy is a non-convulsive form of genetic generalized epilepsy characterized by spontaneous bilateral spike-and-wave discharges (SWDs) in EEG. In contrast to grand-mal epilepsy, absence epilepsy without greatly expressed motor and interictal EEG abnormalities is difficult to detect, especially at the early stages. The WAG/Rij rat strain is a well-validated animal model of childhood absence epilepsy. At the early, preclinical stage, precursors or immature SWDs appear. Then, with age, immature discharges gradually turn into mature ones and mature SWDs prevail at the clinical stage. Mature SWDs, with an amplitude several times higher than the background EEG, can be easily distinguished visually. However, the amplitude of immature discharges is significantly lower than that of mature SWDs and is comparable to the amplitude of sleep spindles. Therefore, it is quite a difficult problem to distinguish immature discharges from sleep spindles. The task is further complicated by the fact that absence seizures mainly appear in a state of drowsiness and slow-wave (non-REM) sleep, when a lot of sleep spindles occur. The purpose of the present study was to develop a diagnostic method that allows us to precisely distinguish immature forms of epileptic seizures from background EEG and sleep spindles. Methods: The idea of analyzing wave-train electrical activity is to investigate the wavelet spectrum, find local peculiarities in this spectrum, and estimate generalized time-frequency peculiarities of the signal in terms of the found local peculiarities. Results: The criteria for diagnosis of the immature form of epileptic discharges and sleep spindles have been developed based on the analysis of wave-train activity with the construction of AUC diagrams (area under the curve diagrams). Conclusions: The method of wave-train analysis with the construction of AUC diagrams can be used for extracting the diagnostic features necessary for the diagnosis of absence epilepsy at the early stages of the disease in people with a genetic predisposition. Full article

Background/Objectives: Cerebral folate transporter deficiency is characterized by pauses and regression in general development stages, with ataxia, choreoathetoid movements, and myoclonic epilepsy generally resistant to treatment. The aim of this study was to comprehensively evaluate cases followed up in two centres in Türkiye for a diagnosis of folate receptor-α deficiency. Methods: The study included nine cases from six different families. Results: The patients comprised 22.2% males and there was parental consanguinity in 88.9% of cases. The mean age at which complaints were first noticed was 3.7 years, and the age of definitive diagnosis was 10.4 years. The most frequently seen first complaints were febrile convulsions and attention deficit-hyperactivity-learning difficulties. The diagnosis most commonly made before the definitive diagnosis was epilepsy, and the first seizure occurred at a mean of 5.2 years. On cranial imaging, white matter involvement, cerebellar atrophy and cerebral atrophy were determined most often. Definitive diagnosis was established solely through clinical findings and genetic analysis. Three different variants in the FOLR1 gene were determined. Treatment with folinic acid at a dose of 5.2 mg/kg/day of PO was started at the age of 9.8 years on average, and intravenous folinate was started at different doses. Conclusions: This study stands out as one of the largest case series in the literature and identifies a previously unreported novel variant. Our study suggests that FOLR1-related CFD should be considered in cases with febrile convulsions, developmental delay, ataxia, autism spectrum disorder, acquired microcephaly, and MRI findings of white matter involvement and cerebellar atrophy. Due to an asymptomatic early period, CFD diagnosis may be delayed, and treatment after symptom onset may be less effective. Incorporating FOLR1 gene analysis into newborn screening programmes could facilitate early diagnosis and treatment. It is thought that the application of vagus nerve stimulation, in addition to folinic acid and anticonvulsant drug treatment, could be effective in seizure control. Full article

Point-of-care electroencephalography (POC-EEG) systems are rapid-access, reduced-montage devices designed to address the limitations of conventional EEG (conv-EEG), enabling faster neurophysiological assessment in acute settings. This review evaluates their clinical impact, diagnostic performance, and feasibility in non-convulsive status epilepticus (NCSE), traumatic brain injury (TBI), stroke, and delirium. A comprehensive search of Medline, Scopus, and Embase identified 69 studies assessing 15 devices. In suspected NCSE, POC-EEG facilitates rapid seizure detection and prompt diagnosis, making it particularly effective in time-sensitive and resource-limited settings. Its after-hours availability and telemedicine integration ensure continuous coverage. AI-assisted tools enhance interpretability and accessibility, enabling use by non-experts. Despite variability in accuracy, it supports triaging, improving management, treatment decisions and outcomes while reducing hospital stays, transfers, and costs. In TBI, POC-EEG-derived quantitative EEG (qEEG) indices reliably detect structural lesions, support triage, and minimize unnecessary CT scans. They also help assess concussion severity and predict recovery. For strokes, POC-EEG aids triage by detecting large vessel occlusions (LVOs) with high feasibility in hospital and prehospital settings. In delirium, spectral analysis and AI-assisted models enhance diagnostic accuracy, broadening its clinical applications. Although POC-EEG is a promising screening tool, challenges remain in diagnostic variability, technical limitations, and AI optimization, requiring further research. Full article

Hepatic encephalopathy (HE) in dogs is a metabolic disorder of the central nervous system that occurs secondarily to liver dysfunctions, whether due to acquired or congenital causes. A portosystemic shunt is the presence of abnormal communications between the hepatic vessels (portal and suprahepatic veins). As a result of this, the blood brought from the digestive tract through the portal vein bypasses the liver, and the unmetabolized components of the portal bloodstream enter directly into systemic circulation, causing clinical symptoms of metabolic encephalopathy (HE). A 3-month-old Bichon canine patient with a history of seizures secondarily to a portosystemic shunt (PS), confirmed through color Doppler ultrasound exam and computed tomography, was presented for evaluation. The typical electroencephalographic (EEG) traces recorded were characterized by the presence of bilateral symmetrical triphasic waves, resembling non-convulsive status epilepticus. The presence of this EEG pattern is useful in choosing the best therapeutic option in order to not accentuate the HE sings and, consequently, to decrease the mortality risk due to a prolonged status epilepticus. Full article

Background: ASH1L (absent, small, or homeotic-like 1), a histone methyltransferase, has been identified as a high-risk gene for autism spectrum disorder (ASD). We previously showed that postnatal Ash1l severe deficiency in the prefrontal cortex (PFC) of male and female mice caused seizures. However, the synaptic mechanisms underlying autism-like social deficits and seizures need to be elucidated. Objective: The goal of this study is to characterize the behavioral deficits and reveal the synaptic mechanisms in an Ash1l haploinsufficiency mouse model using a targeted gene-trap knockout (gtKO) strategy. Method: A series of behavioral tests were used to examine behavioral deficits. Electrophysiological and chemogenetic approaches were used to examine and manipulate the excitability of pyramidal neurons in the PFC of Ash1l^+/GT mice. Results: Ash1l^+/GT mice displayed social deficits, increased self-grooming, and cognitive impairments. Epileptiform discharges were found on electroencephalograms (EEGs) of Ash1l^+/GT mice, indicating absence-like seizures. Ash1l haploinsufficiency increased the susceptibility for convulsive seizures when Ash1l^+/GT mice were challenged by pentylenetetrazole (PTZ, a competitive GABA_A receptor antagonist). Whole-cell patch-clamp recordings showed that Ash1l haploinsufficiency increased the excitability of pyramidal neurons in the PFC by altering intrinsic neuronal properties, enhancing glutamatergic synaptic transmission, and diminishing GABAergic synaptic inhibition. Chemogenetic inhibition of pyramidal neurons in the PFC of Ash1l^+/GT mice ameliorated autism-like social deficits and abolished absence-like seizures. Conclusions: We demonstrated that increased neural activity in the PFC contributed to the autism-like social deficits and absence-like seizures in Ash1l^+/GT mice, which provides novel insights into the therapeutic strategies for patients with ASH1L-associated ASD and epilepsy. Full article

Developing interfaces for seizure diagnosis, often challenging to detect visually, is rising. However, their effectiveness is constrained by the need for diverse and extensive databases. This study aimed to create a seizure detection methodology incorporating detailed information from each EEG channel and accounts for frequency band variations linked to the primary brain pathology leading to ICU admission, enhancing our ability to identify epilepsy onset. This study involved 460 video-electroencephalography recordings from 71 patients under monitoring. We applied signal preprocessing and conducted a numerical quantitative analysis in the frequency domain. Various machine learning algorithms were assessed for their efficacy. The k-nearest neighbours (KNN) model was the most effective in our overall sample, achieving an average F1 score of 0.76. For specific subgroups, different models showed superior performance: Decision Tree for ‘Epilepsy’ (average F1 score of 0.80) and ‘Craniencephalic Trauma’ (average F1 score of 0.84), Random Forest for ‘Cardiorespiratory Arrest’ (average F1 score of 0.89) and ‘Brain Haemorrhage’ (average F1 score of 0.84). In the categorisation of seizure types, Linear Discriminant Analysis was most effective for focal seizures (average F1 score of 0.87), KNN for generalised (average F1 score of 0.84) and convulsive seizures (average F1 score of 0.88), and logistic regression for non-convulsive seizures (average F1 score of 0.83). Our study demonstrates the potential of using classifier models based on quantified EEG data for diagnosing seizures in ICU patients. The performance of these models varies significantly depending on the underlying cause of the seizure, highlighting the importance of tailored approaches. The automation of these diagnostic tools could facilitate early seizure detection. Full article

Oxidative stress develops when there is an excess of oxidants leading to molecular and cellular damage. Seizure activity leads to oxidative stress and the resulting increased lipid peroxidation. Generally, antiseizure medications reduce oxidative stress, although the data on levetiracetam are ambiguous. Exogenous antioxidants (vitamin E, resveratrol, hesperidin, and curcumin) have been documented to exert an anticonvulsant effect in animal models of seizures and some recent clinical data point to curcumin as an affective adjuvant for the therapy of pediatric intractable epilepsy. Melatonin is an antioxidant with an ability to attenuate seizure activity induced by various convulsants in rodents. Its clinical effectiveness has been also confirmed in a number of clinical studies. Experimental studies point to a possibility that endogenous melatonin may possess proconvulsive activity. Moreover, some scarce clinical data seem to express this view; however, a limited number of patients were included. The anticonvulsant activity of exogenous melatonin may involve GABA-mediated inhibition, while endogenous melatonin may act as a proconvulsant due to a decrease in the brain dopaminergic transmission. Antioxidants, including melatonin, may be considered as adjuvants in the therapy of epilepsy and melatonin, in addition, in patients with epilepsy suffering from sleep disorders. Full article

Background: Infant meningitis, particularly caused by Escherichia coli, remains a life-threatening condition, especially in premature and low-weight infants. Infections of the central nervous system can be fatal, necessitating prompt diagnosis and appropriate treatment. Acute infections caused by various pathogens, including E. coli, often present with similar clinical symptoms. The rapid identification of pathogens and their antimicrobial resistance mechanisms is critical for timely and effective treatment. We report the case of an 8-month-old patient who presented with fever, diarrhea, and convulsive seizures and was subsequently diagnosed with meningitis. Despite initial empirical treatment with ceftriaxone, the patient’s condition worsened. Methods: At Bambino Gesù Children’s Hospital, molecular diagnostic tools, including the FilmArray Meningitis/Encephalitis and Blood Culture Identification panels, were employed. Results: Although the Meningitis panel did not detect any pathogens due to the lack of the specific bacterial target, the off-label use of the Blood Culture Identification panel identified a non-K1 Escherichia coli strain carrying the CTX-M resistance gene, an extended-spectrum beta-lactamase (ESBL). Despite the rapid diagnostic approach and adjustment of antibiotic therapy, the patient succumbed to the infection due to the strain’s high virulence and multidrug resistance. Whole-genome sequencing further characterized the strain, revealing that it belonged to the ST131 group, a highly resistant and virulent strain associated with sepsis. Conclusions: This case highlights the importance of integrating advanced molecular diagnostics, such as whole-genome sequencing, with traditional methods to improve pathogen detection, especially in cases of emerging resistant strains that are not covered by standard diagnostic panels. It also emphasizes the need for the continuous adaptation of diagnostic tools to include non-K1 E. coli strains for more comprehensive and timely meningitis diagnosis. Full article

Background/Objectives: Neuronal Ceroid Lipofuscinosis type 2 is a rare pathology affecting mainly the central nervous system (CNS) and retina, and is caused by variants in the gene encoding the lysosomal enzyme tripeptidyl peptidase 1. Therapy with enzyme replacement through the brain infusion of the orphan drug cerliponase alfa, a recombinant human tripeptidyl peptidase 1 enzyme replacement therapy delivered via intracerebroventricular infusion, has been approved for Neuronal Ceroid Lipofuscinosis type 2 disease. The safety profile of cerliponase alfa has been established based on pre-authorization studies; currently, no post-marketing investigation has been performed to confirm it. Here, a descriptive analysis of real-world spontaneous reporting data of suspected adverse reactions (SARs) to cerliponase alfa in the EudraVigilance database was performed to compile clear information on the safety profile. Methods: Suspected adverse reactions to cerliponase alfa reported in the data system EudraVigilance were analyzed for age, sex of the patient, adverse reactions, and the indication for use. Results: Cases with suspected adverse reactions to cerliponase alfa were found to be more frequent in female patients (58.1%) and in children aged 3–11 years. The most common adverse reactions were, in decreasing order, fever/pyrexia, device-related infection, vomiting, seizures/convulsions, pleocytosis, irritability, ventriculitis, and respiratory disorders. Conclusions: The results confirm the safety profile of cerliponase alfa established with pre-registration clinical studies but suggest the need for further studies to investigate the occurrence of adverse reactions, as possible predictive prognostic markers, in more depth. Full article

The detection of adverse events—for example, convulsive epileptic seizures—can be critical for patients suffering from a variety of pathological syndromes. Algorithms using remote sensing modalities, such as a video camera input, can be effective for real-time alerting, but the broad variability of environments and numerous nonstationary factors may limit their precision. In this work, we address the issue of adaptive reinforcement that can provide flexible applications in alerting devices. The general concept of our approach is the topological reinforced adaptive algorithm (TOREADA). Three essential steps—embedding, assessment, and envelope—act iteratively during the operation of the system, thus providing continuous, on-the-fly, reinforced learning. We apply this concept in the case of detecting convulsive epileptic seizures, where three parameters define the decision manifold. Monte Carlo-type simulations validate the effectiveness and robustness of the approach. We show that the adaptive procedure finds the correct detection parameters, providing optimal accuracy from a large variety of initial states. With respect to the separation quality between simulated seizure and normal epochs, the detection reinforcement algorithm is robust within the broad margins of signal-generation scenarios. We conclude that our technique is applicable to a large variety of event detection systems. Full article

Background: Febrile seizures are a common form of convulsions in childhood, with poorly known cellular mechanisms. The objective of this pioneering study was to provide qualitative and quantitative ultrastructural research on the large neuronal perikarya in the cerebellar dentate nucleus (DN), using an experimental model of hyperthermia-induced seizures (HSs), comparable to febrile seizures in children. Methods: The study used young male Wistar rats, divided into experimental and control groups. The HSs were evoked by a hyperthermic water bath at 45 °C for 4 min for four consecutive days. Specimens (1 mm³) collected from the DN were routinely processed for transmission electron microscopy studies. Results: The ultrastructure of the large neurons in the DN affected by hyperthermic stress showed variously pronounced lesions in the perikarya, including total cell disintegration. The most pronounced neuronal lesions exhibited specific morphological signs of aponecrosis, i.e., dark cell degeneration (‘dark neurons’). In close vicinity to the ‘dark neurons’, the aponecrotic bodies were found. The findings of this qualitative ultrastructural study correspond with the results of the morphometric analysis of the neuronal perikarya. Conclusions: Our results may constitute interesting comparative material for similar submicroscopic observations on large DN neurons in HS morphogenesis and, in the future, may help to find potential treatment targets to prevent febrile seizures or reduce recurrent seizures in children. Full article