Seizure Control Research Articles

Ketogenic Diet in the Treatment of Epilepsy.

Epilepsy is one of the most disabling neurological diseases. Despite proper pharmacotherapy and the availability of 2nd and 3rd generation antiepileptic drugs, deep brain stimulation, and surgery, up to 30-40% of epilepsy patients remain drug-resistant. Consequences of this phenomenon include not only decreased a quality of life, and cognitive, behavioral, and personal disorders, but also an increased risk of death, i.e., in the mechanism of sudden unexpected death in epilepsy patients (SUDEP). The main goals of epilepsy treatment include three basic issues: achieving the best possible seizure control, avoiding the undesired effects of treatment, and maintaining/improving the quality of patients' lives. Therefore, numerous attempts are made to offer alternative treatments for drug-resistant seizures, an example of which is the ketogenic diet. It is a long-known but rarely used dietary therapy for intractable seizures. One of the reasons for this is the unpalatability of the classic ketogenic diet, which reduces patient compliance and adherence rates. However, its antiseizure effects are often considered to be worth the effort. Until recently, the diet was considered the last-resort treatment. Currently, it is believed that a ketogenic diet should be used much earlier in patients with well-defined indications. In correctly qualified patients, seizure activity may be reduced by over 90% or even abolished for long periods after the diet is stopped. A ketogenic diet can be used in all age groups, although most of the available literature addresses pediatric epilepsy. In this article, we focus on the mechanisms of action, effectiveness, and adverse effects of different variants of the ketogenic diet, including its classic version, a medium-chain triglyceride diet, a modified Atkins diet, and a low glycemic index treatment.

Differentiating non-epileptic seizures from epileptic seizures in Glut1 deficiency syndrome.

To investigate the clinical characteristics of non-epileptic seizures due to transient brain dysfunction caused by energy deficiency after prolonged fasting or exercise in individuals with glucose transporter type 1 deficiency syndrome (Glut1DS), and then elucidate further the seizure features to distinguish non-epileptic seizures from epileptic seizures. This retrospective case-control study included 57 non-epileptic seizures and 23 epileptic seizures (control group) in 14 individuals (11 males, three females; aged 5-44 years, median = 20 years) with Glut1DS, all with a heterozygous pathogenic SLC2A1 mutation. Non-epileptic seizures were classified as paroxysmal altered consciousness (n = 8), movement disorders (n = 35) (eye-head movements, ataxia, spasticity, weakness, involuntary movement), dysaesthesia (n = 8), and vomiting (n = 6) at the peak ages at onset of 5 to 10 years. Ketogenic diet therapy was effective in 33 of 43 (77%) non-epileptic seizures. Providing supplementary food before high-impact exercise or during attacks prevented or mitigated non-epileptic seizures in some individuals. Glut1DS-associated non-epileptic seizures are fundamentally situation-related seizures with specific provoking and ameliorating factors. Non-epileptic seizures can be distinguished from epileptic seizures by the absence of complete consciousness loss and rapid postictal recovery despite prolonged seizures. Non-epileptic seizures are not well recognized but require different therapeutic approaches compared to epileptic seizures. Awareness of the differentiation of non-epileptic seizures from epileptic seizures is essential when performing preventive or therapeutic decision-making for acute exacerbation seizures. Non-epileptic seizures are invariably situation-related seizures. Non-epileptic seizures were classified as altered consciousness, movement disorders, dysaesthesia, and vomiting. Non-epileptic seizures were characterized by the absence of complete consciousness loss and were accompanied by rapid recovery. Non-epileptic seizures can occur simultaneously or consecutively with another. Supplementary food can be effective in preventing the development of sustained exercise-induced movement disorders.

Surgical Anatomy and Technique of Peri-Insular Hemispherotomy in Pediatric Epilepsy.

Hemispherotomy is a highly complex procedure that demands a steep learning curve. An incomplete brain disconnection often results in failure of seizure control. The purpose of this article was to present a step-by-step guide to the surgical anatomy of this procedure. It is composed of a 7-stage approach, enhancing access to and improving visualization of deep structures. A retrospective analysis of 39 pediatric patients with refractory epilepsy who underwent this technique was conducted. Engel scores were assessed 1 year postsurgery. Cadaveric dissections were performed to illustrate the procedure. Between 2015 and 2022, 39 patients were surgically treated using the peri-insular technique. The technique involved 7 stages: patient positioning, operative approach, opercular resection, transventricular callosotomy, fronto-orbital disconnection, anterior temporal disconnection, and posterior temporal disconnection. Most of the patients (92.30%) were seizure-free (Engel class I) at 1 year postoperative, 5.13% were nearly seizure-free (Engel II), and 2.56% showed significant improvement (Engel III). Complications occurred in 8% of cases, including 1 infection, 2 cases of aseptic meningitis, and 1 non-shunt-requiring acute hydrocephalus. The peri-insular hemispherotomy technique offers excellent seizure control with a low complication rate. Our visual documentation of surgical anatomy, complemented by detailed descriptions of surgical nuances, significantly contributes to a comprehensive understanding of this technique.

Outcomes of stereoelectroencephalography following failed epilepsy surgery in children.

Stereoelectroencephalography (SEEG) is valuable for delineating the seizure onset zone (SOZ) in pharmacoresistant epilepsy when non-invasive presurgical techniques are inconclusive. Secondary epilepsy surgery after initial failure is challenging and there is limited research on SEEG following failed epilepsy surgery in children. The objective of this manuscript is to present the outcomes of children who underwent SEEG after failed epilepsy surgery. In this single-institution retrospective study, demographics, previous surgery data, SEEG characteristics, management, and follow-up were analyzed for pediatric patients who underwent SEEG after unsuccessful epilepsy surgery between August 2016 and February 2023. Fifty three patients underwent SEEG investigation during this period. Of this, 13 patients were identified who had unsuccessful initial epilepsy surgery (24%). Of these 13 patients, six patients (46%) experienced unsuccessful resective epilepsy surgery that targeted the temporal lobe, six patients (46%) underwent surgery involving the frontal lobe, and one patient (8%) had laser interstitial thermal therapy (LITT) of the right insula. SEEG in two thirds of patients (4/6) with initial failed temporal resections revealed expanded SOZ to include the insula. All 13 patients (100%) had a subsequent surgery after SEEG which was either LITT (54%) or surgical resection (46%). After the subsequent surgery, a favorable outcome (Engel class I/II) was achieved by eight patients (62%), while five patients experienced an unfavorable outcome (Engel class III/IV, 38%). Of the six patients with secondary surgical resection, four patients (67%) had favorable outcomes, while of the seven patients with LITT, two patients (29%) had favorable outcomes (Engel I/II). Average follow-up after the subsequent surgery was 37 months ±23 months. SEEG following initial failed resective epilepsy surgery may help guide next steps at identifying residual epileptogenic cortex and is associated with favorable seizure control outcomes.

Transcranial brain parenchyma sonography in patients with juvenile myoclonic epilepsy.

There are rising evidences that subcortical structures, including the basal ganglia, are affected in patients with epilepsy. These structures are thought to influence the modulation and phenotypic expression of epileptic seizures. Our study aimed to evaluate the presence of structural abnormalities in subcortical structures in patients with juvenile myoclonic epilepsy (JME). This cross-sectional study included 51 patients who were diagnosed with JME and who were monitored on an outpatient basis at the Clinic for Neurology and Psychiatry for Children and Youth in Belgrade from January 1985 to October 2017. All patients underwent transcranial parenchymal sonography (TCS) from October 2015 to October 2017. Relation of clinical parameters (seizure control andcognitive functioning,) with TCS results was assessed. Hyperechogenicity of the substantia nigra (SN) was detected in 37.2% of JME subjects and it was significantly more common in patients with JME than in the control group. The marked echogenicity of the red nucleus (RN) was detected in 17.6% of cases, while 11.8% of subjects had hyperechogenic RN. The presence of hyperechogenic RN (both right and left) was significantly more frequent in the group of patients with JME compared to the control group. The third ventricle diameter was larger in patients with JME than in controls. Structural changes of certain subcortical structures, primarily SN and RN, detected in JME patients indicate additional non-lesional abnormalities of the basal ganglia and midbrain structures in these patients.

The role of neuromodulation in the management of drug-resistant epilepsy.

Drug-resistant epilepsy (DRE) poses significant challenges in terms of effective management and seizure control. Neuromodulation techniques have emerged as promising solutions for individuals who are unresponsive to pharmacological treatments, especially for those who are not good surgical candidates for surgical resection or laser interstitial therapy (LiTT). Currently, there are three neuromodulation techniques that are FDA-approved for the management of DRE. These include vagus nerve stimulation (VNS), deep brain stimulation (DBS), and responsive neurostimulation (RNS). Device selection, optimal time, and DBS and RNS target selection can also be challenging. In general, the number and localizability of the epileptic foci, alongside the comorbidities manifested by the patients, substantially influence the selection process. In the past, the general axiom was that DBS and VNS can be used for generalized and localized focal seizures, while RNS is typically reserved for patients with one or two highly localized epileptic foci, especially if they are in eloquent areas of the brain. Nowadays, with the advance in our understanding of thalamic involvement in DRE, RNS is also very effective for general non-focal epilepsy. In this review, we will discuss the underlying mechanisms of action, patient selection criteria, and the evidence supporting the use of each technique. Additionally, we explore emerging technologies and novel approaches in neuromodulation, such as closed-loop systems. Moreover, we examine the challenges and limitations associated with neuromodulation therapies, including adverse effects, complications, and the need for further long-term studies.This comprehensive review aims to provide valuable insights on present and future use of neuromodulation.

Diagnosis and treatment of growth hormone deficiency in children on the ketogenic diet: A case series.

The ketogenic diet (KD) can have a negative impact on the linear growth and body composition of children. The aims of this study were to review two centers' experience with children who developed height deceleration on the KD and determine if the height deceleration was secondary to growth hormone deficiency (GHD), and if growth hormone therapy (GHT) would be effective and safe (not altering ketosis or seizure frequency). Retrospective chart reviews were performed on patients with KD referred to Endocrinology between 2013 and 2018. Seventeen children were identified. Data reviewed included: demographics, growth velocity, KD ratio, protein/calorie intake, lab results, GH dosage, Tanner stage, and seizure frequency, and endocrine recommendations. Descriptive statistics were performed. Of the 17 children referred to the Endocrine Division, seven children were growth hormone deficient and began GHT. Data were provided for six patients (2 males, 4 females; age 2-7 years at the start of KD) on the KD for >6 years and on GHT for >4 years. Growth for all patients stabilized or increased. IGF-1 z-scores normalized. GHT did not affect seizure frequency or ketosis. GHT in those with GHD can be an appropriate option allowing better growth while still maintaining ketogenic therapy and seizure control. PLAIN LANGUAGE SUMMARY: The KD can be an effective treatment for difficult-to-control epilepsy and some disorders of carbohydrate metabolism. The KD can adversely affect the linear growth (height) of children. This case series reviewed six patients who had slow linear growth. It was found that all six children had growth hormone deficiency, grew better with growth hormone treatments, and that their seizures and ketone levels were not affected.

Cell-specific extracellular vesicle-encapsulated exogenous GABA controls seizures in epilepsy

BackgroundEpilepsy affects ∼60 million people worldwide. Most antiseizure medications in the market act on voltage-gated sodium or calcium channels, indirectly modulating neurotransmitter GABA or glutamate levels or multiple targets. Earlier studies made significant efforts to directly deliver GABA into the brain with varied success. Herein, we have hypothesized to directly deliver exogenous GABA to the brain with epilepsy through extracellular vesicles (EVs) from human GABA-producing cells and their progenitors as EVs largely mimic their parent cell composition.MethodsHuman neural stem cells (NSCs), medial ganglionic eminence (MGE) cells, and GABAergic interneurons (INs) were generated from induced pluripotent stem cells (iPSCs) and characterized. EVs were isolated from NSCs, MGE cells, and INs and characterized for size and distribution, morphological features, and molecular markers. Exogenous GABA was passively loaded to the isolated EVs as a zwitterion at physiological pH, and the encapsulated dose of GABA was quantified. Epilepsy was developed through status epilepticus induction in Fisher rats by administration of repeated low doses of kainic acid. The extent of the seizures was measured for 10 h/ day for 3–6 months by video recording and its evaluation for stage III, IV and V seizures as per Racine scale. EVs from INs, MGE cells, and NSCs encapsulated with exogenous GABA were sequentially tested in the 4th, 5th, and 6th months by intranasal administration in the rats with epilepsy for detailed seizure, behavioral and synapse analysis. In separate experiments, several controls including exogenic GABA alone and EVs from INs and MGE cells were evaluated for seizure-controlling ability.ResultsExogenic GABA could enter the brain through EVs. Treatment with EVs from INs and MGE cells encapsulated with GABA significantly reduced total seizures, stage V seizures, and total time spent in seizure activity. EVs from NSCs encapsulated with GABA demonstrated limited seizure control. Exogenic GABA alone and EVs from INs and MGE cells individually failed to control seizures. Further, exogenic GABA with EVs from MGE cells improved depressive behavior while partially improving memory functions. Co-localization studies confirmed exogenous GABA with presynaptic vesicles in the hippocampus, indicating the interaction of exogenous GABA in the brain with epilepsy.ConclusionFor the first time, the study demonstrated that exogenous GABA could be delivered to the brain through brain cell-derived EVs, which could regulate seizures in temporal lobe epilepsy. It is identified that the cellular origin of EVs plays a vital role in seizure control with exogenous GABA.

Efficacy and safety of phenytoin and levetiracetam for acute symptomatic seizures in children with acute encephalitis syndrome: an open label, randomised controlled trial

IntroductionSeizures represent a significant comorbidity in children with acute encephalitis syndrome (AES). Despite this, there is a notable absence of randomized controlled trials (RCTs) directly comparing antiseizure medications (ASMs) in children with AES. Materials and MethodsThis RCT aimed to assess the efficacy and safety of phenytoin and levetiracetam in controlling seizures among children with AES. Both ASMs were administered with a loading followed by maintenance dose. After a 12-week period, children exhibiting a normal electroencephalogram and no seizure recurrence underwent tapering and discontinuation of ASM. Clinical follow-up occurred daily for the first week, and subsequently at 4, 12, and 24 weeks, evaluating seizure recurrence, incidence of status epilepticus, cognition, behavior, functional status, ASM acquisition cost, and adverse effects. ResultsA total of 100 children (50 in each group) were enrolled. Within the first week, 5 and 3 children in the phenytoin and levetiracetam groups expired. Up to 1 week or death (whichever occurred earliest), 46 (92 %) and 44 (88 %) children remained seizure-free. Intention-to-treat analysis for both best and worst-case scenarios showed insignificant differences (p=0.52 and 1.0). No children experienced seizure recurrence after 1 week in either group. The number of patients with breakthrough status epilepticus, need for mechanical ventilation, duration of hospital stay, presence of epileptiform abnormalities in repeat electroencephalogram at 12 weeks, functional outcomes at 1, 12, and 24 weeks, as well as cognition and behavioral profiles at 24 weeks, were comparable in both groups (p>0.05 for all). However, the incidence of treatment-emergent adverse events (TEAEs) causally related to study medications was significantly higher in the phenytoin group (p=0.04). ConclusionLevetiracetam and phenytoin are comparable in efficacy in terms of achieving clinical seizure control in children with acute encephalitis syndrome, although levetiracetam group demonstrated fewer adverse effects.

Prevalence and Risk Factors of Low Vitamin D Level in Adults with Epilepsy: A Cross-sectional Study at a Single Tertiary Neurological Center in Thailand

Background: Epilepsy has a wide-ranging impact on the quality of life in patients of all age groups. Reduced levels of active vitamin D contribute to various bone diseases and may influence seizure control. Nevertheless, the risk factors for low vitamin D levels in patients with epilepsy remain inconclusive and are not well-established. The limited number of studies in Thailand may not be sufficient to provide guideline recommendations for screening vitamin D levels in adults with epilepsy. Objective: To evaluate the prevalence and risk factors of low vitamin D levels in Thai adults with epilepsy taking long-term antiepileptic drugs. To provide supporting recommendations for screening vitamin D levels in patients with epilepsy for early diagnosis and appropriate vitamin supplementation. Materials and Methods: The present study was a cross-sectional study conducted on 87 adults with epilepsy aged 18 to 76 years who were followed up at the Neurological Institute of Thailand between March and October 2023. Patients with comorbidities affecting vitamin D metabolism were excluded from the study. Baseline demographic data, epilepsy-related information, and anti-seizure medication information were analyzed. Blood tests for vitamin D for 25-hydroxyvitamin D [25(OH)D], calcium, phosphorus, and albumin were performed. Results: The prevalence of low vitamin D levels was 85%, including deficiency at 37% and insufficiency at 48%, with the mean (±SD) of serum 25(OH)D being 21.9±7.60 ng/mL. Multivariate analyses revealed that female was significantly associated with low vitamin D levels, adjusted OR 4.97 (95% CI 1.23 to 20.05). There was no significant association among epilepsy-related information, anti-seizure medications, and low vitamin D levels. Conclusion: The prevalence of low vitamin D levels in the present study was significantly higher than that observed in the previous studies, which is consistent with the findings of the recent studies in many countries. The authors strongly recommend screening for vitamin D levels in Thai adults with epilepsy, particularly in females. Early diagnosis and management of this condition are beneficial for patients with epilepsy and can help mitigate the various complications resulting from low vitamin D levels. Keywords: Epilepsy; Low vitamin D level; Vitamin D deficiency; Vitamin D insufficiency; Antiseizure medications; Prevalence; Risk factors

The Effect of Ketogenic Metabolic Therapy on Recurrent High-Grade Gliomas: Case Series

High-grade gliomas represent the most prevalent primary malignant brain tumors in the adult population. Despite extensive efforts dedicated to advance in therapeutic modalities, treatment options remain very limited in this field, leading to a worse prognosis for affected patients. Moreover, a considerable number of cases exhibit refractory disease following the initial management. Ketogenic Metabolic Therapy (KMT) has emerged as a promising adjunctive approach for recurrent high-grade gliomas, offering them a synergistic effect enhancement of the effectiveness of conventional therapies against this type of cancer. The underlying hypothesis relies on the use of high-fat, low-carbohydrate diet, with adequate protein content can potentially induce metabolic reprogramming in cancer cells. Currently, the use of KMT is on the rise and has shown positive effects on the control of selected neurological symptoms and improvements in patient’s quality of life. This is a descriptive observational multicenter study (case series) that includes patients with recurrent high-grade gliomas who underwent Ketogenic Metabolic Therapy (KMT) and were supplemented with a liquid ketogenic formula (in a 3:1 ratio) as a complementary treatment to the ongoing medical regimen for recurrence. The results show a positive impact on seizure control, as well as significant improvements in cognition, memory and functionality, as reported by patients and/or their families (caregivers). Regarding the disease status, assessed by the RANO criteria, the 12-month follow-up evaluation indicated stable disease in 55% and a partial response in 20% of cases. Although the results of this work are promising, more conclusive clinical data are still needed to support the use of KMT in the treatment of high-grade gliomas.

Pregnancy Outcomes and Seizure Control in Underserved Patients with Epilepsy (P4-1.008)

Pregnancy Outcomes and Seizure Control in Underserved Patients with Epilepsy (P4-1.008)

Enhancement of Subjective Quality of Life Following Surgical Intervention in Patients With Drug-Resistant Epilepsy: A Depressive Symptom-Independent Outcome.

To evaluate the impact of depressive symptoms on the subjective perception of quality of life in patients with drug-resistant epilepsy (DRE) after surgical treatment for seizures. Methods: A case-control study with DRE patients who received surgical treatment (n=19) and matched non-operated patients (n=23). We assessed the quality of life using the Subjective Handicap of Epilepsy (SHE) scale, alongside measuring depressive symptoms using the Beck Depression Inventory (BDI). The mean age of the participants was 45 years, with females constituting 52.4% of the patients. A majority (73.8%) had been diagnosed with temporal lobe epilepsy. Those who had undergone surgical intervention showed significantly enhanced performance across all quality-of-life domains on the SHE scale independently of depressive symptoms. The domains of "Work and Activity,""Physical Health,"and "Self-Perception" displayed the greatest improvements, with the surgical group's averages outperforming the control group by factors of 1.87, 2.53, and 2.81, respectively. Influential differences impacting the quality-of-life scores included seizure frequency, the quantity of antiepileptic drugs utilized, and the incidence of convulsive seizures. The findings suggest that surgical control of seizures in drug-resistant focal epilepsy is associated with improvement in quality of life across various domains, independently of the depressive symptoms of the patients.

Disrupted de novo pyrimidine biosynthesis impairs adult hippocampal neurogenesis and cognition in pyridoxine-dependent epilepsy.

Despite seizure control by early high-dose pyridoxine (vitamin B6) treatment, at least 75% of pyridoxine-dependent epilepsy (PDE) patients with ALDH7A1 mutation still suffer from intellectual disability. It points to a need for additional therapeutic interventions for PDE beyond pyridoxine treatment, which provokes us to investigate the mechanisms underlying the impairment of brain hemostasis by ALDH7A1 deficiency. In this study, we show that ALDH7A1-deficient mice with seizure control exhibit altered adult hippocampal neurogenesis and impaired cognitive functions. Mechanistically, ALDH7A1 deficiency leads to the accumulation of toxic lysine catabolism intermediates, α-aminoadipic-δ-semialdehyde and its cyclic form, δ-1-piperideine-6-carboxylate, which in turn impair de novo pyrimidine biosynthesis and inhibit NSC proliferation and differentiation. Notably, supplementation of pyrimidines rescues abnormal neurogenesis and cognitive impairment in ALDH7A1-deficient adult mice. Therefore, our findings not only define the important role of ALDH7A1 in the regulation of adult hippocampal neurogenesis but also provide a potential therapeutic intervention to ameliorate the defective mental capacities in PDE patients with seizure control.

Microsurgical removal of supratentorial and cerebellar cavernous malformations: what has changed? A single institution experience.

BackgroundFeatures associated with a safe surgical resection of cerebral cavernous malformations (CMs) are still not clear and what is needed to achieve this target has not been defined yet. MethodsClinical presentation, radiological features and anatomical locations were assessed for patients operated on from January 2008 to January 2018 for supratentorial and cerebellar cavernomas. Supratentorial CMs were divided into 3 subgroups (non-critical vs. superficial critical vs. deep critical). The clinical outcome was assessed through modified Rankin Scale (mRS) and was divided into favorable (mRS 0–1) and unfavorable (mRS ≥ 2). Post-operative epilepsy was classified according to the Maraire Scale. ResultsA total of 144 were considered eligible for the current study. At 6 months follow-up the clinical outcome was excellent for patients with cerebellar or lobar CMs in non-critical areas (mRS ≤ 1: 91.1 %) and for patients with superficial CMs in critical areas (mRS ≤ 1: 92.3 %). Patients with deep-seated suprantentorial CMs showed a favorable outcome in 76.9 %. As for epilepsy 58.5 % of patients presenting with a history of epilepsy were free from seizures and without therapy (Maraire grade I) at last follow-up (mean 3.9 years) and an additional 41.5 % had complete control of seizures with therapy (Maraire grade II). ConclusionsSurgery is safe in the management of CMs in non-critical but also in critical supratentorial locations, with a caveat for deep structures such as the insula, the basal ganglia and the thalamus/hypothalamus.

Management of seizures in patients with primary mitochondrial diseases: consensus statement from the InterERNs Mitochondrial Working Group.

Primary mitochondrial diseases (PMDs) are common inborn errors of energy metabolism, with an estimated prevalence of one in 4300. These disorders typically affect tissues with high energy requirements, including heart, muscle and brain. Epilepsy may be the presenting feature of PMD, can be difficult to treat and often represents a poor prognostic feature. The aim of this study was to develop guidelines and consensus recommendations on safe medication use and seizure management in mitochondrial epilepsy. A panel of 24 experts in mitochondrial medicine, pharmacology and epilepsy management of adults and/or children and two patient representatives from seven countries was established. Experts were members of five different European Reference Networks, known as the Mito InterERN Working Group. A Delphi technique was used to allow the panellists to consider draft recommendations on safe medication use and seizure management in mitochondrial epilepsy, using two rounds with predetermined levels of agreement. A high level of consensus was reached regarding the safety of 14 out of all 25 drugs reviewed, resulting in endorsement of National Institute for Health and Care Excellence guidelines for seizure management, with some modifications. Exceptions including valproic acid in POLG disease, vigabatrin in patients with γ-aminobutyric acid transaminase deficiency and topiramate in patients at risk for renal tubular acidosis were highlighted. These consensus recommendations describe our intent to improve seizure control and reduce the risk of drug-related adverse events in individuals living with PMD-related epilepsy.

Intranasal delivery of phenytoin loaded layered double hydroxide nanoparticles improves therapeutic effect on epileptic seizures

Improving the efficiency of antiseizure medication entering the brain is the key to reducing its peripheral toxicity. A combination of intranasal administration and nanomedicine presents a practical approach for treating epileptic seizures via bypassing the blood-brain barrier. In this study, phenytoin (PHT) loaded layered double hydroxide nanoparticles (BSA-LDHs-PHT) were fabricated via a coprecipitation − hydrothermal method for epileptic seizure control. In this study, we expound on the preparation method and characterization of BSA-LDHs-PHT. In-vitro drug release experiment shows both rapid and continuous drug release from BSA-LDHs-PHT, which is crucial for acute seizure control and chronic epilepsy therapy. In-vivo biodistribution assays after intranasal administration indicate excellent brain targeting ability of BSA-LDHs. Compared to BSA-Cyanine5.5, BSA-LDHs-Cyanine5.5 were associated with a higher brain/peripheral ratio across all tested time points. Following intranasal delivery with small doses of BSA-LDHs-PHT, the latency of seizures in the pentylenetetrazole-induced mouse models was effectively improved. Collectively, the present study successfully designed and applied BSA-LDHs-PHT as a promising strategy for treating epileptic seizures with an enhanced therapeutic effect.

Etiologies and Seizure Outcome of Neonatal Seizures: A Tertiary University Hospital Experience

Context: Despite the vast developments in medical sciences in recent decades, seizures remain a common occurrence among neonates, associated with high rates of morbidity and mortality. Aims: The aim of this study was to assess and analyze the presentation and outcome of neonates who were previously exposed to seizures. Subjects and Methods: Following a retrospective research design, this study included 50 cases of neonatal seizures (29 males and 21 females), who were admitted to the neonatal intensive care unit at King Abdulaziz University Hospital, Jeddah City, Saudi Arabia. Data were collected from the hospital records and included all visits between January 2022 and December 2022. Results: The most common types of neonatal seizures were clonic and myoclonic seizures (44% and 28%, respectively). Apgar score at 5 min was <7 in 30% of cases. The main diagnosis was hypoxic-ischemic encephalopathy (HIE) in 28 children (56%), and central nervous system (CNS) infection in 18 children (36%). Children with neonatal seizures mainly received phenobarbital, benzodiazepines, or levetiracetam (48%, 46%, and 36%, respectively). Mechanical ventilation was applied to 20 children (40%). A total of 15 children (30%) had developmental delays, being global delay in 7 children (14%), or motor in 8 children (16%), while 6 children died (12%). Seizures could be controlled in 37 children (74%). Children who presented early (during the 1st week of life) and those who had Apgar scores <7 at 5 min had significantly worse outcomes, with higher case fatality and less seizure control than those who had Apgar scores of 7–10 (P < 0.001). Conclusions: Seizures are a common occurrence among neonates, especially males during the 1st week of their lives. HIE and CNS infections are the main diagnoses. The most administered medications are phenobarbital, benzodiazepines, and levetiracetam. Children who present during their 1st week of life and those who have 5-min Apgar scores <7 have significantly higher case fatality and less seizure control.

Multi-omics technologies and molecular biomarkers in brain tumor-related epilepsy.

Brain tumors are one of the leading causes of epilepsy, and brain tumor-related epilepsy (BTRE) is recognized as the major cause of intractable epilepsy, resulting in huge treatment cost and burden to patients, their families, and society. Although optimal treatment regimens are available, the majority of patients with BTRE show poor resolution of symptoms. BTRE has a very complex and multifactorial etiology, which includes several influencing factors such as genetic and molecular biomarkers. Advances in multi-omics technologies have enabled to elucidate the pathophysiological mechanisms and related biomarkers of BTRE. Here, we reviewed multi-omics technology-based research studies on BTRE published in the last few decades and discussed the present status, development, opportunities, challenges, and prospects in treating BTRE. First, we provided a general review of epilepsy, BTRE, and multi-omics techniques. Next, we described the specific multi-omics (including genomics, transcriptomics, epigenomics, proteomics, and metabolomics) techniques and related molecular biomarkers for BTRE. We then presented the associated pathogenetic mechanisms of BTRE. Finally, we discussed the development and application of novel omics techniques for diagnosing and treating BTRE. Genomics studies have shown that the BRAF gene plays a role in BTRE development. Furthermore, the BRAF V600E variant was found to induce epileptogenesis in the neuronal cell lineage and tumorigenesis in the glial cell lineage. Several genomics studies have linked IDH variants with glioma-related epilepsy, and the overproduction of D2HG is considered to play a role in neuronal excitation that leads to seizure occurrence. The high expression level of Forkhead Box O4 (FOXO4) was associated with a reduced risk of epilepsy occurrence. In transcriptomics studies, VLGR1 was noted as a biomarker of epileptic onset in patients. Several miRNAs such as miR-128 and miRNA-196b participate in BTRE development. miR-128 might be negatively associated with the possibility of tumor-related epilepsy development. The lncRNA UBE2R2-AS1 inhibits the growth and invasion of glioma cells and promotes apoptosis. Quantitative proteomics has been used to determine dynamic changes of protein acetylation in epileptic and non-epileptic gliomas. In another proteomics study, a high expression of AQP-4 was detected in the brain of GBM patients with seizures. By using quantitative RT-PCR and immunohistochemistry assay, a study revealed that patients with astrocytomas and oligoastrocytomas showed high BCL2A1 expression and poor seizure control. By performing immunohistochemistry, several studies have reported the relationship between D2HG overproduction and seizure occurrence. Ki-67 overexpression in WHO grade II gliomas was found to be associated with poor postoperative seizure control. According to metabolomics research, the PI3K/AKT/mTOR pathway is associated with the development of glioma-related epileptogenesis. Another metabolomics study found that SV2A, P-gb, and CAD65/67 have the potential to function as biomarkers for BTRE. Based on the synthesized information, this review provided new research perspectives and insights into the early diagnosis, etiological factors, and personalized treatment of BTRE.

483 Network Analysis of the Thalamic RNS in Patients With Drug Resistant Epilepsy: Insights to Improve Surgical Targeting

INTRODUCTION: Approximately 30% of epilepsy patients are refractory to pharmacotherapy. Patients with drug-resistant epilepsy (DRE) with seizure foci located bilaterally or in the eloquent cortex may be ineligible for resective surgery. For such cases, responsive neurostimulation (RNS) is a viable treatment strategy. METHODS: Retrospective analysis of 23 patients treated with thalamic RNS of the centromedian (CM) and anterior nuclei of the thalamus (ANT) from 2015-2022. Clinical features and seizure outcomes were recorded. RNS electrodes were used to model the electrical field using the parameters at last follow up. Patient-specific probabilistic tractography was used to define the network of the seizure onset zone (SOZ) and its thalamic involvement. Each patient’s probabilistic map was used to define the area of highest connectivity of the thalamus with the seizure network. Each of these patient-specific thalamic areas demonstrating highest connectivity with the seizure network were correlated with electrode position, stimulation modeling, and seizure outcomes. RESULTS: Seizure network from neocortical areas were highly connected to the CM and from limbic cortical areas to the ANT, MD, and parafascicularis nuclei. Results of the correlation analysis between connectivity, stimulation modelling of the RNS electrode, and seizure outcomes will be presented along with illustrative cases of patient-specific targeting using tractography for RNS placement. CONCLUSIONS: Probabilistic tractography is useful to define the networks associated with improved seizure control in thalamic RNS. The identification of these networks prior to surgery could help to identify specific corticothalamic connections and their anatomical trajectories to optimize the implantation of the leads for better and more predictable seizure control.