Multiple Antiepileptic Drugs Research Articles

An open-label study evaluating the safety and efficacy of AMO-01 for the treatment of seizures in Phelan-McDermid syndrome.

Phelan-McDermid syndrome (PMS) is a neurodevelopmental disorder caused by haploinsufficiency of the SHANK3 gene. Approximately 25% of individuals with PMS have epilepsy. Treatment of epilepsy in PMS may require multiple anticonvulsants, and in a minority of cases, seizures remain poorly controlled. Converging lines of evidence in different experimental models indicate that the Ras-ERK pathway is implicated in the pathophysiology of seizure generation and neurobehavioral symptoms in PMS. The goal of this study was to evaluate the safety, tolerability, and efficacy in treating seizures in adults and adolescents with PMS using AMO-01, a Ras-ERK pathway inhibitor . A single 6-hour intravenous infusion of AMO-01 at 120 mg/m2 was administered to six participants using an open-label design. Safety was assessed during the infusion and for four weeks post-infusion. Caregivers completed seizure diaries and recorded individual seizures during a baseline period and for four weeks following the infusion. Exploratory clinical and biomarker assessments were completed throughout the study. AMO-01 was well tolerated with no serious adverse events (AEs) reported. All AEs were mild or moderate in severity. Seizures were reduced by at least 25% compared to baseline at each follow-up (Weeks 1, 2, 4). Exploratory clinical measures did not change significantly from baseline, but visual evoked potentials (VEPs) and phosphorylated ERK blood levels revealed trending changes in a subset of participants. These results provide preliminary support for the safety of AMO-01 and its efficacy in reducing seizures in adults with PMS. Future placebo-controlled studies with larger sample sizes and repeated dosing are warranted.

Dysregulated Apoptosis and Autophagy in Childhood Epilepsy: Correlation to Clinical and Pharmacological Patterns.

We aimed to assess the serum levels of caspase-3 as a marker of apoptosis and microtubule-associated protein 1A/1B-light chain 3 (MAP1-LC3) as an autophagy marker in epileptic children with various clinical and pharmacological types. This case-control study was carried out on 90 participants (50 pediatric patients with epilepsy and 40 healthy matched children), the patients were categorized into three groups: Group (A): 25 pharmacosensitive epilepsy, Group (B): 25 pharmacoresistant epilepsy, and Group (C): 40 (age, sex, and body mass index) matched healthy children selected as controls. Serum caspase-3 and MAP1-LC3 were measured in all study groups, using commercially available ELISA kits. Serum caspase-3 was significantly higher among epileptic children, especially in the pharmacoresistant group, cases managed with multiple antiepileptic drugs, and cases with abnormal EEG findings. Conversely, circulating MAP1-LC3 levels showed a significant reduction in epilepsy cases, particularly in pharmacoresistant cases, in cases treated with multiple antiepileptic drugs, and in cases with abnormal EEG data. A significant negative correlation between serum caspase-3 and MAP1-LC3 was found among epileptic children (r = -0.369, p = 0.0083). Serum caspase-3 was a more valid biomarker in helping diagnose childhood epilepsy, while serum MAP1-LC3 was more valid in predicting pharmacoresistant type. The study reveals that serum caspase-3 levels were significantly elevated, particularly in pharmacoresistant cases and those managed with multiple drugs. Conversely, MAP1-LC3 levels were significantly reduced in epilepsy cases, suggesting potential involvement of altered apoptosis and autophagy in childhood epilepsy.

Insights into Anti-Epileptic Drug Therapy: A Cross-Sectional Comparison of Adverse Drug Reactions in Monotherapy vs. Polytherapy at a Tertiary Care Hospital

Epilepsy, a widespread neurological disorder, poses significant challenges to effective treatment, often resulting in a diminished quality of life for affected individuals. Despite its prevalence, managing epilepsy remains a complex task, as many patients experience treatment non-compliance due to adverse effects or perceived lack of efficacy. The conventional approach to treatment involves monotherapy, wherein a single anti-epileptic drug (AED) is prescribed. However, this method often leads to adverse effects necessitating dose escalation, which can ultimately prompt treatment cessation. In recent years, polytherapy has emerged as an alternative strategy for managing epilepsy. Polytherapy involves combining multiple AEDs at reduced doses to mitigate adverse effects and enhance therapeutic efficacy. While monotherapy is favored for its simplicity and historical effectiveness, there is growing interest in exploring the comparative effectiveness and safety between monotherapy and polytherapy.1 Understanding the nuances of these treatment approaches is essential for clinicians and patients alike to make informed decisions regarding epilepsy management, considering factors such as seizure control, adverse effects, and overall quality of life. This review aims to provide a comprehensive analysis of the efficacy and safety profiles of monotherapy and polytherapy in epilepsy treatment. By evaluating existing evidence and clinical outcomes, this study offers valuable insights that can guide clinicians in tailoring treatment regimens to individual patient needs, ultimately improving outcomes and enhancing the overall quality of care for individuals living with epilepsy. Results from our study have established that out of the 563 patients included in our study, about 50% have developed some sort of adverse drug reaction (ADR). Of these 282 patients that have developed an ADR, about 62% of patients were on monotherapy and the remaining 38% were on polytherapy. Establishing the fact that monotherapy is more effective than polytherapy in reducing the incidence of adverse drug reactions.

Exploring the Clinical and Genetic Landscape of Angelman Syndrome: Patient-Reported Insights from an Italian Registry.

Background: The Angelman Syndrome Registry (RISA) was developed as a retrospective study with the following objectives: to evaluate the clinical history of individuals with Angelman Syndrome (AS) in Italy and compare it with the existing literature; to investigate the feasibility of gathering data by directly involving participants in the data collection process; and to explore the relationship between different symptoms and genotypes. Methods: Established in 2018, RISA enrolled a total of 82 participants, with 62 (75.6%) providing complete data. Demographic, clinical, and genetic information was collected using electronic case report forms. Descriptive statistics characterized the sample, while associations between genotype and clinical characteristics were examined. Results: Descriptive analysis revealed a median participant age of 8.0 years, with males comprising 48.8% of the sample. Deletion (58.1%) was the most common genotype. The majority (82.2%) experienced epilepsy, with seizures typically onset before 3 years of age. Most patients (86.2%) required multiple anti-epileptic drugs for control, with generalized tonic-clonic seizures and atypical absence seizures being most prevalent. The deletion group exhibited more severe developmental delays and a trend towards higher seizure severity. Sleep problems affected 69.4% of participants, characterized by difficulties in sleep onset and maintenance. Conclusions: This study offers valuable insights into the clinical history and genetic characteristics of AS in Italy, consistent with the prior literature. Additionally, it underscores the efficacy of patient registries in capturing comprehensive data on rare diseases such as AS, highlighting their potential to advance research and enhance patient care.

SEIZURE CONTROL IN PATIENTS WITH ANTI-NMDAR ENCEPHALITIS : CASE SERIES

<p><strong>Background: </strong>Anti N-methyl-D-aspartate Receptor (anti-NMDAR) encephalitis is a rare, yet has had increasing number of cases. Patients often require airway protection, mechanical ventilation and intensive care because the patients’ complex symptoms accompanied by seizures that are difficult to control. Here, we present two related case reports that discuss intensive care management and focus on the administered sedation/anesthesia methods and their outcomes.</p><p><strong>Case illustration: </strong>Male patients, 19 and 21 years old, presented with neuropsychiatric symptoms, seizures, dyskinesia. Both require airway protection and mechanical ventilation as well as Intensive Care Unit (ICU) care. Radiodiagnostic head Computed Tomography (CT) scan and head Magnetic Resonance Imagng (MRI) showed no cerebral abnormalities. Cerebrospinal Fluid (CSF) examination showed positive NMDAR antibodies. First patient had failed to improve clinically even with multiple anti-convulsants, ketamine, dexmedetomidine, immunotherapy, and chemotherapy. Second patient clinically improved with benzodiazepine (midazolam) and propofol as anti-convulsants followed by plasma exchange immunotherapy. The two cases had different outcomes. The first case deceased from septic shock, while the second case was treated by outpatient procedure.</p><strong>Conclusion : </strong>Our presented cases suggest that midazolam, propofol, dextemedetomidine, ketamine do not provide satisfying results for seizure control in patients with anti-NMDAR encephalitis, unless immunotherapy is carried out as early as possible and optimally.<strong><em></em></strong><strong></strong><p><strong> </strong></p><p><strong> </strong></p>

Temporo-Parieto-Occipital Disconnection by Robot-Assisted Magnetic Resonance Imaging–Guided Laser Interstitial Thermal Therapy for Refractory Epilepsy in a Pediatric Patient: Proof-of-Principle Case Report and Surgical Nuances

Magnetic resonance imaging-guided laser interstitial thermal therapy (MRIgLITT) has been proven safe and effective for the treatment of focal epilepsy of different etiologies. It has also been used to disconnect brain tissue in more extensive or diffuse epilepsy, such as corpus callosotomy and hemispherotomy. In this study, we report a case of temporo-parieto-occipital disconnection surgery performed using MRIgLITT assisted by a robotic arm for refractory epilepsy of the posterior quadrant. A highly realistic cadaver simulation was performed before the actual surgery. The patient was a 14-year-old boy whose seizures began at the age of 8. The epilepsy was a result of a left perinatal ischemic event that caused a porencephalic cyst, and despite receiving multiple antiepileptic drugs, the patient continued to experience daily seizures which led to the recommendation of surgery. A Wada test lateralized language in the right hemisphere. Motor and sensory function was confirmed in the left hemisphere through magnetic resonance imaging functional studies and NexStim. The left MRIgLITT temporo-parieto-occipital disconnection disconnection was achieved using 5 laser fibers. The patient followed an excellent postoperative course and was seizure-free, with no additional neurological deficits 24months after the surgery.

Preparation of a β-cyclodextrin grafted magnetic biochar for efficient extraction of four antiepileptic drugs in plasma samples

Simultaneous monitoring of plasma concentration levels of multiple antiepileptic drugs (AEDs) is essential for dose adjustment in comprehensive epilepsy treatment, necessitating a sensitive technique for accurate extraction and determination of AEDs. Herein, a magnetic solid-phase extraction (MSPE) technique on the basis of modified biochar (BC) is investigated to extract four AEDs from plasma, in conjunction with high performance liquid chromatography. BC derived from Zizyphus jujuba seed shells was activated by phosphoric acid (PBC) and magnetized via coprecipitation to produce MPBC. The MPBCCD obtained after modification with β-cyclodextrin (CD) was characterized and evaluated for adsorption. It exhibited fast adsorption kinetics based on second-order kinetics and satisfactory adsorption capacity for AEDs. Then it was employed as the MSPE adsorbent and the influencing parameters were optimized. The enrichment factor was 18.75. The validation analysis revealed a favorable linearity that ranged from 0.04 to 20 μg·mL−1 along with a low limit of detection of 6.85 to 10.19 ng·mL−1. The recovery of the AEDs ranged from 78.7 to 109.2 %, with relative standard deviations below 6.7 %. Using quantum chemistry theory calculations and experimental results analysis, the adsorption mechanism was investigated. It disclosed that the suggested strategy built upon MPBCCD was appropriate for the assessment of AEDs in plasma and expanded the usage of BC as the environmentally favorable matrix for the analysis of biological samples.

Exacerbation of Mirror Movement Disorder: A Complex Case of Childhood-onset Mirror Movements Aggravated by Essential Tremors, and Parkinson's Disease

Background Mirror movement (MM), also known as bimanual synkinesis, is characterized by simultaneous involuntary movements of homologous muscles accompanying voluntary movements of contralateral body regions. MM can be observed in various neurological conditions, including cerebral palsy, corticobasal syndrome, Parkinson's disease, certain types of symptomatic epilepsies, Creutzfeldt-Jakob's disease, Huntington's disease, and others. Case Description A 52-year-old female with a history of epileptic seizures, essential tremors and mild MM was presented to a neurology clinic for seizure management. She had a long-standing history of seizures since childhood. Initial neurological examination revealed mild MM disorder. During the follow up visits, patient’s mirror movements were exacerbated months before she was diagnosed with Parkinson’s disease. Multiple antiepileptic drug regiments along with Carbidopa-levodopa were used and dose adjustments were done during follow up visits to help stabilize the patient’s symptoms. Conclusion In conclusion, this case highlights the progressive nature of mirror movement disorder (MMD) and its association with other neurological conditions, such as epilepsy, essential tremors, and Parkinson's disease. The primary aim of this study was to showcase that individuals with early childhood onset of MMD may experience a deterioration of their condition as they acquire additional neurological disorders, such as essential tremors or Parkinson's disease. Moreover, this study seeks to elucidate how the exacerbation of mirror movement symptoms in such cases can serve as an early indicator of the onset of Parkinson's disease. Medication adjustments played a crucial role in managing the patient's symptoms, emphasizing the importance of individualized treatment plans and close monitoring.

Effect of levetiracetam on ocular perfusion measure with optical coherence tomography angiography.

To evaluate using optical coherence tomography angiography the macular and optic nerve head blood flow in pediatric patients with epilepsy treated with levetiracetam for at least 12 months. This study included 33 pediatric patients with epilepsy and 30 sex- and age-matched healthy volunteer children were included in the study. Optical coherence tomography angiography was used to evaluate the optic nerve head and macular perfusion changes. The mean ocular perfusion pressures were also calculated. Patients who were using multiple antiepileptic drugs or had a prior history of using different drugs were excluded. The choriocapillaris flow area was significantly lower in the Study Group than in the Control Group (p=0.006). However, the foveal avascular zone and vessel densities of the macula in the superficial capillary plexus, deep capillary plexus, and optic nerve head of the study group were not significantly different from those of the control group (p>0.05). Moreover, no significant difference in means of mean ocular perfusion pressure was found between the two groups (p=0.211). No obvious correlation was found between treatment duration and optical coherence tomography angiography parameters or mean ocular perfusion pressure. Choroidal perfusion was reduced in children taking levetiracetam compared with that in the control group, whereas retinal perfusion was not affected in this optical coherence tomography angiography study.

Clozapine and Modified Electroconvulsive Therapy Resolving Forced Normalization: A Rare Case Report

Abstract Multiple studies have been done in the past to understand the relationship between seizure and psychosis, still no conclusive point has been found yet. The mechanism behind the relationship is unknown. Seizures may cause brain damage, increasing the chance of schizophrenia and psychosis, or the two illnesses may share etiological elements. We present a case of a 45-year-old male with a prior history of viral meningoencephalitis, axonal motor polyneuropathy, encephalopathy, and well-controlled generalized tonic–clonic seizures. However, the patient presented to us with a new onset of behavioral disturbances in the form of severe aggression, disinhibition, homicidality, and suicidality during treatment with multiple antiepileptics drugs but with no response to multiple antipsychotics. This patient had an adequate response to clozapine and modified electroconvulsive therapy. No such case has been reported in literature, till date. During the phase of forced normalization, the patient may experience behavioral issues following the management of their seizures with antiepileptic medications and the normalization of their electroencephalography. Any unusual behavior observed in epilepsy patients following the initiation of therapy and seizure control should alert clinicians to the likelihood of this condition.

Associations between Antiepileptic Use and Hypogammaglobulinaemia: Findings from a Population-Based Case-Control Study Using Data Linkage

Background and Objectives: Increased mortality in epilepsy due to infections (other than pneumonia) has been demonstrated. Small case series of people on antiepileptic drugs (AEDs) have described hypogammaglobulinaemia, which may predispose to infections. It is unclear whether hypogammaglobulinaemia is more frequent in people on AEDs, what AEDs it is associated with, or what clinical impact it has. In this population-based study, we aimed to determine whether AEDs were associated with hypogammaglobulinaemia, which AEDs were associated, and whether the associations may be causal. Methods: We conducted an unmatched case-control study using data linkage of routinely collected biochemistry, prescribing, and morbidity datasets in North-East Scotland from 2009–2021. Cases were participants with immunoglobulin levels less than the reference range. Controls were those with normal/high immunoglobulin levels. Logistic regression was used to investigate associations between AED exposure and any hypogammaglobulinaemia, adjusting for age, sex, and comorbidity. We also analysed low IgA, IgM, and IgG separately. We analysed “any AED” exposure and common individual drugs separately. Cumulative exposure data were used to determine whether an exposure-response relationship was present. Results: 18,666 cases and 127,157 controls were identified. Use of any AED was associated with increased risk of hypogammaglobulinaemia (adjusted odds ratio [aOR] 1.20 [95% CI: 1.15–1.25]). Phenytoin use was strongly associated with low IgA (aOR 5.90 [95% CI: 3.04, 10.43]). Carbamazepine and lamotrigine were also associated with low IgA. Apart from topiramate, which was associated with a non-significant decrease in odds of hypogammaglobulinaemia, there was a consistent increase in odds of hypogammaglobulinaemia across most AEDs studied. Panhypogammaglobulinaemia was associated with any AED use, carbamazepine, lamotrigine, gabapentin, and multiple AED use. There was evidence of an exposure-response relationship between any AED use and any hypogammaglobulinaemia, low IgA, and low IgG. Carbamazepine and probably lamotrigine also had an exposure-response relationship with any hypogammaglobulinaemia. Discussion: AEDs may increase hypogammaglobulinaemia risk. Specific classes of immunoglobulins are differentially affected, and the exposure-response analysis suggests this may be causal. Further work should investigate the clinical impact of these findings. Clinicians should check immunoglobulin levels if unusual or recurrent infections occur in patients treated with AEDs.

The Concurrent Use of Phenytoin and Levetiracetam for Seizure Prophylaxis in ICU Patients: The "Arrowhead Rationale".

The administration of multiple antiepileptic drugs (AEDs) is standard practice for neurological intensive care unit (ICU) patients who cannot obtain seizure control with monotherapy. Phenytoin and levetiracetam continue to be highly utilized AEDs for ICU patients due to their efficacy and relatively low cost. However, there is no randomized control trial to date that assesses the efficacy outcomes of the concurrent use of these two medications for ICU patients in convulsive or silent status epilepticus that combats the toxicity with increasing dosages of a single drug by itself. Here, we have analyzed several studies published over the past two decades to better understand whether the concomitant use of these two medications is more efficacious in treating unremitting seizures in ICU patients. Several factors influence which AED is a better fit for ICU patients due to the complexity of their clinical state. Risk for drug interactions, increased incidence of renal and hepatic impairment, and higher need for patient monitoring are daily barriers that determine AED use. After analysis of past research, while the efficacy of concurrent use of levetiracetam and phenytoin is still not fully clear, we offer the "Arrowhead Rationale" for such dual therapy in a subset of patients at our tertiary care trauma and stroke center in Southern California.

Dyke-Davidoff-Masson syndrome: an unusual cause of epilepsy

Background: Dyke-Davidoff-Masson syndrome (DDMS) is a rare neurological condition with unknown global prevalence and incidence. The characteristic clinical features include facial asymmetry, seizures, and contralateral hemiplegia. Signature neuroimaging findings include unilateral brain volume loss, ventriculomegaly, compensatory bone hypertrophy resulting in cerebral hemiatrophy, calvarial thickening and hyperpneumatization of paranasal and frontal sinuses neuroimaging. Case Presentation: 4-year-old girl patient presented seizures (diagnosed as epilepsy) and complained of left-sided hemiplegia since 1 year ago. Neurological examination revealed left-sided spastic hemiplegia with brisk tendon reflexes and extensor planter response on the left side, increased reflexes physiology in the left limb, and positive Babinski on the left leg. MRI showed right cerebral hemiatrophy with ex vacuo dilatation of the right lateral, III and IV ventricles, with hyper pneumatization of the right ethmoid sinus and right left mastoid Aircell and elevation of the right petrous ridge, and falcine displacement to the right as far as +/- 7mm and blurring right hippocampus, suspected atrophy. Therapy, she got multiple anti-epileptic drugs. Conclusion: Diagnosis of DDMS is made by a triad of hemiplegia, contralateral hemiatrophy, seizures, and classical radiological features. Imaging is important in diagnosing this rare entity and differentiating it from other causes of cerebral hemiatrophy. The long-term prognosis is good, provided the clinical entity is recognized early and managed appropriately.

Investigating the Impact of Epilepsy on Cognitive Function: A Narrative Review.

It has been noted that people who have epilepsy have an increased propensity for cognitive dysfunction. We explored 25 relevant articles on PubMed and Cochrane Library after implementing inclusion criteria. Different factors have been postulated and studied that may cause cognitive dysfunction in these patients; structural brain abnormalities, polypharmacy of antiepileptic medication, and neuropsychiatric disorders are the most common causes. Cognitive assessments such as Montreal Cognitive Assessment (MOCA) and Mini-Mental State Exam (MMSE) are the mainstay tools used to diagnose the degree of cognitive decline, and alterations in EEG (electroencephalogram) parameters have also been noted in people with cognitive decline. The mechanisms and treatments for cognitive decline are still being studied, while attention has also been directed toward preventive and predictive methods. Early detection and treatment of cognitive impairment can help minimize its impact on the patient's quality of life. Regular cognitive assessments are essential for epileptic patients, particularly those on multiple antiepileptic drugs. While proper management of epilepsy and related comorbidities would reduce cognitive decline and improve the overall quality of life for people with epilepsy.

PO-04-033 CARDIONEUROABLATION IN A WOMAN WITH ICTAL-INDUCED CARDIAC ASYSTOLE

Ictal-induced cardiac bradyarrhythmia and asystole is a rare phenomenon. The exact mechanism of ictal-induced cardiac bradyarrhythmia and asystole remains unclear. It was postulated that stimulation of central autonomic network during ictal episode may trigger an abrupt burst of hypervagotonia. Prolonged episode of cardiac bradyarrhythmia and asystole may result in syncope or death due to impairment of cerebral perfusion. The role of cardioneuroablation (CNA) in this condition has not been well-described in the literature. To describe a case of successful CNA in a patient with ictal-induced bradyarrhythmia and asystole. n/a A 47-year-old female has a 1.5-year history of intractable focal epilepsy and COVID-19 infection. She started having multiple episodes of seizures following a mild COVID-19 infection. Electroencephalogram (EEG) and brain MRI revealed right temporal onset seizures without structural lesions. Due to ongoing uncontrolled seizures with multiple semiologies despite multiple anti-epileptic drugs, she was admitted to Epilepsy Monitoring Unit for seizure classification. Her ictal EEGs (Figure 1) showed onset of ictal rhythm in the right temporal region with episodes of severe sinus bradycardia (15-30 bpm) and sinus pauses (15-16 seconds). Telemetry tracings demonstrated PP interval slowing with PR interval prolongation prior to the pauses consistent with a vagally-mediated mechanism. Cardiac electrophysiology team recommended CNA for treating the episodes of ictal-induced bradyarrhythmia and asystole. 3D anatomic maps of the right atrium (RA) and left atrium (LA) were created using CARTO system (Biosense Webster). Right superior ganglionated plexus (RSGP) was localized with fractionation mapping and intracardiac echocardiography guidance. RSGP was targeted from the RA using an irrigated radiofrequency catheter with power limit of 25 W. Post-ablations of RSGP, her heart rate increased from 60 - 99 bpm. Additional lesions were delivered from the LA site but no additional heart rate increase was not seen. An implantable loop recorder was implanted post-ablation procedure. During follow-up of 8 months, she had recurrent focal epilepsy, but no bradyarrhythmias or asystole was noted on her loop recorder. Resting heart rates at long-term follow up were between 70 - 100 bpm. This case highlights the utility of CNA in patient with ictal-induced cardiac bradyarrhythmia and asystole. CNA may be an approach to avoid permanent pacemakers in this population.

A meta analysis of key risk factors for sudden unexpected death in epilepsy

Purpose: To examine the risk factors (RFs), associated with Sudden Unexpected Death in Epilepsy (SUDEP), and the quantitative standards required to measure them Methods: The literature on RFs associated with SUDEP was systematically reviewed up to August 2020 in databases, including PubMed, the Cochrane Database and Embase. Revised Newcastle-Ottawa Scale (NOS) was performed to determine the quality of each study in this meta-analysis (MA), with a score of ≥ 3, indicating good quality. Any controversies in data extraction and quality assessment were resolved through counsel or adjudication with a third researcher. Results: An initial screening of the literature following the search strategy and manual inclusion yielded a total of 767 studies. After excluding duplicates as well as articles that did not match the topic, 112 studies remained. Twenty-nine studies were finally selected based on the inclusion and exclusion criteria. After a careful review of the full text, nine studies were included in the MA. Conclusion: The five RFs for SUDEP included age at the onset of epilepsy ≤15 years, generalized-tonic-clonic seizure, seizure frequency ≥50 seizures/year, treatment with a combination of multiple antiepileptic drugs, and history of alcohol abuse.

Ketogenic Diet Attenuates Refractory Epilepsy of Harel-Yoon Syndrome With ATAD3A Variants: A Case Report and Review of Literature

BackgroundHarel-Yoon syndrome is a disease caused by variants in the ATAD3A gene, which manifest as global developmental delay, hypotonia, intellectual disability, and axonal neuropathy. The aim of this study is to summarize the clinical and gene mutation characteristics of a child with refractory epilepsy caused by ATAD3A gene mutation. MethodsThe whole-exome sequencing combined with copy number variation analysis could help to understand the genetic diversity and underlying disease mechanisms in ATAD3A gene mutation. ResultsWe report a Chinese boy with Harel-Yoon syndrome presenting with refractory epilepsy, hypotonia, global developmental delay, and congenital cataract through whole-exome sequencing. Genetic analysis showed a missense mutation, c.251T>C(p.Thr84Met) in the ATAD3A gene (NM_001170535.1). Further copy number variation analysis identified a novel heterozygous deletion on chromosome1p36.33, which spans ATAD3A exon 1 and 2 regions. Multiple antiepileptic drugs failed to control his seizures. Eventually, seizure was controlled through ketogenic diet (KD). ConclusionOur case shows the potential diagnostic role of whole-exome sequencing in Harel-Yoon syndrome and expands the ATAD3A gene mutation spectrum. Multiple antiepileptic drugs failed to control refractory epilepsy in Harel-Yoon syndrome. The KD therapy may be effective for patients with refractory epilepsy who carry the ATAD3A variants.

Antiepileptic Drugs Modulate Alzheimer-Related Tau Aggregation in a Neuronal Activity-Independent Manner

Introduction: A rapidly increasing number of patients with dementia present a serious social problem. Recently, the incidence of epilepsy in patients with Alzheimer’s disease (AD) is increasing, drawing attention to the pathological relationship between the two conditions. Clinical studies have suggested the protective action of antiepileptic agents on dementia; however, the underlying mechanism remains unknown. We evaluated the effects of multiple antiepileptic drugs using tau aggregation assay systems to determine the effects of antiepileptic agents on tau aggregation, a major neuropathological finding associated with AD. Methods: We evaluated the effects of seven antiepileptic agents on intracellular tau aggregation using a tau-biosensor cell-based high-throughput assay. Next, we tested these agents in a cell-free tau aggregation assay using thioflavin T (ThT). Results: The assay results revealed that phenobarbital inhibited tau aggregation, whereas sodium valproate, gabapentin, and piracetam promoted tau aggregation. In the cell-free tau aggregation assay using ThT, we confirmed that phenobarbital significantly inhibited tau aggregation. Conclusion: Antiepileptic drugs may modify the tau pathology in AD in a neural activity-independent manner. Our finding may provide an important insight into the optimization of antiepileptic drug therapy in older adults with dementia.

Clinical, radiological, and genetic characterization of SLC13A5 variants in Saudi families: Genotype phenotype correlation and brief review of the literature.

SLC13A5 (solute carrier family 13, member 5) encodes sodium/citrate cotransporter, which mainly localizes in cellular plasma membranes in the frontal cortex, retina, and liver. Pathogenic variants of the gene cause an autosomal recessive syndrome known as "developmental and epileptic encephalopathy 25 with amelogenesis imperfecta." Here, we have investigated six patients from three different consanguineous Saudi families. The affected individuals presented with neonatal seizures, developmental delay, and significant defects in tooth development. Some patients showed other clinical features such as muscle weakness, motor difficulties, intellectual disability, microcephaly, and speech problems in addition to additional abnormalities revealed by electroencephalography (EEGs) and magnetic resonance imaging (MRI). One of the MRI findings was related to cortical thickening in the frontal lobe. To diagnose and study the genetic defects of the patients, whole exome sequencing (WES) coupled with confirmatory Sanger sequencing was utilized. Iterative filtering identified two variants of SLC13A5, one of which is novel, in the families. Families 1 and 2 had the same insertion (a previously reported mutation), leading to a frameshift and premature stop codon. The third family had a novel splice site variant. Confirmatory Sanger sequencing corroborated WES results and indicated full segregation of the variants in the corresponding families. The patients' conditions were poorly controlled by multiple antiepileptics as they needed constant care. Considering that recessive mutations are common in the Arab population, SLC13A5 screening should be prioritized in future patients harboring similar symptoms including defects in molar development.

Multiple congenital anomalies-hypotonia-seizures syndrome 3 secondary to phosphatidylinositol glycan class T mutation: a neonatal case report

Multiple congenital anomalies-hypotonia-seizures syndrome 3 (MCAHS3) is caused by genetic defects in glycosyl-phosphatidylinositol transamidase complex synthesis due to mutations in the PIGT gene. The disease encompasses dysmorphism, cardiac, genito-urinary and skeletal anomalies, developmental delay and epilepsy in variable severity. Only 39 such cases have been reported till date in literature. We reported the first Indian case with neonatal presentation and overall the sixth case of MCAHS3 to present in neonatal age. The pro-band was a male baby born to non-consanguineous parents. He had perinatal depression, craniofacial dysmorphism, epileptic encephalopathy, left radio-ulnar congenital fractures and respiratory failure managed with multiple anti-epileptics, invasive ventilation and limb splinting. Clinical exome sequencing revealed an autosomal recessive homozygous PIGT gene mutation on exon 6 of chromosome 20 with a variant nomenclature of C.709G>C with heterozygous parents confirming MCAHS3. This report expands the range of information available on MCAHS3. It highlights the need to elaborately investigate dysmorphic newborns with severe hypotonia along with the described neurological symptoms, so as to pin point this potentially diagnosable entity.