Intractable Seizures Research Articles

An intronic variant in BRAT1 creates a cryptic splice site, causing epileptic encephalopathy without prominent rigidity

BRAT1-related neurodevelopmental disorders are characterized by heterogeneous phenotypes with varying levels of clinical severity. Since the discovery of BRAT1 variants as the molecular etiology of lethal neonatal rigidity and multifocal seizure syndrome (RMFSL, OMIM 614498), these variants have also been identified in patients with milder clinical forms including neurodevelopmental disorder with cerebellar atrophy and with or without seizures (NEDCAS, OMIM 618056), epilepsy of infancy with migrating focal seizures (EIMFS), and congenital ataxia (CA). This study aims to examine the consequences and pathogenicity of a novel homozygous splice site variant in BRAT1 in a patient presenting with migrating focal seizures since birth without prominent rigidity. The patient was born from a consanguineous marriage and has had seizures since the neonatal period. He presented with dysmorphic features, pontocerebellar hypoplasia, and migrating focal seizures. Despite supportive treatment, his symptoms rapidly progressed to intractable myoclonic seizures, bouts of apnea and bradycardia, and arrest of head growth, with no acquisition of developmental milestones. Clinical exome sequencing yielded a novel homozygous splice variant in BRAT1. Genetic analysis based on reverse transcription of the patient’s RNA followed by PCR amplifications performed on synthesized cDNA and Sanger sequencing was undertaken, and the functional effect of a BRAT1 variant on splicing machinery was demonstrated for the first time. The severe clinical presentation of migrating focal seizures and pontocerebellar hypoplasia in the absence of rigidity further expands the genotypic and phenotypic spectrum of BRAT1-related neurodevelopmental disorders.Electronic supplementary materialThe online version of this article (10.1007/s13760-020-01513-0) contains supplementary material, which is available to authorized users.

SYMPTOMATIC PULMONARY AND INTRACRANIAL NODULES IN A PATIENT WITH LONGSTANDING, UNCONTROLLED RHEUMATOID ARTHRITIS

SESSION TITLE: Medical Student/Resident Pulmonary Manifestations of Systemic Disease Posters SESSION TYPE: Med Student/Res Case Rep Postr PRESENTED ON: October 18-21, 2020 INTRODUCTION: Pulmonary manifestations of rheumatoid arthritis (RA) are found in 60-80% of all RA patients and are responsible for 10-20% of RA-related mortality. RA nodules are observed in approximately 20% of RA patients with 20- 32% prevalence pulmonary RA nodules. Rarer intracranial RA nodules have been described in two case studies.1 Here we present a patient who demonstrates significant symptomatic pulmonary nodulosis along with intracranial nodules leading to intractable seizures and ventilator support. CASE PRESENTATION: Our patient was a 67-year-old woman with a 9-year history of RA, recurrent bilateral knee septic arthritis, and three months of focal seizures who presented to the emergency department for breakthrough focal seizures. Prior magnetic resonance imaging (MRI) showed contrast enhancing right temporal and right thalamic nodules up to 4mm consistent with electroencephalogram (EEG) localization of the seizures. Rheumatologically, the patient had RA flares multiple times per month despite maximal doses of hydroxychloroquine, leflunomide, and methrotrexate (MTX). 6 months prior, an outpatient Chest CT ordered for evaluation of dyspnea showed multiple solid and cavitary pulmonary lesions. Endobronchial ultrasound with biopsy of nodules showed necrotizing granulomatous inflammation consistent with RA nodules. During hospitalization, the patient presented with mildly elevated CRP, RF, and anti-CCP, and mildly decreased complement C3 but otherwise normal exam and negative serologic and cerebrospinal fluid tuberculosis, fungal, bacterial, viral, cancer and autoimmune workup. Repeat imaging showed multiple new bilateral pulmonary nodules up to 2.3 cm with stable intracranial nodules despite empiric acyclovir. The patient continued to have seizures in the unit despite maximal doses of intravenous seizure medication, six days later developing, ultimately fatal severe metabolic acidosis, bradycardia, and hypotension. DISCUSSION: This unique case of symptomatic intracranial and pulmonary nodules in the setting of RA does not have much literature accompaniment, but we hope to add our experience to a potential disease etiology. Several case reports, however, do show reduction in pulmonary nodule size with oral steroid courses. There is currently no strong consensus on treatment of RA nodules. While RA nodules are often considered relatively benign, in this patient the EEG and imaging finding suggest that the nodules may have significantly contributed to this patient’s breakthrough seizures. Unfortunately due to this patient’s comorbidities and tenuous medical status, pathologic review of the brain lesions was not obtained. CONCLUSIONS: This report highlights the need to consider RA as a potentially reversible cause when considering unexplained systemic findings, as well as the need for more research into treatment of extraarticular manifestations of RA. Reference #1: Esposito AJ, Chu SG, Madan R, Doyle TJ, Dellaripa PF. Thoracic Manifestations of Rheumatoid Arthritis. Clin Chest Med 2019;40(3):545–560. DISCLOSURES: No relevant relationships by Oleh Hnatiuk, source=Web Response No relevant relationships by adarsh vangala, source=Web Response No relevant relationships by Nicholas Villalobos, source=Web Response

Dysembryoplastic Neuroepithelial Tumor: A Rare Brain Tumor with Excellent Seizure Control after Surgical Resection

Abstract Introduction Dysembryoplastic neuroepithelial tumor (DNET) is a rare cause of intractable epilepsy, which has excellent results in terms of seizure control after surgical resection. We present one such case, because of its rarity, to highlight the effect of tumor removal on seizure control, particularly DNET. Materials and Methods/Case Summary A 9-year-old male patient presented with sudden onset of partial seizures for the past 6 months. There were five episodes. In each episode, the patient engaged in irrelevant talk, followed by deviation of mouth to left and twitching movements. The episode lasted 5 minutes and there was no loss of consciousness. There was no aura or tongue bite, and in one of the episodes, the patient lost consciousness. There was no other significant positive history. On examination, the child was consciously alert, without focal neurological deficit or features of meningitis. There was no papilledema. The patient was on phenytoin sodium, phenobarbitone and clobazam. Magnetic resonance imaging (MRI) of brain was done with and without contrast. MRI revealed a lesion approximately 4.1 × 3.6 × 3.2 cm in the right medial temporal lobe. It was hypointense to brain on T1 and fluid-attenuated inversion recovery (FLAIR), and hyperintense on T2-weighted images. Diffusion restriction was present and there was minimal contrast uptake. There was no evidence of mass effect or midline shift After discussing the risks and benefits with parents, the patient underwent preanesthetic checkup, and was taken up for craniotomy and excision of tumor. Gross total excision was done. The child was started orally on day 1 postoperatively and ambulated. There were no further seizure episodes. The patient was continued on phenytoin and clobazam, and phenobarbitone was tapered gradually. At 6 months, the child was seizure-free. Conclusions DNET are rare tumors occurring early in life and presenting with intractable seizures. Surgical resection offers a good and safe chance for long-term seizure control.

Variant-specific changes in persistent or resurgent sodium current in SCN8A-related epilepsy patient-derived neurons.

Missense variants in the SCN8A voltage-gated sodium channel gene are linked to early-infantile epileptic encephalopathy type 13, also known as SCN8A-related epilepsy. These patients exhibit a wide spectrum of intractable seizure types, severe developmental delay, movement disorders, and elevated risk of sudden unexpected death in epilepsy. The mechanisms by which SCN8A variants lead to epilepsy are poorly understood, although heterologous expression systems and mouse models have demonstrated altered sodium current properties. To investigate these mechanisms using a patient-specific model, we generated induced pluripotent stem cells from three patients with missense variants in SCN8A: p.R1872>L (Patient 1); p.V1592>L (Patient 2); and p.N1759>S (Patient 3). Using small molecule differentiation into excitatory neurons, induced pluripotent stem cell-derived neurons from all three patients displayed altered sodium currents. Patients 1 and 2 had elevated persistent current, while Patient 3 had increased resurgent current compared to controls. Neurons from all three patients displayed shorter axon initial segment lengths compared to controls. Further analyses focused on one of the patients with increased persistent sodium current (Patient 1) and the patient with increased resurgent current (Patient 3). Excitatory cortical neurons from both patients had prolonged action potential repolarization. Using doxycycline-inducible expression of the neuronal transcription factors neurogenin 1 and 2 to synchronize differentiation of induced excitatory cortical-like neurons, we investigated network activity and response to pharmacotherapies. Both small molecule differentiated and induced patient neurons displayed similar abnormalities in action potential repolarization. Patient induced neurons showed increased burstiness that was sensitive to phenytoin, currently a standard treatment for SCN8A-related epilepsy patients, or riluzole, an FDA-approved drug used in amyotrophic lateral sclerosis and known to block persistent and resurgent sodium currents, at pharmacologically relevant concentrations. Patch-clamp recordings showed that riluzole suppressed spontaneous firing and increased the action potential firing threshold of patient-derived neurons to more depolarized potentials. Two of the patients in this study were prescribed riluzole off-label. Patient 1 had a 50% reduction in seizure frequency. Patient 3 experienced an immediate and dramatic seizure reduction with months of seizure freedom. An additional patient with a SCN8A variant in domain IV of Nav1.6 (p.V1757>I) had a dramatic reduction in seizure frequency for several months after starting riluzole treatment, but then seizures recurred. Our results indicate that patient-specific neurons are useful for modelling SCN8A-related epilepsy and demonstrate SCN8A variant-specific mechanisms. Moreover, these findings suggest that patient-specific neuronal disease modelling offers a useful platform for discovering precision epilepsy therapies.

Brain-responsive corticothalamic stimulation in the centromedian nucleus for the treatment of regional neocortical epilepsy

ObjectiveThe aim of the study was to determine if corticothalamic responsive stimulation targeting the centromedian nucleus of the thalamus (CMT) is a potential treatment for neocortical epilepsies with regional onsets. MethodsWe assessed efficacy and safety of CMT and neocortical responsive stimulation, detection, and stimulation programming, methods for implantation, and location and patterns of electrographic seizure onset and spread in 7 patients with medically intractable focal seizures with a regional neocortical onset. ResultsThe median follow-up duration was 17 months (average: 17 months, range: 8–28 months). The median % reduction in disabling seizures (excludes auras) in the 7 patients was 88% (mean: 80%, range: 55–100%). The median % reduction in all seizure types (disabling + auras) was 73% (mean: 67%, range: 15–94%). There were no adverse events related to implantation of the responsive neurostimulator and leads or related to the delivery of responsive stimulation. Stimulation-related contralateral paresthesias were addressed by adjusting stimulation parameters in the clinic during stimulation testing.Electrographic seizures were detected in the CMT and neocortex in all seven patients. Four patients had simultaneous or near simultaneous seizure onsets in the neocortex and CMT and three had onsets in the neocortex with spread to the CMT. ConclusionIn this small series of patients with medically intractable focal seizures and regional neocortical onset, responsive neurostimulation to the neocortex and CMT improved seizure control and was well tolerated. SignificanceResponsive corticothalamic neurostimulation of the CMT and neocortex is a potential treatment for patients with regional neocortical epilepsies.

Biotin–Thiamine Responsive Basal Ganglia Disease Presented as Intractable Seizure in a 1-Month-Old Infant

AbstractBiotin–thiamine responsive basal ganglia disease is a neurometabolic disorder, seen in children presenting with encephalopathy, seizures, and positive family history. The disease is diagnosed based on typical magnetic resonance imaging (MRI) findings and whole exome sequencing but may be initially misdiagnosed as a mitochondrial encephalopathy or an inborn error of metabolism (IEM). We describe the case of an infant who presented with uncontrolled seizures and encephalopathy, responding to high doses of thiamine and biotin. Life-long supplementation of biotin (2–10 mg/kg/day) and thiamine (200–300 mg/day) improves the symptomatology and prevents relapse. Outcomes of the disease are heterogeneous, ranging in scope from complete remission to severe neurological sequelae.

Evaluation of recurrent neural networks as epileptic seizure predictor

Abstract The occurrence of epileptic seizures is a problem that makes everyday life difficult for many people who suffer from this disorder, which may causes risks to the subjects and people around them. The possibility of predicting epileptic seizures could create a way to minimize risks associated with these attacks. Through computational analysis of Electroencephalography (EEG) signals, a variation of Recurrent Artificial Neural Network (RNN), of Long Short Term Memory (LSTM) type, was developed in an attempt to classify segments of EEG signals that occur before the onset of epileptic seizures, segments which evince the pre-ictal state. Using an EEG database of pediatric subjects with intractable seizures, groups of patients were created, then redundant EEG channels were selected and reduced by only 25%. Temporal and spectral features were extracted to improve the evaluation of data patterns related to seizures. Besides using the unprocessed data, two techniques were proposed, first using the superposition of inputs, then anticipating targets in the training data. A third technique was also proposed by joining the first two. Finally, two LSTM structures were created. The proposed Neural Network achieved high accuracies above 99%; however, the results showed that it was not possible to classify pre-ictal regions by using this combination of architecture and individuals. Furthermore, it was observed that the Neural Network was able to classify ictal regions with up to 61% sensitivity and 99% specificity, confirming the capacity of RNNs of LSTM type to assimilate temporal patterns in EEG data.

Optogenetic Interrogation of ChR2-Expressing GABAergic Interneurons After Transplantation into the Mouse Brain.

This paper describes research methods to investigate the development of synaptic connections between transplanted GABAergic interneurons and endogenous neurons in the adult mouse hippocampus. Our protocol highlights methods for retroviral labeling adult-born GCs, one of the few cell types in the adult brain to be continuously renewed throughout life. By precise targeting of the retrovirus, labeling of adult-born GCs can be combined with optogenetic stimulation of the transplanted cells and electrophysiology in brain slices, to test whether the GABAergic interneurons integrate and establish inhibitory synaptic connections with host brain neurons. Modifications to adult neurogenesis are an important contributing factor in the development and severity of TLE and seizures. When combined with retroviral labeling, the approaches we describe in this chapter can be used to determine whether transplantation modifies the process of adult neurogenesis or other properties of the hippocampus. These approaches are helping to define parameters for potential cell replacement therapies to be used in patients with intractable seizure disorders.

Treatment of Low Cerebrospinal Fluid 5-Methyltetrahydrofolate With Leucovorin Improves Seizure Control and Development in PCDH19-Related Epilepsy

This six-year-old girl presented to the Neurometabolic Clinic for evaluation of medically intractable seizures, global developmental delay, and behavioral concerns. Since developing clusters of seizures at age two years, she had tried multiple medications. She had multiple seizure types, consisting primarily of focal seizures with secondary generalization, which were exacerbated by fever. Prior electroencephalographs were normal or were consistent with a right frontal seizure onset. At the time of her initial assessment, her medications were oxcarbamazepine, topiramate, valproic acid, and lacosamide.

Convulsive seizures and some behavioral comorbidities are uncoupled in the Scn1aA1783V Dravet syndrome mouse model.

Dravet syndrome (Dravet) is a severe childhood epileptic encephalopathy. The disease begins with a febrile stage, characterized by febrile seizures with otherwise normal development. Progression to the worsening stage features recurrent intractable seizures and the presentation of additional nonepileptic comorbidities, including global developmental delay, hyperactivity, and motor deficits. Later in life, at the stabilization stage, seizure burden decreases, whereas Dravet-associated comorbidities persist. To date, it remains debated whether the nonepileptic comorbidities result from severe epilepsy or represent an independent phenotypic feature. Dravet mice (DS) faithfully recapitulate many clinical aspects of Dravet. Using wild-type (WT) and DS at different ages, we monitored multiple behavioral features as well as background electroencephalogram (EEG) activity during the different stages of Dravet epilepsy. Behavioral tests of WT and DS demonstrated that some deficits manifest already at the pre-epileptic stage, prior to the onset of convulsive seizures. These include motor impairment and hyperactivity in the open field. Deficits in cognitive functions were detected at the onset of severe spontaneous seizures. Power spectral analysis of background EEG activity, measured through development, showed that DS exhibit normal background oscillations at the pre-epileptic stage, a marked reduction in total power during the onset of severe epilepsy, and a subsequent smaller reduction later in life. Importantly, low EEG power at the stage of severe frequent convulsive seizures correlated with increased risk for premature death. Our data provide a comprehensive developmental trajectory of Dravet epilepsy and Dravet-associated comorbidities in mice, under controlled settings, demonstrating that the convulsive seizures and some nonepileptic comorbidities may be uncoupled. Moreover, we report the existence of an inverse correlation, on average, between the power of background EEG and the severity of epileptic phenotypes, suggesting that such measurements may potentially serve as a biomarker for Dravet severity.

Predictors of early, recurrent, and intractable seizures in low-grade glioma.

Seizures are common among patients with low-grade glioma (LGG) and can significantly affect morbidity. We sought to determine the association between the clinical and molecular factors with seizure incidence and refractoriness in LGG patients. We conducted a retrospective review at the University of Virginia in patients with LGG (World Health Organization, WHO Grade II) evaluated between 2002 and 2015. Descriptive statistics were calculated for variables of interest, and the Kaplan-Meier method was used to estimate survival curves, which were compared with the log-rank test. A total of 291 patients were included; 254 had molecular testing performed for presence of an isocitrate dehydrogenase (IDH) mutation and/or 1p/19q codeletion. Sixty-eight percent of patients developed seizures prior to LGG diagnosis; 41% of all patients had intractable seizures. Using WHO 2016 integrated classification, there was no significant difference in seizure frequency during preoperative and postoperative periods or in developing intractable seizures, though a trend toward increased preoperative seizure incidence among patients with the IDH mutation was identified (P = .09). Male sex was significantly associated with higher seizure incidence during preoperative (P < .001) and postoperative periods (P < .001); men were also more likely to develop intractable seizures (P = .01). Seizures are common among patients with LGG. Differences in preoperative or postoperative and intractable seizure rates by WHO 2016 classification were not detected. Our data showed a trend toward higher seizure incidence preoperatively in patients with IDH-mutant LGG. We describe a unique association between male sex and seizure incidence and intractability that warrants further study.

Compassionate use of everolimus for refractory epilepsy in a patient with MTOR mosaic mutation

The MTOR gene encodes the mechanistic target of rapamycin (mTOR), which is a core component of the PI3K-AKT-mTOR signaling pathway. Postzygotic MTOR variants result in various mosaic phenotypes, referred to in OMIM as Smith-Kinsgmore syndrome or focal cortical dysplasia. We report here the case of a patient, with an MTOR mosaic gain-of-function variant (p.Glu2419Lys) in the DNA of 41% skin cells, who received compassionate off-label treatment with everolimus for refractory epilepsy. This 12-year-old-girl presented with psychomotor regression, intractable seizures, hypopigmentation along Blaschko's lines (hypomelanosis of Ito), asymmetric regional body overgrowth, and ocular anomalies, as well as left cerebral hemispheric hypertrophy with some focal underlying migration disorders. In response to the patient's increasingly frequent epileptic seizures, everolimus was initiated (after approval from the hospital ethics committee) at 5 mg/day and progressively increased to 12.5 mg/day. After 5 months of close monitoring (including neuropsychological and electroencephalographic assessment), no decrease in seizure frequency was observed. Though the physiopathological rationale was good, no significant clinical response was noticed under everolimus treatment. A clinical trial would be needed to draw conclusions, but, because the phenotype is extremely rare, it would certainly need to be conducted on an international scale.

Biallelic variants in ADARB1, encoding a dsRNA-specific adenosine deaminase, cause a severe developmental and epileptic encephalopathy

BackgroundAdenosine-to-inosine RNA editing is a co-transcriptional/post-transcriptional modification of double-stranded RNA, catalysed by one of two active adenosine deaminases acting on RNA (ADARs), ADAR1 and ADAR2. ADARB1 encodes the enzyme ADAR2...

Nine-year prospective efficacy and safety of brain-responsive neurostimulation for focal epilepsy.

ObjectiveTo prospectively evaluate safety and efficacy of brain-responsive neurostimulation in adults with medically intractable focal onset seizures (FOS) over 9 years.MethodsAdults treated with brain-responsive neurostimulation in 2-year feasibility or randomized controlled trials were enrolled in a long-term prospective open label trial (LTT) to assess safety, efficacy, and quality of life (QOL) over an additional 7 years. Safety was assessed as adverse events (AEs), efficacy as median percent change in seizure frequency and responder rate, and QOL with the Quality of Life in Epilepsy (QOLIE-89) inventory.ResultsOf 256 patients treated in the initial trials, 230 participated in the LTT. At 9 years, the median percent reduction in seizure frequency was 75% (p < 0.0001, Wilcoxon signed rank), responder rate was 73%, and 35% had a ≥90% reduction in seizure frequency. We found that 18.4% (47 of 256) experienced ≥1 year of seizure freedom, with 62% (29 of 47) seizure-free at the last follow-up and an average seizure-free period of 3.2 years (range 1.04–9.6 years). Overall QOL and epilepsy-targeted and cognitive domains of QOLIE-89 remained significantly improved (p < 0.05). There were no serious AEs related to stimulation, and the sudden unexplained death in epilepsy (SUDEP) rate was significantly lower than predefined comparators (p < 0.05, 1-tailed χ2).ConclusionsAdjunctive brain-responsive neurostimulation provides significant and sustained reductions in the frequency of FOS with improved QOL. Stimulation was well tolerated; implantation-related AEs were typical of other neurostimulation devices; and SUDEP rates were low.ClinicalTrials.gov identifierNCT00572195.Classification of evidenceThis study provides Class IV evidence that brain-responsive neurostimulation significantly reduces focal seizures with acceptable safety over 9 years.

De novo CACNA1G variants in developmental delay and early-onset epileptic encephalopathies

IntroductionVariants of CACNA1G, which encodes CaV3.1, have been reported to be associated with various neurological disorders. MethodsWhole-exome sequencing of genomic DNA from 348 Japanese patients with neurodevelopmental disorders and their parents was conducted, and de novo variants of CACNA1G were extracted. The electrophysiological properties of each mutant channel were investigated by voltage-clamp and current-clamp analyses of HEK293T cells overexpressing these channels. ResultsTwo patients diagnosed with Rett syndrome and West syndrome were found to have known pathological CACNA1G mutations reported in cerebellar ataxia cohorts: c.2881G > A, p.Ala961Thr and c.4591A > G, p.Met1531Val, respectively. One patient with Lennox–Gastaut syndrome was revealed to harbor a previously unreported heterozygous variant: c.3817A > T, p.Ile1273Phe. Clinical symptoms of the two patients with known mutations included severe developmental delay without acquisition of the ability to walk independently. The patient with a potentially novel mutation showed developmental delay, intractable seizures, and mild cerebral atrophy on MRI, but the severity of symptoms was milder than in the former two cases. Electrophysiological study using HEK293T cells demonstrated significant changes of T-type Ca2+ currents by p.Ala961Thr and p.Met1531Val SNVs, which were likely to enhance oscillation of membrane potential at low frequencies. In contrast, p.Ile1273Phe showed no significant effects in our electrophysiological evaluations, with its pathogenesis remaining undetermined. ConclusionDe novo variants of CACNA1G explain some neurodevelopmental disorders. Our study further provides information to understand the genotype–phenotype correlations of patients with CACNA1G mutations.

Real‐world experience with direct brain‐responsive neurostimulation for focal onset seizures

ObjectiveThe RNS System is a direct brain‐responsive neurostimulation system that is US Food and Drug Administration–approved for adults with medically intractable focal onset seizures based on safety and effectiveness data from controlled clinical trials. The purpose of this study was to retrospectively evaluate the real‐world safety and effectiveness of the RNS System.MethodsEight comprehensive epilepsy centers conducted a chart review of patients treated with the RNS System for at least 1 year, in accordance with the indication for use. Data included device‐related serious adverse events and the median percent change in disabling seizure frequency from baseline at years 1, 2, and 3 of treatment and at the most recent follow‐up.ResultsOne hundred fifty patients met the criteria for analysis. The median reduction in seizures was 67% (interquartile range [IQR] = 33%‐93%, n = 149) at 1 year, 75% (IQR = 50%‐94%, n = 93) at 2 years, 82% (IQR = 50%‐96%, n = 38) at ≥3 years, and 74% (IQR = 50%‐96%, n = 150) at last follow‐up (mean = 2.3 years). Thirty‐five percent of patients had a ≥90% seizure frequency reduction, and 18% of patients reported being clinically seizure‐free at last follow‐up. Seizure frequency reductions were similar regardless of patient age, age at epilepsy onset, duration of epilepsy, seizure onset in mesial temporal or neocortical foci, magnetic resonance imaging findings, prior intracranial monitoring, prior epilepsy surgery, or prior vagus nerve stimulation treatment. The infection rate per procedure was 2.9% (6/150 patients); five of the six patients had an implant site infection, and one had osteomyelitis. Lead revisions were required in 2.7% (4/150), and 2.0% (3/150) of patients had a subdural hemorrhage, none of which had long‐lasting neurological consequences.SignificanceIn this real‐world experience, safety was similar and clinical seizure outcomes exceeded those of the prospective clinical trials, corroborating effectiveness of this therapy and suggesting that clinical experience has informed more effective programming.

L-serine synthesis via the phosphorylated pathway in humans.

L-serine is a nonessential amino acid in eukaryotic cells, used for protein synthesis and in producing phosphoglycerides, glycerides, sphingolipids, phosphatidylserine, and methylenetetrahydrofolate. Moreover, L-serine is the precursor of two relevant coagonists of NMDA receptors: glycine (through the enzyme serine hydroxymethyltransferase), which preferentially acts on extrasynaptic receptors and D-serine (through the enzyme serine racemase), dominant at synaptic receptors. The cytosolic "phosphorylated pathway" regulates de novo biosynthesis of L-serine, employing 3-phosphoglycerate generated by glycolysis and the enzymes 3-phosphoglycerate dehydrogenase, phosphoserine aminotransferase, and phosphoserine phosphatase (the latter representing the irreversible step). In the human brain, L-serine is primarily found in glial cells and is supplied to neurons for D-serine synthesis. Serine-deficient patients show severe neurological symptoms, including congenital microcephaly, psychomotor retardation, and intractable seizures, thus highlighting the relevance of de novo production of this amino acid in brain development and morphogenesis. Indeed, the phosphorylated pathway is strictly linked to cancer. Moreover, L-serine has been suggested as a ready-to-use treatment, as also recently proposed for Alzheimer's disease. Here, we present our current state of knowledge concerning the three mammalian enzymes of the phosphorylated pathway and known mutations related to pathological conditions: although the structure of these enzymes has been solved, how enzyme activity is regulated remains largely unknown. We believe that an in-depth investigation of these enzymes is crucial to identify the molecular mechanisms involved in modulating concentrations of the serine enantiomers and for studying the interplay between glial and neuronal cells and also to determine the most suitable therapeutic approach for various diseases.

Aged heterozygous Cdkl5 mutant mice exhibit spontaneous epileptic spasms

CDKL5 deficiency disorder (CDD) is a devastating neurodevelopmental disorder characterized by early-onset epilepsy, severe intellectual disability, cortical visual impairment and motor disabilities. Epilepsy is a central feature of CDD, with most patients having intractable seizures, but seizure frequency and severity can vary. Clinical reports demonstrate a diversity in seizure semiology and electrographic features, with no pattern diagnostic of CDD. Although animal models of CDD have shown evidence of hyperexcitability, spontaneous seizures have not been previously reported. Here, we present the first systematic study of spontaneous seizures in mouse models of CDD. Epileptic spasms, the most frequent and persistent seizure type in CDD patients, were recapitulated in two mouse models of CDD carrying heterozygous mutations, Cdkl5R59X and Cdkl5KO. Spasm-like events were present in a significant proportion of aged heterozygous female mice carrying either of the two Cdkl5 mutations with significant variability in seizure burden. Electrographically, spasms were most frequently associated with generalized slow-wave activity and tended to occur in clusters during sleep. CDD mice also showed interictal and background abnormalities, characterized by high-amplitude spiking and altered power in multiple frequency bands. These data demonstrate that aged female heterozygous Cdkl5 mice recapitulate multiple features of epilepsy in CDD and can serve to complement existing models of epileptic spasms in future mechanistic and translational studies.

Deciphering the surgical treatment gap for drug-resistant epilepsy (DRE): A literature review.

Patients with drug-resistant epilepsy (DRE) rarely achieve seizure freedom with medical therapy alone. Despite being safe and effective for select patients with DRE, epilepsy surgery remains heavily underutilized. Multiple studies have indicated that the overall rates of surgery in patients with DRE have stagnated in recent years and may be decreasing, even when hospitalizations for epilepsy-related problems are on the rise. Ultimately, many patients with DRE who might otherwise benefit from surgery continue to have intractable seizures, lacking access to the full spectrum of available treatment options. In this article, we review the various factors accounting for the persistent underutilization of epilepsy surgery and uncover several key themes, including the persistent knowledge gap among physicians in identifying potential surgical candidates, lack of coordinated patient care, patient misconceptions of surgery, and socioeconomic disparities impeding access to care. Moreover, factors such as the cost and complexity of the preoperative evaluation, a lack of federal resource allocation for the research of surgical therapies for epilepsy, and difficulties recruiting patients to clinical trials all contribute to this multifaceted dilemma.

Somatic SLC35A2 mosaicism correlates with clinical findings in epilepsy brain tissue.

ObjectiveMany genetic studies of intractable epilepsy in pediatric patients primarily focus on inherited, constitutional genetic deficiencies identified in patient blood. Recently, studies have revealed somatic mosaicism associated with epilepsy in which genetic variants are present only in a subset of brain cells. We hypothesize that tissue-specific, somatic mosaicism represents an important genetic etiology in epilepsy and aim to discover somatic alterations in epilepsy-affected brain tissue.MethodsWe have pursued a research study to identify brain somatic mosaicism, using next-generation sequencing (NGS) technologies, in patients with treatment refractory epilepsy who have undergone surgical resection of affected brain tissue.ResultsWe used an integrated combination of NGS techniques and conventional approaches (radiology, histopathology, and electrophysiology) to comprehensively characterize multiple brain regions from a single patient with intractable epilepsy. We present a 3-year-old male patient with West syndrome and intractable tonic seizures in whom we identified a pathogenic frameshift somatic variant in SLC35A2, present at a range of variant allele fractions (4.2%–19.5%) in 12 different brain tissues detected by targeted sequencing. The proportion of the SLC35A2 variant correlated with severity and location of neurophysiology and neuroimaging abnormalities for each tissue.ConclusionsOur findings support the importance of tissue-based sequencing and highlight a correlation in our patient between SLC35A2 variant allele fractions and the severity of epileptogenic phenotypes in different brain tissues obtained from a grid-based resection of clinically defined epileptogenic regions.