Effectiveness and Safety of Adjunctive Cenobamate in People with Focal-Onset Epilepsy: Evidence from the First Interim Analysis of the BLESS Study.

INTRODUCTION: Despite new anti-seizure medications (ASMs) being introduced into clinical practice, about one-third of people with epilepsy do not reach seizure control. Cenobamate is a novel tetrazole-derived carbamate compound with a dual mechanism of action. In randomized controlled trials, adjunctive cenobamate reduced the frequency of focal seizures in people with uncontrolled epilepsy. Studies performed in real-world settings are useful to complement this evidence and better characterize the drug profile. METHODS: The Italian BLESS ("Cenobamate in Adults With Focal-Onset Seizures") study is an observational cohort study aimed to evaluate the effectiveness, tolerability, and safety of adjunctive cenobamate in adults with uncontrolled focal epilepsy in the context of real-world clinical practice. The study is ongoing and conducted at 50 centers in Italy. This first interim analysis includes participants enrolled until June 2023 and with 12-week outcome data available. RESULTS: Forty participants with a median age of 36.5 (interquartile range [IQR] 26.0-47.5) years were included. The median monthly seizure frequency at baseline was 6.0 (IQR 2.5-17.3) seizures and 31 (77.5%) participants had failed four or more ASMs before cenobamate. At 12 weeks from starting cenobamate, the median reduction in monthly seizure frequency was 52.8% (IQR 27.1-80.3%); 22 (55.0%) participants had a ≥ 50% reduction in baseline seizure frequency and six (15.0%) reached seizure freedom. The median number of concomitant ASMs decreased from 3 (IQR 2-3) at baseline to 2 (IQR 2-3) at 12 weeks and the proportion of patients treated with > 2 concomitant ASMs decreased from 52.5% to 40.0%. Seven (17.5%) patients reported a total of 12 adverse events, 11 of which were considered adverse drug reactions to cenobamate. CONCLUSION: In adults with uncontrolled focal seizures, the treatment with adjunctive cenobamate was well tolerated and was associated with improved seizure control and a reduction of the burden of concomitant ASMs. TRIAL REGISTRATION NUMBER: NCT05859854 (ClinicalTrials.gov Identifier).

Seizure and movement disorder in CACNA1E developmental and epileptic encephalopathy: Two sides of the same coin or same side of two different coins?

Pathogenic variants in CACNA1E are associated with early-onset epileptic and developmental encephalopathy (DEE). Severe to profound global developmental delay, early-onset refractory seizures, severe hypotonia, and macrocephaly are the main clinical features. Patients harboring the recurrent CACNA1E variant p.(Gly352Arg) typically present with the combination of early-onset DEE, dystonia/dyskinesia, and contractures. We describe a 2-year-and-11-month-old girl carrying the p.(Gly352Arg) CACNA1E variant. She has a severe DEE with very frequent drug-resistant seizures, profound hypotonia, and episodes of dystonia and dyskinesia. Long-term video-EEG-monitoring documented subsequent tonic asymmetric seizures during wakefulness and mild paroxysmal dyskinesias of the trunk out of sleep which were thought to be a movement disorder and instead turned out to be focal hyperkinetic seizures. This is the first documented description of the EEG findings in this disorder. Our report highlights a possible overlap between cortical and subcortical phenomena in CACNA1E-DEE. We also underline how a careful electro-clinical evaluation might be necessary for a correct discernment between the two disorders, playing a fundamental role in the clinical assessment and proper management of children with CACNA1E-DEE.

Chronic Visual Abnormality in an Elderly Patient With Temporal Lobe Epilepsy.

A 79-year-old woman visited our department for chronic visual field abnormalities with a floating sensation for two months. Neurological and ophthalmologic examinations yielded normal results, except for brain MRI indicating left hippocampal atrophy. Cognitive function tests were normal. EEG revealed frequent spikes and slow waves in the left frontotemporal region, corroborated by reduced accumulation in 123I-iomazenil single photon emission computed tomography. A diagnosis of temporal lobe epilepsy was established, and treatment with lacosamide resulted in a remarkable improvement in symptoms and EEG findings. Mild focal seizures from the temporal region might cause mild impaired awareness, resulting in the patient's report as a sensation of uncertainty between the self and the outside world, mimicking ophthalmologic abnormalities. The repeated nature of the seizures contributed to the absence of the term "transient" in symptom description. Diagnosing epilepsy in the elderly proves challenging due to nonspecific complaints.

Early cerebral venous drainage associated with focal seizures: a correlation of digital subtraction angiography and electroencephalography. Illustrative case.

BACKGROUND: Early venous drainage is a critical diagnostic feature of arteriovenous malformations (AVMs) and arteriovenous fistulas (AVFs). However, other conditions associated with early venous drainage can mimic AVMs and AVFs and mislead the treating physician team. OBSERVATIONS: The authors present a unique case of a 56-year-old man with new left hemianopsia. Workup with magnetic resonance imaging and magnetic resonance angiography had revealed cortical enhancement and early venous drainage, possibly caused by an AVF or AVM. Catheter angiography confirmed the presence of early venous drainage of specifically the right occipital lobe. The early venous drainage occurred as the result of local hyperperfusion limited to the right occipital lobe. Subsequent electroencephalography confirmed focal seizure activity in the right occipital lobe. After seizure control with multiple antiepileptic medications, the patient regained his vision. Repeat digital subtraction angiography revealed restoration of normal cerebral blood flow. LESSONS: Early venous drainage observed during catheter angiography can be associated with seizure activity. Differentiation from other conditions, such as AVM, AVF, or ischemic stroke, is critical to facilitate prompt and appropriate treatment.

Idiopathic generalized epilepsies in the epilepsy monitoring unit: Systematic quantification of focal EEG and semiological signs.

OBJECTIVE: Focal seizure symptoms (FSS) and focal interictal epileptiform discharges (IEDs) are common in patients with idiopathic generalized epilepsies (IGEs), but dedicated studies systematically quantifying them both are lacking. We used automatic IED detection and localization algorithms and correlated these EEG findings with clinical FSS for the first time in IGE patients. METHODS: 32 patients with IGEs undergoing long-term video EEG monitoring were systematically analyzed regarding focal vs. generalized IEDs using automatic IED detection and localization algorithms. Quantitative EEG findings were correlated with FSS. RESULTS: We observed FSS in 75% of patients, without significant differences between IGE subgroups. Mostly varying/shifting lateralizations of FSS across successive recorded seizures were seen. We detected a total of 81,949 IEDs, whereof 19,513 IEDs were focal (23.8%). Focal IEDs occurred in all patients (median 13% focal IEDs per patient, range 1.1 - 51.1%). Focal IED lateralization and localization predominance had no significant effect on FSS. CONCLUSIONS: All included patients with IGE showed focal IEDs and three-quarter had focal seizure symptoms irrespective of the specific IGE subgroup. Focal IED localization had no significant effect on lateralization and localization of FSS. SIGNIFICANCE: Our findings may facilitate diagnostic and treatment decisions in patients with suspected IGE and focal signs.

Pre-operative predictors of post-operative seizure control in low-grade glioma: a systematic review and meta-analysis.

As many as 80% of low-grade gliomas (LGGs) present with seizures, negatively impacting quality of life. While seizures are associated with gliomas regardless of grade, the importance of minimizing impact of seizures for patients with low grade tumors cannot be understated given the prolonged survival period in this population. The objective of this systematic review and meta-analysis was to summarize existing literature and identify factors associated with post-operative seizure control (defined as Engel I classification) in patients with LGGs, with a focus on pre-operative factors. Patient data extracted include tumor location and histology, pre-operative anti-seizure medication use, extent of resection (EOR), adjuvant treatment, pre-operative seizure type, duration, and frequency, and post-operative Engel classification. A random-effects model was used to calculate the effects of EOR, pre-operative seizure duration, adjuvant radiation, and adjuvant chemotherapy on post-operative seizure control. The effect of tumor location and histology on post-operative Engel I classification was determined using contingency analyses. Thirteen studies including 1628 patients with seizures were included in the systematic review. On meta-analyses, Engel I classification was associated with pre-operative seizure type (OR = 0.79 (0.63-0.99), p = 0.0385, focal versus generalized), frontal lobe LGGs (OR = 1.5 (1.1-2.0), p = 0.0195), and EOR (OR (95% CI) = 4.5 (2.3-6.7), p < 0.0001 gross-total versus subtotal). Pre-operative seizure duration less than one year, adjuvant radiation, adjuvant chemotherapy, and tumor histology were not associated with achieving Engel I classification. In addition to the known effects of EOR, Engel I classification is less likely to be achieved in patients with focal pre-operative seizures and more likely to be achieved in patients with frontal lobe LGGs.

A small frontal lobe cavernoma presenting with headache mimicking migraine and complex focal seizure: A case report.

Cavernoma, or cerebral cavernous angioma, are hamartomatous lesions formed by sinusoidal vascular spaces without cerebral parenchyma in between. Cavernoma is a rare disorder that is diagnosed infrequently and incidentally, so it is called incidentaloma. However, cavernoma can present with seizures, headaches, and other focal neurological deficits, with seizures being the most frequent presentation. Cavernoma is angiographically concealed, and it's diagnosis is challenging. So, the cavernoma is diagnosed based on an MRI. We present the rare case of a patient who presented with a complex focal seizure and migraine-like headache caused by a small frontal lobe cavernoma.

Neurocysticercosis: A neglected but preventable cause of seizure in adults.

Neurocysticercosis is an infection of the central nervous system caused by the larval stage of Taenia solium. Although endemic in sub-Saharan Africa, it is neglected but remains a significant cause of preventable seizure in adults. Its diagnosis is challenging and is frequently missed due to its variable clinical manifestations and lack of diagnostic facilities in most areas of sub-Saharan Africa. This report discusses two cases of parenchymal neurocysticercosis in Ghanaians who presented to the emergency unit of a District Hospital with adult-onset seizures. The two cases highlight the need for a high index of suspicion and also underscore the important role of neuroimaging in the evaluation of patients presenting with adult-onset seizures in neurocysticercosis endemic areas. This is necessary for prompt detection and initiation of appropriate therapy in order to improve prognosis.

How Can a Focal Seizure Lead to a Dacrystic Behavior? A Case Analyzed with Functional Connectivity in Stereoelectroencephalography.

We present a case of a patient with focal non-motor emotional seizures with dacrystic expression in the context of drug-resistant magnetic resonance imaging negative epilepsy. The pre-surgical evaluation suggested a hypothesis of a right fronto-temporal epileptogenic zone. Stereoelectroencephalography recorded dacrystic seizures arising from the right anterior operculo-insular (pars orbitalis) area with secondary propagation to temporal and parietal cortices during the dacrystic behavior. We analyzed functional connectivity during the ictal dacrystic behavior and found an increase of the functional connectivity within a large right fronto-temporo-insular network, broadly similar to the "emotional excitatory" network. It suggests that focal seizure, potentially, from various origins but leading to disorganization of these physiological networks may generate dacrystic behavior.

HCN1 pathogenic variants associated with childhood epilepsy in a cohort of Chinese patients.

OBJECTIVE: HCN ion channel family has a widespread expression in neurons, and recently, increasing studies have demonstrated their roles in epilepsies. METHODS: Clinical data of the patients were gathered in a retrospective study. Exon sequencing was used for the patients with unexplained recurrent seizures and varying levels of developmental delay. RESULTS: In this study, eight de novo variants of HCN1 genes were uncovered in eight patients, including six missense variants, one nonsense variant and one frameshift insertion variant; five of them were reported for the first time. The onset age for eight patients ranges from one month to one year. Their main clinical manifestations are epilepsy and varying degrees of developmental delay, and the main type of seizure is focal secondary generalized tonic-clonic seizure. Importantly, in our study, one case presented with a form of migrating focal seizure that has not been reported in the literature. Seizures from five of the eight children were effectively controlled with antiepileptic drugs including valproic acid, levetiracetam and oxcarbazepine. One child developed normally and four children developed mild delay. One child was treated with topiramate, and the convulsion was partially controlled and showed moderate to severe developmental delay. The antiepileptic treatment failed for the other two children, and the two children were treated with sodium valproate, oxcarbazepine, lamotrigine, chlorbazan, levetiracetam and nitrodiazepam successively, but their convulsions were not controlled and showed moderate to severe developmental delay. SIGNIFICANCE: Our research reported eight variants in HCN1 gene causing epilepsy; among these variants, five variants were never reported before. HCN1-related epilepsy usually starts infantile period, and focal secondary generalized tonic-clonic seizure is the most common seizure type. Importantly, we reported the case with migrating focal seizure was rarely reported. Our study expanded both genotype and phenotype for HCN1-related epilepsy.

Equipotency of lacosamide to levetiracetam in new onset focal epilepsy: A randomized controlled trial.

Objectives: Levetiracetam (LEV) is a well-established broad spectrum antiseizure medication (ASM) effective in focal, generalized, and myoclonic seizures whereas lacosamide (LCM) is a comparatively newer ASM currently approved only as an add-on agent in focal seizures. The aim of the study was to assess the efficacy and the tolerability of oral LCM as monotherapy in adult people with epilepsy (PWE) with new onset focal onset epilepsy compared with those receiving LEV. Materials and Methods: In this open-label single-center non-inferiority trial, PWE aged between 16 and 65 years suffering from new onset focal seizures, with or without secondary generalization were put on LCM monotherapy or LEV monotherapy. Data regarding demographic characteristics, seizure type and etiology, LCM and LEV daily dose, seizure frequency at baseline and at 6 months of follow-up, and seizure freedom rates were recorded. Results: Thirty-five PWE on LCM (24 males), their mean age: 38.20 ± 16.62 years and 35 PWE on LEV (25 males, mean age: 38.91 ± 17.13 years) were enrolled. The most common type of seizure observed was focal to bilateral tonic-clonic seizure >70% followed by focal impaired awareness seizure and focal awareness seizure. Structural epilepsy was found in 21 among LCM group and 22 of LEV group. In the LCM group, the seizure frequency decreased from 3.33 ± 1.88 to 0.85 ± 1.09 (P = 0.001) at 6 months and from 3.61 ± 3.12 to 0.94 ± 1.24 (P = 0.001) in LEV group, intergroup difference (P = 0.74). At 6-month follow-up period, 78.9% in LCM arm and 87.9% in the LEV arm had experienced a 50% of reduction in seizure frequency while seizure freedom was attained in 43.3% of PWE in both the arms (P = 1). The most common treatment emergent adverse effects in the LCM group were fatiguability, dyspepsia, headache, and dizziness, while in the LEV group; somnolence and behavioral abnormality. Conclusion: Treatment with LCM met the non-inferiority criteria when compared with LEV. Therefore, it might be useful as first-line monotherapy for adults with newly diagnosed focal epilepsy.

Characterising people with focal drug-resistant epilepsy: A retrospective cohort study.

OBJECTIVES: To describe the demographics, clinical characteristics, drug treatment outcomes, healthcare resource utilization, and injuries among people with focal drug-resistant epilepsy (F-DRE) analysed separately for six European countries. METHODS: We used electronic medical record data from six European (Belgium, Spain, Italy, France, UK and Germany) primary care/specialist care databases to identify antiseizure medication (ASM) treatment-naïve people (aged ≥ 18 years at F-DRE diagnosis). They were followed from their epilepsy diagnosis until death, the date of last record available, or study end. We used descriptive analyses to characterise the F-DRE cohort, and results were reported by country. RESULTS: One-thousand-seventy individuals with F-DRE were included (mean age 52.5 years; 55.4 % female). The median follow-up time from the first diagnosis to the end of the follow-up was 95.5 months across all countries. The frequency of F-DRE diagnosis in 2021 ranged from 8.8 % in Italy to 18.2 % in Germany. Psychiatric disorders were the most common comorbidity across all countries. Frequently reported psychiatric disorders were depression (26.7 %) and anxiety (11.8 %). The median time from epilepsy diagnosis to the first ASM failure ranged from 5.9 (4.2-10.2) months in France to 12.6 (5.8-20.4) months in Spain. Levetiracetam and lamotrigine were the most commonly used ASM monotherapies in all countries. Consultation with a general practitioner is sought more frequently after F-DRE diagnosis than after epilepsy diagnosis, except in the UK. SIGNIFICANCE: No one ASM is optimal for all people with F-DRE, and the risks and benefits of the ASM must be considered. Comorbidities must be an integral part of the management strategy and drive the choice of drugs.

Anesthesia for a Patient With Cerebrovascular Accident with Seizure Disorder Undergoing Medical Termination of Pregnancy: A Case Report.

The term "total intravenous anesthesia" refers to the preservation of an anesthetic plane with the use of an injectable anesthetic, a sedative that is often given in intermittent boluses. The tendency to have recurrent unprovoked seizures is known as epilepsy. Its prevalence ranges from 0.5% to 1%. The highest incidence rates are in those with anatomical or developmental brain abnormalities, as well as at the extremes of age. The most common triggering factors for epilepsy are stress and fear. The main advantage of total intravenous anesthesia is the patient's rapid recovery and early ambulatory. Conscious sedation is a strategy for giving patients excellent anesthesia and analgesia. In this case report, we will describe a high-risk epileptic patient who required conscious sedation to perform a medical termination.

Co-occurrence of Anti-GAD65 Syndrome, Type 1 Diabetes Mellitus, and Focal Seizures With Impaired Awareness.

Glutamic acid decarboxylase (GAD) is an intracellular enzyme found in the presynaptic end of nerve terminals that functions to synthesize ​​gamma-aminobutyric acid (GABA) via decarboxylation. Autoantibodies to the GAD65 isoform have been found in high levels in neurological disorders including stiff person syndrome (SPS), autoimmune encephalitis, and refractory epilepsy. Low levels of anti-GAD65 have also been noted in type 1 diabetes mellitus. We present the unusual case of a woman with a longstanding history of focal seizures with impaired awareness and type 1 diabetes mellitus who was found to have extremely high titers of anti-GAD65 and clinical presentation suggestive of stiff person syndrome. This case highlights the increasing significance of autoimmune etiologies within neurologic disorders, as well as the importance of maintaining a high index of suspicion for rare anti-GAD65 syndromes. Although uncommon and with an unclear pathophysiology, we discuss the importance of establishing SPS diagnostic criteria to facilitate timely diagnosis and quickly direct patient management towards immunotherapy.

Frequency of non-generalized tonic clonic seizures in a referral population of dogs.

Absence seizures are a type of generalized onset seizure associated in humans with brief activity interruptions, unresponsiveness and staring. Absence seizures are infrequently reported in veterinary patients, visually indistinguishable from focal seizures, and so may be grouped as non-generalized tonic clonic seizures (non-GTCS). The objective of this retrospective study was to provide a preliminary understanding of the frequency of non-GTCS in dogs and estimate its prevalence by evaluating the distribution of seizure types presented to a referral hospital over 4 years (May 2017-April 2021), as determined from the medical record history and electroencephalography (EEG) diagnostic testing where available. A total of 528 cases were included via a medical record search for dogs with epilepsy and/or seizures presented to the neurology or emergency services. Cases were categorized into seizure types based on reported clinical signs. Each year, 53-63 % of seizure cases were described as generalized tonic clonic seizures (GTCS), 9-15 % GTCS with additional events and 29-35 % suspected non-GTCS. EEG confirmed absence seizures in 12 of 44 EEGs, 5 cases having a history of GTCS and seven without prior GTCS. This preliminary study suggests that non-GTCS may be relatively common as one third of seizure cases in the referral population presented with non-GTCS clinical signs. Prospective studies using EEG are merited to definitively determine the prevalence of these different seizure types in dogs. Acknowledging the impact of these seizures will improve awareness, aiding veterinarians in their recognition, diagnosis and potential treatment options.

A Case of Hypermotor Seizures in Posterior Insular Cortex Epilepsy.

Insular seizure is a rare entity. Insular spikes spread to the temporal, parietal, and frontal lobes and clinically manifest with seizure semiology specific to these areas. We report the case of a 19-year-old male patient who presented with complaints of left-sided hemimotor tonic-clonic focal seizures of the limbs occurring three times per day. Neuroimaging showed cortical-subcortical right posterior insular cortex hyperintensities on fluid-attenuated inversion recovery (FLAIR) sequence and T2-weighted MRI with no significant diffusion restriction on apparent diffusion coefficient (ADC) and no post-contrast enhancement, suggesting focal cortical dysplasia of right posterior insular cortex. Electroencephalogram (EEG) showed right frontal epileptiform activity with secondary bilateral synchrony. The patient's atypical hemimotor tonic-clonic focal seizure, the conventional video EEG showing right frontal spikes synchronizing with bilateral temporal ictal spikes, and insular cortical dysplasia on MRI led us to a diagnosis of insular epilepsy.

Clinically important intracranial abnormalities in children presenting with first focal seizure.

BACKGROUND: Management of pediatric patients presenting with first seizure is challenging, especially with regards to emergent neuroimaging. The rate of abnormal neuroimaging findings is known to be higher in focal seizures than in generalized seizures, but those intracranial abnormalities are not always clinically emergent. In this study, we aimed to determine the rate and indicators for clinically important intracranial abnormalities that change acute management in children presenting with a first focal seizure to the pediatric emergency department (PED). METHODS: This study was conducted retrospectively in the PED at a University Children`s Hospital setting. The study population consisted of patients aged between 30 days and 18 years with first focal seizure and who had emergent neuroimaging at the PED between the years 2001 and 2012. RESULTS: There were 65 eligible patients meeting the study criteria. Clinically important intracranial abnormalities requiring emergent neurosurgical or medical intervention were detected in 18 patients (27.7%) at the PED. Four patients (6.1%) underwent emergent surgical procedures. Seizure recurrence and the need for acute seizure treatment in the PED were significantly associated with clinically important intracranial abnormalities. CONCLUSIONS: Neuroimaging study yielding of 27.7% shows that first focal seizure must be evaluated meticulously. From the emergency department`s point of view; we suggest that first focal seizures in children should be evaluated with emergent neuroimaging, if possible with magnetic resonance imaging. Especially patients with recurrent seizures at presentation requires more careful evaluation.

Cerebral Cavernous Malformation Associated With Left Middle Cerebral Artery (MCA) Aneurysm and Bilateral Internal Carotid Artery (ICA) Dissections.

Cerebral cavernous malformations (CCMs) are the second most common type of cerebral vascular lesions. They are often associated with other vascular lesions, typically developmental venous anomalies. CCMs are not known to be associated with cerebral aneurysms and there is a paucity of literature on this occurrence. We report the case of a patient who presented with a focal seizure from a symptomatic CCM with acute hemorrhage and was incidentally found to have a cerebral aneurysm and bilateral internal carotid artery (ICA) dissections secondary to fibromuscular dysplasia. The presence of a cerebral aneurysm has clinical implications as these patients will need closer monitoring.

Chloride ion dysregulation in epileptogenic neuronal networks.

GABA is the major inhibitory neurotransmitter in the mature CNS. When GABAA receptors are activated the membrane potential is driven towards hyperpolarization due to chloride entry into the neuron. However, chloride ion dysregulation that alters the ionic gradient can result in depolarizing GABAergic post-synaptic potentials instead. In this review, we highlight that GABAergic inhibition prevents and restrains focal seizures but then reexamine this notion in the context of evidence that a static and/or a dynamic chloride ion dysregulation, that increases intracellular chloride ion concentrations, promotes epileptiform activity and seizures. To reconcile these findings, we hypothesize that epileptogenic pathologically interconnected neuron (PIN) microcircuits, representing a small minority of neurons, exhibit static chloride dysregulation and should exhibit depolarizing inhibitory post-synaptic potentials (IPSPs). We speculate that chloride ion dysregulation and PIN cluster activation may generate fast ripples and epileptiform spikes as well as initiate the hypersynchronous seizure onset pattern and microseizures. Also, we discuss the genetic, molecular, and cellular players important in chloride dysregulation which regulate epileptogenesis and initiate the low-voltage fast seizure onset pattern. We conclude that chloride dysregulation in neuronal networks appears to be critical for epileptogenesis and seizure genesis, but feed-back and feed-forward inhibitory GABAergic neurotransmission plays an important role in preventing and restraining seizures as well.