Focal Onset Seizures Research Articles

Cenobamate in Generalized Epilepsy and Combined Generalized and Focal Epilepsy.

Cenobamate (CNB) is a United States Food and Drug Administration-approved antiseizure medication (ASM) for focal-onset seizures; however, its potential clinical effectiveness as a broad-spectrum ASM is not established. CNB has a proposed dual mechanism of action with preferential blockade of persistent sodium currents and positive allosteric modulation of the γ-aminobutyric acid-A (GABA-A) receptor. We evaluated the efficacy of CNB in drug refractory patients with genetic generalized epilepsies (GGE) or combined generalized and focal epilepsies (CGFE), including developmental and epileptic encephalopathies. We performed a retrospective review and identified the following: cohort 1 (n = 4) with GGE, of which 2 patients had idiopathic generalized epilepsy, and cohort 2 with CGFE (n = 9), of which 4 patients had Lennox-Gastaut syndrome and 1 had Dravet syndrome. In cohort 1, all 3 patients with frequent generalized tonic-clonic seizures (GTCs) had a greater than 50% reduction in GTCs. In cohort 2, reduction in both generalized and focal-onset seizures was noted. In these groups together, the mean reduction of all seizure types was 58%, and ≥50% responder rate was 70% (SD = ±34.16, median = 50%). No worsening of generalized-onset seizures occurred in either cohort. Seventy-seven percent of patients experienced side effects, warranting a modification of treatment managed by slower titration, dose reduction of CNB, or discontinuing other ASMs. In our retrospective case series, CNB seems to be an effective ASM for patients with drug-resistant GGE and CGFE. The ongoing CNB trial assessing effectiveness for primary GTCs will provide more data on generalized-onset seizures. This study provides Class IV evidence that CNB in generalized epilepsy and combined generalized and focal epilepsy reduces seizure frequency.

Perampanel Monotherapy for Focal and Generalized Epilepsy in Clinical Practice

Objectives. To investigate the effectiveness, safety, and tolerability of perampanel (PER) when used as monotherapy to treat focal or generalized epilepsy in everyday clinical practice, using data from the PERMIT study. Methods. PERMIT was a pooled analysis of 44 real-world studies from 17 countries, in which people with focal and generalized epilepsy were treated with PER. This post hoc analysis included people with epilepsy (PWE) from PERMIT who were treated with PER monotherapy at baseline. Retention and effectiveness were assessed after 3, 6, and 12 months. Effectiveness assessments included ≥50% responder rate and seizure freedom rate (no seizures since at least the prior visit). Safety and tolerability were assessed by evaluating adverse events (AEs) and discontinuation due to AEs. Results. Overall, 268 PWE were treated with PER monotherapy at baseline. Retention was assessed for 168 PWE, effectiveness for 183 PWE, and safety and tolerability for 197 PWE. Retention rates were 91.1%, 87.3%, and 73.3% at 3, 6, and 12 months, respectively. At 12 months, responder rates were 84.2% overall, 82.9% in PWE with only focal-onset seizures at baseline, and 88.0% in those with only generalized-onset seizures at baseline; corresponding freedom rates were 62.9%, 57.7%, and 80.0%, respectively. AEs were reported for 45.2% of PWE. The most frequently reported AEs (≥5% of PWE) were dizziness/vertigo (16.8%), irritability (11.2%), somnolence (9.1%), and depression (6.6%). Over 12 months, 13.7% discontinued due to AEs. Conclusions. PER was effective when used as monotherapy in clinical practice, particularly in those with generalized-onset seizures, and was generally well tolerated.

A Single- and Multiple-Dose Pharmacokinetic Study of Oral Perampanel in Healthy Chinese Subjects.

Perampanel is a once-daily oral anti-seizure medication indicated for focal-onset seizures and generalized tonic-clonic seizures. This study investigated the single- and multiple-dose pharmacokinetics of perampanel in healthy Chinese adults. Study 052 (NCT03424564) was a phase I, single-center, open-label, parallel-group study. In the single-dose part of the study, subjects received a single oral dose of perampanel 2, 4, or 8 mg. In the multiple-dose part, subjects received once-daily oral perampanel 2 mg on Days 1-7 and 4 mg on Days 8-21. Pharmacokinetic parameters were determined from perampanel plasma concentrations using non-compartmental analysis. Dose proportionality after single doses of perampanel was assessed. Safety and tolerability were evaluated. In the single-dose part (N=30), median time to reach maximum concentration (tmax) was 0.75-1.0h, mean terminal elimination phase half-life (t½) was 85.6-122h, mean maximum observed concentration (Cmax) was 77.9-276 ng/mL, and mean area under the concentration-time curve from time zero to time of the last quantifiable concentration (AUC(0-t)) was 4070-15100 ng·h/mL. Single-dose pharmacokinetics were linear for perampanel 2-8 mg. In the multiple-dose part (N=12), Day 21 steady-state (4 mg/day) parameters were median time at which the highest drug concentration occurs at steady state (tss,max), 1.25h; mean t½, 109h; mean maximum observed concentration at steady state (Css,max), 453ng/mL; and mean area under the concentration-time curve over the dosing interval on multiple dosing (AUC(0- τ)), 7540 ng·h/mL. For single- and multiple-dose perampanel, the most common treatment-emergent adverse events were dizziness and somnolence. Single- and multiple-dose pharmacokinetics of perampanel in healthy Chinese adults revealed rapid perampanel absorption, slow elimination, and a linear relationship with single perampanel doses of 2-8 mg. Findings were consistent with previous studies of perampanel pharmacokinetics in other ethnic/racial populations of healthy subjects. Single and multiple doses of perampanel were generally safe and well tolerated. NCT03424564; registered February 2018.

Brivaracetam to Treat Partial Onset Seizures in Adults.

Seizures are a hyperexcitable, and hypersynchronous imbalance between excitatory and inhibitory factors (E/I imbalance) in neurotransmission, and epilepsy is the recurrent manifestation of seizures within a reasonable time frame and without being attributable to a reversible cause. Brivaracetam is a derivative of the antiepileptic agent, levetiracetam, that is used as adjuvant therapy for focal onset seizures. It was approved by the FDA in 2016 and has shown promising results with minimal adverse effect reactions in clinical trials. Brivaracetam has been used in multiple clinical trials at various dosages in adults that have partial-onset seizures refractory to conventional treatment. A meta-analysis in 2016 showed that brivaracetam as adjunctive therapy was statically significant in its reduction of adults with drug-refractory seizure frequency.1 The most commonly reported adverse effects that patients who were taking brivaracetam experienced were somnolence, headache, and dizziness. Further studies are necessary to conclude long term efficacy and safety profile of brivaracetam. The treatment of epilepsy with pharmacologic agents is a difficult task due to balancing the efficacy of the drug with the side effect profile that will allow for the best quality of life for the patient. There are approximately 30 antiepileptic agents for clinicians to choose from. Brivaracetam is a novel antiepileptic agent that was approved for use by the FDA in 2016 and is showing promising results as monotherapy and adjunctive therapy in individuals with drug-refractory focal seizures while minimizing adverse drug reactions.

The effects of cannabidiol and Δ9-tetrahydrocannabinol, alone and in combination, in the maximal electroshock seizure model

In the present study, cannabidiol (CBD), Δ9-tetrahydrocannabinol (THC), and combinations of CBD and THC, were evaluated in the mouse maximal electroshock (MES) seizure test – an animal model of generalized-onset seizures. Male CF-1 mice were injected intraperitoneally (i.p.) with either CBD, THC or a combination of CBD and THC. The MES test was conducted 2 h after the injection of CBD and 1 h after the injection of THC. A wide range of doses was tested to allow the construction of dose-response curves. Toxicity was assessed using a behavioral rating scale. It was found that: 1) the ED50 for THC alone was 52 mg/kg and its therapeutic index (TI) was 1.7; 2) the ED50 for CBD alone was 190 mg/kg and its TI was 2.4; and 3) the ED50 for a 15:1 combination of CBD+THC was 130 mg/kg + 8.6 mg/kg (CBD + THC). Thus, CBD and THC were both effective in the MES model, and CBD was somewhat more effective in the presence of low (non-therapeutic) doses of THC. The improvement in CBD’s effect, however, was less dramatic than that seen in past experiments with the amygdala-kindling model (Fallah et al., 2021). Both CBD alone and CBD+THC in combination might be useful in the treatment of generalized-onset seizures. The advantage of adding THC to CBD, however, might be less than in the treatment of focal-onset seizures.

Number needed to treat and associated cost analysis of cenobamate versus third-generation anti-seizure medications for the treatment of focal-onset seizures in patients with drug-resistant epilepsy in Spain

IntroductionEpilepsy is a serious neurological disease, ranking high in the top causes of disability. The main goal of its treatment is to achieve seizure freedom without intolerable adverse effects. However, approximately 40% of patients suffer from Drug-Resistant Epilepsy (DRE) despite the availability of the latest options called third-generation Anti-Seizure Medications(ASMs). Cenobamate is the first ASM approved in Spain for the adjunctive treatment of Focal-Onset Seizures (FOS) in adult patients with DRE. The introduction of a new drug increases the number of therapeutic options available, making it important to compare it with existing alternatives in terms of clinical benefit and efficiency. PurposeThis study aimed to compare the clinical benefit, in terms of the Number Needed to Treat (NNT), and the efficiency, in terms of Cost per NNT (CNT), associated with cenobamate versus third-generation ASMs used in Spain for the adjunctive treatment of FOS in patients with DRE. MethodsThe Number Needed to Treat data was calculated based on the ≥50% responder rate and seizure freedom endpoints (defined as the percentage of patients achieving 50% and 100% reduction in seizure frequency, respectively), obtained from pivotal clinical trials performed with cenobamate, brivaracetam, perampanel, lacosamide, and eslicarbazepine acetate. The NNT was established as the inverse of the treatment responder rate minus the placebo responder rate and was calculated based on the minimum, mid-range Daily Defined Dose (DDD), and maximum doses studied in the pivotal clinical trials of each ASM. CNT was calculated by multiplying the annual treatment cost by NNT values for each treatment option. ResultsIn terms of NNT, cenobamate was the ASM associated with the lowest values at all doses for both ≥50% responder rate and seizure freedom compared with the alternatives. In terms of CNT, for ≥50% responder rate, cenobamate was the ASM associated with the lowest CNT values at DDD and lacosamide and eslicarbazepine acetate at the minimum and maximum dose, respectively. For seizure freedom, cenobamate was associated with the lowest CNT value at DDD and the maximum dose and lacosamide at the minimum dose. ConclusionsCenobamate could represent the most effective ASM in all doses studied compared to the third-generation ASMs and the most efficient option at DDD for both ≥50% responder rate and seizure freedom. This study could represent an important contribution towards informed decision-making regarding the selection of the most appropriate therapy for FOS in adult patients with DRE from a clinical and economical perspective in Spain.

Risk factors for seizure recurrence after initial withdrawal of anti-seizure medications in children with epilepsy at Aga Khan University Hospital, Nairobi, Kenya.

We sought to determine risk factors associated with seizure recurrence following initial withdrawal of anti-seizure medications (ASM) among children with epilepsy. This was a retrospective observational study of children aged between 2 and 18years with a diagnosis of epilepsy who underwent withdrawal of anti-seizure medication following remission of seizures. All eligible medical records between January 2011 and December 2019 were included. Demographic, clinical, imaging and electroencephalography data of all eligible patients were analyzed against seizure remission within 24months after withdrawal of ASM, using appropriate parametric and non-parametric tests. A total of 49 records of children who underwent withdrawal of ASM out of a total of 613 patients on follow up during the same period were included. The median age at ASM withdrawal was 70months (IQR 52-112months) and 14 (28.6%) were female. Thirteen patients (26.5%) had seizure recurrence within 24months following withdrawal of ASM. Focal onset seizure type was associated with significant risk of seizure recurrence (OR 13.7; 95% CI 0.97, 193.54; P value=0.011). Age at epilepsy diagnosis, abnormal EEG at initiation of treatment and at the time of de-escalation, abnormal MRI findings, first or second degree relative with epilepsy, history of developmental delay, seizure burden, use of 2 or more ASMs and duration of seizure-freedom before de-escalation of ASM were not associated with increased risk of relapse. Focal onset seizure type is associated with increased with risk of seizure recurrence in this cohort.

A Case of Perampanel Overdose Presenting with Respiratory Failure

Perampanel is a novel antiepileptic drug that has been used as an adjunctive treatment for focal-onset seizures. No reports to date have documented respiratory suppression as a side effect of perampanel in adults. Herein, we report a 51-year-old man with focal epilepsy presented with type 2 respiratory failure after accidently consuming of 66 mg of perampanel. Clinicians should consider the possibility of respiratory compromise whenever a high dose of perampanel needs to be administered to patients.

Treatment with Cenobamate in Adult Patients with Lennox–Gastaut Syndrome: A Case Series

Background. Lennox-Gastaut syndrome (LGS) is a developmental and epileptic encephalopathy (DEE) in which drug resistance to antiepileptic drugs (AEDs) is common. Focal-onset seizures (FOS) are among the seizure types characterizing LGS. Cenobamate (CNB) is a new AED indicated for the treatment of FOS and it has shown promising results in terms of seizure frequency reduction in both clinical trials and real-world experience. To date, the use of CNB in patients with DEEs is limited to Dravet syndrome. Methods: This was a retrospective study aimed to determine the 12-month effectiveness and tolerability of CNB in patients with LGS following real-world practice. Results: Four patients with LGS receiving CNB treatment were identified. At 12 months from starting CNB, the reduction in baseline seizure frequency ranged from 25 to 74%, with two patients achieving ≥50% seizure reduction. CNB was generally well tolerated and adjustments in doses of concomitant AEDs were required. Conclusions: CNB may represent a promising therapeutic option in patients with drug-resistant epilepsy associated with LGS. Further research is needed to confirm this preliminary evidence.

GABABR IgG Associated Encephalitis: Clinical Presentations and Measures to Improve Diagnostic Assay Specificity

Objective To review the clinical/oncological presentations of gamma aminobutyric acid-B receptor (GABABR)-IgG and evaluate the clinical specificity of antibody testing methodologies. Background GABABR-IgG is an intermediate-risk paraneoplastic autoantibody commonly associated with encephalitis and/or seizures. Design/Methods GABABR-IgG positive patients tested at Mayo Clinic Neuroimmunology Laboratory were identified. Available archived sera were retested by cell-based assay (CBA) at 1:10 and 1:100 dilutions. Results 105 GABABR-IgG seropositive patients with clinical details were identified (females, n = 56; median age 63 [range 8-82]). Most patients had one of three anti-GABABR encephalitis/seizure presentations: focal-onset seizures with altered mental status (n = 39), new-onset refractory status epilepticus (NORSE [n = 23]) or rapidly progressive dementia (n = 14). Fifty-three of 72 patients (74%) with available data had associated malignancy, primarily small cell lung cancer (SCLC). Two P/Q type VGCC-IgG positive patients had isolated Lambert-Eaton Myasthenic Syndrome. Additionally, 27 patients presented with non-specific symptoms or alternate diagnoses (atypical presentation); none had underlying SCLC (13 with malignancy data). Most patients with anti-GABABR encephalitis/seizure presentations had GABABR-IgG detected in CSF (95%, 52/55; of 3 who were negative, 1 had NMDA-IgG and another AMPA-IgG and CRMP5-IgG) and/or GABABR-IgG detected by CBA in serum at a dilution of 1:100 (76%, 31/41). Five encephalitis/seizure patients with GABABR-IgG detected in CSF were CBA positive only at 1:10 dilution in serum. Forty-eight of 76 patients had samples positive on tissue IFA (serum = 17/42, CSF = 40/49). Among 27 patients with atypical presentations, most did not have GABABR-IgG CSF CBA positivity (91%, 21/23) and/or GABABR-IgG 1:100 serum titer by CBA (0/17). None of 27 cases were tissue IFA positive (serum = 0/27, CSF = 0/21). Conclusions GABABR-IgG is associated with autoimmune encephalitis/seizure presentations. Our study highlights the importance of evaluating CSF and testing serum at both 1:10 and 1:100 dilutions, as seropositivity at only the 1:10 dilution by CBA without CSF GABABR-IgG positivity has poor clinical specificity.

A case of AORPA in an adult presenting as secondary polycythemia

BackgroundPolycythemia refers to a condition of an abnormal increase in the red blood cell (RBC) mass. In men with a hematocrit > 60% or women with a hematocrit > 55%, there is 99% likelihood that the RBC mass is elevated. WHO uses a hemoglobin concentration > 16.5 g/dl in men or 16.0 g/dl in women to define an elevated RBC mass, in its criteria for the diagnosis of polycythemia vera. Congenital cardiac anomalies presenting as polycythemia are very rare in adults.Case presentationIn this case report, the patient presented with non-specific complaint and had an incidental finding of secondary polycythemia, ultimately diagnosed as secondary to AORPA. Our patient, a 43-year-old male, presented to our emergency with focal onset seizures without impairment of consciousness involving left upper and lower limbs. On routine investigations, the patient was found to have grade III clubbing and hemoglobin of 19.8 g/dl with elevated Erythropoietin levels. Further workup of secondary polycythemia revealed anomalous origin of the right pulmonary artery (AORPA) from the ascending aorta with tortuous patent ductus arteriosus (PDA) and pulmonary hypertension. Secondary polycythemia, in our patient, was due to right to left shunt causing Eisenmenger phenomenon, following pulmonary hypertension, making it one of the rarest presentation in adults.ConclusionIn the evaluation of secondary polycythemia, possibility of underlying asymptomatic cardiopulmonary shunt must be considered, though rare.

Epidemiological, clinical and radiological characteristics of people with neurocysticercosis in Tanzania-A cross-sectional study.

Neurocysticercosis (NCC) is common among people with epilepsy in low-resource settings. Prevalence of NCC and radiological characteristics of patients with NCC vary considerably even within small areas but differences have been poorly characterized so far. We conducted a cross-sectional study between August 2018 and April 2020 in three district hospitals in southern Tanzania (Ifisi, Tukuyu and Vwawa). Patients with and without epileptic seizures were included in this study. All patients were tested with a novel antibody-detecting point-of-care test for the diagnosis of Taenia solium cysticercosis. All test positives and a subset of test negatives had a further clinical work-up including medical examination and computed tomography of the brain. NCC was defined according to the Del Brutto criteria. We assessed epidemiological, clinical and radiological characteristics of patients with NCC by presence of epileptic seizures and by serology status. In all three district hospitals, more than 30% of all people with epileptic seizures (PWE) had NCC lesions in their brain (38% in Vwawa, 32% in Tukuyu and 31% in Ifisi). Most PWE with NCC had multiple lesions and mostly parenchymal lesions (at least 85%). If patients were serologically positive, they had in the median more lesions than serologically negative patients (15 [interquartile range 8-29] versus 5 [1.8-11]), and only serologically positive patients had active stage lesions. Furthermore, serologically positive PWE had more lesions than serologically positive people without epileptic seizures (10.5 [7-23]), and more often had active lesions. PWE diagnosed with NCC (n = 53) were older, and more commonly had focal onset seizures (68% versus 44%, p = 0.03) and headache episodes (34% versus 14%, p = 0.06), which were also stronger than in PWE without NCC (p = 0.04). NCC is common among PWE. A combination of clinical and serological factors could help to establish an algorithm to identify patients potentially suffering from active NCC, who benefit from further clinical investigation including neuroimaging.

Long-term follow-up of vagus nerve stimulation in drug-resistant KCNT1-related epilepsy: a case presentation

BackgroundThe KCNT1 gene encodes a Na+-activated K+ channel. Gain-of-function mutations of KCNT1 lead to autosomal dominant sleep-related hypermotor epilepsy, early-onset epileptic encephalopathy, focal epilepsy and other epileptic encephalopathies. In this paper, we report a boy carrying a KCNT1 gene mutation, who presented with drug-resistant focal-onset seizures. He had decreased seizure frequency and improvement of background changes in electroencephalography (EEG) after vagus nerve stimulation (VNS).Case presentationThe case was a nonverbal 9-year-old male who presented with drug-resistant focal-onset seizures since age 3 and had underwent VNS therapy for 2 years. He had hypermotor symptoms, automatism and bilateral asymmetric tonic seizures with cognitive decline and aphasis from age 3. The patient had a variety of seizure types that only occurred at night. The most common seizure type was automatisms, and ictal video EEG showed high-amplitude delta waves, followed by a fast rhythmic sharp activity in the mesial frontal and bitemporal regions. The patient was diagnosed with KCNT1-related epilepsy, epileptic encephalopathy and cognitive disorder. He was refractory to multiple anti-seizure medicines (ASM) and ketogenic diet. After VNS treatment at age 7, the frequency of seizures was reduced significantly and EEG was improved in background slowing.ConclusionsChildren with KCNT1-related epilepsy usually have early onset of disease, are nonverbal, and are refractory to ASM. This boy with drug-resistant KCNT1-related epilepsy showed significantly reduced seizure frequency after VNS. This report may provide reference for management of cases of KCNT1-related epilepsy.

A Prospective Hospital-Based Study on the Clinico-Etiological Profile of the First Episode of a Seizure in Children.

Background This study aims to examine the clinico-etiological profile of children with the first episode of a seizureand categorize seizure types based on age groups in a tertiary care hospital. Methodology This was aprospective observational studyconducted at a tertiary care medical institute in India over two years. Children (one month to 12 years of age) with the first episode of a seizure were included in the study population. The data collected included demographic profile, history, examination, biochemical profile, electroencephalogram (EEG), and neuroimaging.Children were categorized as generalized-onset, focal-onset, and unknown-onset seizures based on the International League Against Epilepsy2017 seizureclassification. Children were also classified according to specific etiologies such as structural, metabolic, or other specific causes. All the children were followed up at the hospital's outpatient clinic or through a telephonic interview. Results A total of 220 children were examined in this study. Among them, 64% were male and 36% were female, with a male-to-female ratio of 1.75:1. Among the 220 children, 21.8% had a family history of seizure. The most common type of seizures were generalized-onset seizures (n = 110, 50%), followed by focal-onset seizures (n = 96, 43.6%). Overall, 9% of children presented with status epilepticus as their first-episode seizure. An abnormal EEG was recorded for 122 (76%) children. While 60% of children had abnormal neuroimaging findings, the remaining had normal neuroimaging. Febrile seizures (n = 92, 41.9%) were the most common cause of the first episode of a seizure. Most of the febrile seizures occurred between the ageof one and four (n = 60, 65.2%). Epilepsy syndromes were the second most common etiology, followed by central nervous system (CNS) infections, structural brain abnormalities, metabolic disorders, vascular lesions, toxins, and immune-mediated causes, in that order. In 14 (6.36%) children, the etiology was unknown at the time of the study. Conclusions First-episode seizures in children cause physical, mental, and financial stress on the parents. The collection of detailed history, examinations, and appropriate investigations can help identifythe etiology of seizures. It was possible to determine the etiology of the first episode of a seizure in the majority of the patients. Generalized-onset seizures were the most common. Febrile seizures, epilepsy syndrome, CNS infections, vascular lesions, and metabolic disorders were the main etiological factors, in that order.

Characteristics of people with epilepsy and Neurocysticercosis in three eastern African countries-A pooled analysis.

Neurocysticercosis (NCC), a zoonotic disease caused by the pork tapeworm T. solium, represents one of the most common causes of secondary epilepsy but remains often undiagnosed due to lack of awareness and diagnostic facilities. We pooled data from four cross-sectional studies on epilepsy and NCC in eastern Africa. Study sites were in Uganda, Malawi and in Tanzania (Dar es Salaam and Haydom). The study in Uganda and Malawi were community-based, the two studies in Tanzania were hospital-based. The same questionnaire was used for assessment of clinical characteristics of patients with epilepsy. Computed tomography (CT) scans and serological testing were performed in order to diagnose NCC. Overall, 1,179 people with epilepsy were included in our analysis. Of those, 941 PWE underwent CT scanning and were pooled for NCC analysis. Seventy patients were diagnosed with NCC, but NCC prevalence differed considerably between sites ranging from 2.0% (95%CI 0.4% to 3.6%) in Dar es Salaam to 17.5% (95%CI 12.4% to 22.6%) in Haydom. NCC prevalence did not show any association with sex but increased with age and was higher in rural than urban settings. In addition, being a farmer, non-Muslim, eating pork and living with pigs close by was associated with a higher NCC prevalence. PWE with NCC experienced their first epileptic seizure around 3 years later in life compared to PWE without NCC and their epileptic seizures seemed to be better controlled (p<0.001). There was no difference between focal onset seizures and focal signs on neurological examination in both groups (p = 0.49 and p = 0.92, respectively). The rT24H-EITB had a sensitivity for the detection of NCC of 70% (95% confidence interval [CI] 51 to 84%), the LLGP of 76% (95%CI 58 to 89%) and the antigen ELISA of 36% (95% CI 20 to 55%). NCC is prevalent among PWE in eastern Africa, although it may not be as common as previously stated. Demographic characteristics of PWE with NCC differed from those without NCC, but semiological characteristics and results on neurological examination did not differ compared to PWE without NCC. Interestingly, seizures seemed to be less frequent in PWE with NCC. Being aware of those differences and similarities may help triaging PWE for neuroimaging in order to establish a diagnosis of NCC.

Graph Theory-Based Electroencephalographic Connectivity via Phase-Locking Value and Its Association with Ketogenic Diet Responsiveness in Patients with Focal Onset Seizures.

Ketogenic diets (KDs) are a promising alternative therapy for pediatric refractory epilepsy. Several predictors of KD responsiveness have been identified, including biochemical parameters, seizure types, and electroencephalography (EEG) examinations. We hypothesized that graph theory-based EEG functional connectivity could explain KD responses in patients presenting focal onset seizure (FOS). A total of 17 patients aged 0-30 years old with focal onset seizures (FOS) were recruited as a study group between January 2015 and July 2021. Twenty age-matched children presenting headache with no intracranial complications nor other medical issues were enrolled as a control group. Data were obtained at baseline and at 12 months after initiating KD therapy (KDT) using the child behavior checklist (CBCL) and brain functional connectivity parameters based on phase-locking value from 19 scalp EEG signals, including nodal strength, global efficiency, clustering coefficient, and betweenness centrality. Compared with age-matched controls, patients presenting FOS with right or bilateral EEG lateralization presented higher baseline functional connectivity, including parameters such as global efficiency, mean cluster coefficient and mean nodal strength in the delta and beta frequency bands. In patients presenting FOS with right or bilateral EEG lateralization, the global efficiency of functional connectivity parameters in the delta and theta frequency bands was significantly lower at 12 months after KDT treatment than before KDT. Those patients also presented a significantly lower mean clustering coefficient and mean nodal strength in the theta frequency band at 12 months after KDT treatment. Changes in brain functional connectivity were positively correlated with social problems, attention, and behavioral scores based on CBCL assessments completed by parents. This study provides evidence that KDT might be beneficial in the treatment of patients with FOS. Graph theoretic analysis revealed that the observed effects were related to decreased functional connectivity, particularly in terms of global efficiency. Our findings related to brain connectivity revealed lateralization to the right (non-dominant) hemisphere; however, we were unable to define the underlying mechanism. Our data revealed that in addition to altered brain connectivity, KDT improved the patient's behavior and emotional state.

Mapping analysis to predict SF-6D utilities from health outcomes in people with focal epilepsy.

Focal-onset seizures (FOS) are commonly experienced by people with epilepsy and have a significant impact on quality of life (QoL). This study aimed to develop a mapping algorithm to predict SF-6D values in adults with FOS for use in economic evaluations of a new treatment, cenobamate. An online survey, including questions on disease history, SF-36, and an epilepsy-specific measure (QOLIE-31-P) was administered to people with FOS in the UK, France, Italy, Germany, and Spain. A range of regression models were fitted to SF-6D scores including direct and response mapping approaches. 361 individuals were included in the analysis. In the previous 28days, the mean number of FOS experienced was 3, (range 0-43) and the mean longest period of consecutive days without experiencing a seizure was 14days (range 1-28days or more). Mean responses on all SF-36 dimensions were lower than general population norms. Mean SF-6D and QOLIE-31-P scores were 0.584 and 45.72, respectively. The best performing model was the ordinary least squares (OLS), with root mean squared error and mean absolute error values of 0.0977 and 0.0742, respectively. Explanatory variables which best predicted SF-6D included seizure frequency, severity, freedom, and age. People with uncontrolled FOS have poor QoL. The mapping algorithm enables the prediction of SF-6D values from clinical outcomes in people with FOS. It can be applied to outcome data from clinical trials to facilitate cost-utility analysis.

Effectiveness and safety of perampanel as adjunctive therapy among Chinese patients with focal-onset epilepsy: A real-world prospective observational study

ObjectivePerampanel (PER) has previously been shown to be effective and tolerable when used as an adjunctive therapy for patients with focal-onset seizures (FOS). This study aimed to evaluate the effect of PER as adjunctive therapy for patients with FOS in the Chinese population under real-world conditions for 1 year. MethodsA prospective, single-center, 1-year observational study was conducted at Huashan Hospital, enrolling both under age (≥4 years old) and adult patients with FOS. Response to PER was assessed at 3-, 6-, and 12-month checkpoints by analyzing the 50 % responder rate, the seizure-free rate, and reduction in seizure frequency. ResultsOne hundred and eight patients (mean age: 26.6 years, 56.5 % males) with FOS were included, with seventy-six patients finishing the 1-year follow-up (retention rate: 70.4 %, mean PER dose: 4.3 mg/day). The seizure frequency was reduced significantly at 3, 6, and 12 months relative to baseline (p < 0.001 for each seizure type). At 12 months, the responder rate was 65.8 %, and the seizure-free rate was 39.5 %. A significantly higher responder rate was found in patients with focal to bilateral tonic–clonic seizures (p = 0.024), among which the percentage of patients with sleep-related epilepsy was significantly high (p = 0.045). Responders had a lower number of concomitant anti-seizure medications (ASMs) than the non-responders (p = 0.009). Drug-related adverse events (AEs) were reported in 37 % of patients, mostly mild or moderate, and the patients who experienced AEs had a higher daily dose of PER than those who did not (p = 0.026). ConclusionPerampanel, an add-on therapy for focal-onset seizures, was found to be effective and tolerable in Chinese patients at 12 months.

Efficacy of the FDA-approved cannabidiol on the development and persistence of temporal lobe epilepsy and complex focal onset seizures

Presently there is no drug therapy for curing epilepsy. Despite many advancements in epilepsy research, nearly 30% of people with epilepsy remain refractory to current antiseizure medications (ASM). Cannabidiol (CBD) has recently been approved as an ASM for pediatric refractory seizures, but it has not been widely tested for adult epileptogenesis and focal onset seizures. In this study, we investigated the efficacy of the FDA-approved CBD in controlling epileptogenesis and complex focal onset seizures using the mouse kindling model of human temporal lobe epilepsy. We also tested combination regimens of CBD with other ASMs. The two primary outcome measures were disease modification and suppression of generalized seizures. In the epileptogenesis study, CBD had a striking effect in attenuating kindling development, with a dose-dependent decrease in behavioral and electrographic seizure activity. In the retention study, mice previously treated with CBD had significantly reduced overall seizure burden, suggesting disease modification. In a fully-kindled seizure study, CBD produced rapid and atypical U-shaped dose-dependent protection against generalized seizures (ED50, 52 mg/kg, i.p.). In a time-course study, CBD showed a maximal protective effect within 1 h of injection, and it declined within 4 h with a biphasic response. In the combination study, CBD produced synergistic/ additive protection when given with midazolam and ganaxolone but not with tiagabine, indicating its strong potential as an adjunct ASM. Finally, the protective effects of CBD were not associated with motor and functional impairments. These preclinical findings demonstrate the potential of adjunct CBD for controlling adult complex focal onset seizure conditions.

Determination of the economically justifiable price of cenobamate in the treatment of focal-onset seizures in adult patients with drug-resistant epilepsy in Spain

Objective To determine the economically justifiable price (EJP) of cenobamate to become a cost-effective alternative compared with third-generation anti-seizure medications in the treatment of focal-onset seizures (FOS) in adult patients with drug-resistant epilepsy (DRE) in Spain. Methods Cost-effectiveness analysis comparing cenobamate with brivaracetam, perampanel, eslicarbazepine acetate and lacosamide. Markov model simulation of treatment pathway over a 60-year time horizon. Determination of effectiveness and quality-adjusted life-years (QALYs) of each health status, and disutilities associated with treatment-related adverse events. Acquisition costs and use of medical resources were obtained from published literature and expert opinion. Base-case of cenobamate’s EJP calculated applying a willingness-to-pay (WTP) threshold of €21,000/QALY. Analyses performed at different thresholds, including dominant price scenario. Results robustness were assessed through sensitivity analyses. Results Base-case shows that cenobamate’s daily EJP of €7.30 is cost-effective for a threshold of €21,000/QALY. At a daily price of €5.45, cenobamate becomes dominant over all treatment alternatives producing cost-savings for the national health system (NHS). Sensitivity analyses supported the robustness of base-case findings. Conclusions Treatment with cenobamate produces incremental clinical benefit over third generation ASMs and at the base-case EJP could represent a cost-effective option for the adjunctive treatment of FOS in adult patients with DRE in Spain.