Efficacy, safety, and tolerability of adjunctive brivaracetam in adult Asian patients with uncontrolled focal-onset seizures: A phase III randomized, double-blind, placebo-controlled trial.

OBJECTIVE: Evaluate efficacy, safety, and tolerability of adjunctive brivaracetam (BRV) in adult Asian patients with focal-onset seizures (FOS). METHODS: Phase III, randomized, double-blind, placebo-controlled study (EP0083; NCT03083665) evaluating BRV 50 mg/day and 200 mg/day in patients (≥16-80 years) with FOS with/without secondary generalization (focal to bilateral tonic-clonic seizures) despite current treatment with 1 or 2 concomitant antiseizure medications. Following an 8-week baseline, patients were randomized 1:1:1 to placebo, BRV 50 mg/day, or BRV 200 mg/day, and entered a 12-week treatment period. Efficacy outcomes: percent reduction over placebo in 28-day FOS frequency (primary); 50% responder rate in FOS frequency; median percent reduction in FOS frequency from baseline; seizure freedom during treatment period (secondary). Primary safety endpoints: incidences of treatment-emergent adverse events (TEAEs); TEAEs leading to discontinuation; serious TEAEs. RESULTS: In this study, 448/449 randomized patients (mean age, 34.5 years; 53.8% female) received ≥1 dose of study medication (placebo/BRV 50 mg/BRV 200 mg/day: n = 149/151/148). Percent reduction over placebo in 28-day adjusted FOS frequency was 24.5% (p = 0.0005) and 33.4% (p < 0.0001) with BRV 50 mg/day and 200 mg/day, respectively, 50% responder rate was 19.0%, 41.1%, and 49.3% with placebo, BRV 50 mg/day, and BRV 200 mg/day, respectively (p < 0.0001 for both BRV groups vs. placebo). Median percent reduction in FOS frequency from baseline was 21.3%/38.9%/46.7% in patients on placebo/BRV 50 mg/BRV 200 mg/day, respectively. Overall, 0, 7 (4.6%), and 10 (6.8%) patients were classified as seizure-free during the treatment period on placebo, BRV 50 mg/day, and BRV 200 mg/day, respectively (p = 0.0146/p = 0.0017 for BRV 50 mg/200 mg/day vs. placebo, respectively). TEAE incidences were similar between patients on placebo (58.4%) and all patients receiving BRV (58.5%); TEAE incidences for BRV 50 mg/day and BRV 200 mg/day were 57.0% and 60.1%, respectively. Overall, 0.7% of patients on placebo and 2.0% of all patients on BRV reported serious TEAEs (incidences for BRV 50 mg/day and BRV 200 mg/day were 1.3% and 2.7%, respectively), 20.1% of patients on placebo and 33.1% of all patients on BRV reported drug-related TEAEs (incidences for BRV 50 mg/day and BRV 200 mg/day were 26.5% and 39.9%, respectively), and 4.7% of patients on placebo and 3.0% of all patients on BRV discontinued due to TEAEs (discontinuation incidences for BRV 50 mg/day and BRV 200 mg/day were 2.6% and 3.4%, respectively). SIGNIFICANCE: Adjunctive BRV was efficacious and well tolerated in adult Asian patients with FOS. Efficacy and safety profiles were consistent with BRV studies in predominantly non-Asian populations. PLAIN LANGUAGE SUMMARY: Brivaracetam is used to treat partial or focal seizures in people with epilepsy. Most studies with brivaracetam tablets have involved people from non-Asian racial backgrounds. In this study, 449 Asian adults with epilepsy took part. One third took 50 mg of brivaracetam, one third took 200 mg of brivaracetam, and one third took a placebo each day for 12 weeks. On average, those who took brivaracetam had fewer seizures than those given the placebo. Most of the side effects were mild and the number and type of side effects seen were as expected for this medication.

Affordability of newer antiseizure medications in Asian resource-limited countries.

OBJECTIVE: One of the objectives of the Intersectoral Global Action Plan on epilepsy and other neurological disorders for 2022 to 2031 is to ensure at least 80% of people with epilepsy (PWE) will have access to appropriate, affordable, and safe antiseizure medications (ASMs) by 2031. However, ASM affordability is a significant issue in low- and middle-income countries, preventing PWE from accessing optimal treatment. This study aimed to determine the affordability of the newer (second and third generation) ASMs in resource-limited countries in Asia. METHODS: We conducted a cross-sectional survey by contacting country representatives in lower-middle-income countries (LMICs) in Asia, including Indonesia, Lao People's Democratic Republic (PDR), Myanmar, Philippines, Vietnam, India, Bangladesh, and Pakistan, and the upper-middle-income country Malaysia, from March 2022 to April 2022. The affordability of each ASM was calculated by dividing the 30-day ASM cost by the daily wage of the lowest paid unskilled laborers. Treatment costing 1 day's wage or less for a 30-day supply of chronic disease is considered affordable. RESULTS: Eight LMICs and one upper-middle-income country were included in this study. Lao PDR had no newer ASM, and Vietnam had only three newer ASMs. The most frequently available ASMs were levetiracetam, topiramate, and lamotrigine, and the least frequently available was lacosamide. The majority of the newer ASMs were unaffordable, with the median number of days' wages for a 30-day supply ranging from 5.6 to 14.8 days. SIGNIFICANCE: All new generation ASMs, whether original or generic brands, were unaffordable in most Asian LMICs.

International League Against Epilepsy classification and definition of epilepsy syndromes with onset at a variable age: position statement by the ILAE Task Force on Nosology and Definitions.

The goal of this paper is to provide updated diagnostic criteria for the epilepsy syndromes that have a variable age of onset, based on expert consensus of the International League Against Epilepsy Nosology and Definitions Taskforce (2017-2021). We use language consistent with current accepted epilepsy and seizure classifications and incorporate knowledge from advances in genetics, electroencephalography, and imaging. Our aim in delineating the epilepsy syndromes that present at a variable age is to aid diagnosis and to guide investigations for etiology and treatments for these patients.

Autoimmune encephalitis in a tertiary hospital in the Philippines.

BACKGROUND: Autoimmune encephalitis (AE) is an emerging disorder in adults and children. Due to its potentially reversible nature, prompt recognition and intervention are of utmost importance. OBJECTIVE: To describe the clinical and paraclinical features, as well as treatment outcomes of patients with AE admitted in a Philippine tertiary hospital. METHODS: Retrospective case series of patients with definite AE. RESULTS: Eighteen (18) patients were included (12 adults, 6 children), majority of whom had anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis. The median age of onset was 32 (IQR: 10.8) years old and 13 (IQR: 4.8) years old in the adult and pediatric population, respectively. In both age groups, most presented with psychiatric symptoms and normal imaging findings. Cerebrospinal fluid (CSF) pleocytosis was detected in 8/12 (66.7%) adults and 2/6 (33.3%) children, while CSF protein elevation was only seen in 6/12 (50%) adults. Most patients presented with seizures, and the most frequent electroencephalography (EEG) abnormality detected was slow activity (70.5%). A high proportion of patients received high dose steroids, alone (35.3%) or in combination with intravenous immunoglobulin (IVIG, 52.9%). Overall, 66.7% had improved outcomes, mostly seen in the pediatric population. CONCLUSION: This study highlighted the broad clinical phenotype, as well as the similarities and differences of AE manifestations in adults and children. It demonstrated the limited but supportive role of laboratory investigations in the diagnosis of AE. It also underscored the importance of early intervention in AE and highlighted factors influencing treatment practices and discharge outcomes in the local setting.

HLA-A*24:07 as a potential biomarker for carbamazepine-induced Stevens-Johnson syndrome/toxic epidermal necrolysis in Filipino patients.

Aim: A case-control study was conducted in Filipino patients to determine the association between HLA alleles and carbamazepine-induced Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN). Materials & methods: A retrospective review of medical records and data collection were performed. A total of 10 carbamazepine-induced SJS/TEN cases and 40 tolerant controls were recruited. Genomic DNA extracted from saliva samples was genotyped. Statistical analysis was done. Results: The HLA-B75 serotype (p = 0.003; odds ratio [OR] = 13.8; 95% CI = 2.5-76.8), HLA-B*15:21 (p = 0.041; OR = 4.7; 95% CI = 1.1-20.8) and HLA-A*24:07 (p = 0.032; OR = 6; 95% CI = 1.2-30.7) were significantly associated with carbamazepine-induced SJS/TEN. Conclusion: The HLA-B75 serotype, HLA-B*15:21 or HLA-A*24:07 may be used for pharmacogenetic screening prior to prescribing carbamazepine in Filipinos.

Association of carbamazepine-induced Stevens-Johnson syndrome/toxic epidermal necrolysis with the HLA-B75 serotype or HLA-B*15:21 allele in Filipino patients.

A case-control study was conducted to investigate the association of HLA-A alleles, HLA-B alleles including HLA-B*15:02 and HLA-B75 serotype with carbamazepine-induced SJS/TEN in Filipino patients. A retrospective review of medical records was performed. Pertinent clinical data were collected. Eight (8) carbamazepine-induced SJS/TEN cases and 32 tolerant controls were recruited. Genomic DNA was extracted from the saliva samples and genotyping was performed by employing allele-specific polymerase chain reaction. Data were analyzed using the Fisher's exact test, Mann-Whitney U test, univariate logistic regression, and multivariate logistic regression. Single allele association analysis was done. The strength of association was expressed as odds ratio with 95% confidence interval. Positive predictive value, negative predictive value, sensitivity, and specificity were computed. Of all the alleles tested, the HLA-B75 serotype (p = 0.007, OR = 23.25, 95% CI = 2.33-232.21) and HLA-B*15:21 (p = 0.026, OR = 7.53, 95% CI = 1.27-44.79) were significantly associated with carbamazepine-induced SJS/TEN. The HLA-B75 serotype or HLA-B*15:21 allele may be used as a genetic risk assessment prior to prescription for prevention of carbamazepine-induced SJS/TEN in Filipino patients.

Underutilization of epilepsy surgery in ASEAN countries.

PURPOSE: This survey was performed to determine the availability of epilepsy surgery, and understand the limiting factors to epilepsy surgery in ASEAN countries with total of 640 million population. METHOD: A cross-sectional survey was completed by national representatives in all ASEAN countries (Brunei, Cambodia, East Timor, Indonesia, Laos, Malaysia, Myanmar, Philippines, Singapore, Thailand, and Vietnam). RESULTS: Overall facilities for initial epilepsy pre-surgical evaluation are available in most countries, but further non-invasive and invasive investigations are limited. Three countries (Brunei, Cambodia, and East Timor) have no epilepsy center, and 2 countries (Laos, Myanmar) have level 2 centers doing tumor surgery only. Level-3 epilepsy centers are available in 6 countries (Indonesia, Malaysia, Philippine, Singapore, Thailand, Vietnam); only 5 countries (Indonesia, Malaysia, Philippine, Singapore, Thailand) has at least one level-4 epilepsy care facility. Indonesia with 261 million population only has one level 3 and another level 4 center. The costs of presurgical evaluation and brain surgery vary within and among the countries. The main barriers towards epilepsy surgery in ASEAN include lack of expertise, funding and facilities. CONCLUSIONS: Epilepsy surgery is underutilized in ASEAN with low number of level 3 centers, and limited availability of advanced presurgical evaluation. Lack of expertise, facilities and funding may be the key factors contributing to the underutilization.

Carbamazepine-induced Stevens-Johnson syndrome/toxic epidermal necrolysis overlap in a Filipino with positive HLA-B75 serotype.

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are two related mucocutaneous disorders with different severities. Although the incidence is low, SJS and TEN are life-threatening and predominantly drug-induced conditions. There is a strong relationship between the HLA-B*1502 allele and carbamazepine-induced SJS and TEN in different Southeast Asian populations. Here, we report a case of Filipino with SJS/TEN overlap probably induced by carbamazepine. The condition was treated with hydrocortisone followed by prednisone. The HLA-B*1502 allele was not found in this case. The patient tested positive for the HLA-B75 serotype, suggesting that carbamazepine-induced SJS/TEN may be serotype specific. Establishing the genotype before initiation of the drug may be advantageous for some patients and will aid physicians in determining the optimal drug therapy. Prevention of adverse drug reactions (ADR) may be done if pharmacists and other healthcare professionals work as a multidisciplinary ADR team to ensure that safe medication practices are realised.

Clinical spectrum of Dyke-Davidoff-Masson syndrome in the adult: an atypical presentation and review of literature.

Dyke-Davidoff-Masson Syndrome (DDMS) is a rare condition usually diagnosed in paediatric patients with clinical features of hemiparesis, seizures, mental retardation and contralateral cerebral hemiatrophy on neuroimaging. This report follows the case of a 22-year-old man presenting with seizures and hemiatrophy and hemiparesis. On review of cases the most common neuroimaging findings were cerebral hemiatrophy (100%) followed by hemicalvarial thickening (71.4%) and hyperpneumatisation of sinuses (71.4%). Apart from our patient, all nine cases with data on epilepsy control had drug-resistant epilepsy. The onset of seizures in adulthood, block vertebra, short stature, absence of mental retardation and well-controlled epilepsy on monotherapy makes our case exceptional-even bringing to mind the possibility of a DDMS variant. This report exhaustively reviews the wide range of clinical and radiological manifestations of DDMS in the adult, thereby adding to the literature on an unusual syndrome that causes significant neurological morbidity.

Research priorities in epilepsy for the Asia-Oceanian region.

The Asia-Oceanian region is the most populous region in the world. Although there has been substantial economic development and improvement in health services in recent years, epilepsy remains generally an underrecognized and understudied condition. To help promote research in the region, the Commission on Asian and Oceanian Affairs (CAOA) of the International League Against Epilepsy (ILAE) appointed the Research Task Force (RTF) to facilitate the development of research priorities for the region. Research that focuses on issues that are unique or of particular importance in the Asia-Oceanian region is encouraged, and that captures the impact of the dynamic socioeconomic changes taking place in the region is emphasized. Based on these considerations, we propose research "dimensions" as priorities within the Asia-Oceanian region. These are studies (1) that would lead to fuller appreciation of the health burden of epilepsy, particularly the treatment gap; (2) that would lead to better understanding of the causes of epilepsy; (3) that would alleviate the psychosocial consequences of epilepsy; (4) that would develop better therapies and improved therapeutic outcomes; and (5) that would improve the research infrastructure.

Efficacy and safety of levetiracetam as adjunctive therapy in adult patients with uncontrolled partial epilepsy: the Asia SKATE II Study.

This study evaluated the safety and efficacy of levetiracetam as adjunctive therapy for partial seizures in everyday clinical practice in Asian populations. Patients aged > or =16 years (N=251) with inadequately controlled partial epilepsy were recruited from 29 centers across Asia. Levetiracetam was added to existing antiepileptic medication for 16 weeks at a starting dose of 500 or 1000 mg/day and titrated to a maximum of 3000 mg/day according to clinical response. The study completion rate was 86.9%. Adverse events were reported by 73.3% of patients and were generally mild, leading to treatment withdrawal in only 7.2%. The most common adverse events were somnolence (30.3%) and dizziness (14.7%). Compared with pretreatment baseline, 44.0% of patients had a > or =50% reduction in seizure frequency, with a median reduction of 46.4%, and 17.7% became seizure free during the treatment period. Levetiracetam was well tolerated and efficacious as adjunctive therapy for partial epilepsy in clinical practice among Asian populations.