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.

Which terms should be used to describe medications used in the treatment of seizure disorders? An ILAE position paper.

A variety of terms, such as "antiepileptic," "anticonvulsant," and "antiseizure" have been historically applied to medications for the treatment of seizure disorders. Terminology is important because using terms that do not accurately reflect the action of specific treatments may result in a misunderstanding of their effects and inappropriate use. The present International League Against Epilepsy (ILAE) position paper used a Delphi approach to develop recommendations on English-language terminology applicable to pharmacological agents currently approved for treating seizure disorders. There was consensus that these medications should be collectively named "antiseizure medications". This term accurately reflects their primarily symptomatic effect against seizures and reduces the possibility of health care practitioners, patients, or caregivers having undue expectations or an incorrect understanding of the real action of these medications. The term "antiseizure" to describe these agents does not exclude the possibility of beneficial effects on the course of the disease and comorbidities that result from the downstream effects of seizures, whenever these beneficial effects can be explained solely by the suppression of seizure activity. It is acknowledged that other treatments, mostly under development, can exert direct favorable actions on the underlying disease or its progression, by having "antiepileptogenic" or "disease-modifying" effects. A more-refined terminology to describe precisely these actions needs to be developed.

Evaluation of the promotion criteria in an academic medical centre in Singapore.

INTRODUCTION: Academic medical centres (AMCs) have the tripartite mission of performing research to advance healthcare delivery, educating future clinicians and providing healthcare services. This study investigates the criteria associated with being promoted in a Singaporean AMC. METHODS: Using a dataset of 255 candidates for promotion at the studied AMC, we employ logistic regression to determine if these factors are associated with the likelihood of promotion. Further, we use interaction effects to test if the relationship between the H-index and likelihood of promotion differs across the academic levels of the candidates. RESULTS: The logistic regression results based on the best of our three tested models suggest that the H-index is positively associated with promotion for those applying to become clinical associate professors (OR=1.43, p=0.01). Moreover, candidates who provide well-developed education portfolios (OR=3.61, p=0.02) and who have held service/leadership roles (OR=6.72, p<0.001) are more likely to be promoted. CONCLUSIONS: This study affirms the correlation between promotion and the advancement criteria outlined by the AMC. This is important for transparency and trust between the AMC and its faculty in their applications for promotion and success in an academic career. Further, our study is one of the few empirical studies linking promotion criteria to promotion outcomes.

Calculator for predicting the probability of faculty promotion in an academic medical centre.

OBJECTIVE: The academic medical centre (AMC), with over 2200 faculty members, annually manages approximately 300 appointments and promotions. Considering these large numbers, we explored whether machine learning could predict the probability of obtaining promotional approvals. METHODS: We examined variables related to academic promotion using predictive analytical methods. The data included candidates' publications, the H-index, educational contributions and leadership or service within and outside the AMC. RESULTS: Of the five methods employed, the random forest algorithm was identified as the 'best' model through our leave-one-out cross-validation model evaluation process. CONCLUSIONS: To the best of our knowledge, this is the first study on the AMC. The developed model can be deployed as a 'calculator' to evaluate faculty performance and assist applicants in understanding their chances of promotion based on historical data. Furthermore, it can act as a guide for tenure and promotion committees in candidate review processes. This increases the transparency of the promotion process and aligns faculty aspirations with the AMC's mission and vision. It is possible for other researchers to adopt the algorithms from our analysis and apply them to their data.

Critique of the 2017 epileptic seizure and epilepsy classifications.

This article critiques the International League Against Epilepsy (ILAE) 2015-2017 classifications of epilepsy, epileptic seizures, and status epilepticus. It points out the following shortcomings of the ILAE classifications: (1) they mix semiological terms with epileptogenic zone terminology; (2) simple and widely accepted terminology has been replaced by complex terminology containing less information; (3) seizure evolution cannot be described in any detail; (4) in the four-level epilepsy classification, level two (epilepsy category) overlaps almost 100% with diagnostic level one (seizure type); and (5) the design of different classifications with distinct frameworks for newborns, adults, and patients in status epilepticus is confusing. The authors stress the importance of validating the new ILAE classifications and feel that the decision of Epilepsia to accept only manuscripts that use the ILAE classifications is premature and regrettable.

Classification of paroxysmal events and the four-dimensional epilepsy classification system.

This educational review describes the classification of paroxysmal events and a four-dimensional epilepsy classification system. Paroxysmal events are classified as epileptic and non-epileptic paroxysmal events. Non-epileptic events are, in turn, classified as psychogenic and organic paroxysmal events. The following four dimensions are used to classify epileptic paroxysmal events: ictal semiology, the epileptogenic zone, etiology, and comorbidities. Efforts are made to keep these four dimensions as independent as possible. The review also includes 12 educational vignettes and three more detailed case reports classified using the 2017 classification of the ILAE and the four-dimensional epilepsy classification. In addition, a case is described which is classified using the four-dimensional epilepsy classification with different degrees of precision by an emergency department physician, a neurologist, and an epileptologist. [Published with video sequences on www.epilepticdisorders.com].

Revisiting the public awareness, attitudes, and understanding towards epilepsy among Singapore residents.

A survey to assess the familiarity, attitudes, and knowledge about epilepsy was done using a questionnaire identical to the one used in 1999. Two hundred forty-six people participated in our survey in 2017 as compared with 214 in the 1999 survey. In terms of familiarity about epilepsy, 76% had heard or read about epilepsy, 55.7% had witnessed a seizure, and 35.8% knew someone with epilepsy (85%, 56%, and 36% respectively in 1999). Forty point five percent were not familiar with or did not know what to do if they witnessed a seizure (44% in 1999); 25.6% would put something in the mouth of a person having a seizure (32% in 1999). In terms of attitudes towards epilepsy, 14.6% would object to their children associating with one with epilepsy while 19.9% would object to their children marrying a person with epilepsy (13% and 36% respectively in 1999). Only 43.1% would employ a person with epilepsy while 68.3% would employ if seizures do not interfere with the job (42 and 66% respectively in 1999). In terms of knowledge of seizures and epilepsy, 66.3% associated epileptic attack with convulsion (68% in 1999). Only 37.5% were aware of nonconvulsive forms of epilepsy (25% in 1999). Twenty-six point eight percent did not know what treatment to recommend to relatives/friends with epilepsy while 60.6% recommend western medicine (22% and 60% respectively in 1999). CONCLUSION: The awareness, attitudes, and understanding towards epilepsy does not seem to show any significant difference when compared with that in 1999. Reluctance to marry and employ a person with epilepsy persists. The awareness about first aid of a patient having a seizure, attitudes towards marrying a person with epilepsy, and the understanding of cause of epilepsy have shown some positive changes over 17 years.

Fine margin between crossed sensory and contralateral sensory loss: A case report.

The well-known sensory deficit in lateral medullary syndrome (LMS) involves crossed ipsilateral trigeminal area and contralateral spinothalamic tract area. A 45 year old man was admitted for sudden onset slurring of speech, unsteadiness and sensory complaints. The diagnosis was right lateral medullary syndrome due to right Vertebral Artery occlusion. In addition to typical lateral medullary syndromes, his sensory deficit involved contralateral half of the face, trunk and limbs. We report this atypical sensory presentation and discuss its neuroanatomical correlation.

Ictal and interictal EEG patterns in patients with nonconvulsive and subtle convulsive status epilepticus.

BACKGROUND: Electroencephalography findings in nonconvulsive or subtle convulsive status epilepticus (NCSE and SCSE, respectively) can be heterogenous. We aimed to study the different patterns on EEG in our cohort of patients. OBJECTIVE: Our objective was to study ictal and interictal EEG patterns in patients with NCSE and SCSE. METHODS: From January 2012 to December 2013, EEGs recorded from patients admitted for altered mental status suspected of having NCSE or SCSE were reviewed retrospectively. Electroencephalography status was defined as having (a) continuous ictal discharges lasting >5 min or (b) >2 discrete bursts of ictal discharges, each lasting <5 min, without returning to previous background rhythm in between these bursts. RESULTS: Among 1698 EEGs recorded for at least 30 min from hospitalized patients, 55 (3.23%) satisfied the criteria of EEG SE. The ictal onset was regional in 37 (67.2%) EEGs, multiregional independent in 8 (14.5%), and generalized in 10 (18.4%). The EEG seizure duration was >5 min in 24 (43.6%) EEGs, between 1 and 5 min in 14 (25.4%), and less than 1 min in 17 (30.8%). Twenty (36.3%) EEGs showed one continuous prolonged seizure episode of >5-minute duration, 15 (27.2%) had 10 or less discrete episodes, 20 (36.3%) had more than 10 episodes, and 11 (20%) had 2 or more ictal patterns. Thirty (54.5%) EEGs had onset ictal frequency of >8 Hz whereas the rest had <8-Hz ictal frequency. In the interictal segment, 29 patients had continuous generalized slow waves, while 12 had intermittent generalized slow waves. Eleven patients had continuous slow waves lateralized to one hemisphere, and these were ipsilateral to the ictal focus in 10 but contralateral in 1. Other interictal waves seen were PLEDS (6), sharp waves (3), suppression (5), and triphasic waves (1). The background alpha rhythm was absent in 36 patients and slow in 14, and normal background alpha was seen in the interictal period in 5 patients. CONCLUSION: The ictal and interictal EEG patterns in NCSE and SCSE can be varied. Further study to look for etiologic and clinical correlates of each pattern could add to its clinical value. This article is part of a Special Issue entitled "Status Epilepticus".

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.

Clinical validation and implications of dried blood spot sampling of carbamazepine, valproic acid and phenytoin in patients with epilepsy.

To facilitate therapeutic monitoring of antiepileptic drugs (AEDs) by healthcare professionals for patients with epilepsy (PWE), we applied a GC-MS assay to measure three AEDs: carbamazepine (CBZ), phenytoin (PHT) and valproic acid (VPA) levels concurrently in one dried blood spot (DBS), and validated the DBS-measured levels to their plasma levels. 169 PWE on either mono- or polytherapy of CBZ, PHT or/and VPA were included. One DBS, containing ∼15 µL of blood, was acquired for the simultaneous measurement of the drug levels using GC-MS. Simple Deming regressions were performed to correlate the DBS levels with the plasma levels determined by the conventional immunoturbimetric assay in clinical practice. Statistical analyses of the results were done using MedCalc Version 12.6.1.0 and SPSS 21. DBS concentrations (Cdbs) were well-correlated to the plasma concentrations (Cplasma): r=0.8381, 0.9305 and 0.8531 for CBZ, PHT and VPA respectively, The conversion formulas from Cdbs to plasma concentrations were [0.89×CdbsCBZ+1.00]µg/mL, [1.11×CdbsPHT-1.00]µg/mL and [0.92×CdbsVPA+12.48]µg/mL respectively. Inclusion of the red blood cells (RBC)/plasma partition ratio (K) and the individual hematocrit levels in the estimation of the theoretical Cplasma from Cdbs of PHT and VPA further improved the identity between the observed and the estimated theoretical Cplasma. Bland-Altman plots indicated that the theoretical and observed Cplasma of PHT and VPA agreed well, and >93.0% of concentrations was within 95% CI (±2SD); and similar agreement (1∶1) was also found between the observed Cdbs and Cplasma of CBZ. As the Cplasma of CBZ, PHT and VPA can be accurately estimated from their Cdbs, DBS can therefore be used for drug monitoring in PWE on any of these AEDs.

Prevalence of drug resistant epilepsy in adults with epilepsy attending a neurology clinic of a tertiary referral hospital in Singapore.

PURPOSE: To determine the proportion of population of adult people with epilepsy (PWE) in Singapore, who suffer from drug resistant epilepsy (DRE). METHODS: All adult PWE who had attended the neurology specialist clinic of a tertiary referral hospital in Singapore were profiled for drug responses according to the definition for DRE as specified by the International League against Epilepsy (ILAE) 2010 consensus. This is a retrospective cohort study. Data collected included demographics, characteristics of seizure and epilepsy, blood biochemistry levels, electroencephalogram and brain imaging findings, and medication histories. The types and dosages of antiepileptic drugs (AEDs) used were retrieved from case notes and checked against pharmacy records. Each patient was counselled upon the diagnosis of epilepsy and taught to maintain a seizure diary. The dates and number of seizures were retrieved from these diaries at each visit. Treatment-related adverse effects were routinely assessed and hence, patients were assumed to not have treatment-related adverse effects when no relevant documentation was encountered. RESULTS: The prevalence rate of DRE in this clinic was 21.5%, while 40.9% of PWE were drug responsive/seizure free at the point prevalence day (n=557). From multivariate analysis, patients with structural-metabolic aetiology [odds ratio (OR) 1.78, 95% confidence interval (CI) 1.003-3.148], mental retardation [OR 2.51, 95% CI 1.073-5.863], psychiatric illnesses [OR 3.349, 95% CI 1.181-9.501] and pre-treatment seizure frequency of more than once monthly [OR 2.775, 95% CI 1.190-6.469] were found to be more likely to have DRE (p≤0.05). Although the influence of Indian ethnicity on the risk of DRE was only found in the univariate analysis, it warrants investigation in a larger cohort. CONCLUSION: The findings may aid policy makers in designing treatment guidelines and allocating resources around PWE, with careful considerations that at any given time, 1 in 5 PWE have DRE.

[Standardized management of acupuncture-moxibustion clinic in Singapore General Hospital].

The standardized management of acupuncture-moxibustion in Singapore General Hospital is introduced. With gradual improvement of outpatient infrastructure, re-training of medical staff, strict disinfection of manipulation, periodical inspection of medical instruments, unified management of writing, saving and processing in medical records and public education of TCM knowledge, a standardized management system in accordance with modernized hospital is gradually established. As a result, efficiency and quality of clinical treatment is continuously increasing. From April of 1998 to December of 2012, a total of 74 654 times of treatment were performed, and treatment amount per day is gradually increased. The unusual condition of acupuncture is avoided. Periodical strict inspection of joint committee authenticated by domestic and overseas medical health organization is repeatedly passed and accepted. Additionally, three clinical researches funded by Singapore Health-care Company are still in progress in acupuncture-moxibustion department.

How do primary care physicians in Singapore keep healthy?

INTRODUCTION: Not much is known regarding how primary care physicians (PCPs) in Singapore keep themselves healthy and mitigate ill health. This study aims to determine the health-seeking behaviour of local PCPs and to identify the predictors of local PCPs attaining the recommended level of exercise. METHODS: This study was a cross-sectional questionnaire survey, which included questions on the demographic characteristics, practice profiles and health-seeking behaviour of PCPs. The sampling frame was the 1,400 listed members of the College of Family Physicians Singapore. The anonymised survey was executed in two phases: a postal survey, followed by a web-based survey on the College of Family Physicians Singapore website. The two data sets were collated; the categorical variables, summarised; and the differences between subgroups (based on exercise engagement), compared using Fisher's exact test. The effect of each risk factor on exercise duration was quantified using odds ratio (OR) estimate and 95% confidence interval (CI). Multivariate logistic regression analysis was performed to identify significant predictors of exercise engagement. RESULTS: A total of 631 PCPs participated in the survey--26% were ≤ 34 years old, 58% were male, 21% were single, 34% were singleton practitioners, and 56% were private practitioners. The percentage of PCPs who exercised ≥ 2.5 hours weekly was 29%, while 28% exercised < 0.5 hours weekly. Of the PCPs surveyed, 1% currently smoke, 0.8% drink more than 14 units of alcohol weekly, 60% undertook health screening, 65% had blood investigations done, and 64% had taken preventive measures such as getting influenza vaccination. CONCLUSION: While local PCPs generally did not have undesirable habits such as smoking and alcohol abuse, they could further increase their exercise intensity and undertake more preventive measures such as getting vaccinated against various diseases.

Estimation and comparison of carbamazepine population pharmacokinetics using dried blood spot and plasma concentrations from people with epilepsy: the clinical implication.

To establish using dried blood spot (DBS) as a surrogate to plasma for therapeutic drug monitoring (TDM) of carbamazepine (CBZ), we compared the population pharmacokinetic (PPK) estimates from concurrent DBS and plasma levels. The dose-concentration relationship, estimated parameter and variability were determined. A total of 98 observations from 97 people with epilepsy (PWE) were included in this study. Data was split into 3:1 ratio for the respective index group and validation group. Non-linear mixed effects regression with one compartment, first order absorption and elimination model was utilized. Covariates were screened for inclusion into final model via forward stepwise addition and backward elimination method. Predictive performances of the final models were assessed for bias and precision. The typical clearance for CBZ was estimated to be 5.85 and 5.68 L/h from plasma and DBS concentrations, respectively. The final models for clearance estimates obtained from plasma concentrations (Cplasma ) included total daily CBZ dose per unit weight (DD) and sex while from DBS concentrations (Cdbs ) included only DD. The final models were both precise and non-bias. The developed PPK models had comparable estimates, errors and predictive performances. Our findings suggest that Cplasma and Cdbs could be used interchangeably for pharmacokinetic studies of CBZ.

Methotrexate induced leucoencephalopathy: A stroke mimic.

With increasing usage of thrombolysis in the treatment of acute ischemic strokes within 4.5- hour window, it is becoming more important to recognize stroke mimics. Though the incidence of stroke mimics being thrombolysed is less than 3%, it is essential to diagnose them so as to avoid wrong thrombolytic treatment which carries potential complications of bleeding. We describe the case of a 17 year old girl with acute lymphoblastic leukemia, who developed stroke like episodes on two consecutive challenges with a chemotherapeutic regime which included intravenous and intrathecal methotrexate. She had MRI changes consistent with acute ischemic stroke on both occasions. Her deficits recovered completely and spontaneously, as did the MRI changes. She did not have any further episodes when methotrexate was excluded from the chemotherapeutic regime.

Methotrexate-induced myelopathy mimicking subacute combined degeneration of the spinal cord.

Methotrexate (MTX), a folate antagonist, is widely used to treat hematological malignancies. Although it is known to cause myelopathy, little is known about the pathophysiology and natural history of this myelopathy. We describe a 42-year-old woman with acute lymphoblastic leukemia who was treated with chemotherapy consisting of intrathecal MTX who developed a progressive myelopathy. The myelopathy mimicked, radiologically, subacute combined degeneration (SACD) of the spinal cord. This myelopathy mimicking SACD could be explained by the folate antagonism of MTX. The progressive clinical signs and serial MRI in this patient further our understanding of the natural progression of this myelopathy.

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.