SLCO5A1 and synaptic assembly genes contribute to impulsivity in juvenile myoclonic epilepsy.

Elevated impulsivity is a key component of attention-deficit hyperactivity disorder (ADHD), bipolar disorder and juvenile myoclonic epilepsy (JME). We performed a genome-wide association, colocalization, polygenic risk score, and pathway analysis of impulsivity in JME (n = 381). Results were followed up with functional characterisation using a drosophila model. We identified genome-wide associated SNPs at 8q13.3 (P = 7.5 × 10-9) and 10p11.21 (P = 3.6 × 10-8). The 8q13.3 locus colocalizes with SLCO5A1 expression quantitative trait loci in cerebral cortex (P = 9.5 × 10-3). SLCO5A1 codes for an organic anion transporter and upregulates synapse assembly/organisation genes. Pathway analysis demonstrates 12.7-fold enrichment for presynaptic membrane assembly genes (P = 0.0005) and 14.3-fold enrichment for presynaptic organisation genes (P = 0.0005) including NLGN1 and PTPRD. RNAi knockdown of Oatp30B, the Drosophila polypeptide with the highest homology to SLCO5A1, causes over-reactive startling behaviour (P = 8.7 × 10-3) and increased seizure-like events (P = 6.8 × 10-7). Polygenic risk score for ADHD genetically correlates with impulsivity scores in JME (P = 1.60 × 10-3). SLCO5A1 loss-of-function represents an impulsivity and seizure mechanism. Synaptic assembly genes may inform the aetiology of impulsivity in health and disease.

Review of Magnetic Resonance Imaging and Post-processing for the Brain Tumor-related Epilepsy Study.

20% of brain tumor patients present with seizures at the onset of diagnosis, while a further 25-40% develop epileptic seizures as the tumor progresses. Tumor-related epilepsy (TRE) is a condition in which the tumor causes recurring, unprovoked seizures. The occurrence of TRE differs between patients, along with the effectiveness of treatment methods. Therefore, determining the tumor properties that correlate with epilepsy can help guide TRE treatment. This article reviews the MRI sequences and image post-processing algorithms in the study of TRE. It focuses on epilepsy caused by glioma tumors because it is the most common type of malignant brain tumor and it has a high prevalence of epilepsy. In correlational TRE studies, conventional MRI sequences and diffusion-weighted MRI (DWI) are used to extract variables related to the tumor radiological characteristics, called imaging factors. Image post-processing is used to correlate the imaging factors with the incidence of epilepsy. The earlier studies of TRE used univariate and multivariate analysis to study the correlations between specific variables and incidence of epilepsy. Later, studies used voxel-based morphometry and voxel lesion-symptom mapping. Radiomics has been recently used to post-process the images for the study of TRE. This article will discuss the limitation of the existing imaging modalities and post-processing algorithms. It ends with some suggestions and challenges for future TRE studies.

Genetic interaction between GABRA1 and ERBB4 variants in the pathogenesis of genetic generalized epilepsy.

Epilepsy is a complex neurological disease that can be caused by both genetic and environmental factors. Many studies have been conducted to investigate the genetic risk variants and molecular mechanisms of epilepsy. Disruption of excitation-inhibition balance (E/I balance) is one of the widely accepted disease mechanisms of epilepsy. The maintenance of E/I balance is an intricate process that is governed by multiple proteins. Using whole exome sequencing (WES), we identified a novel GABRA1 c.448G>A (p.E150K) variant and ERBB4 c.1972A>T (p.I658F, rs190654033) variant in a Malaysian Chinese family with genetic generalized epilepsy (GGE). The GGE may be triggered by dysregulation of E/I balance mechanism. Segregation of the variants in the family was verified by Sanger sequencing. All family members with GGE inherited both variants. However, family members who carried only one of the variants did not show any symptoms of GGE. Both the GABRA1 and ERBB4 variants were predicted damaging by MutationTaster and CADD, and protein structure analysis showed that the variants had resulted in the formation of additional hydrogen bonds in the mutant proteins. GABRA1 variant could reduce the efficiency of GABAA receptors, and constitutively active ERBB4 receptors caused by the ERBB4 variant promote internalization of GABAA receptors. The interaction between the two variants may cause a greater disruption in E/I balance, which is more likely to induce a seizure. Nevertheless, this disease model was derived from a single small family, further studies are still needed to confirm the verifiability of the purported disease model.

Prevalence of seizures in brain tumor: A meta-analysis.

OBJECTIVES: Prevalence of seizures in brain tumors vary substantially between studies even with similar histopathological types. We aimed to identify the seizure prevalence of the commonest types of brain tumors. METHODS: Systematic computerized search of PubMed, Embase, and Web of Science were performed. The meta-analysis of pooled prevalence and 95 % confidence interval (CI) for tumor-related seizures were calculated by using a random effect model. Based on the 2014 epilepsy definition, a mean seizure prevalence of 60 % is used to indicate high seizure prevalence in this study. RESULTS: 74 studies that reported seizure prevalence with 23,116 patients were included in this meta-analysis. These tumors has higher seizure incidence rate (at least 60 %) with pooled prevalence of 63 % for adult with low-grade astrocytoma (95 % CI: 57-68 %), 65 % for oligodendroglioma (95% CI: 57-72 %), 72 % for oligoastrocytoma (95 % CI: 67-77 %), 81 % for ganglioglioma (95 % CI: 66-97 %) and 94 % for DNET (94 % CI: 83-100 %). CONCLUSION: This study highlights the type of brain tumors that carry a high seizure prevalence. Screening for subtle seizures and early management of seizures may be beneficial in patients with low-grade astrocytoma (adult), oligodendroglioma, oligoastrocytoma, ganglioglioma or DNET brain tumor.

Epilepsy surgery program in a resource-limited setting in Vietnam: A multicentered collaborative model.

OBJECTIVE: Although epilepsy surgery is more effective than medical therapy for drug-resistant patients, it is underutilized in both high-income and low- and middle-income countries. In light of our efforts to establish an epilepsy surgery program in a resource-limited setting, this study aimed to determine the outcome of the epilepsy surgery program in Ho Chi Minh City (HCMC), Vietnam. METHODS: In 2018, we developed the HCMC epilepsy core multidisciplinary team with members from various hospitals and centers. The team typically included neurologists, neurosurgeons, neuropsychologists, psychiatrists, and nursing specialists. Presurgical evaluations were performed for patients with drug-resistant epilepsy, fulfilling the ILAE criteria, with an epileptogenic lesion (mesial temporal sclerosis, low-grade gliomas, or focal cortical dysplasia). All epilepsy surgeries were performed in two epilepsy surgery centers in HCMC between 2018 and 2021. The patients were followed up for at least 12 months. RESULTS: Fifty-two patients with drug-resistant epilepsy underwent presurgical evaluation, of which 35 underwent surgery. Among the 52 patients, 20 (38.5%) underwent surgery after showing concordance among the results of standard presurgical assessments such as semiology, scalp interictal or ictal electroencephalography, and brain imaging. Among the 26 people with epilepsy who required more advanced evaluations, 15 underwent surgery with intraoperative electrocorticography to delineate the optimal resection borders. The outcomes of Engel Class I and Class II were achieved in 29/35 (82.8%) and 6/35 (17.2%) patients, respectively. SIGNIFICANCE: The epilepsy surgery program with a multicentered collaborative model in a resource-limited setting showed favorable outcomes in HCMC, Vietnam.

Impact of seizures and antiseizure medication on survival in patients with glioma.

PURPOSE: Seizures are a common presenting symptom among patients with low- and high-grade glioma. However, the impact and inter-relationship between the presence of seizures, anti-seizure medication (ASM) and survival are unclear. We retrospectively analyzed the incidence of seizures and identified the pattern and relationship of anti-seizure medication on survival in our cohort of patients with glioma. METHODS: We evaluated all glioma patients who underwent treatment at the University of Malaya Medical Centre (UMMC) between 2008 and 2020. Demographic and clinical data of seizures and pattern of ASM administration in comparison to overall survival were analyzed. RESULTS: A total of 235 patients were studied, with a minimum of one year clinical follow-up post-treatment. The median survival for low-grade glioma was 38 months whereas high-grade glioma was 15 months. One-third of our glioma patients (n = 74) presented with seizures. All patients with seizures and a further 31% of patients without seizures were started on anti-seizure medication preoperatively. Seizure and Levetiracetam (LEV) were significantly associated with OS on univariate analysis. However, only LEV (HR 0.49; 95% CI 0.23-0.87; p=0.02) was significantly associated with improving overall survival (OS) on multivariate analysis. Once ASM was adjusted for relevant factors and each other, LEV was associated with improved survival in all grade gliomas (HR 0.52; 95% CI 0.31-0.88; p=0.02) and specifically high-grade gliomas (HR 0.53; 95% CI 0.30-0.94; p=0.03). CONCLUSIONS: Pre-operative seizures among patients with glioma indicated a better overall prognosis. The administration of ASM, specifically LEV was associated with a  significant survival advantage in our retrospective cohort of patients.

Seizure remission rates remain low in a resource-limited country, a multicentre comparison study in Malaysia.

Seizure remission rates of 60% with antiseizure medications were reported in developed countries, but might be lower in resource-limited countries. The challenges in epilepsy care in resource-limited regions were highlighted 10 years ago, and still remain an ongoing issue. This study aimed to determine the seizure freedom rates in level-2 epilepsy care centres (centres with general neurologists) compared to level-3/4 centres (centres with epileptologists providing epilepsy surgery evaluation) in Malaysia. This is a retrospective study of 1,347 adult epilepsy patients from two level-2 (n = 290) and two level-3/4 epilepsy care centres (n = 1,057). The seizure remission rates were significantly lower in level-2 centres (42.5%) compared to the level 3/4 centres (61.9%, p < 0.05). Level-2 centres had significantly more patients with undetermined seizure types compared to level-3/4 centres (6.6% vs 3.1%, p < 0.05). Level-3/4 centres had significantly more patients with epilepsy of structural and genetic origins, whereas more patients in level-2 centres had unknown aetiology (46.2% vs. 34.0% in level-3/4, p < 0.05). Level-2 centres had a lower neurologist-to-patient ratio (1:97 vs. 1:50 in level-3/4 centres, p < 0.05). Level-2 centres also had fewer patients, who underwent investigations such as EEG (74.1% vs. 89.6%) and brain MRI (54.1% vs. 72.4%, p < 0.05) in comparison with level-3/4 centres. Our study emphasized the existing challenges in epilepsy care in a resource-limited country to achieve the ideal 60% seizure remission rate.

Incidence of allopurinol-induced severe cutaneous adverse drug reaction in Malaysia.

AIMS: Allopurinol is known to cause severe cutaneous adverse drug reactions (SCAR) in Malaysia. However, the incidence of allopurinol-induced SCAR is unknown. Therefore, we aimed to determine the incidence of allopurinol-induced SCAR in Malaysia over 5 years from 2015 to 2019. METHODS: This retrospective analysis was done in collaboration with the National Pharmaceutical Regulatory Agency (NPRA). All allopurinol-induced adverse drug reaction cases reported to NPRA from 2015 to 2019 were extracted. Allopurinol-induced SCAR cases were identified and the incidence over the 5 years was calculated. RESULTS: Incidence of allopurinol-induced SCAR averaged at 2.5 cases per 1000 new users over the 5-year period, with a reducing trend from 3.2 per 1000 new users in 2015 to 2.25 per 1000 in 2019; despite the increasing number of adverse drug reaction cases being reported over the years. Stevens-Johnson syndrome was the commonest form of allopurinol-induced SCAR reported, at 143 cases (46.8% of total SCAR reported). Among Malaysia's 3 main ethnicities, the Chinese had the highest percentages of allopurinol-induced SCAR when compared to the Bumiputera and Indians (3.18 × 10-4 %). CONCLUSION: The estimated incidence of allopurinol-induced SCAR in Malaysia from 2015 to 2019 was 2.5 cases per 1000 new users. This figure is consistent with the incidence reported in other Asian countries, namely Taiwan and Thailand.

Cause of mortality among people with epilepsy in Malaysia: A hospital-based study.

BACKGROUND: This is a follow-up study on mortality in adult patients in Malaysia. This study aimed to determine the cause of death and the factors associated with epilepsy-related death in PWE in Malaysia. METHOD: Deceased PWE from 2005 to 2020 were identified from the National Registry Department of Malaysia. The details of the cause of death and predictors for epilepsy-related deaths was ascertained from medical records and phone interviews. RESULT: There were a total of 227 deaths, 144 (63.4%) were male, two (0.9%) underwent autopsy and 46.3% passed away in the community. The majority of deaths (55.5%) were due to causes unrelated to epilepsy. Forty-five (19.8%) death were related to epilepsy, of which, 22 (9.7%) were due to death directly related to epilepsy including probable SUDEP (5.3%) and status epilepticus (4.4%). The cause of death was unknown in 56 (24.7%) cases. Binary logistic regression analysis identified 3 predictors for epilepsy-related deaths, i.e., structural causes (OR 3.09, 95% CI 1.100-8.691, p = 0.032), younger age of death (OR 2.35, 95% CI 1.039-5.333, p = 0.040) and history of brain surgery (OR 8.09, 95% CI 2.014-32.510, p = 0.003). Twelve (5.3%) had probable SUDEP. The incidence rate of probable SUDEP was 0.42 per 1000 person-years. The majority of them had intellectual disability (9/12), generalized tonic-clonic seizures (9/12), and 2 or more ASMs (9/12). CONCLUSION: Epilepsy-related deaths accounted for 20% of the deaths in PWE, associated with structural cause, younger age of death, and previous brain surgery. Probable SUDEP is not uncommon in Malaysia and could be under-diagnosed.

EEG Source Imaging (ESI) utility in clinical practice.

Epilepsy surgery is an important treatment modality for medically refractory focal epilepsy. The outcome of surgery usually depends on the localization accuracy of the epileptogenic zone (EZ) during pre-surgical evaluation. Good localization can be achieved with various electrophysiological and neuroimaging approaches. However, each approach has its own merits and limitations. Electroencephalography (EEG) Source Imaging (ESI) is an emerging model-based computational technique to localize cortical sources of electrical activity within the brain volume, three-dimensionally. ESI based pre-surgical evaluation gives an overall clinical yield of 73-91%, depending on choice of head model, inverse solution and EEG electrode density. It is a cost effective, non-invasive method which provides valuable additional information in presurgical evaluation due to its high localizing value specifically in MRI-negative cases, extra or basal temporal lobe epilepsy, multifocal lesions such as tuberous sclerosis or cases with multiple hypotheses. Unfortunately, less than 1% of surgical centers in developing countries use this method as a part of pre-surgical evaluation. This review promotes ESI as a useful clinical tool especially for patients with lesion-negative MRI to determine EZ cost-effectively with high accuracy under the optimized conditions.

48-hour video-EEG monitoring for epilepsy presurgical evaluation is cost-effective and safe in resource-limited setting.

INTRODUCTION: Video-EEG monitoring is one of the key investigations in epilepsy pre-surgical evaluation but limited by cost. This study aimed to determine the efficacy and safety of a 48-hour (3-day) video EEG monitoring, with rapid pre-monitoring antiepileptic drugs withdrawal. MATERIAL AND METHODS: This is a retrospective study of epilepsy cases with VEM performed in University Malaya Medical Center (UMMC), Kuala Lumpur, from January 2012 till August 2016. RESULTS: A total of 137 cases were included. The mean age was 34.5 years old (range 15-62) and 76 (55.8 %) were male. On the first 24 -h of recording (D1), 81 cases (59.1 %) had seizure occurrence, and 109 (79.6 %) by day 2 (D2). One-hundred and nine VEMs (79.6 %) were diagnostic, in guiding surgical decision or further investigations. Of these, 21 had less than 2 seizures recorded in the first 48 h but were considered as diagnostic because of concordant interictal ± ictal activities, or a diagnosis such as psychogenic non-epileptic seizure was made. Twenty-eight patients had extension of VEM for another 24-48 h, and 11 developed seizures during the extension period. Extra-temporal lobe epilepsy and seizure frequency were significant predictors for diagnostic 48 -h VEM. Three patients developed complications, including status epilepticus required anaesthetic agents (1), seizure clusters (2) with postictal psychosis or dysphasia, and all recovered subsequently. CONCLUSIONS: 48-h video EEG monitoring is cost-effective in resource limited setting.

Pathogenic Variants in CEP85L Cause Sporadic and Familial Posterior Predominant Lissencephaly.

Lissencephaly (LIS), denoting a "smooth brain," is characterized by the absence of normal cerebral convolutions with abnormalities of cortical thickness. Pathogenic variants in over 20 genes are associated with LIS. The majority of posterior predominant LIS is caused by pathogenic variants in LIS1 (also known as PAFAH1B1), although a significant fraction remains without a known genetic etiology. We now implicate CEP85L as an important cause of posterior predominant LIS, identifying 13 individuals with rare, heterozygous CEP85L variants, including 2 families with autosomal dominant inheritance. We show that CEP85L is a centrosome protein localizing to the pericentriolar material, and knockdown of Cep85l causes a neuronal migration defect in mice. LIS1 also localizes to the centrosome, suggesting that this organelle is key to the mechanism of posterior predominant LIS.

Recursive independent component analysis (ICA)-decomposition of ictal EEG to select the best ictal component for EEG source imaging.

OBJECTIVE: This study aimed to present a new ictal component selection technique, named as recursive ICA-decomposition for ictal component selection (RIDICS), for potential application in epileptogenic zone localization. METHODS: The proposed technique decomposes ictal EEG recursively, eliminates a few unwanted components in every recursive cycle, and finally selects the most significant ictal component. Back-projected EEG, regenerated from that component, was used for source estimation. Fifty sets of simulated EEGs and 24 seizures in 8 patients were analyzed. Dipole sources of simulated-EEGs were compared with a known dipole location whereas epileptogenic zones of the seizures were compared with their corresponding sites of successful surgery. The RIDICS technique was compared with a conventional technique. RESULTS: The RIDICS technique estimated the dipole sources at an average distance of 12.86 mm from the original dipole location, shorter than the distances obtained using the conventional technique. Epileptogenic zones of the patients, determined by the RIDICS technique, were highly concordant with the sites of surgery with a concordance rate of 83.33%. CONCLUSIONS: Results show that the RIDICS technique can be a promising quantitative technique for ictal component selection. SIGNIFICANCE: Properly selected ictal component gives good approximation of epileptogenic zone, which eventually leads to successful epilepsy surgery.

The Effect of 20-Minute Mindful Breathing on the Perception of Suffering and Changes in Bispectral Index Score (BIS) in Palliative Care Informal Caregivers: A Randomized Controlled Study.

Informal caregivers are at risk of being overwhelmed by various sources of suffering while caring for their significant others. It is, therefore, important for caregivers to take care of themselves. In the self-care context, mindfulness has the potential to reduce caregiver suffering. We studied the effect of a single session of 20-minute mindful breathing on the perceived level of suffering, together with the changes in bispectral index score (BIS) among palliative care informal caregivers. This was a randomized controlled study conducted at the University of Malaya Medical Centre, Malaysia. Forty adult palliative care informal caregivers were recruited and randomly assigned to either 20-minute mindful breathing or 20-minute supportive listening. The changes in perceived suffering and BIS were measured preintervention and postintervention. The reduction in suffering score in the intervention group was significantly more than the control group at minute 20 (U = 124.0, n1 = n2 = 20, mean rank1 = 24.30, mean rank2 = 16.70, z = -2.095, P = .036). The reduction in BIS in the intervention group was also significantly greater than the control group at minute 20 (U = 19.5, n1 = n2 = 20, mean rank1 = 29.52, mean rank2 = 11.48, z = -4.900, P < .0001). Twenty minutes of mindful breathing was more efficacious than 20 minutes of supportive listening in the reduction in suffering among palliative care informal caregivers.

Validation of Malay brief screening instrument for ascertainment of epilepsy.

INTRODUCTION: Prevalence studies of epilepsy in Asia revealed a prevalence ranging from 1.5 to 14.0 per 1000 among Asian populations. However, the prevalence of epilepsy in Malaysia is not available for comparison with other countries. This study aimed to translate and validate a Malay brief screening instruments for ascertainment of epilepsy. METHOD: We translated into Malay a brief screening instrument for ascertainment of epilepsy designed and validated by Ottman et al., using the three-stage cross-cultural adaptation process developed by the International Quality of Life Assessment (IQOLA) project. We then administered the translated questionnaire via online survey to 162 cases (patients with epilepsy under follow-up care at the neurology clinic in University of Malaya Medical Centre, Kuala Lumpur) and 146 controls with no known history of epilepsy for validation. RESULTS: Applying the most liberal definition for a positive screen, we obtained a sensitivity of 96.3% (95% confidence interval [CI]: 91.8-98.5%), with a specificity of 66.4% (95% CI: 58.1-73.0%) and positive predictive value (PPV) of 2.0%. The most stringent definition for a positive screen (only epilepsy) resulted in a sensitivity of 97.4% (95% CI: 62.0-72.6%), specificity of 98.6% (95% CI: 94.6-99.7%), and PPV of 26.6%. Narrowing the definition of a positive screen decreased sensitivity but improved PPVs. When compared to the original English questionnaire, the sensitivities were similar for all four definitions of a positive screen. CONCLUSION: This is the first validated epilepsy screening questionnaire in the Malay language and represents a useful tool for the ascertainment of epilepsy in population-based studies.

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.

Ictal EEG Source Imaging for Presurgical Evaluation of Refractory Focal Epilepsy.

BACKGROUND: Electroencephalography source imaging (ESI) is a promising tool for localizing the cortical sources of both ictal and interictal epileptic activities. Many studies have shown the clinical usefulness of interictal ESI, but very few have investigated the utility of ictal ESI. The aim of this article is to examine the clinical usefulness of ictal ESI for epileptic focus localization in patients with refractory focal epilepsy, especially extratemporal lobe epilepsy. METHODS: Both ictal and interictal ESI were performed by the use of patient-specific realistic forward models and 3 different linear distributed inverse models. Lateralization as well as concordance between ESI-estimated focuses and single-photon emission computed tomography (SPECT) focuses were assessed. RESULTS: All the ESI focuses (both ictal and interictal) were found lateralized to the same hemisphere as ictal SPECT focuses. Lateralization results also were in agreement with the lesion sides as visualized on magnetic resonance imaging. Ictal ESI results, obtained from the best-performing inverse model, were fully concordant with the same cortical lobe as SPECT focuses, whereas the corresponding concordance rate is 87.50% in case of interictal ESI. CONCLUSIONS: Our findings show that ictal ESI gives fully lateralized and highly concordant results with ictal SPECT and may provide a cost-effective substitute for ictal SPECT.