Epilepsy and Attention Deficit Hyperactivity Disorder: Connection, Chance, and Challenges.

Comorbidities are common in children with epilepsy, with nearly half of the patients having at least one comorbidity. Attention deficit hyperactivity disorder (ADHD) is a psychiatric disorder characterized by hyperactivity and inattentiveness level disproportional to the child's developmental stage. The burden of ADHD in children with epilepsy is high and can adversely affect the patients' clinical outcomes, psychosocial aspects, and quality of life. Several hypotheses were proposed to explain the high burden of ADHD in childhood epilepsy; the well-established bidirectional connection and shared genetic/non-genetic factors between epilepsy and comorbid ADHD largely rule out the possibility of a chance in this association. Stimulants are effective in children with comorbid ADHD, and the current body of evidence supports their safety within the approved dose. Nonetheless, safety data should be further studied in randomized, double-blinded, placebo-controlled trials. Comorbid ADHD is still under-recognized in clinical practice. Early identification and management of comorbid ADHD are crucial to optimize the prognosis and reduce the risk of adverse long-term neurodevelopmental outcomes. The identification of the shared genetic background of epilepsy and ADHD can open the gate for tailoring treatment options for these patients through precision medicine.

Clinical and Genetic Features of Dravet Syndrome: A Prime Example of the Role of Precision Medicine in Genetic Epilepsy.

Dravet syndrome (DS), also known as severe myoclonic epilepsy of infancy, is a rare and drug-resistant form of developmental and epileptic encephalopathies, which is both debilitating and challenging to manage, typically arising during the first year of life, with seizures often triggered by fever, infections, or vaccinations. It is characterized by frequent and prolonged seizures, developmental delays, and various other neurological and behavioral impairments. Most cases result from pathogenic mutations in the sodium voltage-gated channel alpha subunit 1 (SCN1A) gene, which encodes a critical voltage-gated sodium channel subunit involved in neuronal excitability. Precision medicine offers significant potential for improving DS diagnosis and treatment. Early genetic testing enables timely and accurate diagnosis. Advances in our understanding of DS's underlying genetic mechanisms and neurobiology have enabled the development of targeted therapies, such as gene therapy, offering more effective and less invasive treatment options for patients with DS. Targeted and gene therapies provide hope for more effective and personalized treatments. However, research into novel approaches remains in its early stages, and their clinical application remains to be seen. This review addresses the current understanding of clinical DS features, genetic involvement in DS development, and outcomes of novel DS therapies.

Association between Exposure to Particulate Matter Air Pollution during Early Childhood and Risk of Attention-Deficit/Hyperactivity Disorder in Taiwan.

(1) Background: Recently, a growing number of studies have provided evidence to suggest a strong correlation between air pollution exposure and attention-deficit/hyperactivity disorder (ADHD). In this study, we assessed the relationship between early-life exposure to particulate matter (PM)10, PM2.5, and ADHD; (2) Methods: The National Health Insurance Research Database (NHIRD) contains the medical records, drug information, inspection data, etc., of the people of Taiwan, and, thus, could serve as an important research resource. Air pollution data were based on daily data from the Environmental Protection Administration Executive Yuan, R.O.C. (Taiwan). These included particulate matter (PM2.5 and PM10). The two databases were merged according to the living area of the insured and the location of the air quality monitoring station; (3) Results: The highest levels of air pollutants, including PM2.5 (adjusted hazard ratio (aHR) = 1.79; 95% confidence interval (CI) = 1.58-2.02) and PM10 (aHR = 1.53; 95% CI = 1.37-1.70), had a significantly higher risk of ADHD; (4) Conclusions: As such, measures for air quality control that meet the WHO air quality guidelines should be strictly and uniformly implemented by Taiwanese government authorities.

Prescription patterns and dosages of antiepileptic drugs in prevalent patients with epilepsy in Taiwan: A nationwide retrospective cross-sectional study.

OBJECTIVE: To evaluate the prescription patterns and prescribed daily dose (PDD)/defined daily dose (DDD) ratios of antiepileptic drugs (AEDs) in prevalent patients with epilepsy in Taiwan. MATERIALS AND METHODS: A nationwide retrospective cross-sectional study was conducted for prevalent patients with epilepsy in 2016 using the Taiwanese National Health Insurance Research Database. The prescription records of AEDs of all prevalent patients with epilepsy were retrieved. The mean PDDs and PDD/DDD ratios of AEDs in adult patients were obtained to evaluate dosing adequacy. A chi-square test and two-sample t test were used to analyze the differences in AED prescription patterns and dosages, respectively, among patients with different ages, sexes, comorbidities, and therapeutic approaches. RESULTS: A total of 118,937 prevalent patients with epilepsy were enrolled. The predominant therapeutic approach was monotherapy, especially in the elder adults, accounting for 82.9% of elder adult patients with epilepsy. The proportion of AED monotherapy was higher in patients with dementia (78.9%) and stroke (80.6%). The top three antiepileptic monotherapies were valproic acid (28.7%), levetiracetam (19.1%), and phenytoin (16.9%); however, oxcarbazepine (22.8%) was substituted for carbamazepine (3.9%) as monotherapy for patients aged 0-17 years. Among adult patients with epilepsy, the PDD/DDD ratio of each AED in monotherapy was less than 1.00. The mean PDD of each AED was higher in polytherapy than in monotherapy (p < 0.01), except for lacosamide. The mean PDDs of all evaluated AEDs in monotherapy were lower in elder adult patients than in younger adult patients, most of which reached statistical significance (p < 0.001). CONCLUSIONS: In Taiwan, valproic acid was the most prescribed AED for prevalent patients with epilepsy. The mean PDDs of most AEDs were lower than the DDDs developed by the World Health Organization.

Clinical Diagnosis and Treatment of Leigh Syndrome Based on SURF1: Genotype and Phenotype.

SURF1 encodes the assembly factor for maintaining the antioxidant of cytochrome c oxidase (COX) stability in the human electron respiratory chain. Mutations in SURF1 can cause Leigh syndrome (LS), a subacute neurodegenerative encephalopathy, characterized by early onset (infancy), grave prognosis, and predominant symptoms presenting in the basal ganglia, thalamus, brainstem, cerebellum, and peripheral nerves. To date, more than sixty different SURF1 mutations have been found to cause SURF1-associated LS; however, the relationship between genotype and phenotype is still unclear. Most SURF1-associated LS courses present as typical LS and cause early mortality (before the age of ten years). However, 10% of the cases present with atypical courses with milder symptoms and increased life expectancy. One reason for this inconsistency may be due to specific duplications or mutations close to the C-terminus of the SURF1 protein appearing to cause less protein decay. Furthermore, the treatment for SURF1-associated LS is unsatisfactory. A ketogenic diet is most often prescribed and has proven to be effective. Supplementing with coenzyme Q and other cofactors is also a common treatment option; however, the results are inconsistent. Importantly, anti-epileptic drugs such as valproate-which cause mitochondrial dysfunction-should be avoided in patients with SURF1-associated LS presenting with seizures.

Analysis of trends and factors determining initial antiseizure medication choice for epilepsy in Taiwan.

PURPOSE: To evaluate the current trends and factors associated with the first anti-seizure medications (ASMs) prescribed for epilepsy in Taiwan. METHODS: Data for patients with epilepsy were collected from the National Health Insurance Research Database, a population-based claims database. We selected patients with newly diagnosed epilepsy from 2013 to 2016. Multivariate logistic regression was used to examine the factors associated with the selection of newer ASMs for the first prescription. RESULTS: A total of 73,891 patients with newly diagnosed epilepsy were eligible for the study, and the annual incidence was approximately 0.79 per 1,000 people. The five ASMs most prescribed for monotherapy were valproic acid, phenytoin, levetiracetam, gabapentin, and oxcarbazepine, accounting for nearly 90% of all ASMs. Valproic acid was the most-prescribed ASM (more than 30%), and levetiracetam has replaced phenytoin as the second choice since 2015. Factors associated with the selection of newer ASMs for the first prescription were patients' year of diagnosis, gender, socioeconomic level, and previous or existing comorbidities and the profiles of the care providers (accreditation level, service volume, geographic location, and degree of urbanization of the surrounding area). CONCLUSION: The data indicated that the trends in ASMs first prescribed for patients in Taiwan accorded with most of the international epilepsy treatment guidelines. However, there were some differences between our results and those in developed countries. In addition, we observed a large urban-rural disparity in the administration of ASMs.

The effect of weather, air pollution and seasonality on the number of patient visits for epileptic seizures: A population-based time-series study.

OBJECTIVE: The objective of the study was to explore the influences of seasonality, meteorological conditions, and air pollution exposure on the number of patients who visit the hospital due to seizures. METHODS: Outpatient and inpatient data from the National Health Insurance Database of Taiwan from 2009 to 2013, meteorological data from the Meteorological Bureau, and air pollution exposure data from the Taiwan Air Quality Monitoring Stations were collected and integrated into daily time series data. The following data processing and analysis results are based on the mean of the 7 days' lag data of the 18 meteorological condition/air pollution exploratory factors to identify the critical meteorological conditions and air pollution exposure factors by executing univariate analysis. The average hospital visits for seizure per day by month were used as an index of observation. The effect of seasonality has also been examined. RESULTS: The average visits per day by month had a significant association with 10 variables. Overall, the number of visits due to these factors has been estimated to be 71.529 (13.7%). The most obvious factors affecting the estimated number of visits include ambient temperature, CH4, and NO. Six air pollutants, namely CH4, NO, CO, NO2, PM2.5, and NMHC had a significantly positive correlation with hospital visits due to seizures. Moreover, the average daily number of hospital visits was significantly high in January and February (winter season in Taiwan) than in other months (R2 = 0.422). CONCLUSION: The prediction model obtained in this study indicates the necessity of rigorous monitoring and early warning of these air pollutants and climate changes by governments. Additionally, the study provided a firm basis for establishing prediction models to be used by other countries or for other diseases.

The Association Between Parkinson's Disease and Attention-Deficit Hyperactivity Disorder.

While Parkinson's disease (PD) and attention-deficit hyperactivity disorder (ADHD) are two distinct conditions, it has been hypothesized that they share several overlapping anatomical and neurochemical changes. In order to investigate that hypothesis, this study used claims data from Taiwan's Longitudinal Health Insurance Database 2000 to provide the significant nationwide population-based evidence of an increased risk of PD among ADHD patients, and the connection between the two conditions was not the result of other comorbidities. Moreover, this study showed that the patients with PD were 2.8 times more likely to have a prior ADHD diagnosis compared with those without a prior history of ADHD. Furthermore, an animal model of ADHD was generated by neonatally injecting rats with 6-hydroxydopamine (6-OHDA). These rats were subjected to behavior tests and the 99mTc-TRODAT-1 brain imaging at the juvenile stage. Compared to control group rats, the 6-OHDA rats showed a significantly reduced specific uptake ratio in the striatum, indicating an underlying PD-linked pathology in the brains of these ADHD phenotype-expressing rats. Overall, these results support that ADHD shares a number of anatomical and neurochemical changes with PD. As such, improved knowledge of the neurochemical mechanisms underlying ADHD could result in improved treatments for various debilitating neurological disorders, including PD.

Impairment in dynein-mediated nuclear translocation by BICD2 C-terminal truncation leads to neuronal migration defect and human brain malformation.

During brain development, the nucleus of migrating neurons follows the centrosome and translocates into the leading process. Defects in these migratory events, which affect neuronal migration, cause lissencephaly and other neurodevelopmental disorders. However, the mechanism of nuclear translocation remains elusive. Using whole exome sequencing (WES), we identified a novel nonsense BICD2 variant p.(Lys775Ter) (K775X) from a lissencephaly patient. Interestingly, most BICD2 missense variants have been associated with human spinal muscular atrophy (SMA) without obvious brain malformations. By in utero electroporation, we showed that BicD2 knockdown in mouse embryos inhibited neuronal migration. Surprisingly, we observed severe blockage of neuronal migration in cells overexpressing K775X but not in those expressing wild-type BicD2 or SMA-associated missense variants. The centrosome of the mutant was, on average, positioned farther away from the nucleus, indicating a failure in nuclear translocation without affecting the centrosome movement. Furthermore, BicD2 localized at the nuclear envelope (NE) through its interaction with NE protein Nesprin-2. K775X variant disrupted this interaction and further interrupted the NE recruitment of BicD2 and dynein. Remarkably, fusion of BicD2-K775X with NE-localizing domain KASH resumed neuronal migration. Our results underscore impaired nuclear translocation during neuronal migration as an important pathomechanism of lissencephaly.

A propositional AI system for supporting epilepsy diagnosis based on the 2017 epilepsy classification: Illustrated by Dravet syndrome.

PURPOSE: The 2017 epilepsy and seizure diagnosis framework emphasizes epilepsy syndromes and the etiology-based approach. We developed a propositional artificial intelligence (AI) system based on the above concepts to support physicians in the diagnosis of epilepsy. METHODS: We analyzed and built ontology knowledge for the classification of seizure patterns, epilepsy, epilepsy syndrome, and etiologies. Protégé ontology tool was applied in this study. In order to enable the system to be close to the inferential thinking of clinical experts, we classified and constructed knowledge of other epilepsy-related knowledge, including comorbidities, epilepsy imitators, epilepsy descriptors, characteristic electroencephalography (EEG) findings, treatments, etc. We used the Ontology Web Language with Description Logic (OWL-DL) and Semantic Web Rule Language (SWRL) to design rules for expressing the relationship between these ontologies. RESULTS: Dravet syndrome was taken as an illustration for epilepsy syndromes implementation. We designed an interface for the physician to enter the various characteristics of the patients. Clinical data of an 18-year-old boy with epilepsy was applied to the AI system. Through SWRL and reasoning engine Drool's execution, we successfully demonstrate the process of differential diagnosis. CONCLUSION: We developed a propositional AI system by using the OWL-DL/SWRL approach to deal with the complexity of current epilepsy diagnosis. The experience of this system, centered on the clinical epilepsy syndromes, paves a path to construct an AI system for further complicated epilepsy diagnosis.

Structural damage and motion rhythm of the spine and hip during trunk lateral bending in ankylosing spondylitis patients with mild to moderate radiographic signs.

BACKGROUND: Ankylosing spondylitis causes structural damage and motion restriction in spine. The study was designed to assess structural damage and incoordination pattern between the spine and hip during trunk lateral bending in ankylosing spondylitis. METHODS: Twenty-three healthy adults and 39 adults with ankylosing spondylitis were recruited from a tertiary care medical centre. Patients with ankylosing spondylitis were divided into two subgroups: sacroiliitis or lumbar-level syndesmophytes (n = 27) and thoracic or cervical-level syndesmophytes (n = 12). An inertia motion system was used to record three-dimensional kinematic data during trunk lateral bending. FINDINGS: Significant differences were observed in lumbar spine syndesmophyte scores, sacroiliitis severity and Bath Ankylosing Spondylitis Metrology Index between the subgroups. The cervical supraspinous ligaments thickness revealed difference between the ankylosing spondylitis and control group, but the Glasgow Ultrasound Enthesitis Scoring System did not revealed difference. Motion analysis revealed that the ankylosing spondylitis group had a larger hip, cervical rotation and smaller lumbar-hip rhythm than the control group; however, the other motions of the spine and hip were smaller. The sacroiliitis or lumbar-level syndesmophytes group had the largest thoracic rotation among the three groups. INTERPRETATION: The different lumbar-hip rhythm between ankylosing spondylitis patients depends on syndesmophyte formation levels. Cervical rotation, the Schober test, the chest expansion test, and lumbar-hip rhythm can indicate the levels of bone damage in ankylosing spondylitis. Clinical examination of ankylosing spondylitis should include kinematic measures of both the spine and hips in the early disease stage.

Targeting Telomerase and ATRX/DAXX Inducing Tumor Senescence and Apoptosis in the Malignant Glioma.

Glioblastoma multiforme (GBM) is a type of brain tumor that is notorious for its aggressiveness and invasiveness, and the complete removal of GBM is still not possible, even with advanced diagnostic strategies and extensive therapeutic plans. Its dismal prognosis and short survival time after diagnosis make it a crucial public health issue. Understanding the molecular mechanisms underlying GBM may inspire novel and effective treatments against this type of cancer. At a molecular level, almost all tumor cells exhibit telomerase activity (TA), which is a major means by which they achieve immortalization. Further studies show that promoter mutations are associated with increased TA and stable telomere length. Moreover, some tumors and immortalized cells maintain their telomeres with a telomerase-independent mechanism termed the "alternative lengthening of telomeres" (ALT), which relates to the mutations of the α-thalassemia/mental retardation syndrome X-linked protein (ATRX), the death-domain associated protein (DAXX) and H3.3. By means of the mutations of the telomerase reverse transcriptase (TERT) promoter and ATRX/DAXX, cancers can immortalize and escape cell senescence and apoptosis. In this article, we review the evidence for triggering GBM cell death by targeting telomerase and the ALT pathway, with an extra focus on a plant-derived compound, butylidene phthalide (BP), which may be a promising novel anticancer compound with good potential for clinical applications.

Prolonged length of stay for acute hospital admissions as the increasing of age: A nationwide population study for Taiwan's patients with cerebral palsy.

BACKGROUND: Studies investigating reasons for the admission and the associated lengths of stay (LOSs) among cerebral palsy (CP) patients are limited. This study determined common reasons for acute hospitalizations and the LOSs among children, adolescents, and young adults with CP. METHODS: We performed a secondary analysis of data. CP patients aged 4-32.9 years were identified by CP registry in the catastrophic illness patient registry of the 2010 Taiwan National Health Insurance Research Database. Data of admission claims from 2010 to 2011 were analyzed. Reasons for admissions were identified according to International Classification of Diseases codes. Common reasons, frequencies of admissions for each reason, and LOSs were reported. RESULTS: Pneumonia, other respiratory problems, and epilepsy were the top three reasons for admissions in all groups. Other common reasons in all groups were sepsis, other respiratory infections, and gastrointestinal problems. The reasons specific to children included orthopedic issues; ear, nose, and throat problems; and urinary tract infections (UTIs). In youths, scoliosis, and contractures, were unique reasons. In young adults, UTIs, blood problems, and mental illness, were special reasons. Most admission reasons appeared to prolong LOS, and the LOS exhibited an increasing trend as age increased. CONCLUSION: The results implied that patients with CP are more susceptible to most disease invasions. Our results also suggest that the current care system in Taiwan is unsuitable for patients with CP. These results can be used as guidance for planning effective multidisciplinary assessments in the future.

Prevalence and demographic characteristics of comorbid epilepsy in children and adolescents with cerebral palsy: a nationwide population-based study.

INTRODUCTION: The nationwide prevalence of cerebral palsy (CP) is unknown due to the lack of a population-based registration system for CP in Taiwan. This study was the largest nationwide, population-based, cross-sectional study to estimate the prevalence of CP, prevalence rates of comorbid epilepsy in patients with CP, and association with socioeconomic status (SES) in Taiwan. The crude prevalence rate and age- and gender-specific prevalence rates were estimated. METHODS: A total of 8419 patients with CP were enrolled, and the estimated prevalence of CP was 1.76‰ in the pediatric population and 1.51‰ and 1.98‰ in girls and boys, respectively. The prevalence rate of epilepsy in patients with CP was 29.8%. RESULTS: The result revealed a higher prevalence of CP and epileptic CP in members of families with lower insurance premiums than those with higher insurance premiums and those from East Taiwan compared with those from other areas of Taiwan. Moreover, a higher prevalence of CP is shown in rural area than urban area. DISCUSSION: SES and geographic variables were significantly associated with the risk of epilepsy in children with CP. Patients with epileptic CP had a higher odds ratio of several neuropsychiatric diseases, including mental retardation, ophthalmologic problems, hearing impairment, and hydrocephalus.

Association of epilepsy and asthma: a population-based retrospective cohort study.

BACKGROUND: Epidemiologic data supporting the epilepsy-asthma association are insufficient. Therefore, we examined this association in this study. METHODS: By using claims data from the National Health Insurance Research Database (Taiwan), we executed a retrospective cohort analysis. Analysis 1 entailed comparing 150,827 patients diagnosed as having incident asthma during 1996-2013 with disease-free controls who were selected randomly during the same period, frequency matched in terms of age and sex. Similarly, analysis 2 entailed comparing 25,274 patients newly diagnosed as having epilepsy with sex- and age-matched controls who were selected randomly. At the end of 2013, we evaluated in analysis 1 the epilepsy incidence and risk and evaluated in analysis 2 the asthma incidence and risk. We applied Kaplan-Meier analysis to derive plots of the proportion of asthma-free seizures. RESULTS: In analysis 1, the asthma group exhibited a higher epilepsy incidence than did the control group (3.05 versus 2.26 per 1,000 person-years; adjusted hazard ratio: 1.39, 95% CI [1.33-1.45]). We also noted a greater risk of subsequent epilepsy in women and girls. In analysis 2, we determined that the asthma incidence between the control and epilepsy groups did not differ significantly; however, some age subgroups including children and individuals in their 30s had an increased risk. A negative association was found in adolescents. The Kaplan-Meier analysis revealed epilepsy to be positively associated with subsequent onset of asthma within seven years of epilepsy diagnosis. DISCUSSION: Asthma may be associated with high epilepsy risk, and epilepsy may be associated with high asthma risk among children and individuals in their 30s. Nevertheless, people with epilepsy in other age subgroups should be aware of the possibility of developing asthma within seven years of epilepsy diagnosis.

Intermittent Demand Forecasting in a Tertiary Pediatric Intensive Care Unit.

Forecasts of the demand for medical supplies both directly and indirectly affect the operating costs and the quality of the care provided by health care institutions. Specifically, overestimating demand induces an inventory surplus, whereas underestimating demand possibly compromises patient safety. Uncertainty in forecasting the consumption of medical supplies generates intermittent demand events. The intermittent demand patterns for medical supplies are generally classified as lumpy, erratic, smooth, and slow-moving demand. This study was conducted with the purpose of advancing a tertiary pediatric intensive care unit's efforts to achieve a high level of accuracy in its forecasting of the demand for medical supplies. On this point, several demand forecasting methods were compared in terms of the forecast accuracy of each. The results confirm that applying Croston's method combined with a single exponential smoothing method yields the most accurate results for forecasting lumpy, erratic, and slow-moving demand, whereas the Simple Moving Average (SMA) method is the most suitable for forecasting smooth demand. In addition, when the classification of demand consumption patterns were combined with the demand forecasting models, the forecasting errors were minimized, indicating that this classification framework can play a role in improving patient safety and reducing inventory management costs in health care institutions.

Current proceedings of cerebral palsy.

Cerebral palsy (CP) is a complicated disease with varying causes and outcomes. It has created significant burden to both affected families and societies, not to mention the quality of life of the patients themselves. There is no cure for the disease; therefore, development of effective therapeutic strategies is in great demand. Recent advances in regenerative medicine suggest that the transplantation of stem cells, including embryonic stem cells, neural stem cells, bone marrow mesenchymal stem cells, induced pluripotent stem cells, umbilical cord blood cells, and human embryonic germ cells, focusing on the root of the problem, may provide the possibility of developing a complete cure in treating CP. However, safety is the first factor to be considered because some stem cells may cause tumorigenesis. Additionally, more preclinical and clinical studies are needed to determine the type of cells, route of delivery, cell dose, timing of transplantation, and combinatorial strategies to achieve an optimal outcome.