Feasibility of mobile phone application "Epilepsy care" for self-management of children and adolescents with epilepsy in Phramongkutklao hospital: A randomized controlled trial.

Epilepsy is a common neurological disorder in children. Mobile applications have shown potential in improving self-management for patients with chronic illnesses. To address language barriers, we developed the first Thai version of the "Epilepsy care" mobile application for children and adolescents with epilepsy in Thailand. A prospective, randomized controlled trial with 220 children and adolescents living with epilepsy who had a smartphone and were treated at the pediatric neurology clinic was conducted, with one group using the mobile application and the other receiving standard epilepsy guidance. The primary outcome assessed epilepsy self-management using the Pediatric Epilepsy Self-Management Questionnaire (PEMSQ) in the Thai version, which comprised 27 questions. These questions aimed to determine knowledge, adherence to medications, beliefs about medication efficacy, and barriers to medication adherence. The secondary outcome evaluated seizure frequency at baseline, 3, and 6 months after initiation of an application. Eighty-five participants who were randomized to a mobile application achieved significantly higher PEMSQ scores in the domain of barriers to medication adherence (p < 0.05) at 6 months follow-up. Other domains of PEMSQ showed no statistically significant difference. Baseline median seizure frequencies per month were 7 in the control group and 5.5 in the intervention group. At 3 and 6 months, these decreased significantly to 1.5 and 1 for the control group and 2.5 and 1 for the intervention group (p < 0.001). In addition, the study revealed that 94.9 % of the participants in a mobile application group were highly satisfied with using application. These findings suggest that the mobile application "Epilepsy care" may serve as an effective adjunctive therapy to enhance self-management and seizure control in children and adolescents with epilepsy.

Efficacy of oral perampanel in status epilepticus and acute repetitive seizures in children at a tertiary care hospital in Thailand.

Status epilepticus (SE) and acute repetitive seizure (ARS) are emergency conditions associated with significant morbidity and mortality in children. Anti-seizure medications (ASMs) need to terminate seizures to prevent brain damage and death. Common challenges that delay the management of SE and ARS in children at Phramongkutklao hospital are difficulty in accessing intravenous route for drug administration and inadequate number of intensive care units (which will be required in case of the use of adverse events to anesthetic ASMs). Oral, non-sedating ASMs could be a potential option to terminate seizures effectively in SE and ARS in children and further studies in this aspect are needed. We performed a prospective, descriptive study in children with SE or ARS < 18 years of age who had contraindication to or their seizures were refractory to the second-line ASMs after benzodiazepine and received oral perampanel. Demographic data, efficacy, and adverse effects of treatment were recorded. Fifteen patients with SE (13.3%) and acute repetitive seizure (86.6%) were enrolled. All patients received an oral perampanel loading dose and the maintenance dose depended on their body weight. The average loading and maintenance dose were 0.24 mg/kg/dose and 0.12 mg/kg/day, respectively. At 48 h after administration of loading dose of perampanel, eight of fifteen patients (53.3%) became seizure free, one patient had seizure reduction of >75% from baseline, and three patients had seizure reduction of 25-50% from baseline. No serious side effects were observed. These results indicate that oral perampanel may be potential treatment option for SE and ARS in children.

Hypovitaminosis D and risk factors in pediatric epilepsy children.

BACKGROUND: Anti-seizure medication (ASM) treatment is one of the significant risk factors associated with abnormal vitamin D status in epilepsy patients. Multiple studies have shown that adult epilepsy patients can exhibit vitamin D deficiency. However, there are few reports investigating pediatric epilepsy patients. In this study, we aimed to identify risk factors related to hypovitaminosis D in pediatric epilepsy patients in Thailand. METHODS: A cross-sectional retrospective cohort study was conducted in 138 pediatric epilepsy patients who received anticonvulsants from April 2018 to January 2019. Demographic data, seizure types, puberty status, physical activity, duration, and types of anti-seizure medications were analyzed. Patients with abnormal liver function, abnormal renal function, and who received vitamin D supplements or ketogenic diet containing vitamin D were excluded. Levels of serum vitamin D (25(OH)D) were measured. RESULTS: All 138 subjects were enrolled, the age ranged from 1.04 - 19.96 years; (mean = 9.65 ± 5.09), the mean serum 25(OH) D level was 26.56 ± 9.67 ng/ml. The prevalence of vitamin D deficiency was 23.2% and insufficiency was 47.8% respectively. Two risk factors-puberty status (OR 5.43, 95% CI 1.879-15.67) and non-enzyme-inhibiting ASMs therapy (OR 3.58, 95% CI 1.117-11.46)-were significantly associated with hypovitaminosis D, as shown by multivariate analyses. CONCLUSIONS: Our study reports the high prevalence of hypovitaminosis D in pediatric epilepsy patients in Thailand despite being located in the tropical zone. These findings can guide clinicians to measure vitamin D status in pediatric epilepsy patients particularly when they reach puberty and/or are using non-enzyme-inhibiting ASMs therapy. Early detection of vitamin D status and prompt vitamin D supplementation can prevent fractures and osteoporosis later in life. TRIAL REGISTRATION: TCTR20210215005 ( http://www.clinicaltrials.in.th/ ).

A post hoc analysis of the long-term safety and efficacy of perampanel in Asian patients with epilepsy.

This post hoc analysis assessed the long-term safety, tolerability, and efficacy of perampanel in Asian patients with refractory focal seizures; an additional analysis assessed the effect of perampanel on focal impaired awareness seizures (FIAS) with focal to bilateral tonic-clonic (FBTC) seizures. In this subanalysis, data from Asian patients ≥12 years of age who had focal seizures with FBTC seizures despite taking one to 3 concomitant antiepileptic drugs at baseline, and who had entered either the long-term extension phase of 3 phase-3 perampanel trials (study 307) or the 10-week extension phase of study 335, were analyzed for the effect of perampanel on duration of exposure, safety, and seizure outcomes. Of 874 Asian patients included in the analysis, 205 had previously received placebo during the double-blind phase-3 trials and 669 had previously received perampanel 2-12 mg/day; 313 had FIAS with FBTC seizures at core study baseline. The median duration of exposure to perampanel was 385.0 days, and the retention rate at one year was 62.6%. Overall, during the first 52 weeks of perampanel treatment, 777 patients (88.9%) had treatment-emergent adverse events (TEAEs), most of which were mild to moderate in severity. The most frequent TEAEs were dizziness (47.1%), somnolence (22.3%), and nasopharyngitis (17.4%). During the first 52 weeks of perampanel treatment, median percent change in seizure frequency per 28 days from pre-perampanel baseline for all focal seizures was -28.1%, and -51.7% for FIAS with FBTC seizures. The 50% responder rate relative to pre-perampanel baseline for all focal seizures was 33.8%, and 51.1% for FIAS with FBTC seizures. Long-term treatment with perampanel in Asian patients had safety, tolerability, and efficacy similar to that of the global population in the phase-3 trials and extension study 307. The safety profile and response rate suggest benefit for an Asian population of patients with refractory epilepsy.

Case series: the paradox of epilepsy surgery and psychiatric disorder.

De novo psychiatric disorder following epilepsy surgery is an infrequent but very interesting phenomenon. The authors described 4 distinct cases with medically intractable epilepsy who had epilepsy surgery and developed postsurgical psychiatric disorder. The onset of psychiatric disorder was during dramatic improvement of their epilepsy after surgery. There was no history of psychiatric disorder in their familial members or in the patients prior to the surgery. Since three patients also had mental retardation, presurgical cognitive impairment may be one of the risk factors for developing postsurgical psychiatric disorder. Potential mechanisms include volume reduction of gray matter in frontal, temporal and parietal cortexes secondary to epilepsy surgery as well as forced normalization. Several other mechanisms may also play important role for this phenomenon and further studies will be required which may reveal the connection between these two aspects.

Survey of local cannabidiol use in parents of children with epilepsy in Thailand: the prevalence, perceptions, and knowledge.

BACKGROUND: In 2019, Thailand legalized cannabidiol (CBD) for intractable epilepsy. The purpose of this study was to collect information regarding the experience and knowledge of CBD use in pediatric epilepsy. To the best of our knowledge, this is the first CBD survey in pediatric epilepsy in Southeast Asia. METHOD: We performed a cross-sectional survey among all parents of pediatric epilepsy patients seen in the Pediatric Neurology Clinic at Phramongkutklao Hospital, Bangkok, Thailand between November 2018 and July 2020. The survey comprised 34 questions that assessed the demographics, knowledge, experiences, and opinions of parents/guardians regarding CBD use. The results were summarized using descriptive statistics. In addition, logistic regression was used to predict the factors for CBD use. RESULTS: Overall, 166 respondents (100%) participated in the study. Among the respondents, 9% have experienced using CBD; 56.25% of these reported reduced seizure frequency. CBD products were mostly obtained from folk healers (31.25%) and foreign products (25%). Common adverse effects included headache and nausea (31.5%). The number of anti-seizure medications (OR: 12.28, 95% CI: 1.27-118.8), knowledge of CBD as treatment for epilepsy (OR: 14.7, 95% CI: 1.43-150.87), and knowledge of CBD side effects (OR: 12.73, 95% CI: 2.77-58.43) were factors significantly associated with CBD use. Regarding CBD knowledge, our survey showed 80.72% of the respondents did not know the CBD compound for treating epilepsy, and 89.16% were not aware of CBD side effects. Interestingly, despite a lack of knowledge, 77.11% of the respondents expressed willingness to participate in future CBD trials. CONCLUSION: Our survey highlights that half of the parents of patients who previously used CBD reported reduced seizure frequency; however, none became seizure-free. Additionally, there were gaps in knowledge regarding the use of CBD. These findings suggest that the implementation of cannabidiol knowledge is crucial for both public and healthcare professionals. Survey limitations due to the retrospective nature of the self-report could have resulted in recall bias.

Standard and high dose ergocalciferol regimens for treatment of hypovitaminosis D in epileptic children and adolescents.

OBJECTIVES: Children with epilepsy are at increased risk of vitamin D deficiency. We aimed to compare the effect of two ergocalciferol regimens given for 90 days. METHODS: Epileptic patients aged 5-18 years who received at least one antiepileptic drug (AED) for more than 6 months and had serum 25-OHD <30 ng/mL were randomized to receive 20,000 IU/10 d (standard dose, n=41) or 60,000 IU/10 d (high dose, n=41) of oral ergocalciferol. Serum Ca, P, Mg, ALP, iPTH and urine Ca/Cr ratio were measured at baseline and after 90 days of treatment. Change in serum 25-OHD and vitamin D status after treatment was evaluated. RESULTS: The initial serum 25-OHD in the standard dose and high dose group was 19.5 ± 4.9 and 18.4 ± 4.6 ng/mL, respectively. Serum 25-OHD after treatment was significantly higher in the high dose group (39.0 ± 11.5 vs. 27.5 ± 8.6 ng/mL, p<0.05). The average increase in serum 25-OHD in the high dose and standard dose group was 20.6 ± 11.4 and 7.2 ± 7.5 ng/mL, respectively (p<0.05). Normalized serum 25-OHD was achieved in 80.5% of the high dose group compared to 36.6% of the standard dose group (p<0.05). No adverse events were found. Patients with a BMI Z-score>0 had a 2.5 times greater risk of continued hypovitaminosis D after treatment compared to those with a BMI Z-score<0 (95% CI: 1.0-5.9, p<0.05). CONCLUSIONS: Oral ergocalciferol 60,000 IU/10 d for 90 days was more effective at normalizing serum 25-OHD than 20,000 IU/10 d in epileptic children and adolescents who were receiving AEDs.

Perampanel as adjunctive therapy in drug resistant epilepsy in adolescents and children waiting for epilepsy surgery: A multicenter observational study in Thailand.

PURPOSE: To evaluate the effectiveness and tolerability of perampanel (PER) in real-world settings in patients between 1 month and 18 years of age with drug resistant epilepsy (DRE) waiting for epilepsy surgery. METHODS: In this multicenter study, patients between 1 month and 18 years of age with DRE treated with PER between January 2020 and June 2021 were selected. The study outcome was effectiveness of PER treatment reported as reduction in seizure frequency and seizure freedom rate. Effectiveness was assessed at 30, 60, 90, 120, 150 and 180 days after initiation of PER. Tolerability profiles were reported as adverse events according to the observations of the patients' family members and physician. RESULTS: Eighty-five patients treated with PER were included in the study. The mean initial dose and mean maximum dose of adjunctive PER was 2 mg/day and 5.8 mg/day, respectively. The mean seizure frequency (rate/week) was 41.3, 25.4, 18.9, 14.3, 11.2, 11.1 and 8.9 seizures at baseline, 30, 60, 90, 120, 150 and 180 days, respectively; the reduction in the mean seizure frequency at all timepoints was significant compared at the baseline (p<0.001). At 180 days, ≥75% seizure reduction was seen in 64.9% (37/57) of the patients and seizure freedom was achieved in 36.8% (21/57). Drowsiness, ataxia, and behavioral changes were the common adverse events observed, and these improved after the dose of PER was reduced. No discontinuation of PER was required due to side effects or intolerance. CONCLUSION: In real-world settings, PER is well tolerated and effective in seizure control in pediatric and adolescent patients with DRE.

Effectiveness and Adverse Effect of Intravenous Lacosamide in Nonconvulsive Status Epilepticus and Acute Repetitive Seizures in Children.

Nonconvulsive status epilepticus (NCSE) and acute repetitive seizures (ARS) are associated with significant morbidity and mortality. Due to the lack of randomized-controlled trials of intravenous antiepileptic drugs (AEDs) in these conditions, trials of a new generation of AEDs in this aspect are needed. A prospective interventional study was conducted in children under 18 years of age with NCSE or ARS who either had contraindication to or were refractory to first-line AEDs and received intravenous lacosamide. Demographic data, the efficacy of treatment, and adverse effects were recorded. Eleven patients with a median age of 11 years, predominantly female (72.7%), were enrolled. Average loading dose was 227 mg (8.3 mg/kg/dose) and average daily maintenance dose was 249 mg (4.6 mg/kg/dose). All patients (100%) experienced a reduction in seizure frequency within 24 hours. Eight of eleven patients (72.7%) experienced a reduction in seizure frequency of more than 50% by the end of the study, and one patient became seizure-free. In terms of adverse events, one patient had a bradycardia without prolongation of the PR interval. Interestingly, there was a case of neuronal ceroid lipofuscinosis in which a significant improvement in seizure control was achieved. The results indicate that intravenous lacosamide may be an alternative treatment for NCSE or ARS in children. To our knowledge, this is the first study on the use of intravenous lacosamide in Asian children. This study is registered to Thai Clinical Trials Registry (TCTR) and the trial registration number is TCTR20180508004.

Pharmacokinetics, exposure-cognition, and exposure-efficacy relationships of perampanel in adolescents with inadequately controlled partial-onset seizures.

OBJECTIVE: To characterize, in adolescents aged 12-17, the pharmacokinetic (PK) profile of perampanel, the impact of intrinsic and extrinsic factors on PK, and the relationships between perampanel exposure and cognitive function, seizure frequency, and responder status. METHODS: Population PK analysis used plasma concentration data from Phase II study 235 (NCT01161524), in which adolescents with inadequately controlled POS despite treatment with 1-3 antiepileptic drugs (AEDs) were randomized to receive once daily oral placebo or perampanel (8-12mg/day) for 19 weeks, pooled with data from adolescent patients in perampanel Phase III studies 304, 305, 306. Exposure-cognition and exposure-efficacy relationships were modelled using data from study 235. RESULTS: Population PK results from 152 adolescent patients revealed a perampanel apparent clearance of 0.729L/h, consistent with previous analyses in adolescents and adults. Clearance was increased with coadministration of inducing AEDs (carbamazepine, oxcarbazepine and phenytoin), and was slightly higher in females. The PK/pharmacodynamics (PD) analysis for cognition (n=110) showed that increasing perampanel exposure had no significant effect on overall cognition, measured by the Cognitive Drug Research global cognition score. The PK/PD analysis for efficacy (n=123) showed a significant decrease in seizure frequency and significant increased probability of being a responder, as perampanel concentration increased - both in the presence and absence of inducing AEDs. Carbamazepine, oxcarbazepine and phenytoin reduced perampanel exposure in adolescents, but reduced the magnitude of seizure frequency reduction and responder probability to a lesser extent. SIGNIFICANCE: Pharmacokinetics of perampanel are similar in adolescents to adults. Increasing perampanel exposure reduces seizure frequency and increases probability of being a responder regardless of concomitant inducers. The lack of relationship between perampanel exposure and cognitive function suggests a benign cognitive profile for this AED in adolescents. We await results from long-term exposure.

Review of clinical studies of perampanel in adolescent patients.

AIM: To assess the clinical trial and real-world data for adjunctive perampanel in adolescents and develop consensus recommendations to guide the use of perampanel in this population in clinical practice. METHODS: In May 2015, 15 epilepsy experts attended a Consensus Development Meeting to assess the clinical trial data for perampanel, specific to the adolescent age group (12-17 years) and develop consensus treatment recommendations. RESULTS AND DISCUSSION: Analysis of the adolescent subgroup data of three pivotal placebo-controlled, double-blind, phase 3 trials investigating perampanel in patients with ongoing focal epileptic seizures despite receiving one to three antiepileptic drugs found that perampanel 4-12 mg was superior to placebo. The tolerability profile of perampanel was generally acceptable. Adolescent patients receiving long-term treatment with perampanel in an open-label extension study maintained improvements in seizure control compared with baseline, with a favorable risk-benefit profile. A phase 2 study showed that perampanel had no clinically important effects on cognitive function, growth, and development. CONCLUSION: Perampanel is a welcome addition to the armamentarium of existing antiepileptic drugs as it represents a new approach in the management of epilepsy, with a novel mechanism of action, and the potential to have a considerable impact on the treatment of adolescents with epilepsy.

Epilepsy surgery in children and adolescence; Phramongkutklao College of Medicine's experience.

OBJECTIVES: To evaluate the safety and efficacy of epilepsy surgery in children and adolescence at Comprehensive Epilepsy Center, Phramongkutklao College of Medicine. MATERIAL AND METHOD: Children and adolescents, who underwent epilepsy surgery at Comprehensive Epilepsy Center, Phramongkutklao College of Medicine were identified from the epilepsy surgery database. The following parameters were evaluated: age at surgery, duration of seizure prior to surgery, presurgical work up, presurgical as well as postsurgical neurological/ seizure status and neuropathology (if applicable). All follow-up data were obtained through clinic visits. RESULTS: Fifteen children who underwent epilepsy surgery between January 1, 2003 and March 31, 2005 were identified. Age at surgery ranged from 2.5 years to 19 years (mean age=8.2 years). Seizure duration prior to surgery ranged from 1 year to 17 years (mean=4.7 years). Eight patients (53%) had partial seizures and underwent excisional procedures [5 temporal lobectomy, 2 left frontal corticectomy, and 1 left functional hemispherectomy]. Seven patients (47%) had generalized seizures and underwent anterior 2/3 corpus callosotomy. Pathological information was available for all 8 cases with partial epilepsy. Four out of eight cases with pathological information demonstrated cortical dysplasia, four revealed hippocampal sclerosis, and two patients had dysembryoplastic neuroepithelial tumor (DNET). At follow-up, all 5 patients with temporal lobectomy and a child who underwent functional hemispherectomy were seizure free (follow up period 3-31 months). Two children with extratemporal resective surgery [left frontal corticectomy] showed remarkable improvement with rare breakthrough seizures (follow up period= 3 and 19 months respectively). Four out of seven patients with corpus collosotomy had worthwhile improvement of seizures (follow up period=4-19 months), while another two children were seizure free during short-termed follow up postoperatively (follow up period=1 and 2 months). All patients did not have significant neurological deterioration or worsening of seizure after the surgery. CONCLUSION: Resective epilepsy surgery in Thai pediatric populations in the authors' experience seems to be safe and effective in selected patients. Most children who underwent callosotomy had a significant reduction in intensity and frequency of tonic, atonic, and tonic-clonic seizures. Dual pathology was common in refractory temporal lobe epilepsy with hippocampal sclerosis. Although the study sample was small, it did advocate several larger studies with the same findings.