Predictors of Seizure Recurrence in Women With Idiopathic Generalized Epilepsy Who Switch From Valproate to Another Medication.

BACKGROUND AND OBJECTIVES: To investigate the predictors of seizure recurrence in women of childbearing age with idiopathic generalized epilepsy (IGE) who switched from valproate (VPA) to alternative antiseizure medications (ASMs) and compare the effectiveness of levetiracetam (LEV) and lamotrigine (LTG) as VPA alternatives after switch. METHODS: This multicenter retrospective study included women of childbearing age diagnosed with IGE from 16 epilepsy centers. Study outcomes included worsening or recurrence of generalized tonic-clonic seizure (GTCS) at 12 months and 24 months after the switch from VPA to an alternative ASM. The comparative effectiveness of LEV and LTG as alternative ASM following VPA discontinuation was assessed through inverse probability treatment-weighted (IPTW) Cox regression analysis. RESULTS: We included 426 women with IGE, with a median (interquartile range) age at VPA switch of 24 (19-30) years and a median VPA dosage of 750 (500-1,000) mg/d. The most common reason for VPA switch was teratogenicity concern in 249 women (58.6%), and the most common ASM used in place of VPA was LEV in 197 (46.2%) cases, followed by LTG in 140 (32.9%). GTCS worsening/recurrence occurred in 105 (24.6%) and 139 (32.6%) women at 12 and 24 months, respectively. Catamenial worsening of seizures, higher VPA dosage during switch, multiple seizure types, and shorter duration of GTCS freedom before switch were independent predictors of GTCS recurrence or worsening at 12 months according to mixed multivariable logistic regression analysis. After internal-external validation through 16 independent cohorts, the model showed an area under the curve of 0.71 (95% CI 0.64-0.77). In the subgroup of 337 women who switched to LEV or LTG, IPTW Cox regression analysis showed that LEV was associated with a reduced risk of GTCS worsening or recurrence compared with LTG (adjusted hazard ratio 0.59, 95% CI 0.40-0.87, p = 0.008) during the 24-month follow-up. DISCUSSION: Our findings can have practical implications for optimizing counselling and treatment choices in women of childbearing age with IGE and may help clinicians in making informed treatment decisions in this special population of patients. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that for women with IGE switching from VPA, LEV was associated with a reduced risk of GTCS worsening or recurrence compared with LTG.

Total valproate versus free valproate in therapeutic drug monitoring for bipolar disorder: A cross-sectional study.

INTRODUCTION: The debate about observing total versus free serum valproate levels for therapeutic drug monitoring (TDM) has been unresolved for decades. This study was planned to assess the agreement between the total versus free valproate levels and the advantage of one method over the other in TDM. METHODS: The present cross-sectional study was done on 93 patients with bipolar disorder. The intraclass correlation coefficient, Bland Altman analysis, and Lin's concordance analysis were done to assess the agreement between the total and free valproate concentrations. Linear and polynomial models were constructed to evaluate the relation between the two measurements. Receiver operating characteristics analysis was done to compare the accuracy for differentiating remission from non-remission on Young's mania rating scale (YMRS). RESULTS: The intraclass correlation coefficient and Lin's concordance correlation coefficient were 0.491 (p = .002) and 0.055 (95% CI:0.037, 0.073), respectively. Bland Altman's analysis showed proportional bias. A polynomial model of second order was found to be the best fit for the prediction of free valproate from the data for total valproate, and 81.4% of the variability in free valproate could be explained when adjusted for albumin levels. The area under the curve for total valproate was 0.60 when compared to free valproate 0.56 for differentiating between remission and non-remission, but the comparison between the two ROC analyses was not statistically significant. CONCLUSION: Free valproate does not provide any added advantage over the total valproate levels; hence, total valproate levels may continue to be used as the marker for drug monitoring.

Social Behavior in Animal Models of Autism Spectrum Disorder.

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder characterized by social deficits and stereotyped, repetitive patterns of behaviors, limited interests, and cognitive impairment. Especially, social deficit has been considered a core feature of ASD. Because of the limitations of the experimental approach in humans, valid animal models are essential in an effort to identify novel therapeutics for social deficits in ASD. The genetic and environmental factors are clinically relevant to the pathophysiology of ASD. Epidemiological studies demonstrate environmental interventions such as prenatal exposure to valproic acid (VPA). Prenatal exposure to VPA represents a robust model of ASD exhibiting face, construct, and predictive validity. Here, we introduce protocols of the social interaction test and the three-chamber test for evaluating social deficits in mice prenatally exposed to VPA.

Status epilepticus: what's new for the intensivist.

PURPOSE OF REVIEW: Status epilepticus (SE) is a common neurologic emergency affecting about 36.1/100 000 person-years that frequently requires intensive care unit (ICU) admission. There have been advances in our understanding of epidemiology, pathophysiology, and EEG monitoring of SE, and there have been large-scale treatment trials, discussed in this review. RECENT FINDINGS: Recent changes in the definitions of SE have helped guide management protocols and we have much better predictors of outcome. Observational studies have confirmed the efficacy of benzodiazepines and large treatment trials indicate that all routinely used second line treatments (i.e., levetiracetam, valproate and fosphenytoin) are equally effective. Better understanding of the pathophysiology has indicated that nonanti-seizure medications aimed at underlying pathological processes should perhaps be considered in the treatment of SE; already immunosuppressant treatments are being more widely used in particular for new onset refractory status epilepticus (NORSE) and Febrile infection-related epilepsy syndrome (FIRES) that sometimes revealed autoimmune or paraneoplastic encephalitis. Growing evidence for ICU EEG monitoring and major advances in automated analysis of the EEG could help intensivist to assess the control of electrographic seizures. SUMMARY: Research into the morbi-mortality of SE has highlighted the potential devastating effects of this condition, emphasizing the need for rapid and aggressive treatment, with particular attention to cardiorespiratory and neurological complications. Although we now have a good evidence-base for the initial status epilepticus management, the best treatments for the later stages are still unclear and clinical trials of potentially disease-modifying therapies are long overdue.

Fourteen-year trends in prescribing patterns for patients with bipolar mania discharged from a public psychiatric hospital in Taiwan.

Bipolar disorder is a complex mental illness. Pharmacological therapy, including antipsychotics and mood stabilizers, is the primary treatment approach for manic episode. The study aimed to analyze prescribing patterns over a 14-year period for patients with bipolar mania discharged from a psychiatric hospital in Taiwan. Patients with bipolar mania discharged from the study hospital between 2006 and 2019 (n = 2956) were included in the analysis. Prescribed drugs for the treatment of manic episode, included mood stabilizers (i.e., lithium, valproate, carbamazepine) and any antipsychotics (i.e., second- and first-generation antipsychotics; SGAs & FGAs). Monotherapy, simple polypharmacy, and complex polypharmacy were also examined. Simple polypharmacy was defined as being prescribed 2 different bipolar drugs (lithium, valproate, carbamazepine, and any antipsychotics), while complex polypharmacy at least 3 bipolar drugs. Temporal trends of each prescribing pattern were analyzed using the Cochran-Armitage Trend test. The prescription rates of valproate, SGAs, and complex polypharmacy significantly increased over time, whereas the prescription rates of any mood stabilizers, FGAs, and simple polypharmacy significantly decreased. Prescription rates of lithium and monotherapy did not significantly change. The study highlights the shifts in prescribing practices for bipolar mania. SGAs were prescribed more while FGAs declined, likely due to SGAs' favorable properties. Complex polypharmacy increased, reflecting the complexity of treating bipolar disorder. Long-term outcomes of these changes require further research.

Risk of Autism after Prenatal Topiramate, Valproate, or Lamotrigine Exposure.

BACKGROUND: Maternal use of valproate during pregnancy has been associated with an increased risk of neurodevelopmental disorders in children. Although most studies of other antiseizure medications have not shown increased risks of these disorders, there are limited and conflicting data regarding the risk of autism spectrum disorder associated with maternal topiramate use. METHODS: We identified a population-based cohort of pregnant women and their children within two health care utilization databases in the United States, with data from 2000 through 2020. Exposure to specific antiseizure medications was defined on the basis of prescription fills from gestational week 19 until delivery. Children who had been exposed to topiramate during the second half of pregnancy were compared with those unexposed to any antiseizure medication during pregnancy with respect to the risk of autism spectrum disorder. Valproate was used as a positive control, and lamotrigine was used as a negative control. RESULTS: The estimated cumulative incidence of autism spectrum disorder at 8 years of age was 1.9% for the full population of children who had not been exposed to antiseizure medication (4,199,796 children). With restriction to children born to mothers with epilepsy, the incidence was 4.2% with no exposure to antiseizure medication (8815 children), 6.2% with exposure to topiramate (1030 children), 10.5% with exposure to valproate (800 children), and 4.1% with exposure to lamotrigine (4205 children). Propensity score-adjusted hazard ratios in a comparison with no exposure to antiseizure medication were 0.96 (95% confidence interval [CI], 0.56 to 1.65) for exposure to topiramate, 2.67 (95% CI, 1.69 to 4.20) for exposure to valproate, and 1.00 (95% CI, 0.69 to 1.46) for exposure to lamotrigine. CONCLUSIONS: The incidence of autism spectrum disorder was higher among children prenatally exposed to the studied antiseizure medications than in the general population. However, after adjustment for indication and other confounders, the association was substantially attenuated for topiramate and lamotrigine, whereas an increased risk remained for valproate. (Funded by the National Institute of Mental Health.).

Sodium valproate treatment reverses endothelial dysfunction in aorta from rabbits with acute myocardial infarction.

Sodium valproate (VPA), a histone deacetylase (HDAC) inhibitor, could be a promising candidate to treat acute myocardial infarction (AMI). In this study, AMI was induced in New Zealand White rabbits by occluding the left circumflex coronary artery for 1 h, followed by reperfusion. The animals were distributed into three experimental groups: the sham-operated group (SHAM), the AMI group and the AMI + VPA group (AMI treated with VPA 500 mg/kg/day). After 5 weeks, abdominal aorta was removed and used for isometric recording of tension in organ baths or protein expression by Western blot, and plasma for the determination of nitrate/nitrite (NOx) levels by colorimetric assay. Our results indicated that AMI induced a reduction of the endothelium-dependent response to acetylcholine without modifying the endothelium-independent response to sodium nitroprusside, leading to endothelial dysfunction. VPA treatment reversed AMI-induced endothelial dysfunction and even increased NO sensitivity in vascular smooth muscle. This response was consistent with an antioxidant effect of VPA, as it was able to reverse the superoxide dismutase 1 (SOD 1) down-regulation induced by AMI. Our experiments also ruled out that the VPA mechanism was related to eNOS, iNOS, sGC and arginase expression or changes in NOx plasma levels. Therefore, we conclude that VPA improves vasodilation by increasing NO bioavailability, likely due to its antioxidant effect. Since endothelial dysfunction was closely related to AMI, VPA treatment could increase aortic blood flow, making it a potential agent in reperfusion therapy that can prevent the vascular damage.

Steven-Jonhson Syndrome in a Patient With Dengue Infection in Peru: A Case Report.

Stevens-Johnson syndrome is an infrequent condition affecting the skin and mucous membranes, it involves cutaneous detachment with high mortality without adequate treatment. We present the case of a 40-year-old male with a history of epilepsy treated with valproic acid and lamotrigine, previously diagnosed with dengue. Evaluation showed erythematous blisters on skin and mucosa with bleeding and desquamation, covering 10% of the body surface. The patient progressed favorably with the medical care received. Stevens-Johnson syndrome should be studied in association with arboviral diseases.

Neurodevelopmental and Functional Outcomes Following In Utero Exposure to Antiseizure Medication: A Systematic Review.

BACKGROUND AND OBJECTIVES: To undertake a systematic review of the available literature to examine the relationship between prenatal antiseizure medication (ASM) exposure and adverse postnatal neurodevelopmental outcomes, focusing on social, emotional, behavioral, and adaptive domains of human function, and the frequency of neurodevelopmental and psychiatric disorders in ASM-exposed offspring. METHODS: Electronic searches of MEDLINE, PsychINFO, and EMBASE were conducted and limited to studies published between 1990 and 2023 in English. Studies were eligible if they prospectively or retrospectively reported neurodevelopmental outcomes of ASM-exposed offspring. The Newcastle-Ottawa scale was used to conduct methodologic quality assessments of included studies, and a narrative synthesis integrated the review findings. RESULTS: Forty-three studies were included. Valproate has been consistently associated with a 2- to 4-fold increased risk of autism spectrum disorder (ASD), 2- to 5-fold increased risk of intellectual disability (ID), and poor adaptive functioning. Growing evidence indicates that topiramate is associated with a 2-fold increased risk of ASD and 3- to 4-fold increased risk of ID. The risks of adverse neurodevelopmental outcomes for valproate and topiramate seem to be dose dependent. Phenobarbital has been suggested to be associated with deleterious neurodevelopmental effects, but data are limited. Levetiracetam has recently been linked with an increased risk of attention deficit hyperactivity disorder and anxiety disorders in a single study. Carbamazepine has been associated with variable neurodevelopmental outcomes. Lamotrigine seems to be "safe" in terms of postnatal neurodevelopment. Data for oxcarbazepine, phenytoin, and clonazepam are limited but seem to have little-to-no risk of adverse outcomes. Evidence for the remaining ASMs, including gabapentin, pregabalin, lacosamide, zonisamide, clobazam, perampanel, ethosuximide, or brivaracetam, is lacking. Several methodologic limitations impeded data synthesis, including heterogeneity in outcome measures and small samples of monotherapy exposures. DISCUSSION: The findings of this review support the conclusion that valproate and topiramate use during pregnancy is associated with a significantly increased risk of neurodevelopmental effects on the fetus. Apart from lamotrigine, which seems to be free of adverse neurodevelopmental effects, data for the other ASMs are mixed or inadequate to draw definite conclusions. Further research into the neurodevelopmental effects of prenatal exposure to ASMs, including most newer agents, is much needed.

[Experimental study of the influence of phenozanic acid and its combination with valproic acid on the development of the epileptic system]. / Izuchenie vliyaniya fenozanovoi kisloty i ee kombinatsii s val'proevoi kislotoi na razvitie epilepticheskoi sistemy v eksperimente.

OBJECTIVE: To study the effect of phenosanic acid (PA) and its combination with valproic acid (VA) on the development of the Epi system. MATERIAL AND METHODS: A model of focal chronic epilepsy in rats was created by applying metallic cobalt to the surface of the sensorimotor area of the cortex. Long-term electrodes were implanted in the sensorimotor cortex of the left and right hemispheres, the hippocampus, and the hypothalamus. The effect of PA (80 mg/kg) and its combination with VA (200 mg/kg) on discharge activity was carried out on the 2nd day and at the stage of generalization of the Epi system - on the 6th day. The stability of the Epi system on day 10 was assessed by provoking the development of epileptic status (Epi status) in response to the administration of thiolactone homocysteine (HMC) at a dose of 5.5 mmol/kg. RESULTS: In rats treated with PA, low discharge activity is observed, which is confirmed by the absence of EEG and motor manifestations of status epilepticus caused by HMC. PA does not suppress paroxysmal activity at the stages of development of the Epi system. VA significantly suppresses paroxysmal activity, but does not affect the formation of new foci of Epi activity in subcortical structures and the contralateral cortex. The epi system of rats treated with VA is characterized by high discharge activity by the 10th day of the experiment and lability to provocation of epi status. The combination of drugs is more pronounced than PA, but less than VA, reduces the numerical characteristics of paroxysmal activity in the brain structures of rats. CONCLUSION: PA when administered alone, in combination with VA, causes a slowdown in the generalization of convulsive foci of Epi activity and prevents the formation of a stable Epi system. VA, having a pronounced anticonvulsant effect, does not weaken the development of the Epi system in the model of focal cobalt-induced epilepsy.

Investigating the synergy of Shikonin and Valproic acid in inducing apoptosis of osteosarcoma cells via ROS-mediated EGR1 expression.

BACKGROUND: Osteosarcoma is the most prevalent malignant bone tumour with a poor prognosis. Shikonin (SHK) is derived from the traditional Chinese medicine Lithospermum that has been extensively studied for its notable anti-tumour effects, including for osteosarcoma. However, its application has certain limitations. Valproic acid (VPA) is a histone deacetylase inhibitor (HDACI) that has recently been employed as an adjunctive therapeutic agent that allows chromatin to assume a more relaxed state, thereby enhancing anti-tumour efficacy. PURPOSE: This study was aimed to investigate the synergistic anti-tumour efficacy of SHK in combination with VPA and elucidate its underlying mechanism. METHODS/STUDY DESIGN: CCK-8 assays were utilized to calculate the combination index. Additional assays, including colony formation, acridine orange/ethidium bromide double fluorescent staining, and flow cytometry, were employed to evaluate the effects on osteosarcoma cells. Wound healing and transwell assays were utilized to assess cell mobility. RNA sequencing, PCR, and Western blot analyses were conducted to uncover the underlying mechanism. Rescue experiments were performed to validate the mechanism of apoptotic induction. The impact of SHK and VPA combination treatment on primary osteosarcoma cells was also assessed. Finally, in vivo experiments were conducted to validate its anti-tumour effects and mechanism. RESULTS: The combination of SHK and VPA synergistically inhibited the proliferation and migration of osteosarcoma cells in vitro and induced apoptosis in these cells. Through a comprehensive analysis involving RNA sequencing, PCR, Western blot, and rescue experiments, we have substantiated our hypothesis that the combination of SHK and VPA induced apoptosis via the ROS-EGR1-Bax axis. Importantly, our in vivo experiments corroborated these findings, demonstrating the potential of the SHK and VPA combination as a promising therapeutic approach for osteosarcoma. CONCLUSION: The combination of SHK and VPA exerted an anti-tumour effect by inducing apoptosis through the ROS-EGR1-Bax pathway. Repurposing the old drug VPA demonstrated its effectiveness as an adjunctive therapeutic agent for SHK, enhancing its anti-tumour efficacy and revealing its potential value. Furthermore, our study expanded the application of natural compounds in the anti-tumour field and overcame some of their limitations through combination therapy. Finally, we enhanced the understanding of the mechanistic pathways linking reactive oxygen species (ROS) accumulation and apoptosis in osteosarcoma cells. Additionally, we elucidated the role of EGR1 in osteosarcoma cells, offering novel strategies and concepts for the treatment of osteosarcoma.

Effects of sodium valproate and levetiracetam on posterior segment parameters in children with epilepsy.

PURPOSE: To evaluate changes in posterior segment parameters in pediatric patients with epilepsy using sodium valproate or levetiracetam monotherapy for at least 12 months. METHODS: This study included 45 children with generalized epilepsy aged 6-17 years and 32 age- and gender-matched healthy subjects. The patients were assigned to three groups: Group 1 included patients using valproate monotherapy at a dose of 20-40 mg/kg/day, group 2 included patients using levetiracetam monotherapy at a dose of 20-40 mg/kg/day, and group 3 consisted of healthy controls. Peripapillary retinal nerve fiber layer (RNFL) and macular ganglion cell layer-inner plexiform layer (mGCIPL) thicknesses were measured using spectral-domain optical coherence tomography (OCT). RESULTS: No significant differences were noted between the groups regarding age, gender distribution, visual acuity, spherical equivalent, and intraocular pressure (p > 0.05). The average and temporal, nasal, and superior quadrants RNFL values were significantly thinner in group 1 than in group 2 (p = 0.001, p = 0.023, p = 0.011, and p = 0.001, respectively) and group 3 (p < 0.001, p = 0.032, p < 0.001, and p = 0.001, respectively). The OCT parameters were similar in groups 2 and 3 (p > 0.05). A negative correlation was observed in group 1 between only the average mGCIPL and the treatment dose (r = - 0.501). In group 2, no significant correlation was found between OCT parameters and the duration of epilepsy treatment, dose of treatment, and age at treatment onset values (p > 0.05). CONCLUSION: These findings support that there is an association between sodium valproate treatment and the reduction of RNFL thickness in epilepsy. Levetiracetam treatment appears to be a safe option, but care should be taken regarding ocular side effects that may occur with long-term and high-dose use of sodium valproate.

Mechanistic Insights about Sorafenib-, Valproic Acid- and Metformin-Induced Cell Death in Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is among the main causes of death by cancer worldwide, representing about 80-90% of all liver cancers. Treatments available for advanced HCC include atezolizumab, bevacizumab, sorafenib, among others. Atezolizumab and bevacizumab are immunological options recently incorporated into first-line treatments, along with sorafenib, for which great treatment achievements have been reached. However, sorafenib resistance is developed in most patients, and therapeutical combinations targeting cancer hallmark mechanisms and intracellular signaling have been proposed. In this review, we compiled evidence of the mechanisms of cell death caused by sorafenib administered alone or in combination with valproic acid and metformin and discussed them from a molecular perspective.

Differential inflammation responses determine the variable phenotypes of epilepsy induced by GABRG2 mutations.

OBJECTIVE: To explore the mechanism involved in variable phenotypes of epilepsy models induced by γ-aminobutyric acid type A γ2 subunit (GABRG2) mutations. METHODS: The zebrafish carrying wild-type (WT) GABRG2, mutant GABRG2(P282S), GABRG2(F343L) and GABRG2(I107T) were established by Tol2kit transgenesis system and Gateway method. Behavioral analysis of different transgenic zebrafish was performed with the DanioVision Video-Track framework and the brain activity was analyzed by field potential recording with MD3000 Bio-signal Acquisition and Processing System. The transcriptome analysis was applied to detect the underlying mechanisms of variable phenotypes caused by different GABRG2 mutations. RESULTS: The established Tg(hGABRG2P282S ) zebrafish showed hyperactivity and spontaneous seizures, which were more sensitive to chemical and physical epileptic stimulations. Traditional antiepileptic drugs, such as Clonazepam (CBZ) and valproic acid (VPA), could ameliorate the hyperactivity in Tg(hGABRG2P282S ) zebrafish. The metabolic pathway was significantly changed in the brain transcriptome of Tg(hGABRG2P282S ) zebrafish. In addition, the behavioral activity, production of pro-inflammatory factors, and activation of the IL-2 receptor signal pathway varied among the three mutant zebrafish lines. CONCLUSION: We successfully established transgenic zebrafish epileptic models expressing human mutant GABRG2(P282S), in which CBZ and VPA showed antiepileptic effects. Differential inflammatory responses, especially the SOCS/JAK/STAT signaling pathway, might be related to the phenotypes of genetic epilepsy induced by GABRG2 mutations. Further study will expand the pathological mechanisms of genetic epilepsies and provide a theoretical basis for searching for effective drug treatment.

Preventive treatment of migraine: Non-specific oral agents.

Migraine headache is highly prevalent and the most common neurologic disorder, affecting one billion people worldwide. It is also the most disabling condition in people under 50, with a huge impact on working ability, family, and social life. Access to effective preventive medication is important and may be considered if the patient has 6 or more migraine days per month, ineffective abortive agents, or disability on 2 or more days per month. Propranolol, metoprolol, candesartan, topiramate, divalproex, lisinopril, amitriptyline, and venlafaxine have the strongest evidence to support for use. Flunarizine and pizotifen may also be effective. Selection of preventive treatments is based on individual characteristics, comorbid conditions, efficacy, contraindications, side effects, cost, compliance, and drug. An adequate trial of migraine prophylaxis is usually 2 months at the target dose, and it is always important to re-evaluate indication for prophylactic use after a period of time.

Treatment guidelines for rare, early-onset conditions associated with epileptic seizures: a literature review on Rett syndrome and tuberous sclerosis complex.

BACKGROUND: Rett syndrome (RTT) and tuberous sclerosis complex (TSC) are two rare disorders presenting with a range of different epileptic seizures. Seizure management requires careful therapy selection, thereby necessitating development of high-quality treatment guidelines. This targeted literature review (TLR) aimed to characterise country-specific and international treatment guidelines available for pharmacological management of seizures in RTT and TSC. METHODS: A TLR was performed between 25-Jan and 11-Mar 2021. Manual searches of online rare disease and guideline databases, and websites of national heath technology assessment bodies were conducted for the following countries: Australia, Canada, France, Germany, Israel, Italy, Japan, Spain, Switzerland, UK, and US as defined by pre-specified eligibility criteria. Search terms were developed for each condition and translated into local languages where appropriate. Eligible publications were defined as guidelines/guidance reporting pharmacological management of seizures in patients with RTT and TSC. Guideline development methodology, geographical focus, author information and treatment recommendations were extracted from guidelines. An author map was generated using R version 3.5.1 to visualise extent of collaboration between authors. RESULTS: 24 total guidelines were included, of which three and six contained only recommendations for RTT and TSC, respectively (some provided recommendations for ≥ 1 condition). Guideline development processes were poorly described (50% [12 guidelines] had unclear/absent literature review methodologies); reported methodologies were variable, including systematic literature reviews (SLRs)/TLRs and varying levels of expert consultation. Most (83% [20/24]) were country-specific, with guideline authors predominantly publishing in contained national groups; four guidelines were classified as 'International,' linking author groups in the US, UK, Italy and France. High levels of heterogeneity were observed in the availability of treatment recommendations across indications, with 13 and 67 recommendations found for RTT and TSC, respectively. For RTT, all treatment recommendations were positive and sodium valproate had the highest number of positive recommendations (Khwaja, Sahin (2011) Curr Opin Pediatr 23(6):633-9). All TSC treatments (21 medications) received either exclusively negative (National Organization for Rare Disorders (2019)) or positive (Chu-Shore et al. (2010) Epilepsia 51(7):1236-41) recommendations; vigabatrin received the highest number of positive recommendations (Kaur, Christodoulou (2019)). CONCLUSIONS: This review highlights the need for the development of international high-quality and comprehensive consensus-based guidance for the management of seizures with pharmacological therapy in RTT and TSC. TRIAL REGISTRATION: Not applicable.

Fucoxanthin mitigates valproic acid-induced autistic behavior through modulation of the AKT/GSK-3ß signaling pathway.

This study aimed to investigate the effects of fucoxanthin, a natural compound found in seaweed, on various aspects of autism using a rat model induced by valproic acid (VPA). Pregnant rats were administered VPA (600 mg/kg) on gestational day 12.5, and male pups were orally administered fucoxanthin at 50, 100, or 200 mg/kg beginning on post-natal day (PND) 23-43. Behavioral assessments were conducted on PND 45-53, and on PND 54, the animals were sacrificed for further biochemical analyses (superoxide dismutase (SOD) and glutathione (GSH), nitric oxide (NO)) via UV spectroscopy. Inflammatory markers (IL-17, TNF-α, and IL-1ß) were also analyzed by sandwich ELISA, and the molecular parameters were evaluated through ELISA. The results revealed that, compared with VPA, fucoxanthin improved behavior and neuronal morphology. Specifically, fucoxanthin administration was found to enhance spatial memory, reduce pain sensitivity, and improve social interaction, locomotor activity, balance, and motor coordination. Fucoxanthin also exhibited anti-inflammatory and antioxidant effects, as indicated by the restoration of SOD and GSH levels and reduced inflammatory cytokine levels. Molecular analyses revealed that fucoxanthin restored the levels of GSK-3ß and AKT. Furthermore, fucoxanthin regulates neurotransmitters, which are related to increasing GABA and reducing glutamate levels in the cortex and cerebellum. The therapeutic effects were dose-dependent, with higher doses (200 mg/kg) showing greater efficacy than lower doses (100 mg/kg) in improving behavioral, biochemical, neurotransmitter, and molecular parameters. Fucoxanthin is a potential treatment for autism, but further research, including clinical trials, is necessary to determine its effectiveness in humans.

The teratogenesis risk associated with antiseizure medication duotherapy in women with epilepsy.

PURPOSE: To investigate rates of occurrence of pregnancies associated with a foetal malformation (FM pregnancy rates) following simultaneous intrauterine exposure to two antiseizure medications in 524 pregnancies in women with epilepsy from the Australian Pregnancy Register who were treated simultaneously with various combinations and dosages of two antiseizure medications (duotherapy). RESULTS: FM pregnancy rates tended to be higher in those exposed simultaneously to two antiseizure medications, each of which was a statistically significant teratogen (valproate, topiramate, or carbamazepine), than when there was exposure to only one such teratogen. When there was exposure to only one such teratogen together with clonazepam or levetiracetam, for neither of which there was statistically significant evidence of heightened teratogenicity, the FM pregnancy rates also tended to be higher, but less so. When lamotrigine was the other component of the duotherapy with an established teratogen, FM pregnancy rates tended to be lower than that for the teratogen used as monotherapy. CONCLUSION: Leaving aside issues in relation to seizure control, our data suggest that it would be best to avoid using established teratogenic antiseizure medications (carbamazepine, valproate and topiramate) in combination with each other due to the increased FM risks. When combining an established teratogenic medication with a less teratogenic one, i.e. lamotrigine, levetiracetam or clonazepam, lamotrigine appears to be the safer option.

Predicting the therapeutic response to valproic acid in childhood absence epilepsy through electroencephalogram analysis using machine learning.

Childhood absence epilepsy (CAE) is a common type of idiopathic generalized epilepsy, manifesting as daily multiple absence seizures. Although seizures in most patients can be adequately controlled with first-line antiseizure medication (ASM), approximately 25 % of patients respond poorly to first-line ASM. In addition, an accurate method for predicting first-line medication responsiveness is lacking. We used the quantitative electroencephalogram (QEEG) features of patients with CAE along with machine learning to predict the therapeutic effects of valproic acid in this population. We enrolled 25 patients with CAE from multiple medical centers. Twelve patients who required additional medication for seizure control or who were shifted to another ASM and 13 patients who achieved seizure freedom with valproic acid within 6 months served as the nonresponder and responder groups. Using machine learning, we analyzed the interictal background EEG data without epileptiform discharge before ASM. The following features were analyzed: EEG frequency bands, Hjorth parameters, detrended fluctuation analysis, Higuchi fractal dimension, Lempel-Ziv complexity (LZC), Petrosian fractal dimension, and sample entropy (SE). We applied leave-one-out cross-validation with support vector machine, K-nearest neighbor (KNN), random forest, decision tree, Ada boost, and extreme gradient boosting, and we tested the performance of these models. The responders had significantly higher alpha band power and lower delta band power than the nonresponders. The Hjorth mobility, LZC, and SE values in the temporal, parietal, and occipital lobes were higher in the responders than in the nonresponders. Hjorth complexity was higher in the nonresponders than in the responders in almost all the brain regions, except for the leads FP1 and FP2. Using KNN classification with theta band power in the temporal lobe yielded optimal performance, with sensitivity of 92.31 %, specificity of 76.92 %, accuracy of 84.62 %, and area under the curve of 88.46 %.We used various EEG features along with machine learning to accurately predict whether patients with CAE would respond to valproic acid. Our method could provide valuable assistance for pediatric neurologists in selecting suitable ASM.