Morbidity and mortality risks associated with valproate withdrawal in young men and women with epilepsy.

Valproate is the most effective treatment for idiopathic generalised epilepsy. Current guidance precludes its use in women of childbearing potential, unless other treatments are ineffective or not tolerated, because of high teratogenicity. This risk was recently extended to men. New guidance will limit use both in men and women aged <55 years, resulting in withdrawal of valproate from men already taking it, as occurs for women. Whether there are risks of personal harm (including injury or death) associated with valproate withdrawal has not yet been quantified for men or women on valproate, meaning clinicians cannot reliably counsel either sex when discussing valproate withdrawal with them, despite that this concern may be at the forefront of patients' and clinicians' minds. We assessed whether there are any morbidity or mortality risks associated with valproate withdrawal in young men and women. We performed a retrospective cohort study of internationally derived electronic health data within the TriNetX Global Collaborative Network. Included were men and women aged 16-54 years with ≥1 epilepsy disease or symptom code between 01/12/2017-01/12/2018 and ≥2 valproate prescriptions over the preceding two years (01/01/2015-30/11/2017). 5-year propensity-matched risks of mortality and a range of morbidity outcomes were compared between those remaining on vs. withdrawn from valproate during the 01/12/2017-01/12/2018 recruitment period, regardless of whether switched to another antiseizure medication. Survival analysis was undertaken using Cox-proportional hazard models, generating hazard ratios (HRs) with 95% confidence intervals (CIs). 8,991 men and 5,243 women taking valproate were recruited. 28% of men and 36% of women were subsequently withdrawn from valproate. Valproate withdrawal was associated with significantly increased risks of emergency department attendance (HRs overall: 1.236 (CI 1.159-1.319), men: 1.181 (CI 1.083-1.288), women: 1.242 (CI 1.125-1.371)), hospital admission (HRs overall: 1.160 (CI 1.081-1.246), men: 1.132 (CI 1.027-1.249), women: 1.147 (CI 1.033-1.274)), falls (HRs overall: 1.179 (CI 1.041-1.336), men: 1.298 (CI 1.090-1.546)), injuries (HRs overall: 1.095 (CI 1.021-1.174), men: 1.129 (CI 1.029-1.239)), burns (HRs overall: 1.592 (CI 1.084-2.337)), and new-onset depression (HRs overall 1.323 (CI 1.119-1.565), women: 1.359 (CI 1.074-1.720)). The risk of these outcomes occurring was 1-7% higher in those withdrawn from valproate than in those remaining on valproate. Overall, valproate withdrawal was not associated with increased mortality. These results may help patients and clinicians have a more informed discussion about personal safety when considering valproate withdrawal.

Cortical dysmorphology and reduced cortico-collicular projections in an animal model of autism spectrum disorder.

Autism spectrum disorder is a neurodevelopmental disability that includes sensory disturbances. Hearing is frequently affected and ranges from deafness to hypersensitivity. In utero exposure to the antiepileptic valproic acid is associated with increased risk of autism spectrum disorder in humans and timed valproic acid exposure is a biologically relevant and validated animal model of autism spectrum disorder. Valproic acid-exposed rats have fewer neurons in their auditory brainstem and thalamus, fewer calbindin-positive neurons, reduced ascending projections to the midbrain and thalamus, elevated thresholds, and delayed auditory brainstem responses. Additionally, in the auditory cortex, valproic acid exposure results in abnormal responses, decreased phase-locking, elevated thresholds, and abnormal tonotopic maps. We therefore hypothesized that in utero, valproic acid exposure would result in fewer neurons in auditory cortex, neuronal dysmorphology, fewer calbindin-positive neurons, and reduced connectivity. We approached this hypothesis using morphometric analyses, immunohistochemistry, and retrograde tract tracing. We found thinner cortical layers but no changes in the density of neurons, smaller pyramidal and non-pyramidal neurons in several regions, fewer neurons immunoreactive for calbindin-positive, and fewer cortical neurons projecting to the inferior colliculus. These results support the widespread impact of the auditory system in autism spectrum disorder and valproic acid-exposed animals and emphasize the utility of simple, noninvasive auditory screening for autism spectrum disorder.

The antiseizure medication valproate increases hemichannel activity found in brain cells, which could worsen disease outcomes.

Glial cells play relevant roles in neuroinflammation caused by epilepsy. Elevated hemichannel (HC) activity formed by connexins (Cxs) or pannexin1 (Panx1) largely explains brain dysfunctions commonly caused by neuroinflammation. Glia express HCs formed by Cxs 43, 30, or 26, while glia and neurons both express HCs formed by Panx1. Cx43 HCs allow for the influx of Ca2+, which promotes glial reactivity, enabling the release of the gliotransmitters that contribute to neuronal over-stimulation. Valproate (VPA), an antiseizure medication, has pleiotropic actions on neuronal molecular targets, and their action on glial cell HCs remains elusive. We used HeLa cells transfected with Cx43, Cx30, Cx26, or Panx1 to determine the effect of VPA on HC activity in the brain. VPA slightly increased HC activity under basal conditions, but significantly enhanced it in cells pre-exposed to conditions that promoted HC activity. Furthermore, VPA increased ATP release through Cx43 HCs. The increased HC activity caused by VPA was resistant to washout, being consistent with in silico studies, which predicted the binding site for VPA and Cx43, as well as for Panx1 HCs on the intracellular side, suggesting that VPA first enters through HCs, after which their activity increases.

Pharmacological inhibition of histone deacetylase alleviates chronic unpredictable stress induced atherosclerosis and endothelial dysfunction via upregulation of BDNF.

Long-term stress is a significant risk factor for cardiovascular diseases, including atherosclerosis and endothelial dysfunction. Moreover, prolonged stress has shown to negatively regulate central BDNF expression. The role of central BDNF in CNS disorders is well studied until recently the peripheral BDNF was also found to be involved in endothelial function regulation and atherosclerosis. The peripheral BDNF and its role in chronic stress-induced atherosclerosis and endothelial dysfunction remain unclear. Therefore, we aimed to elucidate the role of BDNF and its modulation by the HDAC inhibitor valproic acid (VA) in chronic unpredictable stress (CUS)-induced atherosclerosis and endothelial dysfunction. We demonstrated that a 10-week CUS mouse model substantially decreases central and peripheral BDNF expression, resulting in enhanced serum lipid indices, plaque deposition, fibrosis, and CD68 expression in thoracic aortas. Further, parameters associated with endothelial dysfunction such as increased levels of endothelin-1 (ET-1), adhesion molecules like VCAM-1, M1 macrophage markers, and decreased M2 macrophage markers, eNOS expression, and nitrite levels in aortas, were also observed. VA (50 mg/kg, 14 days, i. p.) was administered to mice following 8 weeks of CUS exposure until the end of the experimental procedure. VA significantly prevented the decrease in BDNF, eNOS and nitrite levels, reduced lesion formation and fibrosis in thoracic aortas and increased ET-1, and VCAM-1 followed by M2 polarization in VA-treated mice. The study highlights the potential of epigenetic modulation of BDNF as a therapeutic target, in stress-induced cardiovascular pathologies and suggests that VA could be a promising agent for mitigating CUS-induced endothelial dysfunction and atherosclerosis by BDNF modulation.

Region-Specific Brain Volume Changes Emerge in Adolescence in the Valproic Acid Model of Autism and Parallel Human Findings.

INTRODUCTION: Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by social and communication deficits, cognitive dysfunction, and stereotyped repetitive behaviors. Regional volume changes are commonly observed in individuals with ASD. To examine volumetric dysregulation across adolescence, the valproic acid (VPA) model was used to induce ASD-like phenotypes in rats. METHOD: Regional volumes were obtained via magnetic resonance imaging at either postnatal day 28 or postnatal day 40 (P40), which correspond to early and late adolescence, respectively. RESULTS: Consistent with prior research, VPA animals had reduced total brain volume compared to control animals. A novel outcome was that VPA animals had overgrown right hippocampi at P40. Differences in the pattern of development of the anterior cingulate cortex were also observed in VPA animals. Differences for the posterior cingulate were only observed in males, but not females. CONCLUSION: These results demonstrate differences in region-specific developmental trajectories between control and VPA animals and suggest that the VPA model may capture regional volume changes consistent with human ASD.

Valproic acid increased the efficacy of EGFR TKIs on EGFR/TP53 co-mutated lung cancers and downregulated mutant-p53 levels.

The TP53 tumor suppressor is the most frequently mutated gene in human cancers. For p53-targeted therapy, one of the strategies was targeting mutant p53 for degradation. In EGFR-mutated lung cancer patients, concurrent TP53 mutation was associated with faster resistance to EGFR-TKIs. In this study, we discovered that valproic acid (VPA), a widely prescribed antiseizure medication, had a synergic effect on sensitive as well as acquired resistant lung cancers with EGFR/TP53 co-mutation in combination with EGFR-TKIs. In both in vitro and in vivo models, VPA greatly improved the efficacy of EGFR-TKIs, including forestalling the occurrence of acquired resistance and increasing the sensitivity to EGFR-TKIs. Mechanistically, VPA dramatically promoted degradation of mutant p53 in both sensitive and acquired resistant cells while inhibited mutant TP53 mRNA transcription only in sensitive cells. Together, this study suggested that VPA combination treatment could have beneficial effects on EGFR-mutant lung cancers with concurrent p53 mutation in both early and late stages, expanding the potential clinical applications for VPA.

The Effect of Vitamin D3 and Valproic Acid on the Maturation of Human-Induced Pluripotent Stem Cell-Derived Enterocyte-Like Cells.

Cytochrome P450 3A4 (CYP3A4) is involved in first-pass metabolism in the small intestine and is heavily implicated in oral drug bioavailability and pharmacokinetics. We previously reported that vitamin D3 (VD3), a known CYP enzyme inducer, induces functional maturation of iPSC-derived enterocyte-like cells (iPSC-ent). Here, we identified a Notch activator and CYP modulator valproic acid (VPA), as a promotor for the maturation of iPSC-ent. We performed bulk RNA sequencing to investigate the changes in gene expression during the differentiation and maturation periods of these cells. VPA potentiated gene expression of key enterocyte markers ALPI, FABP2, and transporters such as SULT1B1. RNA-sequencing analysis further elucidated several function-related pathways involved in fatty acid metabolism, significantly upregulated by VPA when combined with VD3. Particularly, VPA treatment in tandem with VD3 significantly upregulated key regulators of enterohepatic circulation, such as FGF19, apical bile acid transporter SLCO1A2 and basolateral bile acid transporters SLC51A and SLC51B. To sum up, we could ascertain the genetic profile of our iPSC-ent cells to be specialized toward fatty acid absorption and metabolism instead of transporting other nutrients, such as amino acids, with the addition of VD3 and VPA in tandem. Together, these results suggest the possible application of VPA-treated iPSC-ent for modelling enterohepatic circulation.

Human Wharton's jelly-derived mesenchymal stromal stem cells preconditioned with valproic acid promote cell migration and reduce renal inflammation in ischemia/reperfusion injury by activating the AKT/P13K and SDF1/CXCR4 pathways.

OBJECTIVE: To determine whether WJ-MSCs pretreated with VPA would enhance their migration to improve functional recovery of renal IRI in rats. METHODS: 150 Sprague-Dawley rats were distributed into 5 groups; Sham, IRI, WJ-MSC, VPA, and WJ-MSCs + VPA. 10 rats were sacrificed after 3, 5, and 7 days. Role of WJ-MSCs pretreated with VPA was evaluated by assessment of renal function, antioxidant enzymes together with renal histopathological and immunohistopathological analyses and finally by molecular studies. RESULTS: WJ-MSCs and VPA significantly improved renal function and increased antioxidants compared to IRI group. Regarding gene expression, WJ-MSCs and VPA decreased BAX and TGF-ß1, up-regulated Akt, PI3K, BCL2, SDF1α, and CXCR4 related to IRI. Additionally, WJ-MSCs pretreated with VPA improved the measured parameters more than either treatment alone. CONCLUSION: WJ-MSCs isolated from the umbilical cord and pretreated with VPA defended the kidney against IRI by more easily homing to the site of injury.

Ethosuximide lowers lamotrigine serum concentrations: Evidence for a clinically relevant interaction.

We investigated the effect of comedication with ethosuximide (ESM) on lamotrigine (LTG) blood levels. Based on observations from clinical practice, we hypothesized that ESM reduces the LTG serum concentration. We additionally evaluated this effect in the presence of concomitant valproic acid (VPA). We retrospectively analyzed samples of inpatients from our department who had been treated with a combination of ESM and LTG between 2017 and 2021. We additionally used data on LTG serum concentrations from a previously published cohort from our center. Generalized estimation equations (GEEs) were used for statistical analyses. We included 523 samples from 209 patients. GEE analyses showed that LTG trough serum concentrations were significantly lower in samples with ESM comedication and significantly higher in samples with concomitant VPA. The effect of ESM was moderated by patients' age; in children and adolescents, LTG serum concentrations were 37% lower than in samples without ESM, whereas in adults, LTG serum concentrations were 14% lower. The effect we found in our data is relevant to daily clinical practice, if patients are not seizure-free despite typical daily LTG dosage, or if they develop side effects during ESM withdrawal. It should be considered especially in children and adolescents.

Spontaneous Calcium Transients Recorded from Striatal Astrocytes in a Preclinical Model of Autism.

Autism spectrum disorder (ASD) is known as a group of neurodevelopmental conditions including stereotyped and repetitive behaviors, besides social and sensorimotor deficits. Anatomical and functional evidence indicates atypical maturation of the striatum. Astrocytes regulate the maturation and plasticity of synaptic circuits, and impaired calcium signaling is associated with repetitive behaviors and atypical social interaction. Spontaneous calcium transients (SCT) recorded in the striatal astrocytes of the rat were investigated in the preclinical model of ASD by prenatal exposure to valproic acid (VPA). Our results showed sensorimotor delay, augmented glial fibrillary acidic protein -a typical intermediate filament protein expressed by astrocytes- and diminished expression of GABAA-ρ3 through development, and increased frequency of SCT with a reduced latency that resulted in a diminished amplitude in the VPA model. The convulsant picrotoxin, a GABAA (γ-aminobutyric acid type A) receptor antagonist, reduced the frequency of SCT in both experimental groups but rescued this parameter to control levels in the preclinical ASD model. The amplitude and latency of SCT were decreased by picrotoxin in both experimental groups. Nipecotic acid, a GABA uptake inhibitor, reduced the mean amplitude only for the control group. Nevertheless, nipecotic acid increased the frequency but diminished the latency in both experimental groups. Thus, we conclude that striatal astrocytes exhibit SCT modulated by GABAA-mediated signaling, and prenatal exposure to VPA disturbs this tuning.

Protein S-nitrosylation is involved in valproic acid-promoted neuronal differentiation of adipose tissue-derived stem cells.

Neuronal differentiation of adipose tissue-derived stem cells (ASCs) is greatly promoted by valproic acid (VPA) with cAMP elevating agents thorough NO signaling pathways, but its mechanism is not fully understood. In the present study, we investigate the involvement of protein S-nitrosylation in the VPA-promoted neuronal differentiation of ASCs. The whole amount of S-nitrosylated protein was increased by the treatment with VPA alone for three days in ASCs. An inhibitor of thioredoxin reductase (TrxR), auranofin, further increased the amount of S-nitrosylated protein and enhances the VPA-promoted neuronal differentiation in ASCs. On the contrary, another inhibitor of TrxR, dinitrochlorobenzene, inhibited the VPA-promoted neuronal differentiation in ASCs even with cAMP elevating agents, which was accompanied by unexpectedly decreased S-nitrosylated protein. It was considered from these results that increased protein S-nitrosylation is involved in VPA-promoted neuronal differentiation of ASCs. By the proteomic analysis of S-nitrosylated protein in VPA-treated ASCs, no identified proteins could be specifically related to VPA-promoted neuronal differentiation. The identified proteins, however, included those involved in the metabolism of substances regulating neuronal differentiation, such as aspartate and glutamate.

Altered prefrontal and cerebellar parvalbumin neuron counts are associated with cognitive changes in male rats.

Exposure to valproic acid (VPA), a common anti-seizure medication, in utero is a risk factor for autism spectrum disorder (ASD). People with ASD often display changes in the cerebellum, including volume changes, altered circuitry, and changes in Purkinje cell populations. ASD is also characterized by changes in the medial prefrontal cortex (mPFC), where excitatory/inhibitory balance is often altered. This study exposed rats to a high dose of VPA during gestation and assessed cognition and anxiety-like behaviors during young adulthood using a set-shifting task and the elevated plus maze. Inhibitory parvalbumin-expressing (PV +) neuron counts were assessed in the mPFC and cerebellar lobules VI and VII (Purkinje cell layers), which are known to modulate cognition. VPA males had increased PV + counts in crus I and II of lobule VII. VPA males also had decreased parvalbumin-expressing neuron counts in the mPFC. It was also found that VPA-exposed rats, regardless of sex, had increased parvalbumin-expressing Purkinje cell counts in lobule VI. In males, this was associated with impaired intra-dimensional shifting on a set-shifting task. Purkinje cell over proliferation may be contributing to the previously observed increase in volume of Lobule VI. These findings suggest that altered inhibitory signaling in cerebellar-frontal circuits may contribute to the cognitive deficits that occur within ASD.

Valproate modulates the activity of multidrug resistance efflux pumps, as a chemoresistance factor in gastric cancer cells.

BACKGROUND: Drug resistance is one of the most critical problems in gastric cancer therapy. This study was performed to investigate the valproic acid effects on the proliferation of sensitive and resistant cell lines of human gastric cancer, and to explore the mechanism of the agent on multi drug resistance and apoptosis genes. METHODS: The cytotoxicity effect of valproic acid on the EPG85.257 and EPG85.257RDB cells was assessed by the MTT assay, and the IC50 concentration was evaluated. Apoptosis, genotoxicity, and drug resistance pump activity were evaluated using comet assay, Real-time PCR, and flow cytometry, respectively. Cell proliferation was assayed using a scratch test. RESULTS: Dose-dependent toxicity was recorded after treatment of cells with valproic acid. Valproic acid represented a significant growth inhibition on EPG85.257 cells with IC50 values of 5.84 µM and 4.78 µM after 48 h and 72 h treatment, respectively. In contrast, the drug-resistant counterpart represented 8.7 µM and 7.02 µM IC50 values after the same treatment time. Valproic acid induced PTEN, Bcl2, P53, Bax, P21, and caspase3 expression in EPG85.257 cells, whereas p21, p53, PTEN, and ABCB1 were overexpressed in EPG5.257RDB. Valproic acid hindered cell migration in both cell lines (P < 0.01). Valproate genotoxicity was significantly higher in the parent cells than in their resistant EPG85.257RDB counterparts. Valproate led to a 62% reduction in the daunorubicin efflux of the MDR1 pump activity. CONCLUSIONS: Valproate can affect drug resistance in gastric cancer via a unique mechanism independent of MDR1 expression.

Benefits of bone marrow mesenchymal stem cells compared to their conditioned medium in valproic acid-induced autism in rats.

BACKGROUND: Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by repetitive behaviors, a limited range of activities, and deficiencies in social communications. Bone marrow mesenchymal stem cells (BM-MSCs), which secrete factors that stimulate surrounding microenvironment, and BM-MSCs conditioned medium (BM-MSCs-CM), which contains cell-secreted products, have been speculated to hold potential as a therapy for ASD. This study aimed to compare the therapeutic effects of BM-MSCs and BM-MSCs-CM on behavioral and microglial changes in an animal model of autism induced by valproic acid (VPA). METHODS AND RESULTS: Pregnant Wistar rats were administered by VPA at a dose of 600 mg/kg at 12.5 days post-conception. After birth, male pups were included in the study. At 6 weeks of age, one group of rats received intranasal administration of BM-MSCs, while another group received BM-MSCs-CM. The rats were allowed to recover for 2 weeks. Behavioral tests, quantitative real-time polymerase chain reaction (qRT-PCR), and immunohistochemistry were performed. Both BM-MSCs and BM-MSCs-CM administration significantly improved some behavioral deficits. Furthermore, these treatments notably reduced Iba-1 marker associated with microgliosis. Additionally, there was a significant reduction in the expression of pro-inflammatory cytokines IL-1ß and IL-6, and an increase in the levels of the anti-inflammatory cytokine IL-10 in rats administered by BM-MSCs and BM-MSCs-CM. CONCLUSIONS: Post-developmental administration of BM-MSCs and BM-MSCs-CM can ameliorate prenatal neurodevelopmental deficits, restore cognitive and social behaviors, and modulate microglial and inflammatory markers. Results indicated that the improvement rate was higher in the BM-MSCs group than BM-MSCs-CM group.

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.

Evaluation of anti-seizure medications and their serum concentration with regard to cardiovascular risk parameters: A cross-sectional study.

OBJECTIVE: Epilepsy is a chronic disease that requires long-term monitoring and treatment. It is suspected that there is a interaction between the use of anti-seizure medications and the risk of cardiovascular disease. The aim of the study is to investigate the association between the intake of phenobarbital, carbamazepine and valproic acid and their serum drug concentrations (SDC) with various cardiovascular risk parameters (homocysteine, folic acid, vitamin B12, total cholesterol (TC), triglycerides, high- and low-density lipoprotein (LDL)). METHODS: This is a cross-sectional study. Data (demographic characteristics and laboratory results) of patients treated for epilepsy in a tertiary care hospital between January 2020 and February 2022 were analyzed retrospectively (n = 2014). Kruskal Wallis, Mann-Whitney U, correlation analysis was used, p < 0.05 was considered statistically significant. RESULTS: The median age of patients was 15 years (IQR:8-31) and 48.3 % were women. The highest homocysteine level was found in patients receiving valproic acid, but it was not statistically significant. Patients receiving phenobarbital had the highest levels of folic acid and B12 and the lowest levels of total cholesterol and low-density lipoprotein cholesterol, which was statistically significant. In patients receiving carbamazepine, a moderately negative significant association was found between serum drug concentration and folic acid levels and a moderately positive significant association was found between TC and LDL levels. CONCLUSION: In our study, the majority of patients were children and adolescents. Regular monitoring of drug serum concentrations and metabolic parameters may be useful to select the safest drug in terms of cardiovascular disease risk. Randomized controlled trials on the long-term effects of anti-seizure treatment are needed.

Effects of valproic acid and levetiracetam monotherapy on balance functions in patients with generalized epilepsy.

BACKGROUND: It is reported that antiepileptic drugs have an effect on balance functions. The aim of the study was to evaluate and compare the effects of valproic acid and levetiracetam monotherapy on balance functions in patients with generalized epilepsy using objective test methods. METHODS: The study included 43 generalized epilepsy patients aged 18-60 years, including 20 patients receiving valproic acid monotherapy, 23 patients receiving levetiracetam monotherapy, and 25 healthy individuals as controls, in the Neurology Clinic of a university hospital in eastern Turkey. The demographic data form was filled out and the Video Head Impulse Test and Vestibular Evoked Myogenic Potentials test were performed. RESULTS: Statistically significant differences were obtained between the groups in lateral, posterior, and anterior semicircular canal gains and RALP and LARP asymmetry values in the V-HIT test (p < 0.05). Statistically significant differences were obtained between the groups in P1, N1 latency and asymmetry values in the C-VEMP test and in N1, P1 latency, amplitude, and asymmetry values in the o-VEMP test (p < 0.05). CONCLUSION: Valproic acid and levetiracetam may affect the vestibulocular and vestibulocolic reflex pathways negatively. In this cohort, valproic acid had more pronounced adverse effects on balance functions as compared to levetiracetam.

Antiepileptic Strategies for Patients with Primary and Metastatic Brain Tumors.

OPINION STATEMENT: Seizure activity is common in patients with primary and metastatic brain tumors, affecting more than 50% of cases over the course of their disease. Several mechanisms contribute to brain tumor-related epilepsy (BTRE), including a pro-inflammatory environment, excessive secretion of glutamate and an increase in neuronal excitatory tone, reduction of GABAergic inhibitory activity, and an increase in 2-hydroxygluturate production in isocitrate dehydrogenase mutant tumors. After a verified seizure in a brain tumor patient, the consensus is that BTRE has developed, and it is necessary to initiate an antiepileptic drug (AED). It is not recommended to initiate AED prophylaxis. Second- and third-generation AEDs are the preferred options for initiation, due to a lack of hepatic enzyme induction and reduced likelihood for drug-drug interactions, especially in regard to neoplastic treatment. The efficacy of appropriate AEDs for patients with BTRE is fairly equivalent, although some data suggests that levetiracetam may be slightly more active in suppressing seizures than other AEDs. The consensus among most Neuro-Oncology providers is to initiate levetiracetam monotherapy after a first seizure in a brain tumor patient, as long as the patient does not have any psychiatric co-morbidities. If levetiracetam is not tolerated well or is ineffective, other appropriate initial AED options for monotherapy or as an add-on anticonvulsant include lacosamide, valproic acid, briviracetam, lamotrigine, and perampanel.

Subcutaneous sodium valproate in palliative care: A systematic review.

BACKGROUND: Seizures are an important palliative symptom, the management of which can be complicated by patients' capacity to swallow oral medications. In this setting, and the wish to avoid intravenous access, subcutaneous infusions may be employed. Options for antiseizure medications that can be provided subcutaneously may be limited. Subcutaneous sodium valproate may be an additional management strategy. AIM: To evaluate the published experience of subcutaneous valproate use in palliative care, namely with respect to effectiveness and tolerability. DESIGN: A systematic review was registered (PROSPERO CRD42023453427), conducted and reported according to PRISMA reporting guidelines. DATA SOURCES: The databases PubMed, EMBASE and Scopus were searched for publications until August 11, 2023. RESULTS: The searches returned 429 results, of which six fulfilled inclusion criteria. Case series were the most common study design, and most studies included <10 individuals who received subcutaneous sodium valproate. There were three studies that presented results on the utility of subcutaneous sodium valproate for seizure control, which described it to be an effective strategy. One study also described it as an effective treatment for neuropathic pain. The doses were often based on presumed 1:1 oral to subcutaneous conversion ratios. Only one study described a local site adverse reaction, which resolved with a change of administration site. CONCLUSIONS: There are limited data on the use of subcutaneous sodium valproate in palliative care. However, palliative symptoms for which subcutaneous sodium valproate have been used successfully are seizures and neuropathic pain. The available data have described few adverse effects, supporting its use with an appropriate degree of caution.

TC-G 1008 facilitates epileptogenesis by acting selectively at the GPR39 receptor but non-selectively activates CREB in the hippocampus of pentylenetetrazole-kindled mice.

The pharmacological activation of the GPR39 receptor has been proposed as a novel strategy for treating seizures; however, this hypothesis has not been verified experimentally. TC-G 1008 is a small molecule agonist increasingly used to study GPR39 receptor function but has not been validated using gene knockout. Our aim was to assess whether TC-G 1008 produces anti-seizure/anti-epileptogenic effects in vivo and whether the effects are mediated by GPR39. To obtain this goal we utilized various animal models of seizures/epileptogenesis and GPR39 knockout mice model. Generally, TC-G 1008 exacerbated behavioral seizures. Furthermore, it increased the mean duration of local field potential recordings in response to pentylenetetrazole (PTZ) in zebrafish larvae. It facilitated the development of epileptogenesis in the PTZ-induced kindling model of epilepsy in mice. We demonstrated that TC-G 1008 aggravated PTZ-epileptogenesis by selectively acting at GPR39. However, a concomitant analysis of the downstream effects on the cyclic-AMP-response element binding protein in the hippocampus of GPR39 knockout mice suggested that the molecule also acts via other targets. Our data argue against GPR39 activation being a viable therapeutic strategy for treating epilepsy and suggest investigating whether TC-G 1008 is a selective agonist of the GPR39 receptor.