Dose Of Valproate Research Articles

The effect of antiepileptic drugs on the evoked potentials of children with epilepsy

Studies using multimodal sensory evoked potentials (SEPs) in children with epilepsy are lacking or few and controversial. We aimed to assess the SEPs, which included: (visual, brainstem and somatosensory evoked potentials) in children with epilepsy treated with carbamazepine (CBZ), valproate (VPA) or lamotrigine (LTG) monotherapy. Forty epileptic children and 25 healthy children were included. Compared to healthy children, children on VPA had prolonged P100 and waves III and IV latencies and reduced P100 amplitude. Children on CBZ had prolonged P100, waves IV and V and N20 latencies and III-V and N9–N20 interpeak latencies. Children on LTG had prolonged N145, waves I, II, III and IV latencies. Significant correlations were identified between the dose of VPA and P100 amplitude (P = 0.001), the dose of CBZ and P100 (P = 0.016); wave V (P = 0.049) latencies and I–III (P = 0.047) and III–V (P = 0.031) interpeak latencies and between the duration of treatment with CBZ and wave IV and V (P = 0.004; P = 0.002) latencies, between the dose of LTG and N9 (P = 0.050), N11 (P = 0.035) and N20 (P = 0.030) latencies and N9–N11 (P = 0.017) and N9–N20 (P = 0.003) interpeak latencies. No significant correlations were identified between SEPs variables and age at onset or duration of illness. This study suggested that antiepileptic drugs (AEDs) might induce changes in central SEPs indicating central nervous system impairment secondary to AEDs. Although none of the children had manifest sensory changes, however, AEDs can induce clinical manifestations with chronic or long-term use.

Prospective assessment of autism traits in children exposed to antiepileptic drugs during pregnancy.

The association between autism spectrum disorders (ASDs) and prenatal anticonvulsant exposure is increasingly investigated, but comprehensive, blinded assessment using a validated instrument for autism within a well-characterized prospective cohort has not been conducted. Thus, existing studies may represent an underestimate of the true risk. Herein we present a prospective cohort study in children exposed to anticonvulsants during pregnancy, with all assessments conducted by examiners who were blinded to drug-exposure status. Participants were 105 Australian children aged 6-8 years who were recruited via the Australian Pregnancy Register for Women on Antiepileptic Medication. Maternal epilepsy, pregnancy, and medical history data were obtained prospectively. Autism traits were assessed using the Childhood Autism Rating Scale (CARS). Eleven children (10.5%) had elevated CARS scores. Two were exposed to valproate monotherapy (2/26; 7.7%), two to carbamazepine monotherapy (2/34; 5.9%), and seven to valproate in polytherapy (7/15; 46.7%). Linear regression analysis showed that the mean valproate dose during pregnancy was a significant predictor of CARS scores after controlling for polytherapy, mean carbamazepine dose, folic acid use, seizures during pregnancy, tobacco and marijuana use, maternal intelligence quotient (IQ), and socioeconomic status. First trimester folic acid supplementation and marijuana use were also significant predictors of CARS scores. Using direct assessment of children in our prospective study, we found an elevated rate of autism traits across the sample. The most important determinant of association with autistic traits was higher doses of sodium valproate exposure. The use of valproate in women who may become pregnant is now generally avoided; however, there are insufficient data regarding the risk of ASD with low-dose valproate. If this risk is no greater than with other antiepileptic drugs (AED)s, it may enable women with genetic generalized epilepsy to retain optimal seizure control as well as minimize harm to their unborn child.

Comparison of short-term efficacy of valproate sustained-release between adult and children as first-line monotherapy in management of partial epilepsy: A multicenter observational open-label study

Background: Management of partial epilepsy is an important issue in the field of neurology.Objective: The purpose of the present study was to collect additional clinical data on efficacy and safety of sustained release sodium valproate chrono formulation as first-line monotherapy in patients newly or recently diagnosed with partial epilepsy in Bangladesh under daily practice condition.Methodology: This open-label, multicenter, non-controlled, prospective, observational study enrolled adults and children ? 6 years newly diagnosed with partial epilepsy with or without secondary generalization between March 2010 and February 2011. Patients were treated with sustained release sodium valproate. Primary evaluation criterion was the remission rate i.e. proportion of seizure-free patients at 6 months. Secondary evaluation criteria included retention rate at 6 months, remission rate at 1 and 3 months, investigator's global clinical impression rating, safety profile assessment.Results: A total of 185 adults and 115 children with mean 4.4 months duration of epilepsy were included. At inclusion the mean daily valproate dose in children was 329 mg and 568 mg in adults. The mean treatment duration in both children and adults was 5.5 months. At the end of 6 months 74.7% of the patients were seizure-free (children and adults; 79.1% vs 71.9%). The number of seizure free patients at 1 month was 109 (36.3%) and 175 (58.3%) at month 3. The treatment retention rate at 6 months was 87.3% with small higher trend in adults than children (88.6% vs. 85.2%). Among the patients 9.3% experienced side effects like drowsiness and weight gain. No severe adverse event was reported.Conclusion: Sodium valproate sustained release formulation is effective for the first-line treatment of partial epilepsy in both adults and children with acceptable tolerabilityJ. Natl Inst. Neurosci Bangladesh 2015;1(1):2-4

Valproate-Related Hyperammonemia in Older Adult Psychiatric Inpatients.

To the Editor: Valproate is indicated for treatment of seizure disorders and mania in bipolar disorder and is prescribed off-label to treat impulsivity, aggression, irritability, and agitation in other disorders. Prescribing information for valproate includes warnings for hyperammonemic encephalopathy in individuals with urea cycle disorders and for hyperammonemia despite normal liver function tests. A cohort study of 123 valproate-treated psychiatric inpatients (mean age of 45.1 years) reported a valproate-related hyperammonemia rate of 51.2%.1 Neuropsychiatric manifestations of valproate-related hyperammonemia can include lethargy, tremor, ataxia, and mental status changes, although patients may be asymptomatic.1–3 In older adult patients, age-related metabolic changes and greater vulnerability of the aged brain may increase risk for mental status changes. Published literature on valproate-related hyperammonemia in older adults is limited to case reports without comparison to patients not taking valproate.4 This study aimed to ascertain the clinical significance of valproate-related hyperammonemia in older adult psychiatric inpatients by determining (1) whether, in the absence of liver disease, valproate-related hyperammonemia is more frequent in older adult psychiatric inpatients taking valproate compared to those not taking valproate and (2) the frequency of clinically significant adverse effects of valproate-related hyperammonemia in older adult psychiatric inpatients. Method. This retrospective chart review study, approved by the University of Maryland Institutional Review Board, examined the medical records of all admissions to the Older Adult Psychiatric Inpatient Unit at the University of Maryland Medical Center, Baltimore, Maryland, from October 2007 to April 2010. A total of 235 patients met the following inclusion criteria: (1) age ≥ 50 years, (2) available routine admission screening levels of ammonia, aspartate aminotransferase (AST) and alanine aminotransferase (ALT), (3) AST and ALT levels less than twice the upper normal limits, and (4) no history of active liver disease. Hyperammonemia was defined as a plasma ammonia level ≥ 35 μmol/L.5 Patients were grouped by valproate status at admission. Continuous variables were analyzed by Mann-Whitney U test for grouped analyses and Spearman ρ for correlations. Categorical variables were analyzed by χ2 tests with continuity correction for 2 group analyses. Analysis by race was limited to the 2 most populated categories. All tests were 2-tailed with statistical significance set as P ≤ .05 and performed using SPSS 21.0 (SPSS Inc, Chicago, Illinois). Results. Median ammonia level and rate of hyperammonemia in patients taking valproate at admission were significantly greater than in patients not taking valproate at admission (Table 1). Otherwise, there were no significant differences between groups on variables assessed. In patients taking valproate, ammonia level correlated significantly with valproate dose (ρ = 0.337, n = 37, P = .042), but not with serum levels of valproate (ρ = −0.015, n = 26, P = .940), AST (ρ = 0.059, P = .718), or ALT (ρ = 0.181, P = .264). Diagnoses (DSM-IV) of the 40 patients taking valproate were mood disorders (n = 18), schizoaffective disorder (n = 10), schizophrenia (n = 6), and dementia with behavioral disturbance (n = 6). The 29 patients with valproate-related hyperammonemia were compared to the 11 patients taking valproate without hyperammonemia; the only variable demonstrating significant difference was valproate dose (U = 81, P = .033). Patients with hyperammonemia had a higher median valproate daily dose of 1,000 mg compared to 750 mg in patients without hyperammonemia. Three of 29 patients with valproate-related hyperammonemia (mean ammonia level of 74 μmol/L) had clinically significant adverse effects—cognitive impairment in all 3 and tremors in one. Table 1 Older Adult Psychiatric Inpatients Grouped by Valproate Use To our knowledge, this is the first study to examine the frequency of hyperammonemia in a sample of older adults taking valproate compared to those not taking valproate. Valproate use increased risk for hyperammonemia 2-fold (relative risk = 2.18, confidence interval = 1.65–2.86). Clinically significant adverse effects occurred in approximately 10% of patients with valproate-related hyperammonemia at ammonia levels around twice the upper normal limit. Clinicians should obtain ammonia levels when mental status changes arise in older adults taking valproate.

Combined Blockade of AMPA and NMDA Receptors Produces Maximal Suppression of the Development of Corasol Kindling in Rats

Chronic enteral administration of the standard antiepileptic drug sodium valproate at a dose of 200 mg/kg suppressed the development of generalized clonic-tonic corasol-kindled convulsions in 100% of rats but prevented kindled clonic convulsions in only 57%. This dose of sodium valproate decreased the mean severity of corasol-kindled convulsions by a factor of 1.7. Chronic enteral administration of IEM-2121, which induces combined blockade of AMPA and NMDA glutamate receptors, and IEM-1676, which blocks AMPA and NMDA receptors, as well as n-cholinoreceptors, given at doses of 10 and 20 mg/kg, respectively, had greater anticonvulsive activity than sodium valproate, as they decreased the mean severity of corasol-kindled convulsions by factors of 2.4–2.7 as compared with controls and prevented kindled clonic convulsions in 87% of rats. Combined blockade of AMPA and NMDA receptors and, possibly, n-cholinoreceptors, produced the greatest suppression of epileptogenesis in relation to both clonic and clonic-tonic corasol-kindled convulsions.

Seminal fluid analysis and testicular volume in adults with epilepsy receiving valproate

Epilepsy and its medications adversely affect reproductive and sexual functions and fertility. This study aimed to assess sperm parameters and testicular volume in men with epilepsy on valproate (VPA). Included were 55 patients with idiopathic epilepsy with a mean age of 31.86±standard deviation (SD) 6.55years, mean illness duration of 12.50±SD 5.10years, and a mean treatment time of 9.55±SD 0.85years. Sex hormone profile, semen analysis, testicular volume and total seminal plasma carnitine were determined. Compared to controls, patients had lower levels of free testosterone (p<0.01), sperm concentration (p<0.0001) and count (p<0.0001), carnitine (p<0.01), and testicular volume (p<0.01), and higher rates of immotile sperm (p<0.001) and abnormal forms (p<0.0001). Significant correlations were identified between sperm count, motility, immotile sperm, abnormal forms, testicular volume, carnitine levels and duration of illness, duration of treatment with VPA and VPA dose. Multivariable analysis demonstrated that duration of treatment with VPA, sperm count, motility and abnormal forms were significantly associated with seminal plasma carnitine. Long-term VPA treatment is adversely associated with reduced sperm count and motility, increased abnormal sperm count and reduced testicular volume. This may contribute to reduced fertility.

Pharmacologically relevant doses of valproate upregulate CD20 expression in three diffuse large B-cell lymphoma patients in vivo.

BackgroundEpigenetic code modifications by histone deacetylase inhibitors (HDACi) have been proposed as potential new therapies for lymphoid malignancies. Diffuse large B-cell lymphoma (DLBCL) is the most common type of aggressive lymphoma for which standard first line treatment is the chemotherapy regimen CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone) combined with the monoclonal anti-CD20 antibody rituximab (R-CHOP). The HDACi valproate, which has for long been utilized in anti-convulsive therapy, has been shown to sensitize to chemotherapy in vitro. Valproate upregulates expression of CD20 in lymphoma cell lines; therefore, 48 hour pre-treatment with valproate before first line R-CHOP in DLBCL stages II-IV is evaluated in the phase I clinical trial VALFRID; Valproate as First line therapy in combination with Rituximab and CHOP in Diffuse large B-cell lymphoma.FindingsPretreatment with valproate at oral doses comparable to anti-convulsive therapy, resulted in upregulation of CD20 mRNA and CD20 protein on the cell surface as measured by qPCR and FACS analysis in lymphoma biopsies from three evaluated patients from the VALFRID study. Valproate-treatment corresponded to increased acetylation of Histone3Lysine9 (H3K9ac) in peripheral blood mononuclear cells (PBMCs), which were employed as surrogate tissue for valproate-related epigenetic modifications.ConclusionsValproate treatment at pharmacologically relevant doses resulted in upregulation of CD20 in vivo, and also in expected epigenetic modifications. This suggests that pre-treatment with valproate or other HDACis before anti-CD20 therapy could be advantageous in CD20-low B-cell lymphomas. Further studies are warranted to evaluate this conclusion.

To stop or not to stop? Combined use of valproate and electroconvulsive treatment

Objective: Clinical decision regarding the combination of valproate and electroconvulsive treatment have been contradictory. Concerns exist that anticonvulsants that are used a mood stabilizers may interfere with seizure during ECT. This report examines the clinical use of concurrent ECT and valproate in full dose and reduced dose for manic episode of bipolar disorder. Methods: We studied the records of 75 consecutive non-epileptic bipolar disorder manic episode patients referred for ECT between the months of April 2010 and July 2013 in an psychiatric hospital. We compared mean stimulus intensity, mean seizure duration, number of ECTs administered and change in Young Mania Scale scores between those who were on full dose valproate, 40% reduced dose valproate and those who were not on valproate or other mood stabilizers. Results: Valproate free group and %40 reduced valproate dose group did not significantly differ in seizure duration (p=0.078) but full dose valproate group had significantly shorter seizure duration than valproate free group (p=0.038). The full dose valproate group had significantly higher number of ECT sessions required. The treatment combination was well tolerated, with no serious adverse events observed in full dose or reduced dose valproate groups. All 75 patients had significantly reduced scores on Young Mania Scale. Discussion: Concurrent use of valproate with ECT in bipolar diorder manic episode seems safe, did not interfere with routine ECT practice, and allowed for transition to maintenance pharmacotherapy. Prospective studies are required to confirm these findings and also to compare cognitive adverse effects.

Seizure worsening caused by low serum valproate levels from an interaction between valproate and meropenem

We present an interaction of meropenem with valproate in an epileptic child, leading to seizure exacerbations owing to the rapid lowering of serum valproate concentration. An increase of seizure frequency and somnolence were observed in the patient after the addition of meropenem to the treatment, and a rapid decline of valproate serum concentrations was observed after two doses of meropenem. This decline was the most likely cause of the increase in seizure frequency. The dosage of valproate was raised and meropenem was stopped. Two days later, the seizures stopped. Five days later, the serum valproate concentrations raised to three fold, and they rose to therapeutic levels four weeks later. To avoid drug interaction that reduces the serum concentration of valproate, meropenem in epileptic patients using valproate for the treatment of epilepsy should be administered cautiously. If concominant administration is essential, close observation of serum concentration of valproate and clinical course of the patient are necessary. Keywords: Carbapenems, Drug interactions, Meropenem, Seizures, Valproate

Is Valproate Depressogenic in Patients Remitting from Acute Mania? Case Series.

Valproate is an effective antimanic agent and is recommended as a first-line medication in the treatment of acute mania. Current evidence based guidelines recommend that valproate should be given as a loading dose as it produces a rapid antimanic and antipsychotic response with minimal side-effects. However, no clear guidelines are available on the appropriate dosing or serum levels of valproate in the continuation or maintenance phase of bipolar disorder. We present 4 clinical cases to hypothesize that the higher doses of valproate, such as those used in the treatment of acute mania, may cause a depressive switch. So consideration should be given to reducing the dose of valproate if a patient develops depressive symptoms following recovery from the manic episode, as a therapeutic strategy. The cases also indicate that relatively lower doses and serum levels of valproate are effective in the maintenance phase compared to those needed in the acute manic phase of bipolar disorder. This is the first set of case series that questions the depressogenic potential of valproate in patients remitting from an acute manic episode. It highlights that different doses and serum levels of valproate may be therapeutic in different phases of bipolar disorder.

Prevalence of UGT1A6 polymorphisms in children with epilepsy on valproate monotherapy.

Valproate is a commonly used anticonvulsant drug. Uridine 5΄-diphospho (UDP)-glucuronosyltransferase (UGT) contributes to around 50% of valproate metabolism and its polymorphisms may be important for explaining the considerable variation in valproate levels in patients with epilepsy. This study was aimed to analyze the genetic polymorphisms of UGT1A6 in Indian children with epilepsy and their potential influence on the pharmacokinetics of valproate. This cross-sectional study was carried out in the Department of Pediatrics, All India Institutes of Medical Sciences (AIIMS), New Delhi, between March 2011 and July 2012. Children aged 3-12 years diagnosed with epilepsy on valproate monotherapy for at least 1 month were enrolled. They underwent a detailed clinical examination. The UGT1A6 polymorphisms were detected by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Random samples were checked by genetic sequencing. The steady-state plasma concentrations of valproate were measured by High Performance Liquid Chromatography (HPLC) and associated with UGT1A6 polymorphisms. A total of 80 children were studied. The prevalence of UGT1A6 T19G was as follows: TT (45%), TG (38.8%), and GG (16.3%); that of UGT1A6 A541G was: AA (48.8%), AG (38.8%), and GG (12.5%); and that of UGT1A6 A552C was: AA (43.8%), AC (40%), and CC (16.3%). The association between valproate doses or standardized serum valproate concentration and the various UGT1A6 genotypes could not be studied reliably in this small study population. The frequencies of UGT1A6 geneotypes and alleles were reported in the study population.

Neurodevelopmental and neurobehavioral aspects of childhood epilepsy

Objective The aim of this study was to declare the frequency of neurodevelopmental, behavioral, and psychiatric comorbidities associated with epilepsy and the relation of these disorders with several variables, including age at onset of epilepsy, duration of epilepsy, type of epilepsy, antiepileptic medications (monotherapy or polytherapy), and seizure frequency. Patients and methods This cross-sectional study included 50 epileptic children selected from those regularly attending the Neurology Outpatient Clinic in Mansoura University Children Hospital and already diagnosed with primary epilepsy and maintained on antiepileptic medications. They were subjected to full general and neurological assessment, Wechsler Intelligence Scale (IQ), Child Behavior Checklist, and Developmental Profile-3. Data were analyzed using SPSS program, version 16. Results Children with prolonged duration and earlier onset of epilepsy performed worse on Developmental Profile-3 assessment as they showed significantly delayed cognition, in addition to more attention problems and low IQ. Increased frequency associated with delayed cognitive, social, and communication development, low IQ, and attention problems were observed. Moreover, those with polytherapy were more significantly affected as regards cognition, communication, IQ, attention, social problems, thought problems, and anxiety depression. No significant differences were found between effects of sodium valproate and carbamazepine, but a high dose of valproate was associated with higher incidence of low IQ and cognitive and attention problems. Cognition, communication, and attention were more affected in patients with generalized epilepsy in comparison with those with partial epilepsy. Conclusion Childhood epilepsy is associated with cognitive deficits, intellectual decline, and behavioral problems, which are multifactorial, such as age of onset, frequency, type of seizure, prolonged seizures, antiepileptic drugs, and duration of epilepsy.

Late-onset neutropenia due to clozapine.

Sir, Clozapine is an antipsychotic drug effective against treatment-resistant schizophrenia. Compared with the classic neuroleptic drugs, clozapine carries a lower risk of extrapyramidal side effects.[1] Despite these advantages, clozapine-induced neutropenia and agranulocytosis can occur with a cumulative incidence of 2.7% and 0.73%, respectively.[2] Although the risk of blood dyscrasias is the highest during the first 6–18 weeks;[3] hence, this side effect can occur even after ≥5 years of treatment with clozapine.[4] Here, we report the case of a 46-year-old woman who developed neutropenia due to clozapine after 8 years of treatment. A 46-year-old woman with a history of schizophrenia since 2004 was treated with therapeutic doses of risperidone for the first 6 months after diagnosis. Because of the lack of improvement in her clinical status, risperidone was replaced by clozapine at an initial dose of 25 mg/day in December 2004; this dose was slowly titrated up to 300 mg/day. Because of her alterations in electroencephalography patterns, valproate 500 mg/day was added in May 2005. Sertraline 100 mg/day was initiated in September 2007 to treat depressive symptoms, and was discontinued in June 2008 because of the clinical improvement. Between 2004 and 2011, the results of hematological monthly monitoring were normal. Although the white blood cell (WBC) count was 6500/mm3 with an absolute neutrophil count (ANC) of 5100/mm3 in December 2011, it declined to 4100/mm3 and 3800/mm3, respectively, over 2 months (ANC was 3170/mm3 and 2660/mm3, respectively). In March 2012, her WBC count had dropped to 2100/mm3 with an ANC of 1280/mm3; however, there were no signs of infection. Laboratory tests and hematological consultations ruled out infectious diseases that could cause neutropenia. The results of her physical examination were unremarkable. After the diagnosis of neutropenia was made, all medications were discontinued, and blood counts were measured weekly. The WBC count reached the normal limit (WBC: 6300/mm3) within 3 weeks after the discontinuation of her medications. Since then, the patient's mental status has been stable with pharmacotherapy, including sertindole 16 mg/day and amisulpride 800 mg/day. Her clinical status remains good, without any recurrence of adverse hematological events. Neutropenia, in this case, could have been due to either clozapine or valproate or a combination of both. A case report described a patient who developed late-onset neutropenia because of sodium valproate; however, the drop in WBC counts emerged after dose escalation in this case.[5] To the best of our knowledge, delayed-onset neutropenia due to a stable dose of valproate has not yet been reported, although it has been observed in the association with a stable dose of clozapine, even after several years.[4] We cannot be certain drugs that caused by the side effect, because of both the drugs were discontinued at the same time, we believe that the neutropenia was most likely to be caused by clozapine. Our case report underscores the importance of regular blood monitoring in patients treated with clozapine. Clinicians should also be aware of other psychotropic medications that can impose the risk of blood dyscrasias. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.

Activation of AKT/GSK3β pathway by TDZD-8 attenuates kainic acid induced neurodegeneration but not seizures in mice

Activation of glycogen synthase kinase3β (GSK3β), an enzyme that regulates a multitude of cellular signaling pathways, is implicated in neurodegenerative processes observed in an array of CNS diseases. We examined the hypothesis that the pathological changes in an acute kainic acid (KA) induced excitotoxicity model, relevant to human temporal lobe epilepsy (TLE), could be sensitive to inhibition of GSK3β by 4-benzyl-2-methyl-1,2,4-thiadiazolidine-3,5-dione (TDZD-8) treatment in Swiss albino mice. Immediate seizure responses due to KA were recorded. Neurodegenerative and morphogenic changes were examined by western blot analysis and light microscopy, respectively, 48h after KA administration. Although tonic–clonic seizure episodes evoked by KA were unaffected, TDZD-8 pretreatment decreased KA mediated elevation in caspase-3 cleavage as well as increased Bcl2 and phospho-GSK3β (Ser9; pGSK3βSer9) expression. Likewise, microscopic examination also revealed that pretreatment with TDZD-8 attenuated cell damage elicited by KA in the CA1, CA3 and DG regions. In all the above parameters, the combined effect of a sub-effective dose of sodium valproate (SVP) with TDZD-8 was higher than that of solitary TDZD-8 treatment. The findings suggest that activated GSK3β orchestrated neurodegenerative alterations following KA treatment and its inhibition by TDZD-8 affords a distinct neuroprotective profile by activating Akt/GSK3β pathway which might act upstream of Bax/Bcl2 and caspase-3 pathways. Compounds targeting GSK3β activity might represent a novel therapeutic option for exploration as an adjunct to conventional anti-epileptic drugs in preventing neurodegenerative processes in TLE.

Gender-Dependent Actions of the Histone Deacetylase Blocker Sodium Valproate on Olfactory Learning in 129Sv Mice during the Early Postnatal Period

The processes of histone acetylation in the brain underlie both the mechanisms supporting the long-term stable effects of early experience, transmitted to offspring generations by epigenetic inheritance, and learning. However, the role of acetylation in learning has previously been studied only in adult animals: high levels of learning can be linked with high levels of histone H3 acetylation in the brain. The role of acetylation processes in the mechanisms of early learning has not been addressed. We report here our studies of the effects of blockade of histone deacetylation with sodium valproate, which increases the level of acetylation of histone H3, on the outcome of training to olfactory discrimination in 8-day-old mice of strain 129Sv, which have low levels of learning with simulation of maternal grooming. Four doses of sodium valproate, given from day 3 to day 6 of postnatal development, were found to have gender-dependent actions: there were selective improvements in learning in males but not females, though females showed this seen after repeated administration of physiological saline. The possible epigenetic mechanisms underlying these gender-related differences are discussed.

Weight and fat distribution in patients taking valproate: a valproate-discordant gender-matched twin and sibling pair study.

Chronic treatment with valproate (VPA) is commonly associated with weight gain, which potentially has important health implications, in particular increased central fat distribution. We utilized a VPA-discordant same-sex, twin and matched sibling pair study design to primarily examine for differences in fat distribution between patients with epilepsy treated with VPA compared to their matched twin or sibling control. Weight, blood pressure, and leptin levels were assessed. Height, weight, waist and hip measurements, exercise, blood pressure (BP), and serum leptin levels were measured. Body composition was measured using dual-energy x-ray absorptiometry (DXA). Abdominal fat was expressed as a percentage of the abdominal region (AFat%); and of whole body fat (WBF); (AFat%WBF). Mean within-pair differences were assessed (VPA-user and nonuser). Restricted maximum likelihood (REML) linear mixed model analysis was fitted to examine associations of anthropometrics, zygosity, gender, menopausal status, VPA dose and duration, with weight and AFat%. We studied 19 pairs of VPA-discordant, gender-matched (five male, 14 female) twins and siblings. Mean (standard deviation, SD) duration of therapy for VPA users was 11.0 (7.4) years. There were no statistically significant within-pair differences in age, height, weight, body mass index (BMI), BP, leptin level, WBF, AFat%, or AFat%WBF. For pairs in which VPA-user was treated for >11 years there were statistically significant mean within-pair differences in AFat%, (+7.1%, p = 0.03, n = 10 pairs), mean BP (+11.0 mm Hg, p = 0.006, n = 8 pairs); but not in AFat%WBF. VPA duration was positively associated with weight (estimate +0.98 kg/per year of VPA, p = 0.03); VPA treatment duration and dose were not significantly associated with AFat%. This study demonstrated a relationship between long-term VPA use and abdominal adiposity (AFat%), which could have significant health implications. We recommend ongoing monitoring of weight, BMI, and blood pressure for patients taking VPA.

Epilepsy doses of valproate combined with the anti-helminthic, niclosamide, synergistically kill myeloma cells: A potent new anti-myeloma drug combination

Using a drug-redeployment screening strategy, we have previously demonstrated that the anti-helminthic niclosamide is an effective anti-myeloma agent that targets the mitochondrial respiratory chain inducing production of mitochondrial superoxide (mitosox) and triggering apoptosis and autophagy. Here we show that rescreening of our drug library against niclosamide identified valproate which when used at anti-epilepsy doses alone, has little or no anti-myeloma activity, but in combination with niclosamide demonstrates potent synergistic myeloma cell killing.

Altered cortical thickness following prenatal sodium valproate exposure.

Prenatal exposure to sodium valproate (VPA) is associated with neurodevelopmental impairments. Cortical thickness was measured in 16 children exposed prenatally to VPA and 16 controls. We found increased left inferior frontal gyrus (IFG; BA45) and left pericalcarine sulcus (BA18) thickness, an association between VPA dose and right IFG thickness, and a close relationship between verbal skills and left IFG thickness. A significant interaction between group and hemispheric IFG thickness showed absence of the normal asymmetry in the IFG region of VPA-exposed children. These data provide preliminary insights into the putative neural basis of difficulties experienced by some VPA-exposed children.

Treatment for continuous spikes and waves during sleep (CSWS): survey on treatment choices in North America.

Current literature does not allow an evidence-based approach to the treatment of continuous spikes and waves during sleep (CSWS). The aim of this study was to describe treatment choices made by clinicians caring for patients with CSWS in North America. A 24-question survey on treatment choices for CSWS was distributed to the members of the American Epilepsy Society (AES). The survey presented a clinical vignette of CSWS. The questions addressed treatment choices for that clinical scenario. Surveys were self-administered and collected using an online survey website (www.surveymonkey.com). Two-hundred thirty-two surveys were completed. Prominent sleep-potentiated spiking was considered to warrant treatment by 81% of respondents. The proportion of patients in whom cognitive improvement occurs when sleep-potentiated spiking is effectively treated is in >75% of patients (according to 16% of respondents), in 25-75% of patients (according to 52% of respondents), in <25% of patients (according to 20% of respondents), and no or unclear cognitive changes (according to 12% of respondents). The preferred first choice to reduce sleep-potentiated epileptiform activity was high-dose benzodiazepines (47%), valproate (26%), and corticosteroids (15%). The preferred second-choice was valproate (26%), high-dose benzodiazepines (24%), and corticosteroids (23%). Among high-dose benzodiazepines, the preferred one was diazepam 1 mg/kg for one night followed by 0.5 mg/kg/day. The preferred dose of valproate was 30-49 mg/kg/day. Among corticosteroids the preferred choice was oral prednisone 2 mg/kg/day. The most commonly considered endpoints of treatment efficacy were (in decreasing order): response of epileptiform activity in electroencephalography (EEG), cognitive function, and seizure reduction. Results were consistent among respondents with different levels of training and clinical experience. There were differences in conceptualization and treatment approaches between pediatric and adult neurologists. Most clinicians considered that prominent sleep-potentiated epileptiform activity should be treated. There was no agreement on best treatment, but potential candidates included high-dose benzodiazepines, valproate, levetiracetam, and corticosteroids.

Alterations in BDNF (brain derived neurotrophic factor) and GDNF (glial cell line-derived neurotrophic factor) serum levels in bipolar disorder: The role of lithium

ObjectiveBrain-derived neurotrophic factor (BDNF) has been consistently reported to be decreased in mania or depression in bipolar disorders. Evidence suggests that Glial cell line-derived neurotrophic factor (GDNF) has a role in the pathogenesis of mood disorders. Whether GDNF and BDNF act in the same way across different episodes in bipolar disorders is unclear. MethodBDNF and GDNF serum levels were measured simultaneously by enzyme-linked immunosorbent assay (ELISA) method in 96 patients diagnosed with bipolar disorder according to DSM-IV (37 euthymic, 33 manic, 26 depressed) in comparison to 61 healthy volunteers. SCID- I and SCID-non patient version were used for clinical evaluation of the patients and healthy volunteers respectively. Correlations between the two trophic factor levels, and medication dose, duration and serum levels of lithium or valproate were studied across different episodes of illness. ResultsPatients had significantly lower BDNF levels during mania and depression compared to euthymic patients and healthy controls. GDNF levels were not distinctive. However GDNF/BDNF ratio was higher in manic state compared to euthymia and healthy controls. Significant negative correlation was observed between BDNF and GDNF levels in euthymic patients. While BDNF levels correlated positively, GDNF levels correlated negatively with lithium levels. Regression analysis confirmed that lithium levels predicted only GDNF levels positively in mania, and negatively in euthymia. LimitationsSmall sample size in different episodes and drug-free patients was the limitation of thestudy. ConclusionCurrent data suggests that lithium exerts its therapeutic action by an inverse effect on BDNF and GDNF levels, possibly by up-regulating BDNF and down-regulating GDNF to achieve euthymia.