Valproate Monotherapy Research Articles

Cognitive outcomes after fetal exposure to carbamazepine, lamotrigine, valproate or levetiracetam monotherapy: Data from the EURAP neurocognitive extension protocol

PurposePrenatal exposure to antiseizure medications (ASMs) has been associated with an increased risk of major malformations and neurodevelopmental disorders, with the latter being mainly associated with valproate (VPA). Our aim was to compare neurocognitive outcome at age 6–7 years in children exposed prenatally to lamotrigine (LTG), carbamazepine (CBZ), valproate (VPA) or levetiracetam (LEV) monotherapy. MethodsEligible mother–child pairs were identified from the observational prospective multinational EURAP cohort study. Assessor-blinded testing was conducted at age 6–7 years using WISC-III and NEPSY-II. Verbal IQ (VIQ), performance IQ (PIQ), full scale IQ (FSIQ) and performance in neuropsychological tasks were compared across ASM groups by ANOVA. Scores were adjusted for maternal IQ, paternal education, maternal epilepsy type and child sex. ResultsOf 169 children enrolled in the study, 162 (LTG n = 80, CBZ n = 37, VPA n = 27, LEV n = 18) had sufficient data from WISC-III, NEPSY-II or both, and were included in the analyses. Observed (unadjusted) PIQ and FSIQ did not differ across exposure groups, but a difference was identified for VIQ (P<0.05), with children exposed to VPA having lower scores than children exposed to LEV (P<0.05) and children from all groups combined (P<0.01). Adjusted VIQ, PIQ and FSIQ scores did not differ significantly across groups, but VPA-exposed children had borderline significantly lower adjusted VIQ scores than children from all groups combined (P=0.051). VPA-exposed children had lower scores in comprehension of instructions before and after adjustment for confounding variables than children exposed to LTG (P<0.001), LEV (P<0.01) or children from all groups combined (p < 0.001). The VPA-exposed group also had lower scores in immediate and delayed memory for faces compared to children exposed to CBZ (P<0.05 and P<0.001, respectively) and LTG (P<0.05 and P<0.02, respectively), and children from all groups combined (P<0.02 and P<0.001, respectively). LEV-exposed children had lower scores in delayed memory for names than children exposed to LTG (P<0.001), CBZ (P<0.001), VPA (P<0.05) and children from all groups combined (P<0.001). ConclusionsConsistent with previous reports, our results provide evidence for an adverse effect of prenatal exposure to valproate on verbal development. Our finding of relatively weaker performance of VPA-exposed children compared to other ASM exposures in both comprehension of instructions and face memory also suggest that children of mothers treated with VPA are at increased risk for compromised memory functions or altered processing of socially relevant information.

Is there any concern of insulin resistance and metabolic dysfunctions with antiseizure medications? A prospective comparative study of valproate vs. levetiracetam

PurposeTo evaluate the incidence of insulin resistance and its association with change in serum anti-seizure medication (ASM) level and their pharmacokinetic, body composition and metabolic hormones after six months of levetiracetam (LEV) exposure in persons with epilepsy (PWE) in comparison to valproate (VPA). MethodsThis prospective-longitudinal study included clinically diagnosed PWE on VPA or LEV monotherapy (for<3 months). At enrolment, body weight/composition, BMI were measured and blood samples were collected for assessing metabolic dysfunctions by estimation of serum insulin, insulin resistance [in terms of Homeostatic Model Assessment of Insulin Resistance (HOMA-IR)], leptin, adiponectin, lipid profile along with ASMs level. Subjects were followed up for six months and all the above parameters were reassessed. ResultsA total of 150 PWE were screened based on inclusion and exclusion criteria, and 105 number of subjects were enrolled (n = 35 in VPA and n = 70 in LEV group). Out of them, 92 subjects (n = 32 in VPA; n = 60 in LEV) completed six months follow-up. After six months, serum insulin level increased significantly in VPA group compared to baseline p < 0.001). Insulin resistance (HOMA-IR>2.5) was observed in 14.28 % of PWE in VPA group. Significantly higher percentage-change in body-weight (p = 0.003), leptin and decreased adiponectin were found in VPA-group compared to baseline ((p = 0.003, 0.02, 0.001, <0.001, respectively). These changes were independent of serum level or pharmacokinetic of VPA. On the other hand, no such changes were observed in LEV-group despite increased serum LEV level and altered pharmacokinetic parameters after six months. ConclusionSix months treatment with VPA resulted in insulin resistance and metabolic dysfunctions in PWE. These alterations were not correlated with change in VPA serum level. These changes were not observed in LEV therapy suggesting its better safety profile. This may be considered while prescribing the ASM like VPA and LEV in adult patients with obesity or insulin resistance and diabetes.

The Effect of Antiseizure Medications on Thyroid Functions in Children With Epilepsy

In this study, we aimed to investigate the effects of antiseizure medications on serum thyroid-stimulating hormone (TSH), free thyroxin (fT4) levels, and the frequency of subclinical hypothyroidism in children with epilepsy. One hundred and eighty-one pediatric patients receiving valproate, phenobarbital, carbamazepine, and levetiracetam monotherapy were included. The serum TSH levels were significantly higher at 6th, 12th, and 18th months of the treatment compared with the pre-treatment levels in valproate-treated patients. Serum fT4 levels in carbamazepine group were significantly lower than levetiracetam, valproate, and phenobarbital groups at 12th and 18th months of the treatment. Serum fT4 and TSH levels in levetiracetam group showed no significant changes at any time point. The frequency of subclinical hypothyroidism at 18th month was 16% in valproate, 11% in phenobarbital, 7% in carbamazepine, and 0% in levetiracetam groups. Our data suggest that levetiracetam monotherapy does not cause thyroid dysfunction.

Effect of SCN1Aand SCN2A gene polymorphisms on the efficacy of valproic acid treatment in Chinese children with epilepsy.

Epilepsy patients exhibit considerable differences in their response to sodium valproate (VPA) therapy, a phenomenon that might be attributed to individual genetic variances. The role of genetic variations, specifically in sodium channels encoded by SCN1A and SCN2A genes, in influencing the effectiveness of VPA in treating epilepsy is still debated. This research focuses on examining the impact of these genetic polymorphisms on the efficacy of VPA therapy among pediatric epilepsy patients in China. Five single nucleotide polymorphisms (SNPs), including SCN1A (rs10188577, rs2298771, rs3812718) and SCN2A (rs2304016, rs17183814), were genotyped in 233 epilepsy patients undergoing VPA therapy. The associations between genotypes and the antiepileptic effects of VPA were assessed, with 128 patients categorized as VPA responders and 105 as VPA non-responders. In the context of VPA monotherapy, SCN1A rs2298771 and SCN2A rs17183814 were found to be significantly associated with VPA response (P< 0.05). Our study suggests the findings of this investigation indicate that the polymorphisms SCN1A rs2298771 and SCN2A rs17183814 could potentially act as predictive biomarkers for the responsiveness to VPA among Chinese epilepsy patients.

Evaluation of Osteoporosis Among Epileptic Patients on Monotherapy

Epilepsy is a common chronic neurological disorder that affects almost 50 million people worldwide. Most patients require long-term, and sometimes lifelong therapy with antiseizure medications (ASMs), our case control study evaluates the long-term effect of carbamazepine (CBZ) and valproate (VPA) on bone mineral density and bone health biochemical markers. 50 patients with newly diagnosed epilepsy who had no history of antiseizure medications (ASMs) intake prior were divided into 2 groups. In the first group, 25 patients started carbamazepine (CBZ) monotherapy, while the second group included 25 patients who started receiving valproate (VPA) monotherapy. Another 25 healthy individuals were considered as a control group. The primary outcome of our study is to evaluate the percentage of osteoporosis compared to the duration of ASM therapy measured by the T score at two different sites in the body at baseline, after 3 and 6 months of therapy, while measurements of bone biomarker variables are considered secondary outcomes. We found that CBZ and VPA significantly decreased the level of vitamin D3, Ca, P, the L3-L5, and right femoral neck T score with prolonged treatment duration, while the level of ALP increased with increasing duration of treatment in patients treated with CBZ but not in the VPA group. Furthermore, CBZ significantly decreased bone health biomarkers and T score before VPA and the control group, as well as there were no significant differences between the two sexes who received CBZ or VPA therapy on bone biomarkers. In conclusion, valproate will not affect bone biomarkers earlier, but with a longer duration of therapy, they may have the same effect as carbamazepine which requires the prescription of supportive vitamin D and Ca along with ASMs.

Effect of Antiepileptic Drugs on Serum Vitamin B12 and Folic Acid Among Children with Epilepsy in Bangalore

In India, there are more than 12 million people diagnosed with epilepsy, and contributes nearly to the one sixth of global burden. Over 60% of diagnosis for epilepsy is done in childhood; hence, it is of major importance to pediatricians. we aimed to assess the levels of Vitamin B12 and Folic acid among children with epilepsy receiving antiepileptic drugs like Carbamazepine, Sodium Valproate and Levetiracetam monotherapy for &gt;1 year. A total of 77 children with epilepsy (&lt;18 years), on monotherapy with SV, CBZ, LEV, for minimum one year, were enrolled after obtaining consent from the parent/guardian. Children with co morbid condition like chronic kidney disease, chronic liver disease, those children who were on multiple AED’s, and children receiving treatment for &lt;1year were excluded from the study. Out of the 77 patients, who were selected for the study, 46 were males and 31 were females. There has been a significant association between duration of treatment and Vitamin B12 and levels of Folic acid. There is also enough evidence to show that age of the patient and Folic acid levels are dependent variables. The proportion of children developing deficiency of Vitamin B12 or Folic acid after treatment with LEV is greater than the proportion treated with CBZ. The proportion of patients developing deficiency of Folic acid after treatment with LEV is greater than the same proportion after treatment with CBZ. Though there were a few significant findings as reported, we, the authors, feel that the study should be continued to ascertain if the AED’s have a significant role in Vitamin B12 and Folic acid metabolism and supplementation should be advised along with the AED’s.

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

To evaluate changes in posterior segment parameters in pediatric patients with epilepsy using sodium valproate or levetiracetam monotherapy for at least 12months. This study included 45 children with generalized epilepsy aged 6-17years 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 20-40mg/kg/day, group 2 included patients using levetiracetam monotherapy at a dose of 20-40mg/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). 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). 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.

Comparative Risk of Major Congenital Malformations With Antiseizure Medication Combinations vs Valproate Monotherapy in Pregnancy.

Valproate should be avoided in pregnancy, but it is the most effective drug for generalized epilepsies. Alternative treatment may require combinations of other drugs. Our objectives were to describe first trimester use of antiseizure medication (ASM) combinations that are relevant alternatives to valproate and determine whether specific combinations were associated with a lower risk of major congenital malformations (MCM) compared with valproate monotherapy. We conducted a population-based cohort study using linked national registers from Denmark, Finland, Iceland, Norway, and Sweden and administrative health care data from the United States and New South Wales, Australia. We described first trimester use of ASM combinations among pregnant people with epilepsy from 2000 to 2020. We compared the risk of MCM after first trimester exposure to ASM combinations vs valproate monotherapy and low-dose valproate plus lamotrigine or levetiracetam vs high-dose valproate (≥1,000 mg/d). We used log-binomial regression with propensity score weights to calculate adjusted risk ratios (aRRs) and 95% CIs for each dataset. Results were pooled using fixed-effects meta-analysis. Among 50,905 pregnancies in people with epilepsy identified from 7.8 million total pregnancies, 788 used lamotrigine and levetiracetam, 291 used lamotrigine and topiramate, 208 used levetiracetam and topiramate, 80 used lamotrigine and zonisamide, and 91 used levetiracetam and zonisamide. After excluding pregnancies with use of other ASMs, known teratogens, or a child diagnosed with MCM of infectious or genetic cause, we compared 587 exposed to lamotrigine-levetiracetam duotherapy and 186 exposed to lamotrigine-topiramate duotherapy with 1959 exposed to valproate monotherapy. Pooled aRRs were 0.41 (95% CI 0.24-0.69) and 1.26 (0.71-2.23), respectively. Duotherapy combinations containing low-dose valproate were infrequent, and comparisons with high-dose valproate monotherapy were inconclusive but suggested a lower risk for combination therapy. Other combinations were too rare for comparative safety analyses. Lamotrigine-levetiracetam duotherapy in first trimester was associated with a 60% lower risk of MCM than valproate monotherapy, while lamotrigine-topiramate was not associated with a reduced risk. Duotherapy with lamotrigine and levetiracetam may be favored to treat epilepsy in people with childbearing potential compared with valproate regarding MCM, but whether this combination is as effective as valproate remains to be determined. This study provides Class II evidence that in people with epilepsy treated in the first trimester of pregnancy, the risk of major congenital malformations is lower with lamotrigine-levetiracetam duotherapy than with valproate alone, but similar with lamotrigine-topiramate.

Urinary N- acetyl - βeta -D- glucosaminidase (NAG) in children with epilepsy treated with sodium valproate monotherapy

Urinary N- acetyl - βeta -D- glucosaminidase (NAG) in children with epilepsy treated with sodium valproate monotherapy

Epilepsy in childhood and school performance: a nation-wide cohort study.

Childhood epilepsy has been linked to poor academic performance, but large-scale studies are lacking. In this nation-wide study of school-aged children, we examined the association between childhood epilepsy and school performance in standardized tests according to phenotypic and treatment-related characteristics. We performed a matched register-based cohort study of children born in Denmark (1997-2009) who participated in the Danish National School Test Programme between 2010 and 2019. We used population and health registers to identify children with epilepsy and a randomly sampled sex- and age-matched reference cohort without epilepsy (ratio 1:10). Norm-based test scores from language and mathematics reflecting performance as a percentile of the nation-wide distribution of scores (scale 1-100) were used to assess academic performance. Adjusted differences in mean standardized scores between children with and without epilepsy were estimated using linear regression models. Among 582 840 children participating in the School Test Programme, we identified 4659 (0.8%) children with epilepsy (52.8% males) and 46 590 matched reference children. Median age at epilepsy onset was 7.5 years (interquartile range: 4.0-10.6). Childhood epilepsy was associated with poorer school performance overall (mean score = 48.2 versus references = 56.7; adjusted difference = -6.7, 95% CI: -7.4 to -6.0), and worse performance was found in all epilepsy subgroups, including in 3534 children with uncomplicated epilepsy (i.e. no other pre-existing neurologic or intellectual disabilities and no identified possible cause for epilepsy; adjusted difference = -6.0, 95% CI: -6.8 to -5.2). No major variation by sex, age or subject was observed, but larger score differences were seen in children using antiseizure medication at time of testing (e.g. valproate monotherapy, adjusted difference = -9.3, 95% CI: -11.5 to -7.0 and lamotrigine monotherapy, adjusted difference = -13.1, 95% CI: -15.0 to -11.3) and in children with psychiatric comorbidity, especially epilepsy with comorbid intellectual disability (adjusted difference = -27.0, 95% CI: -30.0 to -23.9) and epilepsy with comorbid attention deficit/hyperactivity disorder (adjusted difference = -15.7, 95% CI: -19.0 to -12.4). Children with epilepsy scored significantly lower than their unaffected siblings (adjusted difference = -6.2, 95% CI: -7.1 to -5.4). In conclusion, childhood epilepsy was associated with impaired academic performance throughout schooling, which suggest that there is a widespread need for educational support of children with epilepsy, even when the child has no other comorbidities and when the epilepsy appears well-managed.

Effect of Valproate Monotherapy on Thyroid Function Tests and Magnesium Levels in Children With Epilepsy.

Antiseizure drug valproate alters thyroid functions. Magnesium is implicated in the pathogenesis of epilepsy and it may affect the efficacy of valproate and thyroid functions. To study the effect of six months of valproate monotherapy on thyroid functions and serum magnesium levels. To study the association among these levels and the effects ofclinicodemographic profile. Children aged three to 12 years presenting with newly diagnosed epilepsy were enrolled. A venous blood sample was collected for estimation of thyroid function test (TFT), magnesium, and valproate levels at onset and after six months of valproate monotherapy. Valproate levels and TFT were analyzed by chemiluminescence and magnesium by colorimetric method. Thyroid stimulating hormone (TSH) increased significantly from 2.14±1.64 µIU/ml at enrollment to 3.64±2.15 µIU/ml at six months (p<0.001), free thyroxine (FT4) decreased significantly (p<0.001). Serum magnesium (Mg) decreasedfrom 2.30±0.29 mg/dlto 1.94±0.28 mg/dl(p<0.001). At six months, eight out of 45 (17.77%) participants had significantly increased mean TSH levels (p=0.008). Serum valproate levels were not associated significantly with TFT and Mg (p<0.05). There was no effect of age, sex, or repeat seizures on the measured parameters. The TFT and Mglevels are altered by six months of valproate monotherapy in children with epilepsy. Hence we suggest monitoring and supplementation if required.

Effects of sodium valproate monotherapy on reproductive hormonal levels in adult male epileptic patients

Aims: to assess the effects of valproate (VPA) on serum levels of testosterone, prolactin, follicle stimulating hormone (FSH), luteinizing hormone (LH) and estradiol ( E2) in adult male epileptic patients in comparison to healthy controls. Methods: This study was conducted from Oct. 2005 to Aug. 2006. Patients were received from specialist neurology Clinic. Out of 62 patients interviewed only 46 fulfilled the criteria of selection . Apparently healthy 50 subjects were also included in this study as a control group. Blood samples were taken from both patients and controls and assay of testosterone, prolactin ,FSH, LH and E2 were done using radioimmunoassay (RIA) technique. Body mass index (BMI) was calculated using special equation. Results: There was a significantly higher testosterone levels in epileptic male patients on VPA therapy in comparison to healthy controls, with insignificant effect on the levels of prolactin, FSH, LH and E2. The duration of therapy and the dosage of VPA had no effect on the serum levels of the above measured parameters. Conclusion: VPA monotherapy might be associated with significant increase in serum testosterone level with insignificant effects on serum prolactin, FSH, LH and E2 in adult male epileptic patients and the duration of therapy and daily dose have no influence on such effect.

Immunoglobulins, Immunoglobulin G Subclasses and Complement C3,C4 Levels in Adult Epileptic Patients on Carbamazepine and Sodium Valproate

Objective:To assess the effects of long-term antiepileptic monotherapy (carbamazepine or sodium valproate ) on the levels of some immunological parameters ( immunoglobulins IgA, IgG, IgM , immunoglobulins G subclasses IgG1, IgG2, IgG3, IgG4 and complements C3, C4 in adult epileptic patients. Subjects and Methods: Eighty –one adult epileptic patients were included in this study , 43 on carbamazepine monotherapy and 38 on sodium valproate monotherapy , with 50 apparently healthy subjects age and sex matched taken as a control group . From both patients and control group 10 ml venous blood sample were taken and immunoglobulin serum levels (IgA, IgG, IgM) , immunoglobulin G subclass (G1, G2, G3, G4) and complement C3,C4 were assessed using kits ( Fitzgerald Industries Int. USA). Results: There was a significant reduction in IgM and IgG2 in epileptic patients on carbamazepine and a significant reduction in IgM, IgG2 and IgG4 in epileptic patients on valproate in comparison with controls. Conclusion: Carbamazepine and sodium valproate as long-term antiepileptic monotherapy have some effects on the immune-system parameters in adult epileptics.

The Study of Carotid Artery Intima-Media Thickness in Children With Epilepsy on Anti-Epileptic Drugs.

Objectives. To evaluate carotid artery intima-media thickness (CIMT) and lipid profile in children with epilepsy on long-term antiepileptic drug (AED) monotherapy. Methods. We included 60 children with epilepsy receiving valproate, carbamazepine, or levetiracetam monotherapy and 60 controls. A high-resolution B-mode ultrasound was used to measure (CIMT). Measurement of serum lipids was done. Results. Patients on valproate (0.44 ± 0.03, P ≤ .001), carbamazepine (0.43 ± 0.03with P ≤ .001), and levetiracetam (0.44 ± 0.02 with P ≤ .001) monotherapy showed significantly higher CIMT compared to controls. CIMT was correlated with age (P = .041, r = .112) AEDs{valproate (P = .005, r = .731), carbamazepine (P = .038, r = .365), and levetiracetam (P = .036, r = .155)}, duration of treatment (P = .001, r = .313), TC(P = .001, r = .192), TG (P = .014, r = .018), and LDL (P = .001, r = .219). HDL (P = .003, r = -.126). Seizure severity and Apo A1 were insignificantly involved. Conclusion. Long-term monotherapy with valproate, carbamazepine, and levetiracetam in epileptic children was associated with significant abnormalities in CIMT.

Comparison of myocardial perfusion between the users of two antiepileptic medications: valproate vs. carbamazepine.

The prevalence of coronary artery disease (CAD) is high in patients with epilepsy using antiepileptic drugs (AED). Epilepsy, AED, or the type and duration of AED use , may contribute to higher CAD risk.In this study, myocardial perfusion imaging (MPI) was compared between patients using carbamazepine and valproate. Out of 73 patients receiving carbamazepine or valproate monotherapy for more than 2 years, visited at a tertiary referral clinic, 32 patients participated in a 2-day stress and rest phases MPI. For each phase, 15-25 mCi 99mTc-MIBI was injected, at peak exercise or by pharmacologic stimulation for the stress phase. SPECT with cardiac gating was done by a dual-head gamma camera and processed and quantified. Scans with at least one definite reversible hypo-perfusion segment were considered abnormal. Seventeen patients received carbamazepine monotherapy and 15 valproates. Age and duration of AED use were similar between the groups. Two scans were abnormal (6.3%) both in valproate group (13.3%). Duration of AED use was higher in patients with abnormal scans. In patients receiving monotherapy >2 years, the frequency of abnormal MPI was similar between groups (P-value=0.12). In patients receiving monotherapy > 5 years, prevalence of abnormal MPI was higher in the valproate group (28.6% vs. 0.0%; P-value=0.042). Considering valproate subgroup, ischemic patients had higher duration of AED use, comparing with the normal patients (17.0±4.2 vs. 6.4±4.8, P-value=0.014). MPIs were abnormal in patients receiving valproate after 5 years compared to patients receiving carbamazepine. Long-term valproate use may increase the risk of CAD.

Serum Homocysteine Levels in Indian Children on Valproate Monotherapy

Introduction: Various research works have reported elevated serum homocysteine levels with the use of antiepileptic drugs. This may lead to an increased risk of atherosclerosis, a higher seizure frequency and may also cause cognitive decline. Methods: Twenty five children (Two to 12 years) on valproate monotherapy for more than one year and the same number of age and sex-matched healthy controls were enrolled. Venous blood samples were analyzed for serum homocysteine, vitamin B12 and folic acid levels. All biochemical parameters were compared between the groups. Results: The antiepileptic drug users had significantly lower serum homocysteine levels and higher B12 levels as compared to the controls. But serum folate levels were similar between the groups. No correlation of serum homocysteine levels was observed with either serum folate, B12 or valproate. Conclusions: The use of valproate monotherapy for epilepsy in the Indian paediatric population does not increase the risk of hyperhomocysteinemia.

Prognosticators of bone health in pediatrics with epilepsy using anti-epileptic drugs

Introduction: Epilepsy is a common and long-lasting neurological disorder in children who require long-term treatment with Antiepileptic drugs (AED). Such long-term AED use may have negative effects on bone causing bone loss and osteoporosis, necessitating frequent monitoring. Data on the effect of AED on bone health in children is scarce compared to adults and hence this study was undertaken. Aim: To compare and quantify the effects of sodium valproate (SV), carbamazepine (CBZ), and levetiracetam (LEV) on bone health in children using specific bone biomarkers such as vitamin D, calcium, phosphorus, ALP, osteocalcin (OCN), and beta serum cross laps (CTx). Materials and methods: A prospective interventional study was carried out in Rajarajeswari Medical College and Hospital, Bangalore, between October 2019 to March 2022. A total of 79 confirmed cases of epilepsy within the age group of 1-18 years, receiving treatment with sodium valproate (SV), carbamazepine (CBZ), and levetiracetam (LEV) monotherapy for a period of minimum one month were enrolled. Serum samples of calcium (Ca), phosphorus (PO4), alkaline phosphatase (ALP), Vitamin D were analyzed at the time of initiation of study and these levels were considered as baseline levels.

Insulin Resistance in children on Sodium Valproate - A hospital based cross-sectional study in Indian children.

Our objective was to compare the point prevalence of insulin resistance (IR) in children taking sodium valproate (VPA) and phenytoin sodium (PS) monotherapy for >1 year. 150 children, aged 6-18 years, were categorized (50 each) into - group A (VPA), group B (PS) and group C (healthy controls age-sex matched with group A). Groups were compared for metabolic complications and risk factors assessed. The point prevalence of IR and non-alcoholic fatty liver disease was significantly higher in children on VPA (12% and 34% respectively) than on PS and healthy controls, regardless of age, sex, pubertal and nutritional status. The presence of central obesity, acanthosis, hypertension, dyslipidaemia was significantly associated with IR but none showed an independent association on multivariate analysis. Therapy with VPA makes children susceptible to metabolic complications. Close monitoring will facilitate early detection and timely intervention.

Avis d’experts français sur la prise en charge des femmes en âge de procréer et enceintes souffrant d’un trouble bipolaire traitées par valproate

IntroductionThe perinatal period is associated with high risk of relapses in women with untreated bipolar disorder (BD) and can have significant consequences on foetal and child development. Valproate is an effective mood stabilizer in BD but it is also the anticonvulsant associated to the highest risks of neurodevelopmental disorders and congenital malformations. The National Agency for the Safety of Medicines and Health Products (ANSM) changed the conditions of use and prescription of valproate in France in 2015. Its prescription is now contraindicated (i.e., not to be prescribed) in women able to have children unless alternative treatments are ineffective or not tolerated. Moreover, valproate could only be prescribed if the protocol of a specific pregnancy prevention program is followed. MethodsA panel of experts from the French Association for Biological Psychiatry and Neuropsychopharmacology (AFPBN) provided consensus-based recommendations for switching and discontinuation of valproate in women with BD. The development of these recommendations consisted of an adaptation to French clinical practice based on a European expert opinion published in 2019. The experts discussed five real-world clinical situations in light of the scientific evidence and their clinical experience (a. Stable BD patient with valproate monotherapy who is planning pregnancy, b. Stable BD patient with valproate polytherapy who is planning pregnancy, c. Unstable BD patient with frequent relapses and valproate polytherapy who is planning pregnancy, d. Stable BD patient treated with valproate and unexpected pregnancy, e. Unstable BD patient treated with valproate and unexpected pregnancy) and developed, through several rounds of exchange drafts, a French version of clinical recommendations. ResultsFirst of all, some factors need to be considered for establishing personalized practical recommendations for a safe and effective switching or discontinuation of valproate in any clinical situations: planned pregnancy or unplanned pregnancy or current pregnancy, the existence or not of a pregnancy risk minimization program and a complete treatment history. Other factors that should be considered are the predominant polarity, the severity, the stability, the comorbidities associated with BD, the beliefs toward treatments, the family situation and the preference of the patient. The modalities for switching or discontinuation of valproate in women with BD were related to the clinical situation. First-line therapeutic alternatives such as lithium, lamotrigine, quetiapine, olanzapine or aripiprazole were preferred for patients suffering from a clinically stable BD considering pregnancy or pregnant. In patients suffering from clinically unstable BD, to reach stability was considered first. A shared decision-making should be systematically implemented and the patient must be fully informed of the risks related to an in-utero exposure to valproate, and the risks of the discontinuation/switch that is considered. ConclusionAlthough the adaptation to French practice of the recommendations from the European expert opinion highlighted some differences in the criteria taken into consideration to guide the therapeutic decision, this expert advice will guide the clinician for switching and discontinuation of valproate in BD women able to have children or pregnant.

UGT2B7 gene polymorphism and linkage disequilibrium in pediatric epileptic patients and their influence on sodium valproate monotherapy: A cohort study.

Background: Uridine 5′-diphospho glucuronosyl transferase (UGT) is the main enzyme responsible for the glucuronide conjugation, the principal metabolic pathway of sodium valproate. The objective of the study was to explore if there was an association between the UGT2B7 genetic polymorphism and clinical efficacy and safety in paediatric epileptic patients on sodium valproate monotherapy. Methods and materials: The cohort study included 100 pediatric epileptic patients aged 2–18 years who had been on sodium valproate monotherapy for at least 1 month. PCR-RFLP was carried out to assess the genetic polymorphism patterns of UGT2B7 (C161T, A268G, G211T). Based on the extent of seizure control throughout the 1-year follow-up, clinical outcome was assessed in terms of responders and non-responders. Hepatic, renal, and other lab parameters were assayed to determine safety. The SNPstat web software was used to calculate linkage disequilibrium. Results: Out of 100 patients, CC (38%), CT (43%), TT (19%) pattern was observed in UGT2B7 (C161T) gene, AA (15%), AG (39%), GG (46%) in (A268G) gene and GG (80%), GT (18%), TT (02%) in (G211T) gene. There was no statistical difference in clinical outcome with distinct UGT2B7 genetic polymorphism patterns, according to the findings. With low D′ and R2 values, linkage disequilibrium between alleles was statistically insignificant. However, the associations of C161T and G211T with treatment response were significant (p = 0.014) in determining treatment response. Conclusion: Our findings show that the genetic variation of UGT2B7 had no bearing on the clinical outcome of epilepsy. Gene interactions, on the other hand, had an impact on treatment response.