Combination Of Valproate Research Articles

Mitochondrial Protective Role of Curcumin in Sodium Valproate-Induced Nephrotoxicity in Male Rats

Sodium valproate, a medicine for epilepsy and other neuropsychiatric disorders, damages kidney tissue, especially its mitochondria. Thus, the current research was aimed at evaluating the potential of curcumin against the sodium valproate-induced nephrotoxicity. Animals utilized in this research were categorized into six groups including the first group as control, the second as valproate (500mg/kg), the third, fourth, and fifth groups as rats treated with a combination of valproate and curcumin (25 up to 100 mg/kg), and the sixth group only was administrated with curcumin (100 mg/kg). All the treatments were performed for six consecutive weeks. The results indicated that the function and swelling significantly increased while membrane potential decreased in kidney mitochondria by using 100 mg kg-1 curcumin. Moreover, the protein carbonyl and malondialdehyde significantly decreased in kidney tissue, whereas glutathione slightly increased after curcumin treatment. Taken together, our findings for the first time suggested that curcumin confers mitochondrial protection against sodium valproate-induced nephrotoxicity and can be used to antagonize sodium valproate nephrotoxicity. Keywords: Curcumin; Kidney; Mitochondria; Nephrotoxicity.

Treatment outcomes in drug resistant juvenile myoclonic epilepsy: Valproate resistance may not be the end of the road

ObjectiveTo determine treatment responses to various antiseizure medicines (ASMs) in patients with drug resistant juvenile myoclonic epilepsy (DRJME) MethodsWe reviewed records of all JME patients attending epilepsy clinics at 5 centers during a 5-year period. We used International Consensus Criteria to diagnose JME and International League Against Epilepsy Criteria to define drug resistance and sustained seizure freedom. We only used broad spectrum medicines which included valproate, lamotrigine, topiramate, levetiracetam, clobazam, phenobarbitone, clonazepam, and zonisamide. We considered an ASM successful if patient achieved seizure freedom within 3 months of attaining maintenance dose. ResultsWe studied 116 patients (61 males) with DRJME. At terminal followup, 82 (70.7%) patients had achieved sustained seizure freedom with a mean followup of 3.2 ± 1.3 years after last dose change. In patients where valproate failed as first- or second-line ASM (n=70; 60.3%), 49(70%) became seizure-free. In this group, 33(67%) patients became seizure-free after addition of lamotrigine. Success rate of lamotrigine and valproate combination was 69% as compared to 9% with all other combinations (p = 0.001). In patients who were not exposed to valproate as initial therapy (n=46), 33 (71.7%) became seizure-free, 30 (91%) after adding valproate. At last follow-up, 75 (90%) seizure-free patients were receiving valproate including 45 (55%) patients with a combination of valproate and lamotrigine. Only one of 24 patients became seizure-free after failing valproate and lamotrigine combination. ConclusionSeizure freedom can be achieved in two-thirds of patients with DRJME. A combination of valproate and lamotrigine is the most effective duotherapy.

Entry of antiepileptic drugs (valproate and lamotrigine) into the developing rat brain.

Background:Women with epilepsy face difficult choices whether to continue antiepileptic drug treatment during pregnancy, as uncontrolled seizures carry great risk to mother and fetus but continuing treatment may have adverse effects on baby's development. This study aimed at evaluating antiepileptic drug entry into developing brain. Methods:Anaesthetised pregnant, non-pregnant adult females, postnatal and fetal rats were injected intraperitoneally with different doses, single or in combinations, of valproate and lamotrigine,within clinical range. Injectate included 3H-labelled drug. After 30min, CSF, blood and brain samples were obtained; radioactivitymeasured using liquid scintillation counting. Some animals were also exposed to valproate in feed throughout pregnancy and into neonatal period.Drug levelsmeasured by liquid chromatography coupled to mass spectrometry (LC-MS). Resultsgiven as CSF or tissue/plasma% as index of drug entry. Results:Entry of valproate into brain and CSF was higher at E19 and P4 compared to adult and was dose-dependent except at E19; placental transfer increased significantly at highest dose of 100mg/kg. Lamotrigine entry into the brain was dose dependent only at E19. Chronic valproate treatment, or combination of valproate and lamotrigine had little effect on either drug entry, except for reduced valproate brain entry in adult brain with chronic treatment. Placental transfer decreased significantly after chronic valproate treatment. LC-MS measurement of valproate in adults confirmed that rat plasma values were within the clinical range and CSF/plasma and brain/plasma ratios for LC-MS and 3H-valproate were similar. Conclusion:Results suggest that entry of valproate may be higher in developing brain, the capacity of barrier mechanism is mostly unaffected by doses within the clinical range, with or without addition of lamotrigine. Chronic valproate exposure may result in upregulation in cellular mechanisms restricting its entry into the brain. Entry of lamotrigine was little different at different ages and was not dose dependent.

Entry of antiepileptic drugs (valproate and lamotrigine) into the developing rat brain

Background: Women with epilepsy face difficult choices whether to continue antiepileptic drug treatment during pregnancy, as uncontrolled seizures carry great risk to mother and fetus but continuing treatment may have adverse effects on baby’s development. This study aimed at evaluating antiepileptic drug entry into developing brain. Methods: Anaesthetised pregnant, non-pregnant adult females, postnatal and fetal rats were injected intraperitoneally with different doses, single or in combinations, of valproate and lamotrigine, within clinical range. Injectate included 3H-labelled drug. After 30min, CSF, blood and brain samples were obtained; radioactivity measured using liquid scintillation counting. Some animals were also exposed to valproate in feed throughout pregnancy and into neonatal period. Drug levels measured by liquid chromatography coupled to mass spectrometry (LC-MS). Results given as CSF or tissue/plasma% as index of drug entry. Results: Entry of valproate into brain and CSF was higher at E19 and P4 compared to adult and was dose-dependent except at E19; placental transfer increased significantly at highest dose of 100mg/kg. Lamotrigine entry into the brain was dose dependent only at E19. Chronic valproate treatment, or combination of valproate and lamotrigine had little effect on either drug entry, except for reduced valproate brain entry in adult brain with chronic treatment. Placental transfer decreased significantly after chronic valproate treatment. LC-MS measurement of valproate in adults confirmed that rat plasma values were within the clinical range and CSF/plasma and brain/plasma ratios for LC-MS and 3H-valproate were similar. Conclusion: Results suggest that entry of valproate may be higher in developing brain, the capacity of barrier mechanism is mostly unaffected by doses within the clinical range, with or without addition of lamotrigine. Chronic valproate exposure may result in upregulation in cellular mechanisms restricting its entry into the brain. Entry of lamotrigine was little different at different ages and was not dose dependent.

Comparison of Adjunctive Quetiapine Versus Adjunctive Haloperidol in Combination with Sodium Valproate for Treatment of Patients with Mania or Mixed Feature Bipolar I Disorder: A Randomized Double-Blind Clinical Trial Study

Background: Acute mania causes many problems for the patient and others. Therefore, it is very important to eliminate the symptoms quickly. Objectives: The present study made the individual comparison of the therapeutic effects of sodium valproate combined with quetiapine or haloperidol as an add-on among patients with bipolar I disorder experiencing an episode of mania or mixed feature admitted to a Psychiatric Center in Tehran. Methods: The present study was a double-blind clinical randomized trial conducted on 36 patients. All patients were investigated by the Young Mania Rating Scale (YMRS). The study lasted six weeks in total (after raising drug dosage to the maximum level). We prescribed sodium valproate 15 mg/kg plus quetiapine 500 mg daily in one group and sodium valproate 15 mg/kg plus haloperidol 10 mg daily in the other group. In addition, an equivalent dosage of quetiapine and haloperidol was prescribed. This study used different data analysis methods such as Paired t test, ANOVA, and chi-square test. Results: The YMRS scores did not show any statistically significant difference between quetiapine and haloperidol receiving groups (P > 0.05). Conclusions: This paper argued that a combination of sodium valproate with either quetiapine or haloperidol could be effective in the management of acute mania or mixed bipolar I disorder to reduce the severity and duration of symptoms, although there was no statistically significant difference between the efficacy of these two pharmacological therapies.

Entry of antiepileptic drugs (valproate and lamotrigine) into the developing rat brain.

Background: Women with epilepsy face difficult choices whether to continue antiepileptic drug treatment during pregnancy, as uncontrolled seizures carry great risk to mother and fetus but continuing treatment may have adverse effects on baby's development. This study aimed at evaluating antiepileptic drug entry into developing brain. Methods: Anaesthetised pregnant, non-pregnant adult females, postnatal and fetal rats were injected intraperitoneally with different doses, single or in combinations, of valproate and lamotrigine, all within clinical range. Injectate included 3H-labelled drug. After 30min, CSF, blood and brain samples were obtained; radioactivity was measured using liquid scintillation counting. Some animals were also exposed to valproate in feed throughout pregnancy and into neonatal period. Drug levels were measured by liquid chromatography coupled to mass spectrometry (LC-MS). Results are given as CSF or tissue/plasma% as index of drug entry. Results: Entry of valproate into brain and CSF was higher at E19 and P4 compared to adult but was not dose-dependent; placental transfer increased significantly at highest dose of 100mg/Kg. Lamotrigine entry into the brain was dose dependent only at E19. Chronic valproate treatment, or combination of valproate and lamotrigine had little effect on either drug entry, except for reduced valproate brain entry in adult brain with chronic treatment. Placental transfer decreased significantly after chronic valproate treatment. LC-MS measurement of valproate in adults confirmed that rat plasma values were within the clinical range and CSF/plasma and brain/plasma ratios for LC-MS and 3H-valproate were similar. Conclusion: Results suggest that entry of valproate may be higher in developing brain, the capacity of barrier mechanism is mostly unaffected by doses within the clinical range, with or without addition of lamotrigine. Chronic valproate exposure may result in upregulation in cellular mechanisms restricting its entry into the brain. Entry of lamotrigine was little different at different ages and was not dose dependent.

Anticonvulsant Activity of Methanolic Extract of Acorus Calamus Leaves in Albino Mice

Acorus calamus, commonly known as sweet flag, has a long history of use in the treatment of a variety of ailmentsincluding inflammation, chest pain, digestive disorders and some mental illnesses. Its effects on the neurological conditions havebeen well documented for axinolytic and antidepressant activities. With this background, the aim of the present study is evaluatethe anticonvulsant activity of methanolic extract of Acorus calamus leaves in albino mice. The study included albino mice dividedinto 8 groups of 6 mice each. Maximum electroshock induced seizures (MES) and Pentylenetetrazole (PTZ) tests wereperformed on the animal models to evaluate the antiepileptic activity (4 groups were allocated to MES and 4 to PTZ). Themethanolic extract of Acorus calamus leaves exhibited a significant reduction in the duration of hind limb extensor phase in MESmodel (7.116±0.501 seconds for control and 9.116± 0.527 seconds for extract) and delayed the latency of seizures induced byPTZ (485.500±14.941 seconds) when compared with that of the control group (297.000±21.918 seconds). In addition, thegroups administered with the extract and sodium valproate in combination exhibited significant results in both MES and PTZmodels (T2- 92.61% and T4- 21.95 %, respectively). Preliminary phytochemical screening performed in several studies has shownthe presence of triterpenoids, flavonoids, saponins and tannins. The anticonvulsant activity of Acorus calamus may be mediated byits GABA potentiating activity. It can thus be concluded that the observed anticonvulsant effects could be the resultant of asynergistic action of these phytochemicals. Further studies should be undertaken to substantiate these results on various animalmodels along with a thorough phytochemical analysis and in silico studies to understand the mode of action of thesephytochemicals on various GABA receptor-mediated signaling.

Behavioral and Molecular Effects Induced by Cannabidiol and Valproate Administration in the GASH/Sal Model of Acute Audiogenic Seizures.

Despite evidence that supports cannabidiol (CBD) as an anticonvulsant agent, there remains controversy over the antiseizure efficacy, possible adverse effects, and synergistic interactions with classic antiepileptics such as valproate (VPA). The genetic audiogenic seizure hamster from the University of Salamanca (GASH/Sal) is a reliable experimental model of generalized tonic–clonic seizures in response to intense sound stimulation. The present study examines the behavioral and molecular effects of acute and chronic intraperitoneal administrations of VPA (300 mg/kg) and CBD (100 mg/kg) on the GASH/Sal audiogenic seizures, as well as the coadministration of both drugs. The GASH/Sal animals were examined prior to and after the corresponding treatment at 45 min, 7 days, and 14 days for seizure severity and neuroethology, open-field behaviors, body weight variations, and various hematological and biochemical parameters. Furthermore, the brain tissue containing the inferior colliculus (so-called epileptogenic nucleus) was processed for reverse transcription–quantitative polymerase chain reaction analysis to determine the treatment effects on the gene expression of neuronal receptors associated with drug actions and ictogenesis. Our results indicated that single dose of VPA helps prevent the animals from getting convulsions, showing complete elimination of seizures, whereas 7 days of chronic VPA treatment had few effects in seizure behaviors. Acute CBD administration showed subtle attenuation of seizure behaviors, increasing seizure latency and decreasing the duration of the convulsion phase, but without entirely seizure abolition. Chronic CBD treatments had no significant effects on sound-induced seizures, although some animals slightly improved seizure severity. Acute and chronic CBD treatments have no significant adverse effects on body weight, hematological parameters, and liver function, although locomotor activity was reduced. The combination of VPA and CBD did not alter the therapeutic outcome of the VPA monotherapy, showing no apparent synergistic effects. As compared to sham animals, chronic treatments with CBD caused abnormal mRNA expression levels for Trpv1, Adora1, Slc29a1, and Cnr1 genes, whereas no differences in gene expression were found for Htr1a and Sigmar1. Our study shed light on the behavioral and molecular effects of CBD and VPA on the GASH/Sal model and constituted the basis to develop further studies on the pharmacological effects of CBD and its interactions with other anticonvulsants.

Prescription patterns in clinically stable patients with bipolar disorder: Findings from the Bipolar Disorder Course and Outcome from India (BiD-CoIN) study.

To evaluate the prescription pattern of patients with BD, currently in clinical remission. Additional aim of the study was tocompare the prescription pattern across different study centres. Prescription of 773 patients, currently in clinical remission, recruited from the outpatient setting of 14 General Hospital Tertiary Care Units of tertiary care centres in the country were evaluated. Almost all (98.1 %) participants were on medications at the time of assessment. In terms of conventional mood stabilizers, those receiving valproate (44.2 %), out-numbered those receiving lithium (38.9 %). A small proportion (7.4 %) was receiving a combination of both valproate and lithium. About two-third (62.5 %) were receiving at least one antipsychotic medication, with olanzapine (31.7 %) being the most commonly prescribed antipsychotic, followed by quetiapine (11.1 %), and risperidone (9.6 %). About one-third (34.4 %) of the participants were receiving antidepressants, with sertraline (22.6 %) forming bulk of the prescription. Less than half (43.9 %) of the participants were also receiving a benzodiazepine medication at the time of assessment, with chlordiazepoxide (18 %) being the most common agent, followed by clonazepam (14.5 %). There was variation in the prescription patterns across different centres, in terms of monotherapy, polypharmacy, use of preferred conventional mood stabilizers, use of various antipsychotics and antidepressants. Besides conventional mood stabilizers, about two-third of patients with bipolar disorder received concomitant antipsychotics, one-third received concomitant antidepressants and less than half received benzodiazepines.

Defining phenotypes of long-term lithium and valproate response, including combination therapy: a modified application of the Alda scale in patients with bipolar disorders

BackgroundWhen evaluating the long-term treatment response to mood stabilizers using the Alda scale, mood stabilizer combination therapy is typically considered a confounding factor, and patients receiving combination therapy are excluded from the analysis. However, this may result in bias if those under combination therapy are worse treatment responders. This study aims to explore whether the Alda scale is applicable to patients taking lithium and valproate combination therapy. We compared long-term treatment response in patients receiving monotherapy and combination therapy of the two drugs, and investigated clinical correlates of the responses to each drug.MethodsThe study subjects consisted of 102 patients with bipolar I (BD-I) or bipolar II (BD-II) disorder who had been undergoing maintenance treatment with lithium and/or valproate for more than 2 years at a single specialized bipolar disorder clinic. Long-term treatment response was measured using the Alda scale and compared among the lithium monotherapy group, the valproate monotherapy group, and the mood stabilizer combination group. Clinical correlates of long-term treatment response were evaluated in lithium users and valproate users separately.ResultsThere were no significant differences in terms of baseline illness characteristics among groups. The combination group showed the worst treatment response for all the response measurements applied. This group also had the higher rate of ‘poor responder’ with a statistically significant difference compared to valproate group. Older age at onset and (hypo)manic episode at onset showed significant positive associations with total Alda score in lithium users, while comorbid anxiety disorders, obsessive–compulsive disorder and mixed episode showed significant negative associations in valproate users.ConclusionsThe combination group had poorer long-term treatment response but did not show distinct clinical characteristics compared to the monotherapy groups. When exploring the long-term effects of mood stabilizers, excluding patients undergoing combination treatment could result in bias because they may represent a poor response group. The long-term treatment responses of lithium and valproate had different clinical correlates.

Predictors of remission in patients with epilepsy.

To evaluate the rate and factors predicting seizure remission in a large cohort of patients with epilepsy. Patients with epilepsy treated at a university epilepsy clinic were included in this study. The following information was collected by means of a structured questionnaire: age, sex, age at onset of epilepsy, aetiology of epilepsy, the presence of intellectual disability, duration and type of epilepsy, frequency of seizures, treatment of epilepsy, and mechanism of action of antiepileptic drugs (AEDs). A total of 530 adult patients participated in this study (mean age ± standard deviation: 36.1 ± 12.6 years). Of these, 327 (61.7%) were female, and 364 (68.7%) patients had focal epilepsy. Twelve-month seizure freedom was achieved in 246 (46.4%) patients. Logistic regression revealed several independent predictors of seizure freedom: younger age (odds ratio (OR) = 0.98; p = 0.037), male sex (OR = 1.54; p = 0.050), generalised epilepsy (OR = 1.61; p = 0.052), lower number of prescribed AEDs (OR = 0.22; p = 0.001), and taking a combination of valproate and lamotrigine (OR = 2.51; p = 0.024). Most patients with epilepsy enter remission on monotherapy with their first or second AED. However, a substantial proportion of patients may benefit from combination therapy including valproate and lamotrigine polytherapy.

Three-drug combination of lacosamide, phenobarbital and valproate exerts additive interaction in the tonic-clonic seizure model in mice

Three-drug combination of lacosamide, phenobarbital and valproate exerts additive interaction in the tonic-clonic seizure model in mice

Clinical implications of trials investigating drug-drug interactions between cannabidiol and enzyme inducers or inhibitors or common antiseizure drugs.

Highly purified cannabidiol (CBD) has demonstrated efficacy with an acceptable safety profile in patients with Lennox‐Gastaut syndrome or Dravet syndrome in randomized, double‐blind, add‐on, controlled phase 3 trials. It is important to consider the possibility of drug‐drug interactions (DDIs). Here, we review six trials of CBD (Epidiolex/Epidyolex; 100 mg/mL oral solution) in healthy volunteers or patients with epilepsy, which investigated potential interactions between CBD and enzymes involved in drug metabolism of common antiseizure drugs (ASDs). CBD did not affect CYP3A4 activity. Induction of CYP3A4 and CYP2C19 led to small reductions in exposure to CBD and its major metabolites. Inhibition of CYP3A4 activity did not affect CBD exposure and caused small increases in exposure to CBD metabolites. Inhibition of CYP2C19 activity led to a small increase in exposure to CBD and small decreases in exposure to CBD metabolites. One potentially clinically important DDI was identified: combination of CBD and clobazam (CLB) did not affect CBD or CLB exposure, but increased exposure to major metabolites of both compounds. Reduction of CLB dose may be considered if adverse reactions known to occur with CLB are experienced when it is coadministered with CBD. There was a small increase of exposure to stiripentol (STP) when coadministered with CBD. STP had no effect on CBD exposure but led to minor decreases in exposure to CBD metabolites. Combination of CBD and valproate (VPA) did not cause clinically important changes in the pharmacokinetics of either drug, or 2‐propyl‐4‐pentenoic acid. Concomitant VPA caused small increases in exposure to CBD metabolites. Dose adjustments are not likely to be necessary when CBD is combined with STP or VPA. The safety results from these trials were consistent with the known safety profile of CBD. These trials indicate an overall low potential for DDIs between CBD and other ASDs, except for CLB.

Pharmacological prevention of mood episodes in women with bipolar disorder during the perinatal period: A systematic review of current literature.

This review examined the efficacy of mood stabilizers and antipsychotics in patients with bipolar disorder during pregnancy and the postpartum period. PubMed was searched for reports between 01 January 1996 and 31 December 2019 by using combinations of key words bipolar disorder, pregnancy, postpartum period, puerperium, prophylaxis, mood stabilizers, antipsychotics, lithium, lamotrigine, valproate, carbamazepine, oxcarbazepine, olanzapine, risperidone, quetiapine, aripiprazole, haloperidol, and chlorpromazine. The present reports included a total of 256 patients using lithium (n = 143), lamotrigine (n = 73), valproate (n = 17), olanzapine (n = 17), quetiapine (n = 4) and haloperidol (n = 1) during pregnancy or the postpartum period. Recurrence rates in pregnant patients using lithium (n = 79) and lamotrigine (n = 17) were 22.7 % and 41.2 %, respectively. According to very limited data, none of the patients using valproate (n = 2), quetiapine (n = 3) or olanzapine (n = 6) experienced a new episode during pregnancy. A recurrence was reported in 12 (70.6 %) of 17 patients using valproate during the postpartum period. The same recurrence rates in patients using lithium (n = 123), lamotrigine (n = 63), olanzapine (n = 17) and quetiapine (n = 3) were 20.3 %, 7.9 %, 11.7 %, and 33.3 %, respectively. This review suggests that lithium, lamotrigine and olanzapine seem to be effective in preventing new mood episodes in patients with bipolar disorder during the perinatal period.

Adult‐onset frequent non‐convulsive status epilepticus in a patient with ring chromosome 20 syndrome

AbstractWe report a 31‐year‐old woman with ring chromosome 20 syndrome who presented with epilepsy staring from 16 years old and loss of consciousness from 30 years old. Her neurological examinations and psychological testing were normal, without dysmorphic features. No abnormalities were found in neuroimaging. Electroencephalogram recording showed typical non‐convulsive status epilepticus associated with alteration of consciousness. Her diagnosis was based on the cytogenetic analysis indicating that her karyotype was 46, XX, r(20)(p13q13.3)[9]/46, XX[21]. She had refractory epilepsy and improved by a combination of valproate and lacosamide.

Gender characteristics of therapy for genetic generalized epilepsy in adults

Valproate is generally the drug of choice in genetic generalized epilepsy (GGE). But its therapy was changed after the appearance of the 2015 International League against Epilepsy (ILAE) recommendations to limit the dose of valproates in women. Objective: to assess the spectrum of antiepileptic drugs (AEDs) and to evaluate the efficiency of therapy in adults with GGE, in terms of the gender characteristics of the latter and the ILAE recommendations. Patients and methods. A retrospective open-label observational study was conducted. A cohort of patients was formed according to their visits to physicians in 2013 to 2017. Two patient groups were identified. Group 1 included 80 patients (35 males, 45 females); their mean age was 27.1±3.6 years; they were followed in 2013–2014. Group 2 consisted of 137 patients (53 males, 84 females); their mean age was 29.4±4.6 years; they visited their physicians in 2015–2017. The spectrum of AEDs that were used in monotherapy or polytherapy was assessed. The efficiency of therapy was determined by the onset of remission. Results and discussion. The patients of the two groups were matched for the spectrum of GGE syndromes. Most patients received valproates; more than 35% took levetiracetam; lamotrigine was used slightly less often. In Group 2, females used polytherapy more frequently than males (p=0.03). The percentage of achievement of clinical and encephalographic remission (CER) was higher in Group 2 (p=0.05); there was no significant difference in this indicator between men and women in the two groups. In Group 2, among those achieving CER, the percentage of patients receiving monotherapy decreased and that of those having polytherapy increased (p=0.02). The spectrum of AEDs used to achieve CEP remained unchanged in both groups; however, there was a significant difference in the drug dosing regimens. Conclusion. Current therapy for GGE is successful and leads to remission in most patients. After 2015, dual therapy for GGE is used significantly more often in women than in men (p<0.05). The combination of valproate with levetiracetam or lamotrigine predominates.

Incidence of Neutropenia with Valproate, Antipsychotics, and ADHD Medication Combination Treatment in Children and Adolescents.

This study's aim was to investigate whether the incidence of neutropenia was higher in subjects who received a combination pharmacotherapy with valproate (VPA), antipsychotics (APs), and attention deficit hyperactivity disorder (ADHD) medication than in those administered only VPA and APs combination pharmacotherapy. We conducted this study through retrospective review of medical records. We collected the records of 231 children admitted to the National Center for Mental Health. The incidence of neutropenia was significantly higher in the VPA–APs–ADHD combination group than in the other groups (55.2% vs. 25% vs. 12%, VPA + AP + ADHD vs. VPA + AP vs. AP). The presence of the combination of VPA, APs, and ADHD medication was a powerful predictor of neutropenia occurrence after adjusting for age, gender, and body mass index (odds ratio, 6.43; 95% confidence interval, 2.26–18.26; P < 0.001) The combination of VPA, APs, and ADHD medication in children with psychiatric disease appears to increase the incidence of drug-induced neutropenia.

Treatment of refractory and superrefractory status epilepticus with topiramate: A cohort study of 106 patients and a review of the literature.

Novel treatments are needed to control treatment-resistant status epilepticus (SE). We present a summary of clinical cases where oral topiramate (TPM) was used in refractory SE (RSE) and superrefractory SE (SRSE). A review of medical records was carried out to detect TPM administration in SE patients treated in Frankfurt and Marburg between 2011 and 2016. The primary outcome question concerned SE resolution after TPM initiation. In total, TPM was used in 106 of 854 patients having a mean age of 67.4±18.1years, 61 of whom were female (57.5%). The median latency from SE onset to TPM initiation was 8.5days. Patients with SE had previously failed a median of five other antiepileptic drugs. The median initial TPM dose was 100mg/d, which was uptitrated to a median maintenance dose of 400mg/d. Treatment with TPM was continued for a median time of 12days. TPM was the last drug provided to 42 of 106 (39.6%) patients, with a resultant response attributed to TPM observed in 29 of 106 (27.4%) patients. A response was attributed to TPM in 21 (31.8%) of 66 RSE cases and eight (20%) of 40 SRSE cases. Treatment-emergent adverse events were attributed to TPM usage in two patients, one each with pancreatitis and hyperchloremic acidosis, and in 38 patients (35.8%), hyperammonemia was seen. Thirty-four of these patients received a combination of TPM and valproate and/or phenobarbital. The intrahospital mortality rate was 22.6% (n=24). The rate of SE cessation attributed to TPM treatment (27.4%) represents a relevant response given the late treatment position of TPM and the treatment latency of more than8 days. Based on these results and in line with the findings of other case series, TPM can be considered an alternative option for treating RSE and SRSE.

Clinical characteristics and epilepsy in genomic imprinting disorders: Angelman syndrome and Prader-Willi syndrome.

Angelman syndrome (AS) and Prader–Willi syndrome (PWS) are considered sister imprinting disorders. Although both AS and PWS congenital neurodevelopmental disorders have chromosome 15q11.3-q13 dysfunction, their molecular mechanisms differ owing to genomic imprinting, which results in different parent-of-the-origin gene expressions. Recently, several randomized controlled trials have been proceeded to treat specific symptoms of AS and PWS. Due to the advance of clinical management, early diagnosis for patients with AS and PWS is important. PWS is induced by multiple paternal gene dysfunctions, including those in MKRN3, MAGEL2, NDN, SNURF-SNPRPN, NPAP1, and a cluster of small nucleolar RNA genes. PWS patients exhibit characteristic facial features, endocrinological, and behavioral phenotypes, including short and obese figures, hyperphagia, growth hormone deficiency, hypogonadism, autism, or obsessive– compulsive-like behaviors. In addition, hypotonia, poor feeding, failure to thrive, and typical facial features are major factors for early diagnosis of PWS. For PWS patients, epilepsy is not common and easy to treat. Conversely, AS is a single-gene disorder induced by ubiquitin-protein ligase E3A dysfunction, which only expresses from a maternal allele. AS patients develop epilepsy in their early lives and their seizures are difficult to control. The distinctive gait pattern, excessive laughter, and characteristic electroencephalography features, which contain anterior-dominated, high-voltage triphasic delta waves intermixed with epileptic spikes, result in early suspicion of AS. Often, polytherapy, including the combination of valproate, levetiracetam, lamotrigine, and benzodiazepines, is required for controlling seizures of AS patients. Notably, carbamazepine, oxcarbazepine, and vigabatrin should be avoided, since these may induce nonconvulsive status epilepticus. AS and PWS presented with distinct clinical manifestations according to specific molecular defects due to genomic imprinting. Early diagnosis and teamwork intervention, including geneticists, neurologists, rehabilitation physicians, and pulmonologists, are important. Epilepsy is common in patients with AS, and after proper treatment, seizures could be effectively controlled in late childhood or early adulthood for both AS and PWS patients.

Early polytherapy for benzodiazepine-refractory status epilepticus

The transition from single seizures to status epilepticus (SE) is associated with malaptive trafficking of synaptic gamma-aminobutyric acid (GABAA) and glutamate receptors. The receptor trafficking hypothesis proposes that these changes are key events in the development of pharmacoresistance to antiepileptic drugs (AEDs) during SE, and that blocking their expression will help control drug-refractory SE (RSE).We tested this hypothesis in a model of SE induced by very high-dose lithium and pilocarpine (RSE), and in a model of SE induced by sc soman. Both models are refractory to benzodiazepines when treated 40 min after seizure onset. Our treatments aimed to correct the loss of inhibition because of SE-associated internalization of synaptic GABAA receptors (GABAAR), using an allosteric GABAAR modulator, sometimes supplemented by an AED acting at a nonbenzodiazepine site. At the same time, we reduced excitation because of increased synaptic localization of NMDA and AMPA (?-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid and N-methyl-D-aspartate) receptors (NMDAR, AMPAR (?-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor, N-methyl-D-aspartate receptors)) with an NMDAR channel blocker, since AMPAR changes are NMDAR-dependent.Treatment of RSE with combinations of the GABAAR allosteric modulators midazolam or diazepam and the NMDAR antagonists dizocilpine or ketamine terminated RSE unresponsive to high-dose monotherapy. It also reduced RSE-associated neuronal injury, spatial memory deficits, and the occurrence of spontaneous recurrent seizures (SRS), tested several weeks after SE. Treatment of soman-induced SE also reduced seizures, behavioral deficits, and epileptogenesis. Addition of an AED further improved seizure outcome in both models. Three-dimensional isobolograms demonstrated positive cooperativity between midazolam, ketamine, and valproate, without any interaction between the toxicity of these drugs, so that the therapeutic index was increased by combination therapy.The midazolam–ketamine–valproate combination based on the receptor trafficking hypothesis was far more effective in stopping RSE than the midazolam–fosphenytoin–valproate combination inspired from clinical guidelines for the treatment of SE. Furthermore, sequential administration of midazolam, ketamine, and valproate was far less effective than simultaneous treatment with the same drugs at the same dose.These data suggest that treatment of RSE should be based at least in part on its pathophysiology. The search for a better treatment should focus on the cause of pharmacoresistance, which is loss of synaptic GABAAR and gain of synaptic glutamate receptors. Both need to be treated. Monotherapy addresses only half the problem. Improved pharmacokinetics will not help pharmacoresistance because of loss of receptors. Waiting for one drug to fail before giving the second drugs gives pharmacoresistance time to develop. Future clinical trials should consider treating both the failure of inhibition and the runaway excitation which characterize RSE, and should include an early polytherapy arm.This article is part of the Special Issue “Proceedings of the 7th London-Innsbruck Colloquium on Status Epilepticus and Acute Seizures"