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Journal of Neurology Oct 2023To compare the efficacy and safety of antiseizure medications (ASMs), both as monotherapies and adjunctive therapies, for idiopathic generalized epilepsies (IGEs) and... (Meta-Analysis)
Meta-Analysis Review
OBJECTIVES
To compare the efficacy and safety of antiseizure medications (ASMs), both as monotherapies and adjunctive therapies, for idiopathic generalized epilepsies (IGEs) and related entities.
METHODS
Two reviewers independently searched PubMed, Embase, and the Cochrane Library for relevant randomized controlled trials from December 2022 to February 2023. Studies on the efficacy and safety of ASM monotherapies or adjunctive therapies for IGEs and related entities-including juvenile myoclonic epilepsy, childhood absence epilepsy (CAE), juvenile absence epilepsy, or generalized tonic-clonic seizures alone (GTCA)-were included. Efficacy outcomes were the proportions of patients remaining seizure free for 1, 3, 6, and 12 months; safety outcomes were the proportions of any treatment-emergent adverse event (TEAE) and TEAEs leading to discontinuation. Network meta-analyses were performed in a random-effects model to obtain odds ratios and 95% confidence intervals. Rankings of ASMs were based on the surface under the cumulative ranking curve (SUCRA). This study is registered with PROSPERO (No. CRD42022372358).
RESULTS
Twenty-eight randomized controlled trials containing 4282 patients were included. As monotherapies, all ASMs were more effective than placebo, and valproate and ethosuximide were significantly better than lamotrigine. According to the SUCRA for efficacy, ethosuximide ranked first for CAE, whereas valproate ranked first for other types of IGEs. As adjunctive therapies, topiramate ranked best for GTCA as well as overall for IGEs, while levetiracetam ranked best for myoclonic seizures. For safety, perampanel ranked best (measured by any TEAE).
CONCLUSIONS
All of the studied ASMs were more effective than placebo. Valproate monotherapy ranked best overall for IGEs, whereas ethosuximide ranked best for CAE. Adjunctive topiramate and levetiracetam were most effective for GTCA and myoclonic seizures, respectively. Furthermore, perampanel had the best tolerability.
Topics: Humans; Child; Valproic Acid; Topiramate; Network Meta-Analysis; Levetiracetam; Ethosuximide; Anticonvulsants; Epilepsy, Generalized; Seizures; Randomized Controlled Trials as Topic
PubMed: 37378757
DOI: 10.1007/s00415-023-11834-8 -
The New England Journal of Medicine Mar 2024Maternal use of valproate during pregnancy has been associated with an increased risk of neurodevelopmental disorders in children. Although most studies of other...
BACKGROUND
Maternal use of valproate during pregnancy has been associated with an increased risk of neurodevelopmental disorders in children. Although most studies of other antiseizure medications have not shown increased risks of these disorders, there are limited and conflicting data regarding the risk of autism spectrum disorder associated with maternal topiramate use.
METHODS
We identified a population-based cohort of pregnant women and their children within two health care utilization databases in the United States, with data from 2000 through 2020. Exposure to specific antiseizure medications was defined on the basis of prescription fills from gestational week 19 until delivery. Children who had been exposed to topiramate during the second half of pregnancy were compared with those unexposed to any antiseizure medication during pregnancy with respect to the risk of autism spectrum disorder. Valproate was used as a positive control, and lamotrigine was used as a negative control.
RESULTS
The estimated cumulative incidence of autism spectrum disorder at 8 years of age was 1.9% for the full population of children who had not been exposed to antiseizure medication (4,199,796 children). With restriction to children born to mothers with epilepsy, the incidence was 4.2% with no exposure to antiseizure medication (8815 children), 6.2% with exposure to topiramate (1030 children), 10.5% with exposure to valproate (800 children), and 4.1% with exposure to lamotrigine (4205 children). Propensity score-adjusted hazard ratios in a comparison with no exposure to antiseizure medication were 0.96 (95% confidence interval [CI], 0.56 to 1.65) for exposure to topiramate, 2.67 (95% CI, 1.69 to 4.20) for exposure to valproate, and 1.00 (95% CI, 0.69 to 1.46) for exposure to lamotrigine.
CONCLUSIONS
The incidence of autism spectrum disorder was higher among children prenatally exposed to the studied antiseizure medications than in the general population. However, after adjustment for indication and other confounders, the association was substantially attenuated for topiramate and lamotrigine, whereas an increased risk remained for valproate. (Funded by the National Institute of Mental Health.).
Topics: Child; Female; Humans; Pregnancy; Anticonvulsants; Autism Spectrum Disorder; Autistic Disorder; Lamotrigine; Prenatal Exposure Delayed Effects; Topiramate; Valproic Acid; Epilepsy
PubMed: 38507750
DOI: 10.1056/NEJMoa2309359 -
Biomedicines May 2024The safety of the use of psychotropic drugs, widely used in neurological and psychiatric practice, is an urgent problem in personalized medicine. This narrative review... (Review)
Review
The safety of the use of psychotropic drugs, widely used in neurological and psychiatric practice, is an urgent problem in personalized medicine. This narrative review demonstrated the variability in allelic frequencies of low-functioning and non-functional single nucleotide variants in genes encoding key isoenzymes of valproic acid P-oxidation in the liver across different ethnic/racial groups. The sensitivity and specificity of pharmacogenetic testing panels for predicting the rate of metabolism of valproic acid by P-oxidation can be increased by prioritizing the inclusion of the most common risk allele characteristic of a particular population (country).
PubMed: 38790997
DOI: 10.3390/biomedicines12051036 -
JAMA Neurology May 2024Women with epilepsy (WWE) require treatment with antiseizure medications (ASMs) during pregnancy, which may be associated with an increased risk of major congenital... (Observational Study)
Observational Study
IMPORTANCE
Women with epilepsy (WWE) require treatment with antiseizure medications (ASMs) during pregnancy, which may be associated with an increased risk of major congenital malformations (MCMs) in their offspring.
OBJECTIVE
To investigate the prevalence of MCMs after prenatal exposure to 8 commonly used ASM monotherapies and changes in MCM prevalence over time.
DESIGN, SETTING, AND PARTICIPANTS
This was a prospective, observational, longitudinal cohort study conducted from June 1999 to October 2022. Since 1999, physicians from more than 40 countries enrolled ASM-treated WWE before pregnancy outcome was known and followed up their offspring until 1 year after birth. Participants aged 14 to 55 years who were exposed to 8 of the most frequently used ASMs during pregnancy were included in this study. Data were analyzed from April to September 2023.
EXPOSURE
Maternal use of ASMs at conception.
MAIN OUTCOMES AND MEASURES
MCMs were assessed 1 year after birth by a committee blinded to type of exposure. Teratogenic outcomes across exposures were compared by random-effects logistic regression adjusting for potential confounders and prognostic factors.
RESULTS
A total of 10 121 prospective pregnancies exposed to ASM monotherapy met eligibility criteria. Of those, 9840 were exposed to the 8 most frequently used ASMs. The 9840 pregnancies occurred in 8483 women (mean [range] age, 30.1 [14.1-55.2] years). MCMs occurred in 153 of 1549 pregnancies for valproate (9.9%; 95% CI, 8.5%-11.5%), 9 of 142 for phenytoin (6.3%; 95% CI, 3.4%-11.6%), 21 of 338 for phenobarbital (6.2%; 95% CI, 4.1%-9.3%), 121 of 2255 for carbamazepine (5.4%; 95% CI, 4.5%-6.4%), 10 of 204 for topiramate (4.9%; 95% CI, 2.7%-8.8%), 110 of 3584 for lamotrigine (3.1%; 95% CI, 2.5%-3.7%), 13 of 443 for oxcarbazepine (2.9%; 95% CI, 1.7%-5.0%), and 33 of 1325 for levetiracetam (2.5%; 95% CI, 1.8%-3.5%). For valproate, phenobarbital, and carbamazepine, there was a significant increase in the prevalence of MCMs associated with increasing dose of the ASM. Overall prevalence of MCMs decreased from 6.1% (153 of 2505) during the period 1998 to 2004 to 3.7% (76 of 2054) during the period 2015 to 2022. This decrease over time was significant in univariable logistic analysis but not after adjustment for changes in ASM exposure pattern.
CONCLUSIONS AND RELEVANCE
Of all ASMs with meaningful data, the lowest prevalence of MCMs was observed in offspring exposed to levetiracetam, oxcarbazepine, and lamotrigine. Prevalence of MCMs was higher with phenytoin, valproate, carbamazepine, and phenobarbital, and dose dependent for the latter 3 ASMs. The shift in exposure pattern over time with a declining exposure to valproate and carbamazepine and greater use of lamotrigine and levetiracetam was associated with a 39% decline in prevalence of MCMs, a finding that has major public health implications.
Topics: Humans; Female; Anticonvulsants; Adult; Pregnancy; Young Adult; Adolescent; Epilepsy; Abnormalities, Drug-Induced; Middle Aged; Longitudinal Studies; Pregnancy Complications; Prospective Studies; Valproic Acid; Prenatal Exposure Delayed Effects; Phenytoin; Lamotrigine; Carbamazepine; Phenobarbital; Cohort Studies; Oxcarbazepine; Prevalence
PubMed: 38497990
DOI: 10.1001/jamaneurol.2024.0258 -
The Medical Letter on Drugs and... Apr 2024
Topics: Humans; Bipolar Disorder; Antipsychotic Agents; Benzodiazepines
PubMed: 38576143
DOI: 10.58347/tml.2024.1699a -
Journal of Clinical Medicine Sep 2023Long-term medication with valproic acid has been associated with acute pancreatitis. The purpose of this report is to gain insight into the features of this... (Review)
Review
Long-term medication with valproic acid has been associated with acute pancreatitis. The purpose of this report is to gain insight into the features of this pancreatitis. A preregistered literature search (CRD42023438294) was performed on the National Library of Medicine, Excerpta Medica, Web of Science, and Google Scholar. Patients with alcohol abuse disorder, gallstone disease, hypertriglyceridemia or hypercalcemia, patients with acute valproic acid intoxication, and patients with a pre-existing pancreatitis were excluded. For the final analysis, we retained 73 reports published between 1979 and 2023, which described 125 subjects (83 children and 42 adults predominantly affected by an epilepsy) with an acute pancreatitis related to valproic acid. The diagnosis was made 11 (3.0-24) months (median and interquartile range) after starting valproic acid. One hundred and five cases (84%) recovered and twenty (16%) died. Sex, age, dosage or circulating level of valproic acid, latency time, prevalence of intellectual disability, and antiepileptic co-medication were similar in cases with and without a lethal outcome. Nineteen subjects were rechallenged with valproic acid after recovery: sixteen (84%) cases developed a further episode of pancreatitis. In conclusion, pancreatitis associated with valproic acid presents at any time during treatment and has a high fatality rate.
PubMed: 37762984
DOI: 10.3390/jcm12186044 -
CNS Drugs Sep 2023Although one of the major presentations of vestibular migraine is dizziness with/without unsteady gait, it is still classified as one of the migraine categories.... (Meta-Analysis)
Meta-Analysis
INTRODUCTION
Although one of the major presentations of vestibular migraine is dizziness with/without unsteady gait, it is still classified as one of the migraine categories. However, in contrast to ordinary migraine, vestibular migraine patients have distinct characteristics, and the detailed treatment strategy for vestibular migraine is different and more challenging than ordinary migraine treatment. Currently, there is no conclusive evidence regarding its management, including vestibular migraine prophylaxis.
AIM
The objective of this current network meta-analysis (NMA) was to compare the efficacy and acceptability of individual treatment strategies in patients with vestibular migraine.
METHODS
The PubMed, Embase, ScienceDirect, ProQuest, Web of Science, ClinicalKey, Cochrane Central, and ClinicalTrials.gov databases were systematically searched for randomized controlled trials (RCTs), with a final literature search date of 30 December 2022. Patients diagnosed with vestibular migraine were included. The PICO of the current study included (1) patients with vestibular migraine; (2) intervention: any active pharmacologic or non-pharmacologic intervention; (3) comparator: placebo-control, active control, or waiting list; and (4) outcome: changes in migraine frequency or severity. This NMA of RCTs of vestibular migraine treatment was conducted using a frequentist model. We arranged inconsistency and similarity tests to re-examine the assumption of NMA, and also conducted a subgroup analysis focusing on RCTs of pharmacological treatment for vestibular migraine management. The primary outcome was changes in the frequency of vestibular migraines, while the secondary outcomes were changes in vestibular migraine severity and acceptability. Acceptability was set as the dropout rate, which was defined as the participant leaving the study before the end of the trial for any reason. Two authors independently evaluated the risk of bias for each domain using the Cochrane risk-of-bias tool.
RESULTS
Seven randomized controlled trials (N = 828, mean age 37.6 years, 78.4% female) and seven active regimens were included. We determined that only valproic acid (standardized mean difference [SMD] -1.61, 95% confidence interval [CI] -2.69, -0.54), propranolol (SMD -1.36, 95% CI -2.55, -0.17), and venlafaxine (SMD -1.25, 95% CI -2.32, -0.18) were significantly associated with better improvement in vestibular migraine frequency than the placebo/control groups. Furthermore, among all the investigated pharmacologic/non-pharmacologic treatments, valproic acid yielded the greatest decrease in vestibular migraine frequency among all the interventions. In addition, most pharmacologic/non-pharmacologic treatments were associated with similar acceptability (i.e. dropout rate) as those of the placebo/control groups.
CONCLUSIONS
The current study provides evidence that only valproic acid, propranolol, and venlafaxine might be associated with beneficial efficacy in vestibular migraine treatment.
TRIAL REGISTRATION
CRD42023388343.
Topics: Adult; Female; Humans; Male; Migraine Disorders; Network Meta-Analysis; Propranolol; Valproic Acid; Venlafaxine Hydrochloride
PubMed: 37676473
DOI: 10.1007/s40263-023-01037-0 -
Tropical Doctor Oct 2023Post-hypoxic myoclonus (PHM) is a rare neurological complication having two different variants depending on acute or chronic onset after cardiopulmonary resuscitation... (Review)
Review
Post-hypoxic myoclonus (PHM) is a rare neurological complication having two different variants depending on acute or chronic onset after cardiopulmonary resuscitation following cardiac arrest: myoclonic status epilepticus (MSE) and Lance-Adams syndrome (LAS) respectively. Clinical and simultaneous electro-encephalographic (EEG) and electromyographic (EMG) tracing can distinguish between the two. Anecdotal treatment with benzodiazepines and anaesthetics (in the case of MSE) have been tried. Although limited evidence is available, valproic acid, clonazepam and levetiracetam, either in combination with other drugs or alone, have shown to control epilepsy associated with LAS effectively. Deep brain stimulation is a novel and promising advance in LAS treatment.
Topics: Humans; Myoclonus; Hypoxia; Clonazepam; Cardiopulmonary Resuscitation; Valproic Acid; Syndrome
PubMed: 37287278
DOI: 10.1177/00494755231181153 -
Neurology Jan 2024Valproate should be avoided in pregnancy, but it is the most effective drug for generalized epilepsies. Alternative treatment may require combinations of other drugs.... (Meta-Analysis)
Meta-Analysis
BACKGROUND AND OBJECTIVES
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.
METHODS
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.
RESULTS
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.
DISCUSSION
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.
CLASSIFICATION OF EVIDENCE
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.
Topics: Female; Humans; Pregnancy; Cohort Studies; Epilepsy, Generalized; Lamotrigine; Levetiracetam; Topiramate; Valproic Acid; Zonisamide; Infant, Newborn; Drug Combinations
PubMed: 38165339
DOI: 10.1212/WNL.0000000000207996 -
International Journal of Biological... Sep 2023Androgenetic alopecia (AGA) is a transracial and cross-gender disease worldwide with a higher prevalence among young individuals. Traditional oral or subcutaneous...
Fabrication of carboxymethyl cellulose/hyaluronic acid/polyvinylpyrrolidone composite pastes incorporation of minoxidil-loaded ferulic acid-derived lignin nanoparticles and valproic acid for treatment of androgenetic alopecia.
Androgenetic alopecia (AGA) is a transracial and cross-gender disease worldwide with a higher prevalence among young individuals. Traditional oral or subcutaneous injections are often used to treat AGA, however, they may cause severe side-effects and therefore effective treatments for AGA are currently lacking. In this work, to treat AGA, we developed a composite paste system based on minoxidil (MXD)-loaded nanoparticles and valproic acid (VPA) with the assistance of roller-microneedles (roller-MNs). The matrix of composite paste systems is carboxymethyl cellulose (CMC), hyaluronic acid (HA) and polyvinylpyrrolidone (PVP). The roller-MNs can create microchannels in the skin to enhance drug transdermal efficiency. With the combined effects of the stimulation hair follicle (HF) regrowth by upregulating Wnt/beta-catenin of VPA and the mechanical microchannels induced by roller-MNs, the as-prepared composite paste systems successfully boost perifollicular vascularization, and activate hair follicle stem cells, thereby inducing notably faster hair regeneration at a lower administration frequency on AGA mouse model compared with minoxidil. This approach offers several benefits, including the avoidance of efficacy loss due to the liver's first-pass effect associated with oral drug, reduction in the risk of infection from subcutaneous injection, and significant decrease in the side effects of lower-dose MXD.
Topics: Animals; Mice; Minoxidil; Valproic Acid; Hyaluronic Acid; Povidone; Carboxymethylcellulose Sodium; Lignin; Alopecia; Treatment Outcome; Nanoparticles
PubMed: 37517761
DOI: 10.1016/j.ijbiomac.2023.126013