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JAMA Network Open Feb 2024Use of valproate and certain other antiseizure medications (ASMs) in pregnancy is associated with abnormal fetal brain development with potential long-term implications...
IMPORTANCE
Use of valproate and certain other antiseizure medications (ASMs) in pregnancy is associated with abnormal fetal brain development with potential long-term implications for the child.
OBJECTIVE
To examine whether use of valproate and other ASMs in pregnancy among mothers with epilepsy is associated with epilepsy risk in their children.
DESIGN, SETTING, AND PARTICIPANTS
This prospective, population-based register cohort study included singletons born to mothers with epilepsy in Denmark, Finland, Iceland, Norway, and Sweden from January 1, 1996, to December 31, 2017. Data analysis was performed from October 2022 to December 2023.
EXPOSURE
Redeemed prescription for an ASM from 30 days before pregnancy until birth.
MAIN OUTCOMES AND MEASURES
The main outcome was epilepsy in children, assessed using International Statistical Classification of Diseases and Related Health Problems, Tenth Revision diagnoses from hospital care. Adjusted hazard ratios (AHRs) and 95% CIs were estimated using Cox proportional hazards regression. Secondary analyses included dose-response analyses, analyses using children of mothers who discontinued ASM prior to pregnancy as the reference, and sibling analyses.
RESULTS
This cohort study included 38 663 children of mothers with epilepsy (19 854 [51.4%] boys). Children were followed up from birth; the mean length of follow-up was 7.2 years (range 0-22 years). Compared with 22 207 children of mothers not using an ASM in pregnancy, increased risks of epilepsy in children of mothers who used valproate in pregnancy (monotherapy: AHR, 2.18; 95% CI, 1.70-2.79; polytherapy: AHR, 2.10; 95% CI, 1.49-2.96) were observed. However, there was no dose-dependent association, and there was a similar risk of epilepsy in siblings who were exposed and unexposed to valproate (AHR, 0.95; 95% CI, 0.50-1.82). Prenatal exposure to topiramate monotherapy was associated with increased risk of epilepsy (AHR, 2.32; 95% CI, 1.30-4.16), and the risk was greater for higher doses, but the risk attenuated in comparisons with children of mothers who discontinued topiramate before pregnancy (AHR, 1.19; 95% CI, 0.26-5.44). Prenatal exposure to clonazepam monotherapy was also associated with increased epilepsy risk (AHR, 1.90; 95% CI, 1.16-3.12), but limited follow-up and low numbers precluded further analyses. No associations were observed for prenatal exposure to lamotrigine (AHR, 1.18; 95% CI, 0.95-1.47), levetiracetam (AHR, 1.28; 95% CI, 0.77-2.14), carbamazepine (AHR, 1.13; 95% CI, 0.85-1.50), or oxcarbazepine (AHR, 0.68; 95% CI, 0.44-1.05).
CONCLUSIONS AND RELEVANCE
In this cohort study of children born to mothers with epilepsy, the associations found between prenatal exposure to certain ASMs and the child's risk of epilepsy did not persist in sensitivity analyses, suggesting that maternal ASM use in pregnancy may not increase epilepsy risk in children beyond that associated with the maternal epilepsy itself. These findings are reassuring for women in need of treatment with ASM in pregnancy.
Topics: Male; Child; Pregnancy; Humans; Female; Valproic Acid; Topiramate; Cohort Studies; Prenatal Exposure Delayed Effects; Prospective Studies; Epilepsy; Vitamins; Mothers
PubMed: 38407908
DOI: 10.1001/jamanetworkopen.2023.56425 -
Advances in Therapy Apr 2024This article aimed to assess the efficacy and tolerability of adjunctive brivaracetam (BRV) in adults with focal-onset seizures on specific concomitant antiseizure... (Randomized Controlled Trial)
Randomized Controlled Trial
Efficacy and Tolerability of Adjunctive Brivaracetam in Patients with Focal-Onset Seizures on Specific Concomitant Antiseizure Medications: Pooled Analysis of Double-Blind, Placebo-Controlled Trials.
INTRODUCTION
This article aimed to assess the efficacy and tolerability of adjunctive brivaracetam (BRV) in adults with focal-onset seizures on specific concomitant antiseizure medications (ASMs) taken as part of their treatment regimen.
METHODS
This was a post hoc analysis of pooled data from double-blind, placebo-controlled trials (N01252/NCT00490035, N01253/NCT00464269, and N01358/NCT01261325) in patients with uncontrolled focal-onset seizures randomized to BRV (50-200 mg/day) or placebo on the most common concomitant ASMs at trial initiation.
RESULTS
Nine concomitant ASMs were analyzed: carbamazepine (CBZ), lamotrigine (LTG), valproate (VPA), oxcarbazepine (OXC), topiramate (TPM), phenytoin (PHT), lacosamide (LCM), clobazam (CLB), and phenobarbital (PHB). Reduction over placebo in focal-onset seizure frequency per 28 days with BRV ranged from 11.7% (concomitant OXC) to 33.5% (concomitant PHB). The median percentage reduction from baseline in focal-onset seizure frequency per 28 days ranged from 25.5% to 42.8% in patients on BRV (placebo 4.4-21.2%); 50% responder rates ranged from 31.9% to 44.9% in patients on BRV (placebo 11.4-25.2%). In patients on BRV, seizure freedom ranged from 1.4% (concomitant PHT) to 12.5% (concomitant LCM); seizure freedom ranged from 0% to 1.2% in patients on placebo. All efficacy endpoints analyzed were consistently numerically higher in patients on BRV versus placebo. The overall incidence of treatment-emergent adverse events (TEAEs) was generally similar across subgroups by specific concomitant ASMs in patients on BRV (range 60.8-74.5%) or placebo (range 53.8-66.7%). Drug-related TEAEs were numerically higher across all subgroups by concomitant ASM in patients on BRV (range 35.2-48.3%) versus placebo (range 23.9-37.1%). Discontinuations due to TEAEs ranged from 2.9% to 13.3% in patients on BRV and was 0-5.7% for patients taking placebo across subgroups.
CONCLUSION
BRV was efficacious and well tolerated regardless of the specific concomitant ASMs used as part of their treatment regimen. These data show that in patients with focal-onset seizures, BRV provides additional efficacy to a broad range of ASMs.
Topics: Adult; Humans; Treatment Outcome; Drug Therapy, Combination; Seizures; Anticonvulsants; Lacosamide; Double-Blind Method; Pyrrolidinones
PubMed: 38356105
DOI: 10.1007/s12325-024-02795-z -
Therapeutic Advances in Neurological... 2024Paroxysmal kinesigenic dyskinesia (PKD) is a rare neurological disorder, characterized by attacks of involuntary movements triggered by sudden action. Variants in...
BACKGROUND
Paroxysmal kinesigenic dyskinesia (PKD) is a rare neurological disorder, characterized by attacks of involuntary movements triggered by sudden action. Variants in proline-rich transmembrane protein 2 () are the most common genetic cause of PKD.
OBJECTIVE
The objective was to investigate the clinical and genetic characteristics of PKD and to establish genotype-phenotype correlations.
METHODS
We enrolled 219 PKD patients, documented their clinical information and performed screening using Sanger sequencing. Whole exome sequencing was performed on 49 PKD probands without variants. Genotype-phenotype correlation analyses were conducted on the probands.
RESULTS
Among 219 PKD patients (99 cases from 39 families and 120 sporadic cases), 16 variants were identified. Nine variants (c.879+4A>G, c.879+5G>A, c.856G>A, c.955G>T, c.884G>C, c.649C>T, c.649dupC, c.649delC and c.696_697delCA) were previously known, while seven were novel (c.367_403del, c.347_348delAA, c.835C>T, c.116dupC, c.837_838insC, c.916_937del and c.902G>A). The mean interval from onset to diagnosis was 7.94 years. Compared to patients without variants, patients with the variants were more likely to have a positive family history, an earlier age of onset and a higher prevalence of falls during pre-treatment attacks (27.14% 8.99%, respectively). Patients with truncated variants tend to have bilateral attacks. We identified two transmembrane protein 151A () variants including a novel variant (c.368G>C) and a reported variant (c.203C>T) in two PRRT2-negative probands with PKD.
CONCLUSION
These findings provide insights on the clinical characteristics, diagnostic timeline and treatment response of PKD patients. PKD patients with truncated variants may tend to have more severe paroxysmal symptoms. This study expands the spectrum of and variants. Carbamazepine and oxcarbazepine are both used as a first-line treatment choice for PKD patients.
PubMed: 38250317
DOI: 10.1177/17562864231224110 -
Epilepsy & Behavior Reports 2024The management of epilepsy during pregnancy presents particular challenges for neurologists worldwide. Currently, there are no clear recommendations for oxcarbazepine...
The management of epilepsy during pregnancy presents particular challenges for neurologists worldwide. Currently, there are no clear recommendations for oxcarbazepine (OXC) specific target concentration during pregnancy. We conducted this retrospective observational cohort study on pregnant women with epilepsy (WWE) who received OXC monotherapy or polytherapy, at the epilepsy outpatient clinic of a tertiary hospital in eastern China. Sixteen pregnancies of 16 WWE were split into the seizure-free group or the non-seizure-free group, according to whether they had been seizure free for more than one year prior to conception or not. There was a significantly decrease in OXC concentration throughout pregnancy, as indicated by the concentration/dose ratio and the ratio of target concentration (RTC). The second trimester of pregnancy was the period when seizure deterioration occurred the most, particularly in the non-seizure-free group. Lower RTC_OXC was identified to be a risk factor for increasing seizure frequency in both the total group and the non-seizure-free group in both univariate and multivariate analysis, with a threshold of 0.575 for differentiating patients at high-risk and low-risk for seizure deterioration. In conclusion, this study suggested an OXC concentration threshold of 0.575 during pregnancy for assisting neurologists in OXC drug monitoring and dose adaptation.
PubMed: 38235017
DOI: 10.1016/j.ebr.2023.100640 -
Journal of Epilepsy Research Dec 2023Seizure aggravation in women with epilepsy (WWE) tends to occur at two specific times during the menstrual cycle: the perimenstrual phase and the ovulation period.... (Review)
Review
Seizure aggravation in women with epilepsy (WWE) tends to occur at two specific times during the menstrual cycle: the perimenstrual phase and the ovulation period. Antiseizure drugs (ASDs), especially those that induce enzymes, can accelerate the metabolism of hormones in oral contraceptives, rendering them less effective. Estrogen in contraceptive pills increases the metabolism of lamotrigine. Physiological changes during pregnancy can significantly impact the pharmacokinetics of ASDs, potentially necessitating adjustments in dosage for women with epilepsy to maintain seizure control. The use of valproate in pregnant women is associated with the highest risk of major congenital malformations among ASDs. Risks of major congenital malformations associated with lamotrigine, levetiracetam, and oxcarbazepine were within the range reported in the general population. Exposure to valproate can lead to lower IQ in offspring. Reduced folic acid levels are linked to orofacial clefts, cardiovascular malformations, and urogenital and limb anomalies in WWE. Decreased folate levels are expected with the use of enzyme-inducing ASDs. However, a high dose of folate was associated with an increased risk of cancer in children of mothers with epilepsy. Most ASDs are generally considered safe for breastfeeding and should be encouraged. However, no single ASD is considered ideal for childbearing WWE. Lamotrigine and levetiracetam are relatively more suitable options for this situation.
PubMed: 38223363
DOI: 10.14581/jer.23005 -
Medicine Dec 2023Cases with early diagnosis of neonatal tuberous sclerosis syndrome (TSC) are relatively seldom seen, and misdiagnosis of intracranial hemorrhage is even more rare. We...
INTRODUCTION
Cases with early diagnosis of neonatal tuberous sclerosis syndrome (TSC) are relatively seldom seen, and misdiagnosis of intracranial hemorrhage is even more rare. We retrospectively analyzed the clinical data of a case of neonatal tuberous sclerosis with atypical early symptoms and misdiagnosed as more common intracranial hemorrhage of the newborn.
PATIENT CONCERNS
The child was female and had no obvious cause of convulsion 12 days after birth. The local hospital was initially diagnosed as "neonatal intracranial hemorrhage, congenital heart disease," and still had convulsions after 5 days of treatment, so it was transferred to neonatal intensive care unit of our hospital.
DIAGNOSIS
After admission, cardiac color ultrasound, magnetic resonance imaging, and electroencephalogram were performed, and TSC was diagnosed in combination with clinical symptoms. However, no known pathogenic mutations such as TSC1 and TSC2 were detected by peripheral blood whole exon sequencing.
INTERVENTION
After a clear diagnosis, sirolimus, and vigabatrin were given. But there were still convulsions. Topiramate, valproic acid, and oxcarbazepine were successively added to the outpatient department for antiepileptic treatment, and vigabatrin gradually decreased.
OUTCOME
Up to now, although the seizures have decreased, they have not been completely controlled.
CONCLUSIONS
The TSC of neonatal tuberous sclerosis is different from that of older children. It is usually characterized by respiratory distress and arrhythmia, and may be accompanied by convulsions, but the activity between attacks is normal. However, neonatal intracranial hemorrhage can be caused by premature delivery, birth injury, hypoxia, etc. Its characteristics are acute onset, severe illness, and rapid progression. Consequently, the diagnosis of these 2 diseases should not only be based on medical imaging, but also be combined with their clinical characteristics. When the imaging features are inconsistent with the clinical diagnosis, a comprehensive evaluation should be made again. The timing and pattern of onset of neonatal convulsions can help in differential diagnosis. If there is cardiac rhabdomyoma, subependymal or cortical nodule, skin low melanoma, etc, the possibility of neonatal TSC should be considered, and the diagnosis should be made according to its diagnostic criteria to avoid or reduce misdiagnosis.
Topics: Female; Humans; Infant, Newborn; Diagnostic Errors; Fetal Diseases; Hemorrhage; Intracranial Hemorrhages; Mutation; Retrospective Studies; Seizures; Tuberous Sclerosis; Tuberous Sclerosis Complex 2 Protein; Tumor Suppressor Proteins; Vigabatrin
PubMed: 38206725
DOI: 10.1097/MD.0000000000036675 -
Heliyon Jan 2024Previous studies have shown that the rs717620 polymorphism in , the gene encoding multidrug resistance protein 2, influences the therapeutic response to anti-seizure...
BACKGROUND
Previous studies have shown that the rs717620 polymorphism in , the gene encoding multidrug resistance protein 2, influences the therapeutic response to anti-seizure medications (ASMs). However, this result is not consistent, and the mechanism by which rs717620 influences ASM responses is unclear.
AIMS
The present study evaluated the association between rs717620 genotype and ASM efficacy, and examined the potential mechanisms.
MAIN
methods: We conducted a literature search of five electronic databases, Embase, Medline, Web of Science, China National Knowledge Infrastructure, and Wanfang, to identify relevant studies on response to ASM therapy among rs717620 genotypes. Expression quantitative trait loci analysis and drug-gene interaction analysis were also performed to assess the underlying mechanisms.
KEY FINDINGS
The pooled results for 18 studies revealed a significant association between rs717620 genotype and ASM resistance under the recessive model (TT vs. CT + CC: OR = 1.68, 95 % CI = 1.27-2.21, I = 3.1 %). A significant association was also found in the Asian population under the recessive model (TT vs. CT + CC: OR = 1.70, 95 % CI = 1.26-2.29, I = 29.3 %). Further analysis revealed that rs717620 regulates the expression of in human brain, while drug-gene interaction analysis suggested that ABCC2 interacts with oxcarbazepine and carbamazepine.
SIGNIFICANCE
The rs717620 polymorphism influences ASM therapeutic responses by altering brain expression levels of
PubMed: 38192780
DOI: 10.1016/j.heliyon.2023.e23942 -
International Journal of Molecular... Dec 2023Experimental studies reveal that caffeine (trimethylxanthine) at subconvulsive doses, distinctly reduced the anticonvulsant activity of numerous antiseizure medications... (Review)
Review
Experimental studies reveal that caffeine (trimethylxanthine) at subconvulsive doses, distinctly reduced the anticonvulsant activity of numerous antiseizure medications (ASMs) in rodents, oxcarbazepine, tiagabine and lamotrigine being the exceptions. Clinical data based on low numbers of patients support the experimental results by showing that caffeine (ingested in high quantities) may sharply increase seizure frequency, considerably reducing the quality of patients' lives. In contrast, this obviously negative activity of caffeine was not found in clinical studies involving much higher numbers of patients. ASMs vulnerable to caffeine in experimental models of seizures encompass carbamazepine, phenobarbital, phenytoin, valproate, gabapentin, levetiracetam, pregabalin and topiramate. An inhibition of R-calcium channels by lamotrigine and oxcarbazepine may account for their resistance to the trimethylxanthine. This assumption, however, is complicated by the fact that topiramate also seems to be a blocker of R-calcium channels. A question arises why large clinical studies failed to confirm the results of experimental and case-report studies. A possibility exists that the proportion of patients taking ASMs resistant to caffeine may be significant and such patients may be sufficiently protected against the negative activity of caffeine.
Topics: Humans; Lamotrigine; Oxcarbazepine; Caffeine; Topiramate; Anticonvulsants; Seizures; Calcium Channels
PubMed: 38139396
DOI: 10.3390/ijms242417569 -
Molecules (Basel, Switzerland) Nov 2023The objective of the present report was to develop and validate a simple, selective, and reproducible high-performance liquid chromatography method with UV detection...
The objective of the present report was to develop and validate a simple, selective, and reproducible high-performance liquid chromatography method with UV detection suitable for routine therapeutic drug monitoring of the most commonly used antiepileptic drugs and some of their metabolites. Simple precipitation of plasma proteins with acetonitrile was used for sample preparation. 10,11-dihydrocarbamazepine was used as an internal standard. Chromatographic separation of the analytes was achieved by gradient elution on a Phenyl-Hexyl column at 40 °C, using methanol and potassium phosphate buffer (25 mM; pH 5.1) as a mobile phase. The method was validated according to the FDA guidelines for bioanalytical method validation. It showed to be selective, accurate, precise, and linear over the concentration ranges of 1-50 mg/L for phenobarbital, phenytoin, levetiracetam, rufinamide, zonisamide, and lacosamide; 0.5-50 mg/L for lamotrigine, primidone, carbamazepine and 10-monohydroxycarbazepine; 0.2-10 mg/L for carbamazepine metabolites: 10,11-trans-dihydroxy-10,11-dihydrocarbamazepine and carbamazepine-10,11-epoxide; 0.1-10 mg/L for oxcarbazepine; 2-100 mg/L for felbamate and 3-150 mg/L for ethosuximide. The suitability of the validated method for routine therapeutic drug monitoring was confirmed by quantification of the analytes in plasma samples from patients with epilepsy on combination antiepileptic therapy.
Topics: Humans; Anticonvulsants; Chromatography, High Pressure Liquid; Drug Monitoring; Carbamazepine; Oxcarbazepine
PubMed: 38067559
DOI: 10.3390/molecules28237830 -
Cureus Nov 2023Trigeminal neuralgia (TN) is a chronic neuropathic pain disorder characterized by paroxysms of electric shock-like or stabbing pain in the face. This condition is...
Trigeminal neuralgia (TN) is a chronic neuropathic pain disorder characterized by paroxysms of electric shock-like or stabbing pain in the face. This condition is associated with poor quality of life. First-line treatment includes carbamazepine or oxcarbazepine, but some cases show refractory symptoms to this approach. We describe a challenging case of secondary TN due to an advanced head and neck cancer managed by a palliative care team.
PubMed: 38060737
DOI: 10.7759/cureus.48393