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Neurology Apr 2024To undertake a systematic review of the available literature to examine the relationship between prenatal antiseizure medication (ASM) exposure and adverse postnatal...
BACKGROUND AND OBJECTIVES
To undertake a systematic review of the available literature to examine the relationship between prenatal antiseizure medication (ASM) exposure and adverse postnatal neurodevelopmental outcomes, focusing on social, emotional, behavioral, and adaptive domains of human function, and the frequency of neurodevelopmental and psychiatric disorders in ASM-exposed offspring.
METHODS
Electronic searches of MEDLINE, PsychINFO, and EMBASE were conducted and limited to studies published between 1990 and 2023 in English. Studies were eligible if they prospectively or retrospectively reported neurodevelopmental outcomes of ASM-exposed offspring. The Newcastle-Ottawa scale was used to conduct methodologic quality assessments of included studies, and a narrative synthesis integrated the review findings.
RESULTS
Forty-three studies were included. Valproate has been consistently associated with a 2- to 4-fold increased risk of autism spectrum disorder (ASD), 2- to 5-fold increased risk of intellectual disability (ID), and poor adaptive functioning. Growing evidence indicates that topiramate is associated with a 2-fold increased risk of ASD and 3- to 4-fold increased risk of ID. The risks of adverse neurodevelopmental outcomes for valproate and topiramate seem to be dose dependent. Phenobarbital has been suggested to be associated with deleterious neurodevelopmental effects, but data are limited. Levetiracetam has recently been linked with an increased risk of attention deficit hyperactivity disorder and anxiety disorders in a single study. Carbamazepine has been associated with variable neurodevelopmental outcomes. Lamotrigine seems to be "safe" in terms of postnatal neurodevelopment. Data for oxcarbazepine, phenytoin, and clonazepam are limited but seem to have little-to-no risk of adverse outcomes. Evidence for the remaining ASMs, including gabapentin, pregabalin, lacosamide, zonisamide, clobazam, perampanel, ethosuximide, or brivaracetam, is lacking. Several methodologic limitations impeded data synthesis, including heterogeneity in outcome measures and small samples of monotherapy exposures.
DISCUSSION
The findings of this review support the conclusion that valproate and topiramate use during pregnancy is associated with a significantly increased risk of neurodevelopmental effects on the fetus. Apart from lamotrigine, which seems to be free of adverse neurodevelopmental effects, data for the other ASMs are mixed or inadequate to draw definite conclusions. Further research into the neurodevelopmental effects of prenatal exposure to ASMs, including most newer agents, is much needed.
Topics: Pregnancy; Female; Humans; Valproic Acid; Lamotrigine; Topiramate; Autism Spectrum Disorder; Retrospective Studies; Anticonvulsants
PubMed: 38531021
DOI: 10.1212/WNL.0000000000209175 -
Drug Safety Dec 2017β-lactam antibiotics are commonly prescribed antibiotic drugs. To describe the clinical characteristics, risk markers and outcomes of β-lactam antibiotic-induced... (Review)
Review
β-lactam antibiotics are commonly prescribed antibiotic drugs. To describe the clinical characteristics, risk markers and outcomes of β-lactam antibiotic-induced neurological adverse effects, we performed a general literature review to provide updated clinical data about the most used β-lactam antibiotics. For selected drugs in each class available in France (ticarcillin, piperacillin, temocillin, ceftazidime, cefepime, cefpirome, ceftaroline, ceftobiprole, ceftolozane, ertapenem and aztreonam), a systematic literature review was performed up to April 2016 via an electronic search on PubMed. Articles that reported original data, written in French, Spanish, Portuguese or English, with available individual data for patients with neurological symptoms (such as seizure, disturbed vigilance, confusional state, myoclonia, localising signs, and/or hallucinations) after the introduction of a β-lactam antibiotic were included. The neurological adverse effects of piperacillin and ertapenem are often described as seizures and hallucinations (>50 and 25% of cases, respectively). Antibiotic treatment is often adapted to renal function (>70%), and underlying brain abnormalities are seen in one in four to one in three cases. By contrast, the neurological adverse drug reactions of ceftazidime and cefepime often include abnormal movements but few hallucinations and seizures. These reactions are associated with renal insufficiency (>80%) and doses are rarely adapted to renal function. Otherwise, it appears that monobactams do not have serious neurological adverse drug reactions and that valproic acid and carbapenem combinations should be avoided. The onset of disturbed vigilance, myoclonus, and/or seizure in a patient taking β-lactam antibiotics, especially if associated with renal insufficiency or underlying brain abnormalities, should lead physicians to suspect adverse drug reactions and to consider changes in antibacterial therapy.
Topics: Adverse Drug Reaction Reporting Systems; Anti-Bacterial Agents; Drug-Related Side Effects and Adverse Reactions; Humans; Nervous System Diseases; beta-Lactams
PubMed: 28755095
DOI: 10.1007/s40264-017-0578-2 -
The Cochrane Database of Systematic... Feb 2022Seizures after stroke are an important clinical problem and may result in poor outcomes. The indications of antiepileptic drugs (AEDs) for seizure prophylaxis after... (Review)
Review
BACKGROUND
Seizures after stroke are an important clinical problem and may result in poor outcomes. The indications of antiepileptic drugs (AEDs) for seizure prophylaxis after stroke remain unclear. This is an updated version of the Cochrane Review previously published in 2014.
OBJECTIVES
To assess the effects of AEDs for the primary and secondary prevention of seizures after stroke. For primary prevention, we aimed to assess whether AEDs reduce the likelihood of seizures in people who have a stroke but do not have a seizure. For secondary prevention, we aimed to assess whether AEDs reduce the likelihood of further seizures in people who have a stroke and at least one post-stroke seizure.
SEARCH METHODS
We searched the following databases on 9 March 2021: Cochrane Register of Studies (CRS Web), MEDLINE (Ovid, 1946 to March 08, 2021). CRS Web includes randomised or quasi-randomised controlled trials from PubMed, Embase, ClinicalTrials.gov, the World Health Organisation International Clinical Trials Registry Platform (ICTRP), the Cochrane Central Register of Controlled Trials (CENTRAL), and the Specialised Registers of Cochrane Review Groups including Epilepsy and Stroke. We also checked the reference lists of articles retrieved from these searches.
SELECTION CRITERIA
We selected randomised and quasi-randomised controlled studies that recruited participants with a clinical diagnosis of stroke, either ischaemic or haemorrhagic. We excluded studies that only recruited participants with subarachnoid haemorrhage, subdural haemorrhage, extradural haemorrhage, or other non-stroke diagnoses such as tumour- or infection-related infarction or haemorrhage. We also excluded studies that recruited only participants who had undergone neurosurgery. We included participants of all ages suffering any seizure type who were assigned to AEDs or placebo groups.
DATA COLLECTION AND ANALYSIS
In accordance with standard methodological procedures expected by The Cochrane Collaboration, two review authors independently assessed trials for inclusion before evaluating trial risk of bias and extracting relevant data. The primary outcome assessed was the proportion of participants who experienced seizures in the follow-up period. We presented results as summary risk ratios (RRs) with 95% confidence intervals (CIs) for dichotomous outcomes and mean differences (MDs) with 95% CIs for continuous outcomes. Where we had sufficient data, we calculated random-effects (Mantel-Haenszel) meta-analyses for dichotomous outcomes; otherwise, we reported results narratively. We used the I statistic to analyse statistical heterogeneity. We planned to use funnel plots to assess publication bias in meta-analyses with at least 10 included studies. We used the GRADE approach to assess the certainty of the evidence.
MAIN RESULTS
Two studies with a total of 856 subjects were included. AEDs were not shown to be effective in primary prophylaxis of post-stroke seizure (RR 0.65, 95% CI 0.34 to 1.26; 2 studies, 856 participants; moderate-certainty evidence). The first study was a randomised double-blind study comparing valproic acid with placebo for primary seizure prevention up to one year after stroke. The study included 72 adults with intracerebral haemorrhage. There was no difference in the risk of post-stroke seizures (RR 0.88, 95% CI 0.35 to 2.16) or of death (RR 1.20, 95% CI 0.40 to 3.58). The second study was a substudy on the use of diazepam in acute stroke. It was a randomised double-blind study, comparing a three-day diazepam treatment versus placebo for primary seizure prevention up to three months after stroke in 784 adults with acute stroke. There was no evidence of a difference in the risk of post-stroke seizures for all stroke or subgroups of haemorrhagic or ischaemic stroke (RR for all stroke 0.47, 95% CI 0.18 to 1.22). In a subgroup analysis of anterior circulation cortical infarcts, primary prophylaxis with diazepam was associated with a reduced risk of post-stroke seizures (RR 0.21, 95% CI 0.05 to 0.95). Risks of mortality did not differ between the diazepam and the placebo group at two weeks (RR 0.84, 95% CI 0.56 to 1.26) and three months follow-up (RR 0.95, 95% CI 0.72 to 1.26). We assessed both studies to be at a low overall risk of bias. Using the GRADE approach, we assessed the overall certainty of the evidence as low to moderate.
AUTHORS' CONCLUSIONS
There is insufficient evidence to support the routine use of AEDs on the primary and secondary prevention of seizures after stroke. Further well-conducted studies are warranted for this important clinical problem.
Topics: Adult; Anticonvulsants; Brain Ischemia; Humans; Randomized Controlled Trials as Topic; Secondary Prevention; Seizures; Stroke
PubMed: 35129214
DOI: 10.1002/14651858.CD005398.pub4 -
Acta Psychiatrica Scandinavica Sep 2021Polypharmacy is common in maintenance treatment of bipolar illness, but proof of greater efficacy compared to monotherapy is assumed rather than well known. We... (Review)
Review
OBJECTIVES
Polypharmacy is common in maintenance treatment of bipolar illness, but proof of greater efficacy compared to monotherapy is assumed rather than well known. We systematically reviewed the evidence from the literature to provide recommendations for clinical management and future research.
METHOD
A systematic review was conducted on the use of polypharmacy in bipolar prophylaxis. Relevant papers published in English through 31 December 2019 were identified searching the electronic databases MEDLINE, Embase, PsycINFO, and the Cochrane Library.
RESULTS
Twelve studies matched inclusion criteria, including 10 randomized controlled trials (RCTs). The best drug combination in prevention is represented by lithium + valproic acid which showed a significant effect on time to mood relapses (HR = 0.57) compared to valproic acid monotherapy, especially for manic episodes (HR = 0.51). The effect was significant in terms of time to new drug treatment (HR = 0.51) and time to hospitalization (HR = 0.57). A significant reduction in the frequency of mood relapses was also reported for lithium + valproic acid vs. lithium monotherapy (RR=0.12); however, the trial had a small sample size. Lamotrigine + valproic acid reported significant efficacy in prevention of depressive episodes compared to lamotrigine alone.
CONCLUSIONS
The literature to support a generally greater efficacy with polypharmacy in bipolar illness is scant and heterogeneous. Within that limited evidence base, the best drug combination in bipolar prevention is represented by lithium + valproic acid for manic, but not depressive episodes. Clinical practice should focus more on adequate monotherapy before considering polypharmacy.
Topics: Antimanic Agents; Bipolar Disorder; Humans; Lithium Compounds; Polypharmacy; Valproic Acid
PubMed: 33960396
DOI: 10.1111/acps.13312 -
European Journal of Clinical... Aug 2020Cytochrome P450 (CYP) is involved in the metabolism of valproic acid (VPA). Specifically, CYP2C9 and CYP2A6 are the main enzymes responsible for VPA metabolism. However,... (Meta-Analysis)
Meta-Analysis
PURPOSE
Cytochrome P450 (CYP) is involved in the metabolism of valproic acid (VPA). Specifically, CYP2C9 and CYP2A6 are the main enzymes responsible for VPA metabolism. However, the correlation between plasma VPA concentrations and CYP2C9 and CYP2A6 gene variations is uncertain. This meta-analysis aimed to investigate the relationship between CYP2C9 and CYP2A6 variants and plasma concentrations of VPA.
METHODS
The PubMed, Web of Science, and EMBASE databases were searched for qualifying studies published until July 2019. Cohort studies that included standardized plasma VPA concentrations and CYP2C9 and CYP2A6 genotypes were reviewed. The mean difference and 95% confidence intervals (CIs) were evaluated to assess the strength of the relationship. Data analysis was performed using Review Manager (version 5.3) and RStudio (version 3.6).
RESULTS
In total, we analyzed data from six studies involving 807 patients. We found that CYP2C9*3 was associated with standardized plasma VPA concentration; *3 allele carriers had a 0.70-μg/mL higher concentration per mg/kg than non-carriers (95% CI 0.25, 1.15; P = 0.002). We also found a significant association between the CYP2A6*4 and standardized trough VPA concentration; patients with the *4 allele had a 0.48-μg/mL higher concentration per mg/kg than patients without the *4 allele (95% CI 0.10, 0.86; P = 0.01).
CONCLUSION
This meta-analysis demonstrated that CYP2C9*3 and CYP2A6*4 genetic variants affect plasma VPA concentrations. For epilepsy patients with these genotypes, dose adjustment may be necessary to ensure VPA's therapeutic effect.
Topics: Anticonvulsants; Cytochrome P-450 CYP2A6; Cytochrome P-450 CYP2C9; Epilepsy; Humans; Valproic Acid
PubMed: 32385545
DOI: 10.1007/s00228-020-02872-6 -
Seizure Nov 2014Glioblastoma multiforme (GBM) is the most lethal type of primary brain tumor, and patients that undergo the maximum tumor resection that is safely possible and standard... (Meta-Analysis)
Meta-Analysis Review
PURPOSE
Glioblastoma multiforme (GBM) is the most lethal type of primary brain tumor, and patients that undergo the maximum tumor resection that is safely possible and standard radiochemotherapy only achieve a median survival time of 14.6 months. Several clinical studies have reported that valproic acid could prolong survival of GBM patients. However, the results of these studies are inconsistent. We examined relevant studies and conducted a meta-analysis to assess the effects of VPA on survival times and recurrence.
METHODS
A bibliographic search was performed in the EMBASE, MEDLINE, ClinicalTrials.gov and Cochrane Central Register of the Controlled Trials databases to identify potentially relevant articles or conference abstracts that investigated the effects of VPA on the outcome of glioma patients. Five observational studies were included.
RESULTS
Pooled estimates of the hazard ratio (HR) and 95% confidence intervals (CI) were calculated. Our meta-analysis confirmed the benefit of using VPA (HR, 0.56; 95% CI, 0.44-0.71). Sub-group analysis shows that patients treated with VPA had a hazard ratio of 0.74 with a 95% confidence interval of 0.59-0.94 vs. patients treated by other-AEDs and a hazard ratio of 0.66 with a 95% confidence interval of 0.52-0.84 vs. patients treated by administration of non-AEDs. No heterogeneity was observed in the subset analysis.
CONCLUSION
The results of our study suggest that glioblastoma patients may experience prolonged survival due to VPA administration. Sub-analysis confirmed the benefit of VPA use compared to a non-AEDs group and an other-AEDs group. Further RCTs of this subject should be performed.
Topics: Adult; Brain Neoplasms; Glioblastoma; Humans; Neoplasm Recurrence, Local; Survival Analysis; Treatment Outcome; Valproic Acid
PubMed: 25066904
DOI: 10.1016/j.seizure.2014.06.015 -
CNS Drugs Nov 2017The necessity of annual laboratory follow-up in patients treated with valproic acid (VPA) is controversial. (Review)
Review
BACKGROUND
The necessity of annual laboratory follow-up in patients treated with valproic acid (VPA) is controversial.
OBJECTIVE
We investigated the need for annual laboratory follow-up of liver enzymes, electrolytes, and full blood count (FBC) in patients treated with VPA.
PATIENTS AND METHODS
A systematic search in Evidence-Based Medicine Reviews (EBMR), MEDLINE, and EMBASE was undertaken in December 2016 to identify all published articles investigating or citing valproic acid, liver function disorders, electrolyte disorders, and FBC deviations.
RESULTS
This review included 108 articles. As the number of participants and duration of the study was not adequate in most studies to detect rare adverse events, studies did not demonstrate a clear prevalence of hepatotoxicity. While a transient increase of transaminases is common and seldom harmful, severe hepatotoxicity is a rare phenomenon and is not prevented by routine laboratory monitoring. VPA had no relevant effect on serum calcium, sodium, potassium, and albumin. The prevalence of FBC varied from 0.6 to 27.8%, occurred mostly in the first 2 years of therapy, and was usually asymptomatic.
CONCLUSIONS
Long-term monitoring in VPA treatment is only necessary when there have been dose adjustments, co-medication switches, or co-morbidity. In uncomplicated cases, annual laboratory follow-up may be discontinued after 2 years of VPA treatment. Encouraging patients to be vigilant is more effective in the detection of hepatotoxicity than laboratory testing. Follow-up of FBC at 3-6 months, 1 year, and 2 years after start or after a dose increase of VPA or interacting medication is sufficient.
Topics: Anticonvulsants; Blood Cell Count; Clinical Enzyme Tests; Clinical Laboratory Techniques; Diagnostic Tests, Routine; Drug Monitoring; Drug-Related Side Effects and Adverse Reactions; Follow-Up Studies; Humans; Time Factors; Valproic Acid
PubMed: 29214384
DOI: 10.1007/s40263-017-0479-z -
Pharmaceuticals (Basel, Switzerland) May 2021The treatment of bipolar depression is hampered by the inadequate efficacy of antidepressants, moderate effect of mood stabilizers, and the side effects of some... (Review)
Review
The treatment of bipolar depression is hampered by the inadequate efficacy of antidepressants, moderate effect of mood stabilizers, and the side effects of some second-generation antipsychotics. There is limited evidence to date regarding the antidepressant effects of memantine in bipolar depression. The aim of the article was to provide a short review of preclinical and clinical studies on the antidepressant effect of memantine, and to present the case of a bipolar depression patient successfully treated with memantine. The described patient with bipolar disorder was unsuccessfully treated with two mood stabilizers. The addition of memantine at a dose of 20 mg/d to the treatment with lamotrigine and valproic acid resulted in a reduction in the severity of depression measured on the HDRS-17 scale by 35%, and by 47.1% after 7 weeks. The discussion presents experimental evidence for the antidepressant effect of memantine, as well as data from clinical trials in recurrent and bipolar depression. The presented case is the second report in the medical literature showing the antidepressant effect of memantine as an add-on treatment for bipolar depression. The described case and literature analysis indicate that memantine may be an effective and safe method of augmentation of mood stabilizing therapy in bipolar depression.
PubMed: 34070216
DOI: 10.3390/ph14050481 -
Epileptic Disorders : International... Aug 2022Epileptic myoclonus or myoclonic seizures can occur in idiopathic generalized epilepsy (IGE) and progressive myoclonus epilepsy (PME). However, symptomatic myoclonus... (Review)
Review
Epileptic myoclonus or myoclonic seizures can occur in idiopathic generalized epilepsy (IGE) and progressive myoclonus epilepsy (PME). However, symptomatic myoclonus which is stimulus-sensitive and provoked by movement is typically seen in PME and Lance-Adams syndrome. Symptomatic myoclonus is not always associated with epileptiform discharges on the electroencephalogram. Therapeutic interventions such as anti-seizure medications (ASMs), the ketogenic diet and vagus nerve stimulation are not always effective. There is emerging evidence that perampanel (PER), an α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist, may be effective for the treatment of myoclonic seizures and symptomatic myoclonus. We performed a systematic review of the literature to assess the efficacy of PER as treatment for myoclonic seizures and symptomatic myoclonus. Twenty-seven studies with a total sample size of 260 patients were included. The efficacy of PER was analysed separately for myoclonic seizures and symptomatic myoclonus. In the group with myoclonic seizures, 50% responder, 75% responder and seizure freedom rates were reported as 74.3% (101/ 136), 60.3% (82/136) and 57.4% (78/136), respectively, with a follow-up duration of 6-12 months. However, in one post-hoc analysis of data from patients with IGE, the efficacy of PER as treatment for myoclonic seizures during the double-blind phase showed no significant difference compared to placebo. The efficacy of PER for symptomatic myoclonus was reported in a total of 119 patients. Four studies (n=88 patients) reported the efficacy of PER as a decrease in myoclonus score/scale. In the remaining 31 patients, symptomatic myoclonus resolved in three patients, decreased in 21 patients and seven patients showed no improvement. We also analysed the number of patients who were already on levetiracetam (LEV) or valproic acid (VPA) at the time of PER initiation; these data were available for 153 patients. Of these, 56.8% were on LEV and 75.1% were on VPA when PER was initiated. This systematic review suggests that PER maybe effective as treatment for drug-resistant myoclonic seizures and symptomatic myoclonus. It may also be effective in patients who have already failed to respond to LEV and VPA. These findings are preliminary yet encouraging. This study has several limitations, particularly given the scarcity of high-quality randomized controlled trials and marked heterogeneity regarding the type and results of the studies. Hence, the findings of this review should be viewed with considerable reservation.
Topics: Anticonvulsants; Epilepsies, Myoclonic; Epilepsy, Generalized; Humans; Immunoglobulin E; Levetiracetam; Myoclonic Epilepsies, Progressive; Myoclonus; Nitriles; Pyridones; Randomized Controlled Trials as Topic; Seizures; Treatment Outcome; Valproic Acid
PubMed: 35770766
DOI: 10.1684/epd.2022.1439 -
Epilepsy Research Jul 2015To characterize the association between commonly used anti-epileptic drugs (AEDs) and plasma lipid levels in patients with epilepsy. (Meta-Analysis)
Meta-Analysis Review
OBJECTIVE
To characterize the association between commonly used anti-epileptic drugs (AEDs) and plasma lipid levels in patients with epilepsy.
METHODS
We sought observational studies that reported association between commonly used AEDs and plasma lipid levels in patients. The primary outcome was low-density lipoprotein (LDL) cholesterol. High-density lipoprotein (HDL), total cholesterol and triglyceride were secondary outcomes. The control group included healthy controls, pre-treatment patients or patients treated with other AEDs. We conducted a systematic search of major bibliographic databases and review of reference lists of primary articles and reviews. Primary comparisons of interest were: AED monotherapy vs. no AED use, monotherapy with one AED vs. other AED, and AED polytherapy vs. no AED use.
RESULTS
31 studies in 4126 people were identified. Carbamazepine, phenytoin and valproic acid were the most commonly studied drugs and were also implicated in causing considerable changes in plasma lipid levels in treated patients. There was an increase in LDL and total cholesterol levels with use of these three drugs; however, carbamazepine and phenytoin were also associated with higher levels of HDL. We could not identify one particular AED which was worse than the other in head-to-head comparison. We were unable to identify a particular polytherapy regimen that was worse than others.
CONCLUSION
We found evidence to suggest that some AEDs may negatively alter lipids levels in patients with epilepsy. Both treating physicians and people with epilepsy need to be vigilant in managing their vascular risk factors to avoid vascular disease.
Topics: Animals; Anticonvulsants; Databases, Bibliographic; Dyslipidemias; Epilepsy; Humans; Lipids
PubMed: 25986191
DOI: 10.1016/j.eplepsyres.2015.03.002