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The Cochrane Database of Systematic... Aug 2015Head injury is a common event and can cause a spectrum of motor and cognition disabilities. A frequent complication is seizures. Antiepileptic drugs (AED) such as... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Head injury is a common event and can cause a spectrum of motor and cognition disabilities. A frequent complication is seizures. Antiepileptic drugs (AED) such as phenytoin are often used in clinical practice with the hopes of preventing post-traumatic epilepsy. Whether immediate medical intervention following head trauma with either AEDs or neuroprotective drugs can alter the process of epileptogenesis and lead to a more favorable outcome is currently unknown. This review attempted to address the effectiveness of these treatment interventions. This review updates and expands on the earlier Cochrane review.
OBJECTIVES
To compare the efficacy of antiepileptic drugs and neuroprotective agents with placebo, usual care or other pharmacologic agents for the prevention of post-traumatic epilepsy in people diagnosed with any severity of traumatic brain injury.
SEARCH METHODS
We searched The Cochrane Epilepsy Group's specialized register, CENTRAL, MEDLINE, ClinicalTrials.gov and World Health Organization International Clinical Trials Registry Platform (ICTRP) in January 2015. We searched EMBASE, Biological Abstracts and National Research Register in September 2014 and SCOPUS in December 2013. The Cochrane Epilepsy Group performed handsearches of relevant journals.
SELECTION CRITERIA
We included randomized controlled trials (RCTs) that include AEDs or neuroprotective agents compared with placebo, another pharmacologic agent or a usual care group. The outcomes measured included a seizure occurring within one week of trauma (early seizure), seizure occurring later than one week post-trauma (late seizure), mortality and any adverse events.
DATA COLLECTION AND ANALYSIS
Two review authors independently assessed study quality and extracted the data. We calculated risk ratios (RR) and 95% confidence intervals (CI) for each outcome. We used random-effects models in the meta-analyses and performed pre-defined subgroup and sensitivity analyses.
MAIN RESULTS
This review included 10 RCTs (reported in 12 articles) consisting of 2326 participants The methodological quality of the studies varied. The type of intervention was separated into three categories; AED versus placebo or standard care, alternative neuroprotective agent versus placebo or standard care and AED versus other AED. Treatment with an AED (phenytoin or carbamazepine) decreased the risk of early seizure compared with placebo or standard care (RR 0.42, 95% CI 0.23 to 0.73; very low quality evidence). There was no evidence of a difference in the risk of late seizure occurrence between AEDs and placebo or standard care (RR 0.91, 95% CI 0.57 to 1.46; very low quality evidence). There was no evidence of a significant difference in all-cause mortality between AEDs and placebo or standard care (RR 1.08 95% CI 0.79 to 1.46,very low quality of evidence). Only one study looked at other potentially neuroprotective agents (magnesium sulfate) compared with placebo. The risk ratios were: late seizure 1.07 (95% CI 0.53 to 2.17) and all-cause mortality 1.20 (95% CI 0.80 to 1.81). The risk ratio for occurrence of early seizure was not estimable.Two studies looked at comparison of two AEDs (levetiracetam, valproate) with phenytoin used as the main comparator in each study. The risk ratio for all-cause mortality was 0.53 (95% CI 0.30 to 0.94). There was no evidence of treatment benefit of phenytoin compared with another AED for early seizures (RR 0.66, 95% 0.20 to 2.12) or late seizures(RR 0.77, 95% CI 0.46 to 1.30).Only two studies reported adverse events. The RR of any adverse event with AED compared with placebo was 1.65 (95% CI 0.73 to 3.66; low quality evidence). There were insufficient data on adverse events in the other treatment comparisons.
AUTHORS' CONCLUSIONS
This review found low-quality evidence that early treatment with an AED compared with placebo or standard care reduced the risk of early post-traumatic seizures. There was no evidence to support a reduction in the risk of late seizures or mortality. There was insufficient evidence to make any conclusions regarding the effectiveness or safety of other neuroprotective agents compared with placebo or for the comparison of phenytoin, a traditional AED, with another AED.
Topics: Adult; Anticonvulsants; Carbamazepine; Cause of Death; Child; Craniocerebral Trauma; Epilepsy; Humans; Levetiracetam; Magnesium Sulfate; Neuroprotective Agents; Phenytoin; Piracetam; Randomized Controlled Trials as Topic; Valproic Acid
PubMed: 26259048
DOI: 10.1002/14651858.CD009900.pub2 -
Annals of Translational Medicine May 2021Valproic acid (VPA) is a common antiepileptic drug used to treat both generalized and partial epilepsy. Although there is increasing evidence to suggest that gene...
BACKGROUND
Valproic acid (VPA) is a common antiepileptic drug used to treat both generalized and partial epilepsy. Although there is increasing evidence to suggest that gene polymorphisms are associated with interindividual variability of VPA metabolism, the results are debatable. Therefore, in the present study, we conducted a meta-analysis to evaluate the correlation between gene polymorphisms and adjusted plasma VPA concentration.
METHODS
The EMBASE, MEDLINE, and Cochrane Library databases were searched to obtain relevant studies. Eligible articles were reviewed, and data extraction was performed. We calculated 95% confidence intervals (CIs) and mean differences (MDs) to assess the strength of the relationship of gene polymorphisms with adjusted plasma VPA concentration.
RESULTS
The meta-analysis included 6 studies involving 847 patients with epilepsy. The pooled analysis showed that the A1075C (AA AC) polymorphism was related to the adjusted plasma concentration of VPA (P=0.02, I= 82%). Additionally, the AC phenotype statistically significantly increased the adjusted plasma VPA concentration in children compared with the mixed age subgroup (P=0.04, I= 48%). A similar association was observed between the AC phenotype for Asians (P<0.00001, I=0%) but not for Caucasians (P=0.34, I=87%).
DISCUSSION
Age might be a crucial covariate influencing the dosage-adjusted VPA concentration in patients with epilepsy. A reduced VPA dosage may be recommendable for children, particularly Asian children, who are A1075C AC carriers. Further studies could provide high-quality evidence to confirm the correlation between VPA pharmacokinetics and A1075C polymorphisms.
PubMed: 34164480
DOI: 10.21037/atm-21-1459 -
Frontiers in Medicine 2018Valproic acid (VPA) has been approved for the treatment of seizure disorders. It is also commonly used in psychiatric disorders, such as schizophrenia spectrum...
Valproic acid (VPA) has been approved for the treatment of seizure disorders. It is also commonly used in psychiatric disorders, such as schizophrenia spectrum disorders. With increasing administration, reports of intoxications are more frequently reported. The most common findings of VPA intoxication are central nervous system depression, respiratory depression, hypotension, metabolic acidosis, and elevated lactate, among others. We describe a case report of VPA intoxication with hemodiafiltration (HDF) as extracorporeal treatment (ECTR) for removal of VPA. This treatment modality has only rarely been reported in the current literature. In addition, we performed an updated systematic literature review (SLR) of additional cases on the topic ranging from December 1st, 2014 to April 20th, 2018. We searched MEDLINE and Web of Science for relevant references. In the presented case, VPA intoxication occurred in a 46-year-old female patient after oral ingestion of 56 g of VPA. In addition to vasopressors and endotracheal intubation, we administered L-Carnitine (L-Car) and performed hemodiafiltration treatment. After intravenous therapy with L-Car and simultaneous HDF sessions, we observed full recovery without neurological sequelae. The SLR identified 8 additional articles reporting favorable outcomes with extracorporeal treatments in most cases. HDF and other extracorporeal procedures are safe and effective therapeutic options in patients with VPA intoxication. The choice of ECTR modality mainly depends on local experience and the setting. In the present case, ingestion of 56 g was successfully treated with HDF. These findings are in line with several other case reports describing positive outcomes. Extracorporeal treatment, including HDF, should be considered early in the management of VPA intoxication. Supporting evidence is emerging, but it is of limited quality.
PubMed: 30148132
DOI: 10.3389/fmed.2018.00224 -
Seizure Nov 2022To perform a systematic review searching for differences in the side effects of antiseizure medications (ASMs) with respect to sex in pediatric patients with epilepsy. (Review)
Review
PURPOSE
To perform a systematic review searching for differences in the side effects of antiseizure medications (ASMs) with respect to sex in pediatric patients with epilepsy.
METHODS
We carried out a comprehensive literature search of the PubMed database and all results up to April 2020 were included. Titles, abstracts, and full texts of the articles were screened by two independent reviewers. We included all studies evaluating the side effects of ASMs in patients with epilepsy younger than 18 years, with reference to the two sexes. Studies on ASMs used for indications other than epilepsy were excluded.
RESULTS
A total of 5164 studies were identified. Sixty-seven studies were finally included, 5 of them also including adult patients in the sample. Sixteen studies revealed sex-related differences in side effects of ASMs, disclosing a higher frequency of general side effects in girls: a higher risk of overweight, hyperammonaemia, high leptin levels, and carnitine deficiency in girls on valproic acid; a lower height increase, an increased risk of weight loss, the anecdotical occurrence of acute psychosis in girls on topiramate; a higher risk of retinal toxicity in boys on vigabatrin.
CONCLUSION
The effect of sex on susceptibility to side effects of ASMs is poorly investigated with sparse results, and it could be underestimated. The findings of our study point to the presence of sex differences which should be thoroughly investigated to be confirmed, highlighting the need for a systematic evaluation of sex as a determinant variable influencing the response to medications in clinical research.
Topics: Adult; Child; Humans; Female; Male; Anticonvulsants; Sex Characteristics; Epilepsy; Vigabatrin; Topiramate; Drug-Related Side Effects and Adverse Reactions
PubMed: 36156391
DOI: 10.1016/j.seizure.2022.09.013 -
Frontiers in Psychiatry 2024Autism is a multifaceted developmental disorder of the nervous system, that necessitates novel therapeutic approaches beyond traditional medications and psychosomatic...
AIMS
Autism is a multifaceted developmental disorder of the nervous system, that necessitates novel therapeutic approaches beyond traditional medications and psychosomatic therapy, such as appropriate sensory integration training. This systematic mapping review aims to synthesize existing knowledge on enriching environmental interventions as an alternative avenue for improving autism, guiding future research and practice.
METHOD
A comprehensive search using the terms ASD and Enriched Environment was conducted across PubMed, EMBASE, ISI, Cochrane, and OVID databases. Most of the literature included in this review was derived from animal model experiments, with a particular focus on assessing the effect of EE on autism-like behavior, along with related pathways and molecular mechanisms. Following extensive group discussion and screening, a total of 19 studies were included for analysis.
RESULTS
Enriched environmental interventions exhibited the potential to induce both behavioral and biochemical changes, ameliorating autism-like behaviors in animal models. These improvements were attributed to the targeting of BDNF-related pathways, enhanced neurogenesis, and the regulation of glial inflammation.
CONCLUSION
This paper underscores the positive impact of enriched environmental interventions on autism through a review of existing literature. The findings contribute to a deeper understanding of the underlying brain mechanisms associated with this intervention.
PubMed: 38362032
DOI: 10.3389/fpsyt.2024.1328240 -
The Cochrane Database of Systematic... Apr 2016Worldwide, phenytoin and valproate are commonly used antiepileptic drugs. It is generally believed that phenytoin is more effective for partial onset seizures, and that... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Worldwide, phenytoin and valproate are commonly used antiepileptic drugs. It is generally believed that phenytoin is more effective for partial onset seizures, and that valproate is more effective for generalised onset tonic-clonic seizures (with or without other generalised seizure types). This review is one in a series of Cochrane reviews investigating pair-wise monotherapy comparisons. This is the latest updated version of the review first published in 2001 and updated in 2013.
OBJECTIVES
To review the time to withdrawal, remission and first seizure of phenytoin compared to valproate when used as monotherapy in people with partial onset seizures or generalised tonic-clonic seizures (with or without other generalised seizure types).
SEARCH METHODS
We searched the Cochrane Epilepsy Group's Specialised Register (19 May 2015), the Cochrane Central Register of Controlled Trials (CENTRAL; the Cochrane Library; 2015, Issue 4), MEDLINE (1946 to 19 May 2015), SCOPUS (19 February 2013), ClinicalTrials.gov (19 May 2015), and WHO International Clinical Trials Registry Platform ICTRP (19 May 2015). We handsearched relevant journals, contacted pharmaceutical companies, original trial investigators and experts in the field.
SELECTION CRITERIA
Randomised controlled trials (RCTs) in children or adults with partial onset seizures or generalised onset tonic-clonic seizures with a comparison of valproate monotherapy versus phenytoin monotherapy.
DATA COLLECTION AND ANALYSIS
This was an individual participant data (IPD) review. Outcomes were time to: (a) withdrawal of allocated treatment (retention time); (b) achieve 12-month remission (seizure-free period); (c) achieve six-month remission (seizure-free period); and (d) first seizure (post-randomisation). We used Cox proportional hazards regression models to obtain study-specific estimates of hazard ratios (HRs) with 95% confidence intervals (CIs), and the generic inverse variance method to obtain the overall pooled HR and 95% CI.
MAIN RESULTS
IPD were available for 669 individuals out of 1119 eligible individuals from five out of 11 trials, 60% of the potential data. Results apply to partial onset seizures (simple, complex and secondary generalised tonic-clonic seizures), and generalised tonic-clonic seizures, but not other generalised seizure types (absence or myoclonus seizure types). For remission outcomes: HR > 1 indicates an advantage for phenytoin; and for first seizure and withdrawal outcomes: HR > 1 indicates an advantage for valproate.The main overall results (pooled HR adjusted for seizure type) were time to: (a) withdrawal of allocated treatment 1.09 (95% CI 0.76 to 1.55); (b) achieve 12-month remission 0.98 (95% CI 0.78 to 1.23); (c) achieve six-month remission 0.95 (95% CI 0.78 to 1.15); and (d) first seizure 0.93 (95% CI 0.75 to 1.14). The results suggest no overall difference between the drugs for these outcomes. We did not find any statistical interaction between treatment and seizure type (partial versus generalised).
AUTHORS' CONCLUSIONS
We have not found evidence that a significant difference exists between phenytoin and valproate for the outcomes examined in this review. However misclassification of seizure type may have confounded the results of this review. Results do not apply to absence or myoclonus seizure types. No outright evidence was found to support or refute current treatment policies.
Topics: Anticonvulsants; Epilepsies, Partial; Epilepsy, Generalized; Epilepsy, Tonic-Clonic; Humans; Phenytoin; Randomized Controlled Trials as Topic; Seizures; Valproic Acid
PubMed: 27123830
DOI: 10.1002/14651858.CD001769.pub3 -
Seizure May 2022Recent position papers and guidelines encourage women with epilepsy (WWE) to exclusively breastfeed their infants because the benefits to their infants outweigh the... (Review)
Review
BACKGROUND
Recent position papers and guidelines encourage women with epilepsy (WWE) to exclusively breastfeed their infants because the benefits to their infants outweigh the potential adverse effects caused by exposure to antiseizure medications (ASMs).
OBJECTIVE
The objectives of this review were: to evaluate concentrations of ASMs in breastmilk of lactating WWE, qualitatively synthesize evidence that can be used to estimate theoretical doses as estimated daily intake (EDI) and relative infant dose (RID) of ASMs, and to evaluate potential risks to infants as a result of exposure to ASMs from breastmilk.
METHODS
This systematic review was registered in the International Prospective Register of Systematic Reviews (PROSPERO) as CRD42020223645. The databases: MEDLINE/PubMed, EMBASE, CINAHL/EBSCO, COCHRANE, SpringerLink, ScienceDirect, Summon, WHO International Clinical Trials Registry Platform, and SCOPUS were systematically searched. A qualitative synthesis was adopted in this study.
RESULTS
A total of 15 records were included in this systematic review. The included studies reported levels of 8 ASMs in the breastmilk of WWE. The highest RIDs of carbamazepine, lamotrigine, primidone, phenobarbital, gabapentin, valproic acid, ethosuximide, levetiracetam, and topiramate were 3.70%, 36.33%, 4.96%, 3.15%, 4.37%, 1.90%, 31.49%, 12.50%, and 12.18%, respectively. Breastfeeding might be limited or even discontinued when signs of excessive sedation/drowsiness and/or poor weight gain are evident on infants exposed to primidone and phenobarbital, ethosuximide/primidone, or ethosuximide/phenobarbital.
CONCLUSIONS
Concentrations of ASMs can be detected in breastmilk of WWE and plasma/serum of infants exposed via breastmilk. Healthcare providers and WWE might use the findings of this study to make informed decisions on the safety of breastfeeding while taking ASMs.
Topics: Anticonvulsants; Breast Feeding; Epilepsy; Ethosuximide; Female; Humans; Infant; Lactation; Milk, Human; Phenobarbital; Primidone
PubMed: 35427849
DOI: 10.1016/j.seizure.2022.03.017 -
The Cochrane Database of Systematic... Oct 2014Accumulating evidence suggests an association between prenatal exposure to antiepileptic drugs (AEDs) and increased risk of both physical anomalies and... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Accumulating evidence suggests an association between prenatal exposure to antiepileptic drugs (AEDs) and increased risk of both physical anomalies and neurodevelopmental impairment. Neurodevelopmental impairment is characterised by either a specific deficit or a constellation of deficits across cognitive, motor and social skills and can be transient or continuous into adulthood. It is of paramount importance that these potential risks are identified, minimised and communicated clearly to women with epilepsy.
OBJECTIVES
To assess the effects of prenatal exposure to commonly prescribed AEDs on neurodevelopmental outcomes in the child and to assess the methodological quality of the evidence.
SEARCH METHODS
We searched the Cochrane Epilepsy Group Specialized Register (May 2014), Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library (2014, Issue 4), MEDLINE (via Ovid) (1946 to May 2014), EMBASE (May 2014), Pharmline (May 2014) and Reprotox (May 2014). No language restrictions were imposed. Conference abstracts from the last five years were reviewed along with reference lists from the included studies.
SELECTION CRITERIA
Prospective cohort controlled studies, cohort studies set within pregnancy registers and randomised controlled trials were selected for inclusion. Participants were women with epilepsy taking AED treatment; the two control groups were women without epilepsy and women with epilepsy who were not taking AEDs during pregnancy.
DATA COLLECTION AND ANALYSIS
Three authors (RB, JW and JG) independently selected studies for inclusion. Data extraction and risk of bias assessments were completed by five authors (RB, JW, AS, NA, AJM). The primary outcome was global cognitive functioning. Secondary outcomes included deficits in specific cognitive domains or prevalence of neurodevelopmental disorders. Due to substantial variation in study design and outcome reporting only limited data synthesis was possible.
MAIN RESULTS
Twenty-two prospective cohort studies were included and six registry based studies. Study quality varied. More recent studies tended to be larger and to report individual AED outcomes from blinded assessments, which indicate improved methodological quality.The developmental quotient (DQ) was lower in children exposed to carbamazepine (CBZ) (n = 50) than in children born to women without epilepsy (n = 79); mean difference (MD) of -5.58 (95% confidence interval (CI) -10.83 to -0.34, P = 0.04). The DQ of children exposed to CBZ (n = 163) was also lower compared to children of women with untreated epilepsy (n = 58) (MD -7.22, 95% CI -12.76 to - 1.67, P = 0.01). Further analysis using a random-effects model indicated that these results were due to variability within the studies and that there was no significant association with CBZ. The intelligence quotient (IQ) of older children exposed to CBZ (n = 150) was not lower than that of children born to women without epilepsy (n = 552) (MD -0.03, 95% CI -3.08 to 3.01, P = 0.98). Similarly, children exposed to CBZ (n = 163) were not poorer in terms of IQ in comparison to the children of women with untreated epilepsy (n = 87) (MD 1.84, 95% CI -2.13 to 5.80, P = 0.36). The DQ in children exposed to sodium valproate (VPA) (n = 123) was lower than the DQ in children of women with untreated epilepsy (n = 58) (MD -8.72, 95% -14.31 to -3.14, P = 0.002). The IQ of children exposed to VPA (n = 76) was lower than for children born to women without epilepsy (n = 552) (MD -8.94, 95% CI -11.96 to -5.92, P < 0.00001). Children exposed to VPA (n = 89) also had lower IQ than children born to women with untreated epilepsy (n = 87) (MD -8.17, 95% CI -12.80 to -3.55, P = 0.0005).In terms of drug comparisons, in younger children there was no significant difference in the DQ of children exposed to CBZ (n = 210) versus VPA (n=160) (MD 4.16, 95% CI -0.21 to 8.54, P = 0.06). However, the IQ of children exposed to VPA (n = 112) was significantly lower than for those exposed to CBZ (n = 191) (MD 8.69, 95% CI 5.51 to 11.87, P < 0.00001). The IQ of children exposed to CBZ (n = 78) versus lamotrigine (LTG) (n = 84) was not significantly different (MD -1.62, 95% CI -5.44 to 2.21, P = 0.41). There was no significant difference in the DQ of children exposed to CBZ (n = 172) versus phenytoin (PHT) (n = 87) (MD 3.02, 95% CI -2.41 to 8.46, P = 0.28). The IQ abilities of children exposed to CBZ (n = 75) were not different from the abilities of children exposed to PHT (n = 45) (MD -3.30, 95% CI -7.91 to 1.30, P = 0.16). IQ was significantly lower for children exposed to VPA (n = 74) versus LTG (n = 84) (MD -10.80, 95% CI -14.42 to -7.17, P < 0.00001). DQ was higher in children exposed to PHT (n = 80) versus VPA (n = 108) (MD 7.04, 95% CI 0.44 to 13.65, P = 0.04). Similarly IQ was higher in children exposed to PHT (n = 45) versus VPA (n = 61) (MD 9.25, 95% CI 4.78 to 13.72, P < 0.0001). A dose effect for VPA was reported in six studies, with higher doses (800 to 1000 mg daily or above) associated with a poorer cognitive outcome in the child. We identified no convincing evidence of a dose effect for CBZ, PHT or LTG. Studies not included in the meta-analysis were reported narratively, the majority of which supported the findings of the meta-analyses.
AUTHORS' CONCLUSIONS
The most important finding is the reduction in IQ in the VPA exposed group, which are sufficient to affect education and occupational outcomes in later life. However, for some women VPA is the most effective drug at controlling seizures. Informed treatment decisions require detailed counselling about these risks at treatment initiation and at pre-conceptual counselling. We have insufficient data about newer AEDs, some of which are commonly prescribed, and further research is required. Most women with epilepsy should continue their medication during pregnancy as uncontrolled seizures also carries a maternal risk.
Topics: Age Factors; Anticonvulsants; Carbamazepine; Child; Developmental Disabilities; Epilepsy; Female; Humans; Intelligence; Pregnancy; Pregnancy Complications; Prenatal Exposure Delayed Effects; Prospective Studies; Randomized Controlled Trials as Topic; Valproic Acid
PubMed: 25354543
DOI: 10.1002/14651858.CD010236.pub2 -
Antiepileptic drug monotherapy for epilepsy: a network meta-analysis of individual participant data.The Cochrane Database of Systematic... Jun 2017Epilepsy is a common neurological condition with a worldwide prevalence of around 1%. Approximately 60% to 70% of people with epilepsy will achieve a longer-term... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Epilepsy is a common neurological condition with a worldwide prevalence of around 1%. Approximately 60% to 70% of people with epilepsy will achieve a longer-term remission from seizures, and most achieve that remission shortly after starting antiepileptic drug treatment. Most people with epilepsy are treated with a single antiepileptic drug (monotherapy) and current guidelines from the National Institute for Health and Care Excellence (NICE) in the United Kingdom for adults and children recommend carbamazepine or lamotrigine as first-line treatment for partial onset seizures and sodium valproate for generalised onset seizures; however a range of other antiepileptic drug (AED) treatments are available, and evidence is needed regarding their comparative effectiveness in order to inform treatment choices.
OBJECTIVES
To compare the time to withdrawal of allocated treatment, remission and first seizure of 10 AEDs (carbamazepine, phenytoin, sodium valproate, phenobarbitone, oxcarbazepine, lamotrigine, gabapentin, topiramate, levetiracetam, zonisamide) currently used as monotherapy in children and adults with partial onset seizures (simple partial, complex partial or secondary generalised) or generalised tonic-clonic seizures with or without other generalised seizure types (absence, myoclonus).
SEARCH METHODS
We searched the following databases: Cochrane Epilepsy's Specialised Register, CENTRAL, MEDLINE and SCOPUS, and two clinical trials registers. We handsearched relevant journals and contacted pharmaceutical companies, original trial investigators, and experts in the field. The date of the most recent search was 27 July 2016.
SELECTION CRITERIA
We included randomised controlled trials of a monotherapy design in adults or children with partial onset seizures or generalised onset tonic-clonic seizures (with or without other generalised seizure types).
DATA COLLECTION AND ANALYSIS
This was an individual participant data (IPD) review and network meta-analysis. Our primary outcome was 'time to withdrawal of allocated treatment', and our secondary outcomes were 'time to achieve 12-month remission', 'time to achieve six-month remission', 'time to first seizure post-randomisation', and 'occurrence of adverse events'. We presented all time-to-event outcomes as Cox proportional hazard ratios (HRs) with 95% confidence intervals (CIs). We performed pairwise meta-analysis of head-to-head comparisons between drugs within trials to obtain 'direct' treatment effect estimates and we performed frequentist network meta-analysis to combine direct evidence with indirect evidence across the treatment network of 10 drugs. We investigated inconsistency between direct estimates and network meta-analysis via node splitting. Due to variability in methods and detail of reporting adverse events, we have not performed an analysis. We have provided a narrative summary of the most commonly reported adverse events.
MAIN RESULTS
IPD was provided for at least one outcome of this review for 12,391 out of a total of 17,961 eligible participants (69% of total data) from 36 out of the 77 eligible trials (47% of total trials). We could not include IPD from the remaining 41 trials in analysis for a variety of reasons, such as being unable to contact an author or sponsor to request data, data being lost or no longer available, cost and resources required to prepare data being prohibitive, or local authority or country-specific restrictions.We were able to calculate direct treatment effect estimates for between half and two thirds of comparisons across the outcomes of the review, however for many of the comparisons, data were contributed by only a single trial or by a small number of participants, so confidence intervals of estimates were wide.Network meta-analysis showed that for the primary outcome 'Time to withdrawal of allocated treatment,' for individuals with partial seizures; levetiracetam performed (statistically) significantly better than both current first-line treatments carbamazepine and lamotrigine; lamotrigine performed better than all other treatments (aside from levetiracetam), and carbamazepine performed significantly better than gabapentin and phenobarbitone (high-quality evidence). For individuals with generalised onset seizures, first-line treatment sodium valproate performed significantly better than carbamazepine, topiramate and phenobarbitone (moderate- to high-quality evidence). Furthermore, for both partial and generalised onset seizures, the earliest licenced treatment, phenobarbitone seems to perform worse than all other treatments (moderate- to high-quality evidence).Network meta-analysis also showed that for secondary outcomes 'Time to 12-month remission of seizures' and 'Time to six-month remission of seizures,' few notable differences were shown for either partial or generalised seizure types (moderate- to high-quality evidence). For secondary outcome 'Time to first seizure,' for individuals with partial seizures; phenobarbitone performed significantly better than both current first-line treatments carbamazepine and lamotrigine; carbamazepine performed significantly better than sodium valproate, gabapentin and lamotrigine. Phenytoin also performed significantly better than lamotrigine (high-quality evidence). In general, the earliest licenced treatments (phenytoin and phenobarbitone) performed better than the other treatments for both seizure types (moderate- to high-quality evidence).Generally, direct evidence and network meta-analysis estimates (direct plus indirect evidence) were numerically similar and consistent with confidence intervals of effect sizes overlapping.The most commonly reported adverse events across all drugs were drowsiness/fatigue, headache or migraine, gastrointestinal disturbances, dizziness/faintness and rash or skin disorders.
AUTHORS' CONCLUSIONS
Overall, the high-quality evidence provided by this review supports current guidance (e.g. NICE) that carbamazepine and lamotrigine are suitable first-line treatments for individuals with partial onset seizures and also demonstrates that levetiracetam may be a suitable alternative. High-quality evidence from this review also supports the use of sodium valproate as the first-line treatment for individuals with generalised tonic-clonic seizures (with or without other generalised seizure types) and also demonstrates that lamotrigine and levetiracetam would be suitable alternatives to either of these first-line treatments, particularly for those of childbearing potential, for whom sodium valproate may not be an appropriate treatment option due to teratogenicity.
Topics: Adult; Amines; Anticonvulsants; Carbamazepine; Child; Cyclohexanecarboxylic Acids; Epilepsies, Partial; Epilepsy; Epilepsy, Generalized; Fructose; Gabapentin; Humans; Isoxazoles; Lamotrigine; Levetiracetam; Network Meta-Analysis; Oxcarbazepine; Phenobarbital; Phenytoin; Piracetam; Remission Induction; Topiramate; Triazines; Valproic Acid; Zonisamide; gamma-Aminobutyric Acid
PubMed: 28661008
DOI: 10.1002/14651858.CD011412.pub2 -
The Cochrane Database of Systematic... Oct 2018Agitation has been reported in up to 90% of people with dementia. Agitation in people with dementia worsens carer burden, increases the risk of injury, and adds to the... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Agitation has been reported in up to 90% of people with dementia. Agitation in people with dementia worsens carer burden, increases the risk of injury, and adds to the need for institutionalisation. Valproate preparations have been used in an attempt to control agitation in dementia, but their safety and efficacy have been questioned.
OBJECTIVES
To determine the efficacy and adverse effects of valproate preparations used to treat agitation in people with dementia, including the impact on carers.
SEARCH METHODS
We searched ALOIS - the Cochrane Dementia and Cognitive Improvement Group's Specialized Register on 7 December 2017 using the terms: valproic OR valproate OR divalproex. ALOIS contains records from all major health care databases (the Cochrane Library, MEDLINE, Embase, PsycINFO, CINAHL, LILACS) as well as from many trials databases and grey literature sources.
SELECTION CRITERIA
Randomised, placebo-controlled trials that assessed valproate preparations for agitation in people with dementia.
DATA COLLECTION AND ANALYSIS
Two review authors independently screened the retrieved studies against the inclusion criteria and extracted data and assessed methodological quality of the included studies. If necessary, we contacted trial authors to ask for additional data, including relevant subscales, or for other missing information. We pooled data in meta-analyses where possible. This is an update of a Cochrane Review last published in 2009. We found no new studies for inclusion.
MAIN RESULTS
The review included five studies with 430 participants. Studies varied in the preparations of valproate, mean doses (480 mg/day to 1000 mg/day), duration of treatment (three weeks to six weeks), and outcome measures used. The studies were generally well conducted although some methodological information was missing and one study was at high risk of attrition bias.The quality of evidence related to our primary efficacy outcome of agitation varied from moderate to very low. We found moderate-quality evidence from two studies that measured behaviour with the total Brief Psychiatric Rating Scale (BPRS) score (range 0 to 108) and with the BPRS agitation factor (range 0 to 18). They found that there was probably little or no effect of valproate treatment over six weeks (total BPRS: mean difference (MD) 0.23, 95% confidence interval (CI) -2.14 to 2.59; 202 participants, 2 studies; BPRS agitation factor: MD -0.67, 95% CI -1.49 to 0.15; 202 participants, 2 studies). Very low-quality evidence from three studies which measured agitation with the Cohen-Mansfield Agitation Index (CMAI) were consistent with a lack of effect of valproate treatment on agitation. There was variable quality evidence on other behaviour outcomes reported in single studies of no difference between groups or a benefit for the placebo group.Three studies, which measured cognitive function using the Mini-Mental State Examination (MMSE), found little or no effect of valproate over six weeks, but we were uncertain about this result because the quality of the evidence was very low. Two studies that assessed functional ability using the Physical Self-Maintenance Scale (PSMS) (range 6 to 30) found that there was probably slightly worse function in the valproate-treated group, which was of uncertain clinical importance (MD 1.19, 95% CI 0.40 to 1.98; 203 participants, 2 studies; moderate-quality evidence).Analysis of adverse effects and serious adverse events (SAE) indicated a higher incidence in valproate-treated participants. A meta-analysis of three studies showed that there may have been a higher rate of adverse effects among valproate-treated participants than among controls (odds ratio (OR) 2.02, 95% CI 1.30 to 3.14; 381 participants, 3 studies, low-quality evidence). Pooled analysis of the number of SAE for the two studies that reported such data indicated that participants treated with valproate preparations were more likely to experience SAEs (OR 4.77, 95% CI 1.00 to 22.74; 228 participants, 2 studies), but the very low quality of the data made it difficult to draw any firm conclusions regarding SAEs. Individual adverse events that were more frequent in the valproate-treated group included sedation, gastrointestinal symptoms (nausea, vomiting, and diarrhoea), and urinary tract infections.
AUTHORS' CONCLUSIONS
This updated review corroborates earlier findings that valproate preparations are probably ineffective in treating agitation in people with dementia, but are associated with a higher rate of adverse effects, and possibly of SAEs. On the basis of this evidence, valproate therapy cannot be recommended for management of agitation in dementia. Further research may not be justified, particularly in light of the increased risk of adverse effects in this often frail group of people. Research would be better focused on effective non-pharmacological interventions for this patient group, or, for those situations where medication may be needed, further investigation of how to use other medications as effectively and safely as possible.
Topics: Aged; Aggression; Antimanic Agents; Cognition; Dementia; Humans; Psychomotor Agitation; Randomized Controlled Trials as Topic; Treatment Outcome; Valproic Acid
PubMed: 30293233
DOI: 10.1002/14651858.CD003945.pub4