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Annals of Physical and Rehabilitation... Oct 2012Management of a patient with pressure ulcer sore(s) must associate local and general treatment. (Review)
Review
Which medical devices and/or local drug should be curatively used, as of 2012, for PU patients? How can granulation and epidermidalization be promoted? Developing French guidelines for clinical practice.
INTRODUCTION
Management of a patient with pressure ulcer sore(s) must associate local and general treatment.
OBJECTIVES
To determine which medical devices other than supports and which treatments may be used for pressure sore healing (granulation tissue and epithelization/epidermidalization) as of 2012.
METHODS
Systematic review of the literature querying the databases: PASCAL Biomed, PubMed, and Cochrane library from 2000 through 2010.
RESULTS
Data in the literature on granulation tissue and epithelisation/epidermidalization in pressure sore healing are poor. The level of evidence regarding the relative effectiveness of one modern dressing compared to another has remained low. However, the study data on the interest of hydrocolloid dressing compared with impregnated gases are more significant.
DISCUSSION
Studies with heterogeneous results and populations have shown low power. Meta-analyses are difficult due to the wide range of therapeutic aims. Further clinical studies with adequate methodology are needed prior to elaboration of more specific recommendations.
CONCLUSION
The use of hydrocolloid dressing may be recommended to improve granulation tissue development and epithelization/epidermidalization in pressure sore (Level B).
Topics: Bandages; Humans; Phenytoin; Phototherapy; Practice Guidelines as Topic; Pressure Ulcer; Wound Healing
PubMed: 23022367
DOI: 10.1016/j.rehab.2012.08.005 -
The Cochrane Database of Systematic... Jun 2012Seizure activity in the early post-traumatic period following head injury may cause secondary brain damage as a result of increased metabolic demands, raised... (Review)
Review
BACKGROUND
Seizure activity in the early post-traumatic period following head injury may cause secondary brain damage as a result of increased metabolic demands, raised intracranial pressure and excess neurotransmitter release.
OBJECTIVES
To determine the effects of prophylactic anti-epileptic agents for acute traumatic head injury.
SEARCH METHODS
We searched the Cochrane Injuries Group specialised register, MEDLINE and the registers of the Cochrane Stroke Group and Cochrane Epilepsy Group. We contacted pharmaceutical companies who manufacture anti-epileptic agents, the National Institute of Neurological Disorders and Stroke, Epilepsy Division, and the United States' National Institute of Health.
SELECTION CRITERIA
All randomised trials of anti-epileptic agents, in which study participants had a clinically defined acute traumatic head injury of any severity. Trials in which the intervention was started more than eight weeks after injury were excluded.
DATA COLLECTION AND ANALYSIS
Two reviewers independently extracted data and assessed the trial quality. Relative risks and 95% confidence intervals (95%CI) were calculated for each trial on an intention-to-treat basis, which included pre-drug loading exclusions. As long as statistical heterogeneity did not exist, for dichotomous data, summary relative risks and 95% confidence intervals were calculated using a fixed effects model. Where the source of heterogeneity could obviously be related to allocation concealment, drug type, or drug dose, we stratified the analyses on that dimension.
MAIN RESULTS
We identified 10 eligible randomised controlled trials, including 2036 participants, but data was unavailable for four unpublished trials, representing 631 participants and they were excluded. For the remaining six trials, the pooled relative risk (RR) for early seizure prevention was 0.34 (95%CI 0.21, 0.54); based on this estimate, for every 100 patients treated, 10 would be kept seizure free in the first week. Seizure control in the acute phase was not accompanied by a reduction in mortality (RR = 1.15; 95%CI 0.89, 1.51), a reduction in death and neurological disability (RR = 1.49; 95%CI 1.06, 2.08 for carbamazepine and RR = 0.96; 95%CI 0.72, 1.26 for phenytoin) or a reduction in late seizures (pooled RR = 1.28; 95%CI 0.90, 1.81). The pooled relative risk for skin rashes was 1.57 (95%CI 0.57, 39.88).
AUTHORS' CONCLUSIONS
Prophylactic anti-epileptics are effective in reducing early seizures, but there is no evidence that treatment with prophylactic anti-epileptics reduces the occurrence of late seizures, or has any effect on death and neurological disability. Insufficient evidence is available to establish the net benefit of prophylactic treatment at any time after injury.
Topics: Anticonvulsants; Brain Injuries; Humans; Randomized Controlled Trials as Topic; Seizures
PubMed: 22696316
DOI: 10.1002/14651858.CD000173.pub2 -
The Cochrane Database of Systematic... May 2012Antiepileptic drugs have been used in pain management since the 1960s; some have shown efficacy in treating different neuropathic pain conditions. Phenytoin is an... (Review)
Review
BACKGROUND
Antiepileptic drugs have been used in pain management since the 1960s; some have shown efficacy in treating different neuropathic pain conditions. Phenytoin is an established antiepileptic drug that has been used occasionally to treat intractable trigeminal neuralgia.
OBJECTIVES
To assess the analgesic efficacy and adverse effects of the antiepileptic drug phenytoin in neuropathic pain and fibromyalgia.
SEARCH METHODS
We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2012, Issue 2), MEDLINE, and EMBASE to 28 February 2012, together with reference lists of retrieved papers and reviews, and ClinicalTrials.gov.
SELECTION CRITERIA
We planned to include randomised, double-blind studies of eight weeks duration or longer, comparing phenytoin with placebo or another active treatment in chronic neuropathic pain or fibromyalgia.
DATA COLLECTION AND ANALYSIS
Two review authors would independently extract data for efficacy and adverse events, and examine issues of study quality.
MAIN RESULTS
We did not identify any studies that satisfied the inclusion criteria.
AUTHORS' CONCLUSIONS
This review uncovered no evidence of sufficient quality to support the use of phenytoin in chronic neuropathic pain or fibromyalgia.
Topics: Adult; Analgesics; Anticonvulsants; Fibromyalgia; Humans; Neuralgia; Pain Management; Phenytoin
PubMed: 22592741
DOI: 10.1002/14651858.CD009485.pub2 -
The Cochrane Database of Systematic... Apr 2012Febrile seizures occurring in a child older than one month during an episode of fever affect 2% to 4% of children in Great Britain and the United States and recur in... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Febrile seizures occurring in a child older than one month during an episode of fever affect 2% to 4% of children in Great Britain and the United States and recur in 30%. Rapid-acting antiepileptics and antipyretics given during subsequent fever episodes have been used to avoid the adverse effects of continuous antiepileptic drugs.
OBJECTIVES
To evaluate the effectiveness and safety of antiepileptic and antipyretic drugs used prophylactically to treat children with febrile seizures.
SEARCH METHODS
We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2011. Issue 3); MEDLINE (1966 to May 2011); EMBASE (1966 to May 2011); Database of Abstracts of Reviews of Effectiveness (DARE) (May 2011). No language restrictions were imposed. We also contacted researchers in the field to identify continuing or unpublished studies.
SELECTION CRITERIA
Trials using randomised or quasi-randomised patient allocation that compared the use of antiepileptic or antipyretic agents with each other, placebo or no treatment.
DATA COLLECTION AND ANALYSIS
Two review authors (RN and MO) independently applied pre-defined criteria to select trials for inclusion and extracted the pre-defined relevant data, recording methods for randomisation, blinding and exclusions. Outcomes assessed were seizure recurrence at 6, 12, 18, 24, 36 months and at age 5 to 6 years in the intervention and non-intervention groups, and adverse medication effects. The presence of publication bias was assessed using funnel plots.
MAIN RESULTS
Thirty-six articles describing 26 randomised trials with 2740 randomised participants were included. Thirteen interventions of continuous or intermittent prophylaxis and their control treatments were analysed. Methodological quality was moderate to poor in most studies. We could not do a meta-analysis for eight of the 13 comparisons due to insufficient numbers of trials. No significant benefit for valproate, pyridoxine, intermittent phenobarbitone or ibuprofen versus placebo or no treatment was found; nor for diclofenac versus placebo followed by ibuprofen, acetominophen or placebo; nor for intermittent rectal diazepam versus intermittent valproate, nor phenobarbitone versus intermittent rectal diazepam.There was a significant reduction of recurrent febrile seizures with intermittent oral diazepam versus placebo with a relative risk (RR) of 0.67 (95% confidence interval (CI) 0.48 to 0.94) at 24 months), RR of 0.61 (95% CI 0.15 to 0.89) at 48 months, with no benefit at 6, 12 or 72 months. Phenobarbitone versus placebo or no treatment reduced seizures at 6, 12 and 24 months but not at 18 or 72 month follow up (RR 0.60, 95% CI 0.42 to 0.84 at 6 months; RR 0.59, 95% CI 0.46 to 0.75 at 12 months; and RR 0.65, 95% CI 0.49 to 0.88 at 24 months). Intermittent rectal diazepam versus no treatment or placebo also reduced seizures (RR 0.60, 95% CI 0.41 to 0.86 at 6 months; RR 0.65, 95% CI 0.49 to 0.87 at 12 months; RR 0.2, 95% CI 0.1 to 0.39 at 18 months; RR 0.36, 95% CI 0.18 to 0.71 at 36 months), with no benefit at 24 months. Intermittent clobazam compared to placebo at 6 months resulted in a RR of 0.09 (95% CI 0.02 to 0.30), an effect found against an extremely high (83.3%) recurrence rate in the controls and which is a result that needs replication.The recording of adverse effects was variable. Lower comprehension scores in phenobarbitone treated children were found in two studies. In general, adverse effects were recorded in up to some 30% of children in the phenobarbitone treated group and in up to 36% in benzodiazepine treated groups. Evidence of publication bias was found in the meta analyses of comparisons for phenobarbitone versus placebo (8 studies) at 12 months but not at 6 months (6 studies); and valproate versus placebo (4 studies) at 12 months; with too few studies to identify publication bias for the other comparisons.
AUTHORS' CONCLUSIONS
No clinically important benefits for children with febrile seizures were found for intermittent oral diazepam, phenytoin, phenobarbitone, intermittent rectal diazepam, valproate, pyridoxine, intermittent phenobarbitone or intermittent ibuprofen, nor for diclofenac versus placebo followed by ibuprofen, acetominophen or placebo. Adverse effects were reported in up to 30% of children. Apparent benefit for clobazam treatment in one recent trial needs to be replicated to be judged reliable. Given the benign nature of recurrent febrile seizures, and the high prevalence of adverse effects of these drugs, parents and families should be supported with adequate contact details of medical services and information on recurrence, first aid management and, most importantly, the benign nature of the phenomenon.
Topics: Anticonvulsants; Antipyretics; Child; Child, Preschool; Humans; Infant; Randomized Controlled Trials as Topic; Seizures, Febrile
PubMed: 22513908
DOI: 10.1002/14651858.CD003031.pub2 -
BMJ Clinical Evidence Feb 2012About 3% of people will be diagnosed with epilepsy during their lifetime, but about 70% of people with epilepsy eventually go into remission. (Review)
Review
INTRODUCTION
About 3% of people will be diagnosed with epilepsy during their lifetime, but about 70% of people with epilepsy eventually go into remission.
METHODS AND OUTCOMES
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of monotherapy in newly diagnosed generalised epilepsy (tonic clonic type)? What are the effects of additional treatments in people with drug-resistant generalised epilepsy? What are the effects of surgery in people with drug-resistant generalised epilepsy? We searched: Medline, Embase, The Cochrane Library, and other important databases up to August 2011 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
RESULTS
We found 8 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
CONCLUSIONS
In this systematic review we present information relating to the effectiveness and safety of the following interventions: monotherapy using carbamazepine, gabapentin, lamotrigine, levetiracetam, phenobarbital, phenytoin, sodium valproate, or topiramate; addition of second-line drugs (lamotrigine or levetiracetam) for drug-resistant epilepsy; and hemispherectomy for drug-resistant epilepsy.
Topics: Anticonvulsants; Carbamazepine; Epilepsy; Epilepsy, Generalized; Humans; Incidence; Phenytoin; Remission Induction; Valproic Acid
PubMed: 22348419
DOI: No ID Found -
Seizure May 2012The role of new antiepileptic drugs (AED) in the treatment of status epilepticus (SE) is of interest, especially in benzodiazepine-resistant status epilepticus where... (Review)
Review
BACKGROUND
The role of new antiepileptic drugs (AED) in the treatment of status epilepticus (SE) is of interest, especially in benzodiazepine-resistant status epilepticus where phenytoin is deemed inappropriate due to allergy or comorbidity. Levetiracetam (LEV) is a new AED with few side effects. It is easy to administer. Reports exist of its use in SE in adults.
AIMS
To clarify the evidence for use of LEV as an alternative stage two AED in treatment of SE by a systematic review of the literature.
METHOD
An online MEDLINE search identified 118 articles. The abstracts were screened for studies written in English, in which (1) at least two adults had been treated, and (2) LEV had been administered intravenously as the first AED, on its own or together with benzodiazepines. Ten studies were included.
RESULTS
Out of the ten studies, seven were retrospective observational, two prospective observational, and one prospective randomized. The studies described a total of 334 patients. The most common reason for administrating LEV was that standard treatment was deemed inappropriate. The efficacy ranged from 44% to 94%, with higher efficacy reported in the retrospective studies.
CONCLUSIONS
The evidence for use of LEV as an alternative stage two AED in SE is limited. The higher efficacy reported in retrospective studies indicates possible publication bias, and caution is advised when the results of these retrospective studies are considered in clinical decision-making.
Topics: Anticonvulsants; Humans; Levetiracetam; Piracetam; Status Epilepticus
PubMed: 22321334
DOI: 10.1016/j.seizure.2012.01.008 -
Journal (Canadian Dental Association) 2011Long-term use of phenytoin (PHT) causes gingival hyperplasia; however, little is known about the oral side effects of other antiepileptic drugs (AEDs). Through a... (Review)
Review
OBJECTIVE
Long-term use of phenytoin (PHT) causes gingival hyperplasia; however, little is known about the oral side effects of other antiepileptic drugs (AEDs). Through a systematic review of the literature, we explored the effects of AEDs on the oral health of patients with epilepsy.
METHODS
We searched PubMed, EMBASE and the Cochrane library between January 1963 and August 2010. The search strategy retrieved 170 abstracts. We included studies that involved original research and had ≥ 10 patients in our review. We also checked the reference lists of reviews, letters and other manuscripts to find studies that met our selection criteria.
RESULTS
Only 15 articles were included in the final analysis. Gingival hyperplasia was very common in patients taking PHT (16%-94% of patients). Alveolar bone loss occurred in patients taking carbamazepine or PHT. Patients taking valproate, carbamazepine or phenobarbital also had gingival hyperplasia. We found no published studies of newer-generation AEDs.
CONCLUSION
Although several studies examined the effects of PHT on oral health, none have studied those of the newer generation of AEDs. Studies exploring oral side effects of AEDs are needed.
Topics: Alveolar Bone Loss; Anticonvulsants; Carbamazepine; Epilepsy; Gingival Hyperplasia; Humans; Oral Health; Phenobarbital; Phenytoin
PubMed: 22260801
DOI: No ID Found -
The Cochrane Database of Systematic... Jan 2012Pain management is a high priority for patients with rheumatoid arthritis (RA). Despite deficiencies in research data, neuromodulators have gained widespread clinical... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Pain management is a high priority for patients with rheumatoid arthritis (RA). Despite deficiencies in research data, neuromodulators have gained widespread clinical acceptance as adjuvants in the management of patients with chronic musculoskeletal pain.
OBJECTIVES
The aim of this review was to determine the efficacy and safety of neuromodulators in pain management in patients with RA. Neuromodulators included in this review were anticonvulsants (gabapentin, pregabalin, phenytoin, sodium valproate, lamotrigine, carbamazepine, levetiracetam, oxcarbazepine, tiagabine and topiramate), ketamine, bupropion, methylphenidate, nefopam, capsaicin and the cannabinoids.
SEARCH METHODS
We performed a computer-assisted search of the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2010, 4th quarter), MEDLINE (1950 to week 1 November 2010), EMBASE (Week 44, 2010) and PsycINFO (1806 to week 2 November 2010). We also searched the 2008 and 2009 American College of Rheumatology (ACR) and European League against Rheumatism (EULAR) conference abstracts and performed a handsearch of reference lists of articles.
SELECTION CRITERIA
We included randomised controlled trials which compared any neuromodulator to another therapy (active or placebo, including non-pharmacological therapies) in adult patients with RA that had at least one clinically relevant outcome measure.
DATA COLLECTION AND ANALYSIS
Two blinded review authors independently extracted data and assessed the risk of bias in the trials. Meta-analyses were used to examine the efficacy of a neuromodulator on pain, depression and function as well as their safety.
MAIN RESULTS
Four trials with high risk of bias were included in this review. Two trials evaluated oral nefopam (52 participants) and one trial each evaluated topical capsaicin (31 participants) and oromucosal cannabis (58 participants).The pooled analyses identified a significant reduction in pain levels favouring nefopam over placebo (weighted mean difference (WMD) -21.16, 95% CI -35.61 to -6.71; number needed to treat (NNT) 2, 95% CI 1.4 to 9.5) after two weeks. There were insufficient data to assess withdrawals due to adverse events. Nefopam was associated with significantly more adverse events (RR 4.11, 95% CI 1.58 to 10.69; NNTH 9, 95% CI 2 to 367), which were predominantly nausea and sweating.In a mixed population trial, qualitative analysis of patients with RA showed a significantly greater reduction in pain favouring topical capsaicin over placebo at one and two weeks (MD -23.80, 95% CI -44.81 to -2.79; NNT 3, 95% CI 2 to 47; MD -34.40, 95% CI -54.66 to -14.14; NNT 2, 95% CI 1.4 to 6 respectively). No separate safety data were available for patients with RA, however 44% of patients developed burning at the site of application and 2% withdrew because of this.One small, low quality trial assessed oromucosal cannabis against placebo and found a small, significant difference favouring cannabis in the verbal rating score 'pain at present' (MD -0.72, 95% CI -1.31 to -0.13) after five weeks. Patients receiving cannabis were significantly more likely to suffer an adverse event (risk ratio (RR) 1.82, 95% CI 1.10 to 3.00; NNTH 3, 95% CI 3 to 13). These were most commonly dizziness (26%), dry mouth (13%) and light headedness (10%).
AUTHORS' CONCLUSIONS
There is currently weak evidence that oral nefopam, topical capsaicin and oromucosal cannabis are all superior to placebo in reducing pain in patients with RA. However, each agent is associated with a significant side effect profile. The confidence in our estimates is not strong given the difficulties with blinding, the small numbers of participants evaluated and the lack of adverse event data. In some patients, however, even a small degree of pain relief may be considered worthwhile. Until further research is available, given the relatively mild nature of the adverse events, capsaicin could be considered as an add-on therapy for patients with persistent local pain and inadequate response or intolerance to other treatments. Oral nefopam and oromucosal cannabis have more significant side effect profiles however and the potential harms seem to outweigh any modest benefit achieved.
Topics: Administration, Oral; Administration, Topical; Adult; Analgesics, Non-Narcotic; Arthralgia; Arthritis, Rheumatoid; Cannabinoids; Cannabis; Capsaicin; Depression; Humans; Nefopam; Neurotransmitter Agents; Pain Management; Randomized Controlled Trials as Topic
PubMed: 22258992
DOI: 10.1002/14651858.CD008921.pub2 -
Epileptic Disorders : International... Dec 2011In recent years, phenobarbital, as an antiepileptic drug, has become less popular based on adverse events, especially cognitive and behavioural side effects. Despite the... (Meta-Analysis)
Meta-Analysis Review
AIM
In recent years, phenobarbital, as an antiepileptic drug, has become less popular based on adverse events, especially cognitive and behavioural side effects. Despite the development of better tolerated new generation AEDs, phenobarbital is still widely used particularly in developing countries because of its low cost. The purpose of this review was to: (i) investigate whether phenobarbital can be safely used as an antiepileptic drug and (ii) determine the questions which need to be addressed in order to comprehensively and adequately evaluate the safety of phenobarbital for the treatment of epilepsy.
METHODS
The literature was searched using the Cochrane Central Register of randomised controlled trials (1800-2009), Medline (1966-2009), Embase (1966-2009) and three Chinese databases.
RESULTS
Twenty studies were finally included in this systematic review. The determination of adverse effects of combined antiepileptic drugs (AEDs) from different studies was complicated by numerous factors including study design, different descriptions of adverse events and a lack of standardised data collection. These factors may also have been responsible for the heterogeneity present in the meta-analysis. The data did not demonstrate any evidence of association between phenobarbital and a higher risk of adverse events. However, phenobarbital appeared to be associated with a higher rate of adverse drug reaction related withdrawal (ADR-related withdraw), compared to carbamazepine, valproic acid and phenytoin. This may have been due to a concern for possible adverse effects of phenobarbital.
CONCLUSIONS
Phenobarbital was associated with a higher rate of drug withdrawal although there was no evidence to suggest that phenobarbital caused more adverse events compared to carbamazepine, valproic acid or phenytoin. However, in the case of pregnant women, it is important for clinicians to evaluate the benefits and risks of phenobarbital administration before making a final recommendation. Furthermore, unified scales for the assessment of cognitive function should be applied for future studies particularly in children.
Topics: Anticonvulsants; Carbamazepine; Child; Cognition Disorders; Cohort Studies; Cross-Over Studies; Data Collection; Data Interpretation, Statistical; Epilepsy; Female; Humans; Male; Phenobarbital; Phenytoin; Pregnancy; Randomized Controlled Trials as Topic; Research; Research Design; Treatment Outcome; Valproic Acid
PubMed: 21926048
DOI: 10.1684/epd.2011.0444 -
The Cochrane Database of Systematic... Aug 2011Seizures are a common symptom of brain tumours. The mainstay of treatment for seizures is medical therapy with antiepileptic drugs. (Review)
Review
BACKGROUND
Seizures are a common symptom of brain tumours. The mainstay of treatment for seizures is medical therapy with antiepileptic drugs.
OBJECTIVES
To evaluate the relative effectiveness and tolerability of antiepileptic drugs commonly used to treat seizures in adults with brain tumours.
SEARCH STRATEGY
We searched CENTRAL (Issue 2 of 4, The Cochrane Library 2011), MEDLINE (1948 to May week 3, 2011) and EMBASE (1980 to 31 May 2011) databases. In addition, we handsearched articles published since 2000 in the following journals selected by the authors: Epilepsia; The Lancet Neurology and Neuro-Oncology.
SELECTION CRITERIA
Controlled clinical trials with random allocation of the use of antiepileptic drugs to treat seizures in adults with brain tumours.
DATA COLLECTION AND ANALYSIS
Both review authors screened the search results and reviewed the abstracts of potentially relevant articles before retrieving the full text of eligible articles.
MAIN RESULTS
Only one trial met the inclusion criteria for this review which was a small, open-label, unblinded, randomised trial of the safety and feasibility of switching from phenytoin to levetiracetam monotherapy or continuing phenytoin for glioma-related seizure control following craniotomy (Lim 2009). Levetiracetam (a non enzyme-inducing antiepileptic drug) appears to have been at least as well tolerated and as effective as phenytoin (an enzyme-inducing antiepileptic drug) for the treatment of seizures in people with brain tumours. Eighty-seven per cent of participants treated with levetiracetam were free of seizures at six months compared with 75% of participants treated with phenytoin. There is one ongoing study of levetiracetam versus pregabalin for the treatment of seizures in adults undergoing chemotherapy, radiotherapy,or both for primary brain tumours. No data from this study were available at the time of preparing this review.
AUTHORS' CONCLUSIONS
There is a lack of robust, randomised, controlled evidence to support the choice of antiepileptic drug for the treatment of seizures in adults with brain tumours. While some authors support the use of non enzyme-inducing antiepileptic drugs, reliable, comparative evidence to provide clinical justification for this is limited. There is a need for further large, randomised, controlled trials in this area.
Topics: Adult; Anticonvulsants; Brain Neoplasms; Drug Substitution; Humans; Levetiracetam; Phenytoin; Piracetam; Randomized Controlled Trials as Topic; Seizures
PubMed: 21833969
DOI: 10.1002/14651858.CD008586.pub2