Antiepileptic drugs as prophylaxis for post-craniotomy seizures

  • Review
  • Intervention

Authors

  • Jennifer Pulman,

    Corresponding author
    1. Institute of Translational Medicine, University of Liverpool, Department of Molecular and Clinical Pharmacology, Liverpool, Merseyside, UK
    • Jennifer Pulman, Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, Clinical Sciences Centre for Research and Education, Lower Lane, Fazakerley, Liverpool, Merseyside, L9 7LJ, UK. jennifer.pulman@liv.ac.uk.

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  • Janette Greenhalgh,

    1. University of Liverpool, Liverpool Reviews and Implementation Group, Liverpool, UK
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  • Anthony G Marson

    1. Institute of Translational Medicine, University of Liverpool, Department of Molecular and Clinical Pharmacology, Liverpool, Merseyside, UK
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Abstract

Background

The incidence of seizures following supratentorial craniotomy for non-traumatic pathology has been estimated to be 15% to 20%; however, the risk of experiencing a seizure may vary from 3% to 92% over a five-year period. Postoperative seizures can precipitate the development of epilepsy; seizures are most likely to occur within the first month of cranial surgery. The use of antiepileptic drugs (AEDs) administered pre- or postoperatively to prevent seizures following cranial surgery has been investigated in a number of randomised controlled trials.

Objectives

To determine the efficacy and safety of AEDs when used prophylactically in people undergoing craniotomy and to examine which AEDs are most effective.

Search methods

We searched the Cochrane Epilepsy Group's Specialized Register (September 2012), the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library Issue 9, 2012), and MEDLINE (1946 to September 2012). No language restrictions were imposed.

Selection criteria

Randomised controlled trials of people with no history of epilepsy who were undergoing craniotomy for either therapeutic or diagnostic reasons were included. Trials with adequate randomisation methods and concealment were included; these could either be blinded or unblinded parallel trials. No minimum treatment period was stipulated, trials using active drugs or placebo as a control group were included.

Data collection and analysis

Two review authors (JP and JG) independently selected trials for inclusion and carried out data extraction and risk of bias assessments. Any disagreements were resolved through discussion. Outcomes investigated included the number of patients experiencing seizures (early - occurring within first week following craniotomy and late - occurring after first week following craniotomy), the number of deaths and the number of people experiencing disability and adverse effects. Due to the heterogeneous nature of the trials, data from the trials were not combined in a meta-analysis; the findings of the review are presented in narrative format.

Main results

Six RCTs (N = 1398) were eligible for inclusion within the review with publication dates ranging between 1983 and 1999. Two trials compared a single AED (phenytoin) with a placebo. One three-arm trial compared two AEDs (carbamazepine, phenytoin) with no treatment. A second three-arm trial compared phenytoin, phenobarbital and no treatment. Two other trials were head-to-head trials of AEDs (phenytoin vs. valproate and zonisamide vs. phenobarbital). Of the four trials comparing AEDs with controls only one trial reported a significant difference between AED treatment and controls for early seizure occurrence. All other comparisons were non-significant. Of the head-to-head trials, none reported statistically significant differences between treatments for either early or late seizures. One head-to-head trial showed an increase in the number of deaths following one AED treatment compared to another AED treatment. Incidences of adverse effects of treatment were poorly reported, no significant differences between treatment groups were found due to the limited number of reported occurrences.

Authors' conclusions

There is little evidence to suggest that AED treatment administered prophylactically is effective or not effective in preventing post-craniotomy seizures. The current evidence base is limited due to the differing methodologies employed in the trials and inconsistencies in reporting of outcomes. Further evidence from good-quality, contemporary trials is required in order to assess the effectiveness of prophylactic AED treatment compared to control groups or other AEDs in preventing post-craniotomy seizures properly.

Résumé scientifique

Antiépileptiques en prophylaxie pour les crises post-craniotomie

Contexte

L'incidence des crises après une craniotomie sus-tentorielle pour une pathologie non-traumatique a été estimée entre 15 et 20 % ; toutefois, le risque de crise peut varier entre 3 et 92 % sur une période de cinq ans. Les crises post-opératoires peuvent précipiter le développement de l'épilepsie ; les crises surviennent plutôt au cours du premier mois suivant la chirurgie crânienne. L'utilisation d'AE administrés avant ou après l'intervention dans le but de prévenir les crises après une chirurgie crânienne a été examinée dans plusieurs essais contrôlés randomisés.

Objectifs

Déterminer l'efficacité et l'innocuité des AE lorsqu'ils sont utilisés de manière prophylactique chez des personnes subissant une craniotomie et examiner quels AE sont plus efficaces.

Stratégie de recherche documentaire

Nous avons effectué une recherche dans le registre spécialisé du groupe Cochrane sur l’épilepsie (septembre 2012), le registre Cochrane des essais contrôlés (CENTRAL, The Cochrane Library numéro 9, 2012), et MEDLINE (de 1946 à septembre 2012). Aucune restriction de langue n'a été imposée.

Critères de sélection

Ont été inclus les essais contrôlés randomisés portant sur des personnes sans antécédent d'épilepsie qui subissaient une craniotomie pour des raisons thérapeutiques ou de diagnostic. Les essais avec des méthodes de randomisation appropriées et une assignation secrète ont été inclus ; cela pouvait être des essais en parallèle à l'aveugle ou ouverts. Aucune période de traitement minimale n'était stipulée, les essais utilisant des médicaments actifs ou un placebo dans un groupe témoin ont été inclus.

Recueil et analyse des données

Deux auteurs (JP et JG) ont sélectionné de manière indépendant les essais à inclure et ils ont extrait les données et évalué les risques de biais. Les désaccords ont été résolus par la discussion. Les critères de jugement examinés incluaient le nombre de patients faisant des crises (précoce - survenant au cours de la première semaine suivant la craniotomie et tardive - survenant après la première semaine suivant la craniotomie), le nombre de décès et le nombre de personnes rencontrant une incapacité et des effets indésirables. En raison de la nature hétérogène des essais, les données issues des essais n'ont pas été combinées dans une méta-analyse ; les résultats de la revue sont présentés sous forme narrative.

Résultats principaux

Six ECR (N = 1398) étaient éligibles pour inclusion dans la revue avec des dates de publication allant de 1983 à 1999. Deux essais comparaient un AE simple (phénytoïne) à un placebo. Un essai à trois bras comparait deux AE (carbamazépine, phénytoïne) à l'absence de traitement. Un deuxième essai à trois bras comparait la phénytoïne, le phénobarbital et l'absence de traitement. Deux autres essais étaient des essais en face à face d'AE (phénytoïne vs valproate et zonisamide vs phénobarbital). Sur les quatre essais comparant les AE à des témoins, seul un essai a mentionné une différence significative entre le traitement avec AE et les témoins pour une occurrence précoce de la crise. Toutes les autres comparaisons n'étaient pas significatives. Sur les essais en face à face, aucun n'a mentionné des différences statistiquement significatives entre les traitements pour des crises précoces ou tardives. Un essai en face à face a indiqué une augmentation du nombre de décès après un traitement avec AE par rapport à un autre traitement avec AE. Les incidences des effets indésirables du traitement ont été mal signalées, aucune différence significative entre les groupes de traitement n'a été découverte en raison du nombre limité d'occurrences indiquées.

Conclusions des auteurs

Il n'existe pas suffisamment de preuves permettant de suggérer qu'un traitement avec AE administré de manière prophylactique est efficace ou non pour prévenir les crises post-craniotomie. Les preuves actuelles sont limitées en raison des méthodologies différentes utilisées dans les essais et des incohérences pour signaler les résultats. Des données supplémentaires provenant d'essais contemporains de bonne qualité sont nécessaires pour évaluer l'efficacité d'un traitement AE prophylactique par rapport à des groupes témoins ou d'autres AE dans la prévention adéquate des crises post-craniotomie.

Plain language summary

AEDs as prophylaxis for post-craniotomy seizures

Antiepileptic drugs (AEDs) have been used in trials to prevent postoperative seizures occurring in patients with no history of epilepsy prior to undergoing neurosurgery. Several trials have compared different AED treatments while others have compared AEDs to a placebo or no treatment group. This review examined the differences between the AED treatments in relation to number of patients experiencing seizures, number of patient deaths and number of adverse effects experienced following craniotomy surgery (a type of brain surgery most commonly used to remove brain tumours). No evidence was found to suggest that prophylactic AED treatments are effective in reducing occurrences of postoperative seizures, deaths or adverse effects. Further trials of good quality are needed to validate this finding.

Résumé simplifié

Antiépileptiques (AE) en prophylaxie pour les crises post-craniotomie

Les antiépileptiques (AE) ont été utilisés dans des essais pour prévenir les crises post-opératoires survenant chez des patients sans antécédent d'épilepsie avant de subir une neurochirurgie. Plusieurs essais ont comparé différents traitements AE alors que d'autres ont comparé des AE à un placebo ou à un groupe sans traitement. Cette revue a examiné les différences existant entre les traitements AE en lien avec le nombre de patients ayant eu des crises, le nombre de décès chez les patients et le nombre d'effets indésirables rencontrés après une craniotomie (un type de chirurgie du cerveau plus fréquemment utilisé pour retirer les tumeurs cérébrales). Il n'a été trouvé aucune donnée qui permettait de suggérer que les traitements AE prophylactiques sont efficaces pour réduire les occurrences des crises post-opératoires, les décès ou les effets indésirables. Il est nécessaire de réaliser des essais complémentaires de bonne qualité pour valider cette affirmation.

Notes de traduction

Traduit par: French Cochrane Centre 1st March, 2013
Traduction financée par: Pour la France : Ministère de la Santé. Pour le Canada : Instituts de recherche en santé du Canada, ministère de la Santé du Québec, Fonds de recherche de Québec-Santé et Institut national d'excellence en santé et en services sociaux.

Summary of findings(Explanation)

Summary of findings for the main comparison. Antiepileptic drugs as prophylaxis for post-craniotomy seizures
  1. 1 Methodological biases identified in trials (no allocation concealment, one study unblinded, unclear methods of dealing with missing data).
    2 All trials differed in comparisons made.
    3 Beenen et al 1999 found number of seizures was significantly lower in the phenytoin group compared to valproate group.
    4 Foy et al 1992 found large differences in the number of deaths between treatment groups. Statistical significance level unreported.

Antiepileptic drugs as prophylaxis for post-craniotomy seizures
Patient or population: patients with post-craniotomy seizures
Settings: hospital setting
Intervention: antiepileptic drugs
OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of participants
(trials)
Quality of the evidence
(GRADE)
Comments
Assumed riskCorresponding risk
ControlAntiepileptic drugs
Early seizures
(number of seizures)
See commentSee commentNot estimable911
(5 trials)
⊕⊕⊝⊝
low 1,2
4 trials found no significant differences across comparisons examined. 1 trial found a significantly lower number of seizures following use of phenytoin3
Late seizures
(number of seizures)
See commentSee commentNot estimable998
(5 trials)
⊕⊕⊝⊝
low 1
All trials found no significant differences across comparisons examined
Death
(number of deaths)
See commentSee commentNot estimable935
(4 trials)
⊕⊕⊝⊝
low 1,2
3 trials revealed no significant differences over comparisons. 1 trial found 19 deaths in the carbamazepine group, 42 in the phenytoin group and 13 in the no treatment group4
Adverse effects
(number of events)
See commentSee commentNot estimable722
(4 trials)
⊕⊕⊝⊝
low 1
All trials found low numbers of adverse effects, no significant differences across comparisons reported
*The basis for the assumed risk (e.g. the median control group risk across trials) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: confidence interval.
GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

Background

The incidence of epilepsy following supratentorial craniotomy for non-traumatic pathology has been estimated to be 15% to 20% (Foy 1981); however, due to the nature of the underlying disease for which surgery is undertaken, the risk of post-craniotomy seizures may vary from 3% to 92% over a five-year period. It is likely that such seizures may cause epilepsy in previously unaffected people. The probability of de novo seizures occurring in people who have no history of epilepsy decreases over time. The highest incidence of postoperative epilepsy (two-thirds of the seizures) occurs within the first month after cranial surgery (North 1983a), and 75% of those who do develop epilepsy will do so within one year of surgery. Few people (approximately 8%) have their first seizure more than two years after surgery. The risk of seizures for particular groups of people is higher; for example for those with an arteriovenous malformation who have had a spontaneous intracerebral haematoma, the overall risk does not fall below 10% between year two and five after surgery, while people who suffered from an abscess continue to run a risk of developing epilepsy (92%) after five years (Shaw 1991).

Due to the risk of postoperative seizures, the prophylactic use of antiepileptic drugs (AEDs) has been advocated for patients undergoing cranial surgery. Uncontrolled retrospective trials support the use of AED treatment in patients with a predisposition towards developing postoperative seizures (Matthew 1980) and data from pathological trials suggest that certain AEDs could have a neuro-protective action on damaged cerebral cortex (Calabresi 2003).

However, it is also argued that AEDs should not be used prophylactically, but should only be administered following at least one seizure (Temkin 2002). Other investigators maintain that early postoperative seizures do not justify the diagnosis of epilepsy and only late seizures are considered to be true epilepsy (Manaka 2003).

To inform decision-making regarding the prophylactic use of AEDs for people undergoing craniotomy, reliable, high-quality evidence is required. Benefits and harms and any trade-offs between these need to be examined carefully. Potential benefits include reduced short-term seizure recurrence, reduced long-term epilepsy rates, and better surgical outcome and quality of life. Harms include adverse effects and poorer surgical outcome. This review will provide a summary of the currently available evidence from randomised controlled trials (RCTs) regarding the prophylactic use of AEDs for people undergoing craniotomy by examining the following outcomes: occurrence of early and late seizures, occurrence of death, functional disability and occurrence of adverse events.

Objectives

To determine the efficacy and safety of AEDs when used prophylactically in people undergoing craniotomy for all pathologies.

Methods

Criteria for considering studies for this review

Types of studies

  1. RCTs, in which an adequate method of randomisation and allocation concealment was used.

  2. Double, single or unblinded trials.

  3. Placebo (PCB)-controlled, active drug control group or no treatment control group.

Types of participants

People of any age and either gender undergoing a supratentorial or infratentorial craniotomy for either therapeutic or diagnostic reasons for all pathologies, who have had no history of seizures or prior exposure to AEDs.

Types of interventions

  1. The active treatment group receive treatment with any AED administered prior to or immediately post craniotomy.

  2. The control group receive matched PCB, different AED or no treatment.

Types of outcome measures

Primary outcomes
(1) Early seizures

The proportion of people experiencing seizures occurring within the first week following craniotomy.

(2) Late seizures

The proportion of people experiencing seizures after the first week from craniotomy including follow-up period of one, two and five years postoperatively from craniotomy.

Secondary outcomes
(1) Death

The proportions of deaths occurring within the treatment period or during follow-up.

(2) Functional outcome

The proportion of people experiencing disability (partially or fully dependent on others in normal activities of daily living).

(3) Adverse effects

The proportion of people who experience any of the following adverse events:

  • skin irritation;

  • dizziness;

  • fatigue;

  • nausea;

  • headache.

In addition, we decided to look at the proportion of people experiencing the five most common adverse effects mentioned in the included trials if these differed from the list above.

Search methods for identification of studies

See Appendix 1 and Appendix 2 for search strategy used.

Electronic searches

We searched:

  1. the Cochrane Epilepsy Group's Specialized Register (19 September 2012);

  2. the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library Issue 9, 2012) using the search strategy outlined in Appendix 1;

  3. MEDLINE (Ovid, 1946 to September week 1, 2012) using the search strategy outlined in Appendix 2.

No language restrictions were imposed.

Searching other resources

We reviewed the reference lists of retrieved trials to check for additional reports of relevant studies.

Data collection and analysis

Selection of studies

Two review authors (JP and JG) independently assessed articles for inclusion. Any disagreements were resolved through mutual discussion, failing this a third-party (AM) opinion was sought. The same review authors independently carried out data extraction and assessed risk of bias. Again, disagreements were resolved by mutual discussion, failing this a third-party opinion (AM) was sought.

Data extraction and management

The following information was extracted for each trial using a data extraction sheet.

Methodology/trial design
  1. Method of randomisation and concealment.

  2. Method of blinding.

  3. Number of people excluded from analyses.

  4. Duration of baseline, treatment and follow-up periods.

  5. Type of AED and dose tested.

  6. Time of treatment commencement.

Participant demographics
  1. Total number of people randomised to each group.

  2. Age/gender.

  3. Pathological group.

  4. Type of surgery.

  5. Site of lesion.

  6. Number of people with previous acute symptomatic seizures.

Results
  1. Sample size.

  2. Summary data for each intervention.

For all trials we attempted to confirm the above information with trial authors/researchers and sponsors.

Assessment of risk of bias in included studies

Two review authors (JP and JG) independently made an assessment of risk of bias for each trial using the Cochrane 'Risk of bias' table as described in Higgins 2002. Any disagreements were discussed and resolved. Included trials were rated as adequate, inadequate or unclear on six domains applicable to RCTs:- randomisation method, allocation concealment, blinding methods, incomplete outcome data, selective outcome reporting and other sources of bias. A 'Summary of findings' table was created; however, the GRADE approach for determining quality of evidence was not assessed as no trials were combined.

Measures of treatment effect

Treatment effects are presented as they were in the original reports.

Assessment of heterogeneity

Clinical heterogeneity was assessed by examining the differences in trial characteristics in order to inform decisions regarding the combination of trial data.

Assessment of reporting biases

Reporting biases, such as publication bias, were examined by identifying certain aspects of each trial (e.g. sponsors of the research, research teams involved).

Data synthesis

Data were synthesised in a narrative format as meta-analysis was considered to be inappropriate given the differences across trials in AED treatment, trial intervention characteristics and control groups (see Table 1). Data under each comparison listed below were minimal and could not be combined across all outcomes.

Table 1. Comparison of treatment protocols
  1. CBZ: carbamazepine; ITT: intention to treat; PB: phenobarbital; PHT: phenytoin; VAL: valproate; ZNS: zonisamide.

Study

Intervention

and daily dose (N)

Comparator(s) and daily dose (N)Time of administration
(reoperation/postoperation)
Treatment duration

Measurement

period reported -

early

Measurement

period reported -

late

Analysis
BeenenPHT 300 mg
(N = 50)
VAL 1500 mg/day
(N = 50)
Post-op12 months1 week2 weeks to 12 monthsITT
Foy

PHT 300 mg
6 months group

(N = 55)

24 months group (N = 56)

CBZ 600 mg
6 months group (N = 50)

24 months group (N = 56)

Pre-op*
and post-op

(pre- and post-op doses differed)

6 months
24 months
Not reported4 years (median)ITT
FranceschettiPHT 5 mg/kg (N = 16)PB 2 mg/kg
(N = 25)

No treatment
(N = 22)

Pre-op
and post-op

(pre- and post-op doses differed)

Unclear1 weekUnclear

No ITT

24 patients lost to follow-up (for late seizure)

LeePHT 5 to 6 mg/kg
(N = 189)
Placebo
(N = 185)

Pre-op*
and post-op

(pre- and post-op doses differed)

3 days3 daysNot reported

ITT unclear.

Randomised = 400 but 26 deaths prior to treatment

NakamuraZNS 200 mg
(N = 129)
PB 80 mg
(N = 126)

Pre-op
and post-op

(doses changed across course of trial)

12 monthsNot reported1 to 12 months

ITT for 255 patients who received treatment

23 randomised patients were excluded prior to treatment

NorthPHT 300 mg
(N = 140)
Placebo
(N = 141)
Post-op12 months1 week12 monthsITT

Comparisons discussed in the narrative included:

  1. treatment group vs. control group on early seizures;

  2. treatment group vs. control group on late seizures;

  3. treatment group vs. control group on number of deaths;

  4. treatment group vs. control group on functional outcome;

  5. treatment group vs. control group on adverse effects (for each adverse effect see Types of outcome measures).

Each comparison was stratified by type of drug and control group (i.e. PCB, other AED or no treatment).

Results

Description of studies

See: Characteristics of included studies; Characteristics of excluded studies; Characteristics of studies awaiting classification.

The search revealed 86 records identified from the databases outlined in Electronic searches. Ten further records were identified through the reference lists of included trials. Fifty-seven records remained after duplicates were removed, all were screened for inclusion in the review. Thirty-three were excluded at this point leaving 24 full-text articles to be assessed for eligibility. Following this, 15 texts were excluded (see Figure 1 and Characteristics of excluded studies for reasons of exclusion). Six trials from eight reports were included in a qualitative synthesis.

Figure 1.

Study flow diagram.

Six parallel RCTs were found (Beenen 1999; Foy 1992; Franceschetti 1990; Lee 1989; Nakamura 1999; North 1983) examining the effectiveness of AEDs on post-craniotomy seizures. The treatment periods varied across trials from three days to 24 months; in one trial the treatment period was unclear (Franceschetti 1990). People were excluded from five of the trials if they were taking AEDs already and if they had a history of epilepsy (Beenen 1999; Foy 1992; Lee 1989; Nakamura 1999; North 1983). One trial (Franceschetti 1990) included both people who had preoperative seizures (Group A) and those who did not (Group B); Group A and Group B were analysed separately compared to controls. Only data pertaining to Group B were extracted to be included within this review as they did not meet the inclusion criteria for the review.

The trial reported by Beenen et al (Beenen 1999) was a single-centre trial with a treatment period of 12 months. People aged between 18 and 80 years who were undergoing supratentorial craniotomy were eligible to be randomised. One hundred patients were randomised, 50 to phenytoin 100 mg (PHT) and 50 to valproate 500 mg (VAL) both administered intravenously immediately post operation in a recovery room. Outcomes reported included early and late seizures, death and adverse effects. No data were reported for functional outcome.

The trial reported by Foy et al (Foy 1992) was a single-centre, head-to-head (active drug comparison) trial with a treatment phase of either six or 24 months, follow-up occurred for a minimum of three years to a maximum of eight years. People aged over 16 years undergoing supratentorial craniotomy were eligible to be randomised. Two hundred and seventy-six patients were randomised, 50 to carbamazepine (CBZ) for a six-month treatment period, 56 to CBZ for a 24-month treatment period, 55 to PHT for a six-month treatment period, 56 to PHT for a 24-month treatment period and 59 to no treatment. Administration of CBZ (200 mg) was 6 hourly for the 24 hours immediately pre-operation and eight hourly thereafter; PHT (15 mg/kg) was administered 24 hours pre-operation and increased to 100 mg eight hourly thereafter. Outcomes reported included number of patients with seizures and death. No differentiation was made between early and late seizures and no data were reported for functional outcome or adverse effects. All data were reported at six months into the treatment.

The trial reported by Franceschetti et al (Franceschetti 1990) was a single-centre, head-to-head three-arm trial that included a 'no treatment' group. People undergoing surgery for supratentorial neoplasms were randomised and patients with a history of seizures formed Group A and patients who had no history of seizures formed Group B. Sixty-three Group B patients were randomised, 25 to phenobarbital (PB), 16 to PHT and 22 to no treatment. The PB (4 mg/kg) was intravenously administered daily for five days then decreased to 2 mg/kg daily via oral administration. PHT (10 mg/kg) was intravenously administered daily for five days then decreased to 5 mg/kg daily via oral administration. Outcomes reported included early and late seizures, and minimal data on adverse effects were presented.

The trial reported by Lee et al (Lee 1989) was a PCB-controlled trial with a treatment period of three days. People receiving intracranial, supratentorial surgery were eligible to take part in the trial. Four hundred patients were selected for participation and randomised, 26 early deaths occurred leaving 189 people randomised to PHT and 185 people to PCB. PHT (15 mg/kg) was administered 15 to 20 minutes prior to wound closure followed by intravenous PHT (5 to 6 mg/kg) three times daily for the first three postoperative days. Outcomes measured included number of seizures occurring within the three days of the trial. Data for late seizures, death, functional outcome and adverse effects were not recorded.

The trial reported by Nakamura et al (Nakamura 1999) was a multi-centre, head-to-head trial with a treatment phase of one year and a follow-up of two years without medication. People undergoing craniotomy for cerebral tumours, cerebrovascular disease and head trauma were selected for eligibility. Two hundred and seventy-eight patients were randomised, 141 to zonisamide (ZNS, 100 mg twice daily) and 126 to PB (40 mg twice daily). Both drugs were administered orally, at least one week before surgery and then increased (ZNS to 100 mg three or four times daily and PB to 40 mg three or four times daily) for one year followed by a tapering period of six months (three months at 100 mg (ZNS) or 40 mg (PB) twice daily then three months at 100 mg (ZNS) or 40 mg (PB) once daily). Outcomes reported were seizure frequency, death (during follow-up period only) and adverse effects. No data were collected on functional outcome.

The trial reported by North et al (North 1983) was a single-centre, PCB-controlled trial with a treatment period of 12 months. People undergoing supratentorial operation (either burr hole, craniectomy or osteoplastic flap procedures) were eligible for inclusion for the trial. Two hundred and eighty-one patients were randomised, 140 to PHT and 141 to PCB. PHT (250 mg twice daily) was administered in a recovery room intravenously, and then continued with oral medication (100 mg three times daily) for one year. Outcomes reported were early and late seizures, death and adverse effects. No data were collected on functional outcome.

Risk of bias in included studies

Out of the six trials included, only two (Beenen 1999; Foy 1992) were considered to have used adequate methods of randomisation with regards to sequence generation. The other four trials were unclear in their methods or there were no available details in text. One trial (Beenen 1999) described the use of sealed envelopes and pre-coded and packaged medication, the other five trials were rated as unclear. Four trials used adequate blinding methods by using identical treatments, one trial (Foy 1992) was unblinded and one was unclear (Franceschetti 1990). Assessments of incomplete outcome data revealed all trials to have some study attrition, one trial (Lee 1989) was unclear regarding attrition rate and analysis therefore was rated as unclear in bias on this criteria. Two trials (Beenen 1999; North 1983) reported attrition and employed intention-to-treat analysis to deal with these missing data. The other three trials were unclear as to how missing data were managed. No protocols were available for any of the trials (although these were requested from authors) therefore the completeness of reported outcome data was difficult to assess. All trials reported data outlined in the methods section of their papers and appeared to report what was set out to record. No other evidence of bias was found in five of the six trials. One trial (Foy 1992) was rated as unclear on these criteria due to the addition of a third control group after a first analysis showed few differences between groups. See Characteristics of included studies for Foy et al. See Figure 2 for 'Risk of bias' graph.

Figure 2.

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included trials.

Effects of interventions

See: Summary of findings for the main comparison Antiepileptic drugs as prophylaxis for post-craniotomy seizures

Due to the variety of head-to-head drug comparisons within the included trials, the effects of the interventions will be presented by outcome measure as opposed to comparisons under trial. See Table 2 and Table 3 for individual trial results and Table 1 for a comparison of treatment protocols.

Table 2. Study results for seizure data
  1. AED: antiepileptic drug; CBZ: carbamazepine; mo: month; PB: phenobarbital; PHT: phenytoin; VAL: valproate; ZNS: zonisamide.

    * Results from these trials reported the number of patients who had seizures out of the number of patients randomised. However loss to follow up during the trial was unclear.

    ** Results from the trials only reported the number of patients who had seizures out of the number of patients who were followed up. Foy et al followed up 39 patients for late seizures. Franceschetti reported combination of PB and PHT results, cannot differentiate between groups on seizure outcome for all seizures and early seizures.

TrialAll seizuresEarly seizuresLate seizures
 AED groupAED controlNo treatment controlAED groupAED controlNo treatment controlAED groupAED controlNo treatment control
Beenen* (PHT vs. VAL)7/507/50-4/502/50-3/505/50-
Foy* (CBZ vs. PHT)

21/50 (6 mo)

20/56 (24 mo)

21/55 (6 mo)

16/56 (24 mo)

25/59------
Franceschetti** (PB vs. PHT vs. no treatment)--7/223/41-4/22PB 2/15PHT 1/103/14
Lee* (PHT vs. placebo)2/1899/185-2/1899/185----
Nakamura** (ZNS vs. PB)13/12911/126-6/1293/126-7/1298/126-
North* (PHT vs. placebo)18/14026/141-4/14014/141-14/14012/141-
Table 3. Results for deaths and adverse events
  1. AED: antiepileptic drug; CBZ: carbamazepine; mo: month; PB: phenobarbital; PHT: phenytoin; VAL: valproate; ZNS: zonisamide.

    * Results from these trials reported the number of patients who died or experienced adverse events out of the number of patients randomised. However loss to follow-up during the trial was unclear.

    ** Results from the trials only reported the number of patients who died or experienced adverse events out of the number of patients who were followed up.

 DeathsAdverse events
 AED groupControl group/other AEDOther control (no treatment)AED groupAED controlNo treatment control
Beenen* (PHT vs. VAL)13/5010/50-9/504/50-
Foy* (CBZ vs. PHT)

9/50 (6 mo)

10/56 (24 mo)

15/55 (6 mo)

27/56 (24 mo)

13/59---
Franceschetti** (PB vs. PHT vs. no treatment)---1/153/10-
Lee* (PHT vs. placebo)------
Nakamura** (ZNS vs. PB)8/11213/107-28/12930/126-
North* (PHT vs. placebo)20/14024/141-12/1403/141-

Seizures

Beenen 1999 examined seizure outcome between PHT and VAL and reported 4/50 early seizures occurring in the PHT group compared to 2/50 early seizures in the VAL group. Three late seizures occurred in the PHT group compared to five late seizures in the VAL group. Foy 1992 examined three treatment groups, CBZ, PHT and no treatment. They reported 41/106 seizures (early and late) occurring in the CBZ group, 37/111 occurring in the PHT group and 25/59 occurring in the 'no treatment' group at six months. The trial by Franceschetti 1990 also looked at three groups, PB, PHT and no treatment. They reported 3/41 early seizures occurring in the PB and PHT groups and 4/22 early seizures in the 'no treatment' group. Only 39 patients were followed up and they reported 3/25 late seizures in the PB and PHT group and 3/14 late seizures in the 'no treatment' group. Two trials (Lee 1989; North 1983) examined differences between PHT and a PCB control group. In the trial by Lee 1989 patients were treated for three days with no further follow-up, therefore only early seizures within the three days were reported. They found 2/189 seizures occurred in the PHT group compared to 9/185 in the PCB group. In the trial by North 1983, 4/140 early seizures were reported in the PHT group compared to 14/141 in the PCB group. For late seizures, 14/140 occurred in the PHT group compared to 12/141 in the control group. Nakamura 1999 conducted a head-to-head trial of ZNS versus PB. They reported 6/129 early seizures occurring within the ZNS group compared to 3/126 early seizures occurring within the PB group. For late seizures, 7/129 occurred in the ZNS group and 8/126 occurred in the PB group. Overall, only one trial (North 1983) had a significant difference between AED treatment and controls for early seizure occurrence. All other comparisons were non-significant.

Deaths

Across all trials, 13/50 deaths were reported in the PHT group compared to 10/50 in the VAL group (Beenen 1999), 9/50 occurred in the CBZ (six month) group and 10/56 in the CBZ (24 month) group compared to 15/55 in the PHT (six month) group and 27/56 in the CBZ (24 month) group and 13/59 in the no treatment group (Foy 1992), 8/112 occurred in the ZNS group compared to 13/107 in the PB group (Nakamura 1999), and 20/140 occurred in the PHT group compared to 24/141 in the PCB group (North 1983). No data were collected for this outcome in two trials (Franceschetti 1990; Lee 1989).

Adverse effects

Four trials reported information on adverse effects. In the Beenen 1999 trial, 4/50 people experienced a skin reaction, 3/50 people experienced liver dysfunction, 1/50 people experienced thrombopenia and there was one case of nausea within the PHT group (N = 50). In the VAL group there were three cases of liver dysfunction, and one case of a rise in liver enzymes (N = 50). Nakamura 1999 reported two cases of somnolence and six cases of nausea in the ZNS group (N = 129), and seven cases of somnolence and two cases of nausea in the PB group (N = 126). Overall they reported 28/129 adverse effects in the ZNS group and 30/126 in the PB group. The North 1983 trial reported eight cases of rash, one case of involuntary movements, one hirsutism, one headache and one case of discomfort of the face in the PHT group (N = 140) compared to one case of rash, one dizziness and one nausea in the PCB group (N = 141). Franceschetti 1990 reported minimal data on the adverse effects, only that 3/10 people in the PHT group and 1/10 people in the PB group experienced neurological side effects. No data from the remaining trials were provided (Foy 1992; Lee 1989).

Discussion

The trials included in this review were all RCTs investigating the effects of a range of AEDs given either immediately before or after a craniotomy procedure to people with no previous history of seizures or exposure to AEDs. The underlying pathologies for craniotomy surgery were mixed within the studies (e.g. tumour, abscess, meningioma) with a small percentage of patients having surgery as a result of head injuries. One study included a substantial proportion (210/374) of head-injury patients (Lee 1989). This is a major limitation of this review as the objective is to examine outcomes for patients undergoing craniotomy presenting with non-trauma pathology. We acknowledge the possibility of differences in the risk of seizure post surgery depending on the underlying pathology of the patient.

We were unable to meta-analyse any of the data and structuring a narrative summary was difficult for a number of reasons; few trials were available under each comparison examined (see Data synthesis for list of comparisons under investigation) and the interventions varied substantially with regards to duration of treatment period, dose and method of drug administration, country, methodological rigour and underlying pathologies. Reporting of outcomes differed across the trials, not all differentiated between early and late seizures and information about adverse effects of treatment was very limited. Most trials had similar inclusion and exclusion criteria. Patients undergoing supratentorial craniotomy were randomised in five of the six trials; the sixth (Nakamura 1999) did not specify the type of surgery.

For the outcome of incidence of seizures, overall the majority of trials reported no significant difference between treatment with AEDs and no treatment or treatment with AEDs and no treatment. Head-to-head drug comparisons also yielded non-statistically significant results. Only one trial (North 1983) reported any statistically significant findings, the incidence of early seizures was reduced in the AED group (PHT) compared to a PCB (P < 0.05). Overall, results from the individual trials showed no significant differences between AED treatment participants and control participants for outcomes relevant to the number of deaths and adverse effects. None of the trials examined functional outcome of patients.

The outcomes of the risk of bias assessments conducted for each trial are worthy of note. The majority of trials were rated as unclear on several of the criteria. Only two of the six trials (Beenen 1999; Foy 1992) were rated as low in bias due to the method used to generate the randomisation sequence and only one trial (Beenen 1999) used adequate methods for concealing the allocation of intervention. Most trials used adequate methods for blinding participants and outcome assessors; however, one trial was unblinded (Foy 1992) and therefore was rated as high risk of bias for this criteria. There were no protocols available for any of the trials, therefore assessing selective reporting across trials was rated as unclear. Several trials were rated as unclear as to how missing data were managed within their analysis. In most cases attrition was reported and reasons for withdrawal were described.

Authors' conclusions

Implications for practice

The results from this review show that there is not enough evidence of sufficient quality available to suggest that AED treatment can or cannot be recommended to reduce post-craniotomy seizures. There is no evidence on which to base clinical practice.

Implications for research

To evaluate the effectiveness of prophylactic treatment with AEDs in preventing seizures following cranial surgery better, more trials are needed. These trials must address the methodological weaknesses and protocol inconsistencies identified within this review including:

  1. timing of AED administration (pre- or post-surgery);

  2. adequate length of treatment and follow-up period;

  3. head-to-head or other control group;

  4. methodological aspects (well controlled trials with adequate methods employed for generating randomisation sequences and concealing allocation);

  5. outcome reporting (differentiating between early and late seizures, adverse effects of treatment, handling of missing data) or other important outcomes (functional outcomes in terms of activities of daily living including working, driving etc.) not currently addressed.

Acknowledgements

None.

Data and analyses

Download statistical data

This review has no analyses.

Appendices

Appendix 1. CENTRAL search strategy

#1 MeSH descriptor Craniotomy explode all trees

#2 (craniotom*)

#3 (postcraniotom*)

#4 (supratentorial NEXT surgery)

#5 (infratentorial NEXT surgery)

#6 (#1 OR #2 OR #3 OR #4 OR #5)

#7 MeSH descriptor Seizures explode all trees

#8 (seizure*)

#9 (#7 OR #8)

#10 (#6 AND #9)

#11 (postoperative NEXT epilep*)

#12 (post-operative NEXT epilep*)

#13 (postoperative NEXT seizure*)

#14 (post-operative NEXT seizure*)

#15 (#10 OR #11 OR #12 OR #13 OR #14)

 

Appendix 2. MEDLINE search strategy

This strategy is based on the Cochrane Highly Sensitive Search Strategy for identifying randomised trials published in Lefebvre 2011.

1. exp Craniotomy/

2. craniotom$.tw.

3. postcraniotom$tw.

4. supratentorial surgery.tw.

5. infratentorial surgery.tw.

6. 1 or 2 or 3 or 4 or 5

7. exp Seizures/

8. seizure*.tw.

9. 7 or 8

10. 6 and 9

11. postoperative epilep$.tw.

12. postoperative seizure$.tw.

13. 10 or 11 or 12

14. randomized controlled trial.pt.

15. controlled clinical trial.pt.

16. randomized.ab.

17. placebo.ab.

18. clinical trials as topic.sh.

19. randomly.ab.

20. trial.ti.

21. 14 or 15 or 16 or 17 or 18 or 19 or 20

22. exp animals/ not humans.sh.

23. 21 not 22

24. 13 and 23

 

Contributions of authors

Jennifer Pulman and Janette Greenhalgh carried out and completed the review. Anthony Marson supervised the review. Nikola Vojvodic, Aleksandar Ristic and Dragoslav Sokic developed the protocol for this review.

Declarations of interest

None declared.

Sources of support

Internal sources

  • No sources of support supplied

External sources

  • National Institute for Health Research, UK.

    This review presents independent research commissioned by the National Institute for Health Research (NIHR). The views expressed in this publication are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health.

Differences between protocol and review

We were unable to make all the intended comparisons specified in the protocol due to lack of data.

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Beenen 1999

MethodsRandomised double-blind, placebo-controlled, single-centre (Netherlands), parallel trial. 2 treatment arms: phenytoin (PHT) and valproate (VAL). Allocation concealed using sealed envelopes, trial medication identical in pre-coded packaged materials. Treatment period: 12 months
ParticipantsAdults aged 21-78 (mean age in PHT arm = 55 years, mean age in VAL arm = 51 years). Overall 47 males and 53 females, all patients undergoing craniotomy for different pathological conditions. Patients were not taking antiepileptic drugs (AEDs) prior to randomisation and had no history of seizures. 100 randomised: 50 to PHT and 50 to VAL
Interventions

Group 1: PHT 100 mg intravenous 3 times daily administered immediately post-operation in recovery room

Group 2: VAL 500 mg intravenous 3 times daily administered immediately post-operation in recovery room

Patients took medication in oral form as soon as was possible for 12 months

Outcomes

Primary outcome: drug efficacy (number of seizures)

Secondary outcomes: tolerability (number of withdrawals, adverse effects), quality of life and cognitive functioning

NotesIntention-to-treat (ITT) analysis employed for primary outcome, not for other outcomes (quality of life)
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskStudy used computer-generated randomisation method
Allocation concealment (selection bias)Low riskSealed envelopes, pre-coded and packaged medication
Blinding of participants and personnel (performance bias)
All outcomes
Low riskAdequate blinding techniques used for personnel and participants
Incomplete outcome data (attrition bias)
All outcomes
Low riskStudy attrition reported, employed ITT analysis for primary outcome
Selective reporting (reporting bias)Unclear riskNo trial protocol available
Other biasLow riskNo other bias detected

Foy 1992

MethodsRandomised, controlled, parallel, single-centre (UK) trial. 5 treatment arms: carbamazepine (CBZ) 6 months and 24 months, phenytoin (PHT) 6 months and 24 months, no treatment. Patients randomised in blocks of 5 from prepared lists. Treatment period: 6 or 24 months
ParticipantsPatients aged 16 to 77 years (median 45 years), 134 males and 142 females all undergoing supratentorial craniotomy. Patients had no previous history of seizures. 276 randomised: 50 to CBZ (6 months), 56 to CBZ (24 months), 55 to PHT (6 months), 56 to PHT (24 months), 59 to no treatment
Interventions

Group 1: CBZ 200 mg/6 h for 24 h pre-surgery, 200 mg/8 h thereafter for 6 months

Group 2: CBZ 200 mg/6 h for 24 h pre-surgery, 200 mg/8 h thereafter for 24 months

Group 3: PHT 15 mg/kg 24 h pre-surgery, 100 mg/8 h thereafter for 6 months

Group 4: PHT 15 mg/kg 24 h pre-surgery, 100 mg/8 h thereafter for 24 months

Group 5: no treatment

Outcomes

Primary outcome: drug efficacy (number of seizures)

Secondary outcomes: seizure freedom, death

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskUsed blocks of 5 from prepared lists
Allocation concealment (selection bias)Unclear riskNo details in text
Blinding of participants and personnel (performance bias)
All outcomes
High riskTrial was unblinded
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskStudy attrition reported; however, missing data and intention-to-treat analysis is unclear within the text
Selective reporting (reporting bias)Unclear riskNo trial protocol available
Other biasUnclear risk

The first 102 patients were randomised to treatment with CBZ or PHT for 6 or 24 months. Since analysis showed little difference in the incidence of postoperative seizures in this group relative to a retrospective study of postoperative seizures, the subsequent 176 patients were randomised equally between

policies of no treatment, treatment with CBZ and treatment with PHT

Franceschetti 1990

MethodsGroup B participants randomised to 1 of 3 treatment arms: phenobarbital (PB), phenytoin (PHT), no treatment. No details available in text of randomisation or blinding methods employed. Treatment period: unclear
Participants128 patients entered trial, 65 had pre-operative seizures and were treated with antiepileptic drugs (AEDs) (Group A), 63 patients had no seizures prior to operation and were not taking any AEDs (Group B). 3 treatment arms for Group B randomised patients: PB, PHT and no treatment. Mean age 55 years, 34 males and 29 females undergoing supratentorial craniotomy for neoplasms
Interventions

Group 1: PB (4 mg/kg daily for 5 days), followed by 2 mg/kg daily

Group 2: PHT (10 mg/kg daily for 5 days), followed by 5 mg/kg daily

Group 3: no treatment

OutcomesPrimary outcomes: efficacy (number of seizures (early and late seizures), adverse effects
Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNo details in text
Allocation concealment (selection bias)Unclear riskNo details in text
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskNo details in text
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskAttrition unreported, 24 patients with missing data for late seizure outcome
Selective reporting (reporting bias)Unclear riskNo trial protocol available
Other biasLow riskNo other bias detected

Lee 1989

MethodsRandomised, double-blind, placebo (PCB)-controlled trial. 2 treatment arms: phenytoin (PHT) and PCB. Patients randomised using random digits, all patients received identical medication. Treatment period: 3 days. No follow-up of patients
ParticipantsAdults, mean age 39.9 years (PHT) and 37.5 years (PLC) all undergoing intracranial, supratentorial surgery. Patients have no history of seizures and not taking antiepileptic drugs (AEDs) prior to surgery. 400 patients randomised: 189 to PHT and 185 to PLC. 26 died prior to treatment
Interventions

Group 1: PHT 15 mg/kg for 15 to 20 minutes prior to wound closure followed by 5 to 6 mg/kg/day 3 times daily in first 3 post-operative days

Group 2: saline solution administered as described above

OutcomesPrimary outcome: efficacy (number of seizures)
Notes26 patients randomised died prior to treatment, excluded from all data exploration and analysis
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskUsed random digits, unclear how generated, whether open list, etc
Allocation concealment (selection bias)Unclear riskNo details in text
Blinding of participants and personnel (performance bias)
All outcomes
Low riskIdentical medication used for both groups. Adequate blinding methods for key personnel and participants
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskUnclear details on study attrition rate and how data analysed
Selective reporting (reporting bias)Unclear riskNo protocol available
Other biasLow riskNo other bias detected

Nakamura 1999

MethodsRandomised, double-blind, controlled, multi-centre (Japan) trial. 2 treatment arms: zonisamide (ZNS), phenobarbital (PB). Identical medication administered (no details of methods of randomisation). Treatment period: 1 year. Follow-up period: 3 years
Participants278 high-risk epilepsy patients randomised. 129 in ZNS group analysed, 126 in PB group analysed
Interventions

Group 1: ZNS (100 mg twice daily) until 1 month after craniotomy

Group 2: PB (40 mg twice daily) until 1 month after craniotomy

In both groups dose was adjusted to therapeutic serum concentration and continued up to 1 year

Outcomes

Primary outcome: frequency of epilepsy

Secondary outcome: drug concentration, adverse effects

Notes23 unsuitable cases not included in the analysis. 36 cases not followed up for 3 years
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNo details in text
Allocation concealment (selection bias)Unclear riskNo details in text
Blinding of participants and personnel (performance bias)
All outcomes
Low riskIdentical medication administered to both groups. Drug name blinded from participating institutions, only blood concentration values provided
Incomplete outcome data (attrition bias)
All outcomes
Unclear risk23 cases not included within analysis, all excluded prior to treatment. 36 lost to follow-up were included in analysis
Selective reporting (reporting bias)Unclear riskTrial reports data for overall adverse effects, only reports data for 2 individual adverse effects
Other biasLow riskNo other bias detected

North 1983

MethodsRandomised, double-blinded, placebo (PCB)-controlled, parallel, single-centre (Australia) trial. 2 treatment arms: phenytoin (PHT) and PCB. Patients received identical medication (no details available of randomisation methods). Treatment period: 12 months
ParticipantsAdults, mean age 46.7 years (PHT) and 50.21 years (PCB), all undergoing supratentorial craniotomy. Patients had no previous exposure to antiepileptic drugs (AEDs) and no previous history of epilepsy. 281 patients were randomised: 140 to PHT and 141 to PCB
Interventions

Group 1: PHT 250 mg twice daily administered intravenously first dose administered in the recovery room post craniotomy followed by oral medication 100 mg 3 times daily for 12 months

Group 2: PCB medication administered as described above

Outcomes

Primary outcome: efficacy (number of seizures)

Secondary outcomes: survival time (number of days since randomisation to incidence of seizure or to 365 days in seizure-free patients), adverse effects

Notes63 patients in PHT arm and 59 patients in PCB received intended treatment. All cases randomised were analysed
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNo details in text
Allocation concealment (selection bias)Unclear riskNo details in text
Blinding of participants and personnel (performance bias)
All outcomes
Low riskIdentical medication used for both groups. Only pharmacologist aware of serum drug levels and both PHT and PCB group participants had blood samples taken
Incomplete outcome data (attrition bias)
All outcomes
Low riskAttrition reported and intention-to-treat analysis employed. 6 patients lost to follow-up
Selective reporting (reporting bias)Unclear riskProtocol outlined within paper. All outcomes reported
Other biasLow riskNo other bias detected

Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion
Baker 1995Not a randomised controlled trial, retrospective trial
Boarini 1985Not a randomised controlled trial, retrospective study
De Santis 1996Not a randomised controlled trial
De Santis 2002Patients taking antiepileptic drugs prior to randomisation
Grobelny 2009Not a randomised controlled trial, retrospective design
Hayashi 1999Not a randomised controlled trial
Levati 1996Patients taking antiepileptic drugs prior to randomisation
Lim 2009Patients taking antiepileptic drugs and experiencing seizures prior to randomisation
Manaka 2003Review paper
Murri 1992Not a randomised controlled trial
Notani 1984Not a randomised controlled trial
Shaw 1991Review paper
Temkin 1990No craniotomy surgery performed. Brain injury patients
Temkin 1999No craniotomy surgery performed. Brain injury patients
Tsolaki 1997Patients taking antiepileptic drugs prior to study

Characteristics of studies awaiting assessment [ordered by study ID]

Zhang 2000

MethodsNo information available
ParticipantsNo information available
InterventionsNo information available
OutcomesNo information available
NotesNo information available

Ancillary