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Antiepileptic drugs as prophylaxis for post-craniotomy seizures

  1. Jennifer Pulman1,*,
  2. Janette Greenhalgh2,
  3. Anthony G Marson1

Editorial Group: Cochrane Epilepsy Group

Published Online: 28 FEB 2013

Assessed as up-to-date: 17 DEC 2012

DOI: 10.1002/14651858.CD007286.pub2


How to Cite

Pulman J, Greenhalgh J, Marson AG. Antiepileptic drugs as prophylaxis for post-craniotomy seizures. Cochrane Database of Systematic Reviews 2013, Issue 2. Art. No.: CD007286. DOI: 10.1002/14651858.CD007286.pub2.

Author Information

  1. 1

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

  2. 2

    University of Liverpool, Liverpool Reviews and Implementation Group, Liverpool, 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.

Publication History

  1. Publication Status: New
  2. Published Online: 28 FEB 2013

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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


InterventionsGroup 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


OutcomesPrimary 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


InterventionsGroup 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


OutcomesPrimary 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 riskThe 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


InterventionsGroup 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


InterventionsGroup 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


InterventionsGroup 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


OutcomesPrimary 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


InterventionsGroup 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


OutcomesPrimary 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

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

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)
⊕⊕⊝⊝
low1,2
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)
⊕⊕⊝⊝
low1
All trials found no significant differences across comparisons examined

Death
(number of deaths)
See commentSee commentNot estimable935
(4 trials)
⊕⊕⊝⊝
low1,2
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)
⊕⊕⊝⊝
low1
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.

 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.
 
Table 1. Comparison of treatment protocols

StudyIntervention

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

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

FoyPHT 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 weekUnclearNo 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 reportedITT 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 monthsITT 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

 CBZ: carbamazepine; ITT: intention to treat; PB: phenobarbital; PHT: phenytoin; VAL: valproate; ZNS: zonisamide.
 
Table 2. Study results for seizure data

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-

 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.
 
Table 3. Results for deaths and adverse events

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-

 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.