Summary of findings
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.
To determine the efficacy and safety of AEDs when used prophylactically in people undergoing craniotomy for all pathologies.
Criteria for considering studies for this review
Types of studies
- RCTs, in which an adequate method of randomisation and allocation concealment was used.
- Double, single or unblinded trials.
- 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
- The active treatment group receive treatment with any AED administered prior to or immediately post craniotomy.
- The control group receive matched PCB, different AED or no treatment.
Types of outcome measures
(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.
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;
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
- the Cochrane Epilepsy Group's Specialized Register (19 September 2012);
- the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library Issue 9, 2012) using the search strategy outlined in Appendix 1;
- 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.
- Method of randomisation and concealment.
- Method of blinding.
- Number of people excluded from analyses.
- Duration of baseline, treatment and follow-up periods.
- Type of AED and dose tested.
- Time of treatment commencement.
- Total number of people randomised to each group.
- Pathological group.
- Type of surgery.
- Site of lesion.
- Number of people with previous acute symptomatic seizures.
- Sample size.
- 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 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.
Comparisons discussed in the narrative included:
- treatment group vs. control group on early seizures;
- treatment group vs. control group on late seizures;
- treatment group vs. control group on number of deaths;
- treatment group vs. control group on functional outcome;
- 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).
Description of studies
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
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.
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.
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).
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).
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.
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:
Data and analyses
This review has no analyses.
Appendix 1. CENTRAL search strategy
#1 MeSH descriptor Craniotomy explode all trees
#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
#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/
4. supratentorial surgery.tw.
5. infratentorial surgery.tw.
6. 1 or 2 or 3 or 4 or 5
7. exp Seizures/
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.
18. clinical trials as topic.sh.
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
Sources of support
- No sources of support supplied
- 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.
Medical Subject Headings (MeSH)
Anticonvulsants [*therapeutic use]; Carbamazepine [therapeutic use]; Craniotomy [*adverse effects]; Isoxazoles [therapeutic use]; Phenobarbital [therapeutic use]; Phenytoin [therapeutic use]; Randomized Controlled Trials as Topic; Seizures [etiology; *prevention & control]; Valproic Acid [therapeutic use]
MeSH check words
* Indicates the major publication for the study