Antiepileptic drugs as prophylaxis for post-craniotomy seizures.
BACKGROUND
The incidence of seizures following supratentorial craniotomy for non-traumatic pathology has been estimated to be between 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 (RCTs).


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


METHODS
Searches were run for the original review in January 2012. We performed subsequent searches in September 2012 and up to 04 August 2014. We searched the Cochrane Epilepsy Group's Specialized Register, the Cochrane Central Register of Controlled Trials (CENTRAL) and MEDLINE. We did not apply any language restrictions.


METHODS
We included RCTs of people with no history of epilepsy who were undergoing craniotomy for either therapeutic or diagnostic reasons. Trials with adequate randomisation methods and concealment were included; these could either be blinded or unblinded parallel trials. We did not stipulate a minimum treatment period, and we included trials using active drugs or placebo as a control group.


METHODS
Two review authors (JP and JG) independently selected trials for inclusion and performed data extraction and risk of bias assessments. We resolved any disagreements 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, we did not combine data from the included trials in a meta-analysis; we presented the findings of the review in narrative format.


RESULTS
We included eight RCTs (N = 1602), which were published between 1983 and 2013. Three trials compared a single AED (phenytoin) with a placebo or no treatment. One three-arm trial compared two AEDs (carbamazepine, phenytoin) with no treatment. A second three-arm trial compared phenytoin, phenobarbital and no treatment. Three other trials were head-to-head trials of AEDs (phenytoin vs. valproate; zonisamide vs. phenobarbital) and levetiracetam vs. phenytoin. Of the five 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, and the most trials reported no significant differences between treatment groups. However data on adverse events were limited.


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.
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, UK, L9 7LJ.
Jennifer
J
Weston
Janette
J
Greenhalgh
Anthony G
AG
Marson
D000927:Anticonvulsants / Q000009:adverse effects / Q000627:therapeutic use*; D002220:Carbamazepine / Q000627:therapeutic use; D003399:Craniotomy / Q000009:adverse effects*; D006801:Humans; D007555:Isoxazoles / Q000627:therapeutic use; D010634:Phenobarbital / Q000627:therapeutic use; D010672:Phenytoin / Q000627:therapeutic use; D016032:Randomized Controlled Trials as Topic; D012640:Seizures / Q000209:etiology / Q000401:mortality / Q000517:prevention & control*; D014635:Valproic Acid / Q000627:therapeutic use; D000078305:Zonisamide
D000927:Anticonvulsants; D007555:Isoxazoles; D002220:Carbamazepine; D000078305:Zonisamide; D014635:Valproic Acid; D010672:Phenytoin; D010634:Phenobarbital