CURRENT REVIEW

Prophylactic Anticonvulsants
After Neurosurgery
Nancy R. Temkin, Ph. D.
Departments of Neurological Surgery and Biostatistics
University of Washington Seattle, Washington
Six prospective, controlled trials have examined the effects of antiepileptic drugs (AEDs) given to prevent the occurrence of seizures
following neurosurgery. Some studies have concentrated on specific
reasons for the neurosurgery (brain tumor) while others have included people with a variety of indications for surgery. Phenytoin
(PHT) has been studied most, but carbamazepine (CBZ) and phenobarbital (PB) have also been evaluated to some extent. Studies of
people with traumatic brain injury (some of whom were operated
on) provide some, but less direct, evidence of the prophylactic effects
of AEDs after neurosurgery. Despite considerable variation in reasons for the neurosurgery, AEDs given, and study design, the overall conclusions are remarkably consistent. The seizure risk is reduced about 40%50% for the first week after neurosurgery in
those given the older AEDs compared with those given placebo or
no treatment. After the first few weeks, none of the drugs has been
proven to reduce the incidence of seizures and in most situations
the best estimate is essentially no effect, but effects on the order of a
25%50% reduction in late (epileptic) seizures cannot be ruled
out. The new generation of AEDs have not been tested as prophylactic agents after neurosurgery. Although there are no guidelines
for prophylaxis following neurosurgery in general, these results are
consistent with the guidelines of professional organizations for subsets of neurosurgery cases. Those guidelines consider prophylaxis, especially using PHT, to be an option for the first week after surgery
but that the routine use of prophylactic anticonvulsants after the
first week is not warranted.

Introduction: The Need for Prophylaxis and the

Studies Conducted

raniotomies, especially supratentorial ones, are associated

with a high risk of subsequent seizures. Depending on the
reason for the surgery, about 20%50% of patients have at least
one seizure post-operatively(1,2). Several groups have evaluated
whether prophylactic administration of antiepileptic drugs (AEDs)
can reduce this high seizure rate. The strongest evidence comes
from randomized clinical trials. Six prospective, controlled trials
have been reported, two restricted to patients operated on for brain
tumors (3,4) and four including patients operated on for a variety of conditions (1,2,5-7). Phenytoin (PHT) has been evaluated most extensively; carbamazepine (CBZ), valproate (VPA),
and phenobarbital (PB) have also been tested. Two of the studies (3,6) considered only seizures occurring during the first
week after surgery (early seizures, generally considered to be
provoked), while the others considered both early and late seizures (after one week, generally considered to be unprovoked
or epileptic seizures). Five of these studies have been included
in meta-analyses (8,9).
Additionally, studies looking at seizure prevention following traumatic brain injury include many patients who received
a craniotomy as part of the treatment for their injuries. These
studies provide some, less direct information about the effect
of prophylactic AEDs after craniotomy. These studies have
also been included in meta-analyses (9,10).

Effect of Prophylactic AEDs on Early Seizures or the

Combination of Early and Late Seizures

Overall, the five studies that evaluate the effect of PHT on

preventing or suppressing early seizures indicate that PHT decreases the risk of seizures in the first week by 44% [95% CI
(confidence interval): 16% reduction to 62% reduction]. This
is based on the combined evidence from the five studies. Figure 1 depicts the estimates from the individual studies as well
as their combination. Surprisingly, the masked, placebo controlled studies (1,6), which are least likely to be affected by
bias, showed the largest effects. Also surprisingly, the studies
that showed the least effect started the assigned AED preoperAddress correspondence to Nancy R. Temkin, Ph.D., University of
atively (2,4,5) or intraoperatively (3), in addition to being unWashington Box 359924, 325 Ninth Avenue, Seattle, WA 98104.
masked. The traumatic brain injury studies are consistent with
E-mail: temkin@u.washington.edu
these craniotomy resultsafter traumatic brain injury, PHT
Epilepsy Currents Vol. 2, No. 4 (July/August) 2002 pp. 105107
decreased the rate of early seizures (best estimate: 67% reducBlackwell Science Inc.
American Epilepsy Society
tion, 95% CI: 41% reduction to 81% reduction) (9).

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Clinical Science

FIGURE 1 Meta-analysis results for seizure prophylaxis clinical trials following craniotomy. The relative risk for each study is marked by
a square on a line that indicates the 95% confidence interval (CI) for that relative risk. Meta-analysis results for a time period and drug are
marked by a diamond with the center at the overall relative risk estimate and the points extending to the ends of the 95% CI. The authors
name is preceded by an asterisk (*) if the study did not use a placebo control. The seizure rate for the active treatment and control arms,
the relative risk estimate and its confidence interval, and, for the meta-analyses the p-value, accompany each study or combination of studies. A relative risk of one, representing no treatment effect, is marked by the dashed vertical line. Adapted from Temkin NR. Antiepileptogenesis and seizure prevention trials with antiepileptic drugs: Meta-analysis of controlled trials. Epilepsia 2001;42:515524, 2001 with
permission of Blackwell Publishing, Inc.

Only a single study (2,5) evaluated the effect of CBZ on

early seizures following craniotomy. The best estimate is that
CBZ is associated with a 39% reduction in early seizures, but
that reduction is not statistically significant (95% CI: 71% reduction to 29% increase). The single study of CBZ following
traumatic brain injury (11) found a significant 61% reduction
in early seizures (95% CI: 18% reduction to 83% reduction).
PB was evaluated in one study (4), but only the combined results for the PHT and PB arms were given. The results from
both treatments are included in the PHT analysis above. The
effect of valproate (VPA) on seizures after craniotomy was investigated in one study (7). The results presented early and late
seizures combined and showed a nonsignificant 15% reduction with VPA (95% CI: 46% reduction to 36% increase).

Effect of Prophylactic AEDs on Late Seizures

Three studies assessed the effect of PHT on the prevention or
suppression of late or epileptic seizures. Overall, the best estimate is that PHT following craniotomy is associated with a
nonsignificant 11% reduction in epileptic seizures (95% CI:
43% reduction to 38% increase. Fig. 1). This is consistent
with the results for traumatic brain injury (9), where the best
overall estimate is a 30% reduction (95% CI: 67% reduction

to 50% increase). The traumatic brain injury studies show significant variation in the results among studies, with one unmasked study having substantially more favorable results than
the masked studies.
The single study (2,5) looking at CBZ to prevent or suppress epileptic seizure after craniotomy found CBZ associated
with a nonsignificant 30% increase in late seizures (95% CI:
25% reduction to 125% increase). The study of CBZ following traumatic brain injury (11) showed a compatible nonsignificant 20% reduction in seizures (95% CI: 58% reduction
to 49% increase). PB was assessed in a single small study (4) of
craniotomy for supratentorial brain tumors. The best estimate
is that PB is associated with a nonsignificant 38% reduction in
post-operative epileptic seizures (95% CI: 88% reduction to
219% increase). Traumatic brain injury studies (9) showed essentially no effect (best estimate: 2% reduction, 95% CI: 52%
reduction to 104% increase).

Summary of Findings
Despite considerable variation in reasons for the neurosurgery,
AEDs given, and study design, the overall conclusions are remarkably consistent. The seizure risk is reduced about 40%

Clinical Science

50% for the first week after neurosurgery in those given the
older AEDs compared to those given placebo or no treatment.
After the first few weeks none of the drugs has been proven to
reduce the incidence of seizures and in most situations the best
estimate is essentially no effect, but effects on the order of a
25%50% reduction in late (epileptic) seizures cannot be
ruled out.

Future Research Directions

Only PHT has been reasonably well-studied. CBZ, PB, and
VPA have each been assessed in one clinical trial after craniotomy and do not look especially encouraging, especially for
prophylaxis of late seizures. Newer AEDs have not been evaluated at all, despite encouraging suggestions on some from preclinical work. Another important question is whether there are
differences in specific subgroups of patients with respect to the
need for or effectiveness of seizure prophylaxis. Subgroups
based on the type of surgery as well as the location and reason
for neurosurgery should be considered.

Implications for Practice

There are no formal guidelines for seizure prophylaxis after
neurosurgery in general. The Brain Trauma Foundation,
American Association of Neurological Surgeons, Joints Section
on Neurotrauma and Critical Care, have guidelines (12) on
the role of seizure prophylaxis following head injury (traumatic brain injury). They include a treatment option of giving
PHT or CBZ to prevent seizures in high risk patients during
the first week after injury. They have a standard that routine
use of anticonvulsants later than 1 week following head injury
is not recommended for preventing late posttraumatic seizures. The American Academy of Neurology has a practice parameter (13) on anticonvulsant prophylaxis in patients with
newly diagnosed brain tumors. Their standard is that prophylactic anticonvulsants should not be used routinely in patients
with newly-diagnosed brain tumors. Their guideline that tapering and discontinuing anticonvulsants after the first postoperative week is appropriate in patients who have not had a
seizure. The studies reviewed here on prophylaxis for seizures
following neurosurgery are consistent with the above guidelines and suggest similar practices are appropriate for seizure
prophylaxis after supratentorial craniotomy for a variety of
reasons.

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Acknowledgment
This work was supported by NIH/NINDS grant R01 NS
19643.

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