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The efficacy of antiepileptic drug prophylaxis in the prevention of early and late seizures following repair of intracranial aneurysms
Journal of Clinical Neuroscience 18 (2011) 1174–1179
Contents lists available at ScienceDirect
Journal of Clinical Neuroscience journal homepage: www.elsevier.com/locate/jocn
Clinical Study
The efficacy of antiepileptic drug prophylaxis in the prevention of early and late seizures following repair of intracranial aneurysms Daniel M.S. Raper a,⇑, Nima Kokabi b, Martin McGee-Collett c a
Royal North Shore Hospital, Reserve Road, St. Leonards, New South Wales 2065, Australia Wollongong Hospital, Wollongong, New South Wales, Australia c Department of Neurosurgery, Royal Prince Alfred Hospital, Sydney, Australia b
a r t i c l e
i n f o
Article history: Received 28 August 2010 Accepted 19 December 2010
Keywords: Antiepileptic Endovascular Intracranial aneurysm Microsurgery Outcomes Prophylaxis Seizure
a b s t r a c t The efficacy of antiepileptic drug (AED) prophylaxis in patients undergoing aneurysm repair has been questioned, yet these drugs are routinely used in many institutions. To better define the relationship of AED prophylaxis to postoperative seizures, we undertook a review of 259 patients undergoing treatment for intracranial aneurysms. Incidence of late seizures was assessed by telephone interview in 132 patients (mean follow-up, 58.7 months). There were seven early seizures, all in patients who received AED prophylaxis (higher versus [vs.] no prophylaxis, p = 0.019). There were 12 late seizures (nine with prophylaxis vs. three without prophylaxis, p = 0.53). The timing of AED prophylaxis had no effect on the incidence of early or late seizures in either group. AED use was associated with an increased rate of early seizures. Postoperative seizures remain important adverse outcomes following aneurysm repair, but despite their traditional role, the routine use of AED should be reconsidered carefully. Crown Copyright Ó 2011 Published by Elsevier Ltd. All rights reserved.
1. Introduction Following the observation by North in 1980 that prophylactic phenytoin reduced the rate of epilepsy following craniotomy by 53%,1 prophylactic antiepileptic drug (AED) use has been a standard protocol for many neurological procedures, including elective and urgent aneurysm repair. More recently, however, the routine use of AED for patients undergoing neurosurgical intervention has come under question. Low seizure rates have been reported in series of patients treated for aneurysmal subarachnoid hemorrhage (SAH) with either neurosurgical clipping2 or endovascular coiling.3 In reviewing these and other more recent experiences, the Stroke Council of America guidelines, published in 2009, recommend against routine perioperative AED use in ruptured aneurysms due to a paucity of evidence of benefit.4 The risk of epilepsy following intervention for unruptured aneurysms appears to be significantly lower,5,6 and no specific recommendation has been made regarding their routine use for elective aneurysm repair.4 Despite their efficacy in treatment of patients with established epilepsy, anticonvulsant medications have not been proven to prevent the onset of seizure in previously asymptomatic individuals.7 Furthermore, phenytoin, which has been commonly used ⇑ Corresponding author. Tel.: +61 2 9926 6162. E-mail address: [email protected] (D.M.S. Raper).
for prophylaxis in aneurysm patients, has adverse effects and has been correlated with poor functional outcomes and worse cognitive status after SAH.8 The use of AED as a primarily prophylactic measure thus remains controversial. The aim of this study was to evaluate the efficacy of AED prophylaxis in the prevention of early and late seizures following repair of intracranial aneurysms in a cohort of consecutive patients treated at a tertiary referral centre that offers both neurosurgical and endovascular treatment options, and reflects the risk inherent to all intracranial aneurysms. 2. Materials and methods We performed a retrospective review of all patients undergoing open microsurgical or endovascular repair of intracranial aneurysms at the Royal Prince Alfred Hospital between January 2002 and December 2006. Patients with a prior history of seizures were excluded from the study. Information was obtained from patient charts, surgical reports, reviews of radiological investigations, and follow-up visit notes. Patients treated for aneurysmal SAH and unruptured aneurysms were included in the study. Aneurysmal SAH was designated based on clinical signs and symptoms at presentation, CT scans or lumbar puncture findings, and angiographic or operative procedure notes. An unruptured aneurysm was designated based on clinical signs, preoperative imaging and procedure notes. Patients were managed according to standard
0967-5868/$ - see front matter Crown Copyright Ó 2011 Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.jocn.2010.12.042
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anterior circulation and 47 (17%) in the posterior circulation. The mean length of stay for all patients was 17.6 days. There was a significantly higher rate of anterior circulation aneurysms in the ruptured group compared to the unruptured group (p = 0.0001), and in patients treated with neurosurgical clipping compared to endovascular coiling (p = 0.0001). Aneurysms in the endovascular group had a larger mean diameter than those in the neuro surgical group (7.99 mm vs. 6.55 mm, p = 0.0286). Patients with unruptured aneurysms had a significantly shorter length of stay than those with ruptured aneurysms (6.9 vs. 24.1 days, p = 0.0001). AED prophylaxis was used in 40% of patients prior to intervention, 55% of patients in hospital post-intervention, and 27% of patients after discharge. Overall, 57% of patients received some form of AED prophylaxis and 43% of patients received no AED prophylaxis. There was no significant difference in AED use between those with ruptured and unruptured aneurysms either prior to or after aneurysm repair. There was a significantly higher rate of AED use among neurosurgical patients prior to intervention (p = 0.0066), after intervention in hospital (p = 0.0001) and following discharge (p = 0.0030), while those with ruptured aneurysms (p = 0.0014) and those treated endovascularly (p = 0.0001) were significantly more likely to receive no prophylaxis. The outcomes of early and late seizures are detailed in Table 2. Overall, seizure was a presenting feature in 28 patients (10.8%) and occurred in-hospital after treatment in seven patients (2.7%). In the ruptured group, 28 patients presented with seizure. Breakdown of seizure type was as follows: 21 tonic–clonic; two generalized; and one each of complex partial, focal, clonic, tonic and other. Four patients (2%) in the ruptured group and three patients (3%) in the unruptured group experienced in-hospital seizures. There was no significant difference in the type of seizures between the ruptured and unruptured groups either for presentation or early seizures. Nineteen patients (11%) in the neurosurgical group and nine patients (10%) in the endovascular group presented with seizure (p = 1.000). Seven patients (4%) in the neurosurgical group experienced early postoperative seizure, of which three were generalized, three were focal and there was one episode of myoclonic seizure. There were no incidences of early seizure in the endovascular group, but the difference between surgical and endovascular groups did not reach significance in this cohort (p = 0.0991). We also assessed the frequency of late seizures in 132 patients alive at a mean follow-up of 58.7 months. Patient and aneurysm characteristics in this group were not significantly different to the overall cohort. A total of 102 patients in the neurosurgical group were interviewed at a mean follow-up of 58.6 months (range, 26–89 months). There were 11 episodes of late seizure at a mean time from hospital discharge to late seizure of 19 months
protocols. In SAH, all patients were evaluated with angiography within 3 days, and a treatment decision for each patient was arrived at after multidisciplinary discussion including both a neuroradiologist with specialization in coil embolization and a neurosurgeon. Anticonvulsant use was at the discretion of the treating neurosurgeon. In some patients with SAH presenting to an outside hospital, a prophylactic phenytoin loading dose was given prior to transfer. Data collected from medical records included information about sex, age, symptoms at presentation, treatment modality, prophylactic anticonvulsant use, and length of hospital stay. The SAH grade was recorded where possible. Postoperative seizure was determined from the medical records including review of symptoms, findings on neurologic examination, electroencephalogram results, medications, and details of neurologist consultation. Only convulsive seizures were included in the final analysis. Presentation seizures were defined as those occurring prior to the first intervention. Early seizures were defined as those that occurred following intervention during the initial hospital stay. Late seizures were defined as those that occurred following discharge from hospital. Patients, or a designated surrogate, were contacted by telephone to assess late seizures. A standardised interview template was used. Patients were asked specifically about any episodes of convulsive seizure, unexplained loss of consciousness, and unusual ‘‘stereotyped’’ motor or psychomotor attack. Patients were also asked about visits to a neurologist or hospitalisations for any reason. Statistical analyses were performed with the commercially available Statistical Package for the Social Sciences Version 16.0 (SPSS, Chicago, IL, USA). The Chi-squared test (with correction for continuity or Fisher exact test when appropriate) and the odds ratio (OR) with the respective 95% confidence interval (CI) were used for statistical analyses. Significance was judged at p 6 0.05. The study was approved by the institution’s Ethics Committee.
3. Results A total of 267 patients underwent aneurysm treatment at the Royal Prince Alfred Hospital during the study period. Eight patients were excluded from the analysis according to the exclusion criteria, leaving a study cohort of 259 patients. Patient and aneurysm characteristics of this cohort are described in Table 1. The mean patient age was 54.0 years (range, 22–86 years) and 65% were female. There were 281 treated aneurysms (mean aneurysms/patient 1.08, range, 1–4). The mean maximum aneurysm diameter was 7.04 mm (range, 1–20). A total of 234 aneurysms (83%) were located in the
Table 1 Patient and aneurysm characteristics in patients following repair of intracranial aneurysms
Total patients Total treated aneurysms Female Mean age (years) Length of stay (days) Location of treated aneurysm Anterior circulation Posterior circulation Mean aneurysm diameter (mm) AED prophylaxis Prior to intervention In-hospital post-intervention Post-discharge None
All patients (%)
Ruptured aneurysm (%)
Unruptured aneurysm (%)
259 281 169 (65) 54.0 17.6
161 172 102 (63) 54.6 24.1
98 109 67 (68) 53.0 6.9
235 (84) 47 (16) 7.04
149 (87) 23 (13) 6.58
103 (40) 143 (55) 70 (27) 113 (43)
62 86 39 69
(39) (53) (24) (61)
Neurosurgical treatment (%)
Endovascular treatment (%)
0.4920 0.3673 0.001
172 186 112 (65) 53.1 18.9
87 95 57 (66) 55.8 14.9
0.9490 0.1379 0.1105
85 (78) 24 (22) 7.77
0.0001 1.000 0.0662
167 (90) 20 (10) 6.55
67 (71) 27 (29) 7.99
0.0001 0.2156 0.0286
41 57 31 44
0.6893 0.5377 0.2469 0.0014
79 (45) 113 (65) 57 (33) 54 (48)
24 30 13 59
0.0066 0.0001 0.0030 0.5947
(40) (55) (30) (39)
P value
(27) (34) (15) (52)
p-value
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Table 2 Early and late seizures in patients with intracranial aneurysms
Presentation seizure Type of seizure Tonic–clonic Complex partial Generalised Focal Clonic Tonic Other Early (in-hospital) seizure Type of seizure Tonic–clonic Generalised Focal Other Late seizure Type of seizure Tonic–clonic Tonic Complex partial Generalised Time to seizure (range) Mean follow-up
All patients (%)
Ruptured aneurysm (%)
Unruptured aneurysm (%)
P value
Neurosurgical treatment (%)
Endovascular treatment (%)
p-value
28
27 (17)
1 (2)
<0.0001
19 (11)
9 (10)
0.8636
21 1 2 1 1 1 1 7
20 1 2 1 1 1 1 4 (2)
1 0 0 0 0 0 0 3 (3)
0.0025 NS NS NS NS NS NS 1.000
15 1 1 1 0 1 1 7 (4)
6 0 1 0 1 0 0 0
NS NS NS NS NS NS NS 0.0991
0 3 3 1 12
0 1 2 1 9 (13)
0 2 1 0 3 (5)
NS NS NS NS 0.1325
0 3 3 1 11 (11)
0 0 0 0 1 (3)
NS NS NS NS 0.1086
8 2 1 1 21 (6–37 mo) 61.1
5 2 1 1 11 (1 wk–20 mo) 56.1
3 0 0 0 0.2524 0.4850
NS NS NS NS 19 (1 wk–37 mo) 58.6
8 1 1 1 12 58.9
0 1 0 0 NS 0.9636
NS NS NS NS
NS = not significant.
Table 3 Early seizure by timing of Anti-epileptic drug (AED) prophylaxis in patients with intracranial aneurysms %
No. at risk
%
p-value
AED prior to intervention AED prior to intervention and post-op. AED post-op. only No AED
Ruptured aneurysm 7 0 56 3 28 1 70 0
No. at risk
Early seizure
0 5 4 0
Unruptured aneurysm 0 0 40 1 15 2 45 0
Early seizure
0 3 13 0
1.000 0.6929 0.5690 1.000
AED prior to intervention AED prior to intervention and post-op. AED post-op only No AED
Neurosurgical treatment 7 0 72 4 37 3 56 0
0 6 8 0
Endovascular treatment 0 0 24 0 6 0 59 0
0 0 0 0
1.000 0.5553 0.4696 1.000
Post-op. = postoperatively.
(range, 1 week–37 months). Late seizure type was tonic–clonic in eight patients, complex partial in one, tonic in one and generalised in one. Thirty patients in the endovascular group were interviewed at a mean follow-up of 58.9 months (range, 10–115 months). There was one episode of late seizure, which occurred at 12 months. Fewer late seizures occurred in the unruptured group compared to the ruptured group (5% vs. 13%), and in the endovascular group compared to the neurosurgical group (3% vs. 11%), though these differences did not reach statistical significance (p = 0.1325; p = 0.2958, respectively). The occurrence of early seizures were analyzed in relation to timing of AED prophylaxis (Table 3). In the group with ruptured aneurysms, three of 56 patients (5.4%) received AED pre- and postintervention, and one of 28 patients (3.6%) who received AED after intervention, experienced seizure. In the group with unruptured aneurysms, one of 40 patients (2.5%) who received AED pre- and postintervention and two of 45 patients (4.4%) who received AED after intervention had an early seizure. In the neurosurgical group four of 72 (5.6%) who received AED pre- and postintervention and three of 37 (8.1%) who received AED after intervention experienced seizure. In the endovascular group there were no incidences of early seizure. Among the seven patients who received AED prior to intervention only and in the 115 patients who received no AED, there were no episodes of early seizure. There was no statis-
tical difference between any permutation of timing of AED administration and early seizures in any group. For all patients, the total number of early seizures in patients receiving AED was seven and in those not receiving AED was zero. This difference was significant (p = 0.0493). The percentage of patients experiencing early and late seizure, analyzed by aneurysm presentation, treatment strategy and AED prophylaxis, is presented in Fig. 1. The occurrence of late seizures was analyzed in relation to timing of AED prophylaxis (Table 4). In the group with ruptured aneurysms, one of two patients (50.0%) who received AED prior to intervention, three of 14 (21.4%) who received AED throughout their hospital stay, and after discharge, and two of six (33.3%) who received AED postoperatively only and after discharge, and one of seven (14.3%) who received AED postoperatively only in hospital experienced late seizures. In the unruptured group, one of 16 patients who received AED prior to intervention and post-operatively in hospital, one of 14 who received AED throughout their hospital stay and after discharge, and one of 20 who received no AED experienced late seizure. In the neurosurgical group, late seizures occurred in one of two patients who received AED prior to intervention only, one of 24 patients who received AED in hospital but not after discharge, three of 22 who received AED throughout their hospitalisation and after discharge, two of 11 who received AED postoperatively and after discharge, one of 13 who received AED postoperatively in hospital only,
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Fig. 1. Graph of percentage of patients suffering post-intervention seizure, classified by treatment modality (neurosurgical compared to endovascular) and seizure onset (early compared to late) in patients treated for intracranial aneurysms from 2002 to 2006 at the Royal Prince Alfred Hospital, Sydney, showing that in patients with early seizures, those who received antiepileptic drug (AED) prophylaxis had a higher seizure rate than those who did not.
Table 4 Late seizure by timing of antiepileptic drug (AED) prophylaxis in patients with intracranial aneurysms %
No. at risk
%
p-value
AED prior to intervention AED prior to intervention and post-op. in hospital AED prior to intervention, post-op. in hospital and after discharge AED post-op. in hospital and after discharge AED post-op. in hospital only No AED
Ruptured aneurysm 2 1 10 0 14 3 6 2 7 1 30 2
No. at risk
Late seizure
50 0 21 33 14 7
Unruptured aneurysm 0 0 16 1 14 1 5 0 8 0 20 1
Late seizure
0 6 7 0 0 5
1.000 0.4201 0.5892 0.5207 0.9449 0.8079
AED prior to intervention AED prior to intervention and post-op. in hospital AED prior to intervention, post-op. in hospital and after discharge AED post-op. in hospital and after discharge AED post-op. in hospital only No AED
Neurosurgical treatment 2 1 24 1 22 3 11 2 14 1 29 3
50 4 14 18 7 10
Endovascular treatment 0 0 2 0 6 1 0 0 1 0 21 0
0 0 17 0 0 0
1.000 0.7685 0.8509 1.000 0.7821 0.3592
Post-op. = postoperatively.
and three of 29 who received no AED. In the endovascular group there was one late seizure, occurring in a patient who had received AED throughout their hospital stay and after discharge. The overall difference in late seizures between the ruptured and unruptured groups, and between the neurosurgical and endovascular groups, was not significant (p = 0.1325 and p = 0.2958, respectively). There was no statistical difference between any permutation of timing of AED administration and late seizures in any group. For all patients, the total number of late seizures in patients receiving AED was nine, compared to three in those not receiving any AED prophylaxis (p = 0.5340). 4. Discussion Seizures are a well-recognized complication in survivors of subarachnoid hemorrhage treated either by surgical or endovascular methods,3,9 and have also been reported following repair of
unruptured intracranial aneurysms.5,6 However the etiology of these seizures, and the relative contribution of surgical factors, as well as intrinsic pathophysiological factors associated with aneurysm rupture, remains poorly characterised. Seizures represent a serious adverse outcome following intracranial procedures, and have been associated with increased mortality even when in remission.10 Anticonvulsant drugs have been used to prevent the incidence of postoperative seizures, but no clear consensus has been reached regarding the timing or efficacy of prophylactic AED for aneurysm repair in either the urgent or elective setting. AED have shown efficacy in preventing seizures in traditional series of patients undergoing craniotomy.1,11 Early studies investigating postoperative seizure among surgical patients not routinely receiving AED prophylaxis showed slightly higher rates of seizure (9.4% in one study at 1.4 years,12 and 7% in another13) compared to modern series. In contrast, in other cohorts, AED prophylaxis has made no difference to the incidence of postsurgical seizure.14,15
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Likewise, in our cohort, there was no significant difference in the incidence of early or late seizures between those who received AED prophylaxis prior to intervention, after intervention in hospital, or after hospitalisation. Onset seizures in patients with aneurysmal SAH have been associated with poor outcome,16 including an association in some studies with late seizures and rebleeding.17–19 The majority of studies investigating late seizure have, however, failed to find a correlation between onset seizure and late epilepsy.3,17,20 Other studies have shown that early postoperative seizures likewise fail to predict late seizures.6,21 In accordance with these observations we found no significant increase in the rate of late seizures among patients who experienced seizure at presentation. Among those who first experienced a seizure after intervention, there was tendency for an increased rate of late seizure compared to the whole cohort (14.3% vs. 9.1%; p = 0.485), although this was not statistically significant. Late seizure following SAH has been associated with parenchymal irritation, subdural hematoma, infarction, vasospasm and hydrocephalus,9 but following repair of an unruptured aneurysm, seizures have been thought primarily to be due to brain manipulation during surgery, as well as surgical complications such as bleeding or delayed ischemic insult.9 Endovascular treatment of intracranial aneurysms appears to be associated with a lower rate of early and late seizures. In the International Subarachnoid Hemorrhage Trial of ruptured aneurysms, seizure rate was significantly lower among the endovascularly treated patients at 1 year of follow-up (relative risk, 0.52).22 In the largest prospective study of unruptured aneurysms to date comparing open and endovascular repair, the International Study of Unruptured Intracranial Aneurysms, epilepsy following aneurysm repair was not reported, though poor outcomes were associated with large aneurysm size, posterior circulation location, history of ischemic cerebrovascular disease, and symptomatic presentation.23 In our series, there was no significant difference in the rates of early or late seizure between patients with ruptured or unruptured aneurysms (p = 1.000 and p = 0.1325, respectively), though more late seizures were observed in the ruptured group. Likewise, there was no significant difference in early or late seizures between the neurosurgical and endovascular groups (p = 0.0991 and p = 0.2958, respectively). There were no early, and one late seizure observed in the endovascular group, however, which suggested that a statistical difference in early and late seizure outcomes may be observable with a larger cohort. This would bring our results in line with other cohorts observing a lower incidence of post-intervention seizure in coiled patients.9,22 In addition to the lack of clinical evidence for efficacy in aneurysm patients, AED lack a mechanistic justification for use as prophylactics. AED have proven efficacy in reducing incidence of established seizure, and phenytoin may also have a neuroprotective effect against acute ischemic injury that has been suggested as a benefit in SAH.5 In addition, early seizures following aneurysm repair have been correlated with subtherapeutic AED levels in those receiving prophylaxis.6,24 However, AED have not been shown to prevent epileptogenesis in a previously asymptomatic brain.7 The observation from early work that the rate of seizure increased following cessation of AED therapy post-craniotomy1 prompted the suggestion that, instead of providing true seizure prevention, phenytoin may merely mask seizure activity from manifesting clinically.6 Furthermore, AED use is associated with significant morbidity. In aneurysm patients, phenytoin has been associated with poor functional outcome at 14 days and worse cognitive status at 3 months after SAH.8 In addition to dose-dependent toxicity, phenytoin has been associated with hepatotoxicity and hematologic abnormalities.10,25 Intolerable side effects have been reported in up to 18% of patients taking anticonvulsants.26 In our cohort, 15 patients (5.8%) required switching or cessation of AED
therapy due to adverse effects, most commonly altered liver function tests. There were two patients with Stevens–Johnson syndrome. Some have suggested that the use of newer anticonvulsants such as levetiracetam and limiting the duration of AED use to a short in-hospital period may minimise morbidity.27 Yet there is no indication that a short course of AED has efficacy in the prevention of seizures. In our cohort, the use of AED in hospital only did not result in a significantly lower rate of either early or late seizure, and was associated with a higher rate of early seizure. One limitation of our study is that diagnosis of seizure relied upon patient report and was not substantiated by neurologic examination or investigations. Only convulsive seizures were captured in this report, potentially missing a proportion of patients who experienced unreported or unrecognised seizure activity. No standardised measurement of therapeutic drug levels was recorded, which leaves open the possibility that early seizures may have been correlated with subtherapeutic levels of anticonvulsants. Neurological grade was not considered in this analysis and may be a confounder that may have affected the treatment strategy and seizure outcome. The lack of a standardised protocol for the use of AED raises the possibility of selection bias. Indeed, use of AED was at the discretion of individual neurosurgeons, among whom practice differed as to the timing or even application of AED in aneurysm patients. Patients deemed to be most at-risk of developing seizure may thus have preferentially been administered prophylactic AED. Selection bias remains a potential confounding factor for all case series; as such, the objective of this report was not to provide Level 1 evidence for the purposes of guiding clinical practice, but to illustrate the usefulness and limitations of AED in a real-life neurosurgical practice. In the final analysis, no difference was observed in the rates of seizure between those receiving or not receiving AED. This leaves open the possibility that AED prophylaxis, if given only to the highest risk patients, may have a protective effect by preventing an otherwise potentially higher seizure rate.
5. Conclusions Early and late seizures remain an important adverse outcome following both urgent and elective aneurysm repair. In our cohort, neurosurgical clipping resulted in a higher rate of early and late seizure than endovascular coiling. However, the use of AED either before intervention, after intervention in hospital, or following discharge had no effect on the incidence of early or late seizures. Guidelines synthesizing the evidence base for use of these drugs in unruptured aneurysms, such as already exist for ruptured aneurysms, would be welcomed. AED should be used for prophylaxis only when the potential benefit of their use outweighs the likely harm. Despite their traditional use in patients undergoing neurosurgical intervention, the routine use of these drugs should be carefully reconsidered.
References 1. North JB, Penhall RK, Hanieh A, et al. Postoperative epilepsy: a double-blind trial of phenytoin after craniotomy. Lancet 1980;1:384–6. 2. Choudhari KA. Seizures after aneurysmal subarachnoid hemorrhage treated with coil embolization. Neurosurgery 2004;54:1029–30 [letter]. 3. Byrne JV, Boardman P, Ioannidis I, et al. Seizures after aneurysmal subarachnoid hemorrhage treated with coil embolization. Neurosurgery 2003;52:545–52. 4. Bederson JB, Connolly ES, Batjer HH, et al. Guidelines for the management of aneurysmal subarachnoid hemorrhage: a statement for healthcare professionals from a special writing group of the Stroke Council, American Heart Association. Stroke 2009;40:994–1025. 5. Hayashi T, Hadeishi H, Kawamura S, et al. Postoperative anticonvulsant prophylaxis for patients treated for cerebral aneurysms. Neurol Med Chir (Tokyo) 1999;39:828–34.
D.M.S. Raper et al. / Journal of Clinical Neuroscience 18 (2011) 1174–1179 6. Baker CJ, Prestigiacomo CJ, Solomon RA. Short-term perioperative anticonvulsant prophylaxis for the surgical treatment of low-risk patients with intracranial aneurysms. Neurosurgery 1995;37:863–71. 7. Brodie MJ, Leach JP. Success or failure with antiepileptic drug therapy: beyond empiricism? Neurology 2003;60:162–3 [editorial]. 8. Naidech A, Kreiter KT, Janjua N, et al. Phenytoin exposure is associated with functional and cognitive disability after subarachnoid hemorrhage. Stroke 2005;36:583–7. 9. Claassen J, Peery S, Kreiter MA, et al. Predictors and clinical impact of epilepsy after subarachnoid hemorrhage. Neurology 2003;60:208–14. 10. Deutschman CS, Haines SJ. Anticonvulsant prophylaxis in neurological surgery. Neurosurgery 1985;17:510–7. 11. North JB, Penhall RK, Hanieh A, et al. Phenytoin and postoperative epilepsy: a double-blind study. J Neurosurg 1983;58:672–7. 12. Ohman J. Hypertension as a risk factor for epilepsy after aneurismal subarachnoid hemorrhage and surgery. Neurosurgery 1990;27:578–81. 13. Bidzinski J, Marchel A, Sherif A. Risk of epilepsy after aneurysm operations. Acta Neurochir (Wien) 1992;119:49–52. 14. Sbeih I, Tamas LB, O’Laoire SA. Epilepsy after operation for aneurysms. Neurosurgery 1986;19:784–8. 15. Rhoney DH, Tipps LB, Marry KR, et al. Anticonvulsant prophylaxis and timing of seizures after aneurysmal subarachnoid hemorrhage. Neurology 2000;55:258–65. 16. Butzkueven H, Evans AH, Pitman A, et al. Onset seizures independently predict poor outcome after subarachnoid hemorrhage. Neurology 2000;55:1315–20. 17. Hasan D, Schonck RS, Avezaat CJ, et al. Epileptic seizures after subarachnoid hemorrhage. Ann Neurol 1993;33:286–91.
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18. Olafsson E, Gudmundsson G, Hauser WA. Risk of epilepsy in long-term survivors of surgery for aneurysmal subarachnoid hemorrhage: a populationbased study in Iceland. Epilepsia 2000;41:1201–5. 19. Ukkola V, Heikkinen ER. Epilepsy after operative treatment of ruptured cerebral aneurysms. Acta Neurochir (Wien) 1990;106:115–8. 20. Vinuela F, Duckwiler G, Mawad M. Guglielmi detachable coil embolization of acute intracranial aneurysm: perioperative anatomical and clinical outcome in 403 patients. J Neurosurg 1997;86:475–82. 21. Shaw MDM. Post-operative epilepsy and the efficacy of anticonvulsant therapy. Acta Neurochir Suppl (Wien) 1990;50:55–7. 22. Molyneux AJ, Kerr RSC, Yu LM, et al. International subarachnoid aneurysm trial (ISAT) of neurosurgical clipping versus endovascular coiling in 2143 patients with ruptured intracranial aneurysms: a randomised comparison of effects on survival, dependency, seizures, rebleeding, subgroups, and aneurysm occlusion. Lancet 2005;366:809–17. 23. International study of unruptured intracranial aneurysms investigators. Unruptured intracranial aneurysms: natural history, clinical outcome, and risks of surgical and endovascular treatment. Lancet 2003;362:103–10. 24. Kvam DA, Loftus CM, Copeland B, et al. Seizures during the immediate postoperative period. Neurosurgery 1983;12:14–7. 25. Perucca E. An introduction to antiepileptic drugs. Epilepsia 2005;46(Suppl.4):31–7. 26. Mattson RH, Cramer JA, Collins JF, et al. Comparison of carbamazepine, phenobarbital, phenytoin and primidone in partial and secondarily generalized tonic-clonic seizures. New Engl J Med 1985;313:145–51. 27. Zubkov AY, Wijdicks EF. Antiepileptic drugs in aneurismal subarachnoid hemorrhage. Rev Neurol Dis 2008;5:178–81.
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Journal of Clinical Neuroscience journal homepage: www.elsevier.com/locate/jocn
Clinical Study
The efficacy of antiepileptic drug prophylaxis in the prevention of early and late seizures following repair of intracranial aneurysms Daniel M.S. Raper a,⇑, Nima Kokabi b, Martin McGee-Collett c a
Royal North Shore Hospital, Reserve Road, St. Leonards, New South Wales 2065, Australia Wollongong Hospital, Wollongong, New South Wales, Australia c Department of Neurosurgery, Royal Prince Alfred Hospital, Sydney, Australia b
a r t i c l e
i n f o
Article history: Received 28 August 2010 Accepted 19 December 2010
Keywords: Antiepileptic Endovascular Intracranial aneurysm Microsurgery Outcomes Prophylaxis Seizure
a b s t r a c t The efficacy of antiepileptic drug (AED) prophylaxis in patients undergoing aneurysm repair has been questioned, yet these drugs are routinely used in many institutions. To better define the relationship of AED prophylaxis to postoperative seizures, we undertook a review of 259 patients undergoing treatment for intracranial aneurysms. Incidence of late seizures was assessed by telephone interview in 132 patients (mean follow-up, 58.7 months). There were seven early seizures, all in patients who received AED prophylaxis (higher versus [vs.] no prophylaxis, p = 0.019). There were 12 late seizures (nine with prophylaxis vs. three without prophylaxis, p = 0.53). The timing of AED prophylaxis had no effect on the incidence of early or late seizures in either group. AED use was associated with an increased rate of early seizures. Postoperative seizures remain important adverse outcomes following aneurysm repair, but despite their traditional role, the routine use of AED should be reconsidered carefully. Crown Copyright Ó 2011 Published by Elsevier Ltd. All rights reserved.
1. Introduction Following the observation by North in 1980 that prophylactic phenytoin reduced the rate of epilepsy following craniotomy by 53%,1 prophylactic antiepileptic drug (AED) use has been a standard protocol for many neurological procedures, including elective and urgent aneurysm repair. More recently, however, the routine use of AED for patients undergoing neurosurgical intervention has come under question. Low seizure rates have been reported in series of patients treated for aneurysmal subarachnoid hemorrhage (SAH) with either neurosurgical clipping2 or endovascular coiling.3 In reviewing these and other more recent experiences, the Stroke Council of America guidelines, published in 2009, recommend against routine perioperative AED use in ruptured aneurysms due to a paucity of evidence of benefit.4 The risk of epilepsy following intervention for unruptured aneurysms appears to be significantly lower,5,6 and no specific recommendation has been made regarding their routine use for elective aneurysm repair.4 Despite their efficacy in treatment of patients with established epilepsy, anticonvulsant medications have not been proven to prevent the onset of seizure in previously asymptomatic individuals.7 Furthermore, phenytoin, which has been commonly used ⇑ Corresponding author. Tel.: +61 2 9926 6162. E-mail address: [email protected] (D.M.S. Raper).
for prophylaxis in aneurysm patients, has adverse effects and has been correlated with poor functional outcomes and worse cognitive status after SAH.8 The use of AED as a primarily prophylactic measure thus remains controversial. The aim of this study was to evaluate the efficacy of AED prophylaxis in the prevention of early and late seizures following repair of intracranial aneurysms in a cohort of consecutive patients treated at a tertiary referral centre that offers both neurosurgical and endovascular treatment options, and reflects the risk inherent to all intracranial aneurysms. 2. Materials and methods We performed a retrospective review of all patients undergoing open microsurgical or endovascular repair of intracranial aneurysms at the Royal Prince Alfred Hospital between January 2002 and December 2006. Patients with a prior history of seizures were excluded from the study. Information was obtained from patient charts, surgical reports, reviews of radiological investigations, and follow-up visit notes. Patients treated for aneurysmal SAH and unruptured aneurysms were included in the study. Aneurysmal SAH was designated based on clinical signs and symptoms at presentation, CT scans or lumbar puncture findings, and angiographic or operative procedure notes. An unruptured aneurysm was designated based on clinical signs, preoperative imaging and procedure notes. Patients were managed according to standard
0967-5868/$ - see front matter Crown Copyright Ó 2011 Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.jocn.2010.12.042
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anterior circulation and 47 (17%) in the posterior circulation. The mean length of stay for all patients was 17.6 days. There was a significantly higher rate of anterior circulation aneurysms in the ruptured group compared to the unruptured group (p = 0.0001), and in patients treated with neurosurgical clipping compared to endovascular coiling (p = 0.0001). Aneurysms in the endovascular group had a larger mean diameter than those in the neuro surgical group (7.99 mm vs. 6.55 mm, p = 0.0286). Patients with unruptured aneurysms had a significantly shorter length of stay than those with ruptured aneurysms (6.9 vs. 24.1 days, p = 0.0001). AED prophylaxis was used in 40% of patients prior to intervention, 55% of patients in hospital post-intervention, and 27% of patients after discharge. Overall, 57% of patients received some form of AED prophylaxis and 43% of patients received no AED prophylaxis. There was no significant difference in AED use between those with ruptured and unruptured aneurysms either prior to or after aneurysm repair. There was a significantly higher rate of AED use among neurosurgical patients prior to intervention (p = 0.0066), after intervention in hospital (p = 0.0001) and following discharge (p = 0.0030), while those with ruptured aneurysms (p = 0.0014) and those treated endovascularly (p = 0.0001) were significantly more likely to receive no prophylaxis. The outcomes of early and late seizures are detailed in Table 2. Overall, seizure was a presenting feature in 28 patients (10.8%) and occurred in-hospital after treatment in seven patients (2.7%). In the ruptured group, 28 patients presented with seizure. Breakdown of seizure type was as follows: 21 tonic–clonic; two generalized; and one each of complex partial, focal, clonic, tonic and other. Four patients (2%) in the ruptured group and three patients (3%) in the unruptured group experienced in-hospital seizures. There was no significant difference in the type of seizures between the ruptured and unruptured groups either for presentation or early seizures. Nineteen patients (11%) in the neurosurgical group and nine patients (10%) in the endovascular group presented with seizure (p = 1.000). Seven patients (4%) in the neurosurgical group experienced early postoperative seizure, of which three were generalized, three were focal and there was one episode of myoclonic seizure. There were no incidences of early seizure in the endovascular group, but the difference between surgical and endovascular groups did not reach significance in this cohort (p = 0.0991). We also assessed the frequency of late seizures in 132 patients alive at a mean follow-up of 58.7 months. Patient and aneurysm characteristics in this group were not significantly different to the overall cohort. A total of 102 patients in the neurosurgical group were interviewed at a mean follow-up of 58.6 months (range, 26–89 months). There were 11 episodes of late seizure at a mean time from hospital discharge to late seizure of 19 months
protocols. In SAH, all patients were evaluated with angiography within 3 days, and a treatment decision for each patient was arrived at after multidisciplinary discussion including both a neuroradiologist with specialization in coil embolization and a neurosurgeon. Anticonvulsant use was at the discretion of the treating neurosurgeon. In some patients with SAH presenting to an outside hospital, a prophylactic phenytoin loading dose was given prior to transfer. Data collected from medical records included information about sex, age, symptoms at presentation, treatment modality, prophylactic anticonvulsant use, and length of hospital stay. The SAH grade was recorded where possible. Postoperative seizure was determined from the medical records including review of symptoms, findings on neurologic examination, electroencephalogram results, medications, and details of neurologist consultation. Only convulsive seizures were included in the final analysis. Presentation seizures were defined as those occurring prior to the first intervention. Early seizures were defined as those that occurred following intervention during the initial hospital stay. Late seizures were defined as those that occurred following discharge from hospital. Patients, or a designated surrogate, were contacted by telephone to assess late seizures. A standardised interview template was used. Patients were asked specifically about any episodes of convulsive seizure, unexplained loss of consciousness, and unusual ‘‘stereotyped’’ motor or psychomotor attack. Patients were also asked about visits to a neurologist or hospitalisations for any reason. Statistical analyses were performed with the commercially available Statistical Package for the Social Sciences Version 16.0 (SPSS, Chicago, IL, USA). The Chi-squared test (with correction for continuity or Fisher exact test when appropriate) and the odds ratio (OR) with the respective 95% confidence interval (CI) were used for statistical analyses. Significance was judged at p 6 0.05. The study was approved by the institution’s Ethics Committee.
3. Results A total of 267 patients underwent aneurysm treatment at the Royal Prince Alfred Hospital during the study period. Eight patients were excluded from the analysis according to the exclusion criteria, leaving a study cohort of 259 patients. Patient and aneurysm characteristics of this cohort are described in Table 1. The mean patient age was 54.0 years (range, 22–86 years) and 65% were female. There were 281 treated aneurysms (mean aneurysms/patient 1.08, range, 1–4). The mean maximum aneurysm diameter was 7.04 mm (range, 1–20). A total of 234 aneurysms (83%) were located in the
Table 1 Patient and aneurysm characteristics in patients following repair of intracranial aneurysms
Total patients Total treated aneurysms Female Mean age (years) Length of stay (days) Location of treated aneurysm Anterior circulation Posterior circulation Mean aneurysm diameter (mm) AED prophylaxis Prior to intervention In-hospital post-intervention Post-discharge None
All patients (%)
Ruptured aneurysm (%)
Unruptured aneurysm (%)
259 281 169 (65) 54.0 17.6
161 172 102 (63) 54.6 24.1
98 109 67 (68) 53.0 6.9
235 (84) 47 (16) 7.04
149 (87) 23 (13) 6.58
103 (40) 143 (55) 70 (27) 113 (43)
62 86 39 69
(39) (53) (24) (61)
Neurosurgical treatment (%)
Endovascular treatment (%)
0.4920 0.3673 0.001
172 186 112 (65) 53.1 18.9
87 95 57 (66) 55.8 14.9
0.9490 0.1379 0.1105
85 (78) 24 (22) 7.77
0.0001 1.000 0.0662
167 (90) 20 (10) 6.55
67 (71) 27 (29) 7.99
0.0001 0.2156 0.0286
41 57 31 44
0.6893 0.5377 0.2469 0.0014
79 (45) 113 (65) 57 (33) 54 (48)
24 30 13 59
0.0066 0.0001 0.0030 0.5947
(40) (55) (30) (39)
P value
(27) (34) (15) (52)
p-value
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Table 2 Early and late seizures in patients with intracranial aneurysms
Presentation seizure Type of seizure Tonic–clonic Complex partial Generalised Focal Clonic Tonic Other Early (in-hospital) seizure Type of seizure Tonic–clonic Generalised Focal Other Late seizure Type of seizure Tonic–clonic Tonic Complex partial Generalised Time to seizure (range) Mean follow-up
All patients (%)
Ruptured aneurysm (%)
Unruptured aneurysm (%)
P value
Neurosurgical treatment (%)
Endovascular treatment (%)
p-value
28
27 (17)
1 (2)
<0.0001
19 (11)
9 (10)
0.8636
21 1 2 1 1 1 1 7
20 1 2 1 1 1 1 4 (2)
1 0 0 0 0 0 0 3 (3)
0.0025 NS NS NS NS NS NS 1.000
15 1 1 1 0 1 1 7 (4)
6 0 1 0 1 0 0 0
NS NS NS NS NS NS NS 0.0991
0 3 3 1 12
0 1 2 1 9 (13)
0 2 1 0 3 (5)
NS NS NS NS 0.1325
0 3 3 1 11 (11)
0 0 0 0 1 (3)
NS NS NS NS 0.1086
8 2 1 1 21 (6–37 mo) 61.1
5 2 1 1 11 (1 wk–20 mo) 56.1
3 0 0 0 0.2524 0.4850
NS NS NS NS 19 (1 wk–37 mo) 58.6
8 1 1 1 12 58.9
0 1 0 0 NS 0.9636
NS NS NS NS
NS = not significant.
Table 3 Early seizure by timing of Anti-epileptic drug (AED) prophylaxis in patients with intracranial aneurysms %
No. at risk
%
p-value
AED prior to intervention AED prior to intervention and post-op. AED post-op. only No AED
Ruptured aneurysm 7 0 56 3 28 1 70 0
No. at risk
Early seizure
0 5 4 0
Unruptured aneurysm 0 0 40 1 15 2 45 0
Early seizure
0 3 13 0
1.000 0.6929 0.5690 1.000
AED prior to intervention AED prior to intervention and post-op. AED post-op only No AED
Neurosurgical treatment 7 0 72 4 37 3 56 0
0 6 8 0
Endovascular treatment 0 0 24 0 6 0 59 0
0 0 0 0
1.000 0.5553 0.4696 1.000
Post-op. = postoperatively.
(range, 1 week–37 months). Late seizure type was tonic–clonic in eight patients, complex partial in one, tonic in one and generalised in one. Thirty patients in the endovascular group were interviewed at a mean follow-up of 58.9 months (range, 10–115 months). There was one episode of late seizure, which occurred at 12 months. Fewer late seizures occurred in the unruptured group compared to the ruptured group (5% vs. 13%), and in the endovascular group compared to the neurosurgical group (3% vs. 11%), though these differences did not reach statistical significance (p = 0.1325; p = 0.2958, respectively). The occurrence of early seizures were analyzed in relation to timing of AED prophylaxis (Table 3). In the group with ruptured aneurysms, three of 56 patients (5.4%) received AED pre- and postintervention, and one of 28 patients (3.6%) who received AED after intervention, experienced seizure. In the group with unruptured aneurysms, one of 40 patients (2.5%) who received AED pre- and postintervention and two of 45 patients (4.4%) who received AED after intervention had an early seizure. In the neurosurgical group four of 72 (5.6%) who received AED pre- and postintervention and three of 37 (8.1%) who received AED after intervention experienced seizure. In the endovascular group there were no incidences of early seizure. Among the seven patients who received AED prior to intervention only and in the 115 patients who received no AED, there were no episodes of early seizure. There was no statis-
tical difference between any permutation of timing of AED administration and early seizures in any group. For all patients, the total number of early seizures in patients receiving AED was seven and in those not receiving AED was zero. This difference was significant (p = 0.0493). The percentage of patients experiencing early and late seizure, analyzed by aneurysm presentation, treatment strategy and AED prophylaxis, is presented in Fig. 1. The occurrence of late seizures was analyzed in relation to timing of AED prophylaxis (Table 4). In the group with ruptured aneurysms, one of two patients (50.0%) who received AED prior to intervention, three of 14 (21.4%) who received AED throughout their hospital stay, and after discharge, and two of six (33.3%) who received AED postoperatively only and after discharge, and one of seven (14.3%) who received AED postoperatively only in hospital experienced late seizures. In the unruptured group, one of 16 patients who received AED prior to intervention and post-operatively in hospital, one of 14 who received AED throughout their hospital stay and after discharge, and one of 20 who received no AED experienced late seizure. In the neurosurgical group, late seizures occurred in one of two patients who received AED prior to intervention only, one of 24 patients who received AED in hospital but not after discharge, three of 22 who received AED throughout their hospitalisation and after discharge, two of 11 who received AED postoperatively and after discharge, one of 13 who received AED postoperatively in hospital only,
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Fig. 1. Graph of percentage of patients suffering post-intervention seizure, classified by treatment modality (neurosurgical compared to endovascular) and seizure onset (early compared to late) in patients treated for intracranial aneurysms from 2002 to 2006 at the Royal Prince Alfred Hospital, Sydney, showing that in patients with early seizures, those who received antiepileptic drug (AED) prophylaxis had a higher seizure rate than those who did not.
Table 4 Late seizure by timing of antiepileptic drug (AED) prophylaxis in patients with intracranial aneurysms %
No. at risk
%
p-value
AED prior to intervention AED prior to intervention and post-op. in hospital AED prior to intervention, post-op. in hospital and after discharge AED post-op. in hospital and after discharge AED post-op. in hospital only No AED
Ruptured aneurysm 2 1 10 0 14 3 6 2 7 1 30 2
No. at risk
Late seizure
50 0 21 33 14 7
Unruptured aneurysm 0 0 16 1 14 1 5 0 8 0 20 1
Late seizure
0 6 7 0 0 5
1.000 0.4201 0.5892 0.5207 0.9449 0.8079
AED prior to intervention AED prior to intervention and post-op. in hospital AED prior to intervention, post-op. in hospital and after discharge AED post-op. in hospital and after discharge AED post-op. in hospital only No AED
Neurosurgical treatment 2 1 24 1 22 3 11 2 14 1 29 3
50 4 14 18 7 10
Endovascular treatment 0 0 2 0 6 1 0 0 1 0 21 0
0 0 17 0 0 0
1.000 0.7685 0.8509 1.000 0.7821 0.3592
Post-op. = postoperatively.
and three of 29 who received no AED. In the endovascular group there was one late seizure, occurring in a patient who had received AED throughout their hospital stay and after discharge. The overall difference in late seizures between the ruptured and unruptured groups, and between the neurosurgical and endovascular groups, was not significant (p = 0.1325 and p = 0.2958, respectively). There was no statistical difference between any permutation of timing of AED administration and late seizures in any group. For all patients, the total number of late seizures in patients receiving AED was nine, compared to three in those not receiving any AED prophylaxis (p = 0.5340). 4. Discussion Seizures are a well-recognized complication in survivors of subarachnoid hemorrhage treated either by surgical or endovascular methods,3,9 and have also been reported following repair of
unruptured intracranial aneurysms.5,6 However the etiology of these seizures, and the relative contribution of surgical factors, as well as intrinsic pathophysiological factors associated with aneurysm rupture, remains poorly characterised. Seizures represent a serious adverse outcome following intracranial procedures, and have been associated with increased mortality even when in remission.10 Anticonvulsant drugs have been used to prevent the incidence of postoperative seizures, but no clear consensus has been reached regarding the timing or efficacy of prophylactic AED for aneurysm repair in either the urgent or elective setting. AED have shown efficacy in preventing seizures in traditional series of patients undergoing craniotomy.1,11 Early studies investigating postoperative seizure among surgical patients not routinely receiving AED prophylaxis showed slightly higher rates of seizure (9.4% in one study at 1.4 years,12 and 7% in another13) compared to modern series. In contrast, in other cohorts, AED prophylaxis has made no difference to the incidence of postsurgical seizure.14,15
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Likewise, in our cohort, there was no significant difference in the incidence of early or late seizures between those who received AED prophylaxis prior to intervention, after intervention in hospital, or after hospitalisation. Onset seizures in patients with aneurysmal SAH have been associated with poor outcome,16 including an association in some studies with late seizures and rebleeding.17–19 The majority of studies investigating late seizure have, however, failed to find a correlation between onset seizure and late epilepsy.3,17,20 Other studies have shown that early postoperative seizures likewise fail to predict late seizures.6,21 In accordance with these observations we found no significant increase in the rate of late seizures among patients who experienced seizure at presentation. Among those who first experienced a seizure after intervention, there was tendency for an increased rate of late seizure compared to the whole cohort (14.3% vs. 9.1%; p = 0.485), although this was not statistically significant. Late seizure following SAH has been associated with parenchymal irritation, subdural hematoma, infarction, vasospasm and hydrocephalus,9 but following repair of an unruptured aneurysm, seizures have been thought primarily to be due to brain manipulation during surgery, as well as surgical complications such as bleeding or delayed ischemic insult.9 Endovascular treatment of intracranial aneurysms appears to be associated with a lower rate of early and late seizures. In the International Subarachnoid Hemorrhage Trial of ruptured aneurysms, seizure rate was significantly lower among the endovascularly treated patients at 1 year of follow-up (relative risk, 0.52).22 In the largest prospective study of unruptured aneurysms to date comparing open and endovascular repair, the International Study of Unruptured Intracranial Aneurysms, epilepsy following aneurysm repair was not reported, though poor outcomes were associated with large aneurysm size, posterior circulation location, history of ischemic cerebrovascular disease, and symptomatic presentation.23 In our series, there was no significant difference in the rates of early or late seizure between patients with ruptured or unruptured aneurysms (p = 1.000 and p = 0.1325, respectively), though more late seizures were observed in the ruptured group. Likewise, there was no significant difference in early or late seizures between the neurosurgical and endovascular groups (p = 0.0991 and p = 0.2958, respectively). There were no early, and one late seizure observed in the endovascular group, however, which suggested that a statistical difference in early and late seizure outcomes may be observable with a larger cohort. This would bring our results in line with other cohorts observing a lower incidence of post-intervention seizure in coiled patients.9,22 In addition to the lack of clinical evidence for efficacy in aneurysm patients, AED lack a mechanistic justification for use as prophylactics. AED have proven efficacy in reducing incidence of established seizure, and phenytoin may also have a neuroprotective effect against acute ischemic injury that has been suggested as a benefit in SAH.5 In addition, early seizures following aneurysm repair have been correlated with subtherapeutic AED levels in those receiving prophylaxis.6,24 However, AED have not been shown to prevent epileptogenesis in a previously asymptomatic brain.7 The observation from early work that the rate of seizure increased following cessation of AED therapy post-craniotomy1 prompted the suggestion that, instead of providing true seizure prevention, phenytoin may merely mask seizure activity from manifesting clinically.6 Furthermore, AED use is associated with significant morbidity. In aneurysm patients, phenytoin has been associated with poor functional outcome at 14 days and worse cognitive status at 3 months after SAH.8 In addition to dose-dependent toxicity, phenytoin has been associated with hepatotoxicity and hematologic abnormalities.10,25 Intolerable side effects have been reported in up to 18% of patients taking anticonvulsants.26 In our cohort, 15 patients (5.8%) required switching or cessation of AED
therapy due to adverse effects, most commonly altered liver function tests. There were two patients with Stevens–Johnson syndrome. Some have suggested that the use of newer anticonvulsants such as levetiracetam and limiting the duration of AED use to a short in-hospital period may minimise morbidity.27 Yet there is no indication that a short course of AED has efficacy in the prevention of seizures. In our cohort, the use of AED in hospital only did not result in a significantly lower rate of either early or late seizure, and was associated with a higher rate of early seizure. One limitation of our study is that diagnosis of seizure relied upon patient report and was not substantiated by neurologic examination or investigations. Only convulsive seizures were captured in this report, potentially missing a proportion of patients who experienced unreported or unrecognised seizure activity. No standardised measurement of therapeutic drug levels was recorded, which leaves open the possibility that early seizures may have been correlated with subtherapeutic levels of anticonvulsants. Neurological grade was not considered in this analysis and may be a confounder that may have affected the treatment strategy and seizure outcome. The lack of a standardised protocol for the use of AED raises the possibility of selection bias. Indeed, use of AED was at the discretion of individual neurosurgeons, among whom practice differed as to the timing or even application of AED in aneurysm patients. Patients deemed to be most at-risk of developing seizure may thus have preferentially been administered prophylactic AED. Selection bias remains a potential confounding factor for all case series; as such, the objective of this report was not to provide Level 1 evidence for the purposes of guiding clinical practice, but to illustrate the usefulness and limitations of AED in a real-life neurosurgical practice. In the final analysis, no difference was observed in the rates of seizure between those receiving or not receiving AED. This leaves open the possibility that AED prophylaxis, if given only to the highest risk patients, may have a protective effect by preventing an otherwise potentially higher seizure rate.
5. Conclusions Early and late seizures remain an important adverse outcome following both urgent and elective aneurysm repair. In our cohort, neurosurgical clipping resulted in a higher rate of early and late seizure than endovascular coiling. However, the use of AED either before intervention, after intervention in hospital, or following discharge had no effect on the incidence of early or late seizures. Guidelines synthesizing the evidence base for use of these drugs in unruptured aneurysms, such as already exist for ruptured aneurysms, would be welcomed. AED should be used for prophylaxis only when the potential benefit of their use outweighs the likely harm. Despite their traditional use in patients undergoing neurosurgical intervention, the routine use of these drugs should be carefully reconsidered.
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