J Neurosurg 75:371-373, 1991
Unruptured intracranial aneurysms: seizures and antiepileptic drug treatment following surgery ADRIAN L. RABINOWlCZ, M.D., DAVID L. GINSBURG, M.D., CHRISTOPHER M. DEGIoR~IO, M.D., PEGGY S. GOTT, PH.D., AND STEVEN L. GIANNOTrA, M.D. Departments of Neurology and Neurosurgery, Universityof Southern California School of Medicine, Los Angeles, California Twenty-one patients operated on for unruptured intracranial aneurysms were studied retrospectivelyin order to identify the incidence of postoperative seizures, factors predictive of seizures, and the response to discontinuationof antiepilepticdrugs. The overall risk of postoperativeseizures in initiallyseizure-freepatients was 15.7%. Although seizures were not uncommon, antiepileptic drugs were successfullytapered in most of the patients before 12 months. KEY WORDS
9
aneurysm
9 seizure
HE incidence of postoperative epilepsy following craniotomv has been reported to range between 8% and 5()%, and the risk of seizures following ruptured aneurysms ranges from 3% to 26%. 1-3'~H3 Nevertheless, the risk of seizures after surgery for unruptured aneurysms is not well known. It would be expected that this risk would be low, given the lack of preoperative hemorrhage, modern microsurgical techniques, and limited cortical resection. If indeed the risk for seizures is very low, then prophylactic anticonvulsant agents would be contraindicated, given their potential side effects.6 We retrospectively studied 21 patients who underwent surgery for unruptured intracranial aneurysms in order to identify the risk of postoperative seizures, factors predictive of seizures, and the response to discontinuation of antiepileptic drugs.
T
Clinical Material and Methods
We evaluated 28 patients who unde~'ent elective surgery for unruptured intracranial aneurysms between 1984 and 1989. All patients were operated on by the same neurosurgeon (S.L.G.). Data were gathered from clinic charts and patient interviews. Information was collected regarding the type, number, and timing of pre- and postoperative seizures, aneurysm location, antiepileptic drug prophylaxis, side effects, duration of treatment and effect of discontinuation of antiepileptic drugs, pre- and postoperative neurological deficits, and operative complications. Data were complete for analysis of 21 patients. Statistical analysis was performed using the Fisher's exact test. J. Neurosurg. / Volume 75/September, 1991
9 antiepileptic drug
Results
The mean follow-up time from surgery was 24 months (range 2 to 68 months). Overall, five of the 21 patients experienced postoperative seizures. Two of those had suffered seizures for more than 1 year prior to surgery and were not receiving antiepileptic drugs preoperatively. The overall incidence of postoperative seizures in the 19 initially seizure-free patients was 15.7% (three cases). The interval between surgery and the first seizure ranged from 2 days to 13 months (Table 1). Sixteen patients remained seizure-free postoperatively, none of whom had experienced preoperative seizures (Table 2). Perioperative complications were highly predictive of postoperative seizures. All three initially seizure-free patients who developed postoperative seizures had perioperative complications. In contrast, only four (25%) of the 16 patients who remained seizure-free had perioperative complications. This difference was statistically significant (p = 0.036). The temporal lobe was retracted in two (67%) of the three patients with postoperative seizures who were seizure-free preoperatively; both patients, however, also had perioperative complications. None of the seizurefree patients had temporal lobe retraction. Although this is also statistically significant (p = 0.018), it was not possible to evaluate temporal lobe retraction as an independent variable. A history of preoperative seizures was found in two (40%) of the five patients with postoperative seizures, one of whom also had perioperative complications. In contrast, none of the 16 nonseizure patients had a 371
A. L. Rabinowicz, et al. Summao' r
TABLE 1 in sly patient.s with po~v()peralive seizures*
Periop Seizure AED m Compli- Onset Time of TLR cation Postop Seizure I transient 13 mos yes no hemiparesis 2 transient I mo yes yes dysphasia 3 no 2 days yes no 4 transient 3 mos yes no hemiparesis 5 PCA no meningitis 1 mo yes yes * MCA = middle cerebralartery';PCA = posterior cerebralartery; AED = antiepileptic drug administration; TLR = temporal lobe retraclion. Case No,
Location Preop of Seizure Aneurysm ophthalmic no artery basilar no artery MCA yes MCA yes
history of preoperative seizures (p = 0.0476). Again, it was not possible to statistically separate preoperative seizures from perioperative complications. Seventeen patients were treated with antiepileptic drugs. Thirteen (76%) experienced at least one side effect, but no severe side effects were reported. Twelve patients (71%) were seizure-free postoperatively, and 11 of these were successfully tapered from antiepileptic drugs without recurrent seizures; one patient continues to receive antiepileptic drugs. Seven patients (58%) were successfully tapered before 12 months postoperatively and four (33%) were successfully tapered after 12 months. Discussion
The primary finding in this study is that postoperative seizures are not uncommon following surgery for unruptured aneurysms, and that perioperative complications, temporal lobe retraction, and a history of preoperative seizures may be significant risk factors for the development of seizures. However, because some patients with postoperative seizures had more than one risk factor, we were unable to statistically assess each variable independently. Other investigators have identified temporal lobe retraction as a significant risk factor. 2~'5 In addition, the findings suggest that, in this study, most patients who remained seizure-free could be tapered off antiepileptic drugs within 12 months. These findings are in agreement with those of most other studies regarding the incidence of seizures following surgery for ruptured aneurysms, which generally range between 10% and 26%, but are substantially higher than that reported by Sbeih, et al., 13 who reported a 3% rate. ~-3'~~.~2Our incidence (15.7%) is similar to the 16.7% rate reported by North, et at., ~~in patients who underwent craniotomy for various etiologies who, like our patients, did not receive preoperative prophylaxis. Recently, Michenfelder, el al., 9 have shown that intraoperative administration of penicillin lowers the 372
TABLE 2 Summao, qf data in 16 seizure-free patients*
Case No. 6 7 8 9 10 11 12 13 14
Locationof Pefioperative Duration Aneurysm Complications ofAED (mos) ophtbal no 0 MCA no 14 ACA amnesia 14 ACA no 6 ophthal no 9 ACA no 0 MCA hemiparesis 13 opbthal no 0 PCoA transienthemiparesis 27 & dysarthria 15 ophthal no 12 16 ophthal no 6 17 ophthal no 6 18 PCoA no 0 19 bas no 1 20 ophthal no 6 21 MCA dysphasia 69 * No patients in this group had either preoperative seizures or temporal lobe retraction. AED = antiepileptiedrugs; ophthal = ophthalmic artery; bas = basilar artery; MCA = middle cerebral artery; ACA = anterior cerebral artery; PCoA = posterior communicating artery.
seizure threshold of patients undergoing craniotomy, and that the risk of early seizures in this group is 4.7% compared to 1.8% in controls. In our study, none of the patients received intraoperafive antibiotics, thus eliminating this important risk factor as a confounding variable in our study. Our study does not specifically address the issue of prophylaxis; however, given the relatively high rate of seizures, the data support the contention that antiepileptic drugs following surgery for unruptured aneurysms are indicated at least in patients with any of the three risk factors identified. Antiepileptic drugs are not totally benign, however, and mild to severe side effects do occur. For example, the landmark Veterans Administration cooperative study compared the efficacy and toxicity of four of the first-line antiepileptic drugs in 622 individuals with epilepsy. 8 Intolerable side effects leading to drug failure occurred in 14% of patients, and such occurrences as motor disturbance and dysmorphic and idiosyncratic side effects were observed in significant numbers of patients, although severe sequelae were rare. Given the 76% risk of side effects from antiepileptic drugs reported in our study as well as others, 6"7 the physician should be selective in the use of antiepileptic drugs while recognizing that seizures may occur in patients without identifiable risk factors. This is a pilot study, limited by the relatively small sample size and its retrospective nature. In addition, selection bias might be a factor since seven of the 28 patients initially studied did not have sufficient medical records for inclusion in the results. Further prospective studies are indicated in order to define the role of antiepileptic drugs in this patient population. J. Neurosurg. / Volume 75/September, 1991
Seizures after intracranial aneurysm surgery References 1. Biller J, Godersky JC, Adams HP: Management of aneurysmal subarachnoid hemorrhage. Stroke 19:1300-1305, 1988 2. Cabral RJ, King TT, Scott DF: Epilepsy after two different neurosurgical approaches to the treatment of ruptured intracranial aneurysm. J Neurol Neurosurg Psychiatry 39:1052-1056, 1976 3. Deutschman CS, Haines SJ: Anticonvulsant prophylaxis in neurological surgery. Neurosurgery 17:510-517, 1985 4. Kvam DA, Loftus CM, Copeland B, et al: Seizures during the immediate postoperative period. Neurosnrgery 12: 14-17, 1983 5. Matthew E, Sherwin AL, Welner SA, et al: Seizures following intracranial surgery: incidence in the first postoperative week. Can J Nenrol Sci 7:285-290, 1980 6. Mattson RH: Selection of antiepileptic drug therapy, in Levy RH, Dreifuss FE, Mattson RH, et al (eds): Antiepileptic Drags, ed 3. New York: Raven Press, 1989, pp 103-115 7. Mattson RH, Cramer JA, Collins JF: Early tolerance to antiepileptic drug side effects: a clinical trial of 247 patients, in Koella WP (ed): Tolerance to Beneficial and/or AdverseEffects of Antiepileptic Drugs. New York: Raven Press, 1986, pp 149-156
J. Neurosurg. / Volume 75/September, 1991
8. Mattson RH, Cramer JA, Collins JF, et al: Comparison of carbamazepine, phenobarbital, phenytoin, and primidone in partial and secondary generalized tonic-clonic seizures. N Engl ,J Med 313:145-151, 1985 9. Michenfelder JD, Cucchiara RF, Sundt TM Jr: Influence of intraoperative antibiotic choice on the incidence of early postcraniotomy seizures. J Neurosurg72:703-705, 1990 10. North JB, Penhall RK, Hanieh A, et at: Phenytoin and postoperative epilepsy. A double-blind study. J Neurosurg 58:672-677, 1983 11. North JB, Penhall RK, Hanieh A, et al: Postoperative epilepsy: a double-blind trial of phenytoin after craniotomy. Lancet 1:384-386, 1980 12. Rapport RL II, Penry JK: A survey of attitudes toward the pharmacological prophylaxis of posttraumatic epilepsy. J Neurosurg 38:159-166, 1973 13. Sbeih I, Tamas LB, O'Laoire SA: Epilepsy after operation for aneurysms. Nenrosurgery 19:784-788, 1986 Manuscript received October 24, 1990. Accepted in final form February 18, 1991. Address reprint requests to: Christopher M. DeGiorgio, M.D., Department of Neurology, 2025 Zonal Avenue, Los Angeles, California, 90033.
373
Unruptured intracranial aneurysms: seizures and antiepileptic drug treatment following surgery ADRIAN L. RABINOWlCZ, M.D., DAVID L. GINSBURG, M.D., CHRISTOPHER M. DEGIoR~IO, M.D., PEGGY S. GOTT, PH.D., AND STEVEN L. GIANNOTrA, M.D. Departments of Neurology and Neurosurgery, Universityof Southern California School of Medicine, Los Angeles, California Twenty-one patients operated on for unruptured intracranial aneurysms were studied retrospectivelyin order to identify the incidence of postoperative seizures, factors predictive of seizures, and the response to discontinuationof antiepilepticdrugs. The overall risk of postoperativeseizures in initiallyseizure-freepatients was 15.7%. Although seizures were not uncommon, antiepileptic drugs were successfullytapered in most of the patients before 12 months. KEY WORDS
9
aneurysm
9 seizure
HE incidence of postoperative epilepsy following craniotomv has been reported to range between 8% and 5()%, and the risk of seizures following ruptured aneurysms ranges from 3% to 26%. 1-3'~H3 Nevertheless, the risk of seizures after surgery for unruptured aneurysms is not well known. It would be expected that this risk would be low, given the lack of preoperative hemorrhage, modern microsurgical techniques, and limited cortical resection. If indeed the risk for seizures is very low, then prophylactic anticonvulsant agents would be contraindicated, given their potential side effects.6 We retrospectively studied 21 patients who underwent surgery for unruptured intracranial aneurysms in order to identify the risk of postoperative seizures, factors predictive of seizures, and the response to discontinuation of antiepileptic drugs.
T
Clinical Material and Methods
We evaluated 28 patients who unde~'ent elective surgery for unruptured intracranial aneurysms between 1984 and 1989. All patients were operated on by the same neurosurgeon (S.L.G.). Data were gathered from clinic charts and patient interviews. Information was collected regarding the type, number, and timing of pre- and postoperative seizures, aneurysm location, antiepileptic drug prophylaxis, side effects, duration of treatment and effect of discontinuation of antiepileptic drugs, pre- and postoperative neurological deficits, and operative complications. Data were complete for analysis of 21 patients. Statistical analysis was performed using the Fisher's exact test. J. Neurosurg. / Volume 75/September, 1991
9 antiepileptic drug
Results
The mean follow-up time from surgery was 24 months (range 2 to 68 months). Overall, five of the 21 patients experienced postoperative seizures. Two of those had suffered seizures for more than 1 year prior to surgery and were not receiving antiepileptic drugs preoperatively. The overall incidence of postoperative seizures in the 19 initially seizure-free patients was 15.7% (three cases). The interval between surgery and the first seizure ranged from 2 days to 13 months (Table 1). Sixteen patients remained seizure-free postoperatively, none of whom had experienced preoperative seizures (Table 2). Perioperative complications were highly predictive of postoperative seizures. All three initially seizure-free patients who developed postoperative seizures had perioperative complications. In contrast, only four (25%) of the 16 patients who remained seizure-free had perioperative complications. This difference was statistically significant (p = 0.036). The temporal lobe was retracted in two (67%) of the three patients with postoperative seizures who were seizure-free preoperatively; both patients, however, also had perioperative complications. None of the seizurefree patients had temporal lobe retraction. Although this is also statistically significant (p = 0.018), it was not possible to evaluate temporal lobe retraction as an independent variable. A history of preoperative seizures was found in two (40%) of the five patients with postoperative seizures, one of whom also had perioperative complications. In contrast, none of the 16 nonseizure patients had a 371
A. L. Rabinowicz, et al. Summao' r
TABLE 1 in sly patient.s with po~v()peralive seizures*
Periop Seizure AED m Compli- Onset Time of TLR cation Postop Seizure I transient 13 mos yes no hemiparesis 2 transient I mo yes yes dysphasia 3 no 2 days yes no 4 transient 3 mos yes no hemiparesis 5 PCA no meningitis 1 mo yes yes * MCA = middle cerebralartery';PCA = posterior cerebralartery; AED = antiepileptic drug administration; TLR = temporal lobe retraclion. Case No,
Location Preop of Seizure Aneurysm ophthalmic no artery basilar no artery MCA yes MCA yes
history of preoperative seizures (p = 0.0476). Again, it was not possible to statistically separate preoperative seizures from perioperative complications. Seventeen patients were treated with antiepileptic drugs. Thirteen (76%) experienced at least one side effect, but no severe side effects were reported. Twelve patients (71%) were seizure-free postoperatively, and 11 of these were successfully tapered from antiepileptic drugs without recurrent seizures; one patient continues to receive antiepileptic drugs. Seven patients (58%) were successfully tapered before 12 months postoperatively and four (33%) were successfully tapered after 12 months. Discussion
The primary finding in this study is that postoperative seizures are not uncommon following surgery for unruptured aneurysms, and that perioperative complications, temporal lobe retraction, and a history of preoperative seizures may be significant risk factors for the development of seizures. However, because some patients with postoperative seizures had more than one risk factor, we were unable to statistically assess each variable independently. Other investigators have identified temporal lobe retraction as a significant risk factor. 2~'5 In addition, the findings suggest that, in this study, most patients who remained seizure-free could be tapered off antiepileptic drugs within 12 months. These findings are in agreement with those of most other studies regarding the incidence of seizures following surgery for ruptured aneurysms, which generally range between 10% and 26%, but are substantially higher than that reported by Sbeih, et al., 13 who reported a 3% rate. ~-3'~~.~2Our incidence (15.7%) is similar to the 16.7% rate reported by North, et at., ~~in patients who underwent craniotomy for various etiologies who, like our patients, did not receive preoperative prophylaxis. Recently, Michenfelder, el al., 9 have shown that intraoperative administration of penicillin lowers the 372
TABLE 2 Summao, qf data in 16 seizure-free patients*
Case No. 6 7 8 9 10 11 12 13 14
Locationof Pefioperative Duration Aneurysm Complications ofAED (mos) ophtbal no 0 MCA no 14 ACA amnesia 14 ACA no 6 ophthal no 9 ACA no 0 MCA hemiparesis 13 opbthal no 0 PCoA transienthemiparesis 27 & dysarthria 15 ophthal no 12 16 ophthal no 6 17 ophthal no 6 18 PCoA no 0 19 bas no 1 20 ophthal no 6 21 MCA dysphasia 69 * No patients in this group had either preoperative seizures or temporal lobe retraction. AED = antiepileptiedrugs; ophthal = ophthalmic artery; bas = basilar artery; MCA = middle cerebral artery; ACA = anterior cerebral artery; PCoA = posterior communicating artery.
seizure threshold of patients undergoing craniotomy, and that the risk of early seizures in this group is 4.7% compared to 1.8% in controls. In our study, none of the patients received intraoperafive antibiotics, thus eliminating this important risk factor as a confounding variable in our study. Our study does not specifically address the issue of prophylaxis; however, given the relatively high rate of seizures, the data support the contention that antiepileptic drugs following surgery for unruptured aneurysms are indicated at least in patients with any of the three risk factors identified. Antiepileptic drugs are not totally benign, however, and mild to severe side effects do occur. For example, the landmark Veterans Administration cooperative study compared the efficacy and toxicity of four of the first-line antiepileptic drugs in 622 individuals with epilepsy. 8 Intolerable side effects leading to drug failure occurred in 14% of patients, and such occurrences as motor disturbance and dysmorphic and idiosyncratic side effects were observed in significant numbers of patients, although severe sequelae were rare. Given the 76% risk of side effects from antiepileptic drugs reported in our study as well as others, 6"7 the physician should be selective in the use of antiepileptic drugs while recognizing that seizures may occur in patients without identifiable risk factors. This is a pilot study, limited by the relatively small sample size and its retrospective nature. In addition, selection bias might be a factor since seven of the 28 patients initially studied did not have sufficient medical records for inclusion in the results. Further prospective studies are indicated in order to define the role of antiepileptic drugs in this patient population. J. Neurosurg. / Volume 75/September, 1991
Seizures after intracranial aneurysm surgery References 1. Biller J, Godersky JC, Adams HP: Management of aneurysmal subarachnoid hemorrhage. Stroke 19:1300-1305, 1988 2. Cabral RJ, King TT, Scott DF: Epilepsy after two different neurosurgical approaches to the treatment of ruptured intracranial aneurysm. J Neurol Neurosurg Psychiatry 39:1052-1056, 1976 3. Deutschman CS, Haines SJ: Anticonvulsant prophylaxis in neurological surgery. Neurosurgery 17:510-517, 1985 4. Kvam DA, Loftus CM, Copeland B, et al: Seizures during the immediate postoperative period. Neurosnrgery 12: 14-17, 1983 5. Matthew E, Sherwin AL, Welner SA, et al: Seizures following intracranial surgery: incidence in the first postoperative week. Can J Nenrol Sci 7:285-290, 1980 6. Mattson RH: Selection of antiepileptic drug therapy, in Levy RH, Dreifuss FE, Mattson RH, et al (eds): Antiepileptic Drags, ed 3. New York: Raven Press, 1989, pp 103-115 7. Mattson RH, Cramer JA, Collins JF: Early tolerance to antiepileptic drug side effects: a clinical trial of 247 patients, in Koella WP (ed): Tolerance to Beneficial and/or AdverseEffects of Antiepileptic Drugs. New York: Raven Press, 1986, pp 149-156
J. Neurosurg. / Volume 75/September, 1991
8. Mattson RH, Cramer JA, Collins JF, et al: Comparison of carbamazepine, phenobarbital, phenytoin, and primidone in partial and secondary generalized tonic-clonic seizures. N Engl ,J Med 313:145-151, 1985 9. Michenfelder JD, Cucchiara RF, Sundt TM Jr: Influence of intraoperative antibiotic choice on the incidence of early postcraniotomy seizures. J Neurosurg72:703-705, 1990 10. North JB, Penhall RK, Hanieh A, et at: Phenytoin and postoperative epilepsy. A double-blind study. J Neurosurg 58:672-677, 1983 11. North JB, Penhall RK, Hanieh A, et al: Postoperative epilepsy: a double-blind trial of phenytoin after craniotomy. Lancet 1:384-386, 1980 12. Rapport RL II, Penry JK: A survey of attitudes toward the pharmacological prophylaxis of posttraumatic epilepsy. J Neurosurg 38:159-166, 1973 13. Sbeih I, Tamas LB, O'Laoire SA: Epilepsy after operation for aneurysms. Nenrosurgery 19:784-788, 1986 Manuscript received October 24, 1990. Accepted in final form February 18, 1991. Address reprint requests to: Christopher M. DeGiorgio, M.D., Department of Neurology, 2025 Zonal Avenue, Los Angeles, California, 90033.
373
