J Neurosurg 77:201-208, 1992
Fentanyl-induced electrocorticographic seizures in patients with complex partial epilepsy REN~; TEMPEI.IIOFF, M.D., PAUL A. MODICA, M.D., KERRY L. BERNARDO, M.D., AND ISAAC EDWARDS, P.A. Departments of Anesthesiology and Neurology and Neurological Surgery, Washington University School qf Medicine, St. Louis, Missouri u- Although electrical seizure activity in response to opioids such as fentanyl has been well described in animals, scalp electroencephalographic (EEG) recordings have failed to demonstrate epileptiform activity following narcotic administration in humans. The purpose of this study was to determine whether fentanyl is capable of evoking electrical seizure activity in patients with complex partial (temporal lobe) seizures. Nine patients were studied in whom recording electrode arrays had been placed in the bitemporal epidural space several days earlier to determine which temporal lobe gave rise to their seizures. The symptomatic temporal lobe was localized by correlating clinical and electrical seizure activity obtained during continuous simultaneous videotape and epidural EEG monitoring. In each patient, clinical seizures and electrical seizure activity were consistently demonstrated to arise unilaterally from one temporal lobe (four on the right, five on the left). During fentanyl induction of anesthesia in preparation for secondary craniotomy for anterior temporal lobectomy, eight of the nine patients exhibited electrical seizure activity at fentanyl doses ranging from 17.7 to 35.71 ug 9 kg-t (mean 25.75 ug 9 kg-~). More importantly, four of these eight seizures occurred initially in the "healthy" temporal lobe contralateral to the surgically resected lobe from which the clinical seizures had been shown to arise. These findings indicate that, in patients with complex partial seizures, moderate doses of fentanyl can evoke electrical seizure activity. The results of this study could have important implications for neurosurgical centers where electrocorticography is used during surgery for the purpose of determining the extent of the resection. KEY WORDS 9 seizure c o m p l e x partial e p i l e p s y
fentanyl
'HETHE~ fentanyl, a potent narcotic analgesic, possesses either pro- or anticon~'alsant properties during its clinical administration is presently unclear. 29 Although there have been reports of seizure-like motor behavior in nonepileptic patients following fentanyl administration, T M scalp electroencephalographic (EEG) recordings in patients without seizure disorders receiving low to high doses of the drug have failed to demonstrate electrical seizure activity, even in cases where movements mimicking epileptiform activity were also observed. 2432~4~'43"44~5j In epileptic patients, EEG studies have never been performed during fentanyl administration and clinical seizure activity has not been reported. 29 Seizures documented by EEG recordings have been induced by high-dose fentanyl in the limbic system (hippocampus, amygdala, claustrum) of rats. 948 In humans, seizure activity in this area is difficult to detect
W
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electroeorticography
.
anesthesia
9
using standard scalp EEG electrode placements using the International 10-20 System. 5'~2 Thus, studies utilizing more specialized EEG electrode arrays placed in nonstandard areas are still required to determine whether fentanyl-induced seizure activity occurs in humans? 8 Fentanyl is commonly employed during either general or local anesthesia with sedation for patients undergoing craniotomy for excision of epileptogenic foci with or without intraoperative functional localization and electrocorticographic (ECoG) monitoringfl 7'47'49At our institution, patients with complex partial (temporal lobe) seizure disorders who undergo surgical evaluation for possible anterior temporal lobectomy are routinely monitored with intraoperatively placed epidural ECoG electrodes, located bilaterally over the lateral and medial temporal cortex (including the perihippocampal gyrus). This special mode of ECoG monitoring provides 201
R. T e m p e l h o f f , et al. a unique model for the study of the electrical effects of various anesthetic agents in this epileptic patient population. In the following study, we used this ECoG model to either confirm or reject the hypothesis that fentanyl is capable of evoking electrical seizure activity in patients with complex partial epilepsy. Clinical M a t e r i a l and M e t h o d s
Patient Characteristics After approval of the protocol by the Institutional Review Board of the Washington University School of Medicine, nine otherwise healthy patients, 19 to 44 years of age, with intractable complex partial seizures were studied. Characteristics of these patients are summarized in Table 1. Age at the onset of their seizures ranged from 3 to 29 years old and seizure frequency ranged from several per day to between 4 and 10 per month. All study patients were within 20% of their
TABLE 1 Characteristics of nine patients included in the study Case No,
Age (yrs)
Body Weight (kg)
Age at Seizure Onset (yrs)
Seizure
1
19
77
6
2
37
80
17
4-10/rno weeklyclusters
3 4 5 6 7 8 9
44 31 31 44 40 22 3[
75 50 58 60 53 82 80
10 15 3 6 29 13 18
several/day 2/wk weekly clusters 1/day several/day l/wk 7/too
Frequency
ideal body weight, and all had failed to have their seizures controlled medically despite various combinations of every appropriate anticonvulsant drug. In all but one patient, positron emission tomography (PET) scans were obtained prior to surgery.
Patient Management Each patient underwent a three-stage approach to the surgical management of epilepsy. ~~9 Informed consent for this study was obtained from the patients shortly after admission, prior to the first stage. Stage I: Placement of ECoG Electrodes. Under general anesthesia, bitemporal craniotomies were performed so that bilateral epidural ECoG electrode recording arrays could be placed as previously described (Fig. 1). ~"'~'~After closure, the electrodes were checked to be certain that satisfactory artifact-free records could be obtained. Electrode positioning was confirmed with anteroposterior and lateral skull radiographs. After a brief period in the recovery room, the patients were transferred awake and fully oriented to a special observation unit for electrophysiological monitoring. Stage II: Extraoperative ECoG Localization of Symptomatic Temporal Lobe. The symptomatic temporal lobe was localized in each fully awake patient by correlating clinical and electrical seizure activity obtained during continuous simultaneous extraoperative videotape and epidural ECoG monitoring. All nine patients were monitored for a period of 24 to 72 hours, in a quiet setting, without any pharmacological interference from anesthetic or sedative drugs. During this time, anticonvulsant therapy was gradually reduced until one or several spontaneous clinical seizures occurred (Figs. 2A and B and 3A and B). The patient's
FIG. 1. Drawings depicting the temporal electrode array in place and demonstrating the relationships of the electrode position to the various temporal gyri. The most medially situated electrodes lie adjacent to the hippocampal and fusiform gyri. The other two pairs lie approximately over the inferior and middle temporal gyri respectively.(Reprinted from Goldring S, Gregorie EM, Tempelhoff R: Surgery.of epilepsy, in Dudley H, Carter D, Russell RCG (eds): Rob and Smith's Operative Surgery, ed 4. London: Butterworths, 1989, p 436, with permission). 902
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Fentanyl-induced electrocorticographic seizures
FIG. 2. A and B: Electroencephalographic recordings from Case 2 obtained with bitemporal epidural electrocorticographic (ECoG) electrodes during the extraoperative period (stage II). A: The patient is resting (awake). B: A spontaneous clinical seizure is noted originating from the left temporal lobe while the patient is resting (awake). C: Electrocorticographic recordings from the same patient during fentanyl induction. D: Electrocorticographic recordings from the same patient later during fentanyl induction, showing electrical activity originating from the right temporal lobe. Note that this electrical seizure begins on the side opposite that from which the electrical activity associated with the spontaneous clinical seizure arose (see B).
FIG. 3. Electrocorticographic recordings from Case 4 obtained with bitemporal epidural electrodes during the extraopemtive period (stage II). A: Recording while the patient is resting (awake). B: A spontaneous clinical seizure originating from the right temporal lobe is noted during the extraoperative period (stage II). C: Recordings during fentanyl induction. D: Recordings later during fentanyl induction, showing electrical activity originating from the left temporal lobe. Note that this electrical seizure begins on the side opposite that from which the electrical activity associated with the spontaneous clinical seizure arose (see B).
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R. Tempelhoff, et al. behavior and the ECoG were displayed on a split-screen video monitor and recorded on videotape for subsequent review. In each patient, clinical seizures and electrical seizure activity were consistently demonstrated to arise unilaterally from one temporal lobe (four on the right, five on the left). On the basis of these recordings, it was recommended to each patient that an anterior temporal lobectomy be performed on the side from which the clinical seizures were demonstrated to arise. Anticonvulsant therapy was then resumed with the same medications and dosages used prior to the primary craniotomy.
Stage 1II: Electrode Removal and Anterior Temporal Lobe Resection. For the purpose of this study, the usual anesthetic management of the secondary craniotomy ~9was modified and fentanyl alone was used for induction of anesthesia. During fentanyl induction, ECoG recordings were made, as described below. One to 2 hours prior to surgery, each patient received 150 mg ranitidine and 10 mg metoclopramide, both given orally. Upon arrival in the operating room and throughout anesthesia, all patients were monitored with electrocardiography (EKG), a blood pressure (BP) cuff, pulse oximetry, and mass spectrometry. No sedative or analgesic premedication was administered. Prior to induction, with each patient breathing 100% oxygen (02) by mask, the temporal lobe epidural ECoG electrode leads were connected bilaterally to a 10-channel (five channels per temporal lobe) EEG recorder,* and a resting (awake) ECoG record of several minutes duration was obtained. Soon after, when the mass spectrometer indicated 100% nitrogen washout, anesthesia was induced with fentanyl, administered intravenously via a volumetric infusion pump-~ at a rate of 500 ug 9 min -~. Following loss of response to verbal stimuli, muscle relaxation with intravenous vecuronium, 0.2 to 0.3 mg. kg-~, was instituted to facilitate ventilation by mask and to prevent fentanyl-induced chest-wall rigidity. Each patient's ventilation was controlled to maintain an end-tidal CO2 of 30 to 35 mm Hg with an O2 saturation of 98% to 100%. Throughout the period of anesthesia induction, ECoG activity from the lateral temporal lobe and hippocampal gyrus was continuously recorded bilaterally (Fig. 2C and 3C). Each patient's ECoG tracing was obtained and assessed by an electroencephalographer located in a separate room adjacent to the operating room, who was informed via audio contact with the anesthesiologist as to the onset and discontinuation of fentanyl administration. Continuous ECoG recordings were obtained until one of the following two endpoints occurred: 1) a total fentanyi dose of 5000 #g was administered; or 2) electrical seizure activity occurred. If an epileptiform pat* EEG recorder manufactured by Grass Instrument Co., Quincy, Massachusetts. t Volumetric infusion pump manufactured by Travenol Laboratories, Deerfield, Illinois. 204
tern appeared on the ECoG tracing, the anesthesiologist was notified by audio contact, the fentanyl infusion was stopped, and the seizure activity was allowed to resolve spontaneously during the following 30- to 60-second period. If the electrical seizure activity continued for longer periods, thiopental, 4 to 8 mg 9 kg-j, was given intravenously and, if the seizure activity persisted despite this, additional anticonvulsant therapy with diazepam, 0.1 to 0.3 mg 9 kg-j, was given intravenously until the epileptiform pattern abated. The total dose of fentanyl administered from the start of the infusion until the onset of electrical seizure activity (if any occurred) was recorded from the volumetric infusion pump. Following discontinuation of the fentanyl infusion and treatment of any seizure activity, each patient was intubated and anesthetic maintenance was instituted with 70%/30% (N20/O2), 0.2% to 0.3% end-tidal isoflurane, and atracurium infusion for muscle relaxation. Just prior to skin incision, a 1-~g 9 kg-j 9 hr -~ maintenance fentanyl infusion was added. In all nine cases, the epidural ECoG electrodes were removed bilaterally and an anterior temporal lobectomy was performed on the side from which the clinical seizures were demonstrated to arise during the extraoperative monitoring period (Stage II).
Analysis of ECoG Recordings Each intraoperative ECoG recording obtained during anesthesia induction with fentanyl (Stage III) was analyzed postoperatively for the presence of electrical seizure activity by an independent electroencephalographer who was unaware of each patient's history and the conditions under which the ECoG tracings were obtained. The results of this study were based solely on the independent electroencephalographer's ECoG interpretations. Tissue samples of the resected temporal lobe were all examined for pathological diagnosis. Following hospital discharge, all patients were followed at regular intervals in our neurosurgical clinic to evaluate their postor)erarive outcome. Results
Table 2 summarizes the PET findings, the side on which the anterior temporal lobectomy was performed, the location of fentanyl-induced seizure activity, and the fentanyl dose. In the eight patients in whom a PET scan was obtained prior to surgery, a good correlation was found between the side of hypometabolism and the temporal lobe determined to be responsible for the clinical seizures during extraoperative ECoG localization (Stage II). The PET scans showed no metabolic abnormalities in the contralateral temporal lobe. During anesthetic induction for the Stage III craniotomy, eight of the nine patients studied exhibited electrical seizure activity at a fentanyl dose ranging from 17.7 to 35.71 #g 9 kg J (mean 25.75 ug 9 kg-J). Examples of this ECoG seizure activity are illustrated in Figs. 2D
J. Neurosurg. / Volume 77~August, 1992
Fentanyl-induced electrocorticographic seizures TABLE 3 Postoperative pathological findings and seizure frequency
TABLE 2 Temporal lobe PET and ECoG findings related to fentanyl dose* Side of Fentanyl-lnduced Fentanyl Case PET Hypo- Side of ECoG Seizure Dose No. metabolism Lobectomy lpsilat Contralat (#g'kg-~) 1 not done fight (+) ~ + 36 2 left left + 20 3 left left + 33 4 right right (+) *+ 20 5 left left + 17 6 right right + 25 7 right fight (+) ,-+ 19 8 left left + 21 9 left left 50 * PET = position emission tomography;ECoG = electrocorticographic; + = seizure present; - = seizure absent; (+) = seizurespread.
and 3D. Of these eight patients, four (Cases 3, 5, 6, and 8) had onset of the electrical seizure activity in the temporal lobe from which the clinical complex partial seizures had been shown to arise during the extraoperative monitoring period (Stage II). In contrast, electrical seizure activity in the other four patients (Cases 1, 2, 4, and 7) began in the temporal lobe contralateral to that from which the clinical seizures had been shown to arise. There was no significant difference in the average dose of fentanyl in the patients who exhibited electrical seizure activity in the ipsilateral versus the contralateral temporal lobe (23.75 vs. 24 #g 9 kg-~. In three of the four cases of contralateral ECoG seizure activity (Cases 1, 4, and 7), the seizures also spread to involve the clinically symptomatic (ipsilateral) temporal lobe. In all eight patients, the electrical seizure activity was detected in the most medial (perihippocampal) ECoG electrode leads, while five also exhibited significant electrical seizure activity in the lateral leads. Abnormal electrical activity first manifested as delta waves in three patients which, after 10 to 20 seconds, gave way to frank seizure discharge. In four other patients, a single spike or spike and slow wave led immediately to frank seizure discharge. In the eighth patient (Case 5), periodic lateralized epileptiform discharges appeared in the ipsilateral temporal lobe at a fentanyl dose of 17 ug 9 kg-~- Finally, in the remaining patient, no fentanyl-induced electrical seizure activity was detected. Postoperatively, all nine patients were followed routinely in our neurosurgical clinic for at least 7 months and their outcome is summarized in Table 3. A significant decrease in seizure frequency was observed in eight patients; five were seizure-free during a postoperative follow-up period of at least 10 months, including all four patients in whom the fentanyl-induced seizure activity occurred at least initially in the contralateral "healthy" temporal lobe. Pathological examination showed changes consistent with mesial temporal sclerosis in the hippocampus in seven of nine specimens. J. Neurosurg. / Volume 77/August, 1992
Case No. 1 2 3 4 5 6 7 8 9
PathologyFindings
Seizure Follow-Up Frequency Period(mos) mesialtemporal sclerosis none 21 mesialtemporal sclerosis none 24 mild astrocytosisof hippo3-4/mo 22 campus & amygdala (signifdecrease) mesialtemporal sclerosis none 13 mesialtemporal sclerosis none 14 focalmeningeal fibrosis/ no change 13 gliosis in fusiformgyrus mesialtemporal sclerosis none 10 mesialtemporal sclerosis 7 in 8 mos 8 (signifdecrease) mesialtemporal sclerosis 7 in 7 mos 7 (signifdecrease)
Mild astrocytosis in the hippocampus and amygdala was found in one specimen; a significant decrease in seizure frequency was achieved in this patient. In the remaining patient (Case 6), focal meningeal fibrosisgliosis was found in the fusiform gyrus; this patient had exhibited no clinical improvement by 13 months after surgery. Discussion Literature Review
Although EEG seizure activity in response to morphine, ~~ meperidine, x~ or fentanyl 9'j~ and its analogs52 has been well described in animals, the average intravenous dose required to produce convulsions is significantly greater than the amounts employed during daily clinical anesthetic practice in humans. There have been numerous reports of seizure-like motor behavior in nonepileptic patients after administration of low 17"20"21"23"25'28"31"37"38"46 to m o d e r a t e 322"24'36'45 doses of narcotics delivered via the intravenous, intramuscular, oral, or intrathecal routes, but unfortunately intraoperative EEG tracings were not performed during these events. Scalp EEG recordings in patients treated with low to moderate 8'24'34'4~and high 6"7"32"33'41'44'~1 intravenous doses of these opioids have never detected any epileptiform activity, including cases where convulsivelike motor activity was observed in the absence of EEG cortical seizure activity. 8'24'4~ These observations have led some to suggest that these abnormal movements may represent myoclonus 8'2~or an exaggerated form of opioid-induced rigidity.8"4~ Narcotic-induced EEG seizure activity has been previously noted only in nonepileptic patients following chronic oral or intramuscular meperidine administration, and has been attributed to its metabolite normeperidine, t'j7 Thus, the results of our ECoG investigation in patients with complex partial seizure disorders represents the first report of electrical seizure activity following the acute clinical intravenous administration of fentanyl or other opioids commonly employed intraoperatively. 205
R. T e m p e l h o f f , et al.
Analysis of Current Study Although retrospective analysis by Smith, et al., 43 of scalp EEG tracings in 127 patients anesthetized with high doses of fentanyl or its analogs did not support the existence of opioid-induced seizures in the clinical setting, several important differences between their investigation and ours appear to exist. First, the patient populations in the two studies were distinctly different, as they utilized a generalized nonepileptic population, whereas we studied patients with intractable complex partial seizures. Second, our 10-channel (14-electrode) method of ECoG recording was specifically limited to the temporal lobes, in contrast to their two-channel (six-electrode) scalp EEG method which would primarily detect activity from the frontal, parietal and occipital lobes. Thus, while no electrical seizure activity was observed in the recordings obtained by Smith, et al., seizure activity could have arisen from areas of the brain such as the hippocampus or amygdala which are not easily studied with the scalp EEG electrode array utilized in their study. In contrast, our bitemporal epidural EcoG electrodes are more likely to detect electrical seizure activity specifically arising from these structures. Epileptiform activity in this location has been detected during depth electrode recordings obtained in epileptic patients following administration of local anesthetic agenW L30,50and ketamine ~3 and is not always manifested cortically on conventional scalp EEG recordings. Although alfentanil-induced seizures in the limbic system were not detected by the intranasal electrodes employed in the study by Smith, et a1.,43the four nonepileptic patients they studied utilizing this particular electrode placement probably represents too small a number to draw any specific conclusions. Also, intmnasal electrodes are known to be considerably less sensitive than bitemporal epidural or depth electrodes in detecting seizure activity from medial temporal lobe structures. 35 Epileptogenicity of Fentanyl Animal studies have shown that the limbic system appears to be sensitive to multiple stimuli leading to self-sustaining repetitive discharges, 4'~6and that the pyramidal cells of the hippocampus exhibit innate epileptogenic properties normally inhibited by gamma-aminobutyric acid (GABA)-ergic interneurons. 439"42 The limbic system possesses one of the densest clusters of opioid receptors in the brain, 2 and morphine has been shown to produce seizure discharges in rats by disinhibiting the pyramidal cells of the perihippocampal structures located within the limbic system. 26In the rat, fentanyl has been shown to produce seizures in the subcortical limbic system which were associated with increases in local cerebral glucose utilization.4~ These studies illustrate that the subcortical limbic structures appear to be different from the cortex in their organization and response to narcotics, and lend support to our finding that indeed moderate doses of fentanyl can trigger electrical seizure activity in epileptic patients 206
which is restricted primarily to the perihippocampal gyrus and other closely related structures. This may also help to explain why in previous reports conventional scalp EEG recordings were not able to detect electrical seizure activity in patients without pre-existing disorders receiving low to high doses of fentanyl.
Dosage Considerations In this study, the average dose of fentanyl required to trigger electrical seizure activity was 25 #g 9 kg-~. This represents a moderate to high dose in routine anesthesia management. For example, anesthesia for coronary artery bypass grafting will require up to 60 to 100 ug 9 kg-j, while a hysterectomy requires 5 to 10 ug 9 kg-1 when fentanyl is the major component of the anesthetic regimen. However, in a previous study, 47 we have demonstrated the requirement for fentanyl during anesthesia for craniotomies in epileptic patients receiving chronic anticonvulsant therapy, to be up to three times higher than that of nonepileptic patients who were not receiving anticonvulsant medications. Thus, the average dose of 25 ug 9 kg-1 used in this study could well be considered a moderate rather than a high dose in this patient population. There are various techniques for giving "local" anesthesia for craniotomies in epilepsy surgery that include fentanyl. Classically, fentanyl in a 0.5- to l-ug 9 kg-~ intravenous bolus with a loading dose of droperidol is administered at the beginning of the procedure, and analgesia is maintained with an intravenous infusion of fentany127 or repeated boluses titrated to maintain a respiratory rate of 12 breaths/rain. 49 The total dose of fentanyl required may vary from 4 to l0 t~g 9 kg-~ and is administered over 4 to 8 hours throughout the procedure. This is a smaller dose and is administered over a longer period than the doses used in our study (l 7 to 36 ~ 9 kg-~ over 2 to 8 minutes). Considering the difference between the dosage used in our study and that used during "local" anesthesia techniques, as well as the difference between the two rates of administration, we cannot draw any conclusions regarding the risk of triggering electrical seizure activity during craniotomies performed under local anesthesia with fentanyl. Activation of Normal Temporal Lobe It is interesting to note that 50% of the fentanylinduced electrical seizures in this report were initially elicited in the "healthy" temporal lobe (as determined by extraoperative ECoG recordings, PET scans, and clinical outcome), contralateral to the surgically resected temporal lobe from which the clinical complex partial seizures were shown to arise. Although to date we have no entirely satisfactory explanation for this finding, some theoretical possibilities may be enterrained. One explanation may be that opioids such as fentanyl have the potential to induce electrical seizure activity in nonepileptic patients that, similar to our epileptic patients, is restricted to areas of the temporal lobe inaccessible to routine scalp EEG monitoring. Our J. Neurosurg. / Volume 77/August, 1992
Fentanyl-induced electrocorticographic seizures finding of a seizure-free long-term clinical outcome in all four instances of fentanyl-induced seizure activity in the "healthy" temporal lobe lends support to this theory. Another potential explanation for our finding of fentanyl-induced electrical seizure activity in the nonsurgically resected "healthy" temporal lobe is based on the recent finding in patients with complex partial seizures due to unilateral foci that opiate receptor binding as measured by PET is greater in the temporal neocortex on the side of the demonstrated electrical focus than on the opposite "healthy" side/5 This increased binding on the side of electrical seizure activity is due to an increase in affinity or number of unoccupied receptors, and indicates that increased opiate receptors in the temporal neocortex may represent a tonic anticonvulsant system that limits the spread of electrical activity from other temporal lobe structures.~5 Can we say that the increase in opiate receptors in the epileptogenic focus may in some cases act as a shelter against opioid (fentanyl)-induced electrical seizure activity? Unfortunately, this hypothesis does not appear to apply entirely to our findings, because in four of our patients seizure activity was initially elicited by fentanyl in the ipsilateral temporal lobe.
5.
6. 7.
8. 9. 10.
11. 12. 13.
Conclusions
Our findings indicate that, in patients with complex partial (temporal lobe) seizures, moderate doses of fentanyl can elicit electrical seizure activity. Interestingly, these fentanyl-induced seizures often arise from the "healthy" temporal lobe, contralateral to the temporal lobe from which the clinical seizure activity has been shown to arise. This suggests that opioids such as fentanyl may also have the potential to induce electrical seizure activity in nonepileptic patients in areas of the brain that are poorly accessible to routine scalp EEG monitoring. These results could have important implications for neurosurgical centers that rely on intraoperative electrocorticography during epilepsy surgery to determine the extent of cortical resection. Acknowledgments
The authors gratefully thank Sidney Goldring, M.D., for his inspiration and support during this investigation. We also express our gratitude to John Miller, M.D., for his interpretation of the ECoG recordings during fentanyl anesthesia induction. References
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42. 43. 44. 45. 46.
47.
48. 49.
50.
51. 52.
dose fentanyl anesthesia on the electroencephalogram. Anesthesiology 55:203-211, 1981 Siesj6 BK: Cell damage in the brain: a speculative synthesis. J Cereb Blood Flow Metab 1:155-185, 1981 Smith NT, Benthuysen JL, Bickford RG, et al: Seizures during opioid anesthetic induction - - are they opioidinduced rigidity? Anesthesiology 71:852-862, 1989 Smith NT, Dec-Silver H, Sanford TJ Jr, et al: EEGs during high-dose fentanyl-, sufentanil-, or morphine-oxygen anesthesia. Anesth Analg 63:386-393, 1984 Strong WE, Matson M: Probably seizure after alfentanil. Anesth Analg 68:692-693, 1989 Szeto HH, lnturrisi CE, Houde R, et al: Accumulation of normeperidine, an active metabolite of meperidine, in patients with renal failure and cancer. Ann Intern Med 86:738-741, 1977 Tempelhoff R, Modica PA, Spitznagel EL Jr: Anticonvulsant therapy increases fentanyl requirements during anaesthesia for craniotomy. Can J Anaesth 37:327-332, 1990 Tommasino C, Maekawa Y, Shapiro HM, et al: Fentanylinduced seizures activate subcortical brain metabolism. Anesthesiology 60:283-290, 1984 Trop D: Conscious-sedation analgesia during the neurosurgical treatment of epilepsies--practiceat the Montreal Neurological Institute. Int Anesthesiol Clin 24:175-I 84, 1986 Wagman IH, de Jong RH, Prince D: Effects of lidocaine upon spontaneous and evoked activity within the limbic system. Electroencephalogr Clin Neurophysiol 17:453, 1964 (Abstract) Wauquier A, Bovill JG, Sebel PS: Electroencephalographic effects of fentanyl-, sufentanil- and alfentanil anaesthesia in man. Neuropsychobiology 11:203-206, 1984 Young ML, Smith DS, Greenberg J, et al: Effects of sufentanil on regional cerebral glucose utilization in rats. Anesthesiology 61:564-568, 1984
Manuscript received October 8, 1991. Accepted in final form January 30, 1992. This work was presented in part at the Annual Meeting of the American Association of Neurological Surgeons, April 21-25, 1991, New Orleans, Louisiana. Address reprint requests to." Ren6 Tempelhoff, M.D., Department of Anesthesiology, Division of Neuroanesthesia, Washington University School of Medicine, Box 8054, 660 South Euclid Avenue, St. Louis, Missouri 63110.
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Fentanyl-induced electrocorticographic seizures in patients with complex partial epilepsy REN~; TEMPEI.IIOFF, M.D., PAUL A. MODICA, M.D., KERRY L. BERNARDO, M.D., AND ISAAC EDWARDS, P.A. Departments of Anesthesiology and Neurology and Neurological Surgery, Washington University School qf Medicine, St. Louis, Missouri u- Although electrical seizure activity in response to opioids such as fentanyl has been well described in animals, scalp electroencephalographic (EEG) recordings have failed to demonstrate epileptiform activity following narcotic administration in humans. The purpose of this study was to determine whether fentanyl is capable of evoking electrical seizure activity in patients with complex partial (temporal lobe) seizures. Nine patients were studied in whom recording electrode arrays had been placed in the bitemporal epidural space several days earlier to determine which temporal lobe gave rise to their seizures. The symptomatic temporal lobe was localized by correlating clinical and electrical seizure activity obtained during continuous simultaneous videotape and epidural EEG monitoring. In each patient, clinical seizures and electrical seizure activity were consistently demonstrated to arise unilaterally from one temporal lobe (four on the right, five on the left). During fentanyl induction of anesthesia in preparation for secondary craniotomy for anterior temporal lobectomy, eight of the nine patients exhibited electrical seizure activity at fentanyl doses ranging from 17.7 to 35.71 ug 9 kg-t (mean 25.75 ug 9 kg-~). More importantly, four of these eight seizures occurred initially in the "healthy" temporal lobe contralateral to the surgically resected lobe from which the clinical seizures had been shown to arise. These findings indicate that, in patients with complex partial seizures, moderate doses of fentanyl can evoke electrical seizure activity. The results of this study could have important implications for neurosurgical centers where electrocorticography is used during surgery for the purpose of determining the extent of the resection. KEY WORDS 9 seizure c o m p l e x partial e p i l e p s y
fentanyl
'HETHE~ fentanyl, a potent narcotic analgesic, possesses either pro- or anticon~'alsant properties during its clinical administration is presently unclear. 29 Although there have been reports of seizure-like motor behavior in nonepileptic patients following fentanyl administration, T M scalp electroencephalographic (EEG) recordings in patients without seizure disorders receiving low to high doses of the drug have failed to demonstrate electrical seizure activity, even in cases where movements mimicking epileptiform activity were also observed. 2432~4~'43"44~5j In epileptic patients, EEG studies have never been performed during fentanyl administration and clinical seizure activity has not been reported. 29 Seizures documented by EEG recordings have been induced by high-dose fentanyl in the limbic system (hippocampus, amygdala, claustrum) of rats. 948 In humans, seizure activity in this area is difficult to detect
W
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9
electroeorticography
.
anesthesia
9
using standard scalp EEG electrode placements using the International 10-20 System. 5'~2 Thus, studies utilizing more specialized EEG electrode arrays placed in nonstandard areas are still required to determine whether fentanyl-induced seizure activity occurs in humans? 8 Fentanyl is commonly employed during either general or local anesthesia with sedation for patients undergoing craniotomy for excision of epileptogenic foci with or without intraoperative functional localization and electrocorticographic (ECoG) monitoringfl 7'47'49At our institution, patients with complex partial (temporal lobe) seizure disorders who undergo surgical evaluation for possible anterior temporal lobectomy are routinely monitored with intraoperatively placed epidural ECoG electrodes, located bilaterally over the lateral and medial temporal cortex (including the perihippocampal gyrus). This special mode of ECoG monitoring provides 201
R. T e m p e l h o f f , et al. a unique model for the study of the electrical effects of various anesthetic agents in this epileptic patient population. In the following study, we used this ECoG model to either confirm or reject the hypothesis that fentanyl is capable of evoking electrical seizure activity in patients with complex partial epilepsy. Clinical M a t e r i a l and M e t h o d s
Patient Characteristics After approval of the protocol by the Institutional Review Board of the Washington University School of Medicine, nine otherwise healthy patients, 19 to 44 years of age, with intractable complex partial seizures were studied. Characteristics of these patients are summarized in Table 1. Age at the onset of their seizures ranged from 3 to 29 years old and seizure frequency ranged from several per day to between 4 and 10 per month. All study patients were within 20% of their
TABLE 1 Characteristics of nine patients included in the study Case No,
Age (yrs)
Body Weight (kg)
Age at Seizure Onset (yrs)
Seizure
1
19
77
6
2
37
80
17
4-10/rno weeklyclusters
3 4 5 6 7 8 9
44 31 31 44 40 22 3[
75 50 58 60 53 82 80
10 15 3 6 29 13 18
several/day 2/wk weekly clusters 1/day several/day l/wk 7/too
Frequency
ideal body weight, and all had failed to have their seizures controlled medically despite various combinations of every appropriate anticonvulsant drug. In all but one patient, positron emission tomography (PET) scans were obtained prior to surgery.
Patient Management Each patient underwent a three-stage approach to the surgical management of epilepsy. ~~9 Informed consent for this study was obtained from the patients shortly after admission, prior to the first stage. Stage I: Placement of ECoG Electrodes. Under general anesthesia, bitemporal craniotomies were performed so that bilateral epidural ECoG electrode recording arrays could be placed as previously described (Fig. 1). ~"'~'~After closure, the electrodes were checked to be certain that satisfactory artifact-free records could be obtained. Electrode positioning was confirmed with anteroposterior and lateral skull radiographs. After a brief period in the recovery room, the patients were transferred awake and fully oriented to a special observation unit for electrophysiological monitoring. Stage II: Extraoperative ECoG Localization of Symptomatic Temporal Lobe. The symptomatic temporal lobe was localized in each fully awake patient by correlating clinical and electrical seizure activity obtained during continuous simultaneous extraoperative videotape and epidural ECoG monitoring. All nine patients were monitored for a period of 24 to 72 hours, in a quiet setting, without any pharmacological interference from anesthetic or sedative drugs. During this time, anticonvulsant therapy was gradually reduced until one or several spontaneous clinical seizures occurred (Figs. 2A and B and 3A and B). The patient's
FIG. 1. Drawings depicting the temporal electrode array in place and demonstrating the relationships of the electrode position to the various temporal gyri. The most medially situated electrodes lie adjacent to the hippocampal and fusiform gyri. The other two pairs lie approximately over the inferior and middle temporal gyri respectively.(Reprinted from Goldring S, Gregorie EM, Tempelhoff R: Surgery.of epilepsy, in Dudley H, Carter D, Russell RCG (eds): Rob and Smith's Operative Surgery, ed 4. London: Butterworths, 1989, p 436, with permission). 902
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Fentanyl-induced electrocorticographic seizures
FIG. 2. A and B: Electroencephalographic recordings from Case 2 obtained with bitemporal epidural electrocorticographic (ECoG) electrodes during the extraoperative period (stage II). A: The patient is resting (awake). B: A spontaneous clinical seizure is noted originating from the left temporal lobe while the patient is resting (awake). C: Electrocorticographic recordings from the same patient during fentanyl induction. D: Electrocorticographic recordings from the same patient later during fentanyl induction, showing electrical activity originating from the right temporal lobe. Note that this electrical seizure begins on the side opposite that from which the electrical activity associated with the spontaneous clinical seizure arose (see B).
FIG. 3. Electrocorticographic recordings from Case 4 obtained with bitemporal epidural electrodes during the extraopemtive period (stage II). A: Recording while the patient is resting (awake). B: A spontaneous clinical seizure originating from the right temporal lobe is noted during the extraoperative period (stage II). C: Recordings during fentanyl induction. D: Recordings later during fentanyl induction, showing electrical activity originating from the left temporal lobe. Note that this electrical seizure begins on the side opposite that from which the electrical activity associated with the spontaneous clinical seizure arose (see B).
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R. Tempelhoff, et al. behavior and the ECoG were displayed on a split-screen video monitor and recorded on videotape for subsequent review. In each patient, clinical seizures and electrical seizure activity were consistently demonstrated to arise unilaterally from one temporal lobe (four on the right, five on the left). On the basis of these recordings, it was recommended to each patient that an anterior temporal lobectomy be performed on the side from which the clinical seizures were demonstrated to arise. Anticonvulsant therapy was then resumed with the same medications and dosages used prior to the primary craniotomy.
Stage 1II: Electrode Removal and Anterior Temporal Lobe Resection. For the purpose of this study, the usual anesthetic management of the secondary craniotomy ~9was modified and fentanyl alone was used for induction of anesthesia. During fentanyl induction, ECoG recordings were made, as described below. One to 2 hours prior to surgery, each patient received 150 mg ranitidine and 10 mg metoclopramide, both given orally. Upon arrival in the operating room and throughout anesthesia, all patients were monitored with electrocardiography (EKG), a blood pressure (BP) cuff, pulse oximetry, and mass spectrometry. No sedative or analgesic premedication was administered. Prior to induction, with each patient breathing 100% oxygen (02) by mask, the temporal lobe epidural ECoG electrode leads were connected bilaterally to a 10-channel (five channels per temporal lobe) EEG recorder,* and a resting (awake) ECoG record of several minutes duration was obtained. Soon after, when the mass spectrometer indicated 100% nitrogen washout, anesthesia was induced with fentanyl, administered intravenously via a volumetric infusion pump-~ at a rate of 500 ug 9 min -~. Following loss of response to verbal stimuli, muscle relaxation with intravenous vecuronium, 0.2 to 0.3 mg. kg-~, was instituted to facilitate ventilation by mask and to prevent fentanyl-induced chest-wall rigidity. Each patient's ventilation was controlled to maintain an end-tidal CO2 of 30 to 35 mm Hg with an O2 saturation of 98% to 100%. Throughout the period of anesthesia induction, ECoG activity from the lateral temporal lobe and hippocampal gyrus was continuously recorded bilaterally (Fig. 2C and 3C). Each patient's ECoG tracing was obtained and assessed by an electroencephalographer located in a separate room adjacent to the operating room, who was informed via audio contact with the anesthesiologist as to the onset and discontinuation of fentanyl administration. Continuous ECoG recordings were obtained until one of the following two endpoints occurred: 1) a total fentanyi dose of 5000 #g was administered; or 2) electrical seizure activity occurred. If an epileptiform pat* EEG recorder manufactured by Grass Instrument Co., Quincy, Massachusetts. t Volumetric infusion pump manufactured by Travenol Laboratories, Deerfield, Illinois. 204
tern appeared on the ECoG tracing, the anesthesiologist was notified by audio contact, the fentanyl infusion was stopped, and the seizure activity was allowed to resolve spontaneously during the following 30- to 60-second period. If the electrical seizure activity continued for longer periods, thiopental, 4 to 8 mg 9 kg-j, was given intravenously and, if the seizure activity persisted despite this, additional anticonvulsant therapy with diazepam, 0.1 to 0.3 mg 9 kg-j, was given intravenously until the epileptiform pattern abated. The total dose of fentanyl administered from the start of the infusion until the onset of electrical seizure activity (if any occurred) was recorded from the volumetric infusion pump. Following discontinuation of the fentanyl infusion and treatment of any seizure activity, each patient was intubated and anesthetic maintenance was instituted with 70%/30% (N20/O2), 0.2% to 0.3% end-tidal isoflurane, and atracurium infusion for muscle relaxation. Just prior to skin incision, a 1-~g 9 kg-j 9 hr -~ maintenance fentanyl infusion was added. In all nine cases, the epidural ECoG electrodes were removed bilaterally and an anterior temporal lobectomy was performed on the side from which the clinical seizures were demonstrated to arise during the extraoperative monitoring period (Stage II).
Analysis of ECoG Recordings Each intraoperative ECoG recording obtained during anesthesia induction with fentanyl (Stage III) was analyzed postoperatively for the presence of electrical seizure activity by an independent electroencephalographer who was unaware of each patient's history and the conditions under which the ECoG tracings were obtained. The results of this study were based solely on the independent electroencephalographer's ECoG interpretations. Tissue samples of the resected temporal lobe were all examined for pathological diagnosis. Following hospital discharge, all patients were followed at regular intervals in our neurosurgical clinic to evaluate their postor)erarive outcome. Results
Table 2 summarizes the PET findings, the side on which the anterior temporal lobectomy was performed, the location of fentanyl-induced seizure activity, and the fentanyl dose. In the eight patients in whom a PET scan was obtained prior to surgery, a good correlation was found between the side of hypometabolism and the temporal lobe determined to be responsible for the clinical seizures during extraoperative ECoG localization (Stage II). The PET scans showed no metabolic abnormalities in the contralateral temporal lobe. During anesthetic induction for the Stage III craniotomy, eight of the nine patients studied exhibited electrical seizure activity at a fentanyl dose ranging from 17.7 to 35.71 #g 9 kg J (mean 25.75 ug 9 kg-J). Examples of this ECoG seizure activity are illustrated in Figs. 2D
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Fentanyl-induced electrocorticographic seizures TABLE 3 Postoperative pathological findings and seizure frequency
TABLE 2 Temporal lobe PET and ECoG findings related to fentanyl dose* Side of Fentanyl-lnduced Fentanyl Case PET Hypo- Side of ECoG Seizure Dose No. metabolism Lobectomy lpsilat Contralat (#g'kg-~) 1 not done fight (+) ~ + 36 2 left left + 20 3 left left + 33 4 right right (+) *+ 20 5 left left + 17 6 right right + 25 7 right fight (+) ,-+ 19 8 left left + 21 9 left left 50 * PET = position emission tomography;ECoG = electrocorticographic; + = seizure present; - = seizure absent; (+) = seizurespread.
and 3D. Of these eight patients, four (Cases 3, 5, 6, and 8) had onset of the electrical seizure activity in the temporal lobe from which the clinical complex partial seizures had been shown to arise during the extraoperative monitoring period (Stage II). In contrast, electrical seizure activity in the other four patients (Cases 1, 2, 4, and 7) began in the temporal lobe contralateral to that from which the clinical seizures had been shown to arise. There was no significant difference in the average dose of fentanyl in the patients who exhibited electrical seizure activity in the ipsilateral versus the contralateral temporal lobe (23.75 vs. 24 #g 9 kg-~. In three of the four cases of contralateral ECoG seizure activity (Cases 1, 4, and 7), the seizures also spread to involve the clinically symptomatic (ipsilateral) temporal lobe. In all eight patients, the electrical seizure activity was detected in the most medial (perihippocampal) ECoG electrode leads, while five also exhibited significant electrical seizure activity in the lateral leads. Abnormal electrical activity first manifested as delta waves in three patients which, after 10 to 20 seconds, gave way to frank seizure discharge. In four other patients, a single spike or spike and slow wave led immediately to frank seizure discharge. In the eighth patient (Case 5), periodic lateralized epileptiform discharges appeared in the ipsilateral temporal lobe at a fentanyl dose of 17 ug 9 kg-~- Finally, in the remaining patient, no fentanyl-induced electrical seizure activity was detected. Postoperatively, all nine patients were followed routinely in our neurosurgical clinic for at least 7 months and their outcome is summarized in Table 3. A significant decrease in seizure frequency was observed in eight patients; five were seizure-free during a postoperative follow-up period of at least 10 months, including all four patients in whom the fentanyl-induced seizure activity occurred at least initially in the contralateral "healthy" temporal lobe. Pathological examination showed changes consistent with mesial temporal sclerosis in the hippocampus in seven of nine specimens. J. Neurosurg. / Volume 77/August, 1992
Case No. 1 2 3 4 5 6 7 8 9
PathologyFindings
Seizure Follow-Up Frequency Period(mos) mesialtemporal sclerosis none 21 mesialtemporal sclerosis none 24 mild astrocytosisof hippo3-4/mo 22 campus & amygdala (signifdecrease) mesialtemporal sclerosis none 13 mesialtemporal sclerosis none 14 focalmeningeal fibrosis/ no change 13 gliosis in fusiformgyrus mesialtemporal sclerosis none 10 mesialtemporal sclerosis 7 in 8 mos 8 (signifdecrease) mesialtemporal sclerosis 7 in 7 mos 7 (signifdecrease)
Mild astrocytosis in the hippocampus and amygdala was found in one specimen; a significant decrease in seizure frequency was achieved in this patient. In the remaining patient (Case 6), focal meningeal fibrosisgliosis was found in the fusiform gyrus; this patient had exhibited no clinical improvement by 13 months after surgery. Discussion Literature Review
Although EEG seizure activity in response to morphine, ~~ meperidine, x~ or fentanyl 9'j~ and its analogs52 has been well described in animals, the average intravenous dose required to produce convulsions is significantly greater than the amounts employed during daily clinical anesthetic practice in humans. There have been numerous reports of seizure-like motor behavior in nonepileptic patients after administration of low 17"20"21"23"25'28"31"37"38"46 to m o d e r a t e 322"24'36'45 doses of narcotics delivered via the intravenous, intramuscular, oral, or intrathecal routes, but unfortunately intraoperative EEG tracings were not performed during these events. Scalp EEG recordings in patients treated with low to moderate 8'24'34'4~and high 6"7"32"33'41'44'~1 intravenous doses of these opioids have never detected any epileptiform activity, including cases where convulsivelike motor activity was observed in the absence of EEG cortical seizure activity. 8'24'4~ These observations have led some to suggest that these abnormal movements may represent myoclonus 8'2~or an exaggerated form of opioid-induced rigidity.8"4~ Narcotic-induced EEG seizure activity has been previously noted only in nonepileptic patients following chronic oral or intramuscular meperidine administration, and has been attributed to its metabolite normeperidine, t'j7 Thus, the results of our ECoG investigation in patients with complex partial seizure disorders represents the first report of electrical seizure activity following the acute clinical intravenous administration of fentanyl or other opioids commonly employed intraoperatively. 205
R. T e m p e l h o f f , et al.
Analysis of Current Study Although retrospective analysis by Smith, et al., 43 of scalp EEG tracings in 127 patients anesthetized with high doses of fentanyl or its analogs did not support the existence of opioid-induced seizures in the clinical setting, several important differences between their investigation and ours appear to exist. First, the patient populations in the two studies were distinctly different, as they utilized a generalized nonepileptic population, whereas we studied patients with intractable complex partial seizures. Second, our 10-channel (14-electrode) method of ECoG recording was specifically limited to the temporal lobes, in contrast to their two-channel (six-electrode) scalp EEG method which would primarily detect activity from the frontal, parietal and occipital lobes. Thus, while no electrical seizure activity was observed in the recordings obtained by Smith, et al., seizure activity could have arisen from areas of the brain such as the hippocampus or amygdala which are not easily studied with the scalp EEG electrode array utilized in their study. In contrast, our bitemporal epidural EcoG electrodes are more likely to detect electrical seizure activity specifically arising from these structures. Epileptiform activity in this location has been detected during depth electrode recordings obtained in epileptic patients following administration of local anesthetic agenW L30,50and ketamine ~3 and is not always manifested cortically on conventional scalp EEG recordings. Although alfentanil-induced seizures in the limbic system were not detected by the intranasal electrodes employed in the study by Smith, et a1.,43the four nonepileptic patients they studied utilizing this particular electrode placement probably represents too small a number to draw any specific conclusions. Also, intmnasal electrodes are known to be considerably less sensitive than bitemporal epidural or depth electrodes in detecting seizure activity from medial temporal lobe structures. 35 Epileptogenicity of Fentanyl Animal studies have shown that the limbic system appears to be sensitive to multiple stimuli leading to self-sustaining repetitive discharges, 4'~6and that the pyramidal cells of the hippocampus exhibit innate epileptogenic properties normally inhibited by gamma-aminobutyric acid (GABA)-ergic interneurons. 439"42 The limbic system possesses one of the densest clusters of opioid receptors in the brain, 2 and morphine has been shown to produce seizure discharges in rats by disinhibiting the pyramidal cells of the perihippocampal structures located within the limbic system. 26In the rat, fentanyl has been shown to produce seizures in the subcortical limbic system which were associated with increases in local cerebral glucose utilization.4~ These studies illustrate that the subcortical limbic structures appear to be different from the cortex in their organization and response to narcotics, and lend support to our finding that indeed moderate doses of fentanyl can trigger electrical seizure activity in epileptic patients 206
which is restricted primarily to the perihippocampal gyrus and other closely related structures. This may also help to explain why in previous reports conventional scalp EEG recordings were not able to detect electrical seizure activity in patients without pre-existing disorders receiving low to high doses of fentanyl.
Dosage Considerations In this study, the average dose of fentanyl required to trigger electrical seizure activity was 25 #g 9 kg-~. This represents a moderate to high dose in routine anesthesia management. For example, anesthesia for coronary artery bypass grafting will require up to 60 to 100 ug 9 kg-j, while a hysterectomy requires 5 to 10 ug 9 kg-1 when fentanyl is the major component of the anesthetic regimen. However, in a previous study, 47 we have demonstrated the requirement for fentanyl during anesthesia for craniotomies in epileptic patients receiving chronic anticonvulsant therapy, to be up to three times higher than that of nonepileptic patients who were not receiving anticonvulsant medications. Thus, the average dose of 25 ug 9 kg-1 used in this study could well be considered a moderate rather than a high dose in this patient population. There are various techniques for giving "local" anesthesia for craniotomies in epilepsy surgery that include fentanyl. Classically, fentanyl in a 0.5- to l-ug 9 kg-~ intravenous bolus with a loading dose of droperidol is administered at the beginning of the procedure, and analgesia is maintained with an intravenous infusion of fentany127 or repeated boluses titrated to maintain a respiratory rate of 12 breaths/rain. 49 The total dose of fentanyl required may vary from 4 to l0 t~g 9 kg-~ and is administered over 4 to 8 hours throughout the procedure. This is a smaller dose and is administered over a longer period than the doses used in our study (l 7 to 36 ~ 9 kg-~ over 2 to 8 minutes). Considering the difference between the dosage used in our study and that used during "local" anesthesia techniques, as well as the difference between the two rates of administration, we cannot draw any conclusions regarding the risk of triggering electrical seizure activity during craniotomies performed under local anesthesia with fentanyl. Activation of Normal Temporal Lobe It is interesting to note that 50% of the fentanylinduced electrical seizures in this report were initially elicited in the "healthy" temporal lobe (as determined by extraoperative ECoG recordings, PET scans, and clinical outcome), contralateral to the surgically resected temporal lobe from which the clinical complex partial seizures were shown to arise. Although to date we have no entirely satisfactory explanation for this finding, some theoretical possibilities may be enterrained. One explanation may be that opioids such as fentanyl have the potential to induce electrical seizure activity in nonepileptic patients that, similar to our epileptic patients, is restricted to areas of the temporal lobe inaccessible to routine scalp EEG monitoring. Our J. Neurosurg. / Volume 77/August, 1992
Fentanyl-induced electrocorticographic seizures finding of a seizure-free long-term clinical outcome in all four instances of fentanyl-induced seizure activity in the "healthy" temporal lobe lends support to this theory. Another potential explanation for our finding of fentanyl-induced electrical seizure activity in the nonsurgically resected "healthy" temporal lobe is based on the recent finding in patients with complex partial seizures due to unilateral foci that opiate receptor binding as measured by PET is greater in the temporal neocortex on the side of the demonstrated electrical focus than on the opposite "healthy" side/5 This increased binding on the side of electrical seizure activity is due to an increase in affinity or number of unoccupied receptors, and indicates that increased opiate receptors in the temporal neocortex may represent a tonic anticonvulsant system that limits the spread of electrical activity from other temporal lobe structures.~5 Can we say that the increase in opiate receptors in the epileptogenic focus may in some cases act as a shelter against opioid (fentanyl)-induced electrical seizure activity? Unfortunately, this hypothesis does not appear to apply entirely to our findings, because in four of our patients seizure activity was initially elicited by fentanyl in the ipsilateral temporal lobe.
5.
6. 7.
8. 9. 10.
11. 12. 13.
Conclusions
Our findings indicate that, in patients with complex partial (temporal lobe) seizures, moderate doses of fentanyl can elicit electrical seizure activity. Interestingly, these fentanyl-induced seizures often arise from the "healthy" temporal lobe, contralateral to the temporal lobe from which the clinical seizure activity has been shown to arise. This suggests that opioids such as fentanyl may also have the potential to induce electrical seizure activity in nonepileptic patients in areas of the brain that are poorly accessible to routine scalp EEG monitoring. These results could have important implications for neurosurgical centers that rely on intraoperative electrocorticography during epilepsy surgery to determine the extent of cortical resection. Acknowledgments
The authors gratefully thank Sidney Goldring, M.D., for his inspiration and support during this investigation. We also express our gratitude to John Miller, M.D., for his interpretation of the ECoG recordings during fentanyl anesthesia induction. References
1. Andrews HL: Cortical effects of Demerol. J Pharmacol Exp Ther 76:89-94, 1942 2. Atweh SF, Kuhar MJ: Autoradiographic localization of opiate receptors in rat brain, llI. The telencephalon. Brain Res 134:393-405, 1977 3. Bailey PL, Wilbftnk J, Zwanikken P, et al: Anesthetic induction with fentanyl. Anesth Anaig 64:48-53, 1985 4. Ben-Aft Y, Tremblay E, Riche D, et al: Electrographic, clinical and pathological alterations following systemic administration of kainic acid, bicuculline or pentetrazole: J. Neurosurg. / Volume 77/August, 1992
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26.
27. 28. 29. 30. 31. 32. 33. 34.
35. 36. 37. 38. 39. 40.
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Manuscript received October 8, 1991. Accepted in final form January 30, 1992. This work was presented in part at the Annual Meeting of the American Association of Neurological Surgeons, April 21-25, 1991, New Orleans, Louisiana. Address reprint requests to." Ren6 Tempelhoff, M.D., Department of Anesthesiology, Division of Neuroanesthesia, Washington University School of Medicine, Box 8054, 660 South Euclid Avenue, St. Louis, Missouri 63110.
J. Neurosurg. / Volume 77/August, 1992
