And Anticonvulsant Effects of Anesthetics (Part I)

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ANESTH ANALG 303 1990:70:30>15

Review Article

Pro- and Anticonvulsant Effects of Anesthetics (Part I)

Paul A. Modica, MD, Rene Tempelhoff, MD, and Paul F. White, rhD, MD

Key Words: ANTICONVULSANTS. BRAIN, PRO- An epileptic seizure has been defined as a sudden AND ANTICONWLSANTS. COMPLICATIONS, alteration of central nervous system (CNS) function CONVULSIONS. TOXICITY, CONVULSIONS. resulting from a high-voltage electrical discharge. This discharge may arise from an assemblage of Part I neurons in either cortical or subcortical tissues. The Introduction spread of this excitatory activity to the subcortical, Inhalation anesthetics Volatile agents thalamic, and brainstem centers corresponds to the Enflurane tonic phase of the seizure and loss of consciousness Halothane (1). In contrast, myoclonic activity refers to a series of Isoflurane rhythmic or arrhythmic muscular contractions (2). Investigational volatile agents Depending on the electroencephalographic (EEG) Nitrous oxide findings, myoclonus is divided into epileptic and Intravenous analgesics nonepileptic activity (3). Nonepileptic myoclonus Opioid (narcotic) analgesics originates from the brainstem or spinal cord and is Meperidine due to either loss of cortical inhibition (4)or to im- Morphine paired function of spinal interneurons (3,5). Without Fentanyl and its analogues EEG monitoring, it is extremely difficult to determine Summary whether abnormal-appearing seizurelike muscle Part I1 movements are due to epileptiform activity or non- Introduction epileptic myoclonia. Intravenous anesthetics Many anesthetic and analgesic drugs have been Sedative-hypnotics reported to cause seizure activity clinically (Table 1, Barbiturates A). Interestingly, many of these same drugs have also Etomidate been shown to possess anticonvulsant properties Benzodiazepines (Table 1, B). In an effort to explain deficiencies with Ketamine Guedel's original stages of anesthesia, Winters and Propofol colleagues (67) proposed a multidirectional contin- Local anesthetics uum of anesthetic states (Figure 1). For example, Anesthetic adjuncts some agents (e.g., diethyl ether) traverse both CNS Muscle relaxants excitation (stages I, 11) and depression (stage 111). Anticholinesterases Others (e.g., halothane, ultrashort acting barbitu- Anticholinergics rates) progress directly from stage I to 111, whereas Summary still others (e.g., nitrous oxide [N,O], enflurane, ketamine, and narcotics [S]) induce a stage I1 catalep- Part 11 of this review article will appear in the following issue of toid CNS excitation, which on occasion progresses to the journal. Received from the Department of Anesthesiology, Washington myoclonia or generalized convulsions. Based on EEG University school of Medicine, St. Louis, Missouri. Accepted for studies in cats, Winters suggested that both exces- publication October 10,1989. sively disorganized (stage 11) and decreased reticular- Address correspondenceto Dr. White, Department of Anesthe- siology, Box 8054, Washington University School of Medicine, 660 formation activity (stage 111) result in unresponsive- South Euclid Avenue, St. Louis, MO 63110. ness to painful stimuli and amnesia, consistent with

01990 by the International Anesthesia Research Society ANESTH ANALG MODICA ET AL. 304 1990;7030>15

Table 1. Anesthetics and Analgesics Reported to Cause stage 111 agent, has been used in the diagnostic and/or Suppress Seizure Activity in Humans activation of epileptogenic foci (11,12). ~ A. Proconvulsants 8.Anticonvulsants To properly categorize the various anesthetic Nitrous oxide Halothane agents with respect to their effects on the seizure Halothane Enflurance threshold, there are several important factors to con- Enflurane Isoflurane sider. The first consideration is the patient population Isoflurane Thiopental studied. For example, methohexital, in its current Morphine E tomida te formulation (Brevital; Eli Lilly, Indianapolis, Ind.), Meperidine Diazepam Fentanyl Lorazepam will only produce epileptiform activity in patients Sufentanil Midazolam with known seizure disorders (11,12). A second fac- Methohexital Ketamine tor to consider is the method of proconvulsant and Etomidate Prop of o1 anticonvulsant documentation. This had led to con- Diazepam Local anesthetics fusion in the literature regarding the effects of some Ketamine Propofol anesthetics and analgesics on CNS activity. Fentanyl- Local anesthetics induced seizures have been described clinically without the support of EEG documentation (13-15). In some instances, these convulsivelike muscle move- ME TRAZOL, KETAMINE ments may be due to nonepileptic myoclonus. PHENCYCLIOINE f-7 Y HYDROXYBUTYRATE SE, ZUR ES For most drugs used in anesthesia, subsequent EEG evaluation during their administration has MESCAL IN& N20 helped to clarify whether or not a particular agent is ETHER( truly epileptogenic in patients. However, for certain anesthetics, such as ketamine (16), the origin of epileptiform activity involves subcortical neuronal pathways. In humans, subcortical seizures are detected only with implanted EEG depth electrodes, not by standard surface leads. Thus, a third important factor to consider in determining whether or not an anesthetic possesses proconvulsant or anticonvulsant properties is the type of EEG recording electrodes (surface or depth) used during its evaluation. In this review article, we have attempted to ana- lyze the evidence for proconvulsant and anticonvulsant activity of anesthetics and analgesics. This information has been evaluated with respect to (a) patient population (epileptic or nonepileptic); (b) documen- Figure 1. Winter's proposed scheme of reversible progression of tation of pro- and anticonvulsant activity (EEG study CNS states induced by various anesthetic and excitant agents. Stages I, 11, A, B, C, myoclonus, and seizures indicate CNS or clinical report); and (c) method of EEG analysis excitation, whereas stages Ill and IV indicate CNS depression. (surface or depth electrodes). (From Winters WD, Ferrer-Allado T, Guzman-Flores C, Alcaraz M. The cataleptic state induced by ketamine: a review of the neuropharmacology of anesthesia. Neuropharmacology 1972;11:30>15, with permission.) Inhala tion Anesthetics Volatile Agents the anesthetic state. Although both epileptic and anesthetic states possess similar features regarding Enflurune. Abnormal movements consisting of arousal and memory, the categorization proposed by twitching of individual muscle groups, and even Winters fails to adequately explain the actions of tonic-clonic activity, were frequently observed during those anesthetics that appear to possess both procon- the early clinical evaluation of enflurane (17,18). vulsant and anticonvulsant properties (Table 1). For Subsequent EEG recordings in normal patients dem- example, ketamine, an alleged stage I1 anesthetic onstrated epileptiform activity (19,20) and grand ma1 which Winters believed to be contraindicated in epi- seizure patterns (21) (Table 2). These findings with lepsy, has been successfully used to terminate status enflurane have also been confirmed in patients with epilepticus (9, lo), and conversely, methohexital, a temporal lobe epilepsy during both electrocortico- ANESTHETICS AND SEIZURES ANESTH ANALC 305 1990:70:30>15

Table 2. Proconvulsant Effects of Inhalation Anesthetics in Humans Seizure documentation Type of EEG Clinical EEG electrodes Agent Population report study used in study References

Nitrous oxide Nonepileptic + - Surface 58, 64, 96 Epileptic - - Depth 16 Halothane Nonepileptic - - Surface 6M2 Epileptic - - Surface 63 Enflurance Nonepileptic + i Surface 17-21, 26, 28 Epileptic + i Surfaceldepth 22-25 lsoflurane Nonepileptic - - Surface 75-78 Epileptic NIA N/A

Sevoflurane Nonepileptic - - Surface 86 Epileptic NIA NIA Desflurane (1-653) Nonepileptic NIA N/A Epileptic N/A NIA

+, presence of seizures; -, absence of seizures; EEC, electroencephalographic; N/A, information not available.

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Figure 2. Electroencephalographic patterns with increasing concentrations of enflurane. (From Neigh JL, Garman JK, Harp JR. The 0 electroencephalographic pattern during anesthesia with Ethrane: effects of depth of anesthesia, Paco,, and nitrous oxide. Anesthesiol- &6 ogy 1971;35:482-7, with permission.) 15

graphic (22-24) and depth electrode recordings (25). waves-spike and dome activity with intermittent In ten healthy volunteers, grand ma1 seizure patterns periods of burst suppression (Figure 2). In contrast to were precipitated by auditory, visual, and tactile other volatile anesthetics, these burst suppression stimulation at end-tidal enflurane concentrations of patterns are thought to represent an excitatory event 3%-6% (26). This has also been reported during otic (29). microsurgery (27). In both normal (28) and epileptic The ability of enflurane to produce seizure or EEG (U)patients, increasing depth of enflurane anesthe- spiking activity is influenced by both its concentra- sia is characterized by the appearance of high-voltage tion and the Paco, (25,28). At a normal Paco, level, spikes, with the subsequent development of spike spiking is maximal at inspired enflurane concentra- 306 ANESTH ANALG MODICA ET AL. 1990;70303-15 tions of 2%-3%. Higher Paco, concentrations reduce thiopental (42) were found to intensify enflurane- spiking activity (22). Interestingly, N,O does not induced seizures in humans. Larger doses of thiopen- affect the tendency of enflurane to produce spiking tal diminished seizure activity. In cats, enhanced activity (28). With an alveolar enflurane concentration enflurane-induced seizure activity has been demon- between 2.5% and 3%, hyperventilation to an aver- strated with the concomitant administration of diaz- age Paco, of 22 torr produced an increase in the epam, thiopental, methohexital, ketamine (43), and frequency, magnitude, and synchrony of the spiking scopolamine (26). Conversely, in dogs, scopolamine activity in epileptics (25). This technique has since significantly decreased enflurane-induced spiking ac- been used to activate silent epileptogenic foci intra- tivity (44). This may represent species variability to operatively, to delineate the site of seizure activity the CNS effects of scopolamine. Using depth elec- before discrete surgical excision (23,24). trodes in cats, Darimont and Jenkins (43) demon- Conversely, with an enflurane concentration of strated that diazepam lowered the threshold for spik- 3.5%, the addition of CO, to the inhaled gas pro- ing activity by producing a leftward shift in the curve duced a decrease in magnitude and frequency of relating spiking frequency and enflurane concentra- spiking activity (25). At an end-tidal CO, of 91 torr, tion. In view of these contrasting findings, it remains spiking was not observed despite the fact that the unclear whether diazepam or thiopental should be enflurane alveolar concentration was increased to used to treat perioperative seizures associated with 4%. The rela tionship between enflurane concentra- enflurane anesthesia. tion, Paco,, and epileptiform activity was further A variety of studies in animals have examined the evaluated in a volunteer study that demonstrated mechanism of enflurane-induced hyperexcitability. It that the minimum epileptogenic enflurane concentra- is unclear as to whether enflurane induces epilepto- tion was approximately 1% lower when the Paco, genic activity by inhibiting synapses (43,45) or by was 20 torr (vs normocarbia), and 1% higher when stimulating excitatory neuronal transmission (46). In Paco, was 60 torr (26). investigations performed on cats with depth elec- Postoperative seizure activity related to enflurane trodes, it was reported that the seizure activity orig- administration has also been reported, primarily in inated from the limbic system (amygdala and hippo- nonepileptic patients. These seizures may occur in campus) and midline thalamic nuclei (26,43,46). The the immediate postanesthetic period (30-33), within subcortical origin for the epileptogenic properties of hours of surgery (34), and possibly as long as 3-9 enflurane was further supported by the finding in days later (35,36). In a few instances the patients were rats that local cerebral glucose use (LCGU) in the either epileptic (33) or had a familial history of seizure limbic system was preserved or increased, whereas disorders (36). In other reports, only transient (37,38) LCGU in many other structures was significantly or prolonged (39) mvoclonic activity has been ob- decreased during deep enflurane anesthesia (47). served in otherwise conscious patients after enflu- However, similar alterations in limbic system metab- rane. Whether or not these reports of postoperative olism also have been reported for anesthetics without seizurelike activity in normal patients are truly re- epileptogenic properties (e.g., chloral hydrate [48], lated to enflurane administration is unclear. Tran- phenobarbital [49], and halothane [50,51]). Further- sient surface EEG spike (30) or seizure (23,36) activity more, in a recent study in rats (52), the authors has been reported postoperatively, which was absent suggested that intercortical and corticothalamic path- on follow-up EEG studies. However, in volunteers ways are metabolically activated during enflurane exposed to 9.6 MAC hours of enflurane, only diffuse seizure activity. nonepileptiform EEG changes were observed using In more than 300 patients with seizure disorders, surface electrodes for 6-30 days after anesthesia (40). the frequency of convulsivelike EEG activity during Half of these volunteers had exhibited both clinical enflurane anesthesia was less compared with the and EEG seizure activity during enflurane anesthesia. previous sleep and awake EEGs of these epileptics In an animal study (41), high-amplitude spikes were (53). Furthermore, enflurane has been reported to recorded from depth electrodes in the thalamus for inhibit seizure activity arising from epileptogenic foci up to 15 days after exposure to enflurane. Therefore, (54,55). In animals, enflurane suppresses convulsions one cannot exclude the possibility that after enflurane induced by electroshock, pentylenetetrazol, bicucul- anesthesia there is actual subcortical epileptiform line, and penicillin (56,57). In amygdaloid-kindled activity. cats, it was reported that both low (1.5%)and high Various drugs have been reported to either en- (3.5%)concentrations of enflurane suppressed sei- hance enflurane-induced spiking activity or lower its zure activity (57). In children, successful termination threshold. Both diazepam (30) and small doses of of status epilepticus has been demonstrated with ANESTHETICS AND SEIZURES ANESTH ANALG 307 1990;70303-15

Table 3. Anticonvulsant Effects on Inhalation Anesthetics onstrated with halothane (53) (Table 3). In these in Humans cases, the disappearance of spikes and waves was Anticonvulsant evident within 20 min. No seizures were noted after Type of EEG documentation electrodes recovery. These potent anticonvulsant effects com- Clinical EEG used in bined with the lack of clinically important cerebral Agent report study study References excitatory findings for halothane would suggest that Nitrous oxide - - Surface 85 it does not possess proconvulsant properties. Halothane + + Surface 53, 66 Enflurane + + Surface 53, 54 Isoflurune. When administered alone, isoflurane Isoflurane + + Surface 74, 82, 83, 85 has not been found to cause EEG or clinical seizure Sevoflurane N/A N/A activity in anesthetized patients (Table 2). In the Desflurane (1-653) N/A N/A reported cases of isoflurane-related seizures (67-69), +, successful termination of status epilepticus reported; -, failure to N,O was also administered. In two of these cases, eliminate seizures reported; EEG, electroencephalographic; NIA, information not available. abnormal myoclonic movements starting intraopera- tively and lasting into the early postanesthetic period enflurane (53) (Table 3). The disappearance of EEG were the only evidence of seizure activity (67,68). seizure activity was evident 20 min after induction Furthermore, one of these patients was conscious and no further convulsive activity was noted during throughout the recovery period (67). In contrast to recovery. Despite these anticonvulsant findings, en- the reported convulsions after enflurane (23,30,36), flurane has a propensity for inducing epileptiform the postoperative EEG was normal in both reports. activity during anesthesia, especially when high con- Alternative explanations for these seizurelike move- centrations are administered in the presence of hy- ments include nonepileptic myoclonus (3,70) and/or pocarbia. the so-called withdrawal phenomena from N20 (71,72). Halothane. Halothane alone has not been reported In another case report (69), isoflurane-N,O anes- to cause convulsions in humans (Table 2). In the few thesia was associated with tonic-clonic activity early reports (58,59) of halothane-related seizures, N20 during inhalational induction on two separate occa- was also administered. Electroencephalographic sions. Before the second anesthetic, EEG studies monitoring in normal patients had not revealed epi- were entirely normal. With EEG monitoring during leptiform activity during halothane anesthesia (60- the second induction, spike and wave forms were 62). However, nonspecific EEG slowing and rare recorded during the clinical seizure and both ceased sharp wave activity (attributed to the persistence of after administration of thiamylal. In this case, the halothane and its metabolites) was seen in volunteers finding that the spiking activity appeared with induc- during the first week after 13-14 MAC-hours of tion but did not continue during maintenance or halothane administration (60). In three epileptic pa- reappear during recovery implies that N,O may have tients, brief periods (<7 s) of bilateral atypical and precipitated the seizure activity (73). Furthermore, polyspike waves were noted during emergence from N20 alone has been associated with clinical seizures halothane, but were not associated with clinical sei- during induction (58,64), whereas isoflurane’s anti- zure activity during the perioperative period (63). convulsant properties may have prevented further Mild transient clonus has been observed after seizures during the maintenance and recovery peri- halothane anesthesia (37). Epileptic activity has been ods (73,74). reported in cats given a high concentration of In unpremedicated volunteers, induction of isoflu- halothane (7%); however, cerebral blood flow and rane anesthesia is characterized by low-voltage fast metabolism is also markedly altered at this concen- EEG activity that progresses toward high-voltage tration (64).Although depth electrodes have revealed slow wave activity at 1 MAC. Bursts of slow high- occasional hippocampal spikes in cats (46), evoked voltage activity separated by electrical silence are spikes were not detected during halothane anesthesia noted at 1.5 MAC, with electrical silence at 22 MAC in dogs subjected to loud hand-clapping in the pres- (75-77). Epileptic or spiking patterns do not appear, ence of hypocapnia (65). nor can they be evoked by lowering the Paco, or by Inhaled anesthetics, including halothane, have introduction of auditory and visual stimuli (75,77). been recommended for treatment of continuous unpremedicated volunteers did not demonstrate seizures refractory to conventional intravenous anti- clinical or EEG evidence of seizure activity during convulsant agents (66). Successful termination of isoflurane-N20 inhaled induction (77). In premedi- resistant status epilepticus in children has been dem- cated patients undergoing inhaled induction with 308 ANESTH ANAI (; MODICA ET AL. 1990;70:30>15

isoflurane and N,O (78), spikelike wave complexes the slower the EEG activities. No EEG or motor lasting 1-2 s were seen when end-tidal isoflurane was evidence of seizure activity has been reported during increased above 2.5% and end-tidal CO, was inten- anesthesia with sevoflurane (Table 2). It is unknown tionally lowered. In c'its (79,80), isoflurane was asso- whether or not sevoflurane will activate epileptogenic ciated with high-voltage synchronous spikes but not foci in patients with preexisting seizure disorders. seizures. In dogs subjected to loud hand-clapping in Recently, EEG activity during anesthesia with des- the presence of hypocapnia (65), isoflurane caused flurane was compared with isoflurane and enflurane spontaneous spiking without seizure activity. It is in swine (87). In this report, desflurane produced unknown whether or not isoflurane, with or without EEG waveforms and quantitative EEG values almost N,O, will activate epileptogenic foci in patients with identical to those of isoflurane at equipotent concen- preexisting seizure disorders. However, seizurelike trations. At low end-tidal concentrations (0.8 MAC) movements have not been reported during isoflurane of desflurane, paroxysmal fast activity was occasion- anesthesia in epileptic patients. ally noted. Higher concentrations produced progres- Isoflurane has well-characterized anticonvulsant sive slowing of the EEG, and isoelectricity was ob- properties. In animals, isoflurane produced complete served at 1.6 MAC. No EEG or motor evidence of suppression of drug-induced convulsions (81-84). In seizure activity was noted during desflurane admin- patients with status epilepticus resistant to conven- istration. Furthermore, when these animals were tional therapy, isoflurane-0, produced rapid cessa- exposed to either hypocapnia or external auditory tion of seizures with a burst suppression pattern at stimuli, they did not demonstrate seizure activity inspired concentrations ranging from 0.5% to 3.0% during either desflurane or isoflurane anesthesia. In (74,82,83,85) (Table 3). When isoflurane was discon- contrast, EEG and motor seizures occurred during tinued after exposures lasting 1-54 h, seizures re- hypocapnia with and without auditory stimuli in curred in 50% of the patients studied. These reports animals given 3.2% enflurane. The EEG effects of combined with the absence of EEG and clinical sei- desflurane have not been investigated in humans. It zure activity during studies of its administration is also unknown if sevoflurane and desflurane pos- alone indicate that isoflurane is a potent anticonvul- sess anticonvulsant properties. Further studies re- sant in humans. garding the effects of these new volatile agents on CNS electrical activity in humans are clearly needed. lnvestigatioiial volatile agents. Sevoflurane and desflurane (1-653) are newly synthesized volatile anesthetics that are structurally similar to enflurane and isoflurane. The low solubility of both agents makes Nitrous Oxide them potentially usetul when rapid awakening is Animal studies would suggest that N,O stimulates desired (e.g., outpatient anesthesia) (86,87). In un- brain metabolism when combined with other anes- premeditated volunteers, successive incremental in- thetics (88-91). Withdrawal convulsions have been spired sevoflurane doses of 1%, 2%, and 4% pro- described in mice after short exposures to both nor- duced EEG patterns that contrasted with those mobaric (0.6-0.9 atm) and hyperbaric (1.2-1.6 atm) commonly observed during the administration of N,O (92,93). Volunteers exposed to hyperbaric (1.5 most anesthetics (86). In light planes, an increase in atm) N,O exhibited muscle rigidity, jerking move- both frequency (10-14 Hz) and amplitude, associated ments, and occasional hyperactivity alternating with with unconsciousness, was observed in all subjects apparent relaxation (94). In contrast, mice exposed to receiving sevoflurane. At deep levels, slower, low- high pressures of helium and/or 100% 0, did not voltage, 5-8-Hz activity also appeared; however, the display convulsions when removed from these gases predominant 10-14-Hz activity persisted with a fur- (93). ther increase in amplitude. Interestingly, a separate Hypersynchronous epileptoid EEG activity and an exposure of the same volunteers to an initial inspired increase in reticular-formation neuronal activity was sevoflurane concentr'i tion of 4% initially produced reported during N,O anesthesia in cats studied with high-amplitude, rhythmic slow waves (2-3 Hz) that depth electrodes (95). However, EEG studies per- coincided with loss ot consciousness (86). The latter formed in patients receiving N,O alone have not EEG pattern was dominant for 2-3 min, and then was revealed seizure activity (Table 2). In unpremedicated replaced by a pattern identical to that observed dur- epileptic (16) and nonepileptic (96) patients studied ing exposure to a lower concentration of sevoflurane. with depth electrodes and surface EEG, respectively, These findings are opposite to the traditional view 70% N,O produced fast activity (15-35 Hz) but no that the greater the arterial blood level of anesthetics, evidence of seizure activity. The epileptic patients ANESTHETICS AND SEIZURES ANESTH ANALG 309 19Y13;7(1~3O,L1i

Table 4. Proconvulsant Effects of Opioid (Narcotic) Analgesics in Humans Seizure documentation Type of EEG Clinical EEG electrodes Agent Population report study used in study References

Morphine Nonepileptic + - Surface 114, 118, 120 Epileptic + NIA 115 Meperidine Nonepileptic + f Surface 99-101, 103, 104, 111 Epileptic NIA NIA Fentanyl Nonepileptic + - Surface 1~15,114, 128-130. 13.~36,139. 142 Epileptic NIA N/A Sufentanil Nonepileptic + - Surface 131, 132, 135, 137, 143 Epileptic NIA NIA Alfen tanil Nonepileptic + - Surface 133, 135, 138 Epileptic NIA N/A

+, presence of seizures, -, absence of seizures, EEG, electroencephalographlc. N/A, informahon not available exhibited restlessness and hallucinations, whereas ors, myoclonus, and seizures (99) (Table 4). This the nonepileptics remained unresponsive to stimuli. neuroexcitement is attributed to its N-demethylated Although no convulsionlike withdrawal phenomena metabolite normeperidine (100,101). The half-life of were reported, the fast EEG activity persisted for up normeperidine (14-21 h) is significantly longer than to 1 h after discontinuation of N20 (96). In volun- that of meperidine (34 h). Thus, with repeated or teers, diffuse paroxysmal bursts of high-voltage theta continuous meperidine administration, normeperi- activity were observed immediately after cessation of dine can accumulate, leading to neurotoxicity (99- N,O 30% (71). There appears to be only one case 101). The risk of precipitating convulsions is theo- report, without EEG documentation, in which N20 retically greater with chronic oral administration alone precipitated convulsions (Table 2). In a child because it produces lower meperidine and higher who convulsed during a halothane-N,O induction, normeperidine blood levels due to extensive first- subsequent inductions with halothane alone did not pass metabolism (102). However, seizures have oc- precipitate a seizure, whereas use of N,O alone was curred after both chronic oral (99,103) and intramus- associated with seizurelike movements (58,64). cular (100,104) administration. Myoclonus generally N,O alone has never been demonstrated to pos- precedes the seizures, and both resolve over several sess anticonvulsant properties in humans (Table 3). days with discontinuation of meperidine administra- In one patient with refractory convulsions, 60% N20 tion (101,103). alone slowed but did not eliminate tonic-clonic or Anticonvulsants (e.g., phenytoin [ 1051, phenobar- EEG seizure activity (85). In animals, N,O was found bital [106]) and phenothiazines (e.g., chlorpromazine to elevate the local anesthetic seizure threshold (97) [107]) have been demonstrated to increase the con- and to reduce the frequency of EEG spiking activity version of meperidine to normeperidine in humans. during enflurane anesthesia (98). N20 remains the In mice, concomitant administration of prometha- oldest and most widely used anesthetic in clinical zine and meperidine has been shown to be synergis- practice. In view of this long-standing record of safety tic in inducing seizures (108). Concomitant therapy and the available evidence regarding its cerebral with either anticonvulsants (103) or phenothiazines stirnulatory effects, its epileptogenic potential ap- (104,109) may have been a contributing factor in some pears to be extremely low. reports of seizure activity after oral or parenteral meperidine administration. The EEG pattern after intravenous administration of a single high dose (400 mg) of meperidine is Intravenous Analgesics characterized by primarily high-voltage delta waves, Opioid (Narcotic) Analgesics similar to that reported for other narcotics (110). However, in otherwise healthy patients in whom Meperidine. Meperidine neurotoxicity is well seizures occurred after repeated meperidine admin- known and is manifest clinically as shakiness, trem- istration, EEG studies have revealed diffuse slow 310 ANESTH ANAl G MODICA ET AL. 1W0;70: 30% 15

activity and epileptiform discharges (99,111) (Ta- nonepileptic cancer patient (118). These reports sug- ble 4). gest a subcortical origin for morphine-induced sei- Patient subgroups that appear to be more suscep- zures. Electrophysiologic studies in rats support this tible to the neurotoxicity associated with chronic concept as morphine causes disinhibition of the py- meperidine therapy include (a) patients with renal ramidal cells of the hippocampus, leading to seizure failure in whom the normeperidine half-life is pro- discharges (119). A grand ma1 seizure in a 14-yr-old longed (34 h) due to decreased metabolism and boy occurred 90 min after 20 mg of intramuscular excretion (100,103), and (b) patients with advanced morphine and 0.4 mg of scopolamine were adminis- malignancy (100,101) or sickle cell anemia (112), both tered (120). A prodrome of intense itching was expe- of whom receive progressively larger doses of mepe- rienced by the patient, indicating that morphine ridine due to the development of tolerance. Seizure- probably contributed to the seizure activity, although like movements have not been reported in epileptic the well-known excitatory CNS effects of scopola- patients during either acute or chronic meperidine mine may have been an additional contributing factor administration. Furthermore, it is unknown whether in this case. Withdrawal seizures have been reported or not acute or chronic meperidine use will activate clinically, predominantly in neonates born to heroin- epileptogenic EEG foci in patients with preexisting addicted mothers (121). seizure disorders. DeCastro et al. (8) found that an average morphine Meperidine has demonstrated the lowest safety dose of 180 mg/kg, IV, was required to precipitate margin for convulsions of all narcotics studied. In EEG seizure activity in dogs. This was 72 times dogs, EEG seizure activity was induced with an greater than the mean effective intravenous dose (2.5 average intravenous rneperidine dose (20 mg/kg) that mg/kg) for surgical analgesia. In rats, higher systemic was only 2.2 times greater than the mean effective doses of morphine produce epileptiform patterns and intravenous dose (9 mg/kg) for surgical analgesia (8). behavioral convulsions that are not reversed by opi- In mice, naloxone can only partially block the convul- ate antagonists (122). Seizures have also been dem- sions induced by normeperidine, whereas meperi- onstrated after intracerebroventricular administration dine-induced seizures are completely blocked by of morphine in rats (123,124) and after intrathecal prior administration of naloxone (113). Neither me- administration of morphine in dogs (125) and rats peridine nor normeperidine has ever been shown to (126). Although the cerebroventricular-induced sei- possess anticonvulsant properties. Within the range zures are naloxone reversible (124), the intrathecal of meperidine doses used clinically to supplement morphine-induced tonic-clonic movements were not general or regional anesthetic techniques, the procon- naloxone reversible (126). These findings suggest that vulsant effects of the drug appear to be of little the proconvulsant actions of high doses of morphine concern. However, seizures may result from norme- in animals are mediated by both opiate (e.g., mu) and peridine accumulation after prolonged meperidine nonopiate (e.g., y-aminobutyric acid) receptor mech- administration (e.g., patient-controlled analgesia), anisms (122,127). especially in patients with renal failure, sickle cell, Morphine alone has never been demonstrated to and cancer. possess anticonvulsant properties in humans. In rab- bits, intravenous morphine terminated bicuculline- Morphine. Morphine alone has never been demon- and picrotoxin-induced EEG and behavioral seizures strated to produce stlizure activity in humans after (127). In rats, intravenous morphine delayed the intravenous administration. High-dose morphine (1- onset of pentylenetetrazol- and flurothyl-induced sei- 2 mg/kg, IV) during open-heart surgery was associ- zures (122). Although intravenous morphine in high ated with progressive slowing of EEG activity and an doses has both pro- and anticonvulsant properties in increase in low-frequency amplitude. No epilepti- animals, the doses of the drug used in clinical practice form activity was noted (114). Electroencephalo- appear to have little effect on the seizure threshold. graphic investigations have not been performed in This is especially true with noncerebrospinal fluid epileptic patients during high-dose morphine admin- routes of morphine administration. istration. However, A tonic-clonic seizure was reported after administration of epidural morphine to a Fenfanyl and its analogues. There have been several known epileptic (115) (Table 4). There was a 6-h delay reports of grand ma1 seizure-like motor behavior in between epidural administration and the onset of patients after administration of low (1OC-200 pg) seizure, consistent with the known kinetics of mor- (14,15,128,129) to moderate (2250-2500 pg) (13,130) phine in the cerebrospinal fluid (116,117). A convul- doses of intravenous fentanyl. This phenomena has sion has also occurred after intrathecal morphine in a also occurred after sufentanil (40-150 pg, IV [131, ANESTHETICS AND SEIZURES ANESTH ANALG 31 1 1990;7@:30>15

1321) and alfentanil (1500 pg, IV [133]) administration administration (128). In addition, this patient also (Table 4). None of the patients had a history of received etomidate, an anesthetic that produces non- seizure disorder and their EEGs after surgery were epileptic myoclonic activity (144), which occasionally unremarkable. Unfortunately, in these case reports, persists into the postoperative period (145,146). the authors did not have the benefit of EEG recording An alternative explanation is that these move- during the seizurelike event. ments represent an exaggerated form of narcotic- Surface EEG recordings in patients treated with induced rigidity (142). Rigidity can occur after low high intravenous doses of fentanyl (60-150 pg/kg doses of fentanyl (147) and high-dose alfentanil in- [114,134-136]), sufentanil (15 pgkg [135,137]), or ductions have produced rigidity involving all extrem- alfentanil (>50 pgkg [135,138]) are characterized by ities that closely resembles seizures in volunteers high-voltage slow delta waves. Similar EEG findings (148). Recent studies have suggested that rigidity were also demonstrated in patients receiving low-to- may involve neurochemical mechanisms in the stria- moderate doses of fentanyl (139). Except for sporadic tonigral pathways similar to Parkinson’s disease isolated sharp waves noted in two of the high-dose (149-151). Thus, exaggerated rigidity could have been fentanyl studies (134,136), these EEG investigations responsible for the seizurelike movements observed did not detect any epileptic spike waves or other after low-dose sufentanil administration (131). In abnormal patterns (Table 4). The significance of these these two cases, one patient had a history of Parkin- sharp waves is not known as they were nonepilepti- son’s disease, and the other patient was receiving form in appearance and never became generalized chronic metoclopramide therapy. Metoclopramide in- (134). Although they have not been related to tonic- hibits cerebral dopaminergic pathways and can pro- clonic movements, similar sharp waves also have duce extrapyramidal signs (152,153). been noted during the administration of other drugs The tonic-clonic movements reported with admin- known to be epileptogenic (e.g., phencyclidine [140], istration of low-to-moderate doses of fentanyl and intrathecal metrizamide [ 1411). Whether sharp waves sufentanil could also be due to subcortical seizure represent an EEG equivalent of a CNS stimulatory activity. Electroencephalograph-documented cortical action or merely EEG artifact remains unclear. Al- seizures have been induced by high-dose fentanyl though tonic-clonic movements associated with their (8,154,155) and sufentanil (156) in animals. The EEG administration have not been reported in epileptic seizures in rats were accompanied by decreases in patients, EEG studies have never been performed in LCGU in cortical structures and relative increases in this population during anesthesia with fentanyl or its LCGU in the subcortical limbic system (hippocam- analogues alone. pus, amygdala, claustrum) (154,155), an area rich in Abnormal motor activity resembling epileptic con- opioid receptors. In humans, subcortical seizures are vulsions has occurred in the absence of cortical sei- not detected by surface EEG leads, and EEG studies zure activity on simultaneous EEG recordings made with depth electrodes are required to confirm or during low-dose (500-600 pg, IV) fentanyl (132,142) reject the hypothesis that fentanyl and sufentanil and sufentanil (1.3 pglkg, IV) (143) administration. cause seizures in humans (155). Yet, seizurelike movements were not observed dur- Fentanyl and its analogues alone have never been ing EEG studies in patients treated with high doses of demonstrated to possess anticonvulsant properties in fentanyl and its analogues. There are several possible either humans or animals. However, during fentanyl explanations for these observations. The abnormal administration with droperidol and N,O (neurolep- movements observed after low-to-moderate doses of tanesthesia), EEG monitoring in epileptic patients did fentanyl or sufentanil could be due to nonepileptic not demonstrate an increase in spiking activity com- myoclonus produced by the interaction of these nar- pared with their baseline EEG studies (53). In a study cotics with opiate receptors leading to blockade of of 104 patients receiving neuroleptanesthesia, no cortical inhibitory pathways. This would allow lower EEG or clinical signs of seizures were observed dur- CNS centers in the brainstem and/or spinal cord to ing or after neuroradiologic examinations with in- display altered excitability (4,142). Patients treated trathecal metrizamide, a known convulsant (141). As with higher doses of fentanyl and its analogues may suggested by DeCastro et al. (8), these findings have failed to exhibit these seizurelike myoclonic appear to indicate that droperidol may offer some movements because the plasma opioid levels were protection against narcotic-induced neuroexcitation. high enough to depress both higher and lower CNS Whether the seizurelike movements reported dur- centers. In one report, nonepileptic myoclonus was ing clinical administration of fentanyl and its ana- probably responsible for the seizurelike motor activ- logues originate from epileptogenic or nonepilepto- ity observed after recovery from low-dose fentanyl genic mechanisms is unclear. All currently available 312 ANESTH ANAL C; MODICA ET AL. 1990:70:30515

clinical and EEG evidence appears to favor either neuropharmacology of anesthesia. Neuropharmacology 1972; nonepileptic myoclonus or exaggerated rigidity as the 11:30?-15. 7. Winters WD. Epilepsy or anesthesia with ketamine (editori- most likely explanation. However, further studies al). Anesthesiology 1972;36:309-12. regarding the neurochemical mechanisms of narcotic- 8. DeCastro J, van de Water A, Wouters L, Xhonneux R, induced rigidity and the effects of progressively Reneman R, Kay B. Comparative study of cardiovascular, higher doses of fentanyl and its analogues on electri- neurological, and metabolic side effects of eight narcotics in cal activity in the limbic system are needed. dogs. Acta Anaesthesiol Belg 1979;30:6-99. 9. Fisher MMcD. Use of ketamine hydrochloride in the treatment of convulsions. Anaesth Intensive Care 1974;2:266-8. 10. Davis RW, Tolstoshev GC. Ketamine use in severe febrile Summary convulsions (letter). Med J Aust 1976;2:465-6. 11. Gumpert J, Paul R. Activation of the electroencephalogram Many inhaled anesthetics and intravenous analgesics with intravenous Brietal (methohexitone): the findings in 100 have been alleged to produce both proconvulsant and cases. J Neurol Neurosurg Psychiatry 1971;34:646-8. 12. Paul R, Harris R. A comparison of methohexitone and thio- anticonvulsant activity in humans (Table 1). The pentone in electrocorticography. J Neurol Neurosurg Psychi- reasons for these contrasting actions on the CNS are atry 1970;33:10W. poorly understood at the present time. However, 13. Rao TLK, Mummaneni N, El-Etr AA. Convulsions: an un- biologic variability plays an important role in deter- usual response to intravenous fentanyl administration. mining individual patient’s responses to anesthetic Anesth Analg 1982;61:102C-l. 14. Safwat AM, Daniel D. Grand ma1 seizure after fentanyl and analgesic drugs. In addition, variations in the administration (letter). Anesthesiology 1983;59:78. responsiveness of inhibitory and excitatory neurons 15. Hoien AO. Another case of grand ma1 seizure after fentanyl to the central depressant effects of these drugs could administration (letter). Anesthesiology 1984;60:387-8. also explain these apparently conflicting data. De- 16. Ferrer-Allado T, Brechner VL, Dymond A, Cozen H, Crandall pending on the brain concentration, centrally active P. Ketamine-induced electroconvulsive phenomena in the human limbic and thalamic regions. Anesthesiology 1973;38: drugs may produce differing effects on the CNS 333-44. inhibitory and excitatory neurotransmitter systems. 17. Virtue RW, Lund LO, Phelps M Jr, Vogel JHK, Beckwitt H, The availability of increasingly powerful magnetic Heron M. Difluoro-methyl 1,1,2-trifluoro-2-chloroethylether resonance imaging techniques to provide noninva- as an anesthetic agent: results with dogs, and a preliminary note on observations in man. Can Anaesth SOCJ 1966;13:233- sive information about tissue chemistry (e.g., neuro- 41. transmitters and citric acid cycle metabolites) and 18. Botty C, Brown B, Stanley V, Stephan CR. Clinical experi- positron emission tomography to noninvasively eval- ences with compound 347, a halogenated anesthetic agent. uate CNS drug-receptor interactions should lead to a Anesth Analg 1968;47:477-505. more in-depth understanding of the in vivo effects of 19. Lebowitz MH, Blitt CD, Dillon JB, Clinical investigation of anesthetics and analgesics on the CNS. compound 347 (Ethrane). Anesth Analg 1970;49:1-10. In the second part of this review article, we discuss 20. Bart A], Homi J, Linde HW. Changes in power spectra of electroencephalograms during anesthesia with fluroxene, the pro- and anticonvulsant effects of the sedative- methoxyflurane and Ethrane. Anesth Analg 1971;50:5343. hypnotics, local anesthetics, and other anesthetic 21. Wollman H, Smith AL, Hoffman JC. 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