Voss, Logan J. PhD*; Sleigh, James W. MD*; Barnard, John P. M. MBChB*; Kirsch, Heidi E. MD†
Depending on the clinical context, many anesthetic drugs are both pro- and anticonvulsants. However, anesthetic drug-induced clinically apparent seizures are rare, and the formal epidemiological study of this phenomenon is difficult. The fact that neurodepressant drugs can trigger seizures raises some intriguing questions. How can the brain be simultaneously quiescent yet hyperexcitable? What is the context in which drug-induced seizures may occur? Are these seizures clinically important in anesthesia practice? Which anesthetic drugs should be avoided in epileptic patients?
There are significant difficulties with the classification of seizure-like phenomena. Indeed, there is still much disagreement among epileptologists as to the proper description of seizure states. In this article we have followed the definitions proposed by the International League Against Epilepsy and the International Bureau for Epilepsy (Table 1 and following section on incidence of seizures).1 A seizure is characterized by “episodes of abnormal enhanced synchrony in neuronal activity.” We therefore reserve the term “seizure” for clinically manifest events that have a corroborative electroencephalographic (EEG) diagnosis. In contrast, a convulsion is primarily a clinical diagnosis made on the basis of typical movements or patterns of behavior. We term small areas (<1 cm2) of neuronal hypersynchrony as “epileptiform activity.” These are more easily detected on cortical, rather than scalp, brainwave recordings (electrocorticography [ECoG]) and manifest as “spikes” (20–70 msec duration transients which are clearly greater in amplitude than the background activity), or as focal runs of low-voltage fast activity. Because of the small area of cortex involved, these are usually clinically silent. Anesthetic drugs quite commonly induce epileptiform activity, yet they rarely induce seizures. This paradox reflects the complexity and independence of the processes involved in the initiation and spread of seizures. There is a weak association between epileptiform spikes and the development of clinically significant seizures.2,3 An epileptiform spike is thought to be an indicator of the presence of an incipiently unstable neocortex.4
Seizures occur when cortical activity changes from its typical mode of independent and dynamically reactive activity to overwhelming synchronous oscillations in populations of neurons. An electronic analogy of this change is a malfunction in an amplifier feedback loop allowing a circuit to oscillate. Once triggered, the oscillation dominates the circuit’s output and it is described as “howling.”5 It is likely that specific disturbances of neuronal feedback loops explain how some neurodepressant general anesthetic drugs can induce seizures even when net cortical excitation is not increased. Interestingly, there are other physiological states associated with a high degree of neuronal synchrony (e.g., sleep spindles), and it is conceivable that a seizure may sometimes arise from an exaggeration of these states.
Seventeen years ago Modica et al.6,7 published two articles in which they systematically collated published evidence about anesthetic drug-induced convulsions. Since then, anesthetic and neurological practice has changed, and the neuroscience of seizure mechanisms has made some advances. Building on Modica et al.'s work, we will briefly review the relationship between general anesthetics, electrical seizures and convulsions, then discuss some current neurobiological concepts with particular reference to volatile anesthetics, etomidate, and sleep, before finally returning to the clinical arena to draw some tentative conclusions. We do not review local anesthetics. Potentially, the seizurogenic potential of each major anesthetic drug class could justify a review article in itself. We have deliberately focused our mechanistic discussion on those general anesthetics for which there is unequivocal documentation of seizurogenic potential, namely enflurane, sevoflurane and etomidate. In so doing, we have attempted to bridge the gap between clinical epidemiology and current understanding of the neurophysiology of seizures in anesthesia. However, it must be acknowledged that our present understanding of both seizure pathogenesis and the clinical applications is very fragmentary, and often conflicting and confusing.
EPIDEMIOLOGY OF ANESTHESIA- ASSOCIATED SEIZURES
The Incidence of Anesthesia-Related Seizures
No anesthetic drugs have a clear dose-response with respect to seizures and most of them have been used successfully to treat status epilepticus. However there are hundreds of reports documenting convulsions during or shortly after general anesthesia, implicating most anesthetics as being occasionally proconvulsant.8–11 These reports highlight the many idiosyncratic pro-convulsive effects of anesthetics, which are difficult to distinguish from the, more reproducible, epileptiform EEG effects. Adding to this morass is the variability of anesthetic seizurogenic effects from individual to individual.12 Furthermore, most of these reports are based solely on clinical records of suspicious muscle activity (e.g., rhythmic twitching of a limb or of the face) without EEG documentation, and with subjective judgment as to the primary cause of the activity. The purely clinical diagnosis of seizures is often erroneous. In the absence of EEG monitoring, a number of nonseizure-related movements could mimic seizures (e.g., myoclonus, dystonic reactions, extreme shivering). Clearly, abnormal movements during induction are a poor indicator of EEG seizure activity.9,13–15 Conversely, if motor pathways are not involved, cortical seizure activity may be present without any abnormal movement, (e.g., nonconvulsive, partial sensory or psychic seizures in an unconscious patient, or generalized seizures in a patient with full neuromuscular blockade). Given the significant incidence of seizure-like phenomena, a good case could be made for routine peri- and intraoperative EEG monitoring in high-risk groups. However, there is further potential for error, because the scalp EEG itself may miss many brief or spatially limited epileptiform events that might be detectable only with cortical surface electrodes (ECoG) or depth electrodes.16,17 Similar focal episodes of hypersynchrony may occur in subcortical structures, even causing abnormal movements, but again the EEG would be blind to this activity. Thus there is a significant lack of both specificity and sensitivity in detecting true seizures in the operating room (Table 1).
If the requirement for clear EEG evidence is applied, a limited number of anesthetic drugs have proven seizurogenic effects. Reviews by Modica et al.6,7 identified enflurane, etomidate, and local anesthetics as the only drugs with documented EEG evidence of seizurogenic activity in nonepileptic individuals. With the inclusion of more recent data, sevoflurane can be indisputably added, while there remains some uncertainty about opioids, ketamine and propofol.
The incidence of abnormal movements during induction or recovery with sevoflurane has been reported to be about 5%.9 True epileptiform activity (Table 1 for a classification) with sevoflurane anesthesia has been extensively investigated. In 2005, Constant et al.9 published a review of 30 studies which had investigated sevoflurane and epileptiform EEG changes and/or seizure-like movements in both epileptic patients and normal patients. A variable incidence was reported (0%–100%). Deep sevoflurane anesthesia and/or hyperventilation are risk factors. These authors recommended that hypocapnia be avoided and the dose of sevoflurane limited to <1.5 minimum alveolar anesthetic concentration (MAC) during maintenance of anesthesia by the use of adjunctive drugs (either opioids, benzodiazepines, or nitrous oxide) and routine EEG monitoring.
Ketamine may induce subcortical epileptiform activity, and in clinical use it is commonly associated with bizarre movements and posturing.10 However, there are controversial and conflicting data, and ketamine is probably a better anticonvulsant than proconvulsant6,18–20 particularly when co-administered with γ-amino-butyric acid (GABA)ergic drugs. Many intensivists would consider using ketamine as a N-methyl d-aspartate (NMDA)-blocking adjunct when managing status epilepticus.21–24 Theoretically, NMDA blockade of calcium entry into the neurons should be useful in control of seizures and in limiting resultant neurotoxicity, and in vitro NMDA blockade consistently ameliorates seizure-like events.25,26
Whether propofol is always anticonvulsant is not clear.27,28 Theoretically, propofol should be strongly anticonvulsant, as it exhibits both GABAergic effects and persistent sodium current and calcium current blockade.29 However, a literature search of “propofol-associated tonic-clonic seizures” retrieved more than 500 case reports, of which 81 were analyzed in more detail.8 The denominator is missing from these case reports, and hence the true incidence is unknown. In the Thai Anesthetics Incidents Study,30 the detection of seizures relied on the presence of clonic motor activity and subjective clinical judgment to determine the actual cause of the convulsions. Among the 172,592 anesthetics analyzed there were 53 generalized convulsions, of which 16 were thought to be primarily due to anesthesia. Fifteen of these cases were attributed to local anesthetic drug error, anti-epileptic drug withdrawal or cerebral anoxia/hypercarbia. This left a single case where the seizure was thought to be due to the anesthetic, propofol, an incidence of 1 per 172,592 anesthetics.
Potent mu opioid receptor agonists can induce epileptiform activity31 and seizures in both nonepileptic and epileptic patients.32–34 Postulated neuronal mechanisms of seizure induction include opioid-induced disinhibition of GABAergic inteneurons35 and inhibition of hyperpolarization-activated potassium currents.36 The ability to maintain or increase epileptiform activity has led to the routine use of mu agonists as a significant part of anesthesia for epilepsy surgery. Modest doses of these drugs used in combination with propofol to provide anesthesia for electroconvulsive therapy result in lower stimulus amplitude and longer seizures compared to the same dose of propofol alone.37–39 However, mu opioid-induced neocortical seizures, as evidenced by EEG changes, are rare, and in a number of animal models mu agonists are anticonvulsant.40–42 Further, many of the published case histories linking opioids to seizures represent opioid-induced myoclonus and rigidity rather than true seizures.43,44
Most experimental work has emphasized that opioid-induced seizures originate in deep structures (limbic and mesencephalic areas or medial temporal lobes) and hence are not easily seen on the conventional scalp EEG.34,45 The relationship between myoclonus or rigidity, subcortical seizure activity and cortical seizures is not clear. All strong mu agonists can cause myoclonus after an IV bolus, and there is some evidence that the rapid-onset opioids are the worst culprits.44 Drug-induced myoclonus would be a worthy topic for review in its own right. The myclonic effect of an opioid is drug and dose-specific,40,41,46–49 it is also grossly modified by the co-administered drugs42,50,51 and, interestingly, the timing of the administration with respect to a coincident convulsion.52,53
Work in humans with reading-induced seizures54 and temporal lobe epilepsy55 has provided corroborative evidence of the anticonvulsant role of endogenous opioid peptides. The kappa ligand dynorphin is thought to be the principal anticonvulsant peptide involved.56,57 In 1953, Landolt published a case history of a patient with schizophrenia and epilepsy. This patient’s psychosis worsened as their epileptiform EEG activity disappeared. In their fascinating review, Bortolato and Solbrig56 uses this case history to introduce the concept of an anticonvulsant but pro-psychosis role for the endogenous kappa opioid receptor agonist, dynorphin.
Much of the early animal work used opioid doses orders of magnitude larger than those given in routine clinical practice.58 Frenk et al.59 used a dose of 300 mg/kg of morphine in rats. In this study, although the initial epileptiform activity was lessened by the co-administration of the opioid antagonist, naltrexone, the subsequent seizures were enhanced. At the other end of the dose scale are the localized microinjection studies. An example is the study by Cain and Corcoran. Injecting a mu opioid at two different sites within the amygdala generated virtually opposite responses.60 In essence, the seizurogenic potential of exogenously applied opioids is difficult to predict, and will be grossly attenuated by the prior administration of a benzodiazepine.50 Fentanyl may protect the patient against sevoflurane-induced seizures.42
The Clinical Significance of Seizure Activity
Do seizures have any long-term adverse neurophysiological effects? This question is controversial. One extreme view is that seizure activity is a protective mechanism that has been conserved through evolution, and that its prevention is unnecessary on the grounds that it does no harm.61 However, there is strong experimental neurobiological evidence of seizure-induced neuronal damage. Even single brief seizures can cause swelling, apoptosis and excitotoxic cell death, particularly in the hippocampus62–66 and the immature brain.67,68 Animal studies have shown that a seizure event early in development somehow primes the brain for more severe epileptic damage later in life.67,68 In contrast to this experimental evidence, it has been difficult to demonstrate long-term functional behavioral deterioration after single brief seizures in clinical studies.69 Deterioration may occur in some individuals in some circumstances.70 It is conceivable (but completely untested) that subclinical hypersynchronous epileptiform activity could be related to the somewhat idiosyncratic development of postoperative cognitive dysfunction. There is stronger evidence that functional deficits follow repeated and prolonged seizures67,71 and deficits are common after episodes of refractory status epilepticus.72 While there is no convincing evidence from adult human trials that seizures beget seizures in the general population,69,73 this has not been investigated in the specific situation of anesthesia-related seizures in epileptics.
Despite the apparent rarity of anesthetic-induced seizures and lack of evidence of long-term neurological and behavioral defects, the topic remains of some clinical importance. Four distinct clinical scenarios highlight this:
1. There is a greater propensity for anesthetics to induce epileptiform activity in patients with epilepsy than in normal controls.74–76 Not only are anesthetics with known proconvulsant activity, such as enflurane and sevoflurane, hazardous, but even anesthetics that are not reproducibly proconvulsant in the normal brain, such as ketamine, isoflurane and methohexital, can induce seizures in individuals with epilepsy.6,74,77,78
2. Accurate localization of a focus of epileptiform activity is an important prerequisite for successful neurosurgery for intractable epilepsy. If anesthesia suppresses the epileptiform activity, makes the activity more widespread, or causes a sustained seizure, then this localization process will be much more difficult. The seizurogenic effects of enflurane, etomidate, potent opioids and methohexital have been used to facilitate identification of epileptic foci for resection without inducing widespread seizure activity.75,76,79 However, it must be noted that anesthetic drugs might generate seizure activity in nonepileptic brain, thus compromising the accurate localization of the epileptic focus.
3. Anesthesia drug selection and dose used for electroconvulsive therapy will affect both the threshold for seizures and the seizure duration.80,81 Because methohexital is difficult to obtain, there is debate about which induction drug offers the best combination of hemodynamic control and proconvulsant activity. The use of remifentanil appears to be useful, both to augment the seizure and to obtund the resultant cardiovascular stresses.38,39 Somewhat counter-intuitively lidocaine, when given preseizure to limit the hemodynamic response of electroconvulsive therapy, grossly raises the threshold for seizures and decreases seizure duration.82
4. Processed EEG depth of anesthesia monitors are commonly used to guide anesthetic drug dosage. The occurrence of seizure-like activity in the EEG signal will commonly increase, but may decrease, the EEG indices of the currently available monitors (Fig. 1). Unless the anesthesiologist is able to interpret the raw EEG, they will be misled.
During Which Phase of Anesthesia are Proconvulsant Effects Observed
Clinical convulsions largely occur during a different phase of anesthesia as compared with EEG epileptiform activity. Most clinical convulsions occur at the beginning or end of (or even some time after) the anesthetic. In an animal study using cats, Julien and Kavan demonstrated deep cortical electrographic abnormalities persisting for up to 24 days after a single enflurane anesthetic.83 It is likely that the neuropharmacological response to anesthesia persists well into the postoperative period and may explain the phenomenon of seizures occurring late in the recovery period.84–86 There are numerous case reports of convulsion-like muscle activity during induction and emergence from anesthesia with sevoflurane,87–89 enflurane,90–92 etomidate93 and propofol.94 As already discussed, without EEG documentation, classification of many of these events as seizures is difficult. However, some of these convulsions display classical tonic-clonic evolution. It is not clear whether these seizures are due to the disequilibrium created by the rapidly changing anesthetic concentration or, more likely, the fact that there is significant excitatory neuronal activity occurring as the patient is regaining or losing consciousness, in conjunction with some GABAergic anesthetic drug effect.
In contrast to clinical convulsions, high-amplitude nonconvulsive epileptiform discharges can be observed in most subjects during maintenance with high dose (>1.5 MAC) enflurane and sevoflurane9,13,27,95 (Fig. 2 below for examples of ECoG). This may be considered a variation of the burst-suppression EEG pattern commonly seen during very deep anesthesia. Muscle relaxants were not used in most of these studies, so that the lack of convulsive movements is not explained by neuromuscular blockade. Epileptiform activity during deep sevoflurane anesthesia is inhibited by the addition of nitrous oxide to the volatile anesthetic.74 This is further evidence that the combination of NMDA blockade (by nitrous oxide) with GABA augmentation is particularly effective in suppressing seizures.
MECHANISMS OF GENERAL ANESTHESIA-INDUCED SEIZURES
Neurophysiology of Seizures—The Traditional View
An appreciation of the neurophysiology of proconvulsant anesthetic effects provides a rational starting point for clinical management. At the present time there are many data but an absence of basic principles. For neuroscientists, the central nervous system remains a kaleidoscope, complexity increasing in every direction. In our neuropharmacological discussions, we have concentrated on synaptic transmission and the interaction of excitatory and inhibitory neurons in the neocortex. This is likely to be the major site of the proconvulsant effects of anesthetics. We acknowledge that there are a number of other directions that seizure research is taking (e.g., subcortical-cortical interactions,96,97 gap junction transmission,98 congenital ion channel dysregulation,99,100 pharmacogenetics101 and glial cell function102,103), but it remains to be seen whether these will prove to be as important. With the possible exception of gap junctions, we could find no published studies that convincingly describe how anesthetic drugs interact with the above-mentioned neurobiological mechanism to cause or treat seizures. Data suggest a possible role for calcium-dependent glial cell-mediated glutamate release as a unifying mechanism to explain a number of experimental seizure models. It remains to be seen whether anesthetics act through a similar pathway to cause seizures.104,105
The basis of normal brain cortical activity is excitatory neuronal transmission in predominantly glutamatergic pyramidal cells. Pyramidal cell excitation is achieved mostly through recurrent corticothalamic and intracortical excitatory circuits. In a cortex that is functioning normally, activity in these excitatory networks is controlled by multiple subsets of GABAergic interneurons, which provide feedforward, feedback and lateral inhibition. These subpopulations of inhibitory neurons are defined by their morphology and differing propensity to bind to various calcium-binding proteins and neuroactive peptides.106 Dysfunction within each of the subpopulations has very different effects on the dynamics of the cortex and appear to be crucial in seizurogenesis.107 For example, somatostatin containing GABAergic interneurons tend to synapse on the distal pyramidal cell dendrites to control dendritic input and calcium currents, whereas parvalbumin staining GABAergic interneurons synapse at the proximal axonal segment of pyramidal cell and control the pyramidal cell output. Calretinin-expressing double bouquet cells synapse with other GABAergic interneurons, thus “inhibiting the inhibitors” to some extent.108 Some of the possible interactions between neuronal subpopulations are shown diagrammatically in Figure 3. The possible importance of these differences is explained in subsequent sections of this article.
The traditional explanation is that seizure activity results from an imbalance in excitation-inhibition in cortical networks.79,109,110 Neuronal inhibition and excitation are commonly thought of as analogous to the brakes and the accelerator in a car. Thus, poor brakes (weak inhibition), and/or too much accelerator (strong excitation) cause loss of control (seizures). In keeping with this “excitation-inhibition balance” hypothesis, the net action of anesthetics is said to depend on the responsiveness of inhibitory and excitatory targets for any given individual.79,110,111 However, as shown in Table 2, there are numerous neuronal “brakes” and “accelerators,” and there is the conundrum presented by the fact that anesthetics may be both pro and anticonvulsant. This is further complicated by the fact that at an anesthetic drug may be a “brake” at one concentration and an “accelerator” at another. There is clearly a need for a better explanation than a simple “accountant-style” summation of neurological brakes versus accelerators.
Neurophysiology of Seizures—The Role of Inhibition
There is now a growing body of experimental work suggesting that a functioning inhibitory system is a necessary requirement for seizure generation.107 Seizures are therefore not caused simply by “too much excitation,” but rather by excitation applied to a mass of neurons that are primed to react to the excitation by going into an oscillatory seizure state. Surprisingly, increased inhibition is one of the important ways to prime these neuronal populations.
Natural sleep is an example of a state of heightened inhibition and generalized cortical hyperpolarization.112 It shares some neurophysiological processes with anesthesia, such as heightened synchrony in thalamocortical networks. Some forms of epileptic seizures, especially partial seizures, occur more commonly both after a period of sleep deprivation, and during sleep,113 with a much greater frequency during nonrapid eye movement sleep compared with rapid eye movement sleep. The heightened synchrony of slow wave sleep should facilitate the transition from epileptiform activity to seizure113,114 and implicates a central role for thalamocortical synchronizing mechanisms in seizure propagation.115 Given the neurophysiological overlap between sleep and anesthesia, particularly at the thalamocortical level,116,117 it seems reasonable to speculate that the mechanisms underlying sleep-related facilitation of seizure activity may also contribute to anesthesia-induced seizures. In a series of animal experiments and theoretical models, Timofeev and Steriade investigated the neural mechanisms that account for spike-wave seizures. These develop progressively from the EEG waveforms of natural sleep.118 They suggest that seizure activity can be induced when the cerebral cortex is in a GABAergic state because quiescence induces a state of cortical hyper-excitability.
In the following sections, we explore some examples of putative mechanisms by which inhibitory neurophysiological and pharmacological mechanisms might induce seizures. These mechanisms are not mutually exclusive. We have used the seizurogenic effects of enflurane and etomidate as examples because the neurophysiological effects of these drugs are relatively well studied. In summary, the mechanisms could be:
Prolongation of inhibitory feedback loops (enflurane). This will be discussed in relation to quantitative mathematical modeling of enflurane’s effects on neocortical activity.
Preferential inhibition of inhibitory neurons due to the distribution of GABAA receptor subtypes among interneuron populations (etomidate). This hypothesis has been criticized by Bernard et al.119
Alteration of cellular pumps controlling the extracellular-intracellular chloride concentrations may cause the GABAA/Cl channel to become excitatory.
Quantitative Modeling of Enflurane Seizures: Prolonged Inhibitory Postsynaptic Potential (IPSP) Plus Excitation
A major weakness of the brake-accelerator model of seizurogenesis is that it does not consider the properties of a network being more than the sum of the properties of the individual interacting neurons. Indeed, the properties of a complex network may become almost independent of the properties of its elements. It is possible to describe the dynamics of the interactions between populations of inhibitory and excitatory neurons in terms of theoretical mathematical models120–123 which consist of systems of equations describing synaptic dynamics, neuronal excitability, connectivity, and delays. The parameters in the equations may be altered to simulate disease states and drug effects. Although there are undoubtedly many second-order features of brain function that are not captured by these models, their “pseudoEEG” output shows behavior that is in quantitative agreement with changes that are observed in real EEGs during seizures and anesthesia. In these models, the transition to seizures arises from the dynamics of the interaction between populations of neurons. The appeal of using these models is that the transition to a seizure state involves a search for particular changes in the stability of the output from sets of equations using standard methods of mathematics (e.g., eigenvalues).
If we compare the known neuronal actions of enflurane and isoflurane (as examples of a proconvulsant and nonconvulsant anesthetic), we find a complex mix of both excitatory and inhibitory actions for both anesthetics. As shown in Table 3, these actions are common to both drugs, and therefore do not explain why isoflurane is usually anticonvulsant,124 whereas enflurane has some proconvulsant effects. The main point of difference between enflurane and isoflurane is the degree of prolongation of the IPSP. This has been modeled by Wilson et al. and Liley and Bojak,121,123 who have shown the importance of the delay in inhibitory circuits in destabilizing the cortex into an oscillatory seizure-like state.
Figure 4 is a diagram demonstrating how the pseudoEEG from Wilson et al.'s model changes in response to altering these three synaptic-function parameters:
1. The “strength” of inhibitory effect (i.e., the area under the IPSP).
2. The “strength” of excitatory effect (i.e., the amplitude of the excitatory postsynaptic potential).
3. The time course of inhibitory effect (IPSP time constant).
The black areas are the regions of inhibitory and excitatory parameter values in which the model shows oscillatory seizure-like activity. The three diagrams show that, as the IPSP time course is prolonged (left < middle < right diagram), the black seizure area grows. Thus the amount of excitatory activity (vertical axis) required to initiate seizures decreases as the IPSP time course is prolonged (i.e., the black area in the right-hand diagram is bigger and lower than in the left-hand diagram). One MAC of each drug is associated with a relative increase in IPSP amplitude (horizontal axis) of a factor of about 1.5–2-fold.125 For isoflurane, this is associated with a modest increase in the time course of the IPSP. Thus at 1 MAC for isoflurane, a lot of excitation is required before the cortex will enter the seizure area (middle diagram in Fig. 4). In contrast, an equivalent dose of enflurane markedly prolongs the IPSP time course (third diagram in Fig. 4), and therefore a cortex with 1 MAC enflurane requires only a small amount of excitatory activity to enter the seizure area.
The oscillating (howling) electrical circuit requires both an increased amount, and slowing, of inhibition with some residual excitation. It is likely that the howling cortex requires the same. These are exactly the sorts of effects induced by volatile general anesthetic drugs (Table 2). Although this explanation of the seizurogenic activity of enflurane is very plausible, it remains to be seen whether it is correct. There is other corroborative evidence for this “inhibitory-delay” theory for seizure initiation. IPSPs, measured in brain tissue extracted from epileptic patients are longer than those from a normal control group.126 IPSP duration is also lengthened by increases in extracellular potassium,127 which occurs subsequent to GABAA and possibly also GABAB stimulation.128 Furthermore, the GABAB receptor agonist baclofen has significant pro-seizure effects,129 possibly exacerbated when combined with propofol.130
Etomidate Seizures: GABAergic Synaptic Excitation, or Interneuron Subpopulation Specificity?
The seizurogenic effects of etomidate seem to have a different origin from those of enflurane. The EEGs produced by the two drugs are very different in pattern.131–135 Unlike enflurane, which has numerous mechanisms of action, etomidate acts almost purely on β2 and β3 subunits of GABAA receptors and is probably the “cleanest” general anesthetic drug available at present.132,136 There is no evidence of direct induction of neuronal excitation via either synaptic or intrinsic actions. It is unclear whether etomidate excessively prolongs the IPSP.137 We speculate that etomidate may be “too clean.” Its extreme selectivity may be the problem. There are at least two other possible explanations for the proconvulsant effects of etomidate.
Etomidate “inhibits the inhibitory neurons,” i.e., it induces excessive GABAergic activity in one sub-population of interneurons that control the second population of interneurons that then inhibit the excitatory pyramidal cells.107,108 This difference in effect may be exaggerated at different doses of etomidate. The proposal is shown diagrammatically in Figure 3. If the GABAA β2 subunits were more prevalent in interneuron types that themselves targeted the interneurons (which directly inhibit the excitatory cortical pyramidal cells), Wilson et al.'s model would predict an increase in seizure propensity with etomidate due to excitatory activity being allowed to propagate. The localization of specific GABAA receptor subunits to the different populations of interneuron subtypes has been reviewed by Sieghart and Sperk.138 Our understanding of the implications on cortical dynamics of subtle changes in the activity of the many different types on interneurons is still very incomplete. However in two animal models of epilepsy, Nishimura et al. 139 showed differential patterns of expression of β2 and β3 GABAA subunits, as compared with α, γ, and δ subunits. Clearly there is a delicate balance in the normal brain. GABAA receptors containing β2 subunits seem to be preferentially located on GABAergic interneurons,140,141 and excessive activation of these receptors could cause disinhibition of cortical activity and, hence, seizures. Conversely, interneurons that directly project onto pyramidal neurons have a predominance of β3 subunits, and knockout mice, in which these subunits are inactive, are epileptic.142 It is conceivable (but untested) that a small percentage of the patient population has a genetic polymorphism that alters the relative potency of etomidate’s (or perhaps even propofol) action on β3 vs β2 receptors, and hence renders these patients susceptible to etomidate (or propofol)-induced seizures.
In contrast to etomidate’s β2 and β3 subunit sites of action, benzodiazepines act on mainly α GABAA subunits, and are strongly anticonvulsant. As previously mentioned, a similar mechanism of disinhibition may account for some of the seizurogenic effects of opioids.143,144
An alternative explanation of etomidate’s proconvulsant tendencies is that GABA itself may be excitatory in some contexts.145,146 The simple view of GABAergic synapses as purely inhibitory is not correct, and the intense GABAergic effects of etomidate may therefore have an excitatory effect. When open, GABAA receptors allow passage of chloride and bicarbonate ions in a ratio of 4:1. A cortical neuron will have a resting membrane potential of around −60 mV. The reversal potential of chloride is −70 mV and that for bicarbonate is about −10 mV. GABAA receptor opening will lead to an efflux of bicarbonate and influx of chloride. If the chloride movement dominates, the net effect will be inhibitory (Fig. 5a). However, the value of −70 mV is close to the resting membrane potential, so relatively small changes in the intracellular:extracellular distribution of chloride (or in the resting membrane potential) will result in a net excitatory effect.147,148 The concentration of intracellular chloride is controlled by a number of ion transporters, one of the most significant being the KCC2 potassium-chloride cotransporter. Maldistribution of the KCC2 cotransporter has been found in the resected cortical tissue from epileptics149 and the under-expression of this co-transporter is associated with a seizurogenic phenotype in animal studies.150 Failure of this cotransporter, as in immature neurons,151 would favor high intracellular chloride concentrations and an excitatory response to GABAA receptor opening149 (Fig. 5b). Whether etomidate directly blocks KCC2 is unknown, but unlikely. In fact, the one study that evaluated the effect of general anesthetic drugs on KCC2 has shown an enhancement of KCC2 activity,152 which may contribute to an anticonvulsant effect. However, in vivo, GABAergic activity results in localized extracellular hyperkalemia.128 This would inhibit KCC2 activity on the basis of its dependency on the transmembrane potassium gradient151 and also prolongs the IPSP,127 thus invoking both the “excitatory GABA” and “inhibitory delay” mechanisms of seizurogenesis.
Anesthesia-induced seizures are rare, and the underlying basic neurophysiological principles remain mysterious. Clinical recommendations therefore must remain speculative at this stage. Nevertheless some provisional conclusions can be drawn.
1. There is a growing body of experimental work suggesting that seizures are not caused simply by “too much excitation,” but rather by excitation applied to a mass of neurons which are primed to react to the excitation by going into an oscillatory seizure state. Increased inhibition can sensitize the cortex, so that only a small amount of excitation is required to cause seizures.
2. Some anesthetic drugs (enflurane, sevoflurane, and etomidate) induce epileptiform EEG activity commonly, and therefore EEG monitoring should be considered when using these drugs. Under largely unknown conditions, these patterns can progress to full-blown seizures. Of particular interest clinically is the propensity of even “nonconvulsant” anesthetic drugs to be associated with seizures in subjects with preexisting epilepsy. These seizures most commonly occur during induction or emergence from anesthesia, when the anesthetic drug concentration is relatively low. On the basis of case reports the period of risk extends up to 72 h into the postoperative period.153
3. To prevent perioperative drug-induced seizures in epileptic patients the following should be considered:
a. Continue current anticonvulsants or replace with suitable alternatives if the oral administration route is unavailable.
b. b. %Communicate with the patient’s neurologist to discuss the management of the patient. It is important to be cognizant of mutually detrimental pharmacokinetic drug interactions between antiepileptic drugs and anesthetic drugs.154
c. Avoid etomidate.
d. Sevoflurane should only be used if there is a positive indication of its superiority versus alternative anesthetic techniques. The maximal concentration should be limited to <1.5 MAC, and the use of adjunctive nitrous oxide, opioids, or benzodiazepines strongly recommended.
e. Propofol remains an enigma and its safe use in epileptic patients remains controversial. While there is little conclusive evidence to demonstrate that it causes seizures, a large volume of case report literature clearly links the use of this drug to a wide range of abnormal movements, many of which resemble seizures. Clinicians contemplating the use of this drug in epileptic patients should carefully consider the benefits and risks in light of the availability of other less controversial alternatives (e.g., thiopental, midazolam).
f. Consider prophylaxis with:
I. Adjunctive α-GABAA subunit active drugs (benzodiazepines),50,155
II. Drugs that impair calcium entry into neurons [gabapentin and/or NMDA blockers (xenon, nitrous oxide, ketamine)].155,156
III. Drugs that limit excitatory activity (topiramate)157
g. Use EEG monitoring to detect early signs of cortical instability, and to make reasonable diagnosis of seizures if they occur. Be aware that seizures may falsely elevate EEG indices of depth of anesthesia.
4. To treat perioperative drug-induced seizures in epileptic patients the following should be considered:
a. GABAergic drugs (benzodiazepine, thiopental, phenobarbital). The latter two drugs have the advantage of some anti-α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) activity. Very large doses may be needed.
b. Mixed action drugs (phenytoin, valproate).
c. High MAC volatile anesthetic drug (isoflurane, desflurane, halothane).
d. Specific NMDA antagonism as an adjunct (ketamine, nitrous oxide, xenon, magnesium sulfate).These recommendations are mainly derived from those promulgated for the treatment of status epilepticus.158–160 It is unknown if these treatments are useful in the management of nonseizure abnormal motor activity.
5. Future research should be directed towards furthering our understanding of:
a. The neurophysiological mechanisms underlying anesthetic seizure generation, including:
I. Cortical/subcortical interactions
II. The role of gap junctions in seizure initiation and spread
III. Relationship between sleep- and anesthetic-facilitated seizures
IV. Inhibitory mechanisms in seizure promotion, including GABAergic ion channel subtype distribution
b. The context specificity of these effects, including:
I. Pharmacogenetics of susceptibility
II. The role of ion channel dysregulation in susceptible individuals
III. The role of network organization/ reorganization in susceptible individuals
c. The clinical significance of anesthetic seizures, including:
I. The relationship to delayed wakening from anesthesia, and role in postoperative cognitive dysfunction.
II. Neuroanatomical, functional and behavioral consequences
III. A greater understanding of drug -specific seizure incidence
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