The Howling Cortex: Seizures and General Anesthetic Drugs

Voss, Logan J. PhD*; Sleigh, James W. MD*; Barnard, John P. M. MBChB*; Kirsch, Heidi E. MD†

Anesthesia & Analgesia:
doi: 10.1213/ane.0b013e3181852595
Neurosurgical Anesthesiology and Neuroscience: Review Article

The true incidence of seizures caused by general anesthetic drugs is unknown. Abnormal movements are common during induction of anesthesia, but they may not be indicative of true seizures. Conversely, epileptiform electrocortical activity is commonly induced by enflurane, etomidate, sevoflurane and, to a lesser extent, propofol, but it rarely progresses to generalized tonic-clonic seizures. Even “nonconvulsant” anesthetic drugs occasionally cause 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. There is no unifying neural mechanism of anesthetic drug-related seizurogenesis. However, 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 γ-amino-butyric acid (GABA)ergic inhibition can sensitize the cortex so that only a small amount of excitation is required to cause seizures. This has been postulated to occur 1) at the network level by increasing the propensity for reverberation (e.g., by prolongation of the “inhibitory lag”), or 2) via different effects on subpopulations of interneurons (“inhibiting-the-inhibitors”) or 3) at the synaptic level by changing the chloride reversal potential (“excitatory GABA”). On the basis of applied neuropharmacology, prevention of anesthetic-drug related seizures would include 1) avoiding sevoflurane and etomidate, 2) considering prophylaxis with adjunctive benzodiazepines (α-subunit GABAA agonists), or drugs that impair calcium entry into neurons, and 3) using electroencephalogram monitoring to detect early signs of cortical instability and epileptiform activity. Seizures may falsely elevate electroencephalogram indices of depth of anesthesia.

In Brief

IMPLICATIONS: While anesthetic-induced generalized tonic-clonic convulsions are rare, electroencephalographic seizure-like activity is common and may not be entirely benign. The mechanisms of general anesthetic-induced seizures are poorly understood, but may help explain other counter-intuitive aspects of seizurogenesis.

Author Information

From the *Department of Anesthesia, Waikato Clinical School, University of Auckland, New Zealand; and †Department of Neurology, UCSF, California.

Accepted for publication June 17, 2008.

Supported by Departmental funding only.

Address correspondence and reprint requests to J. W. Sleigh, Department of Anesthesia, Waikato Clinical School, Waikato Hospital, Pembroke St, Hamilton, New Zealand. Address e-mail to

Article Outline

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.

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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.

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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.

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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

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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.

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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

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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.

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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.

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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.

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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:

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Prolongation of inhibitory feedback loops (enflurane). This will be discussed in relation to quantitative mathematical modeling of enflurane’s effects on neocortical activity.

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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

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Alteration of cellular pumps controlling the extracellular-intracellular chloride concentrations may cause the GABAA/Cl channel to become excitatory.

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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

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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.

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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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1.Fisher RS, van Emde Boas W, Blume W, Elger C, Genton P, Lee P, Engel J. Epileptic seizures and epilepsy: definitions proposed by the International League Against Epilepsy (ILAE) and the International Bureau for Epilepsy (IBE). Epilepsia 2005;46:470–2
2.Garcia-Morales I, Garcia MT, Galan-Davila L, Gomez-Escalonilla C, Saiz-Diaz R, Martinez-Salio A, de la Pena P, Tejerina JA. Periodic lateralized epileptiform discharges: etiology, clinical aspects, seizures, and evolution in 130 patients. J Clin Neurophysiol 2002;19:172–7
3.Bromfield EB, Cavazos JE, Sirven JI, eds. An introduction to epilepsy. Mary land: Am Epilepsy Society, 2006
4.Dichter MA. Basic mechanisms of epilepsy: targets for therapeutic intervention. Epilepsia 1997;38:S2–S6
5.Bechhoefer J. Feedback for physicists: a tutorial essay on control. Rev Mod Phys 2006;77:783–836
6.Modica PA, Tempelhoff R, White PF. Pro- and anticonvulsant effects of anesthetics (part 2). Anesth Analg 1990;70:433–44
7.Modica PA, Tempelhoff R, White PF. Pro- and anticonvulsant effects of anesthetics (part 1). Anesth Analg 1990;70:303–15
8.Walder B, Tramer MR, Seeck M. Seizure-like phenomenon and propofol. A systematic review. Neurology 2002;58:1327–32
9.Constant I, Seeman R, Murat I. Sevoflurane and epileptiform EEG changes. Pediatr Anesth 2005;15:266–74
10.Ferrer-Allado T, Brechner VL, Dymond A, Cozen H, Crandall P. Ketamine-induced electroconvulsive phenomena in human limbic and thalamic regions. Anesthesiology 1973;38:333–44
11.Poulton TJ, Ellingson RJ. Seizures associated with the induction of anesthesia with isoflurane. Anesthesiology 1984;61: 471–76
12.Greer M. Anesthesia and seizures. Int Anesthesiol Clin 1968;6:351–9
13.Kaisti KK, Jaaskelainen SK, Rinne JO, Metsahonkala L, Scheinin H. Epileptiform discharges during 2 MAC sevoflurane anesthesia in two healthy volunteers. Anesthesiology 1999;91:1952–5
14.Kammer T, Rehberg B, Menne D, Wartenberg HC, Wenningmann I, Urban BW. Propofol and sevoflurane in subanesthetic concentrations act preferentially on the spinal cord: evidence from multimodal electrophysiological assessment. Anesthesiology 2002;97:1416–25
15.Yli-Hankala A, Vakkuri A, Sarkela M, Lindgren L, Korttila K, Jantti V. Epileptiform electroencephalogram during mask induction of anesthesia with sevoflurane. Anesthesiology 1999; 91:1596–603
16.Torre JLF, Alarcon G, Binnie CD. Generation of scalp discharges in temporal lobe epilepsy as suggested by intraoperative electrocorticographic recordings. J Neurol Neurosurg Psychiatry 1999;67:51–8
17.Dezhong Y. High-resolution EEG mappings: a spherical harmonic spectra theory and simulation results. Clin Neurophysiol 2000;111:81–92
18.Celesia GG, Chen R-C, Bamforth BJ. Effects of ketamine in epilepsy. Neurology 1975;25:169–72
19.Winters WD. Epilepsy or anesthesia with ketamine. J Anesthiol 1972;36:309–12
20.Borris DJ, Bertram EH, Kapur J. Ketamine controls prolonged status epilepticus. Epilepsy Res 2000;42:117–22
21.Kofke WA, Bloom MJ, Van Cott A, Brenner RP. Electrographic tachyphylaxis to etomidate and ketamine used for refractory status epilepticus controlled with isoflurane. J Neurosurg Anesthesiol 1997;9:269–72
22.Mewasingh LD, Sekhara T, Christaens FJ, Dan B. Oral ketamine in paediatric non-convulsive status epilepticus. Seizure 2003;12:483–9
23.Sheth RD, Gidal BE. Refractory status epilepticus: response to ketamine. Neurology 1998;51:1765–6
24.Durham D. Management of status epilepticus. Critical Care Resusc 1999;2:344–53
25.Naish HJ, Marsh WL, Davies JA. Effect of low-affinity NMDA receptor antagonists on electrical activity in mouse cortical slices. Eur J Pharmacol 2002;443:79–83
26.Tancredi V, Hwa GG, Zona C, Brancati A, Avoli M. Low magnesium epileptogenesis in the rat hippocampal slice: electrophysiological and pharmacological features. Brain Res 1990;511:280–90
27.Jaaskelainen SK, Kaisti K, Suni L, Hinkka S, Scheinin H. Sevoflurane is epileptogenic in healthy subjects at surgical levels of anesthesia. Neurology 2003;61:1073–8
28.Sneyd JR. Propofol and epilepsy. Br J Anaesth 1999;82:168–9
29.Martella G, De Persis C, Bonsi P, Natoli S, Cuomo D, Bernardi G, Calabresi P, Pisani A. Inhibition of persistent sodium current fraction and voltage-gated L-type calcium current by propofol in cortical neurons: implications for its antiepileptic activity. Epilepsia 2005;46:624–35
30.Akavipat P, Rungreungvanich M, Lekprasert V, Srisawasdi S. The Thai Anesthesia Incidents Study (THAI Study) of Perioperative Convulsion. J Med Assoc Thai 2005;88:S106–S112
31.Kearse LA, Koski G, Husain MV, Philbin DM, McPeck K. Epileptiform activity during opioid anesthesia. Electroencephalogr Clin Neurophysiol 1993;87:374–9
32.Ross J, Kearse LA, Barlow MK, Houghton KJ, Cosgrove GR. Alfentanil-induced epileptiform activity: a simultaneous surface and depth electroencephalographic study in complex partial epilepsy. Epilepsia 2001;42:220–5
33.Sprung J, Schedewie HK. Apparent focal motor seizure with a jacksonian march induced by fentanyl: a case report and review of the literature. J Clin Anesth 1992;4:139–43
34.Tempelhoff R, Modica PA, Bernardo KL, Edwards I. Fentanyl-induced electrocorticographic seizures in patients with complex partial epilepsy. J Neurosurg 1992;77:201–8
35.Lupica CR. Delta and mu enkephalins inhibit spontaneous GABA-mediated IPSCs via a cyclic AMP-independent mechanism in the rat hippocampus. J Neurosci 1995;15:737–49
36.Svoboda KR, Lupica CR. Opioid inhibition of hippocampal interneurons via modulation of potassium and hyperpolarization-activated cation (Ih) currents. J Neurosci 1998;18:7084–98
37.Akcaboy ZN, Akcaboy EY, YigitbasÅ B, Bayam G, Dikmen B, Gogus N, Dilbaz N. Effects of remifentanil and alfentanil on seizure duration, stimulus amplitudes and recovery parameters during ECT. Acta Anaesthesiol Scand 2005;49:1068–71
38.Recart A, Rawal S, White PF, Byerly S, Thornton L. The effect of remifentanil on seizure duration and acute hemodynamic responses to electroconvulsive therapy. Anesth Analg 2003;96:1047–50
39.Vishne T, Aronov S, Amiaz R, Etchin A, Grunhaus L. Remifentanil supplementation of propofol during electroconvulsive therapy: effect on seizure duration and cardiovascular stability. J ECT 2005;21:235–8
40.Honar H, Riazi K, Homayoun H, Sadeghipour H, Rashidi N, Ebrahimkhani MR, Mirazi N, Dehpour AR. Ultra-low dose naltrexone potentiates the anticonvulsant effect of low dose morphine on clonic seizures. Neuroscience 2004;129:733–42
41.Jackson HC, Nutt DJ. Differential effects of selective mu-, kappa- and delta-opioid antagonists on electroshock seizure threshold in mice. Psychopharmacology (Berl) 1991;103:380–3
42.Koyama S, Makino Y, Tanaka K, Morino M, Nishikawa K, Asada A. Fentanyl administration during sevoflurane anesthesia suppresses spike waves from epileptic focus on electrocorticogram. Masui 2002;51:755–8
43.Murkin JM, Moldenhauer CC, Hug CC Jr., Epstein CM. Absence of seizures during induction of anesthesia with high-dose fentanyl. Anesth Analg 1984;63:489–94
44.Smith NT, Benthuysen JL, Bickford RG, Sanford TJ, Blasco T, Duke PC, Head N, Dec-Silver H. Seizures during opioid anesthetic induction–are they opioid-induced rigidity? Anesthesiology 1989;71:852–62
45.Tommasino C, Maekawa T, Shapiro HM, Keifer-Goodman J, Kohlenberger RW. Fentanyl-induced seizures activate subcortical brain metabolism. Anesthesiology 1984;60:283–90
46.Bausch SB, Garland JP, Yamada J. The delta opioid receptor agonist, SNC80, has complex, dose-dependent effects on pilocarpine-induced seizures in Sprague-Dawley rats. Brain Res 2005;1045:38–44 Castro J, Van de Water A, Wouters L, Xhonneux R, Reneman R, Kay B. Comparative study of cardiovascular, neurological and metabolic side effects of 8 narcotics in dogs. Pethidine, piritramide, morphine, phenoperidine, fentanyl, R 39 209, sufentanil, R 34 995. II. Comparative study on the epileptoid activity of the narcotics used in high and massive doses in curarised and mechanically ventilated dogs. Acta Anaesthesiol Belg 1979;30:55–69
48.Manocha A, Sharma KK, Mediratta PK. On the mechanism of anticonvulsant effect of tramadol in mice. Pharmacol Biochem Behav 2005;82:74–81
49.Saboory E, Derchansky M, Ismaili M, Jahromi SS, Brull R, Carlen PL, El Beheiry H. Mechanisms of morphine enhancement of spontaneous seizure activity. Anesth Analg 2007; 105:1729–35
50.Cervantes M, Antonio-Ocampo A, Ruelas R, Contreras-Gomez A, Chavez-Carrillo I. Effects of diazepam on fentanyl-induced epileptoid EEG activity and increase of multineuronal firing in limbic and mesencephalic brain structures. Arch Med Res 1996;27:495–502
51.Viscomi CM, Bailey PL. Opioid-induced rigidity after intravenous fentanyl. Obstet Gynecol 1997;89:822–4
52.Mansour A, Valenstein ES. Changes in responsiveness to mu and kappa opiates following a series of convulsions. Exp Neurol 1985;90:224–37
53.Tortella FC, Long JB, Holaday JW. Endogenous opioid systems: physiological role in the self-limitation of seizures. Brain Res 1985;332:174–8
54.Koepp MJ, Richardson MP, Brooks DJ, Duncan JS. Focal cortical release of endogenous opoids during reading-induced seizures. Lancet 1998;352:952–5
55.Hammers A, Asselin M-C, Hinz R, Kitchen I, Brooks DJ, Duncan JS, Koepp MJ. Upregulation of opioid receptor binding following spontaneous epileptic seizures. Brain 2007;130:1009–16
56.Bortolato M, Solbrig MV. The price of seizure control: dynorphins in interictal and postictal psychosis. Psychiatry Res 2007;151:139–43
57.Loacker S, Sayyah M, Wittmann W, Herzog H, Schwarzer C. Endogenous dynorphin in epileptogenesis and epilepsy: anticonvulsant net effect via kappa opioid receptors. Brain 2007;130:1017–28
58.Tortella FC, Echevarria E, Robles L, Mosberg HI, Holaday JW. Anticonvulsant effects of mu (DAGO) and delta (DPDPE) enkephalins in rats. Peptides 1988;9:1177–81
59.Frenk H, Liban A, Balamuth R, Urca G. Opiate and non-opiate aspects of morphine induced seizures. Brain Res 1982;253:253–61
60.Cain DP, Corcoran ME. Epileptiform effects of met-enkephalin, beta-endorphin and morphine: kindling of generalized seizures and potentiation of epileptiform effects by handling. Brain Res 1985;338:327–36
61.Doman G, Pelligra R. Ictogenesis: the origin of seizures in humans. A new look at an old theory. Med Hypotheses 2003;60:129–32
62.Towfighi J, Housman C, Brucklacher R, Vannucci RC. Neuropathology of seizures in the immature rabbit. Dev Brain Res 2004;152:143–52
63.Bengzon J, Kokaia Z, Elmer E, Nanobashvili A, Kokaia M, Lindvall O. Apoptosis and proliferation of dentate gyrus neurons after single and intermittent limbic seizures. Proc Natl Acad Sci U S A 1997;94:10432–7
64.Scott RC, King MD, Gadian DG, Neville BG, Connelly A. Hippocampal abnormalities after prolonged febrile convulsion: a longitudinal MRI study. Brain 2003;126:2551–7
65.McNamara JO. The neurobiological basis of epilepsy. Trends Neurosci 1992;15:357–9
66.Weiergraber M, Henry M, Radhakrishnan K, Hescheler J, Schneider T. Hippocampal seizure resistance and reduced neuronal excitotoxicity in mice lacking the Ca 2.3 E/R-type voltage-gated calcium channel. J Neurosci 2007;97:3660–9
67.Koh S, Storey TW, Santos TC, Miam AY, Cole AJ. Early-life seizures in rats increase susceptibility to seizure-induced brain injury in adulthood. Neurology 1999;53:915–21
68.Schmid R, Tandon P, Stafstrom CE, Holmes GL. Effects of neonatal seizures on subsequent seizure-induced brain injury. Neurology 1999;53:1754–61
69.Shinnar S, Hauser WA. Do occasional brief seizures cause detectable clinical consequences. Prog Brain Res 2002;135: 221–35
70.Engel J. So what can we conclude - do seizures damage the brain? Prog Brain Res 2002;135:509–12
71.Ben-Ari Y, Holmes GL. Effects of seizures on developmental processes in the immature brain. Lancet Neurol 2006;5:1055–63
72.Mayer SA, Claassen J, Lokin J, Mendelsohn F, Dennis LJ, Fitzsimmons BF. Refractory status epilepticus: frequency, risk factors, and impact on outcome. Arch Neurol 2002;59:205–10
73.Berg A, Shinnar S. Do seizures beget seizures? An aessment of the clinical evidence in humans. J Clin Neurophysiol 1997; 14:102–10
74.Iijima T, Nakamura Z, Iwao Y, Sankawa H. The epileptogenic properties of the volatile anesthetics sevoflurane and isoflurane in patients with epilepsy. Anesth Analg 2000;91:989–95
75.Flemming DC, Fitzpatrick J, Fariello RG, Duff T, Hellman D, Hoff BH. Diagnostic activation of epileptogenic foci by enflurane. Anesthesiology 1980;52:431–3
76.Musella L, Wilder BJ, Schmidt RP. Electroencephalographic activation with intravenous methohexital in psychomotor epilepsy. Neurology 1971;21:594–602
77.Cheng MA, Tempelhoff R. Anesthesia and epilepsy. Curr Opin Anaesthiol 1999;12:523–8
78.Hisada K, Morioka T, Fukui K, Nishio S, Kuruma T, Irita K, Takahashi S, Fukui M. Effects of sevoflurane and isoflurane on electrocorticographic activities in patients with temporal lobe epilepsy. J Neurosurg Anesthesiol 2001;13:333–7
79.Hufnagel A, Burr W, Elger CE, Nadstawek J, Hefner G. Localization of the epileptic focus during methohexital-induced anesthesia. Epilepsia 1992;33:271–84
80.Datto C, Rai AK, Ilivicky HJ, Caroff SN. Augmentation of seizure induction in electroconvulsive therapy: a clinical reappraisal. J ECT 2002;18:118–25
81.Ding Z, White PF. Anesthesia for electroconvulsive therapy. Anesth Analg 2002;94:1351–64
82.Wajima Z, Yoshikawa T, Shiga AT, Inoue T, Ogawa R. The effects of intravenous lignocaine on haemodynamics and seizure duration during electroconvulsive therapy. Anaesth Intensive Care 2002;30:742–6
83.Julien RM, Kavan EM. Electrographic studies of a new volatile anesthetic agent: enflurane (ethrane). J Pharmacol Exp Ther 1972;183:393–403
84.Burrone J, Murthy VN. Synaptic gain control and homeostasis. Curr Opin Neurobiol 2003;13:560–7
85.Echegoyen J, Neu A, Graber KD, Soltesz I. Homeostatic plasticity studied using in vivo hippocampal activity-blockade: synaptic scaling, intrinsic plasticity and age-dependence. PLoS ONE 2007;2: e700. doi:10.1371/journal.pone. 0000700
86.Trasande AC, Ramirez J-M. Activity deprivation leads to seizures in hippocampal slice cultures: is epilepsy the consequence of homeostatic plasticity? J Clin Neurophysiol 2007;24:154–64
87.Murat I, Constant I. Excitation phenomena during induction and recovery using sevoflurane in paediatric patients. Acta Anaesthesiol Belg 2000;51:229–32
88.Moore JK, Moore EW, Elliott RA, St Leger AS, Payne K, Kerr J. Propofol and halothane versus sevoflurane in paediatric day-case surgery: induction and recovery characteristics. Br J Anaesth 2003;90:461–6
89.Ibrahim AE, Ghoneim MM, Kharasch ED, Epstein RH, Groudine SB, Ebert TJ, Binstock WB, Philip BK, Sevoflurane Sedation Study G. Speed of recovery and side-effect profile of sevoflurane sedation compared with midazolam. Anesthesiology 2001;94:87–94
90.Jenkins J, Milne AC. Convulsive reaction following enflurane anaesthesia. Anaesthesia 1984;39:44–5
91.Parke TJ, Jago RH. Focal seizure following enflurane. Anaesthesia 1992;47:79–80
92.Yazji NS, Seed RF. Convulsive reaction following enflurane anaesthesia. Anaesthesia 1984;39:1249
93.Hansen HC, Drenck NE. Generalised seizures after etomidate anaesthesia. Anaesthesia 1988;43:805–6
94.Sutherland MJ, Burt P. Propofol and seizures. Anaesth Intensive Care 1994;22:733–7
95.Voss LJ, Ludbrook GL, Grant C, Sleigh JW, Barnard JP. Cerebral cortical effects of desflurane in sheep: comparison with isoflurane, sevoflurane and enflurane. Acta Anaesthesiol Scand 2006;50:313–9
96.Laich E, Kuzniecky R, Mountz J, Liu HG, Gilliam F, Bebin M, Faught E, Morawetz R. Supplementary sensorimotor area epilepsy. Seizure localisation, cortical propagation and subcortical activation pathways using ictal SPECT. Brain 1997;120:855–64
97.Norden AD, Blumenfeld H. The role of subcortical structures in human epilepsy. Epilepsy Behav 2002;3:219–31
98.Traub RD, Draguhn A, Whittington MA, Baldeweg T, Bibbig A, Buhl EH, Schmitz D. Axonal gap junctions between principal neurons: a novel source of network oscillations, and perhaps epileptogenesis. Rev Neurosci 2002;13:1–30
99.Klein J, Khera DS, Nersesyan H, Kimchi EY, Waxman SG, Blumenfeld H. Dysregulation of sodium channel expression in cortical neurons in a rodent model of absence epilepsy. Brain Res 2004;1000:102–9
100.Steinlein OK, Noebels JL. Ion channels and epilepsy in man and mouse. Curr Opin Genet Dev 2000;10:286–91
101.Tate SK, Depondt C, Sisodiya SM, Cavalleri GL, Schorge S, Soranzo N, Shorvon SD, Sander JW, Wood NW, Goldstein DB. Genetic predictors of the maximum doses patients receive during clinical use of the antiepileptic drugs carbamazepine and phenytoin. Proc Natl Acad Sci U S A 2005;102:5507–12
102.Heinemann U, Gabriel S, Jauch R, Schulze K, Kivi A, Eilers A, Kovacs R, Lehmann T-N. Alterations in glial cell function in temporal lobe epilepsy. Epilepsia 2000;41:S185–S189
103.Kendal C, Everall I, Polkey C, Al-Sarraj S. Glial cell changes in the white matter in temporal lobe epilepsy. Epilepsy Res 1999;36:43–51
104.Stout C, Charles A. Modulation of intercellular calcium signalling in astrocytes by extracellular calcium and magnesium. Glia 2003;43:265–73
105.Tian G-F, Azmi H, Takano T, Xu Q, Peng W, Lin J, Oberheim N, Lou N, Zielke R, Kang J, Nedergaard M. An astrocyte basis of epilepsy. Nat Med 2005;11:973–81
106.Conde F, Lund JS, Jacobowitz DM, Baimbridge KG, Lewis DA. Local circuit neurons immunoreactive for calretinin, calbindin D-28k or parvalbumin in monkey prefrontal cortex: distribution and morphology. J Comp Neurol 1994;341:95–116
107.Trevelyan AJ, Sussillo D, Yuste R. Feedforward inhibition contributes to the control of epileptiform propagation speed. J Neurosci 2007;27:3383–7
108.Sloviter RS. Permanently altered hippocampal structure, excitability, and inhibition after experimental status epilepticus in the rat: the “dormant basket cell” hypothesis and its possible relevance to temporal lobe epilepsy. Hippocampus 1991; 1:41–66
109. McCormick DA, Contreras D. On the cellular and network bases of epileptic seizures. Annu Rev Physiol 2001;63:815–46
110. Downes H, Perry RS, Ostlund RE, Karler R. A study of the excitatory effects of barbiturates. J Pharmacol Exp Ther 1970;175:692–9
111. Kopjas NN, Jones RT, Bany B, Patrylo PR. Reeler mutant mice exhibit seizures during recovery from isoflurane-induced anesthesia. Epilepsy Res 2006;69:87–91
112. Gottesmann C. GABA mechanisms and sleep. Neuroscience 2002;111:231–9
113. Herman ST, Walczak TS, Bazil CW. Distribution of partial seizures during the sleep-wake cycle. Neurology 2001;56:1453–9
114. St Louis EK. To sleep, perchance to seize: the odd marriage of sleep and epilepsy. Am J Electroneurodiagnostic Technol 2003;43:130–63
115. Kurata J, Nakao S, Murakawa M, Adachi T, Shichino T, Mori K. The cerebral cortex origin of enflurane-induced generalized seizure in cats. Anesth Analg 1994;79:713–18
116. Contreras D, Destexhe A, Sejnowski TJ, Steriade M. Spatiotemporal patterns of spindle oscillations in cortex and thalamus. J Neurosci 1997;17:1179–96
117. Alkire MT, Miller J. General anesthesia and the neural correlates of consciousness. Prog Brain Res 2005;150:229–44
118. Timofeev I, Steriade M. Neocortical seizures: initiation, development and cessation. Neuroscience 2004;123:229–336
119. Bernard C, Esclapez M, Hirsch JC, Ben-Ari Y. Interneurons are not so dormant in temporal lobe epilepsy: a critical reappraisal of the dormant basket cell hypothesis. Epilepsy Res 1998; 32:93–103
120. Breakspear M, Roberts JA, Terry JR, Rodrigues S, Mahant N, Robinson PA. A unifying explanation of primary generalized seizures through nonlinear brain modeling and bifurcation analysis. Cereb Cortex 2006;16:1296–313
121. Liley DT, Bojak I. Understanding the transition to seizure by modeling the epileptiform activity of general anesthetic agents. J Clin Neurophysiol 2005;22:300–13
122. Robinson PA, Rennie CJ, Rowe DL. Dynamics of large-scale brain activity in normal arousal states and epileptic seizures. Phys Rev E Stat Nonlin Soft Matter Phys 2002;65:041924
123. Wilson MT, Sleigh JW, Steyn-Ross DA, Steyn-Ross ML. General anesthetic-induced seizures can be explained by a mean-field model of cortical dynamics. Anesthesiology 2006;104: 588–93
124. Kofke WA, Young RS, Davis P, Woelfel SK, Gray L, Johnson D, Gelb A, Meeke R, Warner DS, Pearson KS. Isoflurane for refractory status epilepticus: a clinical series. Anesthesiology 1989;71:653–9
125. Banks MI, Pearce RA. Dual actions of volatile anesthetics on GABA(A) IPSCs: dissociation of blocking and prolonging effects. Anesthesiology 1999;90:120–34
126. Rajasekaran K, Kapur J, Bertram EH. Alterations in GABA-A receptor mediated inhibition in adjacent dorsal midline thalamic nuclei in a rat model of chronic limbic epilepsy. J Neurophysiol 2007;98:2501–8
127. Jensen MS, Cherubini E, Yaari Y. Opponent effects of potassium on GABA-A-mediated postsynaptic inhibition in the rat hippocampus. J Neurophysiol 1993;69:764–71
128. Barolet AW, Morris ME. Changes in extracellular potassium evoked by GABA, THIP and baclofen in the guinea-pig hippocampal slice. Exp Brain Res 1991;84:591–8
129. Motalli R, Louvel J, Tancredi V, Kurcewicz I, Wan-Chow-Wah D, Pumain R, Avoli M. GABA-B receptor activation promotes seizure activity in the juvenile rat hippocampus. J Neurophysiol 1999;82:638–47
130. Manikandan S, Sinha PK, Neema PK, Rathod RC. Severe seizures during propofol induction in a patient with syringomyelia receiving baclofen. Anesth Analg 2005;100:1468–9
131. Hill-Venning C, Belelli D, Peters JA, Lambert JJ. Subunit-dependent interaction of the general anaesthetic etomidate with the gamma-aminobutyric acid type A receptor. Br J Pharmacol 1997;120:749–56
132. O’Meara GF, Newman RJ, Fradley RL, Dawson GR, Reynolds DS. The GABA-A beta3 subunit mediates anaesthesia induced by etomidate. Neuroreport 2004;15:1653–6
133. Zhan R-Z, Qi S, Wu C, Fujihara H, Taga K, Shimoji K. Intravenous anesthetics differentially reduce neurotransmission damage caused by oxygen-glucose deprivation in rat hippocampal slices in correlation with N-ethyl-D-aspartate receptor inhibition. Crit Care Med 2001;29:808–13
134. Yamakura T, Lewohl JM, Harris A. Differential effects of general anesthetics on G protein-coupled inwardly rectifying and other potassium channels. Anesthesiology 2001;95:144–53
135. Zhang Y, Laster MJ, Eger EI II, Sharma M, Sonner JM. Blockade of acetylcholine receptors does not change the dose of etomidate required to produce immobility in rats. Anesth Analg 2007; 104:850–2
136. Reynolds DS, Rosahl TW, Cirone J, O’Meara GF, Haythornthwaite A, Newman RJ, Myers J, Sur C, Howell O, Rutter AR, Atack J, Macaulay AJ, Hadingham KL, Hutson PH, Belelli D, Lambert JJ, Dawson GR, McKernan R, Whiting PJ, Wafford KA. Sedation and anesthesia mediated by distinct GABA(A) receptor isoforms. J Neurosci 2003;23:8608–17
137. Proctor WR, Mynlieff M, Dunwiddie TV. Facilitatory action of etomidate and pentobarbital on recurrent inhibition in rat hippocampal pyramidal neurons. J Neurosci 1986;6:3161–8
138. Sieghart W, Sperk G. Subunit composition, distribution and function of GABA(A) receptor subtypes. Curr Top Med Chem 2002;2:795–816
139. Nishimura T, Schwarzer C, Gasser E, Kato N, Vezzani A, Sperk G. Altered expression of GABA(A) and GABA(B) receptor subunit mRNAs in the hippocampus after kindling and electrically induced status epilepticus. Neuroscience 2005;134:691–704
140. Bacci A, Huguenard JR, Prince DA. Modulation of neocortical interneurons: extrinsic influences and exercises in self-control. Trends Neurosci 2005;28:602–10
141. Bacci A, Rudolph U, Huguenard JR, Prince DA. Major differences in inhibitory synaptic transmission onto two neocortical interneuron subclasses. J Neurosci 2003;23:9664–74
142. DeLorey TM, Handforth A, Anagnostaras SG, Homanics GE, Minassian BA, Asatourian A, Fanselow MS, Delgado-Escueta A, Ellison GD, Olsen RW. Mice lacking the beta3 subunit of the GABAA receptor have the epilepsy phenotype and many of the behavioral characteristics of Angelman syndrome. J Neurosci 1998;18:8505–14
143. Dunwiddie T, Mueller A, Palmer M, Stewart J, Hoffer B. Electrophysiological interactions of enkephalins with neuronal circuitry in the rat hippocampus. 1. Effects on pyramidal cell activity. Brain Res 1980;184:311–30
144. Zieglgansberger W, French ED, Siggins GR, Bloom FE. Opioid peptides may excite hippocampal pyramidal neurons by inhibiting adjacent inhibitory interneurons. Science 1979;205:415–17
145. Kohling R, Vreugdenhil M, Bracci E, Jefferys JG. Ictal epileptiform activity is facilitated by hippocampal GABAA receptor-mediated oscillations. J Neurosci 2000;20:6820–9
146. Staley KJ, Proctor WR. Modulation of mammalian dendritic GABA(A) receptor function by the kinetics of Cl- and HCO3- transport. J Physiol 1999;519(pt 3):693–712
147. Cossart R, Bernard C, Ben-Ari Y. Multiple facets of GABAergic neurons and synapses: multiple fates of GABA signalling in epilepsies. Trends Neurosci 2005;28:108–15
148. Khalilov I, Holmes GL, Ben-Ari Y. In Vitro formation of a secondary epileptogenic mirror focus by interhippocampal propagation of seizures. Nat Neurosci 2003;6:1079–85
149. Huberfeld G, Wittner L, Clemenceau S, Baulac M, Kaila K, Miles R, Rivera C. Perturbed chloride homeostasis and GABAergic signaling in human temporal lobe epilepsy. J Neurosci 2007;27:9866–73
150. Woo N-S, Lu J, England R, McClellan R, Dufour S, Mount DB, Deutch AY, Lovinger DM, Delpire E. Hyperexcitability and epilepsy associated with disruption of the mouse neuronal-specific K-Cl cotransporter gene. Hippocampus 2002;12:258–68
151. Lu J, Karadsheh M, Delpire E. Developmental regulation of the neuronal-specific isoform of K-Cl cotransporter KCC2 in postnatal rat brains. J Neurobiol 1999;39:558–68
152. Wang W, Wang H, Gong N, Xu TL. Cahnges of K+-Cl- cotransporter (KCC2) and circuit activity in propofol-induced impairment of long-term potentiation in rat hippocampal slices. Brain Res Bull 2006;70:444–9
153. Grant IS. Delayed convulsions following enfluranr anaesthesia. Anaesthesia 1986;41:1024–5
154. Kelso AR, Cock HR. Advances in epilepsy. Br Med Bull 2004;72:135–48
155. Sinz EH, Kofke WA, Garman RH. Phenytoin, midazolam, and naloxone protect against fentanyl-induced brain damage in rats. Anesth Analg 2000;91:1443–9
156. Macleod S, Appleton RE. The new antiepileptic drugs. Arch Dis Child Educ Pract Ed 2007;92:182–8
157. Lyseng-Williamson KA, Yang LP. Topiramate: a review of its use in the treatment of epilepsy. Drugs 2007;67:2231–56
158. Lowenstein DH. Treatment options for status epilepticus. Curr Opin Pharmacol 2005;5:334–9
159. Prasad K, Al-Roomi K, Krishnan PR, Sequeira R. Anticonvulsant therapy for status epilepticus. Cochrane Database Syst Rev 2005;CD003723
160. Walker M. Status epilepticus: an evidence based guide. BMJ 2005;331:673–7
161. McKay IDH, Voss LJ, Sleigh JW, Barnard JP, Johannsen EK. Pharmacokinetic-pharmacodynamics modeling the hypnotic effect of sevoflurane using the spectral entropy of the electroencephalogram. Anesth Analg 2006;102:91–7
162. Kawaguchi Y. Physiological subgroups of nonpyramidal cells with specific morphological characteristics in layer II/III of rat frontal cortex. J Neurosci 1995;15:2638–55
163. Lewis DA, Hashimoto T, Volk DW. Cortical inhibitory neurons and schizophrenia. Nat Rev Neurosci 2005;6:312–24
164. Wang XM, Bausch SB. Effects of distinct classes of N-methyl-D-aspartate receptor antagonists on seizures, axonal sprouting and neuronal loss in vitro: suppression by NR2B-selective antagonists. Neuropharmacology 2004;47:1008–20
165. Hadjiyannakis K, Ogilvie RD, Alloway CE, Shapiro C. FFT analysis of EEG during stage 2-to-REM transitions in narcoleptic patients and normal sleepers. Electroencephalogr Clin Neurophysiol 1997;103:543–53
166. Hendricson AW, Maldve RE, Salinas AG, Theile JW, Zhang TA, Diaz LM, Morrisett RA. Aberrant synaptic activation of N-methyl-D-aspartate receptors underlies ethanol withdrawal hyperexcitability. J Pharmacol Exp Ther 2007;321:60–72
167. Allison C, Pratt JA. Differential effects of two chronic diazepam treatment regimes on withdrawal anxiety and AMPA receptor characteristics. Neuropsychopharmacology 2006;31:602–19
168. MacDonald RL, Rogers CJ, Twyman RE. Barbiturate regulation of kinetic properties of the GABAA receptor channel of mouse spinal neurones in culture. J Physiol (Lond) 1989;417:483–500
169. Meldrum BS, Akbar MT, Chapman AG. Glutamate receptors and transporters in genetic and acquired models of epilepsy. Epilepsy Res 1999;36:189–204
170. Zhang G, Raol YS, Hsu FC, Brooks-Kayal AR. Long-term alterations in glutamate receptor and transporter expression following early-life seizures are associated with increased seizure susceptibility. J Neurochem 2004;88:91–101
171. Fujiwara-Tsukamoto Y, Isomura Y, Nambu A, Takada M. Excitatory GABA input directly drives seizure-like rhythmic synchronization in mature hippocampal CA1 pyramidal cells. Neuroscience 2003;119:265–75
172. Schweitzer JS, Wang H, Xiong ZQ, Stringer JL. pH Sensitivity of non-synaptic field bursts in the dentate gyrus. J Neurophysiol 2000;84:927–33
173. George AL Jr. Inherited channelopathies associated with epilepsy. Epilepsy Curr 2004;4:65–70
174. Kaneko S, Okada M, Iwasa H, Yamakawa K, Hirose S. Genetics of epilepsy: current status and perspectives. Neurosci Res 2002;44:11–30
175. Amzica F, Massimini M, Manfridi A. Spatial buffering during slow and paroxysmal sleep oscillations in cortical networks of glial cells in vivo. J Neurosci 2002;22:1042–53
176. Steinhauser C, Seifert G. Glial membrane channels and receptors in epilepsy: impact for generation and spread of seizure activity. Eur J Pharmacol 2002;447:227–37
177. Peterson SL, Armstrong JJ, Walker MK. Focal microinjection of carbachol into the periaqueductal gray induces seizures in the forebrain of the rat. Epilepsy Res 2000;42:169–81
178. Loftis JL, King DD, Colbert CM. Kinase-dependent loss of Na+ channel slow-inactivation in rat CA1 hippocampal pyramidal cell dendrites after brief exposure to convulsants. Eur J Neurosci 2003;18:1029–32
179. Silva AP, Lourenco J, Xapelli S, Ferreira R, Kristiansen H, Woldbye DP, Oliveira CR, Malva JO. Protein kinase C activity blocks neuropeptide Y-mediated inhibition of glutamate release and contributes to excitability of the hippocampus in status epilepticus. FASEB J 2007;21:671–81
180. Singleton MW, Holbert WH II, Lee AT, Bracey JM, Churn SB. Modulation of CaM kinase II activity is coincident with induction of status epilepticus in the rat pilocarpine model. Epilepsia 2005;46:1389–400
181. Yamagata Y, Imoto K, Obata K. A mechanism for the inactivation of Ca2+/calmodulin-dependent protein kinase II during prolonged seizure activity and its consequence after the recovery from seizure activity in rats in vivo. Neuroscience 2006;140:981–92
182. Budde T, Caputi L, Kanyshkova T, Staak R, Abrahamczik C, Munsch T, Pape HC. Impaired regulation of thalamic pacemaker channels through an imbalance of subunit expression in absence epilepsy. J Neurosci 2005;25:9871–82
183. Ziburkus J, Cressman JR, Barreto E, Schiff SJ. Interneuron and pyramidal cell interplay during in vitro seizure-like events. J Neurophysiol 2006;95:3948–54
184. Cossart R, Dinocourt C, Hirsch JC, Merchan-Perez A, De Felipe J, Ben-Ari Y, Esclapez M, Bernard C. Dendritic but not somatic GABAergic inhibition is decreased in experimental epilepsy. Nat Neurosci 2001;4:52–62
185. Abegg MH, Savic N, Ehrengruber MU, McKinney RA, Gahwiler BH. Epileptiform activity in rat hippocampus strengthens excitatory synapses. J Physiol 2004;554:439–48
186. Albensi BC, Ata G, Schmidt E, Waterman JD, Janigro D. Activation of long-term synaptic plasticity causes suppression of epileptiform activity in rat hippocampal slices. Brain Res 2004;998:56–64
187. Hirose T, Inoue M, Uchida M, Inagaki C. Enflurane-induced release of an excitatory amino acid, glutamate, from mouse brain synaptosomes. Anesthesiology 1992;77:109–13
188. Dong H-L, Fukuda S, Murata E, Higuchi T. Excitatory and inhibitory actions of isoflurane on the cholinergic ascending arousal system of the rat. Anesthesiology 2006;104:122–32
189. Dildy-Mayfield JE, Eger EI II, Harris RA. Anesthetics produce subunit-selective actions on glutamate receptors. J Pharmacol Exp Ther 1996;276:1058–65
190. Griffiths R, Boyle E, Greiff JMC, Rowbotham DJ, Norman RI. Choline acetyltransferase activity of rat synaptosomes is sensitive to enflurane, but not halothane or isoflurane. Br J Anaesth 1994;72:577–80
191. Gomez RS, Gomez MV, Prado MAM. The effect of isoflurane on the release of 3H-acetylcholine from rat brain cortical slices. Brain Res Bull 2000;52:263–7
192. MacIver MB, Kendig JJ. Enflurane-induced burst discharge of hippocampal CA1 neurons is blocked by the NMDA receptor antagonist APV. Br J Anaesth 1989;63:296–305
193. Anzawa N, Kushikata T, Ohkawa H, Yoshida H, Kubota T, Matsuki A. Increased noradrenaline release from rat preoptic area during and after sevoflurane and isoflurane anesthesia. Can J Anaesth 2001;48:462–5
194. Lin L-H, Chen LL, Harris RA. Enflurane inhibits NMDA, AMPA, and kainate-induced currents in Xenopus oocytes expressing mouse and human brain mRNA. FASEB J 1993;7:479–85
195. Ming Z, Griffin BL, Breese GR, Mueller RA, Criswell HE. Changes in the effect of isoflurane on N-methyl-D-aspartic acid-gated currents in cultured cerebral cortical neurons with time in culture. Anesthesiology 2002;97:856–67
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