ANESTH ANALG 303 1990:70:30>15 Review Article Pro- and Anticonvulsant Effects of Anesthetics (Part I) Paul A. Modica, MD, Rene Tempelhoff, MD, and Paul F. White, rhD, MD Key Words: ANTICONVULSANTS. BRAIN, PRO- An epileptic seizure has been defined as a sudden AND ANTICONWLSANTS. COMPLICATIONS, alteration of central nervous system (CNS) function CONVULSIONS. TOXICITY, CONVULSIONS. resulting from a high-voltage electrical discharge. This discharge may arise from an assemblage of Part I neurons in either cortical or subcortical tissues. The Introduction spread of this excitatory activity to the subcortical, Inhalation anesthetics Volatile agents thalamic, and brainstem centers corresponds to the Enflurane tonic phase of the seizure and loss of consciousness Halothane (1). In contrast, myoclonic activity refers to a series of Isoflurane rhythmic or arrhythmic muscular contractions (2). Investigational volatile agents Depending on the electroencephalographic (EEG) Nitrous oxide findings, myoclonus is divided into epileptic and Intravenous analgesics nonepileptic activity (3). Nonepileptic myoclonus Opioid (narcotic) analgesics originates from the brainstem or spinal cord and is Meperidine due to either loss of cortical inhibition (4)or to im- Morphine paired function of spinal interneurons (3,5). Without Fentanyl and its analogues EEG monitoring, it is extremely difficult to determine Summary whether abnormal-appearing seizurelike muscle Part I1 movements are due to epileptiform activity or non- Introduction epileptic myoclonia. Intravenous anesthetics Many anesthetic and analgesic drugs have been Sedative-hypnotics reported to cause seizure activity clinically (Table 1, Barbiturates A). Interestingly, many of these same drugs have also Etomidate been shown to possess anticonvulsant properties Benzodiazepines (Table 1, B). In an effort to explain deficiencies with Ketamine Guedel's original stages of anesthesia, Winters and Propofol colleagues (67) proposed a multidirectional contin- Local anesthetics uum of anesthetic states (Figure 1). For example, Anesthetic adjuncts some agents (e.g., diethyl ether) traverse both CNS Muscle relaxants excitation (stages I, 11) and depression (stage 111). Anticholinesterases Others (e.g., halothane, ultrashort acting barbitu- Anticholinergics rates) progress directly from stage I to 111, whereas Summary still others (e.g., nitrous oxide [N,O], enflurane, ketamine, and narcotics [S]) induce a stage I1 catalep- Part 11 of this review article will appear in the following issue of toid CNS excitation, which on occasion progresses to the journal. Received from the Department of Anesthesiology, Washington myoclonia or generalized convulsions. Based on EEG University school of Medicine, St. Louis, Missouri. Accepted for studies in cats, Winters suggested that both exces- publication October 10,1989. sively disorganized (stage 11) and decreased reticular- Address correspondenceto Dr. White, Department of Anesthe- siology, Box 8054, Washington University School of Medicine, 660 formation activity (stage 111) result in unresponsive- South Euclid Avenue, St. Louis, MO 63110. ness to painful stimuli and amnesia, consistent with 01990 by the International Anesthesia Research Society ANESTH ANALG MODICA ET AL. 304 1990;7030>15 Table 1. Anesthetics and Analgesics Reported to Cause stage 111 agent, has been used in the diagnostic and/or Suppress Seizure Activity in Humans activation of epileptogenic foci (11,12). ~ A. Proconvulsants 8.Anticonvulsants To properly categorize the various anesthetic Nitrous oxide Halothane agents with respect to their effects on the seizure Halothane Enflurance threshold, there are several important factors to con- Enflurane Isoflurane sider. The first consideration is the patient population Isoflurane Thiopental studied. For example, methohexital, in its current Morphine E tomida te formulation (Brevital; Eli Lilly, Indianapolis, Ind.), Meperidine Diazepam Fentanyl Lorazepam will only produce epileptiform activity in patients Sufentanil Midazolam with known seizure disorders (11,12). A second fac- Methohexital Ketamine tor to consider is the method of proconvulsant and Etomidate Prop of o1 anticonvulsant documentation. This had led to con- Diazepam Local anesthetics fusion in the literature regarding the effects of some Ketamine Propofol anesthetics and analgesics on CNS activity. Fentanyl- Local anesthetics induced seizures have been described clinically with- out the support of EEG documentation (13-15). In some instances, these convulsivelike muscle move- ME TRAZOL, KETAMINE ments may be due to nonepileptic myoclonus. PHENCYCLIOINE f-7 Y HYDROXYBUTYRATE SE, ZUR ES For most drugs used in anesthesia, subsequent EEG evaluation during their administration has MESCAL IN& N20 helped to clarify whether or not a particular agent is ETHER( truly epileptogenic in patients. However, for certain anesthetics, such as ketamine (16), the origin of epileptiform activity involves subcortical neuronal pathways. In humans, subcortical seizures are de- tected only with implanted EEG depth electrodes, not by standard surface leads. Thus, a third important factor to consider in determining whether or not an anesthetic possesses proconvulsant or anticonvulsant properties is the type of EEG recording electrodes (surface or depth) used during its evaluation. In this review article, we have attempted to ana- lyze the evidence for proconvulsant and anticonvul- sant activity of anesthetics and analgesics. This infor- mation has been evaluated with respect to (a) patient population (epileptic or nonepileptic); (b) documen- Figure 1. Winter's proposed scheme of reversible progression of tation of pro- and anticonvulsant activity (EEG study CNS states induced by various anesthetic and excitant agents. Stages I, 11, A, B, C, myoclonus, and seizures indicate CNS or clinical report); and (c) method of EEG analysis excitation, whereas stages Ill and IV indicate CNS depression. (surface or depth electrodes). (From Winters WD, Ferrer-Allado T, Guzman-Flores C, Alcaraz M. The cataleptic state induced by ketamine: a review of the neuro- pharmacology of anesthesia. Neuropharmacology 1972;11:30>15, with permission.) Inhala tion Anesthetics Volatile Agents the anesthetic state. Although both epileptic and anesthetic states possess similar features regarding Enflurune. Abnormal movements consisting of arousal and memory, the categorization proposed by twitching of individual muscle groups, and even Winters fails to adequately explain the actions of tonic-clonic activity, were frequently observed during those anesthetics that appear to possess both procon- the early clinical evaluation of enflurane (17,18). vulsant and anticonvulsant properties (Table 1). For Subsequent EEG recordings in normal patients dem- example, ketamine, an alleged stage I1 anesthetic onstrated epileptiform activity (19,20) and grand ma1 which Winters believed to be contraindicated in epi- seizure patterns (21) (Table 2). These findings with lepsy, has been successfully used to terminate status enflurane have also been confirmed in patients with epilepticus (9, lo), and conversely, methohexital, a temporal lobe epilepsy during both electrocortico- ANESTHETICS AND SEIZURES ANESTH ANALC 305 1990:70:30>15 Table 2. Proconvulsant Effects of Inhalation Anesthetics in Humans Seizure documentation Type of EEG Clinical EEG electrodes Agent Population report study used in study References Nitrous oxide Nonepileptic + - Surface 58, 64, 96 Epileptic - - Depth 16 Halothane Nonepileptic - - Surface 6M2 Epileptic - - Surface 63 Enflurance Nonepileptic + i Surface 17-21, 26, 28 Epileptic + i Surfaceldepth 22-25 lsoflurane Nonepileptic - - Surface 75-78 Epileptic NIA N/A Sevoflurane Nonepileptic - - Surface 86 Epileptic NIA NIA Desflurane (1-653) Nonepileptic NIA N/A Epileptic N/A NIA +, presence of seizures; -, absence of seizures; EEC, electroencephalographic; N/A, information not available. owdm LO m Figure 2. Electroencephalographic patterns with increasing concentrations of enflurane. (From Neigh JL, Garman JK, Harp JR. The 0 electroencephalographic pattern during anes- thesia with Ethrane: effects of depth of anes- thesia, Paco,, and nitrous oxide. Anesthesiol- &6 ogy 1971;35:482-7, with permission.) 15 graphic (22-24) and depth electrode recordings (25). waves-spike and dome activity with intermittent In ten healthy volunteers, grand ma1 seizure patterns periods of burst suppression (Figure 2). In contrast to were precipitated by auditory, visual, and tactile other volatile anesthetics, these burst suppression stimulation at end-tidal enflurane concentrations of patterns are thought to represent an excitatory event 3%-6% (26). This has also been reported during otic (29). microsurgery (27). In both normal (28) and epileptic The ability of enflurane to produce seizure or EEG (U)patients, increasing depth of enflurane anesthe- spiking activity is influenced by both its concentra- sia is characterized by the appearance of high-voltage tion and the Paco, (25,28). At a normal Paco, level, spikes, with the subsequent development of spike spiking is maximal at inspired enflurane concentra- 306 ANESTH ANALG MODICA ET AL. 1990;70303-15 tions of 2%-3%. Higher Paco, concentrations reduce thiopental (42) were found to intensify enflurane- spiking activity (22). Interestingly, N,O does not induced seizures in humans. Larger doses of thiopen- affect the tendency of enflurane to produce spiking tal diminished seizure activity. In cats, enhanced activity (28). With