Secondary Logo

Journal Logo

Update in Intravenous Anaesthesia: Original Papers

Propofol: pro- or anticonvulsant?

Borgeat, A.

Author Information
European Journal of Anaesthesiology: May 1997 - Volume 14 - Issue - p 17-20



In the normally functioning nervous system, inhibitory factors balance excitatory mechanisms to permit normal activity. For this balance to be maintained, all of the biochemical apparatus of the central nervous system must be intact. Therefore acute changes in energy production, electrolyte balance or neurotransmitter concentration, as well as any abnormalities in protein synthesis or alterations in synaptic, membrane or network structure may provide the conditions leading to a seizure.

The sudden alteration in the central nervous system due to a high voltage electrical discharge corresponds to the definition of an epileptic seizure. This abnormal activity may arise from a group of neurones in either cortical or subcortical tissues. The tonic phase of the seizure and the loss of consciousness corresponds to the spread of the excitatory effect to the subcortical, thalamic and brainstem centres [1]. On the other hand, myoclonic activity refers to a series of rhythmic and/or arrhythmic muscular contractions which may be divided into either epileptic or non-epileptic activity [2]. In clinical practice it is extremely difficult, without EEG monitoring, to determine whether abnormal appearing seizure-like muscle movements are due to epileptiform activity or non-epileptic myoclonia.

Brain electrical stability is maintained by a subtle balance between excitatory and inhibitory impulses. Any event associated with either an increase of excitatory neurotransmitters (glutamate, aspartate), a decrease of inhibitory neurotransmitters (GABA, glycine) or a neuronal hyperexcitability (pentylene-tetrazol) may be linked with an epileptic seizure. Numerous anaesthetics (methohexitone, ketamine, enflurane) and analgesic drugs (high-dose opioids, local anaesthetics) have been reported to cause seizures clinically [3]. The role of propofol in this setting is still controversial. Although systemic investigations in both animals and humans strongly suggest that propofol possesses anticonvulsant properties [4-6], several case reports of post-propofol 'seizures' or opisthotonus have implicated propofol as a proconvulsant [7-9].

Proconvulsant properties

Abnormal movements, posturing and seizure-like activity related to the use of propofol have been reported in the literature. However, the significance of the case reports dealing with propofol as a proconvulsant agent must be interpreted with caution for the following reasons. First, the majority of the reported excitatory movements appeared either in patients with known epilepsy [7,10], or in patients receiving drugs with a known epileptogenic potential [11,12]. Secondly, in none of the reported cases of excitatory movements was a simultaneous EEG recording performed to confirm true cortical epileptic activity. One peculiar case report describes the occurrence of a seizure 5 days after propofol anaesthesia for no apparent reason [13]. In such circumstances it is clearly difficult to implicate propofol as the main factor. Only one case clearly involved propofol as a proconvulsant agent [14]. Here the clinical setting was special in that the patient was scheduled for a temporal lobectomy for intractable temporal epilepsy; infusion of propofol 2 mg kg−1 i.v. was associated with discharges of spikes, polyspikes and spike and slow wave complexes appearing 20-30 s after administering propofol and lasting for up to 7 min. In the same setting, electrocorticogram activation occurred in 17 out of 20 patients undergoing surgery for medically intractable epilepsy; of interest is the increase and extension of spike-waves that were observed with low-dose propofol [15].

Seizure-like behaviour, characterized by clonus of all four limbs, facial grimacing and tongue clonus were observed in mice receiving 75 mg kg−1 or more of propofol via the intraperitoneal route during induction and recovery from anaesthesia [6]. EEG recordings showed a generalized decrease in activity and the absence of any cortical epileptic activity. The timing and the nature of the excitatory movements are similar to those found in children (aged 6-12 years) during induction of anaesthesia with 3 mg kg−1 i.v. of propofol [17].

Dolin et al.[18] hypothesized that glycine antagonism may underlie the excitatory effects of propofol since they showed that strychnine, a glycine antagonist, but not bicuculline, an antagonist at the GABAA receptor, potentiated both excitatory and epileptic-like behaviour; however, their hypothesis remains debatable as they were not able simultaneously to correlate EEG and behaviour as the mice were given a neuromuscular blocking drug when the EEG was recorded.

In summarizing these publications two points emerge: first, propofol has never been proved to cause cortical fits in the absence of severe pre-existing epilepsy. Secondly, the excitatory phenomena reported might be the results of disinhibition in the context of low dosages of propofol depressing inhibitory - but not excitatory - subcortical centres. The fact that inhibitory central nervous system structures are more sensitive to depression than excitation is well known for all hypnotic agents. Thus it is possible to avoid pro-excitatory effects of propofol by using an adequate dosage regimen [17].

Anticonvulsant properties

On the other hand systematic studies in both humans and animals strongly suggest that propofol possesses antiepileptic properties. During electroconvulsive therapy, propofol consistently reduces seizure duration when compared to equipotent doses of methohexitone, whatever the measurement techniques used. Using a Cerebral Function Monitor, Dwyer et al.[19] compared propofol 1.51 mg kg−1 i.v. and methohexitone 1.19 mg kg−1 i.v.: the duration of seizures were 25% shorter with propofol. Simpson et al.[2] observed that seizure durations were 40% shorter following propofol 1.3 mg kg−1 i.v. than those following methohexitone 1.0 mg kg−1 i.v. using an isolated forearm technique. Propofol has been successfully used to control status epilepticus in a patient suffering from an overdose of chlormethiazole and unresponsive to therapeutic doses of phenytoin [2]. In another report, a patient with coxsackie encephalitis developed uncontrolled seizures despite combined treatment with diazepam, phenytoin, phenobarbitone and chlormethiazole. The fits were completely suppressed by a single bolus of propofol 100 mg i.v. and a continuous infusion of 5.7 mg kg−1 h−1[22]. Borgeat et al. successfully used propofol to manage a status epilepticus unresponsive to combined phenytoin, clonazepam and thiopentone boluses in a patient with a drained post-traumatic subdural haematoma [23].

These results are confirmed by animal studies. In mice, Lowson et al.[4] compared intraperitoneal administration of propofol 50 mg kg−1 i.v. and thiopentone 25 mg kg−1 i.v. against epileptiform seizures induced by electroshock and pentylene-tetrazol. Both drugs were equally effective against electroshock seizures but with these doses propofol provided a greater degree of protection against pentylene-tetrazol fits than thiopentone. In rabbits, De Riu et al.[5] demonstrated that a bolus of propofol 12 mg kg−1 i.v. and an infusion of 50 mg kg−1 h−1 suppressed cortical paroxysmal electrical activity in pentylene-tetrazol seizures. The infusion prevented the reappearance of epileptic patterns in the EEG and tonic-clonic attacks. Hartung et al.[24] demonstrated that propofol in a dose-dependent manner prevents, or elevates the threshold for, lignocaine-induced seizures in rats. The same results were obtained by Heavner et al.[25] in the treatment of bupivacaine-induced seizures in rats. Propofol also exhibits a dose-dependent anticonvulsant effect against bicuculline, kainic acid and N-methyl-d-aspartic acid when injected i.p. or i.v. [26].

In patients with documented epilepsy, Ebrahim et al.[27] found that propofol was safe but may interfere with the recording of EEG spikes. During awake craniotomies for surgery of epileptogenic foci, Soriano et al.[28] concluded that propofol has neither proconvulsant nor anticonvulsant effects in this particular setting; they also found that propofol did not disrupt the epileptiform activity on electrocorticography.

Postulated mechanisms of action

Although previous original investigations by Glen et al.[29] did not associate propofol with either anticonvulsant or proconvulsant properties, recent systematic investigations and well-documented case reports strongly support propofol as an effective anticonvulsant agent [4,5,17].

The efficacy of anticonvulsants is based on their ability either to prevent the spread of epileptic activity in the central nervous system or to increase the threshold of discharge of an epileptic focus. In this context, propofol possesses properties that further support the hypothesis of anti-epileptic efficacy.

Propofol, like benzodiazepines and barbiturates, potentiates GABA-mediated pre- and postsynaptic inhibition and interferes with di- and poly-synaptic excitation by decreasing the release of excitatory transmitters [30]. Propofol, in common with many other general anaesthetic agents, reduced membrane conductance and excitability [1,31].

Moreover, when compared to barbiturates whose antiepileptic action is mainly via their effect on GABAA receptors, propofol has a more uniform depressant action on the central nervous system including, in particular, subcortical centres. Thus, propofol may exert antiepileptic activity by interacting with multiple mechanisms involved in the genesis of epilepsy: interactions with GABA transmission membrane excitability and via NMDA receptors by decreasing the release of L-glutamate and L-aspartate - a property not shared by thiopentone - thus explaining its efficacy in patients resistant to conventional treatment and supported by its successful action against epileptic models involving different physiopathological mechanisms [4,5,25,26].

We may surmize that the vast majority of the reported propofol-induced 'seizures' during induction or emergence from anaesthesia were probably due to spontaneous excitatory movements of subcortical origin. We still do not have definitive explanations for the development of postoperative spasms of opisthotonus and myoclonus. Strong subcortical actions of propofol are well known; one of the possible explanations is that propofol would act in the spinal cord as a glycine antagonist like strychnine [32]. The 'cortical-subcortical' interactions of propofol are more pronounced at low plasma levels, which is consistent with the development of these at early induction or during the recovery from anaesthesia. It is unlikely that propofol gives rise to epileptiform convulsions; however, Ahmad and Pleuvry [26] demonstrated in mice that propofol offered no protection against the proconvulsant actions of the opioid drugs. They conclude that propofol may not be proconvulsant in its own right, but it may open the door to seizures elicited by other mechanisms. It may be possible, therefore, in certain susceptible patients whose cortical epileptic foci are inhibited by subcortical activity that propofol at low doses would favour the development of a seizure.


1 Halliday AM. The neurophysiology of myoclonic jerking-a reappraisal. In: Charlton MH, ed. Myoclonic Seizures. Amsterdam: Excerpta Medica, 1975: 1-29.
2 Marsden CD, Hallett M, Fahn S. The nosology and pathophysiology of myoclonus. In: Marsden CD, Fahn S, eds. Movement disorders. London: Butterworth, 1982: 196-248.
3 Modica PA; Tempelhoff R, White PF. Pro- and anticonvulsant effects of anesthetics (Part I). Anesth Analg 1990; 70: 303-315.
4 Lowson S, Gent JP, Goodchild CS. Anticonvulsant properties of propofol and thiopentone: comparison using two tests in laboratory mice. Br J Anaesth 1990; 64: 59-63.
5 De Riu PL, Petruzzi V, Testa C et al. Propofol anticonvulsant activity in experimental epileptic status. Br J Anaesth 1992; 69: 177-181.
6 Mackenzie SJ, Kapadia F, Grans IS. Propofol infusion for control of status epilepticus. Anaesthesia 1990; 45: 1043-1045.
7 Collier C, Kelly K. Propofol and convulsion-the evidence mounts. Anaesth Intensive Care 1991; 19: 573-575.
8 Victory RAP, Magee D. A case of convulsion after propofol anaesthesia (letter). Anaesthesia 1988; 43: 904.
9 Jones GW, Boykett MM, Flok M. Propofol opisthotonos and epilepsy (letter). Anaesthesia 1988; 43: 905.
10 Paech MJ, Storey JM. Propofol and seizures (letter). Anaesth Intensive Care 1990; 18: 585.
11 Hendley BJ. Convulsions after cocaine and propofol. Anaesthesia 1990; 45: 788-789.
12 Wittenstein U, Lyle DJR. Fits after alfentanil and propofol. Anaesthesia 1989; 44: 532-533.
13 Thomas JS, Boheimer NO. An isolated grand mal seizure 5 days after propofol anaesthesia (letter). Anaesthesia 1991: 46; 508.
14 Hodkinson BP, Frith RW, Mee EW. Propofol and the electro-encephalogram (letter). Lancet 1987; ii: 1518.
15 Smith M, Smith SJ, Scott CA, Harkness WFJ. Activation of the electrocorticogram by propofol during surgery for epilepsy. Br J Anaesth 1996; 76: 499-502.
16 Smith MB, Soar J, Morris PJ, Dolin SJ. Propofol-induced seizure-like behaviour in mice. Br J Anaesth 1990; 64: 396-397.
    17 Borgeat A, Dessibourg C, Popovic V, Meier D, Blanchard M, Schwander D. Propofol and spontaneous movements: an EEG study. Anesthesiology 1991; 74: 24-27.
    18 Dolin SJ, Smith MB, Soar J, Morris PJ. Does glycine anatagonism underlie the excitatory effects of methohexitone and propofol? Br J Anaesth 1992; 68: 523-526.
    19 Dwyer R, McCaughey W, Lavery J, McCarthy G, Dundee JW. Comparison of propofol and methohexitone as anaesthetic agents for electroconvulsive therapy. Anaesthesia 1988; 43: 459-462.
    20 Simpson KH, Halsall PJ, Carr CME, Stewart KG. Propofol reduced seizure duration in patients having anaesthesia for electroconvulsive therapy. Br J Anaesth 1988; 61: 343-344.
    21 Yanny HF, Christmas D. Propofol infusions for status epilepticus (letter). Anaesthesia 1988; 43: 514.
    22 Wood PR, Browne GPR, Pugh S: Propofol infusion for the treatment of status epilepticus. Lancet 1988; i: 470-481.
    23 Borgeat A, Wilder-Smith OHG, Jallon P, Suter PM. Propofol in the management of refractory status epilepticus: a case report. Intensive Care Med 1994; 20: 148-149.
    24 Hartung J, Ying H, Weinberger J, Cottrell JE. Propofol prevents or elevates the threshold for lidocaine-induced seizures in rats. J Neurosurg Anesthesiol 1994; 6: 254-259.
    25 Heavner JE, Arthur J, Zou J, McDaniel K, Tyman-Szram B, Rosenberg PH. Comparison of propofol with thiopentone for treatment of bupivacaine-induced seizures in rats. Br J Anaesth 1993; 71: 715-719.
    26 Ahmad I, Pleuvry BJ. Interactions between opioid drugs and propofol in laboratory models of seizures. Br J Anaesth 1995; 74: 311-314.
    27 Ebrahim ZY, Schubert A, Van Ness P, Wolgamuth B, Awad I. The effect of propofol on the electroencephalogram of patients with epilepsy. Anesth Analg 1994; 78: 275-279.
    28 Soriano SG, Rockoff MA, Eldredge EA et al. Use of propofol for resection of tumors and epileptogenic foci during awake craniotomies. Anesthesiology 1996, 85: (suppl 3A) A198.
    29 Glen J. Animal studies of the anaesthetic activity of ICI 35 868. Br J Anaesth 1980; 52: 731-742.
    30 Collins GGS. Effects of the anaesthetic 2,6-diisopropylphenol on synaptic transmission in the rat olfactory cortex slice. Br J Pharmacol 1988; 95: 939-949.
    31 Frenkel C, Urban BW. A molecular target site for propofol: voltage-clamp studies on human CNS sodium channels in bilayers (abstract). Anesthesiology 1989; 71: A590.
    32 Dolin SJ, Smith MB, Soar J, Morris PJ. Does glycine antagonism underlie the excitatory effects of methohexitone and propofol? Br J Anaesth 1992; 68: 523-526.

    Section Description

    Seventh International Symposium on Intravenous Anaesthesia, Lausanne, Switzerland, 2-3 May 1997

    This publication is supported by grants from various pharmaceutical companies. The views in this publication are those of the authors and not necessarily those of supporting companies. Drugs and administration techniques referred to should only be used as recommended in the manufacturers' prescribing information.


    Anaesthetics Intravenous, propofol; Anti-convulsants; Brain, convulsions, electroencephalography

    © 1997 European Society of Anaesthesiology