ANTICONVULSANT ACTIVITY OF ALTHESIN ON EXPERIMENTAL EPILEPSY

Br. J. Anaesth. (1982), 54, 343

ANTICONVULSANT ACTIVITY OF ALTHESIN ON EXPERIMENTAL EPILEPSY P. L. DE RIU, G. SUSINI AND P. Ruju SUMMARY

Anaesthetic doses of Althesin were tested in rabbits using two experimental models of epilepsygeneralized (OHP; oxygen at high pressure-induced seizure) and partial (penicillin conical-induced seizure). Althesin in both models always produced anticonvulsant activity which was more powerful in generalized convulsions. This agent was successful in preventing and treating OHP seizures. The authors conclude that a clinical history of convulsions must not be considered a contraindication to the use of this anaesthetic which has particularly useful properties for neurosurgery

P. L. DE RIU,* M.D., Department of Neurosurgery, University of Turin, Turin, Italy. G SUSINI, M D , P. Ruju, M.D.; Department of Anaesthesiology and Intensive Care, University of Sassan, Sassari, Italy Address for correspondence. Istituto di Fisiologia Umana, Via Muroru, 29, 07100 Sassan, Italia. 0007-0912/82/030343-05 801.00

suppression could be a major factor in the anticonvulsant action of Althesin since it could break the circle of epileptic discharge leading to increased oxygen consumption. Munari and others (1977) showed that seven other cases of status epilepticus resistent to benzodiazepines were successfully treated with an anaesthetic dose of Althesin. Therefore we administered Althesin to two models of experimental epilepsy, focal and generalized in different experimental conditions to determine whether it had any convulsant or anticonvulsant action. MATERIALS AND METHODS

Twenty adult rabbits of either sex weighing 2-3 kg were allocated to two main groups: in the first, 10 animals were exposed to oxygen at high pressure (OHP) to obtain a generalized centrencephalic seizure, while in the second group, 10 animals underwent cortical focal convulsion using penicillin. Group 1 The animals were anaesthetized with ether and two pairs of stainless steel electrodes aseptically implanted in the skull for e.e.g. recording (FplFp2, 01-02). Twenty-four hours afterwards, the right cephalic vein was cannulated with a Teflon catheter under local anaesthesia (2% lignocaine 2 ml) and 3h later the animals were exposed to OHP in a 15-litre hyperbaric chamber which had a device for injecting a drug to the cephalic catheter of the animals. The chamber was flushed with 100% oxygen for 2min, the outlet valve sealed and the pressure increased at a uniform rate over 2 min until a pressure of 6 atm was reached. ©Macmillan Publishers Ltd 1982

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Convulsions during steroid anaesthesia were reported by Selye (1941) who described occasional fits when he injected steroids i.p. to rats. The steroid anaesthetic agents used before Althesin were hydroxydione and GR2/146. The convulsant properties of hydroxydione were first described by Price (1962), but none were reported following GR2/146. In 1973, Uppington reported convulsions following Althesin and another case was described by Rees (1975). It was suggested that Althesin has an action similar to hydroxydione and in epileptics may cause a pre-existing resting focus to discharge and thereby produce seizures (Uppington, 1973). It was also suggested that Althesin could be considered useful to activate e.e.g. patterns in epileptics (Testa, Comelli and Saia, 1977). The appearance of paroxysmal bitemporal abnormalities in e.e.g. traces of epileptic subjects during Althesin anaesthesia was also observed (Sramka, 1975). However, Bimar and Lepouleuf (1973) reported that Althesin greatly increases the cardiazolic threshold in cats, and Emperaire and Bimar (1973) stressed that, in small doses, this drug has a consistent anticonvulsant effect on photic epilepsy in baboons. Recently, two cases of status epilepticus which did not respond to classic drugs such as diazepam and clonazepam, were successfully treated with Althesin by Alati and others (1979). According to these authors, burst

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Group 2 The animals were anaesthetized with ether and one pair of stainless steel screw electrodes implanted in the frontal region (Fpl-Fp2). The next day 1 cm2 on the left temporo-parietal region was exposed through a trephine hole under halothane anaesthesia and the dura was opened. E.e.g. was recorded by the screw electrodes previously attached to the skull while the electrocorticogram (e.co.g) was recorded from silver ball electrodes applied to the pia. Convulsions were produced by applying a small pledget soaked with sodium penicillin G 40 000 u. ml" 1 to the pia. The first spike in the cortical focus appeared 100-120 s after penicillin was applied. When the spikes reached an amplitude of more than 250 |iV, Althesin was injected i.v. in a single dose of 0.1 ml kg" 1 to five rabbits. In the remaining five rabbits, Althesin was injected in the same dose about 20 min after the penicillin application, when the highest spike frequency was reached in the cortical focus. In all experiments, the time of injection of the Althesin was 5 s. At the end of each experiment, the animals were sacrificed with a lethal dose of pentobarbitone. RESULTS

In the first five animals of group 1, Althesin was injected when the preseizure e.e.g. patterns appeared (fig. 1B); in four cases it prevented seizures despite continued exposure to OHP. In one rabbit, an electrical seizure appeared after 46 min of exposure, although the animal showed no clinical symptoms.

Fp1-Fp2

01-02

B ^^^

FIG. 1 A: Normal patterns recorded from frontal and occipital areas B- Preseizure activity characterized by decrease of frequency and increase in voltage of waves which become peaked Time of injection 5 s. c Onset of first epileptic hyperoxic discharge which is shown by appearance of high voltage burst of hypersynchronous spikes. Before the end of injection, paroxysmal electrical activity has completely disappeared. Tune of injection 5 s Arrows denote start and finish of Althesin injection

In the second subgroup of rabbits in group 1, Althesin was injected immediately after seizure began and in all cases stopped clinical and electrical paroxysmal signs immediately after administration (fig. lc). Exposure at 6atm also lasted 1 h in the second subgroup, but after Althesin, none of the OHP-exposed rabbits had convulsions or abnormal electrical activity. None of the animals showed seizure activity during the decompression period. In the second group, Althesin was injected when the isolated spikes reached greatest amplitude. Spikes (fig. 2B) and clonic jerks of the right forelimb were stopped in all cases for at least

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After 17-21 min of continuous exposure at 6 arm, the e.e.g. patterns gradually changed with a marked reduction in frequency and increase in amplitude of the waves. This is considered a preseizure activity which occurs when a convulsive seizure is imminent (Raday et al., 1975). At the exact moment when preseizure activity occurred, Althesin was injected i.v. in a single dose of 0.1 ml kg" 1 . The total exposure at 6 arm was 60 min. Five rabbits were treated in this way. Five other rabbits had an Althesin injection of the same dose at the onset of the first paroxysmal discharge after 20-23 min of continuous OHP exposure at 6 arm. The total exposure time in this subgroup was also 60 min. In all cases, decompression was carried out over 5 min.

ANTICONVULSANT ACTIVITY OF ALTHESIN Fp1-Fp2

345 DISCUSSION

ECoG

B

1s FIG. 2. A. Normal—Fpl-Fp2 = bipolar lead from the frontal fields. ECoG = electrocorticogram bipolar record from the focal area B: Upper tracing—normal e e g. patterns in the frontal fields; lower tracing—high voltage pattern (more than 250 (iV) recorded from the focal area 200 s after penicillin was applied. The paroxysmal epileptic activity disappeared before the end of Althesin administration Time of injection 5 s. c Upper tracing—e e g. patterns recorded from the frontal areas are within the normal range; lower tracing—high frequency burst recorded from the focal area Before the end of Althesin injection, the paroxysmal activity has completely ceased. Time of injection 5 s. D. 6 nun after c. Upper tracing—normal electrical activity; lower tracing—isolated spikes begin to appear again in the focal area. Arrows denote start andfinishof Althesin injection.

6min. In rabbits which received Althesin when the spikes reached the highest frequency, the paroxysmal epileptical activity was abolished in all cases before the end of the administration (fig. 2c). Isolated spikes appeared again following an electric silence lasting about 5 min (fig. 2D) and in a short time reached large amplitude, but high frequency bursts did not reappear.

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D

Seizures induced by hyperbaric oxygen appear to provide a suitable model for the study of epilepsy (Wood, 1972). There are similarities between OHP-induced seizures and human epilepsy: (i) e.e.g. patterns and signs of the two types of seizures are similar (Rucci, Giretti and La Rocca, 1967; Wood, 1972; Hanna et al., 1978); (ii) derangement of cerebral gamma amino butyric acid (GABA) metabolism occurs in OHPinduced seizures as well as in some stages of epilepsy (Wood, 1972). Furthermore, impairment of cerebral GABA metabolism also seems to be involved in focal convulsions produced by local application of cobalt and penicillin (Mutani et al., 1977). It would appear that a similar biochemical mechanism is involved in experimental and human epilepsy and OHP may serve as a model to evaluate potential antiepileptic agents the mode of action of which does not depend on antioxidant properties (Wood, 1972). Our results show that Althesin protects animals exposed to OHP against seizures and also stops hyperoxic convulsions when injected at the onset of the first paroxysmal discharge. Althesin produced a rapid and prolonged anticonvulsant effect in this form of seizures. This may be explained by the following: (a) The primary event in OHP convulsions is probably major neuronal oxidation (Wood, 1972) with reduction of brain GABA concentration a secondary event (Wood, 1972). Althesin reduces cerebral oxygen consumption by about 46% (Sari et al., 1976) and may act prophylactically by reducing oxidation. (b) Vasoconstriction in OHP may protect against neuronal oxidation (Deutrebond and Haldane, 1921). Since Althesin produces cerebral vasoconstriction demonstrated by angiography (Laxenaire, 1975), this may augment the vasoconstrictor effect of OHP. (c) Althesin has a greater depressant effect on the reticular activating system (RAS) than the cerebral cortex (Bimar and Lepouleuf, 1973). The first discharge occurs in the RAS for all types of generalized convulsions (Gastout and Fischer, 1959; Rolston and Langer, 1965) including hyperoxic convulsion (Rucci, Giretti and La Rocca, 1967) and may be prevented by Althesin.

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These three factors could explain the particular Emperaire, N., and Bimar, J. (1973) Etude •* neurophysiologique du CT 1341. Mediterranie Med , 1,237. efficacy of Althesin on hyperoxic seizures. Gastout, H., and Fischer, W. M. (1959) The physiopathology Althesin also showed an anticonvulsant action of epileptic seizures, in Handbook of Physiology, Sect. I (ed. during focal convulsions. Its activity in this J. Field), p. 1. Washington D.C • American Physiology experimental model is constant but of short Society duration and is probably related to the depressant Hanna, M. K., Blackburn, J. G., Ogilvie, R. W , and Campbell, S L (1978). The effect of lidocaine on hyperoxic cortical action. Moreover, it produces prolonged seizure activity in the cat Exp. Neurol., 58, 562. v suppression of high frequency bursts which are Laxenaire, M. C (1975). Action de l'Alfatesine sur le debit signs of increased cortical excitability. This sanguin cerebral global chez l'homme Arm. Anesth. Franf., suggests that Althesin in an anaesthetic dose has a 16, 423 depressant effect on the cerebral cortex which is Munari, C , Modesto, S., Matteuzzi, G., and Pacifico, L (1977) Effects de l'Alfatesine sur l'etat de mal epileptic. mild but more prolonged than expected. Rapport preliminaire. Rev. EEG Neurophysiol., 7, 198. In conclusion, AJthesin seems to have a power- Mutani, R., Durelli, L., Valcnuni, C , Monaco, F , Fumero, ful anticonvulsant action when tested on a model S., and Mondino, A. (1977). Longitudinal changes of brain 4 anuno acid content occurring before, during and after of generalized convulsion and on a model of focal epileptic activity. Brain Res., 122, 513. convulsion. Our findings are in agreement with J. H (1962). EEG changes following the activation of the report that this steroid agent has a depressant Price, the brain using succinic acid ester of hydroxidione activity upon the reticular activating system and (Presuren) Electrotnceph. Exp Neurophyswl., 14, 294. cerebral cortex and first description of the Raday, N , Conforti, N , Harel, D., and Lavy, S. (1975). Analysis of preseizure electrocorticographic changes in rats anticonvulsant properties of this agent on during hyperbaric oxygenation Exp Neurol ,9. ^ cardiazolic convulsions in cats (Bimar and Rees, L. T (1975) Convulsions immediately following Lepouleuf, 1973) and photic seizures in baboons Althesin. Anaesthesia, 30, 54. (Emperaire and Bimar, 1973). Our data also Rolston, L , and Langer, H (1965) Experimental epilepsy of support reports that Althesin was effective in brain-stem origin Electrotnceph Chn. Neurophysiol., 8, 325. treating status epilepticus (Munari et al., 1977; Rucci, F. S., Giretti, M. L., and La Rocca, M. (1967) Changes in electrical activity of the cerebral cortex and of Alati et al., 1979) and suggest that a clinical some subcortical centers in hyperbanc oxygen. history of convulsions must not be considered a Electroenceph. Chn. Neurophysiol., 22, 231. contraindication to Althesin. Althesin also San, A , Maekawa, T , Tohjo, M , Okuda, Y , and Takeshita, H. (1976). Effects of Althesin on cerebral blood flow and reduces intracranial pressure and brain oxygen oxygen consumption in man. Br. J. Anaeslh , 48, 545. consumption (Sari et al., 1976) and should be a H. (1941) Anesthetic effect of steroid hormones. Proc useful anaesthetic for neurosurgery where partial Selye, Soc Exp. Btol Med, 46, 116 or generalized seizures are common. The two Sramka, M (1975). Acttv. Nerv Sup (Praha), 17, 287 examples of generalized convulsion following Testa, G , Comelh, L. F., and Saia, A. (1977). Considerazioni sulle possibilita attivanti di dosi subnarcotiche di alcuni Althesin injection (Uppington, 1973; Rees, 1975) anestetici in elcttroencefalografia chnica. Rw. Pat. Nerv., cannot be explained by the results of our study, 98, 171. v but the suggestion that Althesin can cause a silent Uppington, J. (1973). Epileptiform convuliion with Althesin. epileptic focus to discharge seems unlikely. Anaesthesia, 28, 546 ACKNOWLEDGEMENT

The authors are indebted to Prof. G. B. Azzena, Director of the Institute of Human Physiology, University of Sassan Medical School, where this research was carried out.

Wood, J D (1972) Systemic oxygen derangements; in Experimental Models of Epilepsy (eds D. P. Purpura, J. K. Penry, D. Tower, D M. Woodbury and R. Walter), p. 464. New York: Raven Press. ACTIVITE ANTICONVULSIVANTE DE L'ALFATESINE DANS L'EPILEPSIE EXPERIMENTALE

REFERENCES

Alati, G. L., Non, R., lob, I., and Andnoh, G. (1979). Althesin e stato di male epilettico. Ada Anaest. Ital., 30, 734 Bimar, J., and Lepouleuf, N. (1973). Les effets sur le systime nerveux central du CT 1341. Arm Amsth. Franf., 14, 491 Deutrebond, L., and Haldane, J. S. (1921) The effects of respiration of oxygen on breathing and circulation. J. Physiol. (Land.), 55, 269.

RESUME

On a etudie des doses anesthesiques d'alfatesine chez des lapins, en utihsant deux modeles expenmentaux d'epilepsie. epilepsie generahsee (crise induite par l'OHB = oxygene hyperbare) et localisee (ense provoquee par de la penicilline sur le cortex). Dans les deux modeles experimentaux, Palfatesine a toujours objective une activite anticonvulsivante, plus puissante au cours des crises generalisees. Cet agent a

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ANTICONVULSANT ACTIVITY OF ALTHESIN pennis de prevenir et de traiter les crises dues a l'OHB Les auteurs concluent que des antecedents cliniques de convulsions ne doivent pas etrc consideres comme une contremdicauon a l'usage de cet anesthcsique qui a des propnetes particulierement utiles en neurochirurgie.

zufuhrenden Anfalles Die Autoren schliessen daraus, dass eine AhfaJlsanamnese nicht aJs Kontraindikation fur die Anwendung dieses Anasthetikums angesehen werden sollte, da cs durchaus positive Eigenschaftcn fur den Gebrauch in der neurochirurgie besitzt

ANTIKONVULSIVE AKTIVITAT VON ALTHESIN AUF EXPERIMENTELLE EPILEPSIE

ACTIVIDAD ANTICONVULSIVA DE LA ALTESINA EN EPILEPSIA EXPERIMENTAL SUMARIO

Se Uevaron a cabo ensayos sobre dosis anesteucas de Alteiina en conejos usandos dos modclos experimentalcs de epilepsia: generalizada (OHP; oxigeno en crisis inducida por presion alta) y parcial (crisis inducida corticalmente por pemcilina) En ambos modelos, la AJtesina siemprc produjo una acuvidad anticonvulsiva que se revelo mas potente en las convulsiones generalizadas. Este agente fue exitoso en el tratamiento y la prevencidn de las crisis OHP. Los autores concluyen que un histonal clinico de convulsiones no debe considerarse como una contraindicacion del uso de dicho anestetico que posee propiedades parucularmcnte utiles en la neurocirujia

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ZUSAMMENFASSUNG

Anasthetisch wirksame Dosen von Althesin wurden bie Kaninchen getestet, und zwar expenmentell an zwei Formen einer Epilepsie die generalisierte, aufgrund eines auf Sauerstoffhochdruck zuruckzufuhrenden Krampfes, un die pamelle, durch Penicillin cortikal-induzierte Krampfc. Althesin zeigte in beiden expenmentellen Modellen immer cine annkonvulsive Aktivitat, die jcdoch bei den gencralisierten Krampfen starker ausgepragt war Die Substanz lieferte besonders gute Ergebrusse bei der Verhutung und Behandlung eines auf Sauerstoflhochdruck zuruck-