Folia Psychiatrica et Neurologica Japonica, Vol. 30, No. 3, 1976

Experimental Studies on the Pathogenesis of Temporal Lobe Epilepsy Yoshiaki Mayanagi, M.D. Nerrrosiirgery, T o k y o Metropolitan Police Hospital and T o k y o University, T o k y o

After the introduction of aluminum hydroxide as an epileptogenic agent by Kopeloff (1942),2 this method was used to induce seizures in many parts of the brain and in many kinds of animals. However, the application to the temporal lobe of the monkey has been rare and fragmentary.' fi I ' This study was designed to study the basic mechanisms of temporal lobe epilepsy in a model as similar as possible to clinical psychomotor epilepsy. Alumina cream was applied to the temporal cortex or to the deep medial structures of the temporal lobe in rhesus monkeys, which survived on an average for seven months and developed focal seizures. This paper will mainly deal with clinical manifestations and propagations of epileptic activity during seizures. The details of this experimental project were described in the previous publications." 'I'

date, septum, globus pallidus, subthalamus and mesencephalic reticular formation on one or both sides. These monkeys were kept in observation cages or placed on monkey chairs for EEG recordings. Activation of EEG was made by the intravenous administration of 0.2 ml of 10% Metrazol (pentylenetetrazol). Clinical seizures and the EEG recording were cinephotographed simultaneously. At the conclusion of the experiment, the monkey was sacrificed, the brain was profused by saline and 10% formalin, embedded in celloidin and serially sectioned at 25 microns. Every eighth section was stained for cells (Nissl's method) and the adjacent one for myelin (Weil's method). RESULTS

Although 21 adult monkeys (macaca mulatta, 3.5-5.6 kg) were used in this study, METHODS 12 survived long enough to develop chronic Under general anesthesia, alumina cream epileptic foci within the temporal lobe, They of about 0.2 ml was injected into the tem- were studied from 84 to 407 days (on an poral cortex or the amygdala. At the same average 21 1 days). Fig. 1 shows the brain sections of these time, electrodes were placed on the skull or 12 monkeys. Among the six cortical injecstereotaxically inserted into the amygdala, tions, two cases (M4, M6) developed only hippocampus, thalamus, hypothalamus, causporadic focal spiking. The other four aniAddress for request of reprint: Y.Mayanagi, mals repeatedly showed seizures, which M.D., Tokyo Metropolitan Police Hospital, 2- originated from the temporal tip or the later!.O-41, Fujimi, Chiyoda-ku, Tokyo. al temporal cortex. In the six subcortical injections, all of which produced seizures, Received for publication May 12, 1976.

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localized alum lesions were found, two at the border of the amygdala and putamen (M14, M16), three within the amygdala (M18, M19, M20) and one (M21) mainly in the amygdala with extension to the anterior hippocampus and the inferior horn of the lateral ventricle. Two cases with the lesion in the putamen and amygdala developed seizures initially starting from the amygdala, then shifted their foci to the temporal tip a few months later. In the other four animals, the electroencephalographic origins of the seizures were found not only in thc amygdala

but also in the hippocampus and somat'imes in both simultaneously. Although the shift of the focus could occur among the temporal lobe structures of the ipsilateral side to the alum injection, no seizure was seen to start from the contralateral temporal lobe during the observation period of seven months. M21 may be examined as a representative case (Fig. 2). In this monkey 0.3 ml of alumina cream was injected into the left amygdala. Immediately after the alum injection, a slow wave focus was present in the temporal region, being replaced 39 days

Fig. I : Brain sections of 19 monkeys, showing the locations of injected alumina cream (arrows), which developed epileptic foci.

Pathogenesis of Temporal Lobe Epilepsy later by isolated spikes in the hippocampal gyrus of the same side. T h e first electroencephalographic and clinical seizure was induced by Metrazol on the 66th day after the alum injection, and the first spontaneous seizure was recorded on the 93rd day. Generally, the first isolated spikes were seen, on the average of 12 cases, about one

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month after the alum injection and the first seizures could be induced two inonths later. But, generalized fits could not be elicited by these low dosis of Metrazol until almost the 6th month after the injection. A typical electroencephalogram of a Metrazol-induccd seizure of M21 is shown in Fig. 3. A run of spikes began simultane-

Fig. 2: Sketches to show the site of alum injection (cross hatched) and electrodes positions, both cortical and subcortical (M2 1). The following abbreviations are used in this and following figures: AC-anterior commissure, Am-amygdala, APS-anterior perforated space, AT-anterior temporal cortex, C-central cortex, CG-cingulate gyrus, CL-nucleus centralis lateralis, Col icolliculiis inferior, EG-electrooculogram, EKG-electrocardiogram, EMGelectromyogram, F-frontal cortex, Fo 2-H2 field of Forel, GP-globus pallidus, H-hippocampus, HG-hippocampal gyrus, Hy-hypothalamus, MRFmesencephalic reticular formation, NC-nucleus caudatus, Pf-nucleus parafascicularis, PT-posterior temporal cortex, Put-putamen, Resp-respiration, Sb-subthalamus, Teg-tegmentum, VA-nucleus ventralis anterior, VI-nucleus ventralis inferior, VL-nucleus ventralis lateralis.

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ously in the amygdala and the hippocampal gyrus 5 seconds after the intravenous injection of 0.2 mi of 10% Metrazol. The animal became motionless, stared and did not respond to the most external stimuli (A in Fig. 3). After 5 seconds, slow conjugate eye movement and short automatisms of the upper extremities were seen (B). As the firing in the amygdala and hippocampal gyrus continued briskly in the increased frequency of 13 cps with gradual propagation to the ipsilateral subthalamic nucleus, cingulate gyrus, anterior commissure and the contralateral hippocampal gyrus, respiratory arrest occurred (C).Towards the end of the subcortical discharge, the animal vocalized

loudly, chewed and showed purposeless movements of the extremities (D). Several seconds after the simultaneous termination of the seizure activities, the monkey recovered natural movements and responses. Fig. 4 shows mastication and automatism of the left arm (M21). Although the seizures vary from moment to moment in the same and different monkeys, basic patterns, as described above, recurred frequently. In the early stages of the attack, open eyes or searching ocular movements suggest that the monkey has, at least, some knowledge of its environment. As the seizure develops well, the monkey no longer responds

Fig. 3: A series of tracings to show a focal Metrazol-induced seizure (M21), clinically characterized by akinesis and staring (A), conjugate eye movement and short automatism (B), respiratory arrest (C), and loud vocalization, chewing and movement of the extremities (D).

Pathogenesis of Temporal Lobe Epilepsy to mechanical irritation, given to the face or the torso. In about half of the seizures, the fixation of the globus with the eyelids widely opened, producing a staring expression, is observed. After 5 to 10 seconds of staring, rolling conjugate eye movements become evident usually associated with bilateral blinking and occasionally twitching of an eyelid. The pupillary size changes with the movement of the globus, but does not bear a constant relationship to the course of the seizure. A few irregular purposeless movement or jerks of the limbs initiate the seizure in almost half of the cases, particularly when Metrazol is given, but usually the extremities and trunk maintain an akinetic posture for sometimes as long as one minute. Short abnormal movements of the extremities intersperse the akinetic state. Sometimes turn-

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ing of the head and body towards the opposite side of the alum injection occurs. Twitching of the face muscles and car is seen. Mastication occurs usually towards the end of the seizure. Salivation is rarely seen. Changes in blood pressure and pulse rate are inconsistent, but slowing and shallowing of respiration are common occurrences'in the later stage of the attack. In some animals, hiccoughing, eructations or gagging are observed. Urination and defecation occur at the conclusion of the first seizure and rarely in the successive attacks on the same day. A detailed analysis of the propagation of seizure activity in 112 temporal lobe seizures from 10 monkeys is summarized in Figs. 5 and 6. The three main structures of the temporal lobe, the amygdala, hippocampus and

Fig. 4: A photograph, copied from a movie, to show mastication and abnormal movement of the left arm, associated with the firing in the amygdala and hippocampal gyrus (M21). A mirror was placed on the EEG machine.

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temporal cortex, participate intimately in the development of temporal lobe seizures, irrespective of the site of origin. There seems, however, to be a significant difference in the sites and rates of propagation from lateral temporal and mediotemporal foci. Seizures originating in neocortical foci had rather limited propagation to the ipsilateral amygdala and hippocampus and the contralateral temporal cortex (Fig. 7). On the contrary, seizures starting in the mediotemporal structures involved rapidly many subcortical centers, including the hypothalamus, anterior medial thalamus, subthalamus or septa1 region (Fig. 8). DISCUSSION

A correlation of the clinical manifestations

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with the involvement of different temporal lobe structures is difficult. The fact that many temporal lobe structures fire synchronously in most of the seizures, irrespective of their origin, makes any conclusion difficult to substantiate. However, some differences were noted in the seizures originating from the various temporal lobe structures. In the cortical seizures, staring and twitching of the ear were more commonly observed, whereas chewing, vocalization, vomiting, turning movement and suppression of respiration were more frequent with the subcortical seizures, originating from the amygdala-hippocampal complex, usually in the late phase of the attack. Akinesis or abnormal movement of the eye and extremities, which were commonly the primary response of the attack, occurred with almost the same

Sites of Propagation from Neocortical EpilepticFoci 1 Analysis of 33 seizures in 4 monkeys I Contralateral

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Pathogenesis of Temporal Lobe Epilepsy frequency in the cortical and subcortical seizures. The observations in these experiments would suggest that the anterior temporal cortex, amygdala and hippocampus function as a unit especially in epileptic states. The propagation of the seizure activity from this unit follows preferential pathways similar to those described for acute epileptic lesions of the temporal lobe.” I’ The epileptic activity can originate from any of three main temporal lobe structures: the temporal cortex, amygdala and hippocampus. For the development of temporal lobe seizures, the systems of propagation through the following pathways may be important: 1) pathways connecting the tem-

poral lobe structures, 2) pathways to the diencephalic structures through the stria terminalis and fornix, 3) pathways to the basal ganglia, mesencephalic reticular formation or to the lower frontal cortex, and 4) pathways to the contralateral temporal lobe through the anterior commissure, psalterium and the other interhemispheric connections.

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SUMMARY

In 12 rhesus monkeys the injection of alumina cream into the temporal cortex, amygdala or hippocampus induced seizures after a latent period of six weeks to three months. Clinically the attacks are characterized by an arrest of movement, staring, un-

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Siles of Propdydllon froiri Subcortical Epileptic Foci ( Analysis of 79 seizures in 6 monkeys )

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responsiveness to most stimuli, wandering conjugate eye movements, automatisms, twitching of the contralateral ear and less commonly vocalization, chewing, hiccoughing, vomiting, adversive head movements and twitching of the face. The spiking from the amygdala and hippocampus, which usually fire together, propagates to the temporal cortex and multiple subcortical structures including the hypothalamus, anterior perforated space, anteromedial thalamus, cingulate gyrus, putamen, globus pallidus, subthalamus and mesencephalic reticular formation; from the temporal cortex to the amygdala and hippocampus, and secondarily to the diencephalic centers. There is a fairly consistent sequence of preferential propaga-

tion. Although there are some differences in the occurrences of clinical manifestations depending upon the sites of the focus, no specific structural correlation with clinical manifestations could be established. This experimental condition may provide a proper model for the study of clinical psychomotor epilepsy. ACKNOWLEDGMENT This study was made at the Division of Neurosurgery, the Johns Hopkins University, under the aid of a grant from the National Institutes of Health. The author expresses his cordial gratitude to Professor A. Earl Walker for his constant encouragemcnt.

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REFERENCES I Huertas, J. and Forster, F. M.: Temporal lobe seizures in the monkey, Neurology (Minneap.), 5: 329-332, 1955. 2 Kopeloff, L. M., Barrera. S. E. and Kopeloff, N.: Recurrent convulsive seizures in animals produced by immunologic and chemical means, Am J Psychiat, 98: 881902, 1942. 3 Mayanagi, Y. and Walker, A. E.: Experimental temporal lobe epilepsy, Brain, 97: 423-446, 1974. 4 Mayanagi, Y. and Walker, A. E.: DC potentials of temporal lobe seizures in the monkey, J Neurol, 209: 199-215, 1975. 5 Morrell, F., Roberts, L. and Jasper, H.: Effect of focal epileptogenic lesions and their ablation upon conditioned electrical responses of the brain in the monkey, Electroenceph Clin Neurophysiol, 8: 217237, 1956. 6 Poblete, R., Ruben, R. J. and Walker, A. E.: Propagation of afterdischarge between tem-

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poral lobes, J Neurophysiol, 22: 538-553, 1959. Stamm, J. S . and Pribram, K. H.: Effects of epileptogenic lesions of inferotemporal cortex on learning and retention in the monkeys, J Comp Physiol Psychol, 54: 614-618, 1961. Udvarhelyi, G. B. and Walker, A. E.: Dissemination of acute focal seizurzs in the monkey, 1 . from cortical foci, Arch Neurol, 12: 333-356, 1965. Walker, A. E. and Udvarhelyi, G. B.: Dissemination of acute focal seizures in the monkey, 2. from subcortical foci, Arch Neurol, 12: 357-380, 1965. Walker, A. E. and Mayanagi, Y.: Mechanisms of temporal lobe epilepsy in the monkey, In “Epilepsy: Proceedings of the Hans Berger Centenary Symposium” ed. Harris, P. and Mawdsley, C., Churchill Livingstone, Edinburgh, 1974, pp 48-54. Youmans, J. R.: Experimental production of seizures in the macaque by temporal lobe lesions, Neurology (Minneap.), 6: 179-1 86, 1956.