Tohoku J. Exp. Med., 1990, 161, Suppl., 253-271 Intractability of Complex Partial Seizure with Secondary Generalization: Kindling Studies in Cats MITSUMOTOSATO Department of Neuropsychiatry, Okayama University Medical School, Okayama 700 SATO, M. Intractability of Complex Partial Seizure with Secondary Generali- zation: Kindling Studies in Cats. Tohoku J. Exp. Med., 1990, 161, Suppl., 253- 271•\Among many factors linked to an intractability of partial seizure secon- darily generalized, changes in the brain resulting from repeated epileptic seizures are discussed mainly in light of our evidence obtained from kindling studies in cats. In addition, the literatures on biological mechanisms of the kindling effect are reviewed briefly. The evidence demonstrated and reviewed here indicates that: 1) limbic structure is not susceptable to develop generalized convulsions initially, 2) repeated attacks of limbic seizures result in a profound reduction in seizure threshold at the primary epileptogenic focus in the limbic structures, 3) once a limbic seizure developed to secondarily generalized convulsion, it seldom changes into the original partial seizure, 4) kindled events in the limbic structures are more profound and persistent than that in the cerebral cortex, and 5) repetition of focal cortical or limbic seizures may eventually produce spontaneous convulsive seizures originating in the limbic structures. These findings strongly suggest that the limbic system, rather than the cerebral cortex, is more susceptible to a lasting functional change resulted from seizure repetition, which can lead to an intractability of epilepsy with partial seizure. Lasting changes in the cell mem- brane including long-lasting enhancement of inositol phospholipid hydrolysis of the amygdala stimulated by excitatory amino acid appear important for develop- ment of trans-synaptic changes underlying the kindling-induced seizure susceptibil- ity.•\intractability; limbic seizure; focal cortical seizure; secondary sei- zure generalization; kindling mechanism Epilepsy is one of the most common neurological diseases with an incidence estimated to be between 0.3 to 0.5%. Some epileptic patients suffer from intractability of epileptic seizures. Many factors that lead to a poor prognosis of epilepsy have been documented except for progressive excerbation of some under- lying neurological diseases. Rodin (1968) described 4 factors linked to poor prognosis : 1) partial or mixed seizure types, 2) presence of an abnormal neur- ological or mental state, 3) low IQ, and 4) increase in the number of seizures and duration of epilepsy before referral. Reynolds and others (1983) reported that Present address and reprints requests to : Mitsumoto Sato, Department of Neurop- sychiatry,`Tohoku University School of Medicine, 1-1 Seiryo-machi, Aoba-ku 980, Sendai, Japan. 253 254 M. Sato there was less certainty about the influence of age of onset of epilepsy, of EEG abnormalities, and of genetic factors. The factor that the seizure type links to an intractability of epilepsy has been confirmed by a Japanese epilepsy study group in 1981 (Okuma and Kumashiro). According to the data on seizure control, the remission rates for partial seizures with secondary generalization and some of the combined seizure types such as elementary and complex partial seizures with generalized tonic-clonic seizures were significantly lower than the mean remission rate of seizures overall (Table 1). With regards to the number of seizures and duration of epilepsy as a poor prognostic factor, Gowers (1881) has stated : "when one attack has occurred, whether in apparent consequence of an immediate excitant or not, others usually follow without any immediate traceable cause. The effect of a convulsion on the nerve centres is such as to render the occurrence of another more easy, to intensify the predisposition that already exists. Thus every fit may be said to be, in part, the result of those which have preceded it, the cause of those which follow it "(Reynolds et al.1983). The following evidence that support this Gowers' hypothesis has been available thereafter. Firstly, there are reports of spontane- ous convulsions that appeared in non-epileptic patients with schizophrenia after repeated electroconvulsive therapy too many times. In fact, more than 200 such cases have been reported by at least 14 authors (Sato and Wada 1975). As an example, Naoi (1959) has reported 35 cases with spontaneous convulsive seizures out of 172 schizophrenic patients who had been treated with electroconvulsive therapy : 26 out of these 35 cases had received the therapy more than 50 times. Secondly, the occurrence of spontaneous convulsions as well as an augmented TABLE.1 Outcome of seizure control Remission means disappearance of seizure for more than 3 years. GTC, generalized tonic-clonic convulsion ; n, number of subjects (Okuma and Kumashiro 1981). Epilepsy and Kindling 255 epileptic response after repeated electroconvulsive seizures has been reported in animal experiments by several authors (Alonso-de Florida and Delgado 1958 ; Delgado 1959; Delgado and Sevillano 1961; Herberg and Watkins 1966). God- dard and others (1969) investigated such phenomenon systematically and used the term kindling effect to describe the phenomenon. The kindling effect seems to be an adequate animal model to study the Gowers' hypothesis. Kindling effect and its transference phenomenon The kindling effect is a process whereby repeated induction of local epileptic manifestation results in long-term changes in neural organization, and when repeated many times, eventually results in generalized convulsions (Goddard et al. 1969 ; Racine 1972) and spontaneous seizures (Goddard and Douglas 1976 ; Wada et al. 1974). The kindled events which include readiness for kindled generalized convulsions and produced interictal spike discharges persist for one year without further stimulation (Wada et al. 1974). Related to kindling is the phenomenon called transference, which is a significant saving of kindling stimuli required for re-kindling at a secondary brain site following a primary brain site kindling. Transfer of the primary site kin- dling to a secondary site was confirmed after removal of the primarily kindled brain site (Racine 1972). Accordingly, this phenomenon presumably based on a trans-synaptic change from the primarily kindled site to the secondary site. Moreover, the kindling transfer was found to occur after a 14 day interval between the end of the primary site kindling and the beginning of the secondary site re-kindling (McIntyre and Goddard 1973). These findings indicate that the kindling-induced functional change in the secondary brain site lasts at least for 2 weeks, and is independent of the change in the primary site. The necessary conditions for kindling are recurrent appearance of after-discharges (AD) with an adequate intertrial interval (Racine 1978). Repeated administration of a stimu- lus which intensity is insufficient to produce an AD can not preduce kindling, and repeated stimulations applied at less than 20 min interval often produce adapta- tion rather than kindling (Goddard and Douglas 1976). Thus, it is clear that repeated induction of localized AD results in a lasting increase in seizure suscepti- bility in the brain which presumably based upon a trans-synaptic change originat- ing in the primary epileptogenic focus. General procedures A series of our data described here are restricted to those obtained from kindling in cats. The kindling stimulus was one sec trains of a 60-Hz sine wave at an intensity minimal to produce AD. In kindling session, the kindling stimu- lus was delivered once daily until generalized convulsions were produced on 5 consecutive days. After 7 days from the last convulsion, re-kindling from a secondary brain site was started to examine the transference phenomenon. Our 256 M. Sato previous classification of seizure stages in amygdaloid (Wada and Sato 1974), hippocampal (Sato 1975), septal (Sato 1976, 1980) and Sylvian gyrus (Sato et al. 1980b) kindling in cats was used to assess chronological changes in behavioral seizure manifestations during kindling and re-kindling sessions. Behavioral observation with simultaneous EEG recording was performed before and after each daily stimulation and during spontaneous seizures. Which is more susceptible to produce generalized convulsions, the cerebral cortex or limbic structures ? A one-sec stimulation of one mA intensity was delivered to the sylvian gyrus and limbic structures to examine the first trial generalized convulsions. The first trial generalized convulsions were observed in 5 of 9 cats after Sylvian gyrus stimulation (Table 2). No epileptic response or partial seizure was produced in the other 4 cats. On the contrary, when the amygdala, hippocampus and septum were stimulated, no generalized convulsion was produced in any of the 15 cats examined (Ebara et al., unpublished). This result shows that the Sylvian gyrus is more susceptible to the first trial generalized convulsions than limbic structures when high current stimu- lation was applied. In other word, the limbic structures are less susceptible to produce generalized convulsion than the cerebral cortex, initially. The progres- sive development of partial limbic seizure to secondarily generalized convulsions after seizure repetition may depend upon increased functional connections (God- dard 1981) between the kindled limbic structure and the cerebral motor cortex. Tanaka (1977) reported the appearance