Studies on Ammon's horn sclerosis for the past century and a half have not only contributed greatly to solving the riddles of etiology of epilepsy, but have also given us several important knoweldges for its treatment.
First of all, outstanding classic accomplishments have revealed truths even if they have included some errors. Both these investigators in the 19th century who regarded Ammon's horn sclerosis as the cause of epileptic seizures and those neuropathologists in the twenties of this century who regarded it as the result of seizures touched upon a part of the truth. Today's knowledge allows us to realize that Ammon's horn sclerosis is the cause as well as the result of seizures.
Ammon's horn is now understood to be one of the constituents of the meso-limbic system, and the behavioural changes caused by Ammon's horn sclerosis are interpreted as the limbic hyperconnection syndrome (Bear). Thus a neuropsychological approach has become feasible for the elucidation of the interictal psychopathology of temporal lobe epilepsy.
It is confirmed that seizures leave some neurophysiological or neuropathological trace on the brain. The former was proved by kindling procedures, and the latter was evidenced by Ammon's horn sclerosis. The recognition that epilepsy is progressive-in the sense that, as long as seizures are repeated, traces are aggravated-shows us that overcoming the seizures is the crucial factor in the treatment of the disease.
I have personally learned many things from studies on Ammon's horn sclerosis in the history of epileptology. I sincerely hope my younger colleagues will avail themselves of this learning in the further advancement of the treatment of people with epilepsy.

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A clinical study of psychoses in epilepsy was performed on 1015 patients with epilepsy under observation in Hirosaki University Hospital for 3 years or more. Among the patients, 39 cases (3.8%) manifested psychotic states. The psychotic states could be classified into the following 5. types: schizopherenia-like state, delusional-hallucinatory state, paranoid state, manic-depressive state and ‘Durchgangssyndrom’.
Two cases showed schizophrenia-like state which was difficult to differentiate from schizophrenia. There were 19 cases (44%) of delusional-hallucinatory state, 9 (21%) paranoid, 7 (16%) manic-depressive and 6 (14%)‘Durchgangssyndrom’. Of the cases, 4 showed 2 types of psychotic state in different periods.
Some clinical factors appeared to correlate closely with the psychotic states. Of the cases with delusional-hallucinatory state, 58% had complex partial seizure and the same percent showed temporal spike foci on EEG. However in the other types of psychosis, there were clinico-electroencephalographically no significant findings.
In 24 cases of the subjects, obvious adhesive personality trait was found. Particularly in paranoid state, all of the cases showed the trait and their ability of adaptation to environments was disturbed apparently by the trait.
In 28 cases, on the other hand, some psychologically precipitating factors were found at onset of the psychotic states. All of the cases of the manic-depressive state had the psychological factors.
The authors concluded that there are different types of psychotic state in so-called epileptic psychoses and there appears to be different clinical factors, probably relating to occurrence of the psychotic states. Importance of adhesive personality and psychological factors at onset was stressed in the psychoses.

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Five epileptic patients with distortion of time sense were presented in this paper. Symptomatology: This symptom means the distortion of “temps spatialisé” (after Bergson), but not of “temps vécu”. The symptom was seemed to combine often with other symptoms of psychic seizures. While one case had elemental visual aura accompanied by the symptom.
EEG findings: Interictal EEG revealed antero-temporal spike foci in 3 cases and irregular backgroundactivity in 1 case and HVS burst predominantly in right side in the one. The last case experienced the symptom during EEG recording. Faily rhythmic θ activities appeared in all areas as shown in Fig. 2, however the beginning and the end of seizure manifestation has not been identified clearly.
Neuropsychology: One case had a right parietal lesion in his history. Right dominant EEG abnormalities or lesions were found at three cases in five.
Discussion: From the view point of neuropsychology, Hoff and Potzl classified the changes of time-perspective into following 3 types; 1st. Dehnung oder Verkiirzung des Zeitlebens, 2nd. Zeitrafferphänomen. und Zeitlupenphänomen, 3rd. Ordinativer Störungstypus (Storung des Vor und Nach von Ereignissen in der Zeit). Most of the distortion of time sense in epileptics are 2nd type, rarely to be 1st. Among the cases with the temporal spike foci in interictal EEG, ictal body scheme disturbances or elemental visual aura to be suggested as symptoms of parieto-occipital area were found. The parieto-occipital lesion was supposed in four cases, one from authors' and the others from other reports. Therefore, the symptom could be found in not only the temporal lobe epilepsy but also the parieto-occipital lobe epilepsy. No cerebral dominance has been seen as to the symptom in epilepsy within authors' five cases and the literatures. It is supposed that epileptic discharges propagate rapidly to the opposite hemisphere.

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The clinical characteristics of 70 adult patients with the Lennox-Gastaut syndrome were analysed and compared with those of 103 control group patients who were below the age of 16 and also with the Lennox-Gastaut syndrome.
In the adult group, most patients (83%) had their onset seizures after age 8 and a small number of patients (13%), before age 6. The mean age at the onset of epileptic seizure was 11±5 (s. d.) years. In the control group, most patients (91%) had their first seizures before age 6 and a very small number of patients (4%), after-age 8. The mean seizure onset age was 2.5±2.1 years. The presumed mean age at the beginning of the Lennox-Gastaut syndrome was 17±6 years in the adult, and 4.5±2.8 years in the control group.
The most frequently observed seizure types in the adult patients were: tonic, atypical absence, atonic and astatic seizures. These seizures were commonly resistant to the current antiepileptic drugs. Rather high abnormalities (80%) were found in CT compared with other authors' reports, most common of which was diffuse cerebral atrophy. EEG findings showed normal background activity in 46% and focal abnormalities in 29% of the adult patients. The epileptic recruiting rhythm and the low voltage fast activity were found in 87% of them.
It is concluded that the adult patients with the Lennox-Gastaut syndrome can be classified into two forms: early onset form before age 6 and late onset form after age 8. A large number of the adult patients belong to the late onset. form and only a small number of them to the early onset form which is most commonly seen in children. Thus, the Lennox-Gastaut syndrome should be classified into two in terms of etiological backgrounds: those due to the age-dependent epileptic encephalopathy and to the non-age-dependent epileptic encephalopathy (late onset form).

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DN-1417 (γ-butyrolactone-γ-carbonyl-L-histidyl-L-prolinamide citrate), a TRH analog, was found to have potent central actions and only nominal endocrine activity.
We have reported previously that DN-1417 markedly inhibited activation of paroxysmal discharges with photic stimulation, and improved myoclonus, cerebellar symptoms, psychic activity in one case of degenerative myoclonus epilepsy.
In this paper, we report the clinical effects of DN-1417 on three cases of the Lennox syndrome. In addition to the preceding therapy with conventional anticonvulsants, the patients were injected i. m. with 0.5-1.0mg of DN-1417 everyday for two weeks.
The drug was found to exert an excellent improvement in bradyphrenia and dysphoria. The drug also proved to have antiepileptic effects. The drug inhibited diffuse slow spike and wave complexes and improved dysrhythmia in the EEG. The effects of DN-1417 appeared either on clinical symptoms or the EEG within a week of treatment and persisted for 30 to 70 days after its withdrawal. Neither side effect nor abnormal laboratory findings were observed.

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Clinical seizure types and EEG findings at age 5-10 years were studied on 162 patients of West syndrome seen between 1963 and 1974.
Patients were divided into five groups according to their latest physical and mental status: normal, only physical disability, only mental disability, mild to moderate physical and mental disabilities, and severe physical and mental disabilities.
At ages from 5 to 7 and from 8 to 10, seizure types were analyzed on the basis of international classification of epileptic seizures, and EEG findings were divided into five groups: normal, focal seizure discharges, generalized seizure discharges, hypsarrhythmia, and other abnormalities.
Only 12% of patients showed normal physical and mental development, and 33% showed only mental disability, and 34% had severe physical and mental disabilities.
Throughout all ages, one-third of patients had no seizures at least one previousyear.
About 80% of patients who still had seizures experienced generalized seizures, especially tonic seizures which represented more than 80% of them.
Throughout all ages, about 10% of patients showed normal EEGs, and focal and generalized seizure discharges were almost equally distributed among the patients.
No seizures and normal EEGs were associated with normal development. Patients who had generalized seizures showed a higher percentage of physical and mental disabilities.

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Clinical aspects, long-term prognosis, and the evolution of seizure. types were studied in 304 cases with convulsive disorders in the first year of life. All patients except 45 dead cases were followed until six years of age or older. Seizures during the first year were divided into 5 types according to the clinical features of seizures and the interictal. EEG: 1) unclassified generalized motor seizures (GMS), 2) infantile spasms (IS), 3) seizures belonging to secondary generalized epilepsy other than infantile spasms (SGE), 4) partial seizures (PS), 5) hemiconvulsive seizures (HCS). In patients with GMS during the first year, the prognosis for mental and physical development was the most excellent, and seizures stopped before 3 years of age in most of them. The high incidence of family history of convulsive disorders in them indicates that some genetic factors might be involved in the etiology of GMS. In patients with IS or other SGE, delayed development or neurological abnormality before the onset of seizures were more frequently seen, and the prognosis was the most unfavourable. In patients with PS, the prognosis for mental and physical development and seizures were intermediate between the above two.

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Clinical and electroencephalographic investigations were carried out on newly recognized specific microseizures which appeared in relation to increase of anticonvulsants, especially benzodiazepines in 21 cases of the Lennox syndrome.
1) Clinical symptoms were only irregular respiration and opening the eyes without significant increase in muscle tone. Their duration was very short.
2) The ictal EEG showed peculiar bursts of 8 to 18 c/s diffuse hypersynchronous rapid waves.
3) They appeared exclusively in sleep, mostly in moderate and deep sleep.
4) They accompanied sleep abnormalities, such as decrease in the stage REM and poor differentiation of sleep levels after stage 2.
5) They appeared in relation to an increase of benzodiazepines and were suppressed by their decrease or discontinuation. This fact strongly supports the possibility that these seizures are induced by benzodiazepines.
Benzodiazepines have the dual actions as hypnotics and antiepileptics. On the other hand, the remarkable exaggeration of epileptic discharge in sleep indicates the pathophysiology of the Lennox syndrome is closely related to the sleep mechanism. A higher dose of benzodiazepines exceeding the critical level possibly lowers the level of consciousness. It also exerts a stronger hypnotic effect than the expected antiepileptic effect on the epileptic mechanism in the brain, resulting in induction of a new type of specific microseizure.
Unexpected excessive dosage of anticonvulsants used in the intensive treatment of intractable seizures may sometimes evoke a state which is likely to induce microseizures. On such occasions, better therapeutic results can be achieved by a decrease of antiepileptics to an appropriate dosage which would lead not only to a cessation of seizures but also improved mental function.

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Smooth pursuit eye movements (SPEM) were recorded in 18 normal and 84 epileptic subjects. In epileptics, rate of saccades in SPEM was higher than that of normal controls. Seventy-five of our 84 epileptic patients had been taking one to several kinds of antiepileptic drugs. It was demonstrated that remarkable disorder of SPEM was observable in more than half of epileptic patients receiving antiepileptic medication.
The effect of antiepileptic drugs was supposed to be a cause of the SPEM disorder, because no remarkable saccades were observed in epileptics who were not receiving antiepileptic medication and SPEM disorder in epileptic was seen frequently in patients with a long period of treatment.
With regard to phenytoin, most of the SPEM disorder in epileptics was observed in patients who had been given phenytoin more than 150mg a day for a long period of time.
Although it was suggested that high serum concentration of phenytoin or phenobarbital contributed to a part of SPEM disorder, in most of SPEM disorder in epileptics, there was no correlation between serum concentration of antiepileptic drugs and rate of saccades.
It was also demonstrated that there was a close relationship between conjugate lateral gaze nystagmus and SPEM disorder in epileptics.
It is conceivable that the SPEM disorder in epileptics represents a latent or subclinical chronic cerebellar dysfunction due to phenytoin medication.
It is suggested that the SPEM measurement is a useful tool to find out subclinical side effects of some antiepileptic drugs in the treatment of epilepsy.

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Daily repetitive electrical stimulations to a distinct site of the animal brain result in a progfessive augumentation in neuronic excitability and a lowering of seizure threshold (the. kindling phenomenon). Recent studies have disclosed that the constitutional or aquired convulsive predisposition plays a significant role to modulate the evolution of clinico-electrographic seizure events. In this study a series of long term experiments were designed to determine the effect of parenteral administration of pentylenetetrazol (PTZ) prior to the daily stimulation as a strategy of producing a convulsion-prone condition in cats.
Fourteen cats used were devided into the amygdaloid kindling group (7 cats) and the frontal-cortical kindling group (7 cats); the seven cats of each group were further devided into a control group (3 cats) and a PTZ group (4 cats). The individually determined subconvulsive threshold dosage of PTZ (Range: 14-25mg/kg with a mean of 17.9±SD 3.0) was intramuscularly injected every day immediately before electrical stimulation.
The PTZ group of both the amygdaloid and frontal cortical kindling showed a distinct facilitation of clinico-electrographic seizure developments in comparison with the control group. In addition to the facilitation of kindling stages shown by the PTZ groups, the acceleration of interictal epileptic discharges in time and space which closely correlate with secondarily established neuronic hyper-excitability were also exemplified in the PTZ groups of both the amygdaloid and frontal animals.

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There is increasing evidence that cyclic adenosine 3', 5'-monophosphate (cAMP) and cyclic guanosine 3', 5'-monophosphate (cGMP) have important roles in the pathophysiological mechanisms of epileptic seizures. However, the relationship between persistent epileptogenesis and cyclic nucleotides systems in neural tissue has not been well studied.
The present study, therefore, was performed to examined the hypothesis that kindling itself might produce a long-lasting increase of both nucleotides in the brain, since this could be one mechanism of persistent epileptogenesis. Stimulations (300μa, 50 Hz, 1 sec, twice each day) were delivered to the left amygdala until a full convulsion was achieved on 5 consecutive stimulations. Thirty days after the last stimulation the animals were sacrificed by microwave irradiation.
The concentrations of cAMP and cGMP were measured by radioimmunoassay methods. The concentrations of cAMP had increased remarkably in the right hippocampus (P<0.05) and both occipital cerebral cortices (P<0.02) in kindled animals. In the left amygdala, which had been stimulated, the concentrations of cAMP increased but not significantly (P<0.1). The concentrations of cGMP in the kindled animals increased significantly in the stimulated left amygdala (P<0.05), as well as in both hippocampi (left P<0.05, right P<0.001) and both occipital cerebral cortices (P<0.02).
These data suggest that the persistent regional excitability, which may be associated with synaptic potentiation, produced by kindling may be attributed to a longlasting regional increase of both cyclic nucleotides.

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To investigate the possible roles of cyclic nucleotides in the mechanisms of epi-leptic seizures, dibutyryl-cAMP (db-cAMP) or dibutyryl-cGMP (db-cGMP), either acyclic nucleotide derivative, was injected into the left amygdala of rats in doses of 1.0, 20, 100 and 200μg, and the behavioral and EEG changes were monitored. Afterwards, histological examinations were performed mainly in the dorsal hippo-campus and the injection site (amygdala).
The following results were obtained; 1) Single jerks and sporadic spikes were induced by 1.0 μg of db-cAMP. Facial twitching, searching and sniffing were induced by 20μg of db-cAMP. Seizure development from facial twitching to generalized convulsion was induced by 100μg of db-cAMP, and status epilepticus was induced by 100 big or more of db-cAMP. Very similar seizure patterns were induced by db-cGMP. However, db-cGMP was less potent than db-cAMP for the same dose, and the highest dose of db-cGMP did not cause status epilepticus.
2) At the injection site (amygdala), the histological changes induced by db-cAMP were characterized by neuronal cell losses and gliosis. Similar changes were also produced by db-cGMP.
3) After status epilepticus was induced by db-cAMP, an extensive cell loss in the CA3-4 fields of the pyramidal cell layer was observed in the hippocampus. On the other hand, only minimal changes of the pyramidal cell layer were observed after seizures induced by any dose of db-cGMP and the smaller doses of db-cAMP that did not develop status epilepticus.
4) These results suggest that both db-cAMP and db-cGAMP, in paticular db-cAMP, have neurotoxic and neuroexciting effects similar to those of kainic acid, and that microinjection of these derivatives into the rat amygdala provides a good experimental seizure model for epilepsy and status epilepticus.

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