Ammon's Horn Sclerosis : Its Pathogenesis and Clinical Significance

Tohoku J. Exp. Med., 1990, 161, Suppl., 273-295

KEIJI SANOand TAKAAKIKIRINO Department of Neurosurgery, Teikyo University, Tokyo 173

SANO, K. and KIRINO, T. Ammon's Horn Sclerosis : Its Pathogenesis and Clinical Significance. Tohoku J. Exp. Med., 1990, 161, Suppl., 273-295•\

Sclerosis of the cornu Ammonis or Ammon's horn sclerosis (AHS) is an "often- described, yet hitherto enigmatic phenomen" as Spielmyer put it in 1927. It has

been found in cases with ischemia, anoxia or hypoglycemia and in more than half

of the epileptic brains examined at autopsy. Various theories about its pathogenesis have been propunded. Among them, the "Pathoklise" theory of the

Vogts and the vascular theory of Spielmeyer and his associates were prevailing

until recently. In 1953, two articles were published to contribute to the pathogenesis of ictal automatism (a type of complex partial or temporal lobe seizures).

One is the incisural sclerosis theory by Penfield and his associates and the other is the Ammon's horn sclerosis theory by Sano and Malamud. The former authors

described a diffuse sclerosis of the infero-mesial temporal structures without,

however, specifically relating it to AHS. They considered it was the result of localized anoxia of that portion of the brain caused by incisural herniation

occurring during parturition. Sano and Malamud maintained that AHS is a result

of convulsions, a distinct scar adjacent to which epileptogenic foci may develop in the course of time to cause ictal antomatism. The latter theory was corroborated

by Sano, Falconer and others. Falconer expanded the theory to the assertion that

not only ictal automatism but other types of intractable epilepsy may be due to "mesial temporal (Ammon's horn) sclerosis" . The most recent development in the

pathogenesis of AHS is the excitotoxicity theory. Namely, AHS is caused by excessive excitation of neurons, probably by putative excitatory neurotransmitters,

especially, glutamate. For this theory, there is a significant body of evidence. The problem of AHS, an old research subject and a matter of long-lasting contro-

versy, has now been updated and become one of the newest topics in the field of

experimental neurobiology.•\Ammon's horn sclerosis; historical view; temporal lobe epilepsy; ischemic neuronal damage

Historical account of the term "Hippocumpus" or "Cornu Ammonis" In a book titled "De Humano Foetu" published in 1587, Julius Caesar Arantius (Italian Aranzi) (1530-1589), a pupil of Andreas Vesalius, described a structure in the inferior horn of the lateral ventricle which recalled the image of a "Hippocampus", that is, "Marinus Equulus" (a little horse of the sea) or rather of a "Bombycinus Vermis Candidus" (a white silk worm) (Lewis 1922-1923; Tilney 1938). The term bombycinus vermis, which was more becoming of the two, has never gained popularity and has been forgotten in the literature. The 273 274 K. Sano and T. Kirino

other term hippocampus has left the readers in doubt whether the anatomical

structure was being compared with fish or mythodological horse.

The mythodological hippocampus, the horse of Poseidon (Neptunus) or

Triton, has the shape of a horse in its fore part and that of a fish in its hind

portion. Its forelegs are shown sometimes with horse's hoofs, sometimes with flippers. It was about 100 years later that Diemerbroek (1672, cited from Lewis

1922-1923) named this structure Pes hippocampi because of the similarity of this

and the flippers of the imaginary hipocampus. This nomenclature was again

adopted in INA (1936) and in PNA (1955).

If, however, one is frank enough, he may say the hippocumpus of the brain

is more like a paw of a hippopotamus. Thus, Johan C.A. Mayer (1779, cited from

Lewis 1922-1923) proposed the term •gPes hippopotami major•h for this structure.

By the way, Pes hippopotami minor corresponded to Calcar avis which was

described by Morand (1744, cited from Lewis 1922-1923). The designation of

Mayer may be regarded as a modification of that of Haller (1762, cited from Lewis

1922-1923) who proposed Pes hippicampi major for the hippocampus and pes

hippocampi minor for the calcar avis.

BNA (1895) adopted Hippocampus and at the same time Digitationses

hippocampi, therefore evidently thinking of the mythodological horse under the

name of Hippocampus. This view has been fixed among anatomists since then.

PNA adopted Pes hippocampi, and at the same time, Hippocampus which

includes Pes hippocampi, Alveus hippocampi, and Fimbria hippocampi.

Among neurophysiologists, however, Hippocampus as the sea-horse fish has been prevailing, probably since MacLean (1949). The sea-horse fish, the mythodological horse or the hippopotamus, all these are related with water and are pertinent to that structure which lies in the cerebrospinal fluid. If one takes the structure out of the ventricle, one may notice that it may look like a horn of some

animal. Winslow (1732, cited from Lewis 1922-1923) regarded it a ram's horn and named it Corn arietis (ram's horn). It was de Garengoet (1742, cited from

Lewis 1922-1923) who prefered a more mystical name and called it Cornu

Ammonis (Ammon's horn). Ammon (Amon, Amun, Amen, Amoun), the Hidden , was the first god of Thebes in Ancient Egypt. When the rulers of Thebes found the 12th Dynasty, Ammon became the chief diety of Egypt. In the early picture,

Ammon was expressed as having the head of a ram with ram's horn. As Amon-Re

(Ra, Phra), he was represented in the form of a man wearing on his head a disk surmounted by two tall ostrich plumes. Therefore Cornu Ammonis is identical with cornus arietis. This Cornu Ammonis or Ammon's horn or its German equivalent Ammonshorn has found its favorite place in the German bibliography.

The term hippocampal formation which includes hippocampus, fascia dentata

(gyrus dentatus) and subiculum may probably originate from Formatio Ammonis of Rose (1927). Ammon's Horn Sclerosis 275

Historical account of Ammon 's horn sclerosis (Sclerosis of the Cornu Ammonis)

The first gross description of this lesion is generally credited to Bouchet and

Cazauvielh 1825, cited from Spielmeyer 1927) who observed changes of sclerosis or sofening in the hippocampus of epileptic as well as of nonepileptic psychopathic patients. The first microscopic examination was done in 1880 by Sommer who found the change to be restricted to the band of pyramidal cells of the hippocampus which has since been called •gSommer's sector•h. In 1889, Chaslin described a marginal gliosis in cases of epilepsy and regarded Ammon's horn sclerosis as representing merely a site of predilection for such gliosis. In 1899,

Bratz (1889a, b) confirmed Sommer's findings but noted that the end-plate was as often affected as Sommer's sector and that a portion of the dorsal cell band was resistant in many cases. He found that Ammon's horn sclerosis existed in 25 out of 50 cases of idiopathic epilepsy, and he also noted the same lesion in other diseases associated with convulsive disorders. He regarded Ammon's horn sclerosis as a congenital lesion.

Stauder (1935) found Ammon's horn sclerosis in 36 of 53 patients with long-standing epileptic seizures and he could notice, in most of these 36, clinical pictures related to temporal lobe lesions. In 1953, Sano and Malamud discovered Ammon's horn sclerosis in 29 (58%) of the brain of 50 institutionalized epileptic patients. This Ammon's horn sclerosis was found unilaterally in cases of "idiopathic epilepsy" and bilaterally in cases with malformed brains as was previously noted by Bratz (1920). Sano

Fig. 1. Nomenclature of various divisions of the hippocampal formation according to Rose, Lorente de No or the Spielmeyer's school. Subiculum includes subiculum and prosubiculum of Lorente de NO. 276 K. Sano and T. Kirino and Malamud (1953) plotted sclerotic changes of the hipocampus according to Rose's cell divisions (1927) and found the severest changes in H1 and H5 (CA1 and CA4 of Lorente de NO (1933, 1934) which correspond to the so-called Sommer's sector and the end-plate (Bratz's sector) respectively. Figure 1 shows diagram- matically the correlation between the cell divisions of Rose (1927) and Lorente de NO (1933, 1934) and traditional terms used by Spielmeyer's school (Bodechtel 1930). In contrast to Stauder (1935) who correlated Ammon's horn sclerosis with neurological deficits of the temporal lobe, Sano and Malamud (1953) propounded a theory that psychomotor epilepsy or ictal automatism may be due to firing of foci adjacent to the sclerosed area (e.g. Sommer's sector), especially in cases that developed automatism in the course of repeated convulsive seizures. This will be discussed below. As for the pathogenesis of Ammon's horn sclerosis, there have been keen active discussions between two German schools. The Vogts (Vogt and Vogt 1922; Vogt 1925) regarded it as strong evidence for their theory of Pathoklise, arguing that the sharp differences in cell morphology in Sommer's sector, the end-plate, the portion between them, and the subiculum represented differences in physico- chemical structure. Accoding to Spielmeyer and his associates (Spielmeyer 1925, 1927, 1929, 1930a, b, 1933; Uchimura 1928a, b), the change was explained on a vascular basis. They demonstrated ischemic changes in Sommer's sector and in the end-plate in acute cases of epilepsy and assumed that in chronic cases the degenerated ganglion cells were ultimately replaced by glia, to produce the final picture of sclerosis. Moreover, they observed similar changes in primary vascular or circulatory disorders. In the absence of vascular disease in "idiopathic" epilepsy, they advanced the theory of angiospasm. It is well known that the anteroinferior portion of the hippocampal formation is supplied by the anterior choroidal artery, while its major part is supplied by the posterior cerebral artery. The branches of these two arteries anastomose near the anterior end of the hippocampal formation. According to Uchimura (1928a, b), a pupil of Spielmeyer, Sommer's sector, unlike the other portions, is supplied by only one artery, which he named Sektorgefass. Originating in the above- mentioned branches, this vessel pierces the surface of the dentate fascia and runs in the septum between it and the hippocampus, assuming a relatively long and twisted course to reach Sommer's sector, where it forms a rather poor capillary network (although this is in dispute (Cobb 1929)). This vessel has few branches and, more than any other blood vessel in the brain, possesses the character of an end-artery. The capillary network in the end-plate is also relatively poor. As a result, the ganglion cells of these areas are extremely vulnerable to circulatory insufficiency. Moreover, because of its long, twisted course in the septum, where gliosis tends to occur early, this vessel is predisposed to angiospasm. Altschul (1938) first noted in the human brain that these Sektorgefass (Uchimura's Ammon's Horn Sclerosis 277

Fig. 2. Artierial supply of the hippocampal formation.

1: internal carotid artery (a. ), 2: anterior cerebral a., 3: middle cerebral a., 4: posterior communicating a., 5: anterior choroidal a., 6: posterior cerebral

a., 7: arterial laminae tecti, 8: medial posterior choroidal a., 9: Ammon's horn artery or arteries with •gSektorgefasse•h of Uchimura, 10: lateral poste-

rior choroidal a., 11: basilar a., 12: superior cerebellar a., 13: choroid

plexus, 14: hippocampus.

arteries), consisting of 12 to 15 branches, arise from the trunk in a rake-like pattern

(Fig. 2). Scharrer (1940) found the same vascular pattern in the artery supplying the Cornu Ammonis of the opossum, and he explained on this basis the sclerosis of the cornu Ammonis which follows carbon monoxide poisoning. This observa- tion was confirmed by Nilges (1944) who found such rake-like branching of the blood vessels to the hippocampus in many mammals, including the monkey.

Alexander and Putnum (1938) found that Sommer's sector, unlike other parts of the brain, was supplied by branches not longer than •gvessels of the fourth order•h, and that they were the smallest ones among those of the same order, being 20 to

16ƒÊ in diameter. Suger and Gerard (1938), using the brain potential as an indicator, showed the gray matter of the cerebellum and the cornu Ammonis were the areas of the brain most liable to be affected by anemia.

But, while the particular angioarchitecture of the hippocampal formation accounts for its vulnerability, there is no evidence of any widespread vasoconstric- tion occuring during or immediately preceding a seizure. The studies by Gibbs and associates (Gibbs 1933; Gibbs et al. 1934) and Penfield and associates (1939) showed, rather, an increase of cerebral blood flow during a seizure. The latter authors maintained that such increased circulation occurs in the area of cortex 278 K. Sano and T. Kirino which is involved in the discharge producing the seizure and that it is secondary to that discharge. Other areas of the cortex may show no alteration in circulation, although in some instances there may be decreased curculation of short duration at a distance form the discharging zone. There are two possible expalanations for these discrepancies: 1. The ganglion cells of the cornu Am- monis are involved in the discharge and are damaged, owing to ralative ischemia; i.e., the circulation to that area is insufficient to supply the demand made by the cells, which are working excessively, although the absolute blood flow increases.

2. The cornu Ammonis is not involved in the discharge and is damaged because the blood supply to the discharging regions increases, thereby causing relative decrease in the blood flow to the hippocampus (intracerebral steal).

Why some epileptics show Ammon's horn sclerosis and others do not, and why many patients with •gidiopathic•h epilepsy show unilateral changes and most of those with malformed brains show bilateral changes, is not clear. Those with malformed brain usually have severe convulsive seizures, dating from infancy.

Although the infant's brain is more resistant to anoxia and hypoglycemia, many clinical facts suggest that it is rather less resistant to violent seizure activity than is the adult brain. Thus, the bilateral change could easily occur, particularly since all parts of the cerebral cortex must be involved in the discharge when the brain is malformed. For the unilaterality of Ammon's horn sclerosis seen in many cases of idiopathic epilepsy there seems to be no convincing explanation.

In some cases the hippocampus may be involved in the seizure discharge on one side only. In two cases of post-traumatic epilepsy in the series of Sano and

Malamud (1953), sclerosis of the cornu Ammonis was observed on the same side as the traumatic lesion. A new concept of pathogenesis of Ammon's horn sclerosis will be described in the fourth section.

Ammon 's horn sclerosis and temporal lobe seizure

In 1875, Hughlings Jackson (Jackson 1931-1932) referred to "temporary mental disorders after epileptic paroxysms" as states of mental automatism. He believed that the automatism was always postepileptic and was due to loss of control from the highest centers, which had been paralyzed by the epileptic discharge. He admitted, however, that there are cases in which the automatism is not preceded by a convulsion. This state was later called by Penfield and

Erickson (1941) •gictal automatism•h, implying that the highest level could be paralyzed by a discharge during seizure. This is thought to be identical with a type of epilepsy designated by Gibbs et al. (1937) as •gpsychomotor•h, as a clinical and electroencephalographic entity. Jackson also made a detailed description of a variety of epilepsy which he termed •gdreamy state•h, the characteristic features of which were illusion or hallucinations (Jackson 1931-1932c), sometimes followed by automatism and sometimes preceded by crude sensations of smell; •guncinate fits•h (Jackson 1931-1932d). Ammon's Horn Sclerosis 279

He believed that this type of seizures was due to temporal lobe lesions, and

the first autopsy case with this seizure type was reported by his assistant,

Anderson (1886). As the follower of Jackson who believed that all types of epileptic seizures had a discharging lesion or lesions (focus or foci) (Jackson 1931-

1932a), or , in modern terminology, some populations of neurons which generate high-frequency synchronous discharges (Prince and Connors 1984), Penfield sear- ched for and found the focus of dreamy state seizure in the temporal lobe on the basis of operative findings (Penfield and Erickson 1941; Penfield and Franigin

1950; Penfield 1954; Penfield and Jasper 1954). Jasper and his associates (Jas- per and Kershman 1941; Jasper et al. 1951) concluded from electroencephalographic evidence that ictal automatism also originated in the temporal lobe. Gibbs and associates (1948), using sleep technique, localized the electroencephalographic focus for •gpsychomotor•h epilepsy in the anterior tip of the temporal lobe in the great majority of cases. These two types of epilepsy, which are intimately connected with each other, have thus been called "temporal lobe seizures" (Penfield and Franigin 1950;

Jasper et al. 1951). In the modern international terminology, these types of seizures are now called complex partial seizures.

In 1953, two articles explaining the pathogenesis of ictal automatism appear- ed. One is the incisural sclerosis theory by Penfield and his associates (Earle et al. 1953) and the other is the Ammon's horn sclerosis theory by Sano and Malamud

(1953). The former authors described a diffuse sclerosis of the inferomesial temporal structures without, however, specifically relating it to the earlier description of Ammon's horn sclerosis. They considered it was the result of injury to the brain during parturition ; as a result of excessive moulding of the head of the newly-born, the incisural edge of the tentorium compress branches of the anterior choroidal and posterior cerebral arteries leading to localized anoxia and infarction which in due course ripened into an epileptogenic lesion. This idea was supported by Gastaut (19

However, according53). to Falconer (1968), this concept is untenable and unacce- ptable. There was no difference in the incidence of birth injury or of difficult birth in patients who were shown at operation to have mesial sclerosis and those who were not.

Sano and Malamud (1953) presumed that Ammon's horn sclerosis is a result of convulsions, a scar adjacent to which may develop epileptogenic foci. They stated, •gIf there is a scar in the epileptic brain, either primary, such as one due to trauma, or secondary, due to the seizure itself, epileptogenic foci may develop around it in the course of time. Since sclerosis of the cornu Ammonis represents a distinct scar, one can expect in the epileptic brain discharging foci in neighbor- ing structures, most likely in the prosubiculum and adjacent parts of Sommer's sector. These parts are known to send fibers both to the temporal lobe, possibly the tip, and to the hypothalamus, through the fornix. Thus, a focus in these areas 280 K. Sano and T. Kirino

could fire the temporal tip to produce a secondary focus there, with spike activity manifested in the anterior temporal region, and it could also bombard the hypoth-

alamus. Since the main endings of the fornix fibers are in the mamillary body, the perifornical nucleus, and the septal region, specific symptoms can be expected to develop from bombardment of these regions•h.

Their theory was further corroborated by Sono et al (Sano and Kitamura

1954; Sano 1958) who found, at operation on cases with ictal automatism, spike

foci adjacent to the sclerosed Sommer's sector of the Ammon's horn which was

resected. Sano (Sano and Kitamura 1954 ; Sano 1958) divided psychomotor

seizures or complex partial seizures into the following 3 types (see also Table 1) : I. Ictal automatism This is characterized by behavior abnormalities of any kind from the simple absent-mindedness (except with 3c/s spike-wave patterns) for a short period to complex quasipurposeful automatic movements, of which patients have no memory. No auras (or initial phenomena) precede the attack. During the ictus oral-masticary movements may appear, 64% in his series. II. Dreamy state seizure This is characterized by disorders of apperception, namely, illusion or hallucination, preceded by no auras (or initial phenomena). 6% in his series. III. Automatism or dreamy state preceded by auras or initial phenomena of any kind. Visceral auras are most frequently seen. 3% in his series. Psychomotor epilepsy can be classified also in another way: primary and secondary psychomotor seizures. The latter develop in the course of repeated convulsions, independently of convulsive seizures. The former start as such from the very beginning of the clinical course. In his series 47% of cases are primary and 53% are secondary. In ictal automatism, 37% are primary and 63% are secondary. In dreamy state seizure,. 89% are primary and only 11% are secondary. In those preceded by auras, 58% are primary and 42 are secondary (Table

TABLE1. Complexpartial seizureor psychomotoror temporal lobe seizure

Main three types devided into primary and secondary seizures (320 cases) Ammon's Horn Sclerosis 281

1). As is well known, almost all cases of psychomotor epilepsy (Complex partial seizure) showed spiking in the temporal region in interictal records, especially during sleep. We have been using long insulated needle electrodes inserted into the depth of the skull, besides ordinary electrodes. About 80% of ictal automatism showed most prominent spiking in the medial infratemporal lead, while in dreamy state seizure spikes are found in the lateral temporal leads (Sano and Kitamura 1954). As of March 1973, 41 cases of drug-resistant complex partial seizures under- went resection of the temporal lobe mostly including the uncal-amygdaloid area and the anterior portion of the hippocampal formation. All the cases of secondary ictal automatism showed spike foci in the subiculum (including the prosubiculum) of the hippocampal formation (Fig. 3). Microscopic examination of the removed tissue revealed sclerosis of the cornu Ammonis where sommer's sector just close to the subiculum was most severely affected. These findings are in support of the above-stated theory that in secondary ictal automatism epileptogenic foci developed in connection with Ammon's horn sclerosis. In almost all cases of dreamy state seizures, foci were found in the lateral temporal cortex. Foci in cases with auras or initial phenomena followed by automatism or dreamy state were located in the uncal-amygdaloid area, the anterior temporal tip, the sylvian bank and other areas (Table 2). Foci in the anterior temporal tip or pole (area TG or 38) were found in either type of primary automatism, dreamy state or preceded by auras, though in a relatively small number. The temporal lobe consists of three major areas, different developmentally and cytoarchitecturally: namely, archi-, palaeo-, and neo-cortices (Brodal 1947). From the above-mentioned data, the following deduction might be justified.

Fig. 3. Ammon's horn sclerosis and spike foci. 282 K. Sano and T. Kirino

TABLE2. Spike foci of temporal lobe epilepsy (psychomotor epilepsy) as verified by operation (41 cases)

Numerals are number of cases. I.A., ictal automatism ; D.S., dreamy state.

Epileptogenic foci in the archicortex (hippocampal formation) cause chiefly ictal automatism (type I). Foci in the neocortex cause chiefly dreamy state seizure (type II). Foci in the palaeocortex including the uncal-amygdaloid area (and some areas of the orbito-limbic system) elicit automatism or dreamy state preceded by initial phenomena among which visceral auras are most frequently seen (type III). Foci in the temporo-polar transitional cortex (area TG or 38) may cause any of the three types of seizure according to ways of spreading of discharge from the foci, as is experimental studies in monkeys (Mayanagi and Walker 1974). These are summarized in Table 3. Post-operative psychic changes were as follows : 1) Disturbance of memory, especially of recent one. This was marked in case where operative lesions were chiefly located in the hippocampal formation. 2) Emotional and personality changes. These were seen in cases with hippocampal and uncal-amygdaloid lesions. 3) Disorder of comprehension of abstract concepts. (No changes in I.Q. by unilateral operation) 4) Disorder of verbal memory. (Seen mostly in operation on the dominant side.) These changes were slight and temporary in unilateral operation, but pronounced and persistent in bilateral operations (3 cases). Oral tendencies and hypersex- uality could be see temporarily after bilateral operations. In most cases of ictal automatism; there were non-ictal psychic changes such as emotional instability, irritability or assaultiveness (Gibbs 1951 ; Sano and Malamud 1953). These changes were ameliorated postoperatively, resulting in better social adaptation. Ammon's Horn Sclerosis 283

TABLE3. Complex partial seizures and foci in the neo-, archi-, or palaeo-cortex and the temporopolar transitional cortex (area TG or 38) in relation to the seizure types and the ways of discharge spread

C. S., convulsive seizure.

Electrocorticography during operation and by means of implanted electrodes revealed, besides the above findings, that the so-called hippocampal synchroniza- tion (2 or 6 c/s) was often associated with arousal or attention (Green and Shimamoto 1953), concomitant with neocortical desynchronization. On the other hand, during the seizure of ictal automatism when no memory record was made, seizure discharges (rhythmic spikes) were seen in the hippocampal formation (and often in the amygdaloid complex and the temporo-polar cortex), concomitant with 2 to 6 c/s slow waves in the neocortex (Sano and Malamud 1953 ; Sano and Kitamura 1954). Post-operative follow-up results, as of March, 1973, in the period, 15-22 years after temporal lobe operations. are shown in Table 4. Two-thirds of the cases were seizure-free postoperatively in the follow-up, more than 15 years. The operation mostly consisted of resection of the temporal cortex anterior to the vein of Labbe and removal of the uncal-amygdaloid area and the anterior half of the hippocampal formation. The results are better than the published data of temporal cortical resection (Bailey and Gibbs 1951 ; Green et al. 1951 ; Nadler et al. 1978) and are compatible to those of the recent selective amygdalo- 284 K. Sano and T. Kirino

TABLE 4. 15-22 year Follow-up results of temporal lobe operations (30 cases)

Numerals are number of cases. (-), no seizure; (+), one or more seizures ; Uncal-amyg., uncal-amygdaloid region ; Hipp. form., hippocampal formation; I.A., ictal automatism, D. S., dreamy state. hippocampectomy of Zfflich school (Yasargil et al. 1985; Wieser 1986). If we look at those of cases with ictal automatism, 13 out of 15 cases (87%) in which the hippocampal formation, was resected became seizure free. This is in accordance with the recent report of Delgado-Escueta and Walsh (1985) who asserted that type I complex partial seizure (ictal automatism) are most commonly of hippocampal origin. As for temporal lobe functions, from these data, Sano (Sano and Kitamura 1954) concluded as follows. (1) The archicortex (the hippocampal-fornix system): playing a role in recent memory, attention and emotion. (2) The neocortex, playing a role in apperception and storing memory patterns. (Special neocortical areas subserve speech, audition etc.) (3) The palaeocortex and the amygdaloid complex: playing a role in olfac- tion, emotion and autonomic activities; especially the latter in attention and oral, sexual and endocrine activities. Ammon's Horn Sclerosis 285

As is well- known, Hess (1949) divided the diencephalon into two functional areas, the trophotropic and ergortropic zones or sectors. In anatomophysiological relation to these two zones, parts of the telencephalon, especially of the orbitotemporo-limbic system, may be comprised in two functional circuits or networks, the prosencephalic trophotropic and the prosencephalic ergotropic circuits, although these are widely overlapping. The hippocampal-fornix system, may be serving as the common axis of these two circuits, as it may act as the axis of the emotive circuit of Papez (1937). Sano and Malamud's report (Sano and Malamud 1953) was reconfirmed by Margerison and Corsellis (1966) who lead Falconer (Falconer 1968, 1972, 1974) to perform temporal lobectomy including the sclerosed hippocampus. Falconer further expanded the theory to his assertion that not only ictal automatism but other types of intractable epilepsy orignating in the first two decades of life may be due to mesial temporal (Ammon's horn) sclerosis. The cause of the latter is, accoding to him, infantile febrile convulsion. He did temporal lobectomy in many cases of intractable epilepsy and found Ammon's horn sclerosis in the surgical specimens. Falconer's assertion was recently supported by Mayo Clinic's group (Meyer et al. 1986).

A new -concept on the pathogenesis of Ammon 's horn sclerosis

Recently, a new concept on the pathogenesis of hippocampal injury has emerged (Rothman and Olney 1986). Hippocampal neuronal damages caused not only by epileptic seizures but by ischemic/anoxic insults may be accounted for by this new concept. This hypothesis, however, is fundamentally different from what used to be described in standard textbooks of neuropathology. The new concept has been proposed through approaches to the problem from three different directions. The first one is experimental studies on epileptic neuronal damage.

The second is experimental works on ischemic neuronal injury in selectively vulnerable regions in the brain. The third approach, which played a special role in combining the two approaches as mentioned above and in prompting us to unify hypotheses of pathogenesis, involves research on neuronal damage caused by various neurotoxins. Among these toxins, certain putative neurotransmitters and their agonists have come to attention. There is a significant body of evidence that these substances exerts their noxious effect by causing excessive excitation of neurons. The pattern of the •gexcitotoxic•h damage in the hippocampus were proved to be almost identical to those seen in epileptic patients or in postanoxic/ ischemic brain. It may be justified therefore, to call this new concept on the pathogenesis of hippocampal damage as •gexcitotoxicity•h theory. The most probable candidate of intrinsic excitotoxins is an excitatory putative neurotransmitter, glutamate.

Neuronal damage due to epileptic seizures

Sustained generalized epileptic seizures (status epilepticus) are now well 286 K. Sano and T. Kirino known to produce neuronal damage (Meldrum et al. 1974). A typical example of epileptic brain damage is Ammon's horn sclerosis. Recent pathological study had revealed that Ammon's horn sclerosis is not a fixed, stable lesion. Dam (1980) has shown the progressive nature of Ammon's horn sclerosis in epileptic patients. The lesion develops slowly and gradually, and during this pathological progres- sion, patients do not necessarily suffer from prolonged generalized seizures. It has been, however, rather unpopular to believe that even partial ictal events can induce irreversible neuronal damage in a certain region within the brain. Recent animal research on this subject has involved the use of neurotoxic chemicals such as kainate (Ben-Ani et al. 1980). When kainate is injected into the brain or parenterally, it induces limbic siezures. This seizure activity results in neuronal loss in a circumscribed region in the hippocampus (Nadler et al. 1978 ; Nadler 1981). Since kainate is a well-known agonist of a putative excitatory amino-acid transmitter, glutamate, the excitatory activity of kainate is believed to be the pathogenetic factor (Olney 1978). However, direct cytotoxic property of kainate has not been ruled out. To clarify this possibility, excitatory afferent input to the vulnerable hippocampal area was electrically stimulated. In this case again, a typical neuronal injury in the hippocampus was seen (Solviter 1983). In addition, if excitatory afferents to the hippocampus was destroyed and the kainate was injected, the magnitude of neuronal injury was significantly attenuat- ed (Nadler and Cuthbertson 1980). This experimental results has indicated that kainatelesion is dependent on excitatory afferent input. With all of this experimental evidence, it is unlikely that almost similar neuronal damages in the hippocampus are causes by several independent mechanisms such as cytotoxicity, epileptic discharge, or local hypoxia/anoxia. Instead, it seems more reasonable to hypothesize that excessive excitation of the neuron per se is detrimental to neurons.

Ischemic neuronal damage The problem of the hippocampal .selective vulnerability to ischemia has in the past been studied in autopsy material. It was not usually a matter of experimental trial before the successful production of ischemia in experimental animals, especially in the rodent, became possible. The Mongolian gerbil (Meriones unguiculatus) was introduced as an experimental animal for stroke by Levine and Payan (1966), who noticed that unilateral ligation of the carotid artery at the neck produced cerebral infaction. Later works have revealed that ischemia in the gerbil is due to a lack of the interconnec- tion in the circle of Willis at the base of the skull (Levine and Sohn 1969; Tamura et al. 1981). Almost all gerbils have no connection between the carotid and the vertebrobasilar circulation. At the biginning, the gerbil was used as a focal ischemia model by occluding the unilateral carotid artery (Kahn 1972; Ito et al. 1975; Levy et al. 1975). Later, it has come to be realized that bilateral Ammon's Horn Sclerosis 287

occlusion of the carotid arteries brings about uniform forebrain ischemia, during which the value of blood flow is close to zero (Crockard et al. 1980 ; Suzuki et al. 1983a, b). In most of gerbils subjected to 5 min of ischemia by bilateral carotid occulusion, hippocampal damage is seen throughout the dorsal hippocampus (Kirino 1982; Kirino and Sano 1984a, b). The CA4 (the end-plate) pyramidal cells show a fast change. They become darkly stained with shrunken cell bodies and empty spaces surrounding them. This change become obvious within 3-6 hr following ischemia. The rapid cell change in CA4 corresponds to the previously known ischemic cell change (Brierley and Graham 1984). The change in the CA1 sector (Sommer's sector) develops slowly. On day 1 following brief ischemia, no definite alteration is seen except that the cell nucleus occasionally looks more inhomogeneous than normal. On day 2, the pyramidal cells show a slight clump- ing of the nuclear chromatin and slits develop in the basal side of the cytoplasm. These initial signs of alteration are followed by extensive destruction of most of the pyramidal cells when observed on the 4th day. The change in the majority of the CA1 neurons is slow but progressive. The full-blown pathologic state is only seen after the 2nd day by light microscopy, but an insidious process starts to take place by 24 hours following brief ischemia. This slow change is clearly detected by electron microscopy (Kirino and Sano 1984b). The main findings are an accumulation of increased ER (endoplasmic reticulum) cisterns, an increase of dark granules umbound by a membrane, and a disaggregation of polyribosomes into monoribosomes. These changes are never seen in the normal CA1 neurons. The delayed neuronal death in the hippocampal CA1 subfield is a novel type of cell damage after ischemia. The changes which follow brief ischemic insult have been studied also in the rat (Pulsinelli et al. 1982a, b; Kirino et al. 1984a, b; Smith et al. 1984). Except for several differences in minor detail, pathological alteration in the hippocampus following ischemia are quite similar in both gerbils and rats. In view of the resemblances in pathological findings and structural similarity or the normal hippocampus among various species, the alteration in the hippocampus following ischemia exhibited by various species including man may be fundamentally identical to the changes seen in the rodents. Delayed neuronal death in the CA1 neurons observed following brief ischemia in the rodent is a slow alteration and is not similar to acute ischemic cell death which is well known to develop shortly after relatively prolonged, severe ischemia . It takes almost 2 days to detect definite morphological changes in the CA1 neurons which herald delayed extensive neuronal death. During this period following recirculation, there is no selective decrease in cerebral blood flow in the hippocampus which can account for the selective neuronal damage (Suzuki et al. 1983a b). There is no impairment of energy metabolism which is compatible with extensive neuronal damage in the hippocampus. Arai et al. (1982) examined the CA1 subfield in the gerbil ischemia model biochemically and they confirmed that there is no decrease of ATP that can account for cell deterioration. Pulsinelli and 288 K. Sano and T. Kirino

Duffy(1983) also noticed a similar change in the energy metabolism in their rat

model. They found that the imbalance of regional blood flow and glucose

metabolism does not correlate with the pattern of neuronal injury (Pulsinelli et al.

1982b). All of these experimental results indicate that neurons in the hippocampus die following brief ischemia without any definite •gclassical•h reason to die.

Suzuki et al. (1983b) studied the gerbil CA1 electrophysiologically following brief ischemia. They found that the CA1 neurons are electrically active for one day after ischemia. This means, at least electrophysiologically, the neurons in the CA1 sector are alive for a certain period following brief ischemic insult. If this hypothesis is valid, neurons, following ischemia, are left in an unstable state between death and survial. As a consequence, there is the possibility of salvaging dying neurons following ischemia. To examine this hypothesis, experiments on the drug effect were performed. When pentobarbital is given immediately following ischemic insult, it shows a definite, reproducible favorable effect on the survival of CA1 neurons following brief ischemia (Kirino et al. 1986). The effective dosage is 20 to 40 mg/kg. Other chemical agents such as nizoferone

(Y-9179; Kirino et al. 1984b), or diazepam (Kirino et al. unpublished data) can also ameliorate ischemic hippocampal lesion. All of these drugs are known to have sedative activity on neurons. This result may suggest that CA1 neurons are not only electrically active but they are •ghyperactive•h during the recirculation period following brief ischemia. The reason of the hyperactivity may be ex-

plained by literal hyperexcitation of neurons or by a lack in inhibition which could lead to excessive firing. The lack-in-inhibition hypothesis is not likely

since Francis and Pulsinelli (1982) did not detect any selective decrease in the

activity of glutamic acid decarboxylase (GAD), an enzyme related to GABA, in

the CA1 sector following ischemia. On the contrary, a certain type of interneur-

on, presumably GABAergic, in the CA1 sector is rather tolerant to ischemia

(Johansen et al. 1983). There is increasing evidence that a putative amino acid neurotransmitter, glutamate, is involved in the pathogenesis of ischemic

hippocampal cell damage. In the CA1 subfield, it is well known that most of the

neurons have abundant glutamate receptors. Given with a sufficient concentra-

tion of glutamate, these neurons show sustained burst discharges which trigger

excessive Ca2+ influx. To protect the hippocampal neurons from noxious hyper-

excitation provoked, most likely, by glutamate, Simon et al. (1984) blocked

N-methy-D-aspartate (NMDA) receptors using aminophosphonoheptonoic acid

(AP-7) and showed that AP-7, injected in the hippocampus dramatically reduces the neuronal damage. Recenty, Wieloch et al. (1985) and Pulsinelli (1985)

independently found that removing the glutamergic excitatory input into the

hippocampus protect the hippocampus from ischemic damage. This means that

ischemic injury is dependent on the presence of excitatory afferents. The phe-

nomenon of •gdeafferentation protection•h is also known in the pathogenesis of Ammon's Horn Sclerosis 289

kainate lesion (Nadler and Cuthbertson 1980). All of these experimental results

on ischemic hippocampal damage are compatible with the hypothesis of •ghyperex-

citation•h induced by glutamate.

“Excitotoxicity”of amino acid neurotransmitters

The neurotoxicity of an amino acid, glutamate, has been recognized. Olney and collegues (1971) have tested the toxicity of monosodium glutamate and considered that the excitatory activity of this amino acid is a major cause of this toxicity. They called this effect "excitotoxicity" (Olney and de Gubareff 1978). Since kainate is known to be one of the glutamate agonists, relationship between pathogenesis of wider category of neurological diseases and glutamate toxicity has been studied. In each case, stimulation of excitatory input mediated by glutamate produced similar lesion in the hippocampus and deafferentation of the input resulted in a marked decreased injury. Application of selective antagonist of glutamate could protect the hippocampal neurons from damage. Detrimantal effect of glutamate is not restricted in the hippocampal neurons. Choi (1985) recently found that neocortical neurons are sensitive to brief applications of glutamate, but it takes up to a day to show cell damage if glutamate is washed out quickly. Furthemore, glutamate is blieved to be involved in the pathogenesis of hypoglycemic brain injury (Wieloch 1985). It gradually comes to be realized that vulnerability of neurons to certain noxious insults such as sustained seizure activities, hypoxia/anoxia, or hypoglycemia is inevitably related with the property of neurons . Although any biological organisms which live in an aerobic condition are destined to die when oxygen and metabolic substrates are withdrawn, cell death seen in neurons occurs far earlier than such general cell destruction. Rothman (1983) cultured the rat hippocampal neurons obtained from an embryo and tested their vulnerability to anoxia. He found that, before the establishment of synapses between clutured neurons, they were less susceptible to anoxia. However, as soon an neurons started to communicate by synapses, they became vulnerable to oxygen depriva- tion. At this state he added MgC12to block synaptic activity and noticed that neurons could survive an anoxic insult. This result may suggest that synaptic activity is closely related to the neuronal vulnerability to anoxia or ischemia. The neurotransmitter mediating synaptic communication in these cultured neurons is, presumably, glutamate. This evidence indicates that glutamate neurotoxicity and synaptic transmission are the key phenomena linked in the pathogenesis of neuronal injury in, if not all, epileptic seizure, cerebral ischemia/anoxia, or hypoglycemia.

Future scope Recent advances in this field have proposed an optimistic view that brain can be protected from various detrimental insults by reducing the release of a certain 290 K. Sano and T. Kirino neurotransmitter or by blocking receptors which combine with the transmitter.

This approach seems to dramatically improve our capability in managing epilepsy, cerebral ischemia/anoxia, or hypoglycemia patients. The problem, hewever, may not be that simple. There are at least several barriers to break through in order to put this mode of therapy to practical use. Amino acid antagonists currently available work at a relatively higher concentration and poorly cross the blood brain barrier. Even if more potent and more diffusible chemicals are developed, we must circumvent the possible side effects of the substance. Since amino acid transmitters are found all through the neuroaxis, there is no guarantee that such agent is safely used without unexpected adverse effects on the vital neural functions.

Most of the information accumulated on the glutamate toxicity is related to relatively brief insult which may not induce widespread destruction of the brain.

We have to realize that neurons could be already at an irreversible state when detrimental insults are resolved. It is hard to believe that such cell death is also mediated by neurotransmitter. Nourons are salvageable when suitable therapy is instituted following brief period of status epilepticus, ischemia/anoxia, or hypoglycemia. It seems to be the case, however, only when treatment is initiated early enough. Barbiturates are effective in protecting hippocampal neurons from ischemic damage when they are given immediately following ischemia. This favorable effect of barbiturates is not seen if injection is done 1 hour following ischemic insult, Bodsch and Takahashi (1984) studied protein synthesis following ischemia and showed that synthetic activity in the CA1 neurons is already supressed 2 hours following to brief transient ischemia. The metabolic state of the CA1 neurons seems to be irreversibly disturbed far earlier than any morphological changes are noticed. Barbitutate protection is, however, by no means a specific pharmacological action on neurons. More specific mode of therapy such as the use of antagonist of specific neurotransmitters may elongate the viable period of neurons. Neurons are primarily responsible for normal functions of the brain. Treat- ment of status epilepticus, cerebral ischemia/anoxia, or hypoxia, therefore, should primarily focussed on the protection of neurons. The hypothesis of •gexcitotoxic•h neuronal damage has made the issue more specific and straightforward. One may be able to work out research strategy more easily if the goal is defined more specifically. In this regard, the hippocampus, region within the brain, may have advantage over other areas. The problem of Ammon's horn sclerosis, an old research subject and a matter of long-lasting controversy, has now been updated and become one of the newest topics in the field of experimental neurobiology.

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