Horn Sclerosis Research Articles

Seizure‐like discharges recorded in human dysplastic neocortex maintained in vitro

Application of the convulsant drug 4-aminopyridine (50 to 100 microM) induced spontaneous seizure-like discharges (duration = 76.3 +/- 46.8 sec, mean +/- SD; interval of occurrence = 225.2 +/- 87.9 sec) in slices of neocortex obtained from patients with a diagnosis of focal neuronal migration disorders during neurosurgical procedures for relief of drug-resistant seizures. Similar epileptiform discharges could also be elicited in these slices by single-shock stimuli delivered in the underlying white matter or within the gray matter. By contrast, neocortical slices obtained from patients suffering from temporal lobe epilepsy (which is characterized by Ammon's horn sclerosis but relatively normal neocortex) did not generate any epileptiform activity during 4-aminopyridine application. Thus, our study is the first to provide experimental evidence for the intrinsic epileptogenicity that characterizes neuronal migration disorders.

Surgical treatment of temporal lobe epilepsy: clinical, radiological, and histopathological findings in 178 patients.

The surgical treatment of pharmacoresistant temporal lobe epilepsy is increasing rapidly. The correlation of preoperative MRI, histopathological findings, and postoperative seizure control is reported for 178 patients with chronic medically intractable temporal lobe epilepsy who were operated on between November 1987 and January 1993. Histopathologically there were distinct structural abnormalities in 97.2% of the surgical specimens. Signal abnormalities on MRI were present in 98.7% of patients with neoplastic lesions (n = 79), 76.6% of patients with non-neoplastic focal lesions (n = 55), and 69.2% of patients with Ammon's horn sclerosis (n = 39). Overall, structural abnormalities were detected by MRI in 82.7% of all patients. The mean postoperative follow up period was three years. Some 92% of the patients benefited from surgery: 103 patients (61.7%) were seizure free, 26 (15.5%) had no more than two seizures a year, and 24 (14.4%) showed a reduction of seizure frequency of at least 75%. Fourteen patients (8.4%) had a < 75% reduction of seizure frequency. The percentage of patients who were completely free of seizures after operation was 68.5% for patients with neoplastic lesions, 66.7% for Ammon's horn sclerosis, and 54.0% for patients with non-neoplastic focal lesions. By contrast, none of the patients in whom histopathological findings were normal became seizure free postoperatively. The data show that the presence of focal lesions or Ammon's horn sclerosis as determined by histopathological examination is associated with improved postoperative seizure control compared with patients without specific pathological findings. Brain MRI was very sensitive in detecting neoplasms; however, its sensitivity and specificity were limited with respect to non-neoplastic focal lesions and Ammon's horn sclerosis. Improvement of imaging techniques may provide a more precise definition of structural lesions in these cases and facilitate limited surgical resections of the epileptogenic area rather than standardised anatomical resections.

Hippocampal loss of N-methyl-D-aspartate receptor subunit 1 mRNA in chronic temporal lobe epilepsy.

The hippocampal distribution of mRNA for the N-methyl-D-aspartate (NMDA) receptor subunit 1 (NR1) was examined by non-radioactive in situ hybridization in 21 archival formalin-fixed and paraffin-embedded surgical specimens from patients with pharmacoresistant chronic epilepsy and in normal control specimens obtained at autopsy. Using the digoxigenin-labeling procedure, ribonucleotide probes were found to be significantly more sensitive than synthetic oligonucleotide probes. In normal autopsy specimens and in surgical specimens without Ammon's horn sclerosis there was intense NR1 expression in a great majority of the dentate gyrus granular cells. Many neurons in the hippocampal pyramidal cell layer also revealed a strong signal intensity. The strata oriens and moleculare of Ammon's horn and the molecular layer of the dentate gyrus contained only few labeled neurons. In the subiculum and entorhinal cortex most neurons throughout various layers were positive. In hippocampal specimens of patients with chronic epilepsy there was a loss of NR1-positive cells that was closely related to the overall neuronal loss in the respective specimen and to Ammon's horn sclerosis. These data suggest that the loss of NR1 expression is a secondary phenomenon rather than an event that is relevant for the pathogenesis of epileptic seizures.

Neuropathologic findings in chronic epilepsy

The surgical treatment of chronic epilepsies is increasing rapidly. A review of 279 surgical specimens of patients with chronic pharmaco-resistant epilepsies from the University of Bonn Medical Centre revealed specific histopathological findings in 89% of all well-preserved specimens. The most frequent focal lesions were low-grade brain tumours such as gangliogliomas, pilocytic astrocytomas and dysembryoplastic neuroepithelial tumours. Other common findings were glioneuronal and vascular malformations and Ammon's horn sclerosis. This suggests that chronic intractable epilepsies are frequently caused by structural alterations.

Hippocampal loss of the GABAA receptor alpha 1 subunit in patients with chronic pharmacoresistant epilepsies.

Alterations of gamma aminobutyric acid (GABA)-mediated neurotransmission have been implicated in the pathogenesis of epilepsies. Here we examine the distribution of the GABAA receptor in the hippocampus of 78 surgical specimens from patients with chronic pharmacoresistant focal epilepsies. The receptor was localized immunohistochemically with the monoclonal antibody bd-24 which selectively recognizes the alpha 1 subunit of the GABAA receptor. The results were compared with the receptor distribution of 28 normal hippocampal specimens obtained at autopsy. In the great majority of the surgical specimens a loss of GABAA receptor immunoreactivity was present in CA1 (92.3%), CA4 (78.2%), the dentate granular cell layer (70.5%) and the molecular layer of the dentate gyrus (65.4%). The subiculum revealed a normal staining pattern in all but 4 cases. In no instance did we observe an increase of immunoreactivity in any region or cell population. The decrease of GABAA receptor immunoreactivity was closely related to neuronal loss in the respective specimen and to Ammon's horn sclerosis. There was no correlation between GABAA receptor loss and the patient's age at surgery, duration of seizures, age at onset of seizures and to the presence or absence of secondary generalized tonic clonic seizures. The data suggest that the observed loss of GABAA receptor immunoreactivity is a secondary phenomenon rather than an event that is relevant for the pathogenesis of epileptic seizures.

Glial reaction after seizure induced hippocampal lesion: immunohistochemical characterization of proliferating glial cells

Kainic acid treatment (a model of temporal lobe epilepsy) induces Ammon's horn sclerosis, which is characterized by degeneration of CA3 pyramidal neurons and reactive gliosis. In the present study we have combined autoradiographic analysis of 3H-thymidine incorporation and immunocytochemistry to investigate this glial scarring phenomenon. The present results demonstrate that in the fields showing neuronal degeneration (i.e. CA3-CA4 fields of Ammon's horn and dentate hilus) the glial reaction consists of a proliferation and hypertrophy of astrocytes and microglia-macrophages. In the regions showing exclusively terminal axonal degeneration (i.e. the molecular layer of kainate-treated rats), glial cells do not proliferate but astrocytes show a transient hypertrophy. These results also demonstrate that oligodendrocytes do not proliferate in the hippocampus of kainate-treated rats. In agreement with our previous report we find that hippocampal astrocytes from kainate-treated rats express A2B5 immunoreactivity, a marker of type-2 astrocytes. A2B5 immunoreactivity was expressed by astrocytes not only in areas showing glial proliferation such as CA3-CA4 fields, but also in the molecular layer, where astrocytes do not proliferate. This suggests that in the CNS, normal resident astrocytes acquire the phenotypic properties of type-2 astrocytes.

Interictal discharges in the hippocampus of rats with long-term pilocarpine seizures

Systemic administration of pilocarpine to adult rats induces an acute status epilepticus followed by spontaneous recurrent seizures after a 1–2-week silent period. We recorded field potentials in hippocampal slices obtained from rats with spontaneous recurrent seizures after pilocarpine-induced status. The frequency of the interictal discharges induced in these slices by 4-aminopyridine (4AP) was reduced and their duration was increased. Cutting the Schaffer collaterals caused interictal discharges in CA1 to disappear in normal rats and in rats 3 weeks after pilocarpine-induced status. However, 12 weeks after pilocarpine, these discharges remained in CA1 after such a cut but occurred at a lower frequency. These findings show that in rat hippocampi with a lesion similar to that of human Ammon's horn sclerosis some electophysiological features of 4AP-induced interictal discharges are altered in comparison to those induced in normal hippocampi.

Preferential neuronal loss in layer III of the entorhinal cortex in patients with temporal lobe epilepsy

We report a characteristic pattern of neuropathological change in the entorhinal cortex (EC) from four patients with temporal lobe epilepsy. Specimens of the EC were obtained during the surgical treatment of intractable partial seizures and were studied by light microscopy in Nissl-stained sections. A distinct loss of neurons was observed in the anterior portion of the medial EC in the absence of apparent damage to temporal neocortical gyri. Cell loss was most pronounced in layer III, but also noticed in layer II, particularly in the rostral field. A similar pattern of neurodegeneration in the EC was found in all specimens examined though the degree of neuronal loss varied between cases. These observations provide neuropathological evidence for an involvement of the EC in temporal lobe epilepsy. Since the EC occupies a pivotal position in gating hippocampal input and output, our results further support previous suggestions that dysfunction of this region may contribute, either independently or in concert with Ammon's horn sclerosis, to epileptogenesis in humans.

Surgical Pathology of Chronic Epileptic Seizure Disorders

The surgical treatment of chronic epilepsies is increasing rapidly and involves neuropathologists in the care of patients with chronic and medically intractable seizure disorders. Herein we review the histopathologic findings in 279 consecutive surgical specimens of patients with chronic pharmacoresistant epileptic disorders. Aspects that are relevant to the diagnostic surgical pathologist such as the terminology of developmental lesions and Ammon's horn sclerosis are discussed. In 87 cases (31.2%), there were tumors in which all but two were of low histopathological grade (WHO grade I or grade II). The most common tumors were gangliogliomas, pilocytic astrocytomas, oligodendrogliomas, fibrillary astrocytomas and dysembryoplastic neuroepithelial tumors. Among the most frequent non-neoplastic focal lesions, microscopic glioneuronal hamartias, circumscribed vascular malformations, glioneuronal hamartomas and porencephalic defects were most frequent. The hippocampal formation was structurally well preserved in 71 specimens of patients with temporal lobe epilepsy. In 51 of these (71.8%) cases, Ammon's horn sclerosis was present. The findings suggest that the structural lesions observed in the great majority of the specimens are closely related to the pathogenesis of intractable seizures.

Surgical Pathology of Temporal Lobe Epilepsy. Experience with 216 Cases

The surgical treatment of chronic epilepsies is increasing rapidly. Here we report the histopathologic findings in 216 consecutive surgical specimens of patients with chronic pharmacoresistant temporal lobe epilepsy. In 75 cases (34.7%) there were tumors, all but two of which were of low histopathological grade (WHO grade I or II). The most common tumors were gangliogliomas (34 cases), pilocytic astrocytomas (17 cases), oligodendrogliomas (9 cases), fibrillary astrocytomas (6 cases), and dysembryoplastic neuroepithelial tumors (6 cases). There were 51 cases with non-neoplastic focal lesions and an additional 13 cases with tumors and non-neoplastic focal lesions within the same specimen. The most frequent non-neoplastic focal lesions were microscopic glioneuronal hamartias (32 cases), glioneuronal hamartomas (7 cases), and vascular malformations (13 cases). The hippocampal formation was structurally well preserved in 71 specimens. In 51 of these (71.8%) there was Ammon's horn sclerosis. Presurgical placement of depth electrodes was invariably associated with circumscribed defects of the brain parenchyma. The implantation of subdural electrodes was sometimes followed by chronic inflammatory changes of the leptomeninges. Our findings indicate that in the majority of patients with medically intractable temporal lobe epilepsy there are significant histopathologic findings, many of which are only rarely encountered otherwise.

The neuropathology of temporal lobe epilepsy.

Complex partial epilepsy arising in the temporal lobe has been associated with several types of pathologic lesions including Ammon's horn sclerosis, malformations, neoplasms, and inflammatory scars from infarcts or infection. These lesions are usually situated at various sites in the medial temporal lobe, so that one of the enigmas of attempting to understand the pathogenesis of TLE pertains to the clinical manifestation of a single epileptic disorder which is associated with dissimilar lesions at dissimilar sites. Recent demonstrations of an alteration in temporal lobe anatomy, i.e. malformations of the normal circuitry of the temporal lobe and foci of microdysgenesis, have given rise to the hypothesis that insults which occur during a critical period of brain development could alter the connections within the hippocampus and predispose it to increased excitability and seizurogenesis. Such a hypothesis forces us to reconsider TLE in reference to risk factors which may act as "teratogens" and produce these malformations. These malformations may range from a subtle alteration in the neurotransmitters of the dentate gyrus to large areas of cortical dysplasia or the hamartomatous neoplasms seen in TLE. A reevaluation of the neuroanatomical disruptions created by the various lesions may allow us to define a minimal optimal surgical resection for each lesion; or, the definitions of neurotransmitter deficits may lead to alternative pharmacologic therapies. As neuropathologists we have the exciting opportunity to participate in the definition of the neuropathology of temporal lobe epilepsy.

Hippocampal volumetric and morphometric studies in frontal and temporal lobe epilepsy.

The most common temporal lobe pathology is Ammons Horn sclerosis (AHS), and several different imaging techniques have been utilized to detect this with varying success. We describe the clinical application of magnetic resonance imaging (MRI) using a three-dimensional volume technique which allows total hippocampal volume to be measured and symmetry evaluated. Hippocampal surface area was calculated in sequential 1.5 mm thick contiguous images, using a GE IC workstation. Total volumes and surface areas were calculated. The cross-sectional surface area at 1.5 mm intervals was displayed graphically, permitting morphometric analysis of the hippocampus throughout its length. Focal atrophy within any part of the hippocampal formation (HF) and its extent could thus be assessed. Patients with well-lateralized temporal lobe epilepsy (TLE) (n = 20) and well-defined frontal lobe epilepsy (FLE) (n = 20) were studied, and volumes compared with normal values derived from 10 neurologically normal controls. Asymmetric hippocampal volume loss was demonstrated in all 20 patients with clinically typed TLE, but not in normal controls or patients with FLE. Volume loss distribution was anterior in 12 patients, posterior in one patient and widespread in seven patients. Secondarily generalized seizures were strongly associated with widespread loss. This method of surface area and volumetric analysis of the hippocampus in TLE can demonstrate asymmetry and focal involvement, and help distinguish between hippocampal and frontal pathologies.

Tyrosine hydroxylase—immunoreactive neurons in the temporal lobe in complex partial seizures

The anterior mesial portion of the temporal lobe removed from 16 patients who underwent surgery for the treatment of complex partial seizures was found to contain tyrosine hydroxylase-immunoreactive neurons. The distribution of these neurons was correlated with the underlying neuropathological features. Ammon's horn sclerosis was present in 8 patients; a ganglioglioma, in 7 patients; and an infarction in the distribution of the middle cerebral artery, in 1 patient. Tyrosine hydroxylase-immunoreactive neurons were found in Ammon's horn of 6 of the 8 patients with Ammon's horn sclerosis, and in the subiculum and entorhinal cortex of all 8 patients with the same pathology. None of these neurons were found in Ammon's horn of the 7 patients with a ganglioglioma, but were found in the subiculum of 5 of the 7 patients and in entorhinal cortex of all 7 patients. Tyrosine hydroxylase immunoreactivity was also studied in 13 control autopsy specimens. No tyrosine hydroxylase-immunoreactive neurons were found in Ammon's horn or the subiculum of any of the control specimens, but were found in the entorhinal cortex of 6 of the 13 specimens. The tyrosine hydroxylase-immunoreactive neurons in the mesial portion of the temporal lobe of patients with complex partial seizures may contribute to the increased levels of tyrosine hydroxylase found in neurochemical studies of specimens taken at temporal lobectomy.

Ammon's Horn Sclerosis

Sclerosis of the cornu Ammonis or Ammon's horn sclerosis (AHS) is an "often-described, yet hitherto enigmatic phenomena" 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 propounded. 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 automatism. 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 controversy, has now been updated and become one of the newest topics in the field of experimental neurobiology.

Electrophysiological connections between the hippocampus and entorhinal cortex in patients with complex partial seizures.

The electrophysiological properties of the neural pathways between the hippocampus and the entorhinal cortex were studied intraoperatively in 31 patients undergoing anterior temporal lobectomy for medically intractable complex partial seizures. The hippocampus, removed en bloc, was studied histologically and the pathology was correlated with the electrophysiological findings. In 29 of the patients, entorhinal stimulation evoked a characteristic positive-negative potential in the hippocampus. The entorhinal-evoked hippocampal response closely resembled, or was identical to, the spontaneously occurring hippocampal interictal spike discharge. In patients with Ammon's horn sclerosis in whom there was a major loss of neurons in the hippocampal subfields CA1, CA3, and CA4, the evoked responses were of simple morphology and long latency (mean 21.9 msec to the peak of the first potential). In patients with a ganglioglioma in whom the hippocampus was histologically normal, the evoked responses were of greater complexity and shorter latency (mean 11.8 msec). Stimulation at a single entorhinal site evoked similar waveforms at different hippocampal recording sites. Conversely, stimulation at different entorhinal sites evoked similar responses at a single hippocampal recording site. Stimulation of the hippocampus evoked a potential in the entorhinal cortex and, in some instances, in the amygdala, insula, and lateral temporal cortex. These connections may produce a positive feedback loop that favors seizure generation.

A model of status epilepticus based on electrical stimulation of hippocampal afferent pathways

A new model of status epilepticus has been developed in the unanesthetized rat. The model involves repetitive tetanic stimulation of hippocampal afferent pathways. Pulse trains were delivered according to a fixed schedule (0.2 to 0.4-ms monophasic rectangular pulses, 20 Hz, stimulus current adjusted for maximal synaptic response in area CA3 of the hippocampus, 10-s train duration, 30-s intertrain interval) through electrodes chronically implanted in the angular bundle or fimbria. CA3 pyramidal cells responded to each stimulus in the train with little or no decrement. When 10 consecutive trains each produced 30 s of hippocampal afterdischarge, stimulation was terminated and self-sustained electrographic seizure activity was monitored. This procedure was repeated until it yielded at least 15 min of self-sustained seizure activity. Status epilepticus occurred in about 85% of subjects within less than 7 h. Selfsustained electrographic seizures were associated with limbic motor seizures and with brain lesions that resembled Ammon's horn sclerosis. This model holds promise for analyzing the biochemical and physiological bases of seizures, status epilepticus, and neurocal cell death, because the timing of these events during the stimulation protocol is fairly predictable and because seizures are self-sustaining without the need for drugs, toxins, or prior kindling.

Seizure characteristics, pathology, and outcome after temporal lobectomy.

We analyzed the histories of 58 patients who had temporal lobectomy for seizure control. A good outcome was more likely if a definite lesion was removed. Unlike other pathologies, including nonspecific hippocampal sclerosis (NSHS), Ammon's horn sclerosis (AHS) was strongly related to a history of a prolonged childhood convulsion as the first epileptic event. Partial seizures developed at a younger age in patients with AHS than with NSHS or nonspecific changes. Epigastric rising sensations were associated with a greater chance of a good outcome than were other forms of simple partial seizure.

Comparison of seizures and brain lesions produced by intracerebroventricular kainic acid and bicuculline methiodide

Intracerebroventricular kainic acid produces in rats brain lesions similar to Ammon's horn sclerosis in humans. To test the hypothesis that these lesions result indirectly from prolonged seizure activity and not from a direct action of kainic acid on the neurons that are destroyed, the effects of intracerebroventricular kainic acid and bicuculline methiodide were compared. Although bicuculline methiodide seizures differed dramatically from kainic acid seizures, both electrographically and behaviorally, the resulting brain lesions were similar for a given total limbic seizure duration. These results, in combination with other data, support the view that lesions made by intracerebroventricular administration of convulsants are indeed caused by prolonged limbic seizures. The total duration of seizure activity appears to be one important variable.

Kainic acid seizures and neuronal cell death: insights from studies of selective lesions and drugs.

Hippocampal pathology (Ammon’s horn sclerosis (AHS)) is a well-recognized finding in the brains of temporal lobe epileptics (Meldrum and Corsellis, 1984). Classical AHS involves extensive loss of neurons from hippocampal area CA1 (h1, Sommer sector), a less extensive neuronal deficit in the CA3-CA4 area (h3-h5, endblade, endfolium), and relative sparing of neurons in the h2 area (‘resistant zone’; area CA2 and the adjacent portion of area CA3a which contains the mossy fiber endbulb) and in the fascia dentata. Most commonly, some neuronal loss in other brain regions, particularly the amygdala, thalamus and cerebral neocortex, accompanies the hippocampal lesion. Although the near-total loss of neurons from area CA1 is the most striking feature of AHS in many patients, there is reason to believe that the most vulnerable neurons are the CA3 hippocampal pyramidal cells and the morphologically diverse neurons of area CA4 (Margerison and Corsellis, 1966).

てんかん研究から学ぶ

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.