|History of AD
Paul Blocq and G. Marinesco, 1892
Sur les lésions et la pathogénie de l'épilepsie dite essentielle
LA SEMAINE MEDICALE, 1892, p 445 et 446
The original paper
Although both anatomy and physiopathology of epilepsy said "essential" or "idiopathic" had led to numerous publications, and very recently had the benefit of numerous works, we are still far away from a satisfactory knowledge related to this subject.
Therefore, due to the open-minded kindness of Mr Pr Charcot, we have been able to collect in his department several cases that we have investigated.
Starting from March 1890, we have been able to perform at Salpetriere hospital 9 autopsies of epileptic patients, chosen in that they had presented in their life defined criteria.
These 9 cases were true epileptics, with a clinical presentation and evolution fitting with the classical idiopathic form and moreover that died following an epilepticus status “ de morbus comitialis” and not from an intercurrent affection. Moreover, from these samples, some of them came from aged people (50 to 68 years) but others came from younger patients (29 years in one case).
Using such cases, we meticulously analyzed the central nervous system at the histological level, taking the advantage of different techniques, especially one of them never used, at least on such cases.
For all these autopsies, we have examined the brain stem and different neocortical areas. Results obtained varied according to the method employed. Indeed, while we observed abnormal features, other procedures (eosin, hematoxylin, fushin acid, carmin, etc) gave different patterns according to the method used.
Therfore results will be exposed according to each technique.
1° Marchi method:
This technique is not well known , and it is important to know that all affected structures are stained in black. Among these structures, we have recognized three catagories: fragments of degenerating myelin , cells with myelinic granulations and cells with blood granulations.
All preparations from our epileptic paptients showed constantly two types of lesions: a) perivascular alterations ; b) cellular lesions
A) Vascular alterations are characterized by the infiltration of the walls by granulous bodies. They are found all around the periphery, like a sleeve, sometimes not complete with streakson longitudinal sections.
B) Cellular lesions are found on the superficial nevroglia layer of the cortex (zone limitans) and consist of infiltration of these cells by a black granular material. It is known that for Metchnikoff, the spider -cells would play a phagocytic role in the cortex.
2° Other staining methods. – Results were, as mentioned, variable and the 9 cases can be ranked in the following categories :
- In four cases, there is no abnormalityto report, neither in cells nor in the supporting tissue
- In 4 cases, there are diffuse lesions less and more pronounced of nevroglia, at different degrees, and vascular alterations
- In one case, there are disseminated lesions of nevroglia, and alteration of blood vessels.
- There is nothing to deal with, since nothing abnormal was found
- We will describe the diffuse lesions of neuroglia as observed in the two cases, despite small differences, but in the same category
In on case, regarding a young patient, lesions were essentially beneath the surface. Meningeal vessels, veins, arteries are swollen, filled with blood cells, and in their surrounding we observe infiltrates of blood diffusing. Pia-mater, thicken at different places, is infiltrated by free blood cells. In the upper limitans neuroglia layer, apart from swollen vessels, we note a small hyperplasia of glial cells. The vascular hypertrophy continues in the third and fourth Meynert layers: vessel walls contain blood granular bodies ; small capillaries are coming out of the back, as if they were artificially injected.
Nerve cells, and especially pyramidal cells, and fusiform cells of the fifth Meynert layer are normal.
Centrum semi- oval is also affected and contains perivascular granular lesions.
For the other case, related to an older patient, lesions hardly defined on previous preparations were more accentuated. Superficial limitans layer shows a thickness due to the formation of bands of neuroglia fibrils. Deiters layers are dramatically increased in numbers and volume, and present themselves under the very characteristic aspect described by M. Chaslin (1), in similar cases, that islarger and spiked with fine extensions, sometimes linked to vessels.
As previously described are observed swollen vessels from the pia-mater and cerebral cortex.
C. Lesions that we described as scattered in neuroglia are observed in only one case, and here again with two aspects, one of which being similar to our previous description, and the other, very peculiar, with the form of small nodules.
Limitans layer presents hyperplasia of neuroglial cells. One could observe in addition, non only in this layer, but in deeper layers, focal sclerotic lesions around vessels, with fibrillar tufts as described by M. Chaslin.
Moreover, there are scattered in the different layers of the cortex, small round clusters with an approximate diameter of 60 microns, different from the tissue by a more intense staining, with regular shapes. They appear as such, with a regular distribution on preparations, with a moderately dotted structure, suggesting that some of them are authentic nodules of neuroglia sclerosis.
Similar to other cases, we note hyperplasia in neuroglia cells of the superficial layers, less pronounced than in the previous observation, despite a more pronounced fibrillar sclerosis.
Pyramidal cells seem normal. Vascular alterations are very pronounced ; not only in the cortex but also in semi-oval centrum, swollen vessels are observed, sometimes with small punctiform hemorrhagia , whose focal center is surrounded by blood granular bodies. Around older foci of this type are found altered cells; they are small, without nucleus, similar to granular aggregates, strongly stained by eosin and acidic fushin.
We do notice that, in the last case, vessels from the base were very atheromatous.
Brainstem is normal in all cases, apart from the case previously described, which was presenting small scattered hemorrhages.
We did not find, in any case in particular, sclerosis of olives described by some authors.
If we want to compare our results to those obtained by authors that preceded us, it is important to take into consideration only similar cases, that is with essential epilepsia and not associated with idiocy, porencephalia or infantile hemiplegia.
Most frequent and constant lesions are sclerotic alterations. Indurated plaques multiple and scattered have been described by Féré. Kingsburg observed a proliferation of neuroglia cells which were, simultaneously swollen. Allen J. Smith observed a fatty degeneration of cells.
The most careful study done so far on this subject is the work of M. Chaslin. This author has observed, in five brains, examined more specifically at the level of motor regions, a sclerosis named, wrongly to our opinion, pure neuroglia sclerosis, whose main features are the following: superficial layer is composed of fibrils bundles parallel to the surface taking birth in numerous cells with hypertrophic extensions. These fibrils constitute, by places, large and compact tracts. Vessels do not present inflammation. There is only, at some points, a hyaline transformation of the wall of capillaries.
These alterations, as observed, are similar on several points to those that we observed in several cases; in the same was as M. Chaslin, we have observed fibrillar sclerosis with compact tracts and hyperplasia of spider-cells in the superficial layer. We will see, at the opposite, that our opinion is different on the interpretation of such lesions.
To summarize, and strictly from an anatomic point of view, we give from our observations the following conclusions:
1° In a certain number of idiopathic epilepsy cases, there is no detectable lesions of nervous centers ;
2° When lesions are detected, they are very variable
3° Most constant lesions, when they exist, are found in psycho-motor regions and are characterized : a) by vascular alterations and b) by hyperplasia of neuroglia, either at the surface of the cortex, or in its depth.
What lessons are we authorized to draw from these findings ? First, two aspects seem obvious : 1° Lesions can be absent ; 2° they are variable. Therefore they do not represent specific alterations, the anatomic substratum of essential epilepsy. However, their location shows that epilepsy results from, as mentioned by most authors, a cortical process, and their nature clearly indicates that the process is vascular in nature.
Therefore we are allowed to think, that far from primitive, as mentioned after M. Chaslin by several observators (Feré, Marie), these lesions are, on the contrary, secondary or, simultaneous to attacks. Indeed, first of all, they do not explain the genesis of paroxysms and even less the different somatic signs that usually coexist, in the epilepsy class that we consider. Second, we can observe, in other circumstances, vascular alterations more of less similar to the very lesions that we met systematically in our cases.
For us, these alterations only testify for a functional hyperactivity of the cortical region where there are dominant, the role of granular bodies, which where the most characteristic, being to transport remnants of tissues that are in excess due to their degradation following a transitory excess of activity. This is the repetition more or less frequent of this condition of congestion and hyperactivity that at the end will provoke, to our opinion, neuroglia sclerosis, which, indeed, is maximum in the superficial layer. One can note, from the point of view of the relationship of sclerosis with blood vessels, an accentuation in older subjects, at the very place where vessels tend to be altered in senility.
If lesions that we described are secondary to paroxysm, what can we say about the pathogenesis of the disease?
It is known , following observations from clinicians and the experiments of physiologists, that epileptic convulsions more or less similar to those of essential epilepsy can be provoked either by gross cortical lesions of psycho-motor regions, as observed for tumors, or under the influence of certain intoxications (especially on predisposed persons). But, for essential epilepsy, there is no gross lesions of the brain nor intoxication, at least well visible and defined. However, we have to take into account that, on one hand, this type of epilepsy presents a certain number of permanent character (nervous heredity, presence of degeneration, peculiar state of mind) and on the other hand the disease is observed in paroxysmic bursts, he is logical to conclude that , on one hand, the clinical feature of the epileptic is related to a specific predisposition and that on the other hand there is likely a periodic production of an agent that provoke the paroxysms.
Moreover, experimentation in the hand of M. Brown-Sequard has reproduced the two basic components: the epileptic status and the epileptic agent, generating the disease, namely epilepsy. This author has found that irritation of a specific part of spinal cord is followed, in the guinea pig, by two effects: on consisting of an epileptic state, that is the morbid state that renders possible convulsion attacks with loss of conscience, the other which is the possibility to provoke the attack. There is in the nervous system of the injured animal, a morbid effect strictly limited to the apparition of epileptic attacks, under the influence of agents that would not provoke convulsions on non-operated animals. Therefore, in some guinea pigs with a lesion of spinal cord, and that had no convulsive attack, asphyxia undertaken after provoked a frank and complete epileptic attack , instead of the ordinary convulsions of asphyxia.
By admitting that in epilepsy there is an abnormal excitability of psycho-motor regions, what could be these agents that provoke paroxysms.
The influence of a great number of those agents, most of them accidental, is already known: traumatism, fatigue, coitus, strong emotions, are susceptible in a few patients to provoke an attack.
There is an influence which, these days, seems to play a more and more important role for its involvement in paroxyms: intoxications, and in particular auto-intoxications. M. Pierre Marie, with whom we do not share its point of view related to the accidental origine and infection nature of epilepsy, has the merit to bring attention on the possible influence of infectious intoxications. Recently, M. Féré demonstrated, based upon his research on urotoxia of epileptics, that the toxicity of urines increase in the preparoxystic phase to diminish considerable after the crisis.
More recent studies are in favor of this aspect. M. Herter and Smith in 30 cas of essential epilepsy have examined the urines, not only for the levels of urea and uric acid, but also the indican and substances resulted from the presence and activity of intestinal putrefactions. But they believed from their research that intestinal putrefaction processes (on which bromure, to their opinion, has no effect) play an obvious role on essential epilepsy, in that there is a constant relationship between the intensity of these putrefactions and the frequency and feature of the crises. This excess of putrefaction processes would be a characteristic sign of the epileptic grand mal.
M.J. Cagney noticed, about two cases with peripheral neuritis that occurred in epilepsia, that the epileptic attack is probably determined, on predisposed cases, by a toxic influence more or less obscure, and he allocated this intoxication to the production of the observed neuritis.
For us due to 1° clinical facts showing that essential epilepsy is characterized by permanent manifestations and episodic paroxysms ; 2° experimental facts showing that that is is possible to determine a permanent epileptic state with episodic paroxysms ; 3° and our anatomical observations that establish that the origin of the morbid phenomenon is located in the psycho-motor region, despite the fact that this region does not present anatomical lesions that are possibly epileptogenic, we are in favor of essential epilepsy has the result of an abnormal excitability of cortico-motor regions whose anatomical origin is unknown, and with an excitability that provokes epileptic convulsions, whose production results sometimes and in specific conditions (including the integrity of the blood vessels) of substantial lesions, and for origin specific agents and at least in a few cases that are likely toxic.
Drs PAUL BLOCQ AND G.MARINESCO
CHASLIN. Contribution to the study of cerebral sclerosis (Arch de med. Expér. Et d’anat. Path., 1891, T.III, P305)