Part 10

2. =The megaloblasts.= These are 2-4 times as large as normal red blood corpuscles. Their protoplasm, which constitutes by far the chief portion of the body of the cell, very often shews anæmic degeneration to a greater or less degree. The nucleus is larger than that of the normoblasts, but does not form so considerable a fraction of the cell as in the latter. It is often not sharply defined, and is of a rounded shape. It is distinguished from the nucleus of the normoblast by its much weaker affinity for nuclear stains, which may often be so small that little practised observers perceive no nucleus.

Occasionally very large cells are present of the kind just described, which are therefore called =gigantoblasts=, but which are not distinguishable in other respects from the megaloblasts.

It cannot be denied that it is often difficult to decide whether a particular cell is to be regarded as a specially small megaloblast or a large normoblast. In such cases one would naturally search the preparation for perfect forms of hæmatoblasts, and for the presence of free nuclei or of megalocytes, in order to obtain an indirect conclusion concerning the cells in question.

3. =The microblasts.= These are occasionally present, e.g. in traumatic anæmias, but they are very seldom found, and have not so far attracted particular attention.

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The question of the meaning of the =normoblasts= and =megaloblasts= has led to lively and significant discussions, partly in favour of, partly against the distinction between these two cell forms. After surveying the literature, we are forced to separate the megaloblasts from the normoblasts, in the first place because of their subsequent histories, and the peculiarities of their nuclei, and secondly because of clinical observation.

Rindfleisch arrived at his theory by direct observation of the process described, as it occurred in physiological saline solution with the blood of foetal guinea-pigs and teased preparations of bone-marrow.

E. Neumann regards Rindfleisch's doctrine as untenable, since the process which he observed is chiefly the result of a severe injury of the blood from the sodium chloride solution and the teasing. If a method of preparation be chosen which protects the blood as far as possible, and avoids every chemical and physical alteration, the exit of the nucleus as described by Rindfleisch does not occur.

The view of Kölliker and Neumann that the nuclei gradually decay in the interior of the cell is not supported by the observation of a process, but by the fact that in suitable material, for instance, foetal bone-marrow, liver blood, and leukæmic blood, the transition from erythroblast to erythrocyte is shewn by all phases of nuclear metamorphosis. v. Recklinghausen professes to have directly observed the dissolution of the nucleus within the cell in rabbit's blood, kept living in a moist chamber. Pappenheim's opinion however, that in this case processes are concerned such as Maragliano and Castellino have described as artificial necrobiosis, seems in this connection worthy of consideration.

Just as with regard to the formation of erythrocytes the views differ one from another, so also with regard to the "free" nuclei which come under observation in numerous preparations. Kölliker has taught that these nuclei are not quite free, but are always surrounded by a minute border of protoplasm. On the other hand Rindfleisch regards these nuclei as having migrated from, or having been cast off by the erythroblasts; and Neumann explains them as the early forms of erythroblasts. Ehrlich was the first to endeavour to effect a compromise between the directly opposed views of Rindfleisch and Neumann. He taught that both kinds take part in the production of the red discs. From blood preparations which contain numerous normoblasts, for instance in "blood crises" (see p. 62), an unbroken series of pictures can easily be put together shewing how the nucleus of the erythroblast leaves the cell, and at last produces the appearance of the so-called free nucleus. It must be expressly mentioned that these pictures are only to be found in specimens in whose preparation pressure of any kind upon the blood has been avoided. Further, however rich a blood may be in normoblasts, the metamorphosis of the nucleus as described by Neumann, is practically never to be observed. It is quite otherwise with the megaloblasts. Amongst them, few examples are to be found in which traces at least of the destruction and solution of the nucleus are not shewn, and in a blood preparation of pernicious anæmia, which is not too poor in megaloblasts, one can construct step by step the unbroken series from megaloblasts with a complete nucleus through all stages of Karyorrhexis and Karyolysis to the megalocytes, as the process is described by Neumann.

From Ehrlich's observations it follows, that the normoblasts become normocytes by extrusion or emigration of the nucleus, the megaloblasts become megalocytes by degeneration of the nucleus within the cell.

M. B. Schmidt without making use of the principal distinction made by Ehrlich, also concludes from his researches on sections of the bone-marrow of animals in extra-uterine life, that both kinds of erythrocyte formation occur.

Quite recently Pappenheim, partly in conjunction with O. Israel, has carried out very thorough researches on these particular points. As the subject for observation he chose the blood of embryonic mice. He was able in the first place, like Rindfleisch, to produce the exit of the nuclei from the cells by the addition of "physiological" salt solution to fresh blood, and is of the opinion that the exit of the nucleus from the erythroblasts only takes place artificially.

In embryonic blood the metamorphosis to erythrocytes occurs exclusively by nuclear destruction and solution within the cell, be it in the case of megalo- or gigantoblasts or of cells of the size of the normal red blood corpuscle.

The free nuclei that are observed, whose appearance Pappenheim explains by a preceding solution of the protoplasm (plasmolysis), he regards, in opposition to Rindfleisch and Neumann, not as the beginnings of a developmental series, but as the surviving remnants of the degenerated dying blood cells. Clinical observation, certainly, does not support this conception of Pappenheim's; in as much as in suitable cases with numerous free nuclei (leukæmia, blood crises) transitional forms, which according to Pappenheim must necessarily be present, are not to be found. Moreover, in alluding to a case of leukæmia of this kind, this author himself admits that the appearance of free nuclei can be explained in this instance by the exit of the nucleus.

Although Pappenheim, as above mentioned, recognises no difference between megaloblasts and normoblasts in embryonic blood as far as the fate of the nucleus is concerned, he nevertheless decidedly supports Ehrlich's separation of the erythroblasts into these two groups, as two hæmatogenetically distinct species of cells. He does not regard as distinguishing characteristics, the size and hæmoglobin content of the cells--although as we have described above, these are in general different in normo- and megaloblasts--for these two properties undergo such great variations as to increase considerably under certain circumstances the difficulty of diagnosis of individual cells. The chief characteristic is, as Ehrlich has always particularly insisted, the =constitution of the nucleus=. The nuclei of cells which are with certainty to be reckoned among the normoblasts are marked by the absence of structure, their sharply defined contour, their intense affinity for nuclear stains. That is by properties which histology sums up under the name =Pyknosis= (Pfitzner) and recognises as signs of old age. The nuclei of the megaloblasts are round, shew a good deal of structure, and stain far less deeply.

. The clinical differences. Normoblasts are found almost invariably in all severe anæmias that are the result of trauma, inanition or organic disease of some kind. They are however mostly rather scanty, so that a preparation must be searched for some time before an example is found. But occasionally, most often in acute, but also in chronic anæmias, and even in =cachectic= conditions, every field shews one or more normoblasts.

V. Noorden was the first to describe a case in which in the course of a hæmorrhagic anæmia normoblasts temporarily appeared in such overwhelming numbers in the circulating blood, that the microscopic picture, which at the same time comprised a marked hyperleucocytosis, was almost similar to that of a myelogenous leukæmia. And as in addition to this occurrence the number of blood corpuscles was nearly doubled, v. Noorden gave it the distinctive name "blood crisis."

The following procedure is to be recommended for the investigation of the blood crisis:

1. Estimation of the absolute number of red blood corpuscles.

2. Estimation of the proportion of white to red corpuscles.

3. Estimation of the proportion of nucleated red to white corpuscles by means of the quadratic ocular diaphragm (see page 31) in the dry preparation.

For instance if we find in a case of anæmia, 3-1/2 millions of red blood corpuscles, the proportion of white to red corpuscles = 1/100 and that of the nucleated red to the white = 1/10, then in 1 cubic millimeter there are 3500 nucleated red corpuscles, that is for 1000 ordinary there is 1 nucleated corpuscle.

=Megaloblasts= on the contrary are never found in traumatic anæmias. And in chronic anæmias of the severest degree, the result for example of old syphilis, carcinoma of the stomach and so forth, one looks for them almost always in vain, although they are sometimes to be found in leukæmia. On the contrary, the conditions, apparently much milder, in which from the clinical history, ætiology and general objective symptoms pernicious anæmia is suggested, are almost without exception characterised by the appearance of megaloblasts in the blood. Nevertheless in very late stages of the disease they are always scanty, and a very tedious search through one or more specimens is often required to demonstrate their presence. Hence follows the rule, that the investigation of a case of severe anæmia should never be considered closed, before three or four preparations at least have been minutely searched for megaloblasts under an oil immersion objective.

This clinical difference between the two kinds of hæmatoblasts admits of but one natural conclusion, which primarily leaves untouched the question, so much discussed at the present time, whether the megalo- or normoblasts can change one to the other. In all cases of anæmia, in which the fresh formation occurs according to the normal type, only in greater quantity and more energetically, we find normoblasts. Almost all anæmias resulting from known causes: acute hæmorrhages, chronic hæmorrhages, poverty of blood from inanition, cachexias, blood poisons, hæmaglobinæmia and so forth,--in short all conditions rightly called, secondary, symptomatic anæmias,--may shew this increase of normal blood production. In the conditions, which Biermer, on the grounds of their clinical peculiarities, has distinguished as "essential, pernicious anæmia" megaloblasts on the contrary occur, and represent an embryonic type of development. The extent to which this type participates in the blood formation in pernicious anæmia is most simply demonstrated by the fact that megaloblasts are present in all cases of pernicious anæmia, as Laache first shewed, and in some cases form the preponderating portion of the blood discs. Whilst, therefore, in the ordinary kinds of anæmia we find that the red corpuscles tend to produce small forms, in pernicious anæmia, on the other hand, and exclusively in this form, we find a tendency in the opposite direction. This constant difference cannot be a chance result, but must depend on some constant law: in pernicious anæmia excessively large blood corpuscles are produced. Ehrlich's demonstration of megaloblasts has sufficed for this logical advance. =All researches, which try to obscure or totally deny the distinction between megaloblasts and normoblasts are wrecked by the simple clinical fact that in pernicious anæmia the blood is megaloblastic.=

The appearance of megaloblasts and megalocytes is therefore evidence that the regeneration of the blood in the bone-marrow is not proceeding in the normal manner, but in a way which approximates to the embryonic type. The extreme cases are naturally seldom, such as that of Rindfleisch, in which the whole bone-marrow was found full of megaloblasts. It is sufficiently conclusive for the pernicious nature of the case, "if only considerable portions but not the whole marrow, have lapsed into megaloblastic degeneration." We can now say that the megaloblastic metamorphosis is not a purposeful process, and for the following reasons: 1. Since the fresh formation of red blood corpuscles by means of the megaloblastic method is clearly much slower. This is especially borne out by the fact that the megaloblasts are present in the blood always in small numbers only, whilst the normoblasts, as above mentioned, are often found in much larger quantities. In agreement with this, "blood crises" are not to be observed in the megaloblastic anæmias. 2. Since the megalocytes which are formed from the megaloblasts possess in proportion to their volume a relatively smaller respiratory surface, and so constitute a type disadvantageous for anæmic conditions. This is still more evident when we remember that the production of poikilocytes is on the contrary a serviceable process.

The megaloblastic degeneration of the bone-marrow is no doubt due to chemical influences, which alter the type of regeneration in a disadvantageous manner. We do not for the most part yet know the exciting causes of the toxic process; consequently we are unable to put a stop to it, and its termination is lethal. The Bothriocephalus anæmias, which in general as is well-known offer a good prognosis, by no means contradict this view. They hold their privileged position amongst the anæmias of the megaloblastic type, only for the reason that their cause is known to us, and can be removed. As in many infectious diseases, individuals react quite differently to the presence of the Bothriocephalus. Some remain well; others show the signs of simple anæmia, ultimately with normoblasts; whilst a third group presents the typical picture of pernicious anæmia. For many years, so long as its ætiology was unknown, Bothriocephalus anæmia was not separated on clinical grounds from pernicious anæmia. Severe Bothriocephalus anæmia may be described as a pernicious anæmia, with a known and removable cause. Good evidence for this point of view is afforded by a case of Askanazy, who describes a severe pernicious anæmia, with typical megaloblasts, in which after the complete expulsion of the Bothriocephalus, the megaloblastic character of the blood formation quickly vanished, was replaced by the normoblastic, and the patient rapidly recovered. This observation is so unequivocal, that it is a matter of surprise that Askanazy chooses to deduce from it, the ready transition from megaloblasts to normoblasts; whereas it is clear and definite evidence that =megaloblasts are only produced under the influence of a specific intoxication=. And in this way the presence of megaloblasts in the pernicious anæmias is to be explained. The megaloblastic degeneration of the bone-marrow depends on the presence of certain injurious influences, of which unfortunately we are as yet ignorant. Were it possible to remove them, it is quite certain à priori that the bone-marrow--if the disease were not too advanced--would resume its normal normoblastic type of regeneration. Clinical observation supports this contention in many cases. In megaloblastic anæmias apparent cures are by no means rare, but sooner or later a relapse occurs, and finally leads with certainty to a lethal issue. These cases, familiar to every observer, prove with certainty that the megaloblastic degeneration as such may pass away, and that in isolated cases the conventional treatment by arsenic suffices to bring about this result. A definite cure however under these conditions is not yet attained, since we do not know the ætiological agent, still less can we remove it. =For this reason, the prognosis of megaloblastic anæmia, apart from the group of Bothriocephalus anæmia, is exceedingly bad.=

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