Paper - A study of the causes underlying the origin of human monsters 5
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Mall FP. A study of the causes underlying the origin of human monsters. (1908) J Morphol. 19: 3-368.
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A Study Of The Causes Underlying The Origin Of Human Monsters
Sodium Monsters - Spina Bifida and Anencephaly
Probably the most satisfactory chapter at present in experimental teratology is the subject of spina biﬁda. Under this heading, of course, is meant that kind of spina biﬁda which is due to a lack of closure of the neural canal and not the kind that may be produced in older embryos after the cord is formed perfectly and the vertebral canal remains open. However, it is easy to conceive of the second kind as a variety of the ﬁrst, for in it the development went on normally, but the vertebral arches did not meet in the dorsal mid-line to produce the vertebral canal.
‘See, for instance, Eyclesliymer, Amer. Iour. Anat., VII, 1907.
In 1892 O. Hertwig published his remarkable article on open blastopore in frogs’ eggs and its relation to spina biﬁda. Hertwig was experimenting upon eggs to produce polyspermy, after they had been kept for some time after maturation and found that many of these eggs developed abnormally, due to polyspermy, he believed. A part of the eggs segmented irregularly and developed in a peculiarly pathological fashion, that is the blastopore remained open much longer than it should. The further study of these specimens showed that they grew into embryo monsters with all kinds of deformity of the spinal canal, often producing quite typical specimens of spina biﬁda. Hertwig saw clearly the bearing of these experiments upon the general explanation of spina biﬁda and its relation to the blastopore. This he discusses at great length and with much ability. He was able to show the relation of his work with that obtained by Lereboullet on the pike, by Oellacher on the salmon, and by Rauber on the trout. These investigations had shown that an open spinal canal or even a total ﬁssure of the body may result when the germ ring does not unite properly to form the body of the embryo.
It now became possible for the ﬁrst time to follow spina biﬁda from its very earliest stages in amphibian and ﬁsh embryos up to a time when it is clear that the process is identical with that found in birds and mammals. To be sure, in the latter cases we must take the specimens as they occasionally come to us, for it is impossible at present to experiment upon mammals successfully, and in chicks the experiments are not very satisfactory. This comparison was made by Hertwig with great acumen, using the excellent article of Von Recklinghausen upon spina biﬁda as a representative one for man.
About the same time Morgan and Tsuda in working upon the orientation of the frogs’ eggs, subjected them to a great variety of solutions, and found that a .6 per cent solution of sodium chloride prevented closure of the blastopore. By them the nail was hit upon the head; the other investigators only obtained monsters occasionally (Hertwig incorrectly believed them to be due to polyspermy), but Morgan and Tsuda obtained them in great number. It was found that less than .6 per cent of salt did not affect the embryo and a stronger solution killed it. Successful specimens, and there were many of them, were examined from stage to stage in their development and the exact steps by which the blastopore is closed was followed. This gave them a decided advantage in study over the hap-hazard one in ﬁnding embryos already formed. The experiments were used mainly to study the orientation of the embryo in its relation to the lips of the blastopore.
The crucial experiment of Morgan and Tsuda was immediately seized upon by Hertwig and employed in his experiments on spina biﬁda. Spina biﬁda could now be studied experimentally. Hertwig also found that a .6 per cent solution of common salt delayed the development of frogs’ eggs, the intestines, chorda, myotomes and nervous system developing normally, but gastrulation was postponed for from twelve to twenty-four hours. As a result of this the spinal cord does not close posteriorly as rapidly as it should and permanent spina biﬁda follows. Often the walls of the spinal tube are thin and its lumen is small, showing that there is a general arrest of its development.
In general, Hertwig did not continue the experiments beyond the sixth day, for the salt caused marked changes in the exposed spinal cord. It seemed to be less resistant, inasmuch as it underwent histolysis and cytolysis. The epidermis also showed changes; instead of being smooth on the outside it became rough, grew up into numerous papillomata, as Bardeen found in his X-ray larvae, and as I have often found in pathological human embryos.
Hertwig explained Morgan’s remarkable experimental production of spina biﬁda by assuming that the concentration of the salt retarded the growth of the cells of the egg and that the reduction of energy is unequal in different portions of the egg. Through this change differences in the rate of growth are established unlike those in the normal embryo, which naturally ended in the production of an abnormal embryo, that is, a monster. In this instance Morgan’s sodium larva is the typical embryonic stage of spina biﬁda.
The spina biﬁda, although complete at ﬁrst, rarely remains so, for the neural tube closes more or less, remaining open usually behind and often in front, giving quite typical specimens of anencephaly. It is clear, therefore, that this variety of spina biﬁda is also due to an arrest of development which could easily undergo secondary changes and produce a condition which is often found in foetuses at full term. Hertwig concludes, properly so, I think, that every human ovum has within it the power to develop into a monster, either anencephalic or otherwise, and that it is not due to any abnormal condition of the germ, but to external inﬂuences which affect the growth of the egg. A monster is due to the inﬂuence of external substances which retard the growth of the embryo, usually one portion more than the other. For a long time teratologists have practically stated the same in recognizing that monsters usually represent arrestments of normal development. Not only is this true regarding merosomatous monsters, but every egg has within it the power to develop into a polysomatous monster, or into duplicate twins.
Later Hertwig extended Morgan's experiments to Axolotl, thus making it applicable to at least six species of animals.
In this animal the monster lives much longer than the larvae of frogs and toads do, and for this reason terata with spina biﬁda. or anencephaly are obtained that resemble very much those found in man. It was found that a .5 per cent solution of NaCl produced no perceptible effect on Axolotl, that a .6 per cent solution made half of them grow into monsters, and in a .7 per cent solution all of them had spina biﬁda. In them it was found that the neural tube did not close regularly, and often several dorsal openings remained, some until the embryos were quite large. In frogs gastrulation was affected decidedly by the .6 per cent solution of salt; in Axolotl gastrulation remained normal in the .7 per cent solution, the change being conﬁned to the brain and cord, but did not extend to its caudal end. The exposed cord underwent a certain amount of histolysis and cytolysis with more or less scar formation, thus resembling very much the condition found in spina biﬁda in man. At the conclusion of Hertwig’s paper he rightly asks whether it is not possible for chemical substances in the blood, alcohol, toxines or doses of medicine, to pass from the uterus to the ovum in man and produce monsters. It is clear that he believes that monsters are not germinal and hereditary, but that they may be produced from every normal ovum through inﬂuences in its environment. Schaper“ has shown us, by producing anencephaly in tadpoles by mechanical means, that the rest of the animal grows normally without the presence of a brain. In fact, only the spinal cord degenerates after the brain has been removed. The experiment of Schaper has been further extended by I-Iarrison,7 who removed only the spinal cord, leaving the brain, before the spinal nerves are formed. In these experiments also the tadpole grows normally without a spinal cord or spinal nerves unless the operation interferes with the development of the lymph-heart, when dropsy follows. Harrison produced similar results in embryos in which the action of the whole nervous system is thrown out by means of acetonechloroform. The animals remain perfectly motionless and also develop dropsy, due probably to the effect of the acetone upon the heart of the animal. As I have mentioned above, Knower has shown that simple enucleation of the heart anlage causes an embryo to grow without a heart, which always has more or less dropsy, especially of the pronephros, while those in which the nervous system only has been removed are not thus affected. Therefore, when the nervous system is paralyzed by the action of acetone, which also retards the action of the heart, we must conclude that the dropsy of the embryo is due to the deranged heart and not to the damaged nervous system.
_ ‘Schaper,-:T_c>_L1r. Bost. Soc. Med. Sci., 1898, and Roux’s Archiv, VI,
1898. ‘Harrison, Amer. Jour. Anat., III, 1904.
In their experiments, Panum and Dareste occasionally obtained spina biﬁda in chicks, not including those monsters in which the brain was deformed. Some time later Richter” found three cases of spina biﬁda among several hundred hens‘ eggs upon. which he experimented. Otherwise these chicks were quite normal and no amniotic bands were found. This last point was considered to be of great importance, but now. since monsters are produced in animals without an amnion, it would be well, it seems to me, to relegate the amniotic theory of the production of monsters into the class into which that of maternal impressions has fallen. In Richter’s cases, howd ever, the spina biﬁda was more or less associated with anemcephaly, and there were also specimens of exencephaly as well as a few of spina biﬁda occulta. In other words, the conditions here were more complicated than those found in the frog.
In my own specimens of human embryos there are at least twelve good ones of spina biﬁda. These are among 163 pathological ova, or about one case of spina biﬁda in every 200 pregnancies. Acording to Panum’s table, there were 38 specimens of spina biﬁda among 404 monsters, or again about IO per cent. If one monster results from every hundred pregnancies, as my tables indicate, we then have one foetus with spina biﬁda in 1,000 pregnancies, which is also Koch’s9 proportion. In other words, ﬁve young embryos with spina biﬁda are aborted early, while one goes on to full term or may live after birth.
‘Richter, Anat. Anz., III, 1888.
The smallest embryo with spina biﬁda in my collection is 2.1 mm. long and in general appears normal. However, the brain is atrophic, is quite wide open and may be considered anencephalic. The cord below is also wide open, wider than in other embryos of this age which have been described. A similar but a little larger embryo has been described by Torneau and Martin (Fig 1, Plate I). Their embryo is 8 mm. long, apparently normal in form, with the spinal cord below wide open. Sections of the specimen showed that the spinal ganglia are present, lying on either side of the motor roots, which nearly encircled the chorda. There is also some histolysis of the cord. No. 189 is a case of complete spina biﬁda with marked histolysis and destruction of the superior end of the central nervous system.
The other specimens given in the footnote on page 27 show a variety of forms of spina biﬁda of the cord, probably the most interesting being No. 293, in which there is histolysis of the membrana reunions behind. A specimen like this may represent an early stage of spina biﬁda occulta. Otherwise the remaining specimens show a considerable destruction of tissues, both mesodermal and nervous, which makes them correspond more with the cases found at birth. Here the nervous tissue is quite vascular, often forming peculiar tissues, such as Von Recklinghausenm has pictured.
Recently Voigt<fref>Voigt, Anatom. Hefte, XXX, 1906.</ref> has described a case of cervical spina biﬁda in an embryo 18 mm. long, which was aborted ﬁftyfour days after the last menstrual period. A much more satisfactory account of several specimens is given by Fischel” in his study of anomalies of the central nervous system in young human embryos. Fischel describes a case with multiple but irregular canal formation, which cannot possibly be viewed as a case of arrest of development. His other specimen is an embryo IO mm. long, obtained from a woman who was perfectly healthy and aborted for unknown reasons. This embryo was apparently normal in every respect, with the exception of a well marked dilatation of the cord below just opposite the root of the leg. There was histolysis of the cord and the embryonic skin just over the hydromyelia, which Fischel believes indicates that spina biﬁda is preceded and caused by hydromyelia, that is, he accepts Morgagni’s theory. At any rate, the great variety of malformations of the spinal cord which are grouped under the name of spina biﬁda cannot all be likened directly to Hertwig’s spina biﬁda in amphibia, although in both there is considerable histolysis. Fischel’s specimen, which is a very important one, shows conclusively that there is a destruction of tissues in the formation of spina biﬁda much the same as I have noted in the description of some of my specimens. In other words, the embryo was normal before it developed spina biﬁda. The relations of hydromyelia to spina biﬁda, and of hydrocephalus to anencephaly, have been discussed so much since the time of Morgagni, and my cases, as well as Fischel’s, throw no new light upon the subject. Dropsy of the cavities and tissues of the body accompanies practically all pathological changes in the embryo, and it may be considered an effect just as well as a cause in these cases of spina biﬁda.
‘Koch, Beitrige zur Lehre von Spina Bifida, Kassel, 188:. "Von Recklinghausen, Virch- Archiv, I05.
”Fischel, Ziegler’s Beitréige, XLI, I907.
Embryo No. 6 shows an interesting condition in the lower part of the spinal cord similar to the ﬁrst case described by Fischel. There is a marked vesicle coming off the cord between the motor roots of the two last spinal nerves, as may be seen in the illustrations. The lower end of the cord extends somewhat beyond the vesicle. The vertebral column ends just above the vesicle and is composed of two cartilages. Bardeen has shown that the double arrangement of the last cartilage of the cord is of quite common occurrence among the normal embryos of my collection. I have looked through the normal embryos of about the same stage as No. 6, and in no instance have I found one with a vesicle like it attached. Among the specimens two occur with very small vesicles at the extreme tip of the cord, this being best marked in No. 22, an embryo 20 mm. long. Another embryo, 19 mm. long, No. 229, also shows this dilatation. It seems to me that in these cases there is only a slight exaggeration of the normal, while in No. 6 the vesicle is newly formed.
While the per cent of cases of spina biﬁda among pathological embryos and foetal monsters is about 7 per cent of the total number of monsters in each case, it rises in anencephaly to about 20 per cent, that is, in 1,000 pregnancies there -are I 5 cases of anencephaly aborted very early and one case goes on to full term.
Among the embryos with changes in the brain that indicate the beginning of anencephaly there are many varieties of deformed brains that are exposed more or less. The brain may be escaping from the front of the head, the mid-brain may be exposed, or the medulla is distended and ﬁlls the whole atrophic head, as the various ﬁgures show. In most of the specimens there is a marked histolysis of the surrounding tissues as well as of those of the brain, with vascular metamorphosis of the brain tissue, as is shown in specimens like Nos. 364 and 365. In these cases we cannot speak of a simple arrest of development only, but also of a destruction of tissue, histolysis and necrosis, or parenchymatous inﬂammation, as Panum would call it. These specimens are discussed sufﬁciently under various headings further on, and under the descriptions of the embryos in the last portion of this paper.
It has been shown that typical spina biﬁda and anencephaly can be produced in a number of species of amphibia by Morgan’s experiment, that is, by cultivating the eggs in dilute solutions of NaCl. This causes an arrest of development of the embryo, which is decidedly more marked in the central nervous system than elsewhere. There is also a more or less marked histolysis of the cord and brain. Similar changes can be produced in birds, while in man the number of cases of spina biﬁda and anencephaly are at least ten times as numerous in the embryo as in the fatus.
In man, however, the pathological changes in the embryo are very marked and complicated by an arrest of the development of the heart or by its complete destruction. "In my specimens no doubt the destruction of the heart must be held responsible for the general oedema and the marked histolysis of many of the tissues, including those of the brain. It may be that the faulty implantation of the ovum affects the heart ﬁrst and that the changes in the nervous system are produced secondarily, but our data are too meager to allow us to draw any conclusion regarding the sequence of events. At any rate, there must be other factors at work which make the process more complicated than it would be if there were only a simple arrest of the development of the spinal cord. The other changes are in the region of the spinal cord and canal and aid in producing the various forms of spina biﬁda, including spina biﬁda occulta, which are found in the foetus and at birth.
In some instances, in which the individual lives after birth, the primary change must have been of a slight degree to begin with, and the faulty implantation of the ovum must have been corrected, or in case the ovum was poisoned, the disease must have been eliminated in order to allow the embryo to continue its development. However, very simple or uncomplicated cases must be very rare, for spina biﬁda is usually accompanied with other malformations, as is the case with most monsters.
- Hertwig, Arch. f. mik. Anat., XXXIX, I892.
- Von Recklinghausen, Virch, Arch., 105, 1886.
- Morgan and Tsuda, Quart. Jour. Micr. Sei., N. S. 35, 1894. Also, Morgan, Roux’s Archiv, pp. 266, 269 and 293, 19:2.
- Hertwig, Arch. f. mik. Anat., XLIV, I905.
- Hertwig, Gegenbaur’s Festschrift, II, 1896.
- Bardeen, Amer. Iour. Anat., IV, 1905.