Paper - Description of a young human anencephalic and amyelic embryo
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De Vries E. Description of a young human anencephalic and amyelic embryo. (1927) Anat. Rec.
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Description of a Young Human Anencephalic and Amyelic Embryo
Ernst De Vries
Department of Neurology, Peking Union Medical College, Peking, China
The monstrum described in this paper is the result of the only pregnancy of a Chinese woman, who denies the occur-rence of other deformities in her family. Her Wassermann reaction was negative. The last menstruation occurred one hundred days before the abortion, at which the closed chorionic sac was discharged. The ovum was ﬁxed in toto in formalin, and kept in that condition for over a year. On opening the sac, it contained a 23—mm. embryo with the deformities which form the subject of our description. Paraﬂin sections, 10 p thick, were stained with haematoxylin and eosin; they were cut at right angles to the back of the embryo.
The amnion sac is 10 cm. long and nearly cylindrical. in shape, 4 cm. in diameter. As mentioned already, the embryo itself measures 23 mm., VerteX—breech length, but, due to the abnormal ﬂexures and the partial anencephaly, this length cannot directly be compared with the length of normal embryos. On inspection (ﬁg. 1), We see that the base of the skull is covered by a brown mass, which is separated by a sharp border—line from the White skin which covers the face and forehead. The head has not the protruding eyes of the fullterm anencephalic monster, and the forehead is present, although it slopes backward instead of bulging over the face. The above-mentioned brown mass contains the cerebral hemi 293
um ANATOMICAL RECORD, Von. 36. N0. 4 294 ERNST ma VRIES
spheres and the optic thalamus, which, as we shall see later, is all that is present of the central nervous system. In the center we ﬁnd an opening with torn edges leading into the brain ventricles.
The thoracic part of the back is covered by skin; it is ﬂattened out, and has a groove in the center where the spinal cord and the arches of the vertebrae ought to be. Downward, this groove leads into a canal which will show itself to
Fig. 1 Side View and back View of the embryo.
be the meningeal sac, and can be followed into the tip of the sacral region.
The embryo has a straight back. The normal kyphotic ﬂexure of the whole vertebral column from sacrum to neck is absent. The head is not bent forward, but a little upward.
The umbilical cord is rather short, 2 cm. in total length. It shows a swelling near the abdominal end, which will be discussed afterward. The skin is not intact everywhere, but in some "places strings of tissue are attached to it. These HUMAN ANENCEPHALIC AND AMYELIC EMBRYO
are possibly amniotic bands, but no connection withthe wide amnion has been found.
Age of the embryo
As mentioned above, from menstrual data the age must be between seVenty—tWo and one hundred days. The amnion sac of 10 cm. is as large as that of a three—months embryo, but our embryo itself is considerably smaller. The length, 23 mm., corresponds with eight weeks. The stage of ossiﬁcation of the clavicles and of the long bones of the arms and legs, and the absence of ossiﬁcation in the vertebrae also point to an age of eight weeks. Yet the end phalanges of the ﬁngers are already cartilaginous—a stage, which, according to the text—books of embryology, does not begin before the third month.
The conﬁguration of the mouth is, as far as I can ascertain, normal for the length of the embryo. There are erythrocytes without nuclei, profusely in symmetrical places, lateral to the central nervous system, and much less clear in the larger blood vessels or in the heart, where they have probably disappeared through hemolysis.
The development of those parts of the brain that are actually present is certainly not delayed. So far as can be inferred from material available for comparison, the brain cortex and the ﬁber systems of the internal capsule in this embryo are approximately the same as in a normal 27-mm. human embryo.
My conclusion as to the age of our specimen is that the ovum is about twelve weeks old, but that the embryo shows a retardation in its development. Mall accepted the same explanation for many of his cases which also showed an amnion several weeks older than the embryo within. The embryo has an average age of eight weeks, some parts, as the hands and perhaps the hemispheres of the brain, being more advanced in development. It is interesting to note, in this connection, that Naﬁagas found, in comparing the body di— mensions of anencephalics and normal fetuses, that the for296 ERNST nu VRIES
mer invariably had much longer arms, and that other parts of the body also were not harmoniously developed.
Presemzation of the embryo
The preservation of the embryo was not very good. Throughout the body the mucous membranes are badly preserved, their cells lying in groups in the cavities of the organs. The brain also is not well preserved, its structure is often obscured by postmortem disintegration. The cells of liver and heart do not take nuclear stains, but the lungs and kidneys are much better preserved. Red blood corpuscles are found especially well preserved under the dorsal covering of the head. In most blood vessels and in the heart itself they cannot be distinguished easily. On the other hand, it is of interest that the brain and retina show a great number of mitotic cell divisions, and that these occur also, to a less degree, however, in the kidneys and tongue muscle. This must mean that the death of the embryo occurred abruptly. VVe are led, therefore, to believe that the embryo developed at a slower rate than the amnion sac, but died at the same moment as the latter.
There are a certain number of tags on the skin, especially around the mouth, on the arms, and on the thorax. The epidermis is absent in these parts, and a thin tissue is attached to the skin, covered by irregular connective-tissue cells. There is no evidence of a connection of these structures with the amnion, but it is possible, of course, that such a connection existed at an earlier period. a
The umbilical cord contains a tumor—like mass, which on section turns out to be a gland-like structure, connected with the omphalo-enteric duct. It is not within the scope of this article to deal fully with the particulars, but it is interesting to note that a number of mitotic cell divisions were seen in the epithelial cell layers. HUMAN ANENCEPHALIC AND AMYELIC EMBRYO 297
The abnormal ﬂexures of the back and neck are the same as seen in the majority of cases of anencephaly and amyelia. The wall of the hemispheres and _the retina show abnormal foldings, in consequence of which their cavities are nearly ﬁlled up. This phenomenon is often seen in poorly preserved embryos, whether otherwise normal or not. As far as I know, no satisfactory explanation of it has been given.
Little need be said about the non-nervous organs. With the exception of the epiphysis, of which no trace could be found, all other organs are present. The hypophysis is large, at least in its glandular part, and has a connection with the infundibulum. The adrenals are present, but, due to the bad preservation of the specimen, I was not able to distinguish between its cortex and marrow. The choroid plexus in each lateral ventricle is large and ﬁlls up a considerable part of the ventricle. The third ventricle at this period of development still lacks a plexus, and the plexus of the fourth ventricle together with the whole hindbrain is undeveloped.
As far as the state of preservation permits us to judge, the muscles are well developed. There is no difference in development between the eyeball muscles, tongue, masseters, and muscles of the extremities.
The membrane covering the head and neck, and the meninges
As the covering of the nervous defect may be a guide to the origin of this deformity, I will give a detailed description of the various structures found. We can divide the whole into three ﬁelds—the head, the thoracic and the lumbosacral portion. For all three ﬁelds we can state that the skin, the epidermis as well as the corium, is not continuous with any of the structures to be mentioned. Wherever skin covering and another membrane come together, there is a sharp border-line, as if out with a knife, and, as a rule, the skin forms a wall several cell layers thick. The normal skin runs above the eyes backward for a certain distance, more than is usual in full-term ancncephalies (ﬁg. 1). This is bordered in the frontal and the parietal region by a layer of cubic epithelial 298 ERNST ms yams
cells, one cell thick. This cubic cell layer is of horseshoe shape, and therefore does not cover the wl1ole defect, and does not border tl1e skin of the neck. It often shows verru— cous growths; the normal corium, the ﬁbrous layer present in normal skin, is absent in the whole area, but in some places there is a dense subepithelial tissue in which occur many erythrocytes (possibly hemorrhages).
The remaining part of the head area is either covered by a plate cell, probably connective—tissue scar, or by larger cells, lying scattered on the former, and whose nature cannot be determined, but sometimes resembles ependyma cells. It is possible that these cells, in an earlier period, formed a continuous layer. At the opening in the covering, at the vertex, the meninges are continuous with the mesodermal layer. It is therefore also possible that the larger cells were continuous with the ependyma of the third ventricle, but no proof for this suggestion can be found, as these tissues are all badly damaged. Meninges around the brain are present, although not everywhere differentiated to the same degree. They follow the larger ﬁssures in the lateral aspect of the hemispheres and also lie between both hemispheres and the thalamus.
In the thoracic part (ﬁg. 2) of the embryo the skin is continuous over the back. There is no indication in the midline that an original defect in that position has been secondarily covered by an extension of the epidermis from both sides. There is no sign of meninges under the skin, but mesodermal tissue, of course, is present. The spinal ganglia have no distinct _membrane, no meningeal cavity is present, such as is found in the sacral part.
At the lower thoracic level the epidermis splits in the median line, and this gap becomes gradually wider as it proceeds caudally, the floor of the groove being covered by mesodermal tissue. Gradually the groove becomes deeper, and ﬁnally the walls close again in the median line. Then a tube is formed, lined by mesodermal tissue, the meninges, and the surface is covered again by normal epidermis (ﬁg. 3). HUMAN ANENCEPHALIC AND AMYELIC EMBRYO
This meningeal sac of the lumbosacral region shows an incomplete division into two halves at several levels, caused by a septum projecting from the anterior wall into the cavity. This is very probably the anterior septum of the pia project Fig. 2 Diagram of cross—section of upper thoracic part of the body. Note the spinal ganglia ($11., of which the right is much more dense than the left) on both sides of the groove in the skin. No meninges present. Note the sympathetic ganglia (S) onyboth sides of the body of a vertebra, and some ﬁbers arising from them (white communicating branch). The vagus nerve, on both sides of the oesophagus (0) is not drawn. P, lungs; T, trachea; R, rib.
ing into the anterior ﬁssure of the spinal cord—an assumption which is corroborated by the existence in some places of spinal-cord tissue Within the sac. The spinal ganglia of the lumbar portion lie lateral to the meninges. In the sacral part they are attached to the pia. A dura does not exist as a separate membrane. 300 ERNST rm: VRIES
Central nervous system
The central nervous system of this embryo, therefore, consists of both hemispheres and the thalamus at one end, and some remains of lumbosacral spinal cord at the other end. In the segments between these two parts, only spinal ganglia and some cranial nerves are present.
The cerebral hemispheres are not much deformed. Owing to the deformation of the whole head, their position is more
Fig. 3 Diagram of cross—section through the lumbosacral part. The spinal ganglia lie laterally of the empty meningeal sac (fallen together by shrinkage). The organs in the pelvis not drawn. P, pelvis; D, meningeal sac.
backward than in the normal embryo, but their size is probably normal. As stated above, the wall of the vesicle is often folded. One ﬁssure runs on the lateral side from the top of the hemisphere downward and can be compared with the sylvian ﬁssure, as it is around this ﬁssure that we ﬁnd the anlage of the striate body (ﬁg. 4, BG.) It is also in this part that we ﬁnd a primitive cortex (0) of the same distribution as in slightly older normal embryos. It spreads only over the lateral aspect of the hemisphere. The choroid plexus is HUMAN ANENCEPHALIC AND AMYELIC EMBRYO
rather massive and is ﬁlled with dense connective tissue; its ependymal cell layer can often be distinguished in parts where the postmortem maceration is not too severe. The olfactory lobes and nerves are present; the foramcn of Monro is rather large.
Fig. 4 Photograph of a section through the brain, at the level of the opening on top of the skull (between 56-40), and through the foramen Monroi. Note the large basal ganglia (B.G.) with cortex formation (0) on their surface. Note choroid plexus (C.P.) in both lateral ventricles. The ventricle of the thalamus seems to open at the back.
Between both hemispheres lies a part of the brain that, I think, must be the optic thalamus (ﬁoa 4, th). The basal structures are quite typical. As shown on the accompanying diagram (ﬁg. 5), the optic nerves and chiasma are distinctly developed. But an optic tract cannot be found as a compact ﬁber bundle. The ﬁbers from the chiasma cannot be traced caudally of their crossing for a.11y considerable distance. The 302 ERNST ms VRIES
third ventricle opens into the foramen of Monro in the lower part of this communication between the two hemispheres. From there backward the roof of the thalamus is not membranous, but rather thick. This organ itself is a rather massive structure, with a small ventricle, which, however, has
Fig. 5 Diagram showing projection of the thalamus and cranial nerves on a sagittal plane. A, median section of thalamus; B, foramen Monroi; C, septum pellucidum; D, chiasma, below which lies the hypophysis; E, place where the internal capsule perforates from the striate nucleus into the thalamus. Roman ﬁgures II to XII, the cranial nerves; CI, ﬁrst cervical nerve. Sy, sympathetic nerve and superior cervical ganglion. The three eye muscles are the m. trochlearis, m. rect. sup., and m. rect. ext. The V and VII nerves have not been drawn to theirperipheral termination. The gaserian ganglion and the surrounding nerves are drawn in the diagram more caudally, in order not to get their projection covering the chiasma. HUMAN ANENCEPHALIC AND AMYELIC EMBRYO 303
two lateral processes leading into lateral masses of nervous tissue, of which I cannot ﬁnd the homologue in the normal embryo. The roof of the thalamus is discontinued in two places; one is the opening in the covering of the nervous system, where the ventricle opens into the amnion cavity. Owing to the bad preservation of the embryo, I have not been able to determine whether the ependyma is continuous with the covering or not. The second opening lies more backward and is covered by mesodermal tissue. It is possible that an epen— dymal roof covered the ventricle here, but was macerated after the death of the embryo.
The internal capsule can be seen in the diagram (ﬁg. 5, E). Fiber tracts run from the primitive cortex and from the striate nucleus into the thalamus, where a part of them bends upward (striothalamic tract) and another part runs backward (corticostriomesencephalic tract). This distribution of the ﬁbers and the direction of the tractus habenularis, which is clearly present, make me feel sure that all, or by far the larger part, of this nervous ganglion is thalamus, and not mesencephalon} In the normal embryo these parts are pressed in a frontal direction by the mesencephalon and by the pons, which lies very close to the optic chiasma.
I cannot determine which part of the thalamus, as we see it now, was connected with the mesencephalon, but probably it must have been the lower caudal opening. When we admit a destruction of the mesencephalon and all more caudal nervous structures, the extreme posterior position of the hemispheres and the thalamus is easily explained by a pressure on the frontal region without any counterresistance at the back of the head.
The spinal cord is absent in the cervical and thoracic region, where no meningeal cavity exists. No motor ‘roots can be found, but the connecting branches from the spinal ganglia to the sympathetic ganglia are present. However, as far as I know, the point is not yet settled whether these nerves
‘We will see later that the distribution of the cranial nerves also is in favor of this conclusion. 304 ERNST DE VRIES
carry only motor ﬁbers, whose cells lie in the lateral part of the anterior horn, or also sensory ﬁbers from t.he internal organs, going to the spinal ganglion. The presence of these communicating nerves does not imply the presence of motor ﬁbers in this part of the embryo. Searching for motor end plates in the muscles of the extremities was not practicable,
Fig. 6 Photograph of lower sacral vertebral canal. .In the meningeal sac (M) are remnants of nervous tissue, in which various elements of the emliryonal cord can be distinguished. No spinal ganglia present in this section.
because the ﬁxation of the tissues was insufficient for the appropriate staining methods.
In the lumbosacral part we ﬁnd a meningeal sac (ﬁg. 6), and in this sac some scattered nervous tissue can be found in places. Often neuroblasts and embryonal white matter can be clear].y distinguished, but the particles of tissue are mostly Very small and are for long stretches entirely absent. HUMAN ANENCEPI-IALIC AND AMYELIC EMBRYO 305
Sometimes this nervous tissue is connected with the pia, but in most places it lies free in the cavity. I nowhere found a connection with the places where the posterior or anterior root would, in normal cases, perforate the meninges. In this part, as in the thoracic, spinal ganglia are beautifully developed, and their nerves run through the intervertebral foramina, giving branches to the sympathetic ganglia. From the ganglia root_ ﬁbers can often be traced for a short distance, running in a caudal direction, without any further connection with the pia or the skin. They do not run upward as is described in older cases of amyelia. No anterior root ﬁbers are present.
The spinal ganglia still lie in the groove of the vertebrae; not so far lateral that they lie in the interspinal canal; they form a continuous row, but each is distinct from the others. Their ganglion cells are numerous and well developed; the ventral cells being, as a rule, larger than the dorsal cells.
I have not been able to make out whether or not there are motor nerve ﬁbers in the periphery of the body. As we know, a so-called motor nerve always carries, in addition to the motor ﬁbers, the sensory ﬁbers coming from the muscle spindles, and is therefore always a mixed nerve. This probably also is true for the phrenic nerve, present as a very thin bundle in my case, which, however, carries also some sympathetic ﬁbers.
The olfactory and optic nerves are present, and have.normal connections with their sense organs, and the olfactory nerve also with the olfactory lobe of the brain. The optic nerves form a chiasma, as described above, but their ﬁbers disappear behind this in the general indistinct mass of nervous tissue. The eye-muscle nerves can be seen in the diagram (ﬁg. 5). From the muscles arise nerve bundles, which run backward for various distances, and end somewhere in the connective tissue, without any connection with the central nervous system. The nerve bundle coming out of the easily 306 ERNST on VRIES
recognizable trochlear muscle, ends abruptly beside the gasserian ganglion, whereas the nerve from the superior rectus runs far backward and can be traced behind the thalamus to very near the dorsal median line, where it comes quite close to the same nerve from the opposite side, without, however, crossing as the trochlear nerve does. This must be the oculomotor nerve, which in the embryo originates far backward from the mesencephalic ﬂexure. From the external rectus muscle nerve ﬁbers can be traced to the trigeminal nerve, perhaps consisting only of sensory ﬁbers from the muscle spindles. I did not follow the other branches of the oculomotor nerve, but the details given in the diagram are essentially the same on both sides.
Thetrigeminal nerve is represented by a large gasserian ganglion, from which branches divide into their various peripheral end organs. From the ganglion a huge root runs backward, passes the petrosal bone, and spreads out in the loose mesenchymatous tissue; here it ends in connection with the horny covering of the skin defect, or just underneath this (ﬁg. 7). I have not been able to ﬁnd a motor branch of the ﬁfth nerve, so this must be absent at least in the intracranial part of the nerve.
The branches of the facial nerve form a distinct bundle of ﬁbers, running into the petrosal bone, where the geniculate ganglion can easily be discovered. From this ganglion we can trace the chorda tympani ﬁbers, joining the trigeminal nerve. The larger part of the facial nerve ﬁbers, however, pass this ganglion without any connection, and run in a central direction for some length alongside the eighth nerve, which has gathered its ﬁbers from the cochlear. and vestibular organs, where their respective ganglion cells can be easily recognized. These ﬁbers can be traced for a short distance inside the skull, where they end abruptly without any connection with the central nervous system, although quite close to it, and separated from it only by the meninges.
The glossopharyngeal and vagus nerves cannot be distinguished from one another. They begin as a very shallow HUMAN ANENCEPHALIC AND AMYELIC EMBRYO 307
bundle of ﬁbers just inside of the foramen jugulare, and form a ganglion jugulare. They then run outward and downward to form a large ganglion nodosum. Many small branches go oﬁ here, partly to the upper cervical ganglion of the sym Fig. 7 Drawing (section 63), showing cranial nerves. III, The branch of the oculomotor nerve, cut twice, going posteriorly; GG, the gasserian ganglion; V, root of trigeminus, ending in the thin horny layer; VII, facial nerve, lying between the gasserian ganglion and the aeustic nerve (VIII). The shaded fields are central nervous tissue; to the left the tip of the temporal lobe; in the center the thalamus (th). The mouth is open; the tongue lies inside, as a separate mass between the alveolar process.
pathetic nerve. The main nerve trunk goes downward and can be followed to the stomach; a recurrent laryngeal nerve is quite clearly seen. This nerve is supposed to carry nonsympathetic motor ﬁbers, but normally it probably carries also a number of sensory ﬁbers from muscle spindles. The accessory nerve is represented, as the diagram shows, only 308 ERNST pm vnms
by a small nerve bundle running from the meninges to the sympathetic ganglion. Motor ﬁbers running to the sternemastoid or trapezius muscles cannot be found.
The nerve trunk of the hypoglossus can be followed from the tongue muscles backward as a very small bundle, not half as thick as the vagus. It crosses the ganglion nodosum, with which it has probably connections; its stem is then very much thinner and continues centrally to the ﬁrst cervical ganglion. It is clear, therefore, that a true hypoglossal nerve is not present, but we ﬁnd that some ﬁbers from the ﬁrst cervical ganglion and others from the vagus ganglion run in the twelfth nerve course, perhaps together with peripheral parts of the true hypoglossus, in the same manner as we found for the facial and oculomotor nerves.
The cervicothoracic sympathetic trunk is, as has already been pointed out, quite large, and seems normal in its distribution, its ganglia, and connections. That the ganglia get branches from the spinal ganglia has also been mentioned above.
Histological examination of the nerves, although diﬁicult because of the maceration of the tissues, gives the impression that there is no difference in structure between the most peripheral parts of the eye—muscle nerves and the facial on one side and the vagus and spinal nerves on the other; but the nearer we approach the central ending of the ﬁrst-mentioned nerves, the more the histological picture becomes indistinct, so that in the central part only a loose meshwork is present, probably consisting only of the cells of Schwann’s sheath. This makes it probable that these nerves are actually degenerating, but their most peripheral parts are still normal.
1. The ovum described above is approximately three months old; the embryo within has followed a slower course of de— velopment, so that it is, generally speaking, comparable with an eight weeks’ human embryo. The hands and the cerebral hemispheres are a little (perhaps one to two weeks) in ad Vance of other organs. (See also 6, infra.) HUMAN ANENCEPHALIC AND AMYELIC EMBRYO 309
2. Representing the central nervous system, the hemispheres and the thalamus are present, and the former are normally developed. The hemispheres show folding of the thinner parts of the wall, as often noted when the state of preservation of embryos is not perfect. The thalamus shows extensions to both sides, of unexplained signiﬁcance.
3. The mesencephalon and hindbrain are absent. As th_e motor nerves from thesepparts are developed, the motor ganglion cells must have been present in their neuroblastic stage or later, and they must have disappeared afterward. Whetlier they were part of a, theretofore, normal neural tube, or merely isolated groups of neuroblasts with retained power of development, cannot be made out.
4. Of the cervical and thoracic parts of the spinal cord no trace can be found. No motor roots are present. Of the lumbosacral part of the cord some remains are still present in a normal meningeal sac. As there are no anterior roots present in this part, we may conclude that a normal cord has not existed as such, but that some parts of the anlage of the spinal cord have differentiated into the marginal zone and cellular zone that we found. The normal closing of the mesenchyma around the spinal cord is in favor of a late destruction. Originally, a spinal cord must have protruded in the opening of the skin of the back, as we ﬁnd also in cases of pure anencephaly, where the cervical part of the cord forms the center of the area cerebrovasculosa of the brain.
5. The horseshoe-shaped layer of cubic epithelial cells, bordering the skin in the anterior and lateral parts of the area cerebrovasculosa, is not yet fully explained. This can be a persistent, non-differentiated part of the neural plate.
6. Mitotic ﬁgures in the brain and other tissues point to death of the embryo shortly before abortion took place.
7. The abnormally straight back and the absence of the normal neck ﬂexure are easily explained as secondary to a faulty development of the central nervous system. This latter, by growing faster in normal embryos than the noto THE ANATOMICAL RECORD, voL. 36, N0. 4 310 ERNST pm vams
chord and primitive vertebral column, gives rise to the typical ﬂexures of the back and head.
The literature does not supply many cases of anencephaly or amyelia in very young embryos. I was able to ﬁnd the records of only ﬁve human cases, of which I will give a brief abstract.
Lebedeff, as early as 1881, was the ﬁrst to describe an early case of the deformity that interests us now. The length of the embryo is 9 mm. The amniotic sac has reached the size of an egg and the umbilical cord is 4 mm. long. The normal ﬂexures of the back and neck are absent; the embryo is straightened, with slight lordosis of the thoracic part. The forebrain vesicles are formed, but their walls are folded, so that the vesicles do not protrude over the eyes, which seem to be normal. The thalamus opens dorsally; its ependyma is continuous with the skin. From that point caudally the medullary groove is open, but although Lebedeff does not deﬁnitely say so in his very short description, I infer that it closes again at the lumbosacral level, and that the lower part is covered by skin. Part of the exposed medullary plate is degenerated, and in these places the mesodermal tissue lies open on the surface, but small particles of nervous tissue have grown into this tissue and are still persistent. No mention is made as to the cranial nerves, auditory vesicle, or spinal ganglia.
Frazer described, in 1921, a human embryo of 17 mm. with anencephaly, in which the oblongata was still present (so-called hemicephaly). The general bodily development points to a nearly eight-weeks-old embryo. Eyes and ears are present, as is the spinal cord. Of the brain only the oblongata and the optic stalks are present. The pituitary gland could easily be found; some very irregular nervous tissue lies around it, and it looks as if the optic nerves end here. Portions of all cranial nerves are present; the oculomotor seemed degenerated, the others rather normal. None of these nerves, however, runs into the cranial cavity; they end someHUMAN ANENCEPHALIC AND AMYELIC EMBRYO 311
where outside or in the meninges. Even the last pairs are not present between the base of the skull and the oblongata (Frazer does not give any data about nerve roots or their nuclei in the oblongata). According to Frazer, the nerves must have been broken off by a straightening process of the embryonal ﬂexures of the brain, but he does not say at which period this should have occurred. As he gives very few further data, it is not possible to form an opinion about the process of destruction in this case. Frazer himself thinks that the brain was not normal when the catastrophe occurred.
An embryo described by Cull of nearly the same length as Frazer’s embryo, was in such a bad state of preservation that no details could be made out. There was rachischisis, with some nervous remains between the spinal ganglia, covered by loose cellular tissue. Hemispheres and brain stem were present, covered by the same tissue. An opening in the vertex led into the cranial cavity.
The fourth case is that of Bohmig——an embryo of 20 mm., very much like the monster described by me above. As, how« ever, B6hmig’s interest lay chieﬂy in the skull, his description of the nervous system is rather scanty. The age, according to the length of the embryo, is six weeks; according to the structure, however, it is probably one to two weeks older. No data about the membranes were available. The back is straight and the‘ head slightly bent upward. Remnants of the brain are covered by a membrane with an opening in the center. Hemispheres could be made out, but the poor preservation of the embryo made it impossible to form an exact opinion about the thalamus. The mid—brain and hind~ brain were absent. The cervicothoraoic part of the back was covered by skin, underneath which the spinal ganglia were lying just in the same way as in my specimen. No meningeal cavity was present. At the level of the seventh thoracic vertebra the skin opened; the spinal cord appeared in the opening and seemed in direct continuation with the skin. From there downward a meningeal sac existed, covered by normal skin, and containing spinal cord. It was impossible 312 ERNST ma vams
to make out whether this had been normal up to the death of the embryo and macerated afterward or was already abnormal before death. No reference is made to anterior nerve roots.
A ﬁfth case, somewhat similar, is given by Mall. The human embryo was 20 mm.; the amnion sac, 80 mm. There had been endometritis; the chorion contained many purulent foci. No skin was present over the brain, an opening in the mesodermal membrane at the vertex exposed the brain, but did not lead into the ventricle. The eyes had grown together; there was one optic nerve. The brain ended posteriorly in a mass of tissue back of the ears, of which no further description is given. The back is covered with smooth skin. The spinal cord is present from the upper cervical to the upper lumbar region and seems to be normal in this part; caudally, it ends in a ﬁbrous mass. Downward from this point the spinal canal (i.e., vertebral canal) is ﬁlled with mesodermal tissue. Spinal nerves and ganglia are present in this latter part.
I will not try to give a review of the literature on rachis— chisis, because our knowledge of the various forms of this deformity is not yet suﬂicient to allow us to give a general explanation of this anomaly, either as to cause or as to morphogenesis.
There are still some obscure points, which have to be cleared up by detailed study of the specimen, before we can venture upon a general hypothesis. I will mention three questions which presented themselves to me during the study of the embryo. First, what is the signiﬁcance of the layer of cubic epithelium which lines the anterior end of the area cerebrovasculosa, as described above? This is so typical a structure, that its presence cannot be merely accidental, but must have some bearing on the ulterior development of the tissues which lie in the very young embryo in the frontal part of the neural plate. A
A second point which can only be solved by the study of adequate material is the signiﬁcance of the opening in the HUMAN ANENCEPHALIC AND AMYELIC EMBRYO 313
vertex of the head. This opening was found in four out of the ﬁve cases of anencephaly in young embryos referred to above, whereas in the ﬁfth case (Frazer’s case) the injury to the skull makes it impossible to know whether such an opening had been present or not. Of fourteen cases‘ of anencephaly in the collection of the Department of Anatomy of the Peking Union Medical College, which I could examine in regard to this point, I found the opening present in eleven, doubtful in two, and absent in one. This last case had no remnants of brain whatever (a rare ﬁnding), and the normal skin of the face did not come up to the level of the eyebrows in the median line, but ended on the back of the nose. In several other cases in literature this opening has been described, but explained as traumatic. Lebedeff remarks that it leads into the brain cavity in his case and is lined with ependyma, which is continuous with the skin. I was able to examine a case of hemicephaly (partial anencephaly) in serial sections, and there too the opening was present, but led into the rhombencephalic ventricle. This opening cannot be the anterior neuroporus, as that structure lies at the frontal end of the neural tube, somewhere in the lamina terminalis, near the preoptic recess.
In discussing the morphogenesis of the above-described monster, I think we are safe in saying that the injurious agent or trauma operated after the outgrowth of the motor roots of the cranial nerves from the central nervous system. This process begins in embryos of about 10 somites, 2.1 to 2.5 mm. in length. There is a rather considerable variation in the various early human embryos reported, but in this stage the neural tube has closed in its cervical part. According to some authors, closing of the tube begins in the mesencephalic region; according to others, in the upper cervical region, and proceeds from there in frontal and caudal directions_. It may be that the motor roots develop before the closing of the midbrain or after it, but the upper part of the spinal cord is always closed at that period. The embryo is still straight, only the prosencephalic groove is bent at about 314 ERNST mm vmns
a right angle to the axis of the body, the diencephalon forming the top of the ﬂexure. At the caudal end the neural groove is practically straight, but the primitive streak is also bent ventrally. There is no kyphosis. In some embryos there may be even a slightly lordotic curvature. Bartelmez and Evans state that most of the bends and ﬂexures found in young human embryos are postmortem changes, due to collapse and wrinkling of the yolk sac.
The‘ maaimum lesion lies in most cases of rachlsclnsis in the mesencephalic region. In the ordinary cases of anencephaly, as we know them from the text-books of pathology, nothing is left of the mesencephalic structures except the motor nerve ﬁbers in the periphery and the gasserian ganglion with its branches; all central nervous tissue has disappeared. The diencephalon is rarely totally destroyed, the chiasma and infundibular region being present in many cases, often with. more or less nervous tissue around them. In the above-described case, as in those of Bohmig and Lebedeif, the thalamus was present. Remains of the forebrain are always present; olfactory lobes could be found in nearly every case, and structures resembling the choroid plexus are also a very common ﬁnding. The choroid plexus develops as a fold from the mesial wall of the hemisphere, and is therefore a differentiation from the dorsal part of the neural tube. A great many anencephalics have in the area cerebrovasculosa more or less differentiated islands of nervous tissue, in which Veraguth was able to ﬁnd ganglion cells arranged more or less as a brain cortex. These also must therefore belong to the dorsal structures.
At the occipital end we often ﬁnd a total absence of the hindbrain, as in all cases in which anencephaly is combined with amyeli.a; but we know, too, that when the spinal cord is not involved, more or less tissue of the rhombencephalon may still be present; in some cases (called hemicephaly or partial anencephaly) even the entire oblongata and the basal part of the pens are formed (de Vries). From this we may draw another conclusion: The dorsal parts of the neural axis are always aﬂeoted more than the ventral parts. HUMAN ANENCEPI-IALIC AND AMYELIC EMBRYO 315
Looking tothe spinal cord, we ﬁnd facts in favor of our ﬁrst conclusion. Speaking about the vertebral column in rachischisis, Kermauner says that in all caseslwithin his knowledge the sacral bone was closed. When we examine the remnants of spinal cord in these cases, we often ﬁnd that in the cervicodorsal part no nervous tissue is left, whereas in the lower part the cord lies ﬂattened out as area medullovasculosa, often with ganglion cells still present, from which anterior roots originate. In some specimens of the collection of the Department of Anatomy (Peking Union Medical College) I found the upper part of the cord present as a plate, but the lower part as a solid tube, covered by a thin, transparent membrane. The opposite was never noticed (when we do not take spina biﬁda into account here), only in one of these cases the upper and lower parts of the cord were both present as plates, whereas the central part was absent. This corresponded in position to the very marked kyphosis of the vertebral column.
In this respect Holmdahl’s work is of special interest, in which he states that there is a difference in the first development of the neural tube in the cervicothoracic level from the mode in which it develops in the lumbosacral part of the embryo, where no neural groove exists, but the cord develops at once from a group of indifferent cells. Disunion of this problem and its bearing on the localization of spina biﬁda would lead us too far in the present discussion.
This conclusion is in contrast with the fact that spina biﬁda is found much more frequently in the lumbar part than in the cervicothoracic, so that for its explanation we must probably search in different directions.
The subject of spina biﬁda brings us to a short discussion of the relation between nervous and mesoblastic tissue in
.these deformities. There is a general parallelism in the
development of the neural axis and its surrounding tissues, but when one is more fully developed than the other, it is the nervous tissue that is in the better condition. Strange as this may seem, we shall have to reckon with the facts before 316 ERNST um VRIES
a ﬁnal explanation can be given. In spina biﬁda occulta great defects of the vertebral arches and dura may exist without any change in the spinal cord. In spina biﬁda aperta, also, skin (consisting only of epidermis, while the eorium is absent), bone, and membrane changes are often present to a large extent, while the spinal cord seems normal or simply hydromyelic. The opposite, absence or gross deformity of the spinal cord without any fault in development of the vertebrae or the skin, does not occur. In so-called amyelia I saw in two cases out of seven the lower part of the cord lying normally (to the naked eye) under a transparent membrane. I could not exactly determine which segments of the cord were present (probably they were from the ﬁfth lumbar downward) and whether they corresponded to the skin covering the sacral region. Kermauner, in his statement that the sacral bone is nearly always closed, does not mention the nervous tissue in this relationship.
In cases of total rachischisis, with ﬂattening of the medulla, there is always a very marked lack of connective tissue beneath and lateral to the nervous tissue and an absence of the corium. The pia may be present with its vessels, but the cord is not attached to the vertebrae; the roots run through a cavity, and there is often no trace of bony arches found; but the muscles of the spine are all present, although they cannot; take their normal positions.
In anencephaly there is, as far as I know, always close correspondence between the development of skin and bone and that of nervous tissue.
The explanation of the spinal-cord ﬁndings in my case is diﬁicult ; but in view of what has been said about the connective tissue, I am inclined to think that in the lumbosacral part a spinal cord must have been present, which has degenerated afterward from some unknown cause. The remnants of cord found lying in the meningeal sac point to the same conclusion. As far as I know, a similar ﬁnding has never been mentioned in literature. The embryo that most closely resem bles mine, that of-Biihmig, had a normally developed lower spinal cord. HUMAN ANENCEPHALIC AND AMYELIC EMBRYO 317
I am not able to explain the ﬁndings in the cervicodorsal part, where normal skin covers only the spinal ganglia and the bodies of the vertebrae.
LEBEDEFF 1881 Entstehung der Anencephalie bei Vogeln und Menschen. VirchoW’s Arch., Bd. 86, S. 263.
JACOBY 1897 Ueber sehr friihzeitige Stiimngen in der Entwickelnng des C.N.S. Virch. Arch., Bd. 147, S. 149.
MALL 1900 Study of pathology of early human embryos. The Johns Hopkins Hospital Rep., vol. 9, p. 1.
VERAGUTH 1901 Nieder diiferenzierte Missbildungen des C.N.S. Arch. f. Entwicklmeeh, Bd. 12, S. 53.
KEEMAUNER. 1909 Missbildung der ausseren Form. Schwalbe’s Handb. (1. Missb. ti. Menschen.
ERNST 1909 Missbildungen des Nervensystems. Ibid.
CULL 1909 Spina biﬁda with associated disturbances in human embryo 17 mm. long. Johns Hopkins Hospital Bn1l., vol. 30, p. 181.
FRAZER. 1921 Report on an anencephalic embryo. J. of Anat., vol. 56.
BOEHMIG 1922 Priinordialcranium e. menschl. Embryos mit Craniorachischisis. Zeitsch. 'f. Anat., Bd. 65, S. 570.
DE Vmns 1922 Ein Fall von Hemicephalus. Schweiz. Arch. f. Neur., Bd. 10, S. 32.
NAFIAGAS 1925 Comparison of growth of body dimensions of anencephalic human fetuses with normal. Am. Jonr. Anat., vol. 35, p. 455.
HOLMDAHL 1924, 1925 Die erste Entwicklung des K61-pets, u.s.w. Morphol. Jahrb., Bd. 54, S. 333; Bd. 55, S. 112.
BARTELMEZ AND EVANS 1926 Development of the human embryo during 2- to 16-somite formation. Contrib. to Embry01., vol. 17, Carnegie Inst. of Wash.