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Mall FP. Cyclopia in the human embryo. (1917) Contrib. Embryol., Carnegie Inst. Wash. Publ. 226, 6:

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Franklin Mall (1911)

Cyclopia in the Human Embryo

Contributions to Embryology

by Franklin P. Mall

With three plates and seven figures.

The progress made in recent years on the study of teratology has been so marked that it is now possible to reconsider the whole subject and to place it upon a permanent scientific basis. For this progress we are indebted almost exclusively to the experimental embryologists. Problems which formerly seemed impossible of solution — for example, the formation of the double monsters — have yielded as by magic to the embryologist, who made experimental studies upon the living egg. Perhaps the best example that can be brought forward to illustrate this point is the question of the cause of cyclopia. As soon as it was possible to experiment on eggs in such a way that practically all of them developed into Cyclopean monsters the explanation of this condition was at hand. For this work we are indebted entirely to Stockard.

Before reviewing the four specimens which I have to report it may be well to give an account of the theories regarding the origin of the c3'clopean condition. There are two chief theories, both resting upon an embryological basis. The first of these is that the eggs begin to develop normally and that subsequently, on account of an imperfect development of the head, the eyes coalesce to form a single eye. This theory can be traced back to Meckel. The second is that the eyes arise normally from the midventral line of the brain as a single structure, which in the course of development divides into two eyes. This view was first advanced by Huschke, who believed cyclopia to be due to an arrest of the development of the brain at the time the eyes are forming. Although Huschke's opinion seemed to be quite sound at the time it was advanced, it did not attach itself firmly to literature, nor could we well accept it at present as resting upon a sound embryological basis. The figures which he gives in illustration shows first an early stage of development of the brain, with a marked forebrain, and then an embryo with two eye-vesicles hanging to the forebrain. He apparently confounded the whole forebrain wdth the eye primordium.

Meckel's studies rest upon much sounder embryological and anatomical evidence, and his views gradually made their way into the Uterature of teratology. Until a decade ago it was practically impossible to find any description of cyclopia in which Meckel's studies were not reflected in the background. According to Ahlfeld, Meckel states that cyclopia is characterized by a coalescence of the eyeballs as well as of the orbital cavities. In case the orbital cavities unite very early in development they distend evenly in a lateral direction. The tissues which normally separate these cavities are absent or are pushed aside. In fact, the structures whi?h give the frame to the nose are most rudimentary, or absent, while the nose itself is represented as a membranous snout, varying in form and located above the confluent ej^es. The mouth is frequently involved in this type of monster and is usually rudimentary, while in some instances it, as well as the snout, is missing altogether. Since the eyeballs are developed from pouches which arise from the forebrain, it follows that the primaiy cause of this anomaly is not to be sought in the development of the skull, but in the development of the brain itself. We find in these cases that the width of the forebrain and midbrain diminishes in the course of their development, corresponding to the union of the orbital cavities and the ej^eballs, making the brain appear at term much like that of an embryo of the twelfth week. In addition to the atrophy of these parts, the formation of the hemispheres as a single body is especially noticeable — that is, they have not been divided into two lobes. This division often is only slightly indicated. The ventricles have united to form a single large cavity. In most of the cases at birth the quantity of fluid within the ventricle is increased, so that as a rule we have a large, bladder-like body in place of the forebrain. In this way is the fact explained that in spite of the rudimentary development of the brain there is no diminution of the size of the fore part of the head, as most cases of cyclopia are accompanied with hydrocephalus. There are cases, however, in which there is no hydrocephalus, which naturally result in a small head. This is most pronounced in cases of cyclopia in double monsters in which the head contains two brains. In these cases a symmetrical development of the brain is very rarely found. The rudimentary brain can no doubt be held responsible for the most pronounced specimens of cyclopean faces. In may be taken for granted that the nerves which are to supply the deformed eye and face are simple in their development, corresponding in amount with the degree of the anomaly.

This general description of the anatomy of the eye and face in cases of cyclopia is one which will be found in most teratologies, and in all of these accounts it would appear as though the authors mean to say that the eyes must arise from the forebrain and that they subscquentl}' unite into a single compound eye, more or less hourglass-shaped, due to an arrest of the growth of the brain which in some way interfered with the development of the forehead and eventually left the nose above the cj^clopean eye. Teratologists are inclined to believe that the accompanying hydrocephalus is to be viewed as the primary cause of the anomaly, although in many instances they try to trace this back to amniotic bands, which, however, are not found in human specimens of cyclojiia, and of course such bands could play no role in the formation of this anomaly in animals which develop without an amnion. Furthermore, the explanation of the formation of monsters by means of amniotic bands is alluded to in recent teratologies onl}' as one of the myths of teratology.

In my paper on monsters some ten years ago I gave a review of the experimental work upon cyclopia as it appeared at that time. These statements I shall recapitulate in part in order to bring out more dearly the recent jirogress made in the study of cyclopia.

In numerous experiments upon frog's eggs, born, in 1897, occasionally produced monsters by sphtting the head through its sagittal midplane after the medullary plate was formed, and then readjusting the two halves. The pieces united at once, but in a few instances a double cj-e was formed. Later Spemann, making similar experiments, also produced cj'clopean embryos. In some of Spemann's experiments triton eggs were ligated in the sagittal plane during segmentation, and frequently embryos with double heads resulted, one or both being Cyclopean. Spemann believes this experiment proves that in its differentiation the Cyclopean eye is defective from its beginning and is not produced by concrescence of two eyes which started to develop normally. Levy also produced Cyclopean monsters by cutting off the front of the head of triton larvae. In the course of two weeks the two eyes approached each other and formed a double eye, but they did not fuse. However, the pigment layer was destroyed, or absent, at the point of contact. The two optic cups touched each other, but did not unite.

In 1906 Harrison produced a new variety of cyclopia bj' removing the entire brain from frog embryos. In these specimens the eye moved to the back of the head and appeared to unite in a single vesicle in the region usually occupied by the pineal eye. These specimens are still unpublished.

By pricking the extreme anterior end of the embryonic shield in Fundulus eggs, Lewis found that many of the eggs developed into cyclopean monsters. All grades of defective eye were formed — from a double ej-e and hourglass-shaped eye with two lenses to oblong eyes with two lenses or with but a single lens. The optic cups blended absolutely, thus apparently showing the mode of development of these ej'es. Lewis also found that in many of the embrj-os the brain had not been injured at all, but that the prick had destroyed the nose only. This experiment seems to show conclusively that it is the absence of tissues between the eye primordia which allows them to come together and unite, and that a rudimentary brain is unnecessary.

In his remarkable experiments on the artificial production of a single median eye in the fish embryo by means of sea-water solutions of magnesium chloride, Stockard found that 50 per cent of the embryos developed cj'clopia. In these embryos the optic cups were fused at an early developmental stage, much as was the case in Lewis's specimens, in which the embryonic shield had first been pricked. The union of the two cups formed a large compound eye, which in turn derived its lens from the epidermis immediately overlying it in the midhne of the embryo. How the magnesium acts ui)on the embryo is not clear from Stockard's description. No doubt it will be found that it retards the growth of the frontal process, much as in Lewis's experiments. The salt, however, acted upon the whole body of the embryos, for their development was retarded, thus making them smaller than usual, and their circulation w^as feeble, but they did not die. In these embryos, as in Lewis's sjiecimens, the growth of the brain was normal. The remarkable experiments of Stockard set at rest all germinal theories of cyclopia and prove that every egg has in it the power to develop cyclopean monsters.

These experiments, as well as the numerous pathological embryos with deformed heads and faces which I have studied, prove at any rate that in the formation of many monsters there is an extensive destruction and shifting of tissues. This is also well illustrated in the production of club-foot in the human embryo. It has frequently been noticed that tadjioles whose growth has been arrested develop stubby or club tails and fins — a condition which corresponds well with club-shaped extremities in man. Our collection contains 18 embryos with deformed legs and feet, with catalogue numbers less than 400, ranging from the verj' earliest period until the fetus is well formed. The leg-buds are irregular in shape and are filled with condensed mesenchyme; sometimes they are stubby on one side of the body and normal on the other. The study of the larger embryos shows that there is a variety of inflammation of the tissues which is especially well marked in the tendons and around the cartilages. In general this condition may be accounted for by an arrest of development due to impjaired nutrition. At any rate, embryos that are not developing well — experimental larvae and human embryos with other malformations — often have club-shaped arms, legs, fins, or tails.

The inference to be drawn from the above summary is that after the eyes have become well formed they do not pass out to the side of the head as in normal development, but approach each other and more or less unite, and thus form cyclopia. Recent embryological studies of Stockard and of Spemann show conclusivelj' that this view can not be correct, for it is found that the cyclopean condition can be followed back through earlier and earUer embryos, and that all varieties of cyclopia are present while the eyes are still firmly attached to the brain. It is now maintained by Stockard that, from its very beginning, the eye primordium is in the midventral line of the brain, and that in cyclopean embryos there is an arrest of its develojiment, the eye remaining median or dividing in part, forming the hourglass-shaped cyclopean eye with two lenses, etc. This view is combated more or less by Spcmann; but I must confess that it is difficult for me clearly to understand his view as given in his various papers.

Through his well-known magnesium experiments, Stockard has been able to procure an abundance of material for the study of the early development of cyclopia. He proves first of all that the condition of cyclopia is present in the earliest stages in which it would be possible to recognize it. At no stage are there two normal eyes which subsecjuently blend to form a single eye. The cj'^clopean condition is present in the eyes while they are still closely attached to the brain. Stockard observes, secondly, that the cyclopean eye is rarely equal in extent and size to the sum of two normal eyes combined. A cyclopean eye is, as a rule, very slightly if any larger than one normal lateral eye, and in fact it is often much reduced or actually minute in size as comi)ared with a normal eye. According to Stockard, this fact indicates most decidedly that the eye material, as such, has been injured or arrested in development and differentiation. He believes that we are scarcely warranted in assuming, as have various authors at different times, that cyclopia is due to a fusion of the eyes after they have arisen from the brain and that the earlier in develoi)ment the fusion occurs the more intimately associated the two eye components become. This view, according to Stockard, has been i)roved incorrect by actual ob.servation on cyclopean monsters, where it is found that the cyclopean condition of the eye whether large and hourglassshaped or of small size resembling a normal eye — is present from the earliest appearance of the optic vesicle from the brain. In other words, the several degrees of the Cyclopean eye come off from the brain in their final condition.

The idea of the fusion of the eye parts, Stockard continues, was deep-rooted, however, and e.xists in the recent views of Spemann in a refined form. Spemann believes, as others have previously suggested, that cyclopia is due to an absence of non-ophthalmic tissue in the median region of the medullary plate or groove. This lack of median tissue allows the eye primordia, which he holds to be lateral in position, near the borders of the medullary plate, to come together and fuse in the median plane and later give rise to a cyclopean eye. Cyclopia, according to this view, occurs in a more or less passive manner, and is actually a fusion of the eye primordia of the two sides during development. Stockard adds that he is certain that this fusion e.xplanation, which has now been forced entirely back into the medullary plate, is as false as its bolder predecessor, which assumed the fusion to take place outside of the brain-tissues after the optic vesicles or cups had arisen. He says that Spemann did not at first advocate this late-fusion view, but claimed (from his experiment on Triton) that the cyclopean eye arose out of the medullary tissues in its final condition; subsequently, however, he assumed the role of a most ardent sujiporter of the view that the fusion of the optic primordia takes place within the medullary plate.

It may be added that there is no known instance of the formation of cyclopia by experimental methods after the eyes are fairly well formed in normal development. All the experiments in which cj'clopia has been produced were made upon the embryo at a stage before the eyes could be recognized under the microscope. One must recall that Stockard's magnesium experiment is effective only when it is done before the embryo is 15 hours old. In fact, Stockard found that the best results were obtained if the eggs were placed in magnesium-chloride solution immediately after fertilization. If the eggs are not placed in the solution until 15 hours after fertilization, before the germ-ring forms and begins its downward growth from the yolk-mass, no cyclopia occurs. Cyclopia is less frequent in eggs which are treated at later stages than in eggs immersed in magnesium-chloride solution during the fourth and eighth cell stage. It appears, then, that the critical stage at which cyclopia is best produced with magnesium is shortly before the germ-ring is formed. According to Stockard, a 15-hour embryo has the germ-ring beginning to form and descend over the j'olk-sphere; the embryonic shield is scarcely indicated, but appears soon afterward. embryos of later stages subjected to the same treatment develop normally, or at least do not show cyclopia, while embryos younger than 15 hours, and at as early a stage as the first cleavage, are much more readily affected in such a manner as to cause the cyclopean defect. The optic vesicles appear at about 30 hours after fertiUzation, but the stimulus must be applied at a time sufficiently long before this process occurs, since a number of important steps in eye formation are doubtless taking place before the visible signs of optic vesicles are present.

It is interesting to note that the Lewis pricking experiment is made at a stage in which cyclopia can no longer be produced by placing the eggs in a magnesium solution. According to Lewis, the experiment should be made on the second day. Although he does not give his experiment in hours, his illustrations show the stage of development. According to these the embryonic sliield is well formed. The experiments of Lewis were first described in my monograph on monsters, but they have since been reported in detail by their author. As has been stated, Lewis produced cj'clopia in Fundulus by pricking the middle of the anterior end of the embryonic shield two days after fertilization. In the course of a few days it became apparent that in some of the eggs operated upon the eyes had developed normally, wliile in others they had become cyclopean. Most of the specimens were killed after 15 days. Pricking of the embryonic shield was accompanied by the escape of a shght amount of tissue, and as there is little or no regeneration of the central nervous system in Fundulus, the defect caused at the time of pricking subsequently became more and more apparent as development proceeded. Both Lewis and Stockard have found that cyclopean Fundulus embryos usually develop with a normal brain, thus no doubt accounting for the vitality of this special Cyclops. Furthermore, it appears that the eye primordium in Fundulus is more circumscribed than in many other animals.

In a number of his experiments Lewis found that the material withdrawn with the needle-point came from one side of the anterior end of the embryonic shield, with a resulting abnormahty of the eye on that side. In a specific case, at the time of hatching, the right eye of the specimen consisted of a small bit of retina connecting with the otherwise almost normal brain-wall. The left eye was apparently normal, as were also the brain and the nasal jnt. In other specimens, in which the operation was about medial and was done at the time the embryonic shield was beginning to form, the embryos developed with the two eyes in contact, with two optic nerves and two lenses. Among other specimens there is one with a cyclopean eye, having a layer of pigment narrowing between the two eyeballs. In specimens operated upon at a little later stage there is a median cyclopean eye with two lenses, one i)upil, and one cup cavity. Using Lewis's language, the large optic cup shows in sections a very beautiful median eye with complete continuity of the laj'^ers of the retina of two components about a single large cup cavity of a single lens.

According to Lewis, the explanation of these various abnormalities is in a way comparatively simple, if we assume that in the early embryonic-shield stage the various parts of the central nervous system and the eyes are jH-olxibly already predetermined, and, secondly, that there is very little or no power of regeneration in this tissue. Numerous experiments on regeneration indicate very clearly that there is little or no regeneration of the tissue (at least of that of the central nervous system) extruded at the time of the operation. The repair which takes iilace after the operation consists merely of a rai)id closing together of the ]iarts left remaining, and thus a healing of the wound occurs without regeneration of lost parts. This closing of tlie woimd is accompli.shed in a few minutes, and primordia are thus brought into contact which normally are fjuite widely sejjarated — those of tlie two eyes, for example. The subseciuciit (lilTciviif iation adjusts itself to the new relations of these primordia with the resulting abnormal forms. Thus, as one examines these developing embryos, from the time the eye primordia are first visible in the living specimens under the binocular microscope, they appear to have the same amount of fusion or loss of eye that is clearly to be found in the same individual at later stages and at the time of hatching. So we can explain these Cyclopean forms by a fusion of the primordia of the two eyes immediately after the operation, even though at this time no primordia are visible. Differentiation of the eye-tissues evidently occurs some time before it is visible by our crude microscopic methods.

Briefly summarizing the experiments of Stockard and Lewis, it may be said that Stockard produced cyclopia by immersing Fundidus eggs in a magnesium solution before the formation of the germ-ring, while Lewis operated upon the embryonic shield after it had arisen from the germ-ring. According to Stockard, the magnesium solution possesses a decidedly anesthetic effect and inhibits the growth of the optic out-pocketings ; and therefore the condition of cyclopia must be present before the formation of the optic cup — which he believes to be median — the anesthetic effect preventing the medial cup from dividing, thus bringing about the cyclopean condition. According to Lewis, the optic primordia are brought together through the removal of a small amount of tissue which normally lies between them. The primordia then unite and produce all degrees of the cyclopean condition. For practical purposes either theory will suffice to explain the condition as found in man, and there is at present no evidence which can decide which of the two is correct, for I maj' add that (as Dr. Lewis informs me) the optic primordia arise very close to the ventral midline of the brain, being separated by only a few cells.

Stockard has recently attempted to define more accurately the eye primordia in Amhly stoma by operating upon the medullary plate. First of all, he found that pricking the medullary plate, as Lewis pricked the germ-shield in Fundulus, had no effect whatever upon the growth of the eyes. They invariably grew in a normal way. He then removed various parts of the medullary plate and found that the removal of a median strip about one-fourth to one-third the width of the medullary plate resulted in eyeless embryos. The entire eye primordium apparently lies within this median strip. When a narrower strip was removed the embryos developed with one eye, with defective eyes, or with no eyes at all. From these experiments he concludes that the primordia of Amblystoma arise in the anteromedian portion of the medullary plate, and not from two independent primordia, as is beUeved by Lewis.

It may be added that the earlier papers of Lewis and of Stockard were wTitten partly to demonstrate that cyclopia is not an hereditary but an acquired quaUty. This opinion is much at variance with that of Wilder, who upholds the hereditary theory. In this relation may be stated that there are two records of cyclopia in twins. One, by Ellis, is referred to by Ashfeld on page 283 and is also illustrated in figures 11 and 12, plate 47, of his Atlas. The other is by Van Duj'se, and is referred to by Schwalbe and Josephy on page 210. The Van Duyse case is interesting, as both parents and grandparents were perfectlj' healthy and monsters were not known to have occurred in the family. The mother had been pregnant eight times, four of the pregnancies ending in abortions. The first child had harelip, the second had cleft palate, the third was normal, and the fourth pregnancy resulted in the cyclopean twins. In my own experience I can report an even more remarkable case. In 1900 a pig uterus was brought to me which contained a •number of normal embryos and three cyclopean embryos, all of about the same stage of development. The cj'clopean jiigs measured about 40 mm. in length, and each of them had a marked depression in the front of the head and a single pigmented eye with a snout over it. Unfortunately I did not keep the uterus of this specimen, so that it was impossible for us to examine it with care.

The somewhat lengthy discussion on the differentiation of the eye from the medullary plate is justifiable, because at least one of the specimens I have to report is practically a perfect one, which enables me to discuss the origin of the cyclopean eye in a somewhat connected way, from the condition found in normal embryos. After a description of this specimen I purpose to compare the eyes and brain with the same structures in several younger embryos in the Carnegie collection, as well as with those found in the hterature. I shall begin with the smallest specimen to be described, namely. No. 559.

Embryo, CR 6.5, Normal in Form, with Cyclopia, Carnegie Collection, No. 5.59.

This interesting specimen was sent to me by Dr. Merrill, of Stillwater, Minnesota, on December 21, 1911. Dr. Merrill writes that the specimen came from a white American, who is the mother of one child, 9 years old. The patient gives a subsequent historj^ of three of four abortions which took place early in pregnancy. The last menstrual period before the present abortion occurred on October 27, 1911. The abortion followed on December 20. No particulars are obtainable to account for the abortion and there is no evidence of its having been produced by mechanical means. The patient has a history of irregular menstruation and has been treated for metritis and endometritis. It is impossible to obtain any history of venereal disease.

The unopened ovum, measuring 20 by 15 by 12, came to us (i.xcd in foiinalin. It is almost entirely covered with villi which branch three of four times and ari> about 3 mm. long. On one side there is a small area without villi, covered only l)y the transparent chorionic membrane. Through this can he seen a well-formed embryo, ajiparently normal, measuring about 8 or 9 mm. in length and filling about one-half of the ovum. The remaining half is filled with dense reticular magma. The umbilical vesicle is spherical, measuring about 3.5 mm. in diameter. The ai)pearance of the ovum before and after o])ening is shown on plate 2, figures 2 and 5. The embryo was removed by cutting the umbilical cord near its attachment to the chorion. Photograi)hs were then made at both sides of the embryo, at one diameter enlargement, care being taken to get the exact profile pictured. Numerous other photographs were taken, and it then became apparent that we were dealing with an embryo with a very curious deformity of the head. \\'e also made profile outlines of the two sides of the specimen, being careful to have them in geometrical projection. The branchial region of the two sides of the head were then very carefully drawn. These drawings are reproduced in plate 1, figures 2 and 4. The specimen was dehydrated l)y placing the entire specimen in several grades of alcohol. It was opened a year later, January 1913, at which time the photographs were made. The specimens were prepared for embedding in February 1914. At this time the embryo measured in absolute alcohol GL 8.6 mm., CR 6.5 mm. In xjdol the GL measurement was reduced to 8.2 mm. It remained in several changes of xylol for 30 minutes and then was rapidly transferred through several dishes of paraffin, the entire time of this operation being one hour. The aim was to embed the specimen as quickly as possible in order to avoid any undue shrinkage. It was then cut into transverse sections 20 /x thick. These were stained upon glass slides in hematoxyUn and Congo red. It was now found that we had an unusually good series of practically prefect sections, none of them being distorted. Many cell divisions were found in the tissues of different parts of the embryo. We now readily reahzed the condition of the head, as we found in the sections a perfect series of an exquisite cyclopean embryo. A month later the half of the chorion which was removed to expose the embryo was also cut into serial sections 20 ju thick and stained with hematoxylin and eosin. Further examination of the part of the chorion from which the embryo was peeled showed the amnion close to the chorionic wall, at the point where the cord had been cut. At the point of juncture there is no complete cord, but in its place are numerous single blood-vessels, making the chorionic attachment of the cord appear like the hairs of a camel's-hair brush. This part of the chorion was now stained in toto with alum cochineal and cut into serial sections, in order to determine the exact nature of the tissue of the cord as it spreads out into the chorion; for the anomaly here seen had not been encountered by us before.

A superficial survey of the villi of the chorion shows it to be apparently normal, but the interior of the ovum, on account of the great amount of magma encircling the embryo, indicates that the ovum is pathological. Furthermore, the chorion is much too small for a normal embryo of this size. As a rule, pathological embryos are contained in ova which are larger than normal. The attachment of the cord to the chorion is also anomalous and a superficial glance at the head of the embryo shows that it is atrophic. The whole front of the head is occupied by the midbrain. There is no lateral bulging to correspond with the cerebral vesicle. The small pigmented eyes are buried deeply in the head and there is a pronounced frontal process in front of them. On the right side of the head, just in front of the eye, was a small protruding villus-like body which subsequently proved to be the snout (plate 1, fig. 2; plate 2, fig. 7; and plate 3, fig. 5). A more detailed description of the anatomy of the eye region will be given in considering the sections of this specimen. In order to interpret the sections properly a plaster-ofparis model of the brain and head was made at a scale of 50 diameters. Later it was found that this model was on too small a scale to include the muscles of the eye, and a second model of the eye region was made at a scale of 100 diameters.

The two halves of the chorion having been cut into serial sections, it was possible to ascertain with greater precision the attachment of the umbilical cord as well as the amniotic adhesions spoken of above. It was found that the cord was attached to one half and that there were delicate amniotic adhesions in the other half of the specimen. The attachment of the cord was by means of blood-vessels passing directly from the embryo to the chorion, while the adhesions in the second half were by means of loose strands of mesenchyme cells binding the amnion to the chorion.

The tissue of the chorion appears much like that in normal ova. It is of about the same quantity and is possibly a little more fibrous. The mesenchyme of the villi well infiltrated with embryonal blood-cells, and their trophoblast is quite scanty. At points the villi are stuck together with maternal blood, in which are found islands of syncytial cells, showing that the infiltration of blood took place before the time of the abortion. The mesenchyme of a few of the villi takes on an intense hematoxylin stain, which indicates that it is degenerating. In fact, the cells of the mesenchyme in many of the villi have mostly disintegrated.

The reticular magma stains intensely with eosin. Scattered through the dense network composing it are numerous large protoplasmic cells containing nuclei. In certain places the cells accumulate in large masses, forming colonies. No doubt these are the so-called Hofbauer cells, so well described by Essick.

The embryo had been cut into a very perfect series of transverse sections, which show that very little unequal shrinkage took place while it was being embedded. Nearly the entire wall of the central nervous system is in apposition with the surrounding mesenchyme. However, there are occasional separations along the dorsal midhne in the head region, the most pronounced one being around the midbrain, but this is not marked. The thin roof-plate of the hindbrain has collapsed only to a sUght extent. All in all, the preservation, embedding, mounting, and staining of this sjiecimen is quite perfect.

There are numerous cell divisions in the brain-tube around the central canal as well as in the retina of the cyclopean eye. Furthermore, these cell divisions are found also in the atrophic cerebral vesicle, showing that at the time of the abortion the atrophic cerebral vesicle, as well as the cyclopean eye, was growing actively.

The form of the head is well shown in the figures. In order to study the head with greater care a model was made of the external form at a scale of 50 diameters. This model shows the shrinkage of the head while the specimen was being embedded. It was made so that the entire head could be removed from the body in order to give a face view of the embryo, which could not lie obtained from the specimen before it was cut into sections (plate 1, fig. 3). The model also shows the midbrain to be very jirominent, the frontal process being jironounced but small. The eyes are shown deep in the head, and the snout jirotrudes above the mouth from a point immediately below the process and just in front of the eye. The body otherwise apjiears to be normal in ff)rm, and a microscopic survey of the sections shows that the tissues ;ire also normal in structure.

The lateral view of the head as given in the illustrations on plate 1 may be compared with a normal embryo of the same size; for this purpose I will take the Huber embryo No. 3, pictured by Streeter in figure 86, Volume II, of the Manual of Human Embryology-. In the Huber specimen the floor of the forebrain is unusuall}' large, as may be observed by comparing the above-named figure (86) with Streeter's figure 83, which is taken from His's embryo Brs. This region is also somewhat smaller in the Huber embryo than in a model of the brain of our No. 163 made by Dr. Lewis. No. 163 is 9 mm. long, and a profile drawing of its brain is shown in figure 428 in the second volume of the Manual. Careful comparison of the model of the brain of the cyclopean embryo No. 559 with models of the brain of normal embryos shows clearly that there is a decided ventral median defect of the brain of this embryo, from the mammillary bodies to the front end of the brain. This defect naturally takes away the tissues between the eyes and between the cerebral vesicles. In other words, the floor-plate, as shown in figure 55 in the Manual, reaching from the mammillarj' bodies to the neuropore, has been cut out. In the cyclopean specimen the hj'pophysis is also absent. The eyestems have been taken out, the olfactory lobes are absent, and the brain is reduced to a single vesicle, as is the case in older specimens of cyclopia. Such an extreme destruction of the base of the bram rareh' occurs in cyclopean Fundulus embryos, as in this animal, according to Stockard and Lewis, the brain is frequently entirely normal, the eyes alone being deformed; but in man marked brain defects have always been found to accompany cases of cyclopia.

The optic vesicles in No. 559 form an hourglass-shaped bodj^ with two lenses, as shown in plate 1, figure 1, and plate 3, figure 4. The tissues are beautifully preserved and apparentlj' normal in structure. The primary chambers of the eyes communicate freely with each other (plate 3, fig. 4), and through a common eye-stalk, which in turn communicates with the ventricle of the brain (plate 3, fig. 2). The tapetum nigrum covers the optic vesicles and crosses the midUne on the dorsal side of the e^'es — that is, between the eyes and the common cerebral vesicle. The tapetum stops abruptly at the optic stem and passes down shghtly along the anterior wall wliich joins the two retinas. The choroidal fissures reach clear through the front of the eyes, running almost together as they approach the common eye-stem, as shown in plate 1, figure 1. The topograj^hy of the optic stem, ganglion layer of the retina, and tapetum is in the order given, starting from the midline, in the normal embryo, as is probably the relation of their primordia in the normal neural plate, judging by the work of Eycleshymer and of Lewis. Eycleshymer showed that very early in development the eye appears, in amphibia, as two pigmented spots lying quite close to the midhne in the anterior end of the medullary plate. If these groups of pigmented cells are destined to form the tapetimi, then the ganglion layer of the retinas would form nearer the midline, while the cells which cross the midline would probably form the optic stem. That Eycleshj'mer s view is correct is indicated by the work of Locy in his studies upon the shark and by Keibel in his studies upon the pig. According to these authors, the eye primordia arise from small depressions near the midline of the anterior end of the medullary plate. According to Lewis, certain groups of cells in the medullary plate are predetermined to form the tapetum, the retina, and the optic stem. Lewis's theory has been objected to by Bell, but it has been amply confirmed by Spemann. At any rate, the arrangement of the structures in our cj'clopean embryo indicates that the optic stems have been cut out and that the primordia of the retina and tapetum of the two sides have united, blending absolutely with each other across the midventral line.

The tissues of the midbrain and most of those of the interbrain appear to be normal, but our knowledge of the normal brain at this period of developrnent is so scanty that it is dangerous to make any definite statement. Single groups of cells may be wanting or may be blending without our noticing the change. Such a blending is clear only when it involves a sharply circumscribed structure like the eye. However, the tissues of the hypothalamus seem to be disarranged (plate 3, fig. 2), and those of the single imited cerebral vesicle (plate 3, fig. 5) are certainly dissociated. In the cerebral vesicle the cells form a uniform layer, which is not beautifully stratified, as is the case in normal develojmient. Over the most anterior part of the brain (plate 3, fig. 5), crossing the midline, is a crescentshaped cap covering the outside of the brain and reaching back to the hyiK)thalamus just below the point of attachment of the common optic stem (plate 3, fig. 3). This cap is composed of i)ale cv\U of uniform size, undoubtedly belonging to the neural tube. It is located on the part of the brain which gives rise to the olfactory lobes in normal development; and it may represent these lobes in a degenerated form.

It was necessary to make a model (enlarged 100 diameters) of the eye region in order to study carefully the anatomy of the structures of the orbit. In this model the nerves, from the third to the seventh, were worked out to their terminations. The muscle masses, as far as they could be determined, are also included in this model.

Fig. 1. — Semi-diagrammatic section through the interbrain and cyclopean eye of emhrjo No. 559. X50. The cranial nerves are marked with Roman numerals. .Sup. Ob., superior oblique; E-M., eye-niusclc; At, mouth.

The first branch of the fifth nerve is much thinner than the second and third, and passes directly from the Gasserian gangUon back of the eye on either side of the optic stalk; the branches anastomose with each other through several deUcate filaments back of the ej'es, and then a larger bundle and several very small ones enter the snout, to be lost there. The nerves are shown in section in the figures on plate 3 and in reconstruction in plate 1 and figure 1.

The fourth nerve takes its usual route and finally ends in a verj' large premuscle mass lateral to the eye and to the first branch of the fifth nerve. It may be noted that this arrangement of the fourth and first branches of the fifth appears to be the reverse of the normal distribution according to Lewis's reconstruction of our embryo No. 163 (fig. 368 of the Manual). In the Lewis reconstruction all of the muscle of the primordium of the eye is blended into a single muscle mass, wliile in the cyclopean embrj-o the premuscle mass of the superior oblique muscle is entirelj' separated from the remaining i;)remuscle mass of the orbit.

The sixth nerve takes its usual course and ends independently in the hourglass-shaped premuscle mass which crosses the midhne between the cyclopean eye and the hindbrain (fig. 1). It is interesting to know that the transverse median muscle mass, as well as the median anastomosis of the third nerve, occurs at the point through which the pharynx gives rise to the hypophysis. In this embryo the chorda ends in the pharynx behind this muscle mass and the pontine flexure of the hindbrain. It appears as though, on account of the great amount of kinking, the region of the infundibulum of the interbrain were pushed away from the pharynx, thus making it impossible for the hj'pophysis to reach it. As a result of this the third nerve and its muscle masses cross the midline. It may be that the curious cytological changes in the muscle masses (plate 3, fig. 1, Oc.) indicate that destructive changes are taking place in them, and that these small round nuclei correspond with the Hofbauer cells as described by Essick in his studies of the transitorj^ cavities in the corpus striatum of the human embryo. The primordium of the eye-muscles show some very remarkable cytological changes. As the sixth nerve approaches the muscle mass of the lateral rectus it is at once observed that this muscle falls into two sharply defined groups of cells, namely, a median grouj) which appears to be normal, and a lateral mass of smaller round cells, the nuclei of which stain intensely. The same grouping is present in the muscle mass of the third nerve. Near the midline the cells appear to be normal, and laterally they are again composed of small round cells. The premuscle mass at the end of the fourth nerve — that is, the superior oblique muscle — can be outlined only with difficulty.

The third nerve shows most remarkable changes in this specimen. It passes along its usual course until it reaches the common eye-stem, over which it circles, for the nerves from the two sides anastomose here, without any diminution in size, within the common median primordium of the eye-muscle (fig. 1). This pronounced anastomosis is also found in another cyclopean embryo, Xo. 201, in our collection, as shown in figure 3.

Wilder pictures and describes a cyclopean pig (Wilder's fig. 1, plate 2) in which the third nerve arises as a pair in the usual way, which unites after passing through the superior orbital fissure. The union is in the neighborhood of the orbital muscles. He also described the orbit of the cyclopean eye in a large doubleheaded fetus. By dissection of the head he found that the two third nerves, one coming from each brain, unite with each other and form a common trunk stretched transverselj' across the midline back of the eyeball. From this anastomosis small twigs arise to supply the muscles of the eyes (Wilder's fig. G, plate 3). In his work on monsters (page 282), Ahlfeld states that Delle Chiaie described a specimen having a similar anomaly, which was published in Naples in 1840. Delle Chiaie gives an excellent illustration of this specimen, with a diagrammatic section of the head, showing the eye and its attachments. This picture is copied by Ahlfeld on plate 46, figure 18. It is somewhat difficult to identify all the structures given, but he apparently pictures the two third nerves anastomosing before the}' reach the single eye. He also pictures a branch of the fifth nerve passing into the snout, which, as in our specimen, contains a cavity. I have been able to find one more specimen in the Uterature in which there is an anastomosis of the two third nerves within the orbit in cyclopia. This is in the excellent description of Dr. Black on the nervous system of a cyclopean specimen at birth. Black alludes to the third nerve in a single sentence. He says (on page 204) that in the region of the central tendon the third nerve divides into a number of small branches, each of which communicates with its fellow on the opposite side. I have given these references, as they are the only ones which I can find in the Uterature, and they invariably accompany the description of the orbit in cyclopia. The anatomy of cyclopia in monsters is rarely given; and it may be remarked that until we have numerous good descriptions (like that of Black) of the eyes, central nerves, and face in cyclopia, we shall not understand fully the anatomy of this most interesting type of specimen.

In a Janus monster (No. 1178, a and h) at birth with cyclopia on one side, Dr. Theodora Finney has demonstrated a large anastomosis behind the orbital branches of the third nerve before they are distributed to the eye-muscles. An account of her specimen with a figure is given on page 30.

It remains to attempt to correlate what has been said above regarding cyclopia with the form of the brain and the oi)tic vesicle in early human embryos. Before undertaking this attention is called to two papers by Tandlor on the form of the early brain in Tarsius and in Platydnclylus. Tandlcr's papers are especially noteworthy for the reason that the topography of the forebrain has been determined with a greater precision than has been carried out in the human embryo, except possibly in the most recent work of His. There is sufficient material at hand to make similar studies upon the human brain, but until this is done I must content myself with what has already been i)ublisho<l, alhuling occasionally to .several of the specimens in our own collection.

A specimen 3.2 mm. long, with 13 or 14 myotomes, was described with much care by His in his last i)ublication upon the brain. He has illustrated this specimen by a sagittal median section through the body as well as by the external and internal forms of the brain. These illustrations are given in the His monograph as figures 2 and 33, and they are also copied by Streeter in his article on the brain in the Manual. It may be stated that figure 33 shows the neuropore nearly closed, the optic stalk being still represented as a wide-open canal which reaches to the midventral line. Dorsal to the optic stem is a shghtly marked pocket which reaches to the neuropore, and it is beUeved by His that this represents the beginning of the cerebral hemisphere. It is interesting to note that Keibel and Else state in their Normal Plates (page 100) that the cerebral vesicles are just beginning in embryos 4.5 to 5 mm. long. It may be that His exaggerates this pocket slightly in his model, but it is of great value to us to have his opinion regarding the location of the primordia of the cerebral hemispheres in the brain-tube before the neuropore is closed. According to Watt, the cerebral hemispheres arise much more dorsal than is indicated by His in his figures.

Keibel and Else give excellent illustrations of the form of the brain up to the time of the closure of the neural tube. No doubt the Kroemer-Pfannenstiel embryo, which contains five or six myotomes, represents a normal stage with medullary plates wide open, and in this embryo there is no indication whatever of an eye primordium. The same is true in the Kollmann embryo, containing 14 myotomes, which is illustrated by Keibel and Else as figure 4. This specimen also seems to me to represent a normal embryo, as we have in our collection a stage that is practically identical with it. Our embryo No. 391 contains seven pairs of somites, and has been carefully studied and pubhshed by Dandy. A model of it, as well as sections through the head, has also been pictured by Evans in figures 408 and 409, Volume II, of the Manual, and it shows no out-pockctings in the anterior part of the brain to represent the eye primordia. However, when we reach Keibel and Else's figure 5, which is taken from the Pfannenstiel III embryo, two marked diverticula are seen to arise from the front end of the neural tube, which Keibel, in his article on the eye in the Manual of Embryology, beheves to represent the primordia of the eye.

As Keibel and Else have reproduced numerous figures of sections through the head of this embryo, it is easy to ascertain the exact form of its neural tube. However, I am of the opinion that we can hardly view the neural tube in this embryo as normal, as it is not sufficiently advanced in development for an embryo of this stage and as it corresponds very much in form with the brain of our embryo No. 12, which I beUeve to be pathological. At this time the neural tube should be nearl}^ closed, while in Keibel and Else's specimen and in our No. 12 it is still wide open. The Pfannenstiel III embryo contains the same number of somites — that is, 14 — as our embryo No. 12, and the form of the brain and of the eye-vesicles is very similar in both embryos. A picture of the external form of embryo No. 12 will be found in my article on the development of the intestines (plate 19, fig. 2). My reason for believing that the brain form in both of these embryos can not be viewed as normal is that in other young specimens published recently by WaUin and bj' Bremer quite a different form of the brain-tube is shown for this stage of development. The AVallin specimen, which contains 13 somites, has the brain tube pretty well closed up, leaving a large neuropore in the front. The Bremer specimen is slightly in advance of this. We have also in our collection a similar embryo (No. 470) in which the brain form corresponds exactly with that in the specimens of WalUn and of Bremer.

Furthermore, the twin specimens of Watt, which contain 17 or 18 somites, correspond very closely with the three above-named embryos. In the Watt specimen the neuropore is nearly closed and the eye-vesicles reach all the way across the front of the brain-tube. The Pfannenstiel III embryo and the Bremer embryo are found pictured by Bach and 8eefelder, both in profile and in sections, but I do not think we should unreservedly accept their description of the beginning of the eye-vesicles as final for the human embryo.

It seems to me that our knowledge of the form of the forebrain before closure of the neuropore is much in need of revision, and towards this revision we have assembled several new models of young embryos. The first is a model by Dr. Bartelmez of our No. 1201 (University of Chicago, No. 87) from an embryo with 8 pairs of somites, which seems to me to bear very much upon this question. The neural plate flanges out into a large tongue with a slightly hourglass-shaped depression running across the midventral line (plate 2, fig. 6.) The larger lateral depressions no doubt indicate the foveola, and the groove connecting them across the midline is in the position in which the optic stalk develops later on. It would probably be better if we accepted Froriep's designation of torus opticus for this connection. The torus opticus seems very insignificant in this specimen, as shown in the illustration {t. o.), but when we consider to what extent the torus may be stretched, as illustrated by Bach and Seefelder (fig. 2, plate 13), we recognize the importance of this structure. I am inchned to believe that the form of the brain in the Bartelmez embryo must be viewed as normal, as it corresponds so well in a series with that of several older human embryos, namely, those recently described by WaUin and by Bremer and our No. 470.

There is another ridge already indicated in the brain-tube of His's specimen EB reaching across the midline just below the neuropore. This is the torus transversus of Kupffer; and those who are interested in this structure are referred for greater details to the articles by Tandler, KuplTer, and Johnston. The neuropore is found just closed in our embryos No. 148, published by Mrs. Gage, and No. 836, which has been modeled by Dr. Evans, as well as a specimen of the same size modeled by Johnston. Dr. Johnston has been good enough to send me photographs of his model, so that I am able to compare it with our own. It is clear to me that the large "optic vesicle," extending over the whole lateral wall of the front jiart of the neural tulie, represents more than the ojitic vesicle, as it must also include the primordium of the cerebral hemispheres, since the torus transversus touches the lower border of the neuropore and the optic vesicles fall below this line. This large so-called optic vesicle must resolve itself into the optic vesicle and brain hemisphere in subsequent development. In this process the torus opticus gradually must become more pronounced.

It is somewhat easy to compare the medullary plate of the Bartelmez embryo No. 1201 with the medullary plate in amphibia. The lateral foveola corresponds with Eycleshymer's pigmented spots, and if these areas were cut out eyeless embryos should be produced, as Stockard found in his experiments on Amblystoma. If it is admitted that the eye primordia communicate across the midline through the torus opticus, then Stockard's experiments upon the medullary plate maj' be interpreted as follows:

No important organ develops from the midline of the medullary plate, and this is represented only by a thin layer of cells. It has been called by His the floor-plate. The motor nuclei arise from the thickenings on either side of the floor-plate, and these are known as the basal plates. The narrow, thin floorplate reall}' forms the ventral midseptum of the spinal cord of the brain, and subsequently commissural fibers grow through it to form the raphe. If we view the basal plate from above, as shown in embryo No. 1201 (plate 2, fig. 6), we find that this raphe should extend forward to the neuropore, at which point the raphe fibers are the anterior commissure mthin the torus transversus. Back of this we have the torus opticus, and its commissural fibers are the fibers of the optic nerve. At an early period in its development the torus opticus must widen rapidly and push through the rest of the bram, for the optic stalk api)ears quite suddenly, and an injury to the medullary plate at tliis time would jjrobably make itself felt more upon the optic stalk than upon the eye, for the short period in which it grows verj?^ rapidly is its critical period. If we cut out the optic stalk or the torus opticus, as Stockard and Lewds did in their experiments, then the foveola would remain together and form cj^clopia. Stockard and Lewis also note that in their experiments they frequently obtained embryos with but one eye which appeared to be quite normal. This is to be expected when experiments are made upon two primordia which he very close together; and when either the left or right eye primordium is removed, left or right-eyed embryos are produced, but not cyclopia. Lewis had to destroy only the midline of the embryonic shield in order to produce true cj'clopia. It may be added that the anatomical changes found in our small Cyclopean human embryo, as well as in all cyclopean human monsters, can be explained by removal of the structures represented along the line of the raphe of the medullary plate reaching from the mammillary bodies to the neuropore. This includes the torus transversus, which naturally involves the olfactory region and the anterior commissure. Thus we can explain by a study of this specimen the anatomical changes of the brain found in human cyclopia.

Stunted Embryo, GL 20, with Cyclopia, Carnegie Collection, Xo. 201.

The second specimen of cyclopia in our collection is a pathological embryo, which is not very well preserved, measuring GL 20 mm. This specimen came from Dr. Schelly of Baltimore, who obtained it from an abortion on February 7, 1902. He brought it to 'Sir. Brodel, and subsequentlj^, because it was pathological, it was given to me. The embiyo was incased in an ovum covered with a ragged decidua, together measuring 80 bj- 60 by 50 mm. Upon opening this ovum it was found filled with a jelly-like fluid forming a type of magma described in my paper upon this subject. Sections were cut of the fleshy chorion and it was found that the wall is composed of a true chorionic membrane, villi, maternal blood, fibrin, decidua, blood sinuses, and trophoblast, with an extensive infiltration of leucocytes often accumulating in large masses or small abscesses. These layers are not in any regular order, but are intermingled, and show various stages of disintegration. The mesenchyme of the vilh is fibrous, and many of these are invaded by trophoblast cells as well as by leucocytes. The trophoblast also invades the blood-clot, and maternal-blood sinuses are frequently found filled either with trophoblast cells or with leucocytes. There are certain groups of tissue in which the interminghng of the trophoblast cells within the fibrinoid substance appears, in sections, very much like cartilage. Most of the decidua adjacent to active trophoblast on the tips of some of the villi has the usual fibrinoid laj'er characteristic of normal development. It may be added that the structures of the chorionic membrane, as well as those of the embryo, stain unusually well, which indicates that the tissues were active and alive at the time of the abortion.

After the embryo was received it was photographed from one side (plate 2, fig. 1), and this record proved to be ver}^ useful in making several reconstructions. The embryo was then cut into serial sections 50 mm. thick; finally, in order to study more carefully the structures within the head, a reconstruction of its external form, as well as of the form of the brain and the eye, was made in plaster of paris at a scale of 40 diameters.

Most extensive changes have taken place within the embryo. The brain is greatly deformed and is severed from the spinal cord through a growth of tissue in the region of the medulla back of the deformed ear. In fact, a part of the brain is included within the cajvlike body on top of the head. The spinal cord begins again rjuite abruptly in the upper cervical region and ends with the same abruptness in the upiier lumbar region. At its low(>r end there is a curious fibrous tumor measuring half the diameter of the cord. The cord, so far as it is developed, appears to be normal, but it is markedly dissociated. Below the upper lumbar region the spinal cord is wholly wanting and the spinal canal is filled with mesodermal tissue which is rich in blood-vessels. Where the cord is missing most of the spinal nerves still remain, and many dorsal ganglia can be made out, showing that the changes in the central nervous system in this region took place after the spinal nerves had been developed from it.

Fig. 2. — Roconstiuction of the head of embryo No. 201. X25. The outline of the head was obtained from a photograph, the brain and eyes from a plaster reconstruction, and the nerves were added from the sections. C. //., oerebral hemisphere; Af, midbrain; H, hindhrain; S, rudimentary snout; V, fifth nerve; VHI, cichth nerve; K, externa! car.

Most of the epidermis is intact, but it is broken through at the back of the head, where there is found an extensive ulcer or necrotic mass, which is very rich in blood-vessels and involves the walls of the brain but does not reach into its ventricle. At the highest point of the head the epidermis has developed into a papilHform body, and below this there is a large necrotic area in which there is a great quantity of yellow pigment granules.

The mouth is closed completely, although the alimentary canal, from the mouth to the stomach, is open and appears normal. The intestine is matted together; the cloaca and anus are obliterated. The epithelium of the upper portion of the intestine gives rise to marked growths into the matted mass.

The thoracic region, liver, and vascular system have undergone practically no change. The extensive dissociation of the tissues throughout the embryo has caused an extensive destruction and arrest in the development of the muscular system. This is marked by all kinds of secondary changes in the connective tissue, especially in that of the skin, where the change is pronounced, as may be seen in plate 2, figure 4. In this region the The cranial nerves are marked with Roman numerals.

Fig. 3.— Diagrammatic reconstruction of the eye and iir>£ A Til" „il„ the surrounding structures of embryo No. 201. X25.

pVipno-P i« «n o-rpnf thqf it nhlitprntPS entirelv V", first branch of fifth nerve; S, rudimentary snout ; Cnange is so great, mat 11 OOllieidieS eniliei^ ^ ^^ eye-muscle; Sup. Ob., superior obUque muscle.

the external auditory canal.

A reconstruction of the brain and upper part of the spinal canal enabled me to determine with greater precision the parts of the brain wliich are within the head of this embryo. Subsequently it was possible to find the remnants of the gangUon of the eighth nerve; then that of the fifth nerve was determined. Their position is shown in the profile diagram of the outhnes of the brain and these nerves (fig. 2). It at once becomes apparent that the portion of the brain extending up in the necrotic cap on the top of the head consists of the midbrain and hindbrain. With this idea in mind it was possible to answer the question in the serial sections, as the walls of the midbrain are thick and the ventricle relatively small, and the w^Us of the hindbrain are thin and its ventricle relative large. The pointed process which reaches towards the gangUon of the fifth therefore represents the pontine flexure of the medulla. It is now easy to interpret the

-Section through the cyclopean eye of erabrjo No. 201 . 1, first branch of fifth nerve; S, snout.

isolated braiii-inays between the eye and the large mass just described. By comparing these structures with a i)rofile reconstruction of the forebrain of the cyclopean embryo No. 559 (plate 1, fig. 1), the larger mass just above the ganglion of the fifth undoubtedlj'^ represents the interbrain, as the free end of the optic nerve reaches just to its base but does not enter it. The crescentshaped mass of the brain in front of the interbrain is the unpaired single cerebral vesicle, which communicates freely with the ventricle of the interbrain. The structure of the wall of this degenerated cerebral vesicle corresjjonds very closely with that of the small vesicle in embryo No. 559. With these structures established, as shown in the ])rofile reconstruction, it is possible to identif}' some of the remaining structures of the orbit. However, the tissues are very greatly dissociated, and for the present it is impossible for me to follow them farther than is given in the following description. First of all, the three branches of the fifth nerve can be followed to their termination. The first branch reaches up to the rudimentary snout, where it anastomoses with its fellow from the opposite side — shown also in the diagram (fig. 3). This snout, by the way, is represented l)y a slight elevation in the middle of the face above the eye, and sections through it show that it is composed of a relatively large, irregular of cells which are .separated more or less from tlie surrounding mesenchyme. Within the middle of this mass is a small pearl-like l)ody about 0.1 mm. in diameter. Just behind this body the first branch of the fifth nerve anastomoses across the midline.

The second branch of the fifth runs below the eye on either side and reaches nearly to the skin, where it spreads out into several large branches. The third branch of the fifth nerve runs deep into the neck and is separated from the second by a pronounced ossification center representing, of course, the maxillary bone.

-Section tlirough the cyclopean eye and optic nerve of eml>r\o No. 201. X40.

The two eyes are united, forming an hourglass-shaped body with a double retina, a single pigmented layer, and a single optic nerve which arises from the retinas as they approach each other (figs. 4 and 5). The tapetum is continuous over the superior surface of the eyes, but it is broken below, repeating the condition found in the eye of embryo No. 559. The optic nerve reaches to the base of the interbrain, where it ends abruptly. It is impossible to determine with precision the arrangement of the muscle masses of the orbit or of the nerves passing to them. That no trace of the sixth nerve could be made out is shown in figure 3, and this may be accounted for by the fact that the organ which gives rise to the sixth nerve has undergone extensive degeneration. However, the peripheral ends of the third and fourth nerves can be found, but they can not be traced back very far in the direction of their origin. The fourth nerve is thicker than normal and ends on the lateral side in an enlargement which may represent the superior oblique muscle. Below the optic nerve is a common muscle mass which crosses the midhne, and to either side of this there are two independent muscle masses. Before the third nerve reaches these muscle masses lateral branches are given oflf, which pass to the second lateral muscle mass, as shown in the diagram. The two nerves then approach each other and communicate freely through the unpaired muscle mass, and then pass forward under the cyclopean eye and finally end just beneath the skin.

A comparison of plate 1, figure 1, and text-figure 1 with text-figure 3 shows that the first branch of the fifth nerve in both embryos anastomoses across the midventral line in the region of the snout and that the two third nerves anastomose with each other through the main muscle primordium of the orbit. Both of these anastomoses must be viewed as secondarj-, for the two nerves must have been single when they arose from the brain. This observation favors the theory that the eye promordia must also have been bilateral — that is, they must have been separated by a narrow strip of non-ocular tissue in the normal medullary plate.

Fetus Comphessus with Cyclopia, Carnegie Collection No. 1165.

This embryo was sent to me by Dr. Ralph S. Perkins, of Exeter, New Hampshu-e. Only the embrj^o was received, which measures 43 mm. CR. It was found to be greatly distorted; the umbilical cord is of thread-like thinness, and the development of the different parts of the bodj' seems to be unequal. Apparently some of the joints are dislocated, but at present it is impossible to say whether or not these distortions are due to mechanical manipulation after the embryo was. aborted. This is possible, because the embiyo had been wrapped in a towel some time before it was fixed in formalin, but a careful study of the sections demonstrates that the specimen is quite a tj-pical fetus compressus.

The embryo came from a white woman, 35 years old. Her first child is 16 years of age; the second died at the age of 2, and the third is 12 years old. These are all by her first marriage. The first pregnancy of her second marriage ended in an abortion at 5 months, and then she gave birth to a cliild wliieh is now 21 months old. The next pregnane}' resulted in an al)ortion at 5 months, and the last one gave the specimen under consideration.

Her last normal menstrual period began on February 25, 1915. The next period began on March 21 and continued for only one day; and this was followed by the abortion on jNIaj^ 2. There are no other data bearing upon this case except that 15 years ago the woman had an operation for suspension of the uterus.

Upon careful inspection of the head of the specimen a mechanical injury just below the lower jaw was found, as shown in figure 6. The ear seems to be distorted or abnormal, and in place of the nose and eyes there is a depression in front of the face, and running from it is a cleft reaching to the mouth. Apparently we have here a fetus compressus with cyclopia and harehp.

Tlie head of tlie embryo was stained //; toto in cochineal and embedded in paraffin. It was cut into serial sections 50 /x thick. The sections show that all the tissues are markedly dissociated, and in addition the brain is comjiletely macerated. In fact, the brain-cavity ai)])ears like a bag filled with debris, which reaches down into the cervical region of the neck and terminates abruptly where the spinal canal is filled with a new formation of fibrous tissue. The primordial skull is composed of cartilages which have undergone some fibrous changes, and their borders are not sharply defined, but grade over into the surrounding connective tissue. The cartilages at the base of the skull appear to b(! enlarged and extentled; but this point can not be established without making an elaliorate reconstruction. In the cervical region the bodices of the vertebra; are displaced backward into the spinal canal, which in turn is largely filled up with the newly formed fibrous tissue as well as with numerous round cells. The ti.ssues of the various ossification centers have undergone a curious change, reminding one of necrosis. It appears as though the ossification centers had died while the surrounding cartilage had continued growing. It is diflicult to define precisely the muscles and nerves in all of the various sections, while at points certain muscle groups seem to retain llicir normal form.

Imo. G. — DireiTl ilrawiiim ui lin- lic:i( tissue of the lower jaw is injured, eye extends clown into the njoutli,

oi iMiil.ry.i N.i. m;:). X4.,"). the The depression from the cyclopean forming hare-lip.

Most of the epidermis is wanting and in the region of the face are large skin protuberances composed principally of round cells. Such protuberances form the Uds of the cyclopean eye, as shown in plate 2, figure 3. The orbital cavity lies upon the cribriform primordia of the maxillary bones and is filled with a single group of pigmented cells, which is surrounded by an infiltration of round cells. Back of this pigmented mass are the primordia of the eyo-mu.^clcs. but their dissociation is so complete that it is impossible to locate the individual muscles, nor can any of the nerves be made out with precision. Aside from the pigmented mass there are no remnants of the layers of the retina, these having undergone complete dissociation. In the upper part of the orbital mass is a curious glandlike structure badly dissociated, which may represent the lacrymal gland. We have, therefore, in this specimen the remnant of a single median eye represented by an irregular but rounded mass of the tapetum situated below the dej^ression of the skin. In turn this depression is partly covered with folds of dissociated tissue which may be recognized as the eyehds of the cyclopean eye.

Carnegie Collection No. 1178 a and b.

The double female monster, 205 CR and 350 GL long, weighing 1,624 grams was sent to us by Dr. J. I. Butler, Rodgers Hospital, Tucson, Arizona, on May 14, 1915. The mother is a Chinese woman, age 24, who has given birth to three children at term and has had two abortions. Apparently the uterus is normal and there is no history of venereal diseases. There is nothing else in the historjthat bears upon this case. The specimen has been completely dissected by Dr. Theodora Finney, who has given me the notes for the following description of the muscles of the orbit and the nerves of the cj'clopean eye. A more detailed account of the anatomy of this interesting specimen will be published by Dr. Finney at some sub.sequent date.

The fetus is composed of two nearh' complete bodies which he with their anterior surfaces toward each other, and, as the name implies, are fused from the umbiUcus up, forming one thoracic trunk and one head. There are two independent spinal columns, eight extremities, and two composite fronts, every sj'mmetrical part of which is formed half of one and half of the other individual. There are also two faces, one of which is well formed, while the other is a sj'note with a cyclopean eye and snout situated above it. In dealing with the cj^clops, then, it must be noted that its left half is formed from the left side of one individual, while its right half is from the right side of the other individual.

Internally the thoracic and abdominal viscera are double, with the exception of the esophagus, the stomach, and the upper part of the intestine, which are united with a single canal. There are two central nervous systems, separate and complete to above the level of the two hj'pophj^si, where fusion occurs. As much tissue was lost from the region of the thalami in remo\dng the brain, the mode of union of the base of the brain could not be determined. An optic chiasm, however, belonging to the well-formed face, remains in situ immediatelj' behind the orbits. Tliis shows there is a true normal union for tlie two indi\ itluals at tliis point. In the cranial cavity behind the cyclopean eye one oi)tic nerve-stalk, composed of two bundles pre.ssed together, is observed.

The dome of the cranium is filled by three cerebral bodies; two of these are recognizable hemispheres, though much shortened antero-posteriorly. Their position is normal, behind the well-formed face. They possess well-defined but shallow cortical sulci. The third cerebral division consists of a kidney-shaped lobe. Its cortex is smooth, except for two or three atypical creases near the j^oles. It lies transversely across the cyclopean side of the cranial cavity with its two poles directed inferior ly, the convex portion between them straddling the single orbit. It represents fused cerebral tissue obtained from both individuals.

The Cyclops has a well-formed eyeball to which four pairs of muscles are attached; their arrangement is shown in figure 7. These muscles can be identified by their nerve-supply as being the muscles of the upper and outer parts of the two fused eyes. These muscles are changed from their normal positions, so that they entirelysurround the eye. The muscles are the superior obUques, the levator palpebral the sujierior and lateral recti. The two superior obliques lie near to the midline on the superior surface. Slightly lateral to these, though still on the superior surface, he the two levator palpebral. On the sides, in the place usually occui)ied by the lateral recti, lie the superior recti, which are shifted downward from their normal position through an arc of 90°. About the same amount of shifting causes the lateral recti to lie close together on the inferior surface of the ej^el^all. The inferior oblique muscles and the medial recti are completely eliminated. The inferior recti are entirely absent at the bulbar end. There is a short bundle of muscles underneath the proximal end of the lateral recti, which probably represents remains of the inferior recti. The lacrymal glands have participated in the change of positicjn and fusion. Their tissues lie as a broad single gland-mass on the inferior surface of the bulb.

In order to be sure that the idciitilicatioii of tli(> nerves jiassing to the muscles of the cycloi)ean eye was made correctly, they were carefully com])ared with the normal nerves of the eyes of the well-developed face. This comparison left no doubt as to which nerves were being traced to the single eye, as the points of origin from the brain-stem of the third, fourth, fifth, and sixth nerves were symmetrical for both faces. The arrangement of the nerves on the cyclopean side are as follows:

1. The olfactory nerves are absent.

2. The origin of the optic nerve was lost. Two small and flattened optic nerves, however, pass out together in the dura. finally fuse into one stalk which ends in the bulb. This stalk, 2 mm. in diameter, is about the .same size as the normal optic nerves of the well-formed face on the opposite .side.

3. The two third nerves which belong to the cjxlops are 0.5 mm. in diameter at their point of origin and throughout their course, while the third nerves on the opposite side which pass to the perfect face are twice that size. The cj^clopean oculo-motor nerves pass into the dura, where thej' run toward each other to the place where the eye-muscles arise. Here these nerves lie within 3 mm. of each other. Branching occurs in this region. Two of these branches fuse immediately. There are two other pairs of main branches which innervate the levator palpebral and the superior recti on each side of the single eye. There are some finer branches whose course could not be definiteh' ascertained.

4. The cyclopean fourth nerves are equal in size with those of the normal ej-e. They run as two fine threads to within a few millimeters of each other, when they turn anteriorly and run parallel on the surface of the superior oblique muscles, in which they terminate.

5. The two Gasserian ganglia of the cyclops are somewhat smaller than those of the normal face. Each has three divisions: ophthalmic, ma.xillary, and mandibular. The two ophthalmic divisions have each three main branches. One of these branches passes along the roof of the orbit and makes several x-sha])ed anastamoses with its fellow near the front of the eyeball. Another runs forward, parallel with its fellow, out into the skin, where they are both cut; so if anastamosis occurred it could not be determined. The third and last branch, one on each side of the eye, ends in the lacrymal gland.

6. The sixth nerves of the cyclops, about U.S mm. in diameter, are equal in size with the sixth nerves, passing to the well-developed face. They converge to the base of the orbit when they run parallel to each other on the upper side of the lateral recti muscles, in whose substance they terminate after making several X-shaped anastamoses.

Fig. 7. — Diagram of cyclopean eye and ita appendages of the Janus monster, No. 1178 a and b, from a sketch and dissection by Dr. Finney. Kor the sake of clearness the superior oblique muscles are moved forward. The cranial nerves are marked with Roman numerals. •S. oh., superior oblique muscles; L. p., levator piilpebrse; S. r., superior rectus; L. r., lateral rectus; M, rudimentary musdo-niass, probably the remains of the inferior recti. It is noticed that the first branch of the fifth norve gives rise to a trunk which anastanmses across the midline. The same is true of the third and sixth nerves.


1. Ahlfeld, Joh. Fhiedrich. Die Missbildungen dcs Menschen. Leipzig, F. W. Grunow. 1880, p. 277.

2. Bach, L., and R. Seefelder. Atlas zur EutwickluiiRsgeschichte des menschlichen Auges. Leipzig, 1011.

3. Bell, E. T. Sonic experiments on tlie development and regeneration of the eye and the nasal organ in frog embrjos. Arch. f. Entwicklungsmeclm. d. Organ., Leipz., 1907, xxiii, 457-478, 7 pi.

4. Black, D. D. The central nervous system in a case of cyclopia in homo. Jour. Compar. Neurol., Phila., 1913, XXIII. 193-257.

5. Bremer, J. L. Description of a 4 mm. human embryo. Amer. Jour. Anst.. Bait.. 1906, v. 459-480.

6. Dandy, W. E. A human embryo with seven pairs of somites measuring about 2 mm. in length. Amer. Jour. Anat., Phila., 1910, x, 8.5-108, 6 pi.

7. Dareste, Camille. Recherches sur la production artificielle des monstruositfe. Paris, C. Reinwald et Cie., 1877.

8. Ellis, R. On a rare form of twin monstrosity. Trans. Obst. Soc. Lond., 1866, vii, 160-164.

9. EssicK, C. R. Transitory cavities in the corpus striatum of the human embrjo. Contributions to Embrvologj'. No. 6. Carnegie Inst. Wash. Pub. No. 222, 1915.

10. EvcLESHYMER, A. C. The development of the optic vesicles in amphibia. Jour. Morphol.. Bost., 1893, viii, 189-194.

11. pRORiEP, A. Die Entwicklung des Auges der Wirbeltiere. Handbuch d. vergleichenden u. experimentellen Entwicklungslehre der Wirbelticrc (O. Hertwig), Jena, 1905, ii, 2 Teil, 139-266.

12. Gage, Susanna P. A three weeks' human embryo, with special reference to the brain and nephric system. Amer. Jour. Anat., Bait., 1906. iv, 409-443. 5 pi.

13. His, W. Die Entwicklung des menschlichen Gehirns. Leipzig. S. Hirzel. 1904.

14. HoscHKE. E. Ueber die erste Entwicklung des Auges und die damit zusammenhiingende Cyklopic. Arch. f. Anat. u. Physiol. (Meckel's), Leipz.. 1832. VT. 1-47, 1 pi.

15. Johnston, J. B. The morphology of the forebrain vesicles in vertebrates. Jour. Compar. Neurol.. PhUa.. 1909, XIX, 457-5.39.

16. . The evolution of the cerebral cortex. Anat. Record, Phila., 1910, iv, 14.3-166.

17. Keidel, F. Normentafcl zur Entwicklungsgeschiihtc des Schweines. Jena, G. Fischer, 1897.

18. The development of the sense-organs. In Manual of Human Embryology (Keibcl and Mall), Phila. and Lond., 1912, ii. 180-290;aJso, Handbuch d. Entwicklungsgesch. d. Menschen (Keibcl and Mall). Leipz., 9111. II. 179-281.

19. Keibel. F., and C. Elce. Normentafeln zur Entwicklungsgeschichte der Wirbcltiere, Heft 8. Jena, G. Fischer, 190K.

20. KuPFFER. Die Morphologic des Cciitralnervensystcms. Handbuch d. vergleichenden u. experimentcllcn Entwicklungslehre d. Wirlxjitiere (O. Hertwig), Jena, 1903, ii, 2 Teil. 1-272.

21. Lewis, AV. H. The experimental production of cyclopia in the lish embryo (Fundulus heteroclitus). Anat. Record, Phila., 1909. iii. 175-181.

22. Experiments on the origin and difTerontiation of the optic vesicle in amphibia. Amer. Jour. Anat., Bait.. 1907, VII, 259-276, 1 pi.

23. The development of the muscular system. In Manual of Human Enil)ryolog>- (Keibel and Mall), Phila. and Lond., 1910, i, 454-522. Also: Handbuch. d. Entwicklungsgesch, d. Menschen (Keibel & Mall) Leipz., 1910, I, 457-526. LocY, W. A. Contributions to the structure and development of the vertebrate' head. Jour. Morphol., Bost., 1895, XI, 497-594, 5"pl. . The optic vesicles of elasmobranchs and their serial relations to other structures on the cephalic plate. Jour. Morphol., Bost., 1894, ix, 115-122. M.4LL, Franklin P. A study of the causes underlying the origin of human monsters. _ Jour. Morphol..

Phila., 1908, xix, 3-368. . Ueber die Entwicklung des menschlichen Darmes und seiner Lage beim Erwachsenen..Vrch. f. Anat. u. Entwcklungsgesch., Leipz., 1897.

Supplement (His Festschrift). 403-434. 10 pi. Meckel, J. F. Ueber die Prioritiit der^centralen Theile vor den peripherischcn. Arch. f. Anar. u.

Physiol. (Meckel's), Leipz., 1826, i, 310-315. Naegeli, Otto. Ueber eine neue mit Cyclopie verknijpfte Missbildung des Centralnervensystems.

Arch. f. Entwiklungsmechn. d. Organ., Leipz., 1897, V, 168-218, 4 pi. ScawALBE, E., and H. Josephy. Die Morphologic der Missbildungen, Jena, 1913, 3. Teil. 1. Abt., 205-246. Spemann, H. Ueber die Entwickelung umgedrehtcr Hirnteile bei Amphibienembryonen. Zoologische Jalu-b. Supplement 15, Bd. 3. Jelia, 1912. Stockard, C. R. The artificial production of a single median csclopean eye in the fish embryo by means of sea-water solution of magnesium chlorid. Arch.

f. Entwcldungsmechn. d. Organ., Leipz., 1907, xxiii, 249-258. . The artificial production of one-eyed monsters and other defects, which occur in nature, by the use of chemicals. Anat. Record, Phila.. 1909, III.

167-173. — . The development of artificially produced Cyclopean fish — the "magnesium embryo." Jour.

Expcr. Zool.. Phila.. 1909, vi, 285-338, i pi. — . The influence of alcohol and other anEesthetics on embryonic development. Amer. Jour. Anat., Phila., 1910, X, 309-392.

An experimental study on the position of the optic aniage in Amblystoma punctatum, with a discussion of certain eye defects. Amer. Jour.

Anat., Phila., 1913-14, xv. 253-289. Stheeter, C. L. Development of the nervous system.

Chap. 15, Manual of Human Embryology, Keibel and Mall, vol. 2, Phila., 1912. Tandler, J. Beitriigo zur Entwicklungsgeschichte des Vertebratengehirns. i. Anatomische Hefte 1 Abt., Wiesb., 1907, xxxiii, .55.3-665, 8 pi. •. Beitriige zur Entwicklungsgeschichte des Verteliratengehirns, Ihid., 1915, Lii, p. 85. Vax Drv.sE. Cyclopie avec crytophtalmos et kystes rolobomateux. .Vrch. d'opht., Paris, 1909, xxix.

65-77. I. E. A human embryo of thirteen somites.

Amer. Jour. Anat.. Phila.. 1913-14. xv, 319-331. Watt, J. C. Description of two young twin human embryos with 17-19 paired somites. Contributions to Embryology, No. 2, Carnegie Inst. Wash.

Pub. No. 222. 1915. W iiKK.R, H. H. The morphology of Cosmobia; speculations concerning the significance of certain types of monsters. Amer. Jour. .\nal., Phila.. 19()S, VIII, :{55-440, 4 pi.

Explanation of Plates

Plate I.

1 . Plaster recon.struftioii of the brain and cyclopcan eye of embryo Xo. oo9. X 2o. Cranial ner\-e8 are marked with Roman numerals, o. i., optic vesicle; s, snout: m, mouth.

2. View of the right side of embr>-o Xo. oo9. X 9. Only the face region is worked out in detail. I', v., umbiUcal vesicle. :5. Face of embryo Xo. 559. X 16. The drawing is made from a plast«r-of-paris reconstruction. S, snout. 4. \'iew of the left side of cyclopean embrj-o Xo. 559. X 9. The drawing was made directly from the specimen in formalin.

Plate 2.

1. From the photograph of embryo Xo. 201. X Ij.

2. Photogi-aph of o\'um, Xo. 559. X 1.

3. Section through the cyclopean eye, Xo. 1165. X 40. E, eye; e. I., eyelid. Behind the eye are seen the ocular muscles.

4. Section through the external ear of embrj-o Xo. 201. X75. There is an invagination of the epidermis and tissues of the ear are dissociati-d.

5. Photograph of the ovum, Xo. 5.59, showing the embrj-o in position. X 3. The exoca-lom is filled with a dense magma.

6. OutUne of brain of embryo No 1201. X 100. From a plaster reconstruction made by Dr. Bartehiiez. The wideopen flange in front contains two depressions, the optic vesicle, which unite through a common groove, the torus opticus, as marked on the drawing. The depression behind this flange no doubt represents the cavity of the midbrain and hindbrain. This specimen is Xo. S7 of the collection of the T'nivcrsity of Chicago and contains eight pairs of myotomes.

7. Photographof section through the snout of .specimen Xo. .559. X 60. The frontal process contains the common cerebral vesicle, c. v., and below the snout there is the upper jaw, u. j.

Plate 3. Ail the photographs are from the sections of the embryo Xo. 559. Figs. 1 and 2, X50; figs. ;{, 4, o, X40.

1. Section through the ocular muscle, showing the terminal fibrils of the third and si.xth nerves. Oc. mus., ocular muscle; n, notochord; vt, mouth: v, fifth nerve.

2. Section through the eye at its attaclmient to the interbrain. T. o., torus opticus; i', i", i'", branches of the fifth nerve; it/*, terminal filament.s of the fourth nerve ending in the primordia of the superior obUque muscle 3. Section through the lower tip of the cerebral hemisphere The peculiar tissue surrounding the nerve-body ma\ represent a degenerated olfactory region. .Vbout this is seen a section of the interbrain, and below a process containing the cyclopean eye. Fb, &Tst branch of fifth nerve; m, mouth.

4. Section through the middle of the cyclopean eye. /. b., interbrain; Fb, first branch of fifth nerve; m, mouth.

5. Section through the cerebral hemispheres as they communicate with the interbrain. /. 6., interbrain; c. h., cerebral hemisphere; s, snout; u. j., upper jaw. Over the lamina terminalis is seen the peculiar thickening of the outside of the body which may represent the degenerated olfactory region also shown in the flat section of figure 3.

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