View source for Talk:Paper - Abnormal development of the brain in an 8 mm pig embryo (1938)

ABNORMAL DEVELOPMENT OF THE BRAIN
IN AN 8 MM. PIG EMBRYO .

By J. S. BAXTER anv J. D. BOYD

Anatomy School, Cambridge

‘Tue specimen, which is described here, is one of a series of 8 mm. pigembryos
prepared for routine class teaching in this Department. In order to determine
its developmental age it has been compared with a number of normal pig
embryos from our collection, and it corresponds essentially with a normal pig
embryo of 8 mm. c.R. length. We have therefore used an embryo of this size
as a standard of comparison in our study of the abnormal embryo. At the
outset it should be stressed that the latter is in excellent histological condition.
As may be seen from PI. I, fig. 6, the tissues have been preserved in a very
good state, mitotic figures being numerous and clear. It is not an unreasonable
assumption then, that this embryo has been obtained and fixed while still in
a living condition. In a survey of the literature upon developmental defects
in the cephalic part of the central nervous system we have been impressed
by the fact that, so far as we have been able to ascertain, all recorded specimens
of comparable abnormalities are in a poor histological state; this may, in some
cases, be due to post-mortem change; in others, secondary mechanical and
pathological processes have obscured the picture of the primary defect. Our
specimen, then, is of considerable significance, as its age and histological
condition rule out such complications.

DESCRIPTION OF SPECIMEN

The embryo was one of a batch which had been stained in bulk with
haematoxylin and eosin, the amnion in each case being intact. It was therefore
only after sectioning that the abnormality was discovered. Consequently two
reconstructions of the head end of the embryo have been prepared, each made
at a magnification of 50 diameters. The first is a plaster of Paris model of the
external form of the head (constructed by Lewis’s modification of Born’s
method), while the second is a conventional Born wax-plate model of the
corresponding portion of the central nervous system.

Text-figs. 1 and 2 depict the left lateral aspect of these reconstructions.
On comparison of the two it is clearly to be seen that a certain part of the
cephalic portion of the neural tube has been splayed out upon the surface of
the head of the embryo. This eversion of the neural folds extends from the
rostral limit of the metencephalon to the neighbourhood of the upper border
Abnormal Development of the Brain in Pig Embryo 423

 

Text-fig. 1. External form of the head end of the embryo.

  

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Rathke’s

pouch

 

Optic
Telencephalic stalk
vesicle

Text-fig. 2. Reconstruction of the cranial end of the nervous system.
424 J. S. Baxter and J. D. Boyd

of the lamina terminalis. The line of demarcation between the neural tissues
and the somatic ectoderm is everywhere quite distinct (Pl. I, fig. 1). The roof
of the hind brain appears to be essentially normal in its configuration. The
deep cavity to be seen (Text-fig. 2) just rostral to the metencephalon leads
caudally into the cavity of the hind brain. The telencephalic vesicles are
present on either side, and are comparable in their form and structure with
those of the control embryo. Just behind the telencephalic vesicles are the
optic stalks, the development of which has proceeded to a rather greater
degree on the right than on the left, but even here the condition of the optic
diencephalic outgrowth is much arrested as compared with the normal embryo
of this stage. In association with this condition there is failure of development
of the lens placode. On the left side there is no trace of an ectodermal
thickening to form the primordium of the lens; on the right side, where the
neural optic evagination is somewhat better developed, there is a slight
ectodermal thickening (PI. I, fig. 4). In the case of the 8 mm. control embryo
the lens placode has already separated on each side from the ectoderm and
is lying in the primitive optic cup. There has obviously, then, been a marked
retardation in the development of the optic primordia in this specimen. In
order to lay further stress upon this point we present in Text-fig. 3 camera
lucida drawings of four consecutive sections through the optic primordia on
the right side of this embryo; and it will readily be seen in these figures that
the lens primordium is merely a slightly thickened area of ectoderm in
continuity with the general somatic ectoderm. There is only a small depression
to indicate its future possible invagination. On the left side neither ectodermal
thickening nor indication of invagination are present.

The neural and stomodaeal components of the hypophysis appear to be
normal (PI. I, fig. 5). .

The attachments of the trigeminal, acoustico-facial and glossopharyngeal
nerves to the brain stem are indicated in the second reconstruction (see also
Pl. I, fig. 2). These nerves in their entire course are quite comparable with
those of the control embryo. The otic vesicle also appears quite normal. The
vagus, accessory and hypoglossal nerves (which however have not been
modelled) are normal, but, in striking contrast, there is no trace of the oculomotor, trochlear or abducens nerves. These latter three nerves were clearly
to be seen in our control embryo.

Anteriorly the reconstructions present several significant features. There
are two foramina of Munro to be seen at the anterior edge of the exposed
neural tissue, and they lead into the telencephalic vesicles. Immediately
inferior to this level the end of the neural tube is closed so that a small rostral
cul-de-sac is formed. We take the closing membrane to be (PI. I, fig. 8, Textfig. 4) the lamina terminalis, and the cul-de-sac must then be the telencephalic
part of the third ventricle. This is in accordance with the description of
Streeter (1912) regarding the two component parts of the third ventricle.
Thalamic swellings can be seen exposed on the surface immediately behind the
Abnormal Development of the Brain in Pig Embryo 425

 

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Text-fig. 3. Successive sections through the right optic primordium.

Exposed neural tissue

IVth ventricle

 
  
 
        
 

    

Rathke’s pouch Lamina

Telencephalic terminalis
part of

IlIrd ventricle

Text-fig. 4. Sagittal graphic reconstruction of the head end of the embryo.
426 J. S. Baxter and J. D. Boyd

foramina of Munro. These swellings are separated by a deep cleft which is
continued throughout the exposed mid-brain as a median fissure.

A sagittal graphic reconstruction of the brain (Text-fig. 4) emphasizes
several of the points previously mentioned. The extent of defective union of
the neural folds is shown; the intact lamina terminalis is seen bounding the
telencephalic part of the third ventricle and behind this cavity is seen Rathke’s
pouch. A further point, not hitherto stressed, is the marked upward “ buckling”
of the whole of the neural plate in the region of the mid brain. This may also
be seen in Text-fig. 2. If this embryo had developed further, it is possible that
solution of continuity of the nervous system might have occurred in this
region (cp. Frazer, 1921).

We have been able to satisfy ourselves that the blood vessels of the head
of the embryo are normal. The internal carotid arteries may be seen on PI. I,
fig. 1, and these vessels could be traced throughout their course. The significance
of this observation will be discussed later.

The remainder of the specimen calls for no comment except that its
condition is everywhere that of an ordinary 8 mm. pig embryo. This is shown
in Text-fig. 1 where the external appearance of the branchial arch region is .
perfectly normal. Particular attention was paid to the primordia of the
ductless glands in the study of the sections in view of the stress which has
been laid by some writers upon changes in these glands in similar developmental abnormalities of the nervous system. We found no discernible changes
from the normal picture of the endocrine gland primordia in an 8 mm. pig embryo.

DISCUSSION

The obvious lesion in this abnormal embryo is non-closure of the neural
’ folds in the mesencephalic and diencephalic regions. Associated with this
abnormality is absence of the oculo-motor, trochlear and abducens nerves of
each side and defective development of the optic outgrowths and, particularly,
the lens primordia. ,

A comparable abnormality has been described by Sternberg (1927). He
had available for study a human embryo of 5 mm. G.L. in which there were
three clefts in the dorsal part of the medullary tube. The first of these he
judged, from its relations, to be the still open anterior neuropore. There was
a further rhomboidal cleft in the region of the mid-brain separated from the
first by a connective tissue bridge, while a third small fissure was present in
the upper part of the spinal cord. The gross and microscopic condition of this
embryo was admittedly poor. Nevertheless certain important features could
be made out. A number of the cranial nerves and their attachments to the
brain stem were discernible; they were the trigeminal nerve, the acousticofacial complex, the glossopharyngeal, vagus, and cranial portion of the accessory
nerves. Both optic outgrowths were present, each communicating widely with
the cavity of the diencephalon. There was a slight degree of ectodermal
thickening indicating the lens primordia, more marked upon the right side,
Abnormal Development of the Brain in Pig Embryo 427

and a minor degree of cupping here to indicate future invagination of the
optic vesicle.

The resemblances between this specimen and the pig embryo we have
described are striking. In both, a non-union of the neural folds in the mesencephalic and diencephalic regions is associated with defective development of
the optic primordia. Further, in the pig embryo there is failure of development
of the IIIrd, [Vth and VIth cranial nerves. Sternberg does not refer to these
nerves in the description of his abnormal embryo. The presence of marked
optic abnormalities in the two embryos prevents them from being regarded
as early examples of what is usually designated ‘“‘anencephaly’’.

What the subsequent developmental history of these embryos might have
been can only be surmised. An abnormal human embryo of 35 mm. c.R. length
described by Hunter (1984) as a case of “‘extroversion of the cerebral hemispheres” probably represents such a later stage in so far as the brain itself is
concerned. His specimen showed a marked exposure of neural tissue on the
surface of the head in the mid- and forebrain regions. This neural tissue was
continuous laterally with the body ectoderm but bulged over it. A portion
of the exposed tissue showed the structure of normal choroid plexus and
projected from the surface into the amniotic cavity. It is clear that the
condition of the brain found by Hunter could easily have been derived from
an earlier abnormality such as is present in Sternberg’s and our specimens.
Continued growth of exposed neural tissue in such embryos could easily result
in the bulging of this tissue over the somatic ectoderm to produce the condition
which Hunter has called ‘“extroversion”’.

To none of these three specimens can the term anencephaly properly be
applied as, in each of them, there is present an intact neural plate, abnormally
developed in a certain region, but with no evidence whatsoever of rupture of
the brain stem. The latter has been emphasized by Frazer (1921), and later
by Mann (19387) as the essential lesion in anencephaly. Thus Mann writes
(1987, p. 57): “in any case the essential lesion is a transverse solution of
continuity of the brain stem. This will account for most of the known facts
and is borne out by examination of a human embryo with the defect in process
of developing”. The embryo referred to here is the one described by Frazer
but, in our opinion, the condition of ‘“‘anencephaly ” is already well established
in his specimen and there is no clue to the nature of the primary defect.
Frazer and Mann both stress rupture of the internal carotid arteries distal to
the origin of the ophthalmic arteries as an important secondary factor in the
production of the final condition. They both admit, however, that the primary
factor is a cerebral defect due, according to Mann, to “a sudden fortuitous
accident occurring during an otherwise normal development rather than a
dysgenic process present and acting from the first”. This explanation may be
applicable to some cases of anencephaly but, if our specimen had continued
to develop, a cerebral condition closely resembling anencephaly would
probably have resulted. This condition would primarily have been due to
428 J. S. Baxter and J. D. Boyd

failure of union of the neural folds and any secondary processes resulting in
solution of continuity of the brain stem (such as excessive “‘buckling” of the
neural plate or stretching of the internal carotid arteries) are superimposed
upon this primary lesion. We find this explanation more acceptable than one
which implies normal closure of the neural tube and then invokes supposititious
foetal hydrocephalus to rupture the roof plate and initiate the abnormality.
Our explanation has the further advantage of bringing anencephalic conditions
into line with spina bifida, the former being, in the first instance, examples
of encephalon bifidum.’ The two conditions, spina bifida and encephalon
bifidum, occasionally coexist (see Wrete, 1924) in which case there has been
non-closure of the whole length of the neural folds.

Our conception of the condition known as anencephaly, then, is that it is
the result of secondary changes masking the primary lesion which we believe
to be non-closure of the neural folds. This may, occasionally, be a fortuitous
accident of development, but that it can be a dysgenic, hereditary defect is
shown by the fact that in certain inbred strains of rabbits a high proportion
of the offspring have anencephaly (Dr J. Hammond, personal communication).
The secondary changes which result in frank anencephaly may, in part, be
due to the unrestrained growth of the exposed neural tissue and to its upward
buckling. To these mechanical effects of non-closure of the neural plate may
be added vascular changes (as suggested by Frazer, but which are not present
in our specimen), interference with normal nervous metabolism as a result of
the disorganized production and circulation of the cerebrospinal fluid and the
exposure of the nervous tissue itself on the surface of the embryo.

It is impossible to be dogmatic about the relation between the non-closure
of the neural folds in the mesencephalic and diencephalic regions of our embryo
and the abnormal development of its optic apparatus and the associated
nerves. We incline to the opinion that the two are closely connected and that
the lesion is essentially a dysgenic one involving those parts of the embryo
which have to do with the development of the visual apparatus.

Our thanks are due to Miss Joan Loewenthal for her kind assistance in
the preparation of Text-figs. 1 and 2.

SUMMARY ’

An abnormally developed nervous system in an 8mm. pig embryo is
described. The abnormality consisted in non-closure of the neural folds in its
mesencephalic and diencephalic regions, the complete absence of any trace of
the IIIrd, IVth and VIth cranial nerves and markedly retarded development
of the optic primordia. The excellent histological condition of the sectioned
material enables one to state that no secondary pathological changes had
supervened. The relationship of this abnormality to anencephaly is discussed.
BAXTER anp BOYD—AsyormaL DEVELOPMENT OF THE BRAIN IN Pia Empryo.

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Journal of Anatomy, Vol. LX XII, Part 3

Plate I
Fig.

Fig.

Fig.
Fig.

Fig.

Fig.

Abnormal Development of the Brain in Pig Embryo 429

REFERENCES

Frazer, J. E. (1921). J. Anat., Lond., vol. tv, p. 12.

Hunter, R. H. (1934). J. Anat., Lond., vol. ux1x, p. 82.

Many, I. (1937). Developmental Abnormalities of the Eye. Cambridge.
STERNBERG, H. (1927). Z. ges. Anat. 1. Z. Anat. EntwGesch. Bd. Lxxxtl, p. 747.
STREETER, G. L. (1912). In Keibel and Mall’s Human Embryology, vol. 11.
Wrete, M. (1924). Z. mtkr.-anat. Forsch. Bd. 1, p. 563.

EXPLANATION OF PLATE I

1. Section through the diencephalic region of the embryo. The exposed neural tissue is shown
and, on the left side, its continuity with the somatic ectoderm can be seen. Note the intact
internal carotid arteries on either side of the basal portion of the nervous system. ( x 85.)

. 2. Section through the hind brain. On the left side can be seen the trigeminal ganglion with

its sensory root, the acoustico-facial ganglion, the ganglion superius of the glossopharyngeal
nerve and the vagus nerve. The otocysts are seen on either side of the hind brain. ( x 55.)
3. Section to show the lamina terminalis region. ( x 85.)

4. Section through the right optic outgrowth. The thickening of the ectoderm where the lens
should have developed is shown. ( x 85.)

5. Section through the optic stalks near their attachment to the diencephalon. The upper
part of Rathke’s pouch is seen in the lower part of the microphotograph making contact with
the floor of the IIIrd ventricle. ( x 85.)

6. Section at a higher magnification through a portion of the exposed neural plate. The
excellence of the histological condition of the sectioned material is obvious. Mitotic figures
can be seen on the surface of the exposed medullary plate epithelium. ( x 250.)