STRUCTURE OF THE LEPROMA.
The leprous nodes have on section a smooth, white, glistening surface,
if they are still sufficiently young. If one examines, microscopically,
sections or teased preparations of fresh nodules, one sees little else
but cells, with distinct nuclei, usually of the size of a white blood
corpuscle, or rather larger. There are also a few larger so-called
epithelioid cells, with larger nuclei, and among the cells, fragments
of connective tissue and of blood vessels. With a higher power, one
sees in the fluid of the preparation small straight rods, which are not
destroyed by addition of potash. These are the lepra bacilli, and thus
were they first discovered in the year 1871.
If one teases out preparations in osmic acid solution, or soaks a
nodule in the solution some hours before teasing, the rods are coloured
faint brown, and one finds them lying mostly in the cells (_Plate VI,
Fig. 1_). If one adds water to a fresh preparation, the bacilli move
actively; even in the cells swollen up with water, one sees the bacilli
moving; and this led us to regard them as movable, although we at the
same time indicated a doubt whether the movement was not simply a
molecular one; for the movements were equally vigorous in strong osmic
acid solution as in water, and on the addition of glycerine or strong
solution of albumen to the preparations, the movements ceased. All
later observers, with the exception of Unna, regard the bacilli as
motionless. We have no ambition to decide this question, because we
know no absolutely trustworthy distinction between molecular movement
and independent movement of the bacilli.
The older the nodules become, the more large multinuclear cells are
found, and in nodules of the skin and cornea one always finds small
flat cells with processes, and with oblong nuclei, which we recognise
as the connective tissue and corneal cells (_Plate VI, Figs. 2_ and
_3_).
The protoplasm of these cells is clear, while that of the round cells
is more or less granular. The nuclei of the latter are also round, and
usually very granular; the flat cells are much less stained by carmine
than the round cells, and one sees the flat cells lying on connective
tissue bundles. The nodules are richly supplied with blood vessels; in
the nodules of the skin it cannot be determined whether the vessels
are newly formed, or only those already present in the cutis. They
are, however, always of embryonic type. One sees very plainly their
formation from cells, and in the cornea, indeed, the vessels _must_
be newly formed. Here the vessels penetrate into the cornea before the
nodule forms, and round these vessels, penetrating into the cornea,
there are always visible collections of cells which are apparently
migrated white blood corpuscles (_Plate VI, Fig. 4_).
One meets also in old nodules, among apparently only unproductive
elements, blood vessels surrounded by young cells (_Plate VI, Fig. 5_).
This appears definitely to favour the view that the tumour cells are,
at least for the most part, migrated blood corpuscles. These results
have been obtained by examination of fresh nodules, and of those
hardened in Müller’s fluid. As we have recently, while hardening the
nodules in Fleming’s chromic and osmic acid mixture, and staining the
sections with hæmatoxylin, been unable as yet to find any mitoses, and
further, have found, by bacillary staining of an old section from a
corneal node, an appearance like _Plate VI, Fig. 7_, we must maintain
provisionally that in the lepromata the new formations are, at least
chiefly, formed by the immigration of white blood corpuscles. As the
round cells infiltrate the connective tissue, the fibres are pressed
asunder, and form a network closely resembling that of a lymph gland
with nuclei in the angles (_Plate VI, Fig. 6_).
When the nodule softens, which takes place almost always exactly in the
middle, it attains a brownish tint, which is due to the transparent
softened part. If one divides the softened nodule, the central part
has a distinct brown colour, and the constituents of this part readily
fall out. If this is examined under a microscope, one sees, almost
exclusively, larger or smaller clumps of a brownish colour, and very
granular. They are partly elastic, but partly brittle and fragile, so
that by pressure on the cover glass they are easily broken up. One
often sees clearly that the clumps lie _in_ the cells, the nucleus and
the cell substance being still evident (_Plate VII, Fig. 1_). Sometimes
only one lies in a cell, which then has the appearance of a signet
ring, in whose circle the clump lies, but sometimes several lie in
one cell. One finds similar clumps in all other organs affected with
leprosy, as in the liver, the spleen (_Plate VII, Fig. 2_), the nerves,
lymphatic glands, the testicle and the eyes (_Plate VII, Fig. 3_,
which shows two clumps from the retina). In the nodes of the skin, but
particularly in the testicles, one may find them so large that they may
even be seen by the naked eye. Both in the small and the larger clumps
there are usually vacuoles, not infrequently several. From the cornea
we have often got preparations in which the corneal corpuscles are more
or less completely filled with brown granules (_Plate VIII, Fig. 1_).
One sees here definitely the cell nucleus in the middle of the brown
granular material.
We have described these elements as we first observed them in fresh
and carmine-stained preparations, in which they stand out very
definitely, as the brown masses do not take up the carmine stain.
These brown elements, if one knows their characteristic appearance,
may very well serve as diagnostic indications for leprous affections,
for, according to our experience, one never fails to find them except
in very young nodules. Since the discovery and easy recognition of
the lepra bacillus, they have indeed lost their value as diagnostic
signs, unless one is examining perfectly fresh preparations. Later
investigation has proved that these brown clumps are nothing else
but collections of lepra bacilli broken down into granules, and they
have received from Neisser the well-chosen name of “globi,” as they
usually appear in spherical form. Unna declares, in accordance with
his view of the position of the lepra bacilli outside the tumour cells
in the lymph spaces, that these “globi” are collections of bacilli in
the lymph vessels, and that the vacuoles have arisen from the falling
out of bacilli in the middle. In particular, Neisser, Touton, and we,
ourselves, have opposed this view, in that we have all seen the bacilli
definitely in the cells, and have figured them so. In view of the
above description of the discovery of bacilli in fresh preparations and
of these brown clumps, there can scarcely be any doubt of the position
of the bacilli, and of the cellular nature of the brown clumps.
Further, it may be noted that in the testicles the “globi” are chiefly
in the lumen of the seminal canals, where no lymph vessels exist, and
if Unna says of the “globi”[2] that “no one has certainly determined
their cellular character,” he must have said this in ignorance of
our earlier publications in Norwegian. The above description and the
drawings were published by us in 1869 and 1870, in the _Nordiskt
Medicinsk Arkiv_.
[2] Unna, zur Histologie der Leprösenhaut; in Leprastudien, Monatshefte
für practische Dermatologie, Ergänzhungsheft, 1885.
In connection with the vacuole, we have found in a testicle a
“globus” with vacuoles, and in the vacuoles small granules which were
recognised as remains of the nuclei (_Plate X, Fig. 2_). We add to
this the picture of a “globus,” or rather a developing “globus,” with
two nuclei, from a skin nodule (_Plate VIII, Fig. 4_). We have seen
earlier, however, that the brown clump may lie in the cell without
enclosing the nucleus, and also that the nucleus may lie in the middle
of the brown mass. Now, if the vacuoles are transformed nuclei, as we
believe, then it would be comprehensible that the vacuoles would be
absent in many “globi,” and that in others which have developed from
multinuclear cells, several vacuoles would be found. That appears,
at least, the simplest explanation of their presence. But there are
certain very small “globi” with vacuoles, such as are represented in
_Plate VII, Fig. 2, c_, and those small vacuoles can scarcely represent
nuclei; small “globi” may however arise, as is evident at _x_ and _x^1_
of the same figure, from clumps of bacilli in the cells. The vacuoles
of the larger “globi” of _x_ and _x^1_ may indeed possibly represent
nuclei, but not the vacuoles in _Plate VII, Fig. 2, a-k_, nor the
vacuole in one of the small “globi” in _x^1_. Possibly the vacuoles
are also the result of a specific degeneration, either of the bacilli
themselves, or of the cell protoplasm lying in the middle of the group
of bacilli, but on this we would rather not express an opinion.
We have repeatedly demonstrated the position of the bacilli _in_ the
cells, and explained them in diagrams, but in many preparations it
is impossible to distinguish where the bacilli lie. The best method
of definitely noting their position, which we know, appears to be
the fixing of small nodes or small pieces of organs in Fleming’s or
Müller’s fluid, with subsequent dehydration and hardening in alcohol;
sometimes one gets excellent preparations by simply hardening in
absolute alcohol. If the preparations are stained with fuchsin,
and counter-stained with methyl blue, or still better, stained with
gentian violet, decolourised by Gram’s method, and counter-stained
with Bismarck brown or with Bismarck brown and eosin, one will never
fail to see the bacilli lying definitely in the cells (_Plate VI, Fig.
8_). Even in such preparations there are many places where one cannot
definitely distinguish the position of the bacilli; but as one always
finds bacilli in the cells where the preparations are sufficiently
clear, we may safely conclude that the bacilli lie everywhere _in_ the
cells. In the connective tissue spaces one often sees bacilli in and
round the nuclei of the connective tissue cells (_Plate X, Fig. 8_),
and although the body of the cell is not visible, we may conclude that
the bacilli lie in the cell body, and not free in the lymph spaces. We
have found in many sections of the blood vessels in a testicle (_Plate
X, Figs. 5_ and _6_), and in a liver (_Plate VIII, Fig. 6_, and _Plate
IX, Fig. 1_), white blood corpuscles filled with bacilli, and in both
cases only slight affection of the organ, and we also observed many
bacilli in the endothelium of the vessels, as Touton and Unna have
observed in skin nodules where we, we may remark in passing, have never
seen them. From these observations we draw the conclusion that these
two organs have been infected through the blood. As we do not know the
manner and method of the primary infection of the organ, we must devote
our attention to the search for discoveries like those described above,
and to the localisation of the bacilli in general, in order to form an
idea of the method of action of the bacilli.
As we have already noted, we found in the examination of an excised
piece of a recent eruption, in a nodular case of leprosy, chiefly,
round cells surrounding dilated vessels, and only after long search, a
few bacilli. It thus appears not improbable that during the eruption
a toxin (which is circulating in the blood), and only a few bacilli,
escape from the vessels at various places, or, it may be, only the
bacilli, which produce the toxin locally; that further, the toxin
causes the emigration of white blood corpuscles, and that the escaped
bacilli only after some time slowly increase in number and gradually
fill the cells. From the presence of the bacilli in the endothelium
of the vessels and in the connective tissue cells, one may speculate
that the bacilli are passively forced into them by the blood or lymph
pressure; we have certainly found, in the testicle referred to,
bacilli free between the red blood corpuscles in the vessels (_Plate
X, Fig. 7_). Such a fresh eruption may remain stationary or slowly
develop into a nodule, or it may apparently completely disappear,
and only after several years again become apparent, it may be
during a fresh eruption. We fancy that in these cases a few bacilli
are deposited at the time of the first eruption, and that they have
needed years to become so much increased that a permanent nodule
has finally formed. That the vessels receive lasting injuries from
the leprous infection, appears to us to be proved by the following
observations. In an epidemic of measles in one of our institutions,
we saw in anæsthetic patients the previous leprous spots, which had
long disappeared from view, definitely reappear, the _hyperæmia_ and
turgescence being on these places general, so that the earlier spots
stood out as well defined, red, and somewhat swollen areas. All this
appears to point to the fact that the bacilli increase very, very
slowly, and that possibly they also produce a toxin, usually only in
small quantities, which causes no particular injury to the organism,
since the patients, in spite of numerous nodules, with millions or
milliards of bacilli, may remain in pretty good health for years. We
may also conjecture that the toxin which is produced, usually only
acts immediately around the bacilli, leading to dilatation of the
vessels and favouring the migration of white blood corpuscles. Only
occasionally does the production of toxin or the multiplication of the
bacilli appear to become so vigorous that toxin and bacilli get into
the blood and cause an eruption; possibly this is favoured by peculiar
anatomical conditions, for it is very striking with what varied
frequency eruptions appear in different patients. That the bacilli
in the nodules are all of them dead, as has been assumed, we cannot
admit, so long as the nodules still grow. It appears to us preferable
to ascribe the character of the disease to the relative benignancy and
slight viability of the bacilli, as Unna has already suggested. As we
believe, as explained above, that the bacilli lie almost exclusively in
the cells, the question arises whether the cells digest the bacilli,
or not. As we often find cells with only one or two bacilli, and as we
find in most cells balls or clumps of bacilli, we must admit that the
bacilli multiply in the cells. In some cells the bacilli remain lying
in separate collections, in others they fill the entire cell body, but
they never penetrate into the nucleus. Finally, the bacilli break down
into small granules, and this breaking down corresponds, according to
our view, to a degeneration of the bacilli. Unna and Lütz have indeed
stated that this granular appearance of the bacilli is constant, and is
a mark of their structure, that they really consist of small rows of
cocci, and Unna has therefore described them as coccothrix. This actual
(!) structure of the bacilli, however, only becomes evident under the
action of free iodine. But we have seen in our preparations, however
they were treated, _smooth and granular bacilli lying close to each
other_, and we cannot, therefore, corroborate the view of Unna and Lütz.
Neisser first drew attention to clear spaces in the bacilli; these
Neisser regards as spores; we regard them as the first sign of breaking
down of the bacilli into granules, and for the following reasons. We
have made numerous attempts to cultivate the bacilli, and have attained
in all our investigations only (the breaking down of the bacilli into)
granules, and in examining a piece of a nodule which lay eight days
on broth peptone agar, found all the bacilli beset with clear spaces.
And as the result has always been the breaking down into granules, we
believe we are right in regarding the appearance of these holes as the
commencement of degeneration, and that we are not as yet familiar with
spores of the lepra bacillus. It appears as if all bacilli in time
break down into granules, particularly in the internal organs, where
it occurs much earlier than in the skin nodules; whether this is the
result of digestion on the part of the cell, we cannot say; but as the
bacilli at first multiply in the cells, and the breaking down appears
most definitely and freely when the cells are crammed full of bacilli,
it is equally possible that it is the result of diminished nutrition,
and as they break down more rapidly in the internal organs, it is
also possible, indeed probable, that the higher temperature in these
organs favours this disintegration. As we have unfortunately not been
able to cultivate the bacilli, it is at present impossible to form a
conclusion. At all events, we regard the transformation into granules
as a degeneration, and believe that the bacilli thus altered are dead.
In the skin nodules we have only once found bacilli in the epidermis;
this was in a nodule with many fissures in the epithelium, and partly
covered with exudation. We have not been able to decide from our
preparations whether the bacilli lie in the epithelial cells or only
_between_ them, possibly enclosed in wandering cells.[3] Touton found
bacilli in the epithelium of the sweat glands, and he and Unna in the
hair sheaths also; this situation of the bacilli we have never observed
with certainty, and it can only be exceptional, and can scarcely give
origin to a “constantly flowing bacterial spring,” as Unna suggests. As
a rule, no bacilli are found in the epithelium.
[3] In a nodule, with exudation, which we have recently examined, we
have found bacilli in the epithelium, and there are in several places
distinct leucocytic nuclei in the bacillary groups, thus showing
emigrated cells with bacilli in the epithelium.
Of the presence of bacilli in affections of the eye, it may be said
in general that everywhere, where infiltration is present, bacilli
are found. In the clouding of the upper part of the cornea described
above, which we recognise as keratitis punctata, there are found groups
of granularly degenerated bacilli close under the epithelium. This we
have only once been able to determine on the living by excision of
a lamella of the cornea; in this case the affection was, according
to our own view, disappearing, because the bacilli were granularly
degenerated. This corresponds with the fact that this characteristic
affection of the cornea always ultimately disappears; the granules are
probably absorbed. We have already stated that blood vessels precede
the nodule into the cornea, and that they are surrounded by round
cells. Here, as in the middle of the nodule, the corneal corpuscles
are found apparently intact or filled with brown granules (_Plate VI,
Fig. 3_, and _Plate VIII, Fig. 1_). The same is the case in nodules in
the iris, in which one finds the stellate cells intact (_Plate VIII,
Fig. 2_). Round cells are also found in the spaces in the cornea near
the nuclei of the corneal corpuscles (_Plate VIII, Fig. 3_). All this
appears to us definitely to indicate that at least most of the cells of
the growth are migrated white blood corpuscles.
Dr. Boeckmann has introduced, in the treatment of the nodules growing
into the cornea, the division of the cornea in front of the nodules;
through the scar formed by the healing of the wound, they hardly ever
grow. We have seen such a case in which, on the one side of the
scar, no actual nodules, but only a clouding appeared, and we were
later able to examine the eye anatomically. The nodule reached like a
rampart close up to the scar, and all its cells were full of bacilli.
On that side of the scar in the clouded part of the cornea, there
were found only a few scattered cells containing bacilli; no vessels
had penetrated the scar, and only a very few cells had succeeded in
making their way through. The treatment is therefore a very desirable
one in order to preserve the pupil free. We have been able to prepare
no bacillary preparations from the _retina_, as we have not seen the
affection since the discovery of the bacilli; the two brown clumps
which are figured in _Plate VII, Fig. 3_, lay in the outer granular
layer of the retina.
As already indicated, the testicles are affected with leprosy in all
nodular cases. The affection is both inter-tubular and intra-tubular.
In a testicle only slightly affected, we found bacilli everywhere in
the endothelium of the vessels, and in several dilated vessels white
blood corpuscles filled with bacilli (_Plate X, Figs. 5_ and _6_);
and in some places also bacilli lying free between the red blood
corpuscles (_Plate X, Fig. 7_). At the same time, and especially where
the affection is more marked, the bacilli penetrate into the seminal
canals, and lie grouped in their walls around the nuclei (_Plate IX,
Figs. 4_ and _5_, _Plate X, Fig. 1_), and their epithelial cells are
more or less filled with them (_Figs. 1, 2_ and _4_).
The bacilli appear rapidly to break down into granules, and one finds,
especially in the seminal canals, globi, sometimes enormously large,
as if they were formed by the running together of several epithelial
cells. We have found here globi where a nucleus and a little protoplasm
were evident (_Plate X, Fig. 3_), and a globus where there lay in the
vacuole small fragments stained with Bismarck brown (_Plate X, Fig.
2_). As it has been proved that a man affected with nodular leprosy may
beget children, and as the globi lie in the seminal canals, it is not
altogether impossible that these may be thrown off with the spermatic
fluid, and that in this way the ovum is infected. But as, according to
our view, these globi contain only broken down and degenerated bacilli,
it must be regarded as very doubtful whether they are still infective.
In examining the contents of the seminal vesicles, we have found in
them neither bacilli, nor globi, nor any spermatozoa. It is an old
conception that lepers suffer from satyriasis. This is, according to
our experience, certainly not the case. The leprous testicle is finally
completely destroyed by the scar-like contraction of the connective
tissue, and one finds only here and there traces of the seminal canals
around the globi which they enclose.
When the liver is severely affected with leprosy, there are evident
macroscopically, fine white, or yellow, streaks or points, which shine
through the capsule and are more evident on the cut surface (_Plate IX,
Fig. 2_); they evidently lie in the acini. One also finds round cells
with bacilli along the portal vessels and in the capsule of Glisson.
Here and there we find also scattered bacilli in the acini, and as is
evident from a specimen hardened in Fleming’s solution, the bacilli lie
in the endothelium of the blood vessels (_Plate IX, Fig. 1_). In the
liver cells we have never seen bacilli, but we have found here also, in
the vessels, white blood corpuscles containing bacilli (_Plate VIII,
Fig. 6_, and _Plate IX, Fig. 1_).
The affection of the spleen may also be recognised macroscopically
by the yellow streaks and points in its substance (_Plate IX, Fig.
3_), but the affection must be pretty severe to be recognised
macroscopically; the cut surface is then somewhat dry. The affection
has its seat in the arterial sheaths and the Malpighian bodies; and in
this organ also one can in good preparations definitely recognise the
position of the bacilli in the cells (_Plate VIII, Fig. 5_).
The glands in the hilum of the liver are, when that organ is affected
with leprosy, definitely leprous, and the affection of the glands is
often more evident than that of the liver itself. In the hilum of the
spleen we have once or twice found leprous lymph glands.
This leprous affection of the glands is macroscopically very readily
recognisable. The glands are swollen as a whole, without any alteration
in their form. On section, one sees the ampullæ and the medullary
cords of a yellow or yellowish brown colour; this colour gives to
the glands such a characteristic aspect that they can hardly be
mistaken. The affection is best studied on the inguinal glands, and
the retro-peritoneal ones in connection with them. The lowest inguinal
gland is always most swollen, reaching sometimes to the size of a
pigeon’s egg; the ampullæ and trabeculæ are coloured throughout a deep
yellow; but the somewhat thickened capsule and the connective tissue
framework have retained their greyish semi-transparent appearance, so
that the structure of the gland stands out very clearly, especially if
the lymph sinuses are injected with blood pigment, which is sometimes
the case when there have been peripheral hæmorrhages in the nodules.
As we advance upwards the glands are gradually less swollen, and the
yellow colouring of the ampullæ and trabeculæ less intense, and one can
further follow in the retro-peritoneal glands a gradual diminution of
the affection until, about the level of the kidney or rather higher,
normal glands are once more met with. The glands are permeable, but
penetration is evidently more difficult, for the lymph vessels leading
to them are dilated, especially those of the lowest and most swollen
glands.
With great patience and moderate pressure one can succeed in
artificially injecting the lymphatics without causing extravasation.
It may even be the case that only one, or at most one or two ampullæ
are affected. Microscopically the ampullæ and trabeculæ are found more
or less filled with brown bodies or globi. These are evidently lymph
cells which have become filled with bacilli and their degenerative
products--granules.
One could hardly have a better demonstration of the functions of
the lymphatic glands, as filters, than in these leprous glands. The
circulation through them is not arrested; nevertheless, the glands
retain the infectious product, and if it pass one gland it is arrested
and retained in the next. Sometimes the quantity of this infection is
so small that one or two ampullæ are sufficient to retain the whole
of it. This indicates that the circulation in the gland does not
take place exclusively through the lymph sinuses, but that the lymph
reaching the gland must at once enter the ampullæ. A similar process is
seen in tubercular lymphatic glands, in which one often finds only one
or one or two ampullæ infiltrated with tubercle.
In the nerves the bacilli are found partly in round cells, which lie
around the vessels and between the nerve fibres, and partly in the
cells of Schwann’s sheath; here also they break down into granules, and
in time completely disappear. The finer details of the affection of the
nerves are best studied on the ciliary nerves when the eye is affected,
because there one can examine the finest nerves without cutting
sections or putting them through any manipulation which might injure
them. One often sees the myelin sheath pressed in by bacilli or cells
filled with granules (_Plate XII, Fig. 2_), and one finds nerve fibres
without a myelin sheath and with a more or less atrophic axial cylinder
(_Plate XII, Fig. 1_). These drawings clearly explain how the pressure
on the axial cylinder at first causes pain, and later, when atrophy has
set in, anæsthesia. And one can also understand that when the leprous
affection passes off without complications, the axial cylinders are
again restored and become functionally active.
But on those places above referred to, where the nerves run
superficially over bones or joints, and are exposed to pressure and
stretching, secondary inflammation is added to the process.
While the primary leprous affection hardly appreciably thickens the
nerves, the secondary inflammation causes a very marked thickening.
The ulnar nerve at the elbow may attain a diameter of 7 to 8 mm. or
more, and when the secondary inflammation disappears the connective
tissue contracts, and the previously thickened nerve becomes thinner
than normal. This whole process usually advances very deliberately,
and years are required before anæsthesia is developed to its full
extent. While the section of the thickened nerve is quite smooth and
of a pale brown colour from the numerous globi present, the section of
the atrophic nerve, though also smooth, is as pale as the section of
a tendon. It consists almost exclusively of connective tissue; every
trace of bacilli has disappeared, and one sees hardly a suggestion of
nerve fibres. The leprous affection is healed, but only a completely
functionless rudiment of the nerve remains.[4]
[4] Just as the manuscript of this treatise was completed, a year
and a half ago, we obtained at an autopsy a lung in which there
was tuberculosis, but at the same time probably leprosy also. Most
unfortunately the bronchial glands were not preserved for microscopical
examination. Dr. Lie also permits me to state that he has found leprosy
bacilli in two kidneys and in one lung. He had diagnosed tuberculosis
of the lung, but at the autopsy he found only an indurating pneumonia,
containing lepra bacilli, and no tuberculosis. In the kidneys, of
the same case, he found lepra bacilli in the glomeruli, and in the
interstices between the cortical tubules. He will describe the case
more fully later. This is a mere preliminary note.