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ON THE RELATIONSHIP BETWEEN
INFLAMMATION AND SUNDRY
FORMS OF FIBROSIS.

J. GEORGE ADAMI, M.A., M.D. (Camb.),

Professor of Pathology, McGill University,
Montreal.

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BEING THE MIDDLETON - GOLDSMITH LEC-
TURES FOR THE YEAR 1896, DELIVERED
BEFORE THE PATHOLOGICAL SOCIETY
OF NEW YORK, AND REPRINTED FROM
THE MEDICAL RECORD OF MARCH 14TH
AND 21ST, AND APRIL 4TH AND iith.

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New Youk: The Publishers' Printing Company, isae.

'":\:i^<

MIDDLETON-GOLDSMITH LECTURES '—ON
THE RELATIONSHIP BETWEEN INFLAM-
MATION AND SUNDRY FORMS OF FI-
BROSIS.

By J. GEORGE ADAMI, M.A., M.D. Camh.,

PROFESSOR OF PATHOLOGY, m'gII.I. UNIVF.KSITV, MONTREAL.

Mr. President and Gentlemen: I cannot proceed
to the delivery of these lectures without in the first
place extolling the beneficence of him throucjh whose
regard for this society and generosity it has been
made possible for you to institute this series of lec-
tures — of him whom thus you are bound to keep in ever
green remembrance. And in the second place I owe
it not only to you but to myself to give utterance to
my very sincere gratitude for the honor done me in
inviting me to attempt to fill a position in which al-
ready the great pathologists of this continent have one
after the other added new leaves to their laurels. For
myself I cannot hope to vie with my illustrious pre-
decessors. I can but exceed them in appreciati n of
the honor done to me, and through me to the city • nd
university of my adoption. I feel acutely your kind-
ness in thus inviting to deliver these lectures one
who is a stranger among you, one who as yet can
scarce feel himself other than a stranger to this con-
tinent. For my university it does not need that I should
be specially empowered to announce to you how, striv-
ing toward higher things, that university appreciates
and is encouraged by every act of recognition from
the larger world.

It might, perhaps, sir, be expected by that larger

' Delivered before the New ^'ork l\'itliological Society.

world that I should here make due and telling refer-
ence to my presence among you at the present epoch,
I am inclined to think that when the universality of
science and our common brotherhood in it are so ob-
vious to all of us, and the insistence thereupon is to us
so much of a truism, it were almost an insult to your
intelligence and good will did 1 say anything, how-
ever much I may personally appreciate your kind in-
vitation at this especial juncture. The most I dare
venture is to express the fervent wish that the same
fellowship may bind together the nations which now
unites all those striving after good works in all branches
of science.

Throughout the days of this generation, and to an
increasing extent in these latter days, there has been
and there continues to be a lively discussion as to
what is and what is not to be included in the scope of
inflammation. And as of late among a narrow sect of
surgeons or surgical pathologists there has been mani-
fest the revival of what, were I a theologian, I should
denominate a (not unqualified) heresy, but what, as a
pathologist, I prefer to describe as, in my opinion, a
serious misconception, I have thought it well, not only
from the interest excited by the subject in our body
but also from the recrudescence of this misconception,
to select as the subject of these lectures this matter of
inflammation and the relationship existing between it
and fibrosis or fibrous hyperplasia in its various forms.

Even at the best this is a subject involved in diffi-
culties. How involved I did not wholly realize until
some months ago I was called upon by my friend.
Prof. Clifford Allbutt, of Cambridge, England, to dis-
cuss the matter succinctly in the course of an article
upon the " Pathology of Inflammation in General,"
and was forced to face the matter straightly. As I
doubt not, most here present have found it is one thing
to have general opinions, another to place them in

■i

logical sequence upon paper. When I came to at-
tempt the latter, and again lo consult the accounts
given in the leading articles and text-books, I discov-
ered not only the inconsequential nature of many of
my previous views but also that most of what had al-
ready been written read like the writing of scribes
rather than of those having authority; and after having
written the article or section of an article alreadv re-
ferred to I cannot but feel that what is there stated
merits the same reproach, and since the manuscript
left my hands the more I have deliberated the more
dissatisfied have I felt over my own writing. I am
glad to have this opportunity to revise and advance
my views upon the subject, and even before the article
in question is published to amend it and carry to a
more logical conclusion the treatment of the princi-
ples upon which the article is based. I cannot hope
to solve all or any of the problems that a study of this
relationship between inflammation and fibrous-tissue
growth opens up; at most, suggesting rather than dic-
tating, I may possibly help others toward solution and
may indicate the lines along which future research
would seem to promise satisfactory results.

We are accustomed to employ the termination " itis"
with the prefix "chronic" in almost if not quite every
case in which there is replacement of the cell ele-
ments proper of a tissue by new fibrous-tissue growth.
That is to say, we assume all these conditions to be of
like origin, to be manifestations of chronic inflamma-
tion, or as the attempt at repair following upon acute
inflammation.

Fibroid areas in the heart muscle are all grouped
together under the convenient term of chronic inter-
stitial myocarditis. Fibrosis of the valves of the
heart with its sequelae we speak of as chronic endo-
carditis. Arteriosclerosis is indifferently spoken of
as chronic arteritis or endarteritis. Whatever the
form of fibroid change occurring in the kidney, it

comt's under the hca(lin<j; of chronic interstitial ne-
piiritis. In the case of tlie liver it is true the conven-
iently non-committal name of cirrhosis is in Knglish-
speakinj; countries the term most usually employed to
denote libroid chan^je, yet there are not wanting those
who speak of chronic interstitial hepatitis.

1 might similarly pass in order organ after organ
of the body, with its chronic "-itis." Lax indeed is
the employment of this common denomination of
chronic inflammation, and its sole merit is its conven-
ience in cloaking our ignorance of the exact causa-
tion of most of the conditions to which it is applied.
In these lectures I wish to discuss how far and in
what cases we are justified in the employment of the
term, and to what extent the development of fibrous
tissue in the more noble organs of the body is the re-
sult of inrtammatory disturbance.

In such a discussion everything depends upon the
definition of inflammation which is found acceptable,
and the conclusions reached must stand or fall in the
exact ratio in which the definition enunciated com-
mends itself to other workers. Thus, first, it will be
absolutely necessary for me to state clearly and dis-
tinctly what I understand by the term " infiammation."

Two courses, it seems to me, and only two are open
to us with regard to our appreciation of the term.
Either we can, with Thoma, agree that it is so unsat-
isfactory and that the discussions which have arisen
as to its scope, or, more truly, as to the processes that
are rightly to be included under the term, are so bar-
ren and profitless that we decide absolutely to expunge
it from our vocabulary; or, on the other hand, we
must determine to include in our idea of inflamma-
tion all processes having a like origin and tendency.
There is no logical intermediate course unless it be
to confine the term strictly to its primitive meaning
and to determine that there can be inflammation only
where there is "flaming," where there is redness and

heat. No one is prepared nowadays to take this
course, for this necessitates physiol()p;ical active con-
<j;estion of a superficial or^an being considered as in-
Hamniatory. Sfor ajjain are there many who, wedded
to' tradition and cardinally virtuous, with Celsus only
see inHanimation when rubor, calor, dolor, and tumor
are present. For these cannot deny that identical
processes may occur when one or two or more of these
cardinal symptoms are wanting. Thus, nowadays,
those who would define inflammation etymologically
are non-existent, while the partisans of tradition are
" minished and brought low," forming a small and an
impossible remnant. Hence, to return to my previous
statement, there are but two logical courses open to
us. Can we accept the first alternative and banish
the idea of inflammation? I trow not — the suggestion
is too quixotic. It is not within the power of any
workers in any one branch of our science, even if that
branch be pathology, to expunge at will a term of uni-
versal employment, a term that has come down to us
through the ages — a term which, however loosely and
variously employed, does nevertheless for all cover a
greater or less number of processes of common oc-
currence. We cannot in a widespread science sud-
denly create a "tabula rasa" and start anew. Just as
were we to do away with the plutocracy and start
equally endowed with worldly possessions, while in
twenty years the old plutocratic families would per-
chance be non-existent as such, yet the amassing of
money and possessions in the hands of a few would
inevitably be manifested, so were we to banish "in-
flammation" from our vocabulary, in the same time or
even less some other word would be surely in common
employment to denote the same idea. It cannot be
done, and as a consequence the adoption of the second
alternative is our only practical course.

We have, that is to say, so to employ the term that
it will embrace all processes having a like origin and

like import. Thus, then, starting from the generally
accepted basis that the process is in its essence local
and that the prime cause of all inflammations is in-
jury to the tissues, if we are prepared to admit that one
common or allied train of results follows upon all in-
juries, we must as our provisional definition state that
inflammation is the series of changes constituting the
local reaction to injury.

This is to all intents and purposes Burdon-Sander-
son's definition and is that which for the last quarter
of a century has been most generally accepted. For
myself 1 cordially accept it as a good working defini-
tion ; but at the same time I cannot but consider that
the researches made since 1880 have materially added
to our comprehension of the phenomena associated
with the process and of their tendency, and permit us
now to acknowledge the import as well as the origin
of the process. Those researches have shown us that
a very definite meaning is to be attached to the main
vital processes which follow injury to a part. They
have proved that the accumulation of leucocytes in the
injured area is purposeful ; that, whether by intra- or
extra-cellular action, these cells are capable, up to a
certain extent, of counteracting the irritant and of re-
moving dead and effete material ; they have satisfac-
torily proved that the inflammatory serum possesses
both digestive and bactericidal powers greater than
the serum of the circulating blood; they have demon-

strated that the

migration

of the leucocvtes into the

inflammatory area is not a passive process, but an ac-
tive one directly dependent upon the extent of the
stimulus exerted upon these cells by chemical altera-
tions in their environment; thev have demonstrated
that the amount of fluid exuded into any one region
of the body varies inter alia directly according to the
intensity of the irritant — the more intense the irritant
the greater the extent to which it is diluted; while,
further, the part played by the fixed cells in the im-

mediate neighborhood is equally evident and equally
purposeful, tending manifestly to result in the cutting
off of the damaged area from the surrounding healthy
tissue and again to replace the tissue that has under-
gone destruction. Hence I am impelled to define in-
flammation as the local attempt at repair of injury,
or, more fully, inasmuch as there is a certain small
class of cases in which all the symptoms of inflamma-
tion are present as a consequence of nervous disturb-
ance wholly unassociated with previous local injury,'
as the scries of chcviges uiJiich constitute the local at-
tempt at repair of actual or referred injury to a part.
So that needless objections be not raised, let me em-
phasize the fact that I do not regard inflammation as
synonymous with repair. Attempt at repair and repair
are two very different things, and no more to be con-
founded than attempted suicide and suicide, or, not
to approach too closely to a very delicate subject, than
the Emperor William's recent telegram to the Boers
and actual war between two considerable European
nations.

This, then, is the definition I am inclined to lay
down. Save in the small matter of the wording, I do
not claim any originality, for others in different lands
have given forth definitions embracing the same idea.
Thus Neumann, in Germany, defines inflammation as
'" the series of local phenomena which are developed
in consequence of primary lesions of the tissues and
which tend to heal these lesions." '" Bland Srtton, in
England, is somewhat more restricted. '' It is," says
he, "the method by which an organism attempts to

' The most striking example of this class is to be seen in the
experiment which has been frequently repeated, among others by
my colleague, Dr. James Stewart, of assuring a susceptible in-
dividual under hypnotic influence that the hand or other region
has been burned or blistered, when within a very short period
the part becomes reddened, swollen, and, it may be, the seat of
marked serous effusion.

■■'Ziegler's "Beitriige," v., 1889, p. 347.

render inert noxious elements introduced from without
or arising within it." ' I doubt whether Sutton is
right in speaking of it as a method and to me the
larger view appeals, not simply of counteraction
against the irritant but also of attempt to bring about
a return of the region toward a functional condition —
but the definition contains the same recognition of the
purposive nature of the process. And lastly, here at
home, Councilman acknowledges the same. In his
most lucid article in Dennis' " System of Surgery" he
defines inflammation as " the sum of the phenomena
which take place in the tissue as the effect of an in-
jury. The object of these various phenomena is to
overcome or to diminish the effects of the injury." "

Whatever justice there might have been a few years
ago in the objection that this view of inflammation is
teleological, now, with the facts at our disposal, the
objection is no longer valid. As well may the state-
ment that the function of the heart is to propel the
blood into the arteries be condemned as teleological,
or objection be taken to the statement that digestion
is the series of processes whereby matters received
into the alimentary tract tend to be converted to the
uses of the tissues of the body. We are ready enough
to admit the deductions drawn from physiological ex-
periments; we must equally accept the results of ex-
perimental pathology.

But the definition here enunciated is altogether too
broad for many to accept, and ever since Hiiter pro-
pounded the view that the term inflammation ought to
be restricted to those conditions in which there is in-
fection by micro-organisms, with pus formation, there
have not been wanting adherents of the narrower view.
And as what is to follow must largely stand or fall ac-
cording to the acceptance of the definition herein set

' I here quote from Professor Senn, not having been able to
discover the original passage.

'■^Dennis' "System," vol. '., 1895, p. 144.

forth, and inasmuch as this confounding of infection
and pyogenesis with inflammation appears to be grow-
ing more and more popular upon this continent, I
needs must for a short time discuss the propriety and
soundness of the movement.

I do this, sir, with some hesitation, for I feel that
I am reverting to very elementary pathology; never-
theless it is just because the matter is so elementary,
so fundamental, so all-important for a right compre-
hension of all pathology, and because the distinction
with which you have honored me affords an almost
unique opportunity for calling attention to this mat-
ter, that I make bold to utilize this opportunity to
urge a broad and logical consideration of the subject.
Dr. Senn, professor of the principles of surgery in
the Rush Medical College, Chicago, whose writings
have obtained a wide circulation and whose influence
in the North and West perhaps transcends that of any
other surgeon, states in his " Principles of Surgery"
that inflammation, in the widest and most comprehen-
sive meaning of the word, should be made to embrace
pathological conditions which are caused by the action
of pathogenic microbes or their ptomaines upon the
histological elements of the blood and fixed-tissue
cells, and that " true inflammation is always caused by
the presence of one or more kinds of pathogenic mi-
crobes," a statement which, it may be added in paren-
thesis, does not prevent him from employing figures
from Hamilton and others to illustrate the stages of
the process, although those figures represent the re-
sults obtained by the use of chemical and not bacte-
rial irritants.

Dr. Roswell Park, professor of surgery in the Uni-
versity of Buffalo, in a straightforward address read
before the American Surgical Association in May of
last year ' is inclined toward the same opinion, and, as
he at the onset especially invites kindly criticism, I
' Mp:dical Ri'XORi), New York, i., 1895, p. 705.

may say that his challenge has perhaps more than
anything else led me to take up the subject here. He
urges first the revolutionary thesis that the combina-
tion of the four cardinal symptoms should not be re-
garded as indicating inflammation. We should dis-
miss from our minds the associated idea, and should
refer to the redness and heat as hyperaemia, the swell-
ing as exudation, the pain as the result of pressure.
Only when these become developed or modified by
the growth of micro-organisms in an injured area or
by the action of their products should we venture to
speak of inflammation. And the term should then
comprise not only the local but also the general effects
produced by the growth of the micro-organism. In
fact, the existence of these general effects (as, for ex-
ample, the rise of bodily temperature associated with
the appearance of a small furuncle upon the nose) is
given as a distinction between what Dr. Park regards
as true inflammation and the non-inflammatory reac-
tions of the tissues to non-microbic lesions.

While epitomizing Dr. Roswell Park's argument, I
believe that I have accurately stated his main con-
tentions.

Let us see what is the logical outcome of this idea.
First and foremost the frequent association of redness,
swelling, heat, and pain which may result from mi-
crobic invasions of the body is not in itself to be re-
garded as symptomatic of inflammation. The associ-
ation is common to microbic and many other lesions.
Only the extension of this series of symptoms in
special directions under the continued influence of
bacterial irritation is to be considered as inflamma-
tory; or, to carry this view to its logical conclusion,
the surgeon must no longer depend upon the presence
of cardinal symptoms; he must only call a region in-
flamed when he has either personally or through a
bacteriologist determined the existence of bacteria
therein. There is no attempt made by Dr. Roswell

1 1

Park to limit inflammation to pyogenvjsis, and while
this view of inflammation for surgical purposes, in
the main, undoubtedly separates suppurative from
other lesions, it is in the terms of this definition im-
possible to regard suppuration in itself as an inflam-
matory manifestation, simply because, as is well
known, suppuration may be induced by caustics and
severe chemical and physical irritants, apart from the
action of bacteria. As above stated, the bacteriologi-
cal is to become the sole sufficient test of inflamma-
tion. While it is true that the general adoption of
this view would result in rendering it absolutely neces-
sary that every general practitioner should continually
practise himself in elementary bacteriology, or else
should banish the term inflammation from his diag-
nostic vocabulary — a not undesirable consummation,
it may be — I cannot but fear that the general practi-
tioner will still continue to speak of the inflammation
of scalded surfaces, of black eyes, and of fractured
limbs; for he will still require some useful and gen-
erally accepted term to embrace the train of symptoms
following upon every-day injuries. This attempt on
the part of members of one branch of our profession
to delimit our idea of inflammation largely for practi-
cal purposes must fail when put into practice.

Or let us examine the proposal from another side.
"Without infection," says Dr. Roswell Park, "no
genuine inflammation; with infection, inflammation
and, what always goes with conflagration, more or less
destruction. Congestion and exudation provoke little,
ordinarily no constitutional symptoms; inflammation
always does. ... I would," he states later (after
discussing hypera^mia, congestion, and " cirrhotic"
changes) " in an entirely distinct chapter and in an
unmistakably separate way, take up the matter of in-
flammation — />., infection." To all intents and pur-
poses Dr. Roswell Park would substitute a word
which, I think most will agree, has wisely been re-

s^''ictecl to local disturbances for a word which has
snown itself most useful as indicating the changes
which may occur in the organism at large in conse-
quence of microbic invasion. Up to the present time
inflammation has been understood to indicate the local
changes following upon an injury; fever and infection
to indicate the more remote effects upon the organism
at large. And I am forced to point out to Dr. Ros-
well Park that in '' infection" he has a most useful word
which will indicate everything that he wishes to in-
clude in his restricted idea of inflammation, and, that
being so, there can be no valid reason why he should,
with those "big, merciless hands" attributed by the
late poet laureate to one of our surgical brethren, ap-
propriate a word to which can be given a wdder and at
the same time a more exact use. The terms " wound
infection," " local infection" and '* general infection,"
and " infective inflammation," are in common and sat-
isfactory employment and there can be little or no
doubt as to their meaning. I beg Dr. Park to con-
sider this before urging further the adoption of his
proposals.

But while one is only too glad to have a word " in-
fection" capable of covering the series of local and
general effects induced by the presence and growth of
micro-organisms within the body, its employment in
nowise tells upon the fact that every change in the
blood elements and tissues brought about by microbes
and their products may be induced by irritants of an-
other nature. While it is true that micro-organisms
frequently lead to pus production and that suppurative
inflammation is almost entirely induced by these
agents, it is equally true, as was first clearly proved
by Councilman, that sundry chemical substances can
occasionally set up an identical process. And as Leber
has shown, the purulent fluid produced by this latter
means has definite powers of breaking up and digest-
ing proteid matter; no clear distinction can be made

has

between the septic and the aseptic pus save that the
one is of microbic origin, the other not. A broad
idea of inflammation to include all like processes
throughout the higher animals must take cognizance
of these facts.

Nor again, may I add, is it possible to distinguish
one series of micro-organisms as essentially pyogenic.
To attempt this is to draw a line between human and
comparative pathology. While it is true that certain
forms in man are peculiarly liable to induce abscess
formation, those same forms by no means necessarily
exhibit the same liability in other animals, and even
in man they do not always lead to pus formation ; in
short, suppuration is the expression, not of the pres-
ence of certain specitip microbe*}, but of a definite
grade of intensity of irritation, or, in other words, it is
a phenomenon representing a certain ratio between
the virulence of the irritant and the resisting powers
of the organism. Increase the virulence of a micro-
organism or diminish the resisting power of the or-
ganism, and in members of the same species similarly
treated we may have every grade of acute inflamma-
tion, from local hyperremia and slight diapedesis of
leucocytes through local abscess formation, to spread-
ing sero-purulent cellulitis and general septicaemic
infection. Much has been done experimentally to
prove the truth of this statement, while the recent
work in the laboratories of this continent upon cases
of typhoid and gonorrhoea has abundantly shown how
micro-organisms which in ordinary are not pyogenic
can be the prime causes of abscess formation. Indeed
it may be said with some truth that the main bacte-
riological work of the past year has been in the direc-
tion of confirming this statement and in demonstrat-
ing in case after case this liability on the part of
bacteria ordinarily non-pyogenic to lead to abscess
formation.

If this be so and if bacteria can thus be the cause

of a series of reactive changes on the part of the tis-
sues, advancing by imperceptible gradations from the
simplest transient local inflammatory change up to the
most profound generalized septiceemic disturbance,
and if again, as all must admit, they can induce either
profound local destruction of tissues or well-marked
local tissue overgrowth, then surely it is impossible to
to separate the lesions produced by micro-organisms
from the parallel and identical series capable of being
produced by other noxce.

I trust, therefore, that I have made it clear that we
are compelled to range together the series of changes
induced locally in the tissues as the result of injury
under the common heading of inflammation, and this
irrespective of the nature of the irritant.

For pathologists in general, for those studying not
merely gross anatomical lesions but finer also, for
those dealing with lesions of internal organs as well
as with lesions having an outward manifestation, for
those whose pathology and study of medicine is not
confined to man and who strive to base their knowl-
edge of disease and its processes upon a study of the
same throughout the animal kingdom, no other course
is open and practical.

Following this train of thought it becomes evident
that we must regard as of inflammatory origin all those
changes in the tissues which we can prove to result
from direct injury to those tissues, whatever the na-
ture of the irritant, and which we can regard as tend-
ing toward repair. We can separate the various
degenerations of the tissues, for these form a well-de-
fined series of changes from the inflammatory lesions
proper; we may regard them as associated with but
not inherent in the inflammatory change.

Of these local attempts at repair the most durable
and, when the process has come to an end or when,
being of moderate intensity, it has continued for some
little period, the most evident is the formation of

fibrous tissue. Now, in studying this formation and
the broader subject of fibrosis ' in general, the first
point to be settled, one which will materially affect
our whole comprehension and classification of the
fibroses, is whether it is possible to distinguish be-
tween new connective-tissue formation which is di-
rectly the result of injury and that which is indi-
rectly the result, and if we can determine this we can
with greater freedom attack the question of the classi-
fication of the fibroses in general and can more surely
state which of them are to be considered of inflamma-
tory origin and constituting chronic " -itides," which
non-inflammatory.

The first question is one of peculiar difficulty, and
the problem presented for solution may perhaps be
best approached by a consideration of two widely
separated cases. A study of the various stages of the
development of a tubercle demonstrates that in man
and most mammals the first result of the lodgment and
growth of the tubercle bacilli in the tissues is to stim-
ulate tissue formation. Only at a later period, with
continued action of the products of the germs and as-
sociated disturbed nutrition of the central area of the
granuloma, does tissue destruction become manifest.
There is perhaps no better demonstration than this,
unless it be that afforded by lepra nodules, of injury
leading directly to connective-tissue growth.

On the other hand, we may consider the processes
which occur in the central nervous system following
upon atrophy and destruction of ganglion cells or

' Here let me state that I have no liking for this mongrel term
" fibrosis " ; nevertheless, I know of none which can satisfactorily
replace it. The terms ' ' sclerosis " and " cirrhosis "indicate only
the secondary consequences of fibroid overgrowth, and " fibrous
hyperplasia" is a little clumsy, while "fibrosis" undoubtedly
conveys clearly its meaning; and in its favor (although two blacks
do not make one white) it may be urged that in common usage
we have such other mongrel terms as *' fibroma," " fibro-enchon-
droma," and so on.

upon separation of axis-cylinder processes from their
trophic nerve cells. The results can best be seen
when the injury affects secondarily all the members
of an ascending or descending tract, and they are to
be summed up as consisting of degeneration of the
fibres forming the tract with replacement by fibrous
tissue. Here there has been no irritant circulating in
the lymph bathing the fibres and leading directly by
its action to their destruction. The degeneration and
atrophy has followed upon injury inflicted at a dis-
tance, an injury to another region of the body. If any
irritant be present it is of intrinsic origin. All the
same, we see that the atrophied fibres become replaced
by connective tissue.

Are we to regard this " replacement*' fibrosis as a
form of chronic inflammation.-* Against so regarding
it it can be argued that, as already stated, no specific
irritant of external origin can be adduced as having
acted upon the tract of degeneration, and that in case
after case where the degeneration has been gradual
none of the ordinary symptoms of inflammation are
recognizable, neither the coarser conditions of hyper-
nemia and exudation nor those finer ones of determi-
nation of leucocytes (though this phenomenon is at
times quite distinct), multiplication of capillaries and
other microscopical evidences of removal of destroyed
tissue, and active new growth. Almost imperceptibly
the atrophied nerve fibres are replaced by connective
tissue, and it may be that of all the accompaniments
of ordinary inflammation the sole distinguishable is
the "functio la^sa."

But there is another aspect of the condition that we
are forced to regard, and I may best approach this in-
directly. What satisfactory distinction, it may with
justice be asked, can be drawn between this more in-
sidious replacement fibrosis and the grosser replace-
ment occurring in the case of infarcts? In the latter
the normal course of events is, that, infective agents

as a

being absent, the necrosed area becomes surrounded
by a zone of hyperaimia, the dead tissue undergoes
disintegration and absorption and is replaced by new
fibrous tissue. In such a case, it is true, we can rec-
ognize the distended peripheral vessels, the invasion
by leucocytes, the formation of new vessels, all the
main microscopical and most of the macroscopical
signs of inflammation. But, as in our previous exam-
ple, no extrinsic agent has set up the disturbances.
It is difficult, indeed impossible, to arrive at any other
conclusion than that the products of necrosis act as
the irritant and that they must be regarded as the
cause of the inflammation and subsequent fibrous-tis-
sue development. It is competent for us to assume
the existence of a cryptic inflammation in the former
case, and to hold that a like cause, namely, tissue ne-
crosis, has led to a like effect, namely, fibrosis. And
indeed if we adhere to the definition of inflammation
that I have laid down, both of these cases of replace-
ment fibrosis so obviously represent the local attempts
at repair following upon injury to the tissues, that
unless we further define what is meant by injury
we are forced to regard them as equally of inflammatory
origin.

We see thus that two different types of fibrous-tis-
sue development, one hyperplastic, the other, as I have
termed it, replacement, may be of inflammatory origin,
and the more one examines into the subject the more
difficult is it found to recognize inflammatory fibroses
by their histological characters. While it is true that
in certain cases we have histological evidence of pro-
gressive inflammation — the presence of newly formed
vessels, of an increased number of extravascular leu-
cocytes and small round cells, and it may be of a cer-
tain amount of exudation — in cases of the same nature
at a later date all these signs may be wanting, and
again, in other allied cases, from the very onset both
microscopical and macroscopical indications of inflam-

miition may l)c peculiarly rare. We cannot depend
upon hisloloj^ical evidence alone. At the most
we can classify the various forms according to the
evidence in our possession as to their origin and
tendencies.

The considerations I have brought forward up to
this point would lead us to distinguish at least two
main types of fibroid change associated with inflam-
mation, one of which in default of a better name may be
termed productive, the other replacement, fibrosis. In
the former there is no causal relationship between the
amount of new connective tissue resulting from the
inflammatory action and the amount of tissue dis-
placed; in the latter the amount of new fibrous tissue
developed appears to be primarily governed by and
proportioned to the extent of the destructive process,
but both equally tend toward repair and arrest of in-
jury.

This division will, I think, be found useful, and it
will be seen that the leading forms of inflammatory
fibroid change are to be grouped under one or other of
these heads.

Under the first are to be included sundry localized
fibroses of which the main forms are the focal areas of
new connective-tissue growth induced by the presence
of certain micro-organisms, that is to say, the more
chronic or less acute forms of infective granulomata —
the new growths (tubercles) induced by the tubercle
bacilli, those (gummata) induced by the not surely
determined organism of syphilis, the fibroid nodules
caused by the presence of the leprosy bacilli, and, again,
the more chronic type of actinomycotic and glanders
lesions. Examples are not wanting of similar focal
areas of fibroid growth induced by simple irritation.
As such may, I think, be safely cited the earliest stage
tof one form of cheloid. Although, as I shall point out
later, cheloid growths must be included among the
fibromata, nevertheless, in many cases of what is some-

xr.

times termed and rejijarded as spontaneous cheloid,
localized connective-tissue growths can L<^ excited by
local irritation of the sui fj-^e. Mils was well ob-
served in a case which has recently been very fully
studied by one of my students, Mr. K. H. Martin. In
this, the mere scratching with a pin was sufficient to
give rise to the new growth. I am myself fullv pre-
pared to regard sundry cases of focal growth as non-
inflammatory — as due to stimulation rather than to in-
jury. The difficulty is that there is no line separating
the one from the otiier; there is no sharply defined
boundary between simple hyperplasia and that which
is obviously reparative.

Merging at times imperceptibly into the previous
group there are the capsular fibroses, comprising
those cases of connective-tissue development induced
around an irritant, whether infective or not. Here
the zone or capsule of tissue formation is a develop-
ment of so much new material, laid down, it would
seem, irrespective of previous tissue destruction in the
immediate region of its appearance. Examples of
this form will be immediately called to mind. Among
the infective we have the thick capsules forming
around obsolescent tuberculous masses, around chronic
abscesses and phthisical cavities; among the simple
irritative are to be classed the capsules developed
around such foreign bodies as exercise little more
than a mechanical irritation, whether those bodies be
solitary and of large size, as, for example, impacted
bullets, or minute and very numerous, as inhaled
particles of coaly or silicious matter. Whether the
capsules formed around and merging into the frame-
work of benign tumors are to be classed as of simple
irritative or of infective origin may possibly give rise
to debate; provisionally I must refer them to the
former class.

Another type of productive fibrosis, one that can-
not satisfactorily be classed either as localized or

iiiii

generalized, is that due to inflammation of serous
surfaces, a form including the fibroid thickening of
serous superficies and organized inflammatory ad-
hesions.

Besides these, there exist also generalized produc-
tive fibroses of inflammatory origin, which again may
either be of infective origin (induced by bacteria or
their products) or the result of continued non-infec-
tive irritation. The chronic interstitial pneumonia
following upon subacute pleurisy may be cited among
the former; among the latter, in all probability, the
generalized interstitial fibrosis of so-called chronic
parenchymatous disease, of which a good example is
afforded by the condition of productive parenchymatous
nephritis. But, as I shall have later occasion to point
out, some forms at least of interstitial fibrous over-
growth are rather to be counted among the replacement
than among the productive forms.

The local and general forms may merge, the one
into the other. Thus, a liver presenting gummata
may exhibit also well-marked generalized interstitial
fibroid overgrowth; a kidney the seat of chronic tuber-
culosis may show the same; or again, in the inhalation
pneumonias the deposit of foreign particles along the
lymph spaces of the lungs may be so extensive and
the growth thereby excited be so great that the organs
present the characters of a generalized interstitial in-
flammation. Nevertheless, the distinction between
local and general is in the main useful and not
pedantic.

To turn now to the replacement fibroses; among
these we can distinguish certain well-defined types.
All may in truth be termed cicatricial, but it may be
well to restrict this designation to the ordinary surgi-
cal cicatrix, to the connective tissue developed after
breach of continuity in a part. Speaking broadly, it
may be said that every such breach of continuity re-
sults in the destruction of a certain number of cells.

.1 !

serous
ning of
)ry ad-

produc-

in may

eria or

n-infec-

;umonia

1 among

lity, the

chronic

mple is

ymatons

to point

as over-

acement

the one
^ummata
terstitial
ic tuber-
halation
long the
live and
s organs
itial in-
between
and not

among
d types,
may be
■y surgi-
ed after
Dadly. it
luity re-
)f cells,

and that in the absence of infective agents the new
connective-tissue formation maintains a definite rela-
tionship to the amount of previous destruction, never
exceeding it. Very closely allied is the development
following upon the complete and sudden necrosis of
all the elements of a tissue; of this, as previously
hinted, a most satisfactory example is seen in the heal-
ing of a simple infarct.

If we, following what is not unusual nowadays, re-
gard the blood as a tissue, the organization of thrombi
must be placed under the same heading of fibrosis fol-
lowing tissue necrosis; if we are more conservative in
our employment of the term " tissue," we must regard
the gradual substitution of the coagulated and ne-
crosed blood by fibrous tissue as a closely allied phe-
nomenon, namely as a fibrosis occurring in and re-
placing a necrotic mass.

Associated with these we can recognize two other
forms. I would not insist upon their separation, but
there is a slight difference in their mode of origin.
In the one the essential cause of the death of the
cells is local, from impaired nutrition, in the other
the nobler elements of the tissue undergo atrophy
and death irrespective of local conditions. The
two forms may be termed dystrophic and atrophic
respectively.

Of the atrophic I have already furnished an exam-
ple, namely, the sclerosis following degeneration of
ascending or descending nerve tracts. Of the dys-
trophic the heart furnishes the most frequent exam-
ples, though I am inclined to regard much of the
fibroid change seen in the senile kidney as of the
same nature. As M. H. Martin ' was, I think, the
first to point out explicitly, and as Weber'" has shown
in a very careful research, where there is an "obliter-

' II. Martin: Kevue de Medecine, May, iS8i.
- A. Weber: " Contributioii a I'Etude Anatomo-patholoj^iciue de
rArterio-sclerose du Coeur," Paris, Steinheil, 1887.

2 2

ating endarteritis" of the coronary vessels with over-
growth of the intima and consequent diminution of
the lumen, there must result a diminished nutrition of
the area supplied by each affected artery or arteriole,
and as these are of the nature of end arteries there is
developed no satisfactory collateral nutrition. The
result affords a very striking picture, more especially
if the most frequent seat of the change be examined,
namely, one of the papillary muscles of the left heart.
In these the fibres run longitudinally and so also, en-
tering at the base, do the nutrient arteries, and the
condition is so common that I have never had diffi-
culty in obtaining material for my class in morbid
histology. In a typical fairly advanced case in trans-
verse section of the muscle, the arterioles with thick-
ened intima are seen cut transversely; around each
is a zone of fairly healthy fibres also cut transversely.
Passing outward from the artery these give place to
fibres that present atrophy and pigmental degenera-
tion with intermingling of new connective tissue,
while the outer zone of supply of the arteriole is rep-
resented by a ring of clear, transparent fibrous tissue
with relatively few nuclei and here and there the last
remnant of a degenerated muscle fibre. This, I may
remark, is but one form of cardiac sclerosis. It
would be difficult to find a more demonstrative case
of this dystrophic replacement fibrosis.

But while thus we are able to recognize examples
of the uncomplicated occurrence of one or other form
of inflammatory fibrosis, and while I hold that it is
useful to us both as students of medical science and
as practical physicians and surgeons to seek to ana-
lyze the nature and character of every morbid change,
it has to be admitted, if we look honestly at things as
they are, that case after case presenting itself to our
notice cannot possibly be docketed and pigeonholed
under one heading. Time and again we come across
what can only be classified as mixed forms of the

conditions already indicated, not to mention mixture
of these with fibroid conditions which I have still to
take into consideration. I can only urge that it is
well to strive to cultivate our garden and not to allow
our ideas of chronic inflammation to continue a riot-
ous and tangled growth. Only by such cultivation
can we hope to gain good fruit.

It is when we come to study the chronic inflamma-
tions affecting glandular organs that our great diffi-
culty begins in comprehending the essential nature
and causation of connective-tissue growth. Let us
take the commonest case, namely, that of continued
parenchymatous inflammation. Here the first obvious
disturbance in the tissue is an affection of the glan-
dular cells. With this there is an accompanying con-
gestion of the interstitial vessels, and this gives place
eventually to a condition in which the collections of
gland cells are separated from each other by increased
connective tissue, while coincidently the gland cells
themselves show signs of atrophy. Two conditions
might produce this picture: either the atrophy of the
gland cells might be primary and the increased fibrous
tissue an indication of replacement fibrosis; or, on
the other hand, the picture might indicate, as is usually
held, a productive interstitial fibrosis with the malnu-
trition and atrophy of the gland cells as a secondary
consequence of irritation, impaired nutrition, and
pressure exerted by the new-formed tissue combined.
It is only by a very full and cautious observation that
it is possible to arrive at a decision in any given case
as to which form of fibrosis is represented and often,
indeed, one is induced to take the middle course and
consider both in operation.

If, for example, we study the various forms of cir-
rhosis of the liver, both experimentally and by histo-
logical examination of various cases, this difficulty is
very forcibly borne home to us. We can occasionally,
it is true, make out with certainty the existence of a

■«■

productive fibrosis; thus we frequently meet with
what appears to be the earliest stage of ordinary so-
called alcoholic cirrhosis, in which we observe small
masses of small-celled infiltration along the portal
sheaths. The condition looks definitely productive;
it appears to be an inflammation around the interlobu-
lar branches of the portal vein, and the cells in the
immediate neighborhood of these accumulations show
no very decided signs of degeneration and atrophy.
We can, again, as is occasionally the case in early
stages of biliary obstruction, find the bile ducts en-
larged and dilated and surrounded each with new con-
nective tissue, so that the picture given is that of a
productive inflammation immediately around these
ducts. We can also, more frequently than is usually
recognized, make out signs of fibrous-tissue over-
growth around the branches of the hepatic artery ; out
of eighty-eight post-mortems performed during last
year, I found this periarteritis to be well marked in
six cases; but in advanced cases of ordinary cirrhosis
of the atrophic type it seems to me more than doubt-
ful whether malnutrition of the cells does not become
an important factor and their atrophy be not followed
by replacement fibrosis, rather than be the result of
pressure and encroachment of the newly developed
connective tissue.

In this connection it is interesting to note how the
majority of observers who have attempted experi-
mentally to induce cirrhosis of the liver have noticed
changes of a degenerative character in the hepatic
cells as a first effect of irritation rather than produc-
tive inflammation in the interstitial substance. This,
of course, is what might be expected, the nobler cells
of the tissue being the more sensitive. I merely draw
attention to it because it is so common to regard
hepatic cirrhosis as primarily an interstitial distur-
bance. I do not wish to give the impression that
this may not be so in certain cases ; very frequently,

t with
ary so-
small
portal
Lictive;
srlobu-
in the
show
rophy.
early
cts en-
w con-
at of a
these
isually
over-
:y; out
ig last
keel in
rrhosis
doiibt-
)ecome
llowed
suit of
eloped

ow the
ixperi-
loticed
lepatic
roduc-
This,
r cells
^ draw
regard
iistur-
n that
lently,

I feel as sured, it is not. I need but remind you
how strongly the recent studies by Flexner ' uphold
this view.

Here I may briefly refer to certain studies which
have occupied me during the last two years upon the
causation and nature of a very remarkable disease
affecting the cattle in a limited region of Nova Scotia,
the so-called Pictou cattle disease. I do not wish
here to publish a detailed and circumstantial account
of my observations, for to do so would not be just to
Professor Welch, to whom I have promised my com-
pleted paper upon the subject. I may, however, re-
peat what is stated in my reports to the Dominion
government, namely, that the disease is of an infec-
tious nature and due to a minute bacillus, character-
ized, as are so many of the pathogenic micro-organisms
of lower animals, by an intense polar staining, so that
frequently it has the appearance of a diplococcus
rather than of a bacillus.

The disease is apparently of slow onset; the affected
cattle eventually suffer from an abundant dark-colored
diarrhcea, present a moderate amount of ascites, fail
to give milk, and then the end is ushered in either by
a condition of violent excitement or by progressive
muscular weakness.

At the post-mortem the most characteristic features
are the ascites, a remarkable submucous oedema of
portions of the intestine (I have seen similar submu-
cous cedema in cirrhosis of the liver in man), enlarge-
ment of the abdominal lymphatic glands, and a very
extensive cirrhosis of the liver. It is in the lymph
glands and the hepatic cells that the bacilli are pres-
ent in greatest abundance.

The cirrhosis is generalized and of the pericellular

type, and if the livers from a large number of cases

be examined the earliest stages would appear to be

those of swelling and vacuolation of the hepatic cells

M^lexner: Medical News (Phila.) , ii., 1894, p. 116.

with great irregularity in the size of the nuciei.
There may be great congestion of the hepatic (venous)
capillaries, but this is unaccompanied by any notable
small-celled infiltration. Following upon this stage
of swelling, the hepatic cells undergo atrophy, sundry
lobules and portions of the liver showing the process
at a more advanced stage than do other portions.
And this process may be so extensive that over large
areas of the organ only isolated liver cells or clumps
of three or four degenerating cells are to be recog-
nized. With this the organ is not diminished, in-
deed the edges often tend to be slightly rounded and
full; there is replacement of the degenerating cells
and lobules by a delicate somewhat oedematous con-
nective tissue. A characteristic of this new tissue is
the relative absence of the ordinary signs of produc-
tive inflammation in the shape of small round cells.
Of these there are a few, but very few ; more frequent
are small irregular cells, evidently degenerated liver
cells and others of the " spider-cell" variety, with
fairly numerous delicate processes.

In short, the impression gained by studying nu-
merous sections obtained from many animals dying
in different stages is that there is here a primary irri-
tation or overstimulation of the hepatic cells by the
bacilli, followed by an atrophy of the same and coin-
cident replacement fibrosis. I will not say that this
replacement fibrosis is the only form of connective-
tissue hyperplasia present in these cases; there are
occasional indications of productive change. But it
is, I feel assured, the main form present.

This generalized pericellular cirrhosis is, of course,
not strictly comparalDle with the more usual foiais of
hepatic cirrhosis met w-ith in the human being. I:--
interest lies in this, that occasionally, more especially
in children, we observe a curiously similar condition
of the liver without any clear evidence of syphilis,
and in children also the victims of congenital syphi-

si
b
s:

P
o

n
tl

stage

in-

d and

cells

con-

sue is

roduc-

cells.

jquent

liver

with

I:^

lis, even as to a less extent in adults presenting tertiary
syphilis, we are apt to meet with a more or less exten-
sive pericellular cirrhosis. In such cases it may well
be that the cirrhosis is of like origin, due, that is to
say, to the direct irritation of the hepatic cells by
pathogenic bacteria or their products, to the atrophy
of these cells and their replacement by delicate con-
nective tissue.

Thus far, therefore, we have been able to recognize
the following forms of fibrosis of inflammatory origin :

A. " I'roductive" fibroses.

(i) Localized -, ^ ',
^ ' / capsular,

, , , , 1 n • i local.

(2) Serous and adhesive • ,
^ ' I general.

(3) Interstitial,

li. " Replacement " fibroses,
(i) Cicatricial.

(2) (rost)-necrotic,

(3) (]^ost)-alrophic.

(4) (I'osti-dystrophic.
C. Mixed fibroses.

But this classification does not nearly include all
the examples of connective-tissue overgrowth and scle-
rosis occurring in the organs of the body.

One further group of cases may at first sight appear
to be sharply defined, namely, the group of the true
fibroid neoplasms, the fibromata proper. Neverthe-
less, a study of the forms usually included in this
group reveals the fact that there has been in the past
not a little confusion as to what constitutes a fibroma,
and an attempt to classify the various forms cannot
but lead to the conclusion that the line separating in-
flammatory new formation from fibroid neoplasms can
be drawn only with a cautious hand.

As I have pointed out, one result of irritation may
be overgrowth of connective tissue. Ordinarily this
appears to be not greatly in excess of the needs of the
injured area, nevertheless at times it exhibits itself

■ft

greatly in excess of these needs. When infective
agencies interfere with the normal course of cicatri-
zation of a wound and the healing becomes delayed,
when, in short, superadded to the normal tendency for
fibrous tissue to be developed so as to repair a wound
there is a stimulus to connective-tissue proliferation
from the presence of b?i:teria and their products, then
it would appear that fibrous tissue may be developed
in excess of the requirements of the part. This
"false" cheloid, it is clear, originates primarily after
inflammation, and we may have every gradation from
what may be regarded without second thought as re-
dundant cicatricial tissue up to what, from its con-
tinued and very extensive growth, it is difficult to re-
gard as other than a frank neoplasm. Another form
I have already referred to, namely, the " spontaneous"
cheloid developing where there has been no breach of
continuity of the tissues. On this continent among
the colored population (and the negro appears to be
peculiarly prone to be affected) cases have been re-
corded in which the new formation has attained enor-
mous proportions.

As an example of so-called spontaneous cheloid let
me here briefly describe the case already referred to,
studied by Mr. R. Martin, for it throws light upon
sundry important features in this class of tumors.
The patient was a French Canadian girl, aged twenty,
who had always been healthy until about four years
ago, when she noticed a very small growth which
looked like a little pimple on her left shoulder. This
gradually enlarged and in about a year began to be
painful, causing sharp, stinging pains. At the end of
two years it was two inches long and three-quarters
of an inch wide, and was then removed by the knife.
About three weeks after the operation it recurred and
became as large as before. An operation four months
later was again follow^ed by a recurrence. Three or
four months later it was removed "■ by means of a

m^.

plaster." It has never returned, but there remains a
very large cicatrix, larger in fact than the original
tumor. The patient was free from any further
growths until about a year ago, when another small
pimple appeared on the outer side of the right arm
just above the elbow, which gradually grew larger
until in April, 1895, it was one inch long, about a
third of an inch wide, and elevated above the skin.
The edges where it passed into the surrounding skin
were irregular and claw-like. On further examination
another similar tumor was found on the back, and
when the skin was made tense in several places, prin-
cipally on the outer side of the right arm, clusters of
flat, small round cicatricial spots were noted, of a white
and glistening appearance. Each cluster contained
about four or live spots. Upon relaxing the skin
these clusters were unnoticeable. In July the clus-
ters had all disappeared and there remained only the
tumor on the back, which was also diminishing in
size. At this time needle scratches were made on the
left arm. When seen again in September, 1895, little
nodular lines of cicatricial aspect were to be observed
corresponding to the previous slight scratches caused
by the needle. It may be added that microscopical
examination of the tumor removed from the arm in
April presented all the characters of true cheloid.

Here, then, we have a case apparently of sponta-
neous cheloid, in which nevertheless the subsequent
history, results of operation, and of experimental
slight cutaneous disturbance show that the fibroid
hyperplasia was to be induced by injury, so that pre-
sumably the primary growth had a similar origin, not
improbably, as in certain recorded cases, from an acne
pustule. The case affords an example of what might
very easily in its earlier stages have been classified
as spontaneous cheloid.

In fact, from this case and from a study of the liter-
ature of cheloid, I am led with Jonathan Hutchinson

.:; 1

to doubt whether the conception of a spontaneous che-
loid is possible or consonant with facts.

Thus, it can be shown that in those exhibiting a ten-
dency to the disease- -those in whom cheloid masses
already exist — a minimal irritation as, for example,
the scratch of a pin, may induce the subsequent ap-
pearance of a mass of subcutaneous fibrous tissue in
the region. Where this is the case it is difficult to
deny that the condition originates as a productive in-
flammatory fibrosis, and the fact that at times some if
not all of the multiple nodules undergo absorption
and disappear (as happened in Mr. Martin's case to
which I have already referred) is against regarding
the condition as typically fibromatous. It is equally
difficult, in fact impossible, to maintain that a mass oi
new tissue, which occasionally attains to the weight
of a pound or more, projecting from the head or trunk
is an example of inliammatory fibrosis. It is difficult
to see where the line is to be drawn, unless, as I have
recently urged in an address before the Mcdico-Chi-
rurgical Society at Montreal,' we recognize that in
inrtammation the new-tissue formation ceases with the
removal or cessation of the irritant, whereas in neo-
plasms the cells, having once commenced to proliferate
rapidly (whether as the result of chronic inflamma-
tion of moderate intensity or from other cause or
causes), gain a habit of growth and continue to prolif-
erate independently of any due stimulus. Assuredly,
in these multiple cheloids as in the cicatricial forms
growth of the tissue is continued after the irritant has
ceased to be in evidence, and consequently I am
bound from their course to classify them as among the
fibromata— as fibromata of inflammatory origin.

I am not prepared to do the same with another
form, the so-called " lamellar fibromata," whereof the
most frequent examples are to be encountered as

1 "The Habit of Growth," Montreal ^Medical Journal, Febru-
ary, 1896.

^.I

clie-

<lense, sharply defined, whitisli nodules and small
plaques upon the surface of the spleen. So far as I
have been able to follow their development, these ap-
pear to be examples of pure and simple intlammatory
jijrowth. I can see in them no evidence of continued
growth independent of injury or irritation.

l^esides these two forms we have the group of typi-
cal fibromata, isolated, sharply defined neoplasms of
in general slow growth. While among the cheloids
we can postulate an inHammatory origin, in these we
cannot as yet venture to assign a satisfactory causa-
tion. Nor is the time quite ripe to make a positive
statement concerning the massive interstitial tissue
occurring in sundry mixed tumors, in fibrolipomata,
fibromyxomata, scirrhous cancer, etc. Studying these
and comparing the outer border with the more internal
parts, 1 gain the impression that in many cases we
have, as in cheloid, to deal with a productive inflam-
matory fibrosis which merges insensibly into neoplas-
tic incontinent growth. This is my impression, and I
dare make no more definite statement,

I'luis we can divide the forms contained under the
title of fibroma into:

A. I'ure or true f"il)ronia.

(i) Of inllamnialory orij^in (most if not all examples of

cheloi<l).
(2) Of undetermined causation (typical hard and soft
tibromata).
1). Mixed tibroma, beniijn, cancerous, and sarcomatous (admix-
ture of fibroid overjjrowth with over^n^wth (jf other tissues).
(-". i'alse fibroma (due to simple productive inflammation, I'-j^''.,
"lamellar" libromata).

LHCTURE II.

In my last lecture, having laid down my definition of
inflammation — namely, that it is the series of changes
constituting the local attempt at repair of injury or re-
ferred injury to a part — I proceeded to discuss the
forms of fibrous hyperplasia which in the terms of this
definition might well be lield to be of inflammatory
origin, and showed or attempted to show that such
forms might be divided into the two main classes of
productive and replacement fibrosis. Following upon
this, I discussed the group of localized neoplastic
fibrous hyperplasias, and pointed out that two groups
might be recognized: the neoplasms of inflammatory
origin and those of as yet undetermined causation —
the true fibromata.

A consideration of neoplastic growth leads almost
insensibly to the inquiry whether it is requisite that
injury should precede new connective-tissue formation.
The answer must, I think, be an unhesitating No.

In the nobler tissues of the body we know full well
that increased work leads to hypertrophy or, more cor-
rectly, to hyperplasia; that is to say, a physiological
stimulus leads to multiplication of the cell elements.
What are the exact steps whereby this is brought about
must perhaps always remain a matter of supposition,
the most that we can say being that the call for in-
creased work is followed by increased blood flow to
the part with presumably increased nutrition, and that
the increased work necessitates greater activity and in-
creased metabolism in the individual cells. In con-
nection with the basal connective tissue of the body it
is difficult to grasp the idea of active work; to attempt
to formulate such an idea may perhaps justly lay me
open to the charge of dealing in transcendental pa-
thology, and yet, as I shall proceed to show, a consid-

eration of several forms of ribrous-tissiie hyperplasia
in connection witii the dilTerent or<jjans and diverse in
character, forms in which it is ditticult tt) decide any
clear inHammator orij^in, leads to the conclusion that
there is a certain bond of union between them, that in
them the exi:itence of an increased strain upon the tis-
sue is to be reco;j;nized, and that if we could group
them together as being of the nature of " functional"
hyperplasias or hyperplasias of increased function, we
should advance materially in our grasp and compre-
hension of the same.

I had at one time thought that increased nutrition
would be sufficient to explain these cases, and indeed
1 have l:)een inclined to press this point until quite re-
cently. It is certainly true (as is best shown by the cases
of dystrophic sclerosis already mentioned) that a nu-
trition insufficient for the nobler elements of an organ
suffices often for the active growth of connective tissue.
This fact that a nutrition ample and suitable for one
tissue does not suffice for another has long attracted
attention, while the converse, or rather the corollary,
was proved more than a century ago by John Hunter
in his classical experiment of grafting the scantily-
nourished cock's spur upon the cock's comb, and in
this richly vascular and well-nourished area obtaining
a remarkable, if temporary, hypertrophy of the grafted
organ. Under certain conditions, then, active increase
of nutrition of a part may lead to hyperplasia of its
cells. Where the specific cells of a tissue undergo
atroph) 't may well be that there results a definite in-
crease in the amount of nutritive fluid at the disposal
of the baser interstitial cells, and that this has to be
taken into consideration as w^ell as any more direct
stimulus to proliferation afforded by the products of
tissue degeneration.

If this be so we are met with the likelihood that in
conditions tending to altered nutrition of a part — lead-
ing to the tissues becoming bathed with lymph, either

in excess of the needs of the specific and nobler cells
of that tissue or of a quality not suited for the uses of
those cells— there may be induced an overgrowth of
connective tissue, a fibrosis, to be ascribed primarily
to nutritional disturbances; or, in other words, it be-
comes likely that there may be nutritional fibroses as
distinguished from inflammatory. Plausible as this
seems, a fuller study of those cases which at first
appear to be examples of simple nutritional fibrous
overgrowth leads to the conviction that there is some
further factor also at work. Or otherwise, increased
nutrition, even if long-continued, does not inevitably
lead to increased connective-tissue overgrowth, and
therefore when we find this factor most in evidence in
the production of any form of fibrosis we are bound to
assume that there must be some additional directive
factor. What I mean will best be shown by a study
of the cases I am about to brins: before vou.

Take in the first place chronic obstruction to the
flow of lymph. Where such obtains — whether by pres-
sure of tumors upon the main lymph channels of a
part, by blocking of the same, or by diseased states of
the lymph glands — it is a matter of frequent observa-
tion that in the absence of satisfactory collateral tracts
the part becomes swollen and gradually the fluid swell-
ing gives place to a generalized, if not very extreme,
connective-tissue overgrowth. In such cases the cir-
culation of the blood through the afi^ected area is main-
tained, there are no positive signs of inflammation evi-
dent either macroscopically or microscopically. We
cannot recognize in the condition an attempt at repair.
The primary injury has been at a distance from the
region of fibrosis. Nevertheless, it may be argued that
the stagnating lymph acts in these cases as an irritant
to the connective-tissue cells and that the condition
must be regarded as a productive inflammatory fibro-
sis.

While this view deserves full consideration, its ac-

I
■if

ceptance must lead us almost inevitably to a point at
which we become bound to regard as of inflammatory
origin every condition of fibroid overgrowth, whatever
be the stimulus. Some limit, I think, must be given
to our conception of what is included in the process.
It will be seen that thus far every example given by
me until the present case has been strictly within the
limits of the definition laid down, namely, it has been
reparative in its tendency and has been due to evident
injury to the part which becomes the seat of the fibroid
change. We must, I take it, decline to consider a le-
sion as an infiammatory fibrosis in the development
of which these two conditions cannot be clearlv recoc:-
nized.

Failing inflammatory origin, can we regard the ex-
ample given above as being brought about by perverted
nutrition pure and simple? 1 am inclined to think
that we cannot. We should expect perverted nutrition
to tell first upon other and higher tissues, but in mai.y
of these cases we find singularly little evidence of pri-
mary degeneration of nobler tissues (the muscles and
skin of an affected extremity, for example). Where
the circulation of healthy blood persists through such
a region there must occur constant interchange between
blood and lymph, and the blood must carry away the
products of tissue change to a considerable extent. In
deed we know that it is capable of vicariously remo^'-
ing much of the lymphatic fluid. With our present
knowledge, all that it is absolutely safe to say is that
we are here dealing with a quantitative disturbance in
the lymph of the region, coupled with a mechanical
disturbance, namely, increased extravascular and in-
terstitial pressure; or, to put it otherwise, the cells of
the connective tissue are subjected to an altered ten-
sion. The qualitative disturbance is of doubtful extent.

With these cases of obstructed lymph flow in a part
certain examples of elephantiasis Arabum would ap-
pear to be classed — provisionally. So little has been

accomplished in establishing the real nature of this
disease, or more truly of this group of diseases, that
the most I dare venture to say is that disturbed out-
flow of lymph from the affected region seems to be in
operation in some cases (elephantiasis lymphangiec-
tatica), while others present indications of venous dis-
turbance (elephantiasis telangiectodes) ; others again
(the neuromatous and lipomatous forms) can only
safely be described as hypertrophic conditions ap-
proaching peculiarly close to generalized neoplastic
formation.

Without discussing further the intimate nature of
the fibrous hyperplasia in these cases at the present
time, let me pass on to consider another class of cases.
Increased bathing of the tissue with lymph and in-
creased lymph tension may also result from active and
from passive hyperaimia. From either of these causes
there may be passage outward of lymph from the
blood-vessels in amount exceeding the efferent capac-
ity of the lymphatics. Here again mere increased
amount of lymph does not seem to lead necessarily to
fibrosis. Some other factor or factors must be in-
voked. Thus in the liver, while extreme congestion
leads especially to dilatation of the vessels with pres-
sure atrophy of the specific cells, and though presuma-
bly there is here increased exudation, we get little evi-
dence of fibrosis; long-continued moderate congestion
induces, on the other hand, a very evident fibrosis,
most marked, it is true, in the walls of and immedi-
ately around the intralobular branches of the hepatic
vein, but seen also in the interstitial substance of the
neighborhood. The peculiar arrangement of the new
fibrous tissue shows that it cannot be regarded simply
as an example of replacement fibrosis. The history
in these cases points to the long-continued action of
two factors — increased effusion of a not greatly altered
lymph and long-continued (and probably varying) pres-
sure affecting especially the central parts of the lobule.

)f this
s, that
id out-
) be in
ingiec-
Lis dis-
again
only
ns ap-
plastic

til re of
Dresent

cases,
nd in-
ve and

causes
t)m the

capac-
creased
arily to

be in-
gestion
;h pres-
esuma-
tle evi-
gestion
ibrosis,
iiimedi-
hepatic
; of the
he new
simply
history
:tion of
altered
g) pres-
lobule.

The relative rarity and the slight extent of the
fibrous hyperplasia accompanying well-marked passive
congestion is in itself an indication that the quality
of the effused lymph plays a part in the development
of the hyperplasia. Neither increased amount of
lymph of poor quality in a part nor increased intersti-
tial tension alone, it would seem, is capable of induc-
ing overgrowth.

From this brief and hasty consideration of fibroid
changes associated with the lymphatic and venous sys-
tems which are not to be regarded as of inflammatory
origin, I will now pass on to discuss in somewhat
greater detail what appear to me to be allied condi-
tions affecting the heart and arterial system.

In ordinary practice apart from malformations, neo-
plasms, and the direct effects of trauma, the patholog-
ical changes of the heart valves are divided into the
two broad classes of acute and chronic endocarditis,
and although the non-committal name of arterio-scle-
rosis is in frequent use and although its employment
appears to indicate a doubt as to the exact etiology of
the condition, it must, I think, be admitted that such
arterio-sclerotic changes are regarded as inflammatory
in character, while sporadically the attempt is made
to explain them by suggesting or presupposing the ex-
istence of some irritant substance in the blood which
by direct action upon the vessel walls leads to injury
and to reaction in the shape of connective-tissue over-
growth. I see, for example, that in a recent number
of the British Medical Journal \\\^ apostle of uric acid,
Dr. Haig, suggests that a cause for sclerosis of the
heart valves is to be found in the irritant action of
his beloved uric-acid crvstals.'

The existence of inflammation as a cause of sclero-
sis is more frequently to be determined in connection

' Alexander Haig : " Arthritis and Endocarditis Due to Drugs
which Diminish the Solvent Power of the lilood for Uric Acid,"
Britisli Medical Joiinial, December 28, 1S95.

with the heart valves than with the arterial intima.
Thus, it is well recognized that acute valvular disease
may be followed by chronic thickening of one or more
segments, that similar thickening may follow rupture
of a segment, and that a valvule which has from any
cause become injured, whether from simple roughen-
ing of its surface or more usually from the develop-
ment upon it of vegetations, may by friction induce
inflammatory disturbances in the parts with which it
comes into contact.

In general these forms present an irregular or vari-
cose type of fibrosis, but it is often difficult, if not im-
possible, to distinguish from them sundry cases of
chronic generalized thickening in which through de-
generation localized disturbances have occurred in the
thickened valves with, it may be, ulceration, deposit
of fibrin, and subsequent organization. There are,
that is to say, doubtful cases in which it is practically
impossible to declare whether we are dealing with
processes following upon localized valve lesions or
with the sequelae of a generalized lesion.

Apart from these undoubtedly the most common
form of valve lesion met with in the post-mortem the-
atre is a generalized thickening. Perhaps generalized
is not a wholly correct designation, for in the slightest
forms it manifests itself more especially along the
edges of the mitral segments, and in the aortic valvules
it is below the line of apposition, and again at the in-
sertion of each segment, that the fibrosis is most
marked. So common is the condition that in general
we disregard it and, accepting it as almost physiologi-
cal, make no note thereof. But in the examination
of a series of hearts we may pass almost impercep-
tibly from one case to another until we reach condi-
tions of extreme mitral stenosis, with such extensive
generalized thickening of the whole valve and conse-
quent shortening of the new connective tissue laid
down that the mitral veil becomes converted into a

:ima.
sease
more
pture
any
;hen-
elop-
icluce
ich it

circular plate, or more generally into a short blunt
funnel with button-hole passage. And we come across
case after case of this category which shows no sign
of localized valvular disturbance either old or recent.
The condition affects the whole of the valve and affects
also the chorda: tendinete, which are thickened and
shortened.

While in acute endocarditis and in the nodose or
verrucose sclerosis following upon such we find clear
evidence of vascularization of the valves, and sections
show fairly frequent vessels, this is not the case in
the generalized thickening here referred to. The es-
sential characteristic as revealed in sections is the
rarity of the vessels; the fibrous tissue is laid down
in layers parallel to the surface, and the most recent,
the most cellular layers are those nearest to the endo-
thelium — while the deepest layers, those most remote
from the surface, show a peculiar tendency to degener-
ative changes. This tendency to hyaline swelling,
fatty degeneration, and other evidences of necrobiosis
— in short, to atheroma — is in itself a demonstration
of lack of due vascularization and of malnutrition.
Indeed, although I know that Luschka and others
have described vessels throughout the extent of the
mitral valve segments, my own injections of healthy
hearts of several species have led me to the more gen-
erally accepted conclusion that the outer two-thirds of
the mitral are almost, of the aortic valves are quite
non-vascular, and to the further conclusion that
healthy valvules gain their nutrition in the main from
the blood circulating within the heart. It is, I hold,
by passage or circulation of the plasma through the
stomata of the lining endothelial cells into the lymph
spaces between the layers of connective tissue forming
the supporting frame of each normal valvule that the
main nutrition of the non-vascular areas of the valves
is effected. While a layer of the vascular myocardium
is contained in the proximal third or so of the seg-

ments, the outer two-thirds is scarce anything but a
fold of the endocardium.

That the endocardium of the heart in general gains
its nourishment from the blood within the chambers
and that the nourishing plasma may even extend for
some little distance beyond, is very prettily shown in
some cases of advanced sclerosis of the papillary mus-

FiG. I. — Transverse section of a papillary muscle exhibiting dystrophic
sclerosis to show xone of intact muscle fibres immediately beneath the en-
docardium, a^ Layer of intact muscle fibres beneath endocardium ; />, scle-
rosed areas— replacement of atrophied muscle tissue by fibrous tissue. In this
are venules and occasional atrophied .uiscle fibres; c\ arterioles cut trans-
versely, exhibitinii' thickened and sclerosed coats, and surrounded by intact
muscle fibres; </, periarterial sclerosis.

cles, which present complete fibroid metamorphosis of
the central area of the pillars with a zone of healthy
fibres all around the periphery immediately beneath
the endocardium. These healthy fibres present no ac-
companying arteries; all the arterioles coursing up
the papillary muscle may exhibit advanced proliferat-
ing endarteritis. The only and the obvious expla-
nation why these peripheral fibres remain is that they

have gained their nourishment through tlie endocar-
dium.

Wherever we find well-marked vascularization of the
outer two-thirds of the mitral valve, for example, we
may feel assured that there has been inflammation
present. The vascularization is strictly comparable
to that obtaining in the cornea and other non-vascular
areas, and indicates a development secondary to acute
disturbance of the organ. In the generalized thicken-
ing to which I have referred one is struck by the pecu-
liar* rarity or almost complete absence of vessels and
by the fact that the hypertrophic fibroid tissue is laid
down after the plan of the normal connective layers of
the region. And while obviously the neAv growth is
continuing and the newest tissue is situated immedi-
ately beneath the endothelium, we do not there recog
nize any characteristic presence of small round cells.
The appearances in this region are those of an orderly
hypertrophy.

Two hypotheses may be adduced to explain this
state of affairs : Either that the sclerosis is of inflam-
matory origin, the residt of an irritant mild in charac-
ter, causing little reaction but acting continuously over
a long period, or that it is non-inflammatory and com-
parable to the fibroses already referred to in connection
with the lymphatic system.

It is, I must frankly confess, impossible to adduce
sufficient proof to entirely refute the former hypothesis
— there may be chronic intoxications, auto-intoxica-
tions, or otherwise, due to substances which manifest a
special tendency to act upon the endocardium: but
such substances have not yet been isolated. Increased
pressure upon the valves may directly damage them
and the fibrosis may be the indication of a reaction to
chronic injury, but the thickening would appear to be
progressive and to continue until a condition is reached
out of all proportion to the injury. We find, therefore,
no absolute and sufficient reason for regarding the con-

dition as of inflammatory origin. Nevertheless, the
mere fact that we at present are ignorant of any imme-
diate cause for the production of this lesion is not
suflicient ground for flatly denying the existence of
such cause, and even the fact that the microscopic ap-
pearances are not those of ordinary inflammation is not
proof positive that the process which has led to the
lesion has not been essentially of an inflammatory na-
ture.

I cannot, that is to say, hold it proved or disproved
that generalized sclerosis of the cardiac valves is in all
cases of inflammatory nature. And the matter being
thus an open one, it may be well to hold it possible
that the second alternative may be correct and to seek
for evidence in support of it.

Now, it is interesting to note that just those conditions
in which there is a liability for the production of gen-
eralized thickening of the heart valves are clinically
conditions in which there is found heightened arterial
tension, conditions which also bring about arterio-scle-
rosis. It is just in these conditions that we might ex-
pect to have, with increased pressure, increased nutri-
tion of the endocardium and of the intima — increased
passage of plasma from the intracardiac blood through
the endothelium, or perhaps, more correctly, between the
endothelial cells. And I cannot but consider that this
increased nutrition coupled with increased strain may
afford a satisfactory explanation for this condition of
so-called chronic endocarditis. Such a proof as one
would desire of the correctness of this opinion is diffi-
cult if not impossible to devise, for the condition is the
production not of a few hours but, not to exaggerate, of
many weeks. Experiments upon the subject are al-
most if not quite outside the range of experimental pa-
thology. Yet certain considerations appear to support
the view. Roy and I,' for example, found that by con-

' Roy ami Adami : " On Failure of the Heart from Overstrain,"
British Medical Jounial, December 15, 1 888.

striding the first part of the aorta in the clog and in
the rabbit and thereby raising the blood pressure within
the heart, we were able in the course of a few minutes
to bring about the production of numerous small pearly
vesicles along the edges of apposition of the mitral and
aortic valves, and we could onlv account for this devel-
opment by assuming that with the increased blood
pressure the plasma of the blood had been driven into
the substance of the valve, and that the pearly vesicles
of lymph (or plasma) appeared where they did because
at these regions the difference between the pressure on
one side of the valve segments and on the other was most
in evidence. We obtained, so we held, clear proof that
with increased blood pressure increased fluid penetrates
the valve substance. It is important to note that simi-
lar pearly elevations are generally regarded as the first
indication of valve disease.

But, as I have already pointed out, it is unsafe to re-
gard increased nutrition alone as a cause of connective-
tissue hypertrophy, and if we cast round to find what
other factor there may be 1 am inclined to consider
that it may briefly be entitled increased strain or ten-
sion acting upon the individual connective-tissue cells.

The idea may at first appear transcendental ; we are
not accustomed to think of the connective-tissue frame-
work of the organism as being strained or, to carry this
view to its logical conclusion, performing work. We
only regard the nobler tissues as workers — the muscle
fibres, the nerve cells and the specific cells of the
glands. Nevertheless, we acknowledge freely that in-
creased work thrown upon one of the connective tissues
— namely, bone — does lead to its hypertrophy. It is
a matter of common observation that not only are the
bones of those accustomed to active exercise larger and
heavier than the bones of the sedentary, but also that
where any muscles are strongly developed there bony
ridges and bony overgrowths are most developed at their
origins and insertions.

The factors leading to this overgrowth may be
suninied up under the comprehensive title of increased
work. And in connection w ith connective tissue where
there is any force in action tending to draw apart and
pull upon the constituents of the tissue — whether the
force acts from without or (as in cases of increased
effusion of lymph) from within the tissue — where, in
short, there is a strain upon the components of the tis-
sue — there, if we regard the work of the connective tis-
sues, as is most plausible, as being to bind together and
support other tissues, undoubtedly that work is in-
creased and, granting that at the same time the nutrition
remains good, we have a condition favorable to in-
creased growth. A /(>rt/(?r/ wti img}\t expect such hy-
pertrophy where simultaneously the amount of nutrition
is increased.

I suggest this very tentatively, for I have a horror of
far-fetched pathology and an accompanying belief that
the fuller our knowledge of a subject the simpler and
more straightforward do we find the laws governing the
associated phenomena, and it is only because the idea
is straightforward and is in harmony with our knowl-
edge of occurrences in connection with other tissues
that I venture to formulate it. My aim in these lec-
tures is throughout not to dictate but to suggest and
call attention to the many diverse conditions which may
bear a part in the production of increased fibrous tis-
sue. At most I will here urge that it is possible that
increased functional activity of the connective tissues
results under favojable conditions in increased growth
of the same.

Passing now to the arteries, we find that just as the
muscular walls and pericardium of the heart are nour-
ished by the coronary vessels, so the media and ad-
ventitia of the arteries are nourished by the vasa
vasorum, whereas in health the intima appears to be
non-vascular. Indeed, where it is well developed, the
internal elastic lamina appears to constitute a boun-

clary line between the vascular and non-vascular areas
of the arteries. We are forced, I hold, to re<;ard the
intinia as nourished from the blood circulating^ within
the arteries.

The diseases to which the arterial walls are subject
are closely comparable with those of the heart.
There can, for example, be undoubted inflammation;
we may even have collections of pus cells separating
the intima from the media, although this is very
rare and is always secondary to a purulent mesarte-
ritis, the pus cells wandering into the intima from the
vessels of the media. Facu in cases of septic embo-
lism or thrombosis, necrosis is the lirst noticeable
change in the intima, and the invasion of leucocytes
appears to be associated with the later inHammation
of the media and adventitia. Rather more frequent
is an acute productive inHammation, seen especially in
the first portion of the aorta. 'I'his appears to be sec-
ondary to simi; ir verrucose, subacute, and ulcerous in-
flammation of the aortic valvules. It is characterized
by the development of almost papillomatous or warty
processes projecting into the lumen of the aorta, and
these are richly cellular and also vascularized from the
vasa vasorum. They are often covered by a layer of
coagulum.

But these ob\'iouslv inHammatorv conditions are
relatively rare. The most common form of arterial
disease in the larger arteries is that termed by Vir-
chow endarteritis chronica nodosa sive deformans, the
arterio-sclerosis of Lobstein, or atheroma. I need not
here enter into statistics concerning its frequency, or
take up your time by details concerning the forms that
it may assume. I will accept Dr. Councilman's classi-
fication,' simply modifying his terminology to indicate
my doubts as to the endarteritic or inflammatory na-

^ Councilman: " On the Relations between Arterial Disease and
Tissue Changes.

Trans. Association American I'hysicians, vi.,

1S91, p. 179.

4'''

ture of tlic coiulilions. With him, therefore, I would
clistin<;uish i^a) a uocluhir arterio-sclerosis, {/>) senile
arterio-sclerosis, and (c) diffuse arlerio-sclerosis; and
would with him acknowledge that these three forms
merj^e one into the other, l-'or our purpose, as throw-
in*; lijj;ht upon the nature of the conditif)n, the nodu-
lar form, the true endarteritis nodosa of Virchow, is
that to which I would more especially call your at-
tention.

'J'he process ]ie<:jins l\v the development of semi-
transparent, almost gelatinous, plaques here and there
upon the walls of the aorta and larger vessels, most
often in the neighborhood of and around the orifice
of some side branch. Where the process is older the
placjues are found firm, dense, and of almost cartilag-
inous hardness, and with this stage the deeper regions
of the pla(.(ues exhibit manifest degenerative changes,
passing on to the deposit of calcareous salts in the
necrol)iotic substance.

If we examine these plaques we are struck by the
following peculiarities: (i) The endothelium over the
plaque is continuous and apparently unaffected ; (2)
the new tissue is laid down regularly in layers paral-
lel to the endothelium; (3) the connective tissue of
the intima in the immediate neighborhood of the
plaque passes imperceptibly into the hypertrophied
connective tissue forming the plaque; there is no
boundary line to be made out; (4) the oldest layers
of the plaque are evidently those nearest to the elastic
lamina, the most recent are beneath the endothelium
and farthest away from the vasa vasorum of the media;
and (5) the plaque is devoid of vessels save and except
in those cases in which there is an evident attempt at
the removal of the necrosed atheromatous material, and
vessels penetrate into the atheromatous mass from the
media in a manner comparable with their passage into
a thrombus. Such passage, it will be recognized, is
of purely secondary nature — the fibrous tissue has de-

veloped and undergone degeneration before it takes
place.

The picture presented is not one usually associated
with intlamination. The picture is ratiier what we
sh(Hild exj^ect to find in an orderly connective-tissue
hypertrophy, while the degeneration appearing in the
deeper layers is what might i)e expecteil to occur in a
non-vascular area in which layer after layer of con-

Fir,. 2. — Section of the Aorta from a Case of N'odosc Artcrio-scltrosis. i,
Thick Ia\'er of iiypfrplastic coniuTtivc tisMic iyinj,^ immccliatcly bt-iicath the
endothfcliiim; 2, hyaline and fatty dcxciR-ration of tlic lower layers of tlie
intinia; 3, internal layers of the media, staining poorly and havin.i,' a liyahnd
appearance; 4, outer layers of the media— cellular infiltration around the
vasa vasorum.i

nective tissue cut off these deeper parts from their or-
dinary source of nutrition. Indeed, the sharp defini-
tion of the necrosed and calcareous tissue at the in-
ternal elastic lamina is often very remarkable and

' For this specimen and that from which Fig. 3 has been made
I am indebted to Dr. G. H. Mathewson, who is studying the
cases of arterio-scierosis occurring at the Royal Victoria Hospi-
tal, Montreal.

would appear not only to afford a proof of the correct-
ness of the view that the intima is nourished from the
interior of the artery, but also would suggest that the
internal elastic lamina performs a very definite func-
tion in separating two vascular areas.

This, however, is not the whole picture. Con-
stantly accompanying and indeed preceding the
changes in the intima, there is to be recognized an
injury or degeneration of the outer coats, whether
of specific, inflammatory causation (as in cases re-
corded by Thoma and Peabody), or whether due to
more obscure alterations in nutrition associated with
disturbances of the vasa vasorum. In many cases
these small vessels are congested and present either an
infiltration of small round cells in their immediate
neighborhood or the development of surrounding
fibrous tissue. The muscle fibres of the media fre-
quently exhibit hyaline and other degenerative
changes, and there may be some replacement fibrosis,
or again evidences of more extensive failure of nutri-
tion and of necrobiosis in the shape of small areas of
calcareous deposit. That is to say, the media is very
definitely affected and, as Thoma's experiments have
fully proved, each plaque of overgrowth of the intima
corresponds to a localized giving way of the arterial
wall, to a localized slight bulging of the same; for
by injecting affected arteries with paraffin under a
pressure of one hundred and sixty millimetres of mer-
cury, Thoma obtained a smooth cylindrical mould
showing no signs of depressions corresponding to any
projecting plaques; the hypertrophied intima fills and
obliterates the slight bulgings or pouches of the outer
coats. However produced, there can be no question
that we have here to deal with a compensatory hyper-
trophy of the intima.

In the diffuse form also Thoma has demonstrated
that the growth of connective tissue in the intima has
a similar compensatory nature.

Is this process to be denominated an inflammation?

Thoma and his pupils have shown that a thicken-
ing of the intima which they regard as strictly analo-
gous is to be met with in the arteries of amputated
limbs, in the portion of the aorta between the ductus
Botalli and the offset of the umbilical arteries imme-
diately following upon birth, in the uterine arteries
after menstruation has set in, and still more clearly
after childbirth; so to a less extent in the splenic ar-
teries. All these latter cases must surely be classed
among physiological rather than pathological reac-
tions. Surely it is impossible to class a normal con-
stant change, such as the overgrowth of the aortic
intima following upon birth, as an inflammation. Nev-
ertheless Thoma refers — or referred — to all these as
conditions of compensatory endarteritis. But if he is
right — and I do not see that he is not — in grouping
all these cases, physiological and pathological, into
one common class and ascribing to all a common
causation, then not one ought strictly to be regarded
as of inflammatory origin.

Thoma would explain his compensatory endarteritis
according to the following law, namely, that the con-
dition is to be ascribed to a slowing of the blood cur-
rent. If this slowing be not arrested by a contraction
of the media and consequent narrowing of the artery,
leading to more rapid flow, then there occurs a new
growth in the intima which leads to the same end —
causing the lumen to become narrowed and the cur-
rent to be restored to its normal rate.

He thus holds, and in this we must agree with him,
that the primary lesion in arterio-sclerosis is a defect,
a giving way, of the media, due to loss of elasticity
however produced — and the only factor that he judges
capable of explaining both the physiological and the
pathological cases of connective-tissue overgrowth in
the intima, and which is common to all cases, is rela-
tive slowing of the blood current. It is difficult to

follow his explanation of the mechanism whereby such
slowing induces the hyperplasia of the fibrous tissue.
Even if this slowing leads, as he indicates, to func-
tional disturbance of the vasa vasorum, I cannot see
how these vessels influence the nutrition of the intima.
As I have said, I cannot find evidence that in healthy
arteries or in the earlier stages of arterio-sclerosis any
branches of these vessels pass into the intima. The
process within the " bandelette " (as French histolo-
gists term the internal elastic lamina) appears to be at
first sharply cut off from that occurring outside the
same, and to be of a different nature— the new growth
does not appear to develop from the neighborhood of

Fic;. 3.— Section of the Aorta from a Case of Nodose Arlcrio-sclerosis, to show
the bulging and thiiininsj; of the media, prepared by Dr. JMatliewson ;
ma.Lcnified 8 diameters. The section sliows also the hyaline de;tjeneration of
the deeper layers of the overgrown intima, and the persistence of a fine
layer of less altered intima tissue immediately beneath the media. The
media in this case showed evidences (jf calcareous degeneration in patches,
with some hyaline change.

the " bandelette" and in the proximity of branches of
the vasa vasorum entering the intima, did they exist
(save, as I have already stated, secondarily to degener-
ative changes), but occurs at a region farthest away
from such branches. At most a thin and in general
hyaline degenerated layer may frequently be found
lying between the calcified atheromatous mass in the
overgrown intima and the internal elastic lamina.
This would indicate that a small amount of nutrition
is derived from the media. On the other hand, the
examination of numerous sections would indicate that
after the degeneration of the lower layers of the intima

and the deposit there of a dense calcareous mass,
growth still occurs actively and new layers become
formed immediately beneath the endothelium. Were
the main nutrition from the vasa vasorum of the media

'ic. 4. — Section of an Arti'ry of Medi-
um Size, from the collection at
McGill University. ['I'his had
been employed as a test specimen
for the class and its label removed
so that its exact oriifin cannot be
stated.] I, Intact endothelium;

2, layers of fibrous hyperplasia ;

3, hyaline degeneration of the
fibrous tissue ; 4, layer of calcare-
ous degeneration lying in immediate:
proximity to 5, the internal elas-
tic lamina, .somewhat swollen ; 6,
media presenting no distinct evi-
dences of disease.

Fk;. 5.— Section of Coronary Artery
from a Case of general Arterio-
.sclerosis, to show the persistence of
a layer of but slightly altered con-
nective tissue between the internal
elastic lamina and the layer of
calcareous degeneration. In this
artery there had evidently been, as
indicated at 4, two successive
periods of sclerotic thickening of
the intima, corresponding to a giv-
ing way of the media in two places.

this would not be possible, and malnutrition in conse-
quence of disturbances in these vessels would lead to
the production of wedges of degeneration extending
toward the lumen, rather than to plaques of degenera-

tion lying deep down in the thickened intima close to
the internal elastic lamina.

Thus I cannot but conclude that disturbances in the
vasa vasorum are incapable of immediately originat-
ing the changes that occur in the intima. There may
be fibroid, hyaline, and necrotic changes in all the
coats of an artery, but the sequence of changes in the
intima does not maintain a strict dependence upon
and direct association with the sequence in the media
and adventitia.

Alterations in the vasa vasorum failing to explain
the new growth, I am compelled to fall back upon al-
tered tension as a factor to be adduced in partial ex-
planation of these cases of increased growth. With
Thoma we may possibly also call in the agency of the
sensory and trophic nerves as governing the growth,
but here we enter further upon speculative ground.
They may play — they probably play — an active part,
but we have no direct evidence that they do.

The most that we can safely urge is that with rela-
tive expansion of an artery or portion of an artery there
must be an altered tension acting upon the cells of the
intima of the affected region — that accepting the view
that the intima is nourished from within the lumen,
anything which will lead to increased passage of the
blood plasma into the subendothelial layers of the in-
tima may at the same time lead to an increased strain
upon the connective-tissue cells of the intima, and so
to increased proliferation of the same.

If this be so, we may have another ground than the
histological appearance for regarding the condition as
non-inflammatory; we have to deal with a stimulus
rather than injury to the cells of the intima, and may
see in the fibrous hyperplasia a response to a physio-
logical stimulus rather than a reaction to injury. In
any case with our present knowledge, limited as it is, I
would urge that the non-committal term of arterio-
sclerosis is preferable to that of chronic endarteritis.

Than this latter the term chronic arteritis is more ac-
ceptable, for in connection with the artery as a whole
as distinguished from the intima there is in the giving
way and thinning of the media evidence of injury, and
in the intima as well as in the media, and it may be
in the adventitia also, evidence of repair — of the

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Fig. 6. — From a Section of the left Ventricle of a Patient dyinjj; from aortic
stenosis with general arterio-sclerosis, to show mixed dystrophic (ci) and
periarterial fibrosis {//).

artery as a whole, not of the intima ; an arteritis, not
an endarteritis.

The distinction I admit is fine drawn, yet I am com-
pelled to acknowledge that it exists. I cannot ac-
knowledge a physiological inflammation, and if, as
Thoma points out, the initial process is identical in
physiological overgrowth of the intima and that occur-

ring in arterio-sclerosis, then the latter process must
be regarded as functional. Were some irritant discov-
ered capable of directly inducing the hyperplasia of
the intima, the case might present a different facies.
That such i ; irritant exists is, it seems to me, highly
improbable. The peculiar contrast between the pul-
monary and the systemic arteries in their liability to
arterio-sclerotic changes is strongly suggestive of the
action of differences in the circulation as explaining
the contrast and not of the action of any irritative
component of the blood.

I do but suggest this, and suggest it most tentative-
ly. I shall feel rewarded if the suggestion leads to
increased study into the phenomena underlying some
of the commonest and most important forms of con-
nective-tissue overgrowth. We are so woefully igno-
rant of the causation of such common conditions as
chronic valve disease and arterio-sclerosis that I feel
that, even if the views here enunciated originate strong
and successful opposition, the stimulus they may have
given to further investigation will be an ample
reward.

The whole matter, as it appears to me, resolves it-
self into this : " Can we regard fibrous connective tis-
sue as following the same laws as the higher tissues
and so as undergoing hypertrophy in consequence of
increased work or increased strain brought to bear
upon it?" If we can, then it would seem that we can
divide off an important series of fibroses from the
huge class of inflammatory fibroses. If we cannot,
then we must continue to regard all fibroses save the
neoplastic as chronic " itides."

Provisionally, therefore, I would divide the various
forms of fibrosis as shown in the diagram, namely:

A. Of inflammatory origin :

1. Replacement.

2. Productive.

J St
)V-

of
es.
ily
il-
to
he

ng
ve

re.-
to
ne
>n-

10-

as
id

ng
ve

)le

it-

is-
es
of
;ar
an
he

Dt,

he
us

3. Combined productive and replacement.

4. Neoplastic.

B. Neoplastic, of undetermined causation:

I. True fibromata.

C. Of functional origin :

1. Lymphatic.

2. Venous.

3. Arterial.

There are very many individual cases of fibroid
change that I have not discussed in these two lectures.
To have done so would have consumed too much time
and would have carried us still farther into conjectural
regions. But the cases that I have brought before you
represent, 1 believe, the main types of fibrosis; and
those not here taken into consideration will, I believe,
fall into one or other of the main classes here indi-
cated.

In conclusion I beg, Mr. President, to thank you
and all the members for your great courtesy in endur-
ing so patiently the long discourse that I have in-
flicted upon you, and once again to thank you for the
honor you have conferred upon me in inviting me to
deliver these lectures.