VOL'JME 79
I\UMB£R 14
EXOPHTHALMIC GOITER—LIEB
- : ; Ringer,,* from a clinical point of view, expresses his
dissatisfaction, with our present views in regard to the
' ' •-?•• -of -'nephritis, 'stating as his belief that the
i infections and intoxications which are usually
1 be. responsible play but a secondary role, i. e.,
nierely an exciting role, and that the primary seat of
trouble lies in the kidney itself. He sa}rs, "We can
readily conceive of organs in the human body at birth
being of functional capacity below "par." He quotes
Stockard as saying : "Every person dies from the
disease with which he is born, . . . and . . .
during the period of differentiation the organ is marked
out which is the weak link in the chain." Ringer
then concludes that, so long as the individual remains
well, the renal condition goes unrecognized ; but *any
insult, in the form of infection, or any strain, as
pregnancy, may cause a break in the weak link, with
the onset of a clinically recognizable nephritis.
Babes s has observed six cases of chronic renal
disease occurring in young, frail and anemic subjects,
usually- under the age of 30, with no history of previous
nephritis or conditions supposed to cause nephritis. In
each case, a slight infection precipitated a sudden grave
uremia, '• with coma and death in a few days. In a
discussion of the kidney findings at necropsy, he men-
tions an excessive diminution of volume and certain
characteristics of indurated and granular atrophy, or
of arteriosclerotic kidney, differing essentially from the
two forms or their combination. Therefore he states
that in these cases it is not a question of ordinary
sclerotic nephritis, of simple arteriosclerosis, of insuf-
ficiency of the arteries; or of' a combination' of these
pathologic processes, but rather a particular state of
the^kiey : a true hypogenesis. He believes that during
the^Rtime of the individual the kidneys are at the
limit of their capacity, and that a comparatively minor-
infection results in a fatal uremia. He concludes that
one must think of a nephritis grafted on a hypogenetic
k.idney if, in a young poorly developed subject without
renal-.. antecedents but with hypertrophy of the. heart,
a fulminating uremia follows a slight malady.
'",!'," CONCLUSION
: It i is. impossible, of course; to be certain . regarding
the etiology of the renal lesion in the three cases on
which this report is based. It does seem, however,
that they correspond closely to those outlined by Babes.
The subjects may therefore be regarded as individuals
congenitally predisposed to the development of a renal
lesion, probably because of a "weak link" (hypogenetic
kidneys) in the cardiovascular-renal chain, with a deter-
mining factor in the form of an infection or strain
resulting in the rapid onset of a fatal uremia.
It is obvious that such a suggestion, partly based on
the gross and microscopic appearance of the kidneys, is
not in keeping with the modern clinical classification
of :nephritis on a functional rather than a structural
basis; But I do not believe we are wholly justified in
disregarding the appearance of the kidneys at necropsy
and, although the justice of "the present day clinical
classification is acknowledged, still it is to be regretted
that the tendency is away from the pathologic basis,
which is necessary for a just conception and further
pro i the study of disease.
- 1< nut" Street. _ •_ • Seventy-Third Annual Session of the American Medical Association
A* Kijiger, A. I." Chronic Nephritis, from the Point of View of
the Gc-ncral Practitioner: Its Diagnosis, Prosrnosis and Treatment,
AiTV../,..M. Sc. 161:795 (June) 1921. -
. 5. Babes. V. : La nephrite hvpogenetique, Seninine met!.- 25:63
(Feb. S N ) 1905. " '. -
ET AL.
1
A STUDY OF EXOPHTHALMIC GOITER
AND THE INVOLUNTARY
NERVOUS SYSTEM
VIII. A CLINICAL AND LABORATORY STUDY OF THE
INVOLUNTARY NERVOUS SYSTEM *
CHARLES C. LIEB, M.D.
HAROLD THOMAS HYMAX, M.D.
AND
LEO KESSEL, M.D.
NEW YORK
Our clinical study * of exophthalmic goiter suggested
an investigation of the involuntary nervous system.
The manifestations of exophthalmic goiter may be
divided into the metabolic disturbance measured by the
basal metabolism, and the sympathomimetic symptoms
(tachycardia, exophthalmos, polyrrhea, sweating, etc.).
The latter have been so called because the}' may be
produced by stimulation of the thoracicolumber division
of the involuntary nervous system. Not all persons
'with sympathomimetic symptoms have elevation of the
basal metabolism. To a clinical association 'of svm-
pathomimetic symptoms and normal basal metabolism,
we have applied the term "autonomic imbalance." -
Our clinical studies of autonomic imbalance failed
to reveal the predisposing causes. The exciting causes
may be divided into physiologic and pathologic. The
most prominent physiologic factor is the sex epochs,
particularly in. the • female, and the most frequent
pathologic factor is foci of infection in. the. naso-
pharynx. Our patients showed considerable range in
their symptoms: In some but one organ, such as the
heart,, was involved; .in. others the symptoms were so
widespread that there was a general imbalance.
The commonest symptom was lability of the pulse
rate, and in every patient an apparently idiopathic
tachycardia was present at one time or another.
Thyroid enlargement was second in frequency. About
20 per cent, of the patients presented one or more of
the eye signs of exophthalmic goiter. A tremor ; was
noted in about one fifth of all patients. In 84 per
cent., both tachycardia and goiter were present;' in
12 per cent., tachycardia, goiter and eye signs;.hi 10
per cent., tachycardia, goiter and tremor; and in "11
per cent, of the eighty-six patients, the four clinical
cardinal symptoms of exophthalmic goiter were simul-
taneously observed. In only one of the eighty-six
patients was basal metabolism elevated, and in her it
was found only in the first of three determinations.
It is apparent, therefore, that while these persons pre-
sented many or even all of the classical clinical symp-
toms of the textbook picture of exophthalmic goiter,
they did not suffer from that disease. The necessity
for accurate differentiation from exophthalmic goiter
was urgent. Nearly all had been told that they were
suffering from thyroid disease, and many had already
received specific treatment referable to the thyroid
gland. ••'•'
* From the Department of Medicine,^ Mount Sinai Ho5L-iraI, and the
Department of Pharmacology, College of Physicians and Surgeons.
* Read before the Section on . Pharmacology and Therapeutics at the
St. Louis, May, 1922. . ; ..•.,'.'
1. Kessel, Leo, and Hyman, H. T.: A Study of Fifty Consecutive
Cases of Graves' Syndrome; to be published-.' '• • ' ;
2. Kessel, Leo, and Ifyman, .H. T.: The Clinical;. ^lanife^ations of.
Disturbances of the Involuntary Nervous System (Autonoituc Imbalance,
to be published.
 1100 EX OPPITHALM 1C GOITER—LI EB . ET AL. JODR. A. M. A.
SEPT. 30, 1922

Interesting phenomena were frequently encountered edly injected at short intervals caused a progressively
in- those patients suffering from symptoms referable to increasing vascular response, which we interpret as an
but one organ. Six patients had such prominent artificial "^K^I "sensitization."
t^^^±;^±:^ » An A _ analysis
1,._:_ of_x tin's
*.-<-•- phe-
cardiac symptoms that they had previously been treated nomenon was undertaken in the hope of throwing light
in cardiac clinics. In addition to tachycardia, there on the mechanisms of autonomic imbalance and
were- various abnormalities in the cardiac rhythm : exophthalmic goiter. The negative effects of extirpa-
extrasystoles, auricular flutter and paroxysmal tachy- tion and of injections of potent extracts of various
cardia. The general picture was that of the cardiac ductless glands excluded them as participants in the
war neuroses.' The abdominal symptoms resembled sensitization (thyroid, suprarenal, parathyroid, spleen
closely the clinical picture of gastric or duodenal ulcer and kidney, by ablation; /thyroxin, epinephrin,
or of "chronic appendicitis." Neuroses or psychoneu- pituitary extract and ovarian extract, by intravenous
roses were observed in six patients; the most prominent administration). Since .every known variable was
were of the anxiety and sexual types. In almost every carefully controlled, we were forced to conclude that
case a diagnosis of disease of the organ presenting the the phenomena of sensitization were the result of a
symptoms had previously been made, and in none was . physicochemical change • induced by epinephrin and
the role of the involuntary nervous system recognized. - involving the myoneural junctions of- the thoracico-
In attempting to discover a pathognomonic clinical lumbar system. We disagree with the interpretation
test, we were led to investigate the response to various that an increased- response to epinephrin signifies
drugs, especially atropin and epinephrin. As controls, hypersecretion of the thyroid. We have found no evi-
two groups of "normal" persons were studied: thirty dence that thyroxin increases the epinephrin response; *
medical students at -we- have .produced
the College of Physi- iUTOSOUJO I3IEALA1IOE {A. I.) sensitization in the
iTABLE ISVOlUTfTAK BERVOUS STSTZH
cians and Surgeons, 1IORJUI.'
Potential cases with, absence .of the-thy-
• Ifc drug sensitiveness
and fifty convales- Jto eympathomiiuatio manifes- XUDIViroAlS drug.sensitiveness
roid ; we have found '
tations :
cents at Mount Sinai IN- .sensitiveness ' t o
Hospital. Of these epinephrin" in 'a' large
"normals," a few number of "normal"
gave evidence of a human subjects. We
mild grade of auto- commons
are therefore con-
nomic imbalance, but Uantal and physical
vinced t h a t the
33 per cent, reacted 1-4- *.. I
epinephrin '' reaction.;/;...
to epinephrin and 25 (Goetsch) is"_ hide-.
per cent, to atropin. pendent not only of
This 'indicates' that the normal but also
• AUTOJIOJIIC IMBALANCE
abnormal drug reac- ACTIVE CASES with drug sensitiveness
of the hyperplasric
(usually), evmpathomijEetio manlfas-
tions "can exist in tations Calways) and nonn&l B. M. .•thyroid gland. -- We------
the absence 'of active -also believe that an
autonomic i -m b a 1- increased reaction to
ance. D r u g tests epinephrin is no in-
were made on a few EXOPHTHALMIC OOITXR dication of: excessive
patients with active with A. I. and
aleratfld B. 51.
tontis of'the thorac-
autonomic imbalance icolumbar5 (sym-_...
and fifty cases of Role of involuntary nervous system, in "normals," autonomic imbalance and exoph- pathicotonia). Con-
exophthalmic goiter. thalmic goiter. firmation of our be-
The type of reaction lief is found in the
did not-permit clinical' grouping into sympathicotonia . law that a tissue in high tonus is less reactive to a
arid 'vagotonia; the intensity of drug reactions did not stimulus than the same tissue in a state of low tonus
• parallel the severity of the presenting symptoms. • Only or atony. Therefore, an increased response to epi-
6 .per cent, of these patients failed to react to one or the nephrin is suggestive of a. low rather than of a high -
other drug. The absence of response may be explained tonus of the tboracicolumbar. ' -
pharmacologically: epinephrin stimulates the myo- Attempts to alter the epinephrin response of the
neural junctions of the thoracicolumbar, and atropin pithed cat were made with a view to a therapeutic -appli- .
paralyzes those of the bulbosacral division of the cation of-the findings. Injections of .the buffer salts
involuntary nervous system. . These responses are not (sodium acid phosphate, sodium carbonate and sodium'
indicative of the tonicity of the involuntary nervous bicarbonate) ; of the cations (sodium [Na*], hydrogen
system. [H*], potassium [K+] and calcium [Ca**]}; of t h e . '
In our animal experiments 8 we attempted to find an anions (chloric! [Cl~], sulphate ' [SO4~], carbonate •"--
index of the activity of the involuntary nervous system, [CO3=], bicarbonate [HCO3-], acid phosphate
and through it to study the natural and artificial regula- [H3PO4=], iodid [I-], bromid [Br], oxalate [C2O4=]
tion of this system. The response of the pithed cat and citrate), and of the alkaloids (morphin, atropin,
-1 to repeated injections of similar closes of epinephrin physostigmin ), failed to alter the reaction. Magnesium
was finally. accepted as' the most serviceable index. .suiphate depressed strongly, and cocain augmented
obtainable. It was soon found that epmephnn repeat- greatly the degree of the response.
3. Lieb, C. C, and Hyman, H. T.: The Vascular Response of Hie Previous workers, using the same preparation and
'ithed Cat to Single Intravenous Injections of Adrenaline^ The_Vas- obtaining similar results, have invariably interpreted
cular Response of the Pithed Cat to R icated Injections of Equal Doses
of Adrenaline; Attempts to Alter the 'ascular Response of the Pithed
Cat to Repeated-'Injections of Similar 'Doses-of Adrenaline; On the 4. Levy, R. L.: Studies on the Conditions of Activity- of the Endo-
Mechanism of the 'Sensitization of _the Pithed Cat to the Subcutaneous crine Glands, Am. J. Physio]. 49:492 (Oct.) 1916.
Injections of Adrenaline, to be published. .5. JEppinger and Hess: Vagotonia.
i
 'NCM.BEK. 14
VOLUME 79
MASTOID OPERATION—PIERCE
.this "sensitization" as a specific hormone effect. That
thfl^Eiisitization is not a hormone effect is amply dem-
, oi^jplted by our inability-to obtain sensitization with
dry-toxin'a'nd:dtlie'r hormones, and by the occurrence of
sensitization: after extirpation of the endocrine glands.
The'factors regulating the tonicity of the involuntary
nervous system remain unknown. There is certainly
no proof that they are the secretions of the ductless
"glands; nor have we been able to find any evidence in
support of a theory assuming that these hormones are
capable of acting as emergency stimulants of the invol-
untary nervous system. It seems unwise to designate
the conditions of exophthalmic goiter and autonomic
imbalance as endocrine disorders, and we therefore
favor the abolition of such terms as "hyperthyroidism",
'"dysthyroidism" and "suprarenal insufficiency."
Autonomic imbalance presents all the symptoms of
exophthalmic goiter with the single exception of
increased basal metabolism. TJhejmaJprity of patients
presenting1 exophthalmic goiter give a history, past or
present; of autonomic imbalance. The actual transi-
tion from autonomic imbalance to exophthalmic goiter
has been, observed, sThe transition is characterized by
an augmentation of the symptoms of autonomic imbalr-
ance plus a metabolic upset, as evidenced by an elevated
basal metabolism;
Though thyroid enlargement and autonomic imbal-
ance may be independently present, their frequent
association is probably more than a mere coincidence.
The causative relation between these has not yet been
determined, but it seems improbable that thyroid hyper-
is the cause of the imbalance,
have but one therapeutic suggestion to offer—
namely, the use of atropin in disturbances of the bulbo-
sacral division of the involuntary nervous system.
Whether tonus is increased or decreased, atropin may
be employed. If the tonus is low, small doses are indi-
cated ; they stimulate the center without affecting the
nerve endings. If the tonus is high, large doses
paralyze the endings, and nullify the excessive central
action. ..
ABSTRACT OF DISCUSSION
• DR. A. J. CARLSON, Chicago: This report deserves attention
because of the analytic and critical manner of attack of a
problem,: not infrequently considered settled. If "hyper-
thyroidism" was more frequently subjected to similar search-
ing analyses, we should make more rapid progress in this
difficult field. There is a tendency among internists to con-
sider the visceral nervous system and the endocrine glands
as being supplementary, if not identical, in function. I need
not:Say that theories and therapies based on this assumption
are not only guesswork, but probably in many instances wrong
guessing at that. The uncritical use of such terms as "hyper-
thvroidism," "vagotonia" and "sympatheticotonia" in the
sense of established etiologj' of well known disease complexes
retards medical progress. I hope that the authors themselves
regard their present work as a "report of progress," rather
than as a final conclusion. I further hope that they will also
give some attention to the sensory side of the visceral nervous
system. It is not improbable that visceral sensory factors
may raise the basal metabolic rate above the normal, even
without reflex hyperactivity of any endocrine gland. Physiol-
---'-*- are now gradually realizing that we must be careful in
ig physiologic conclusions from experiments on animals
anesthesia. That is equally true of experiments on
:brated .animals, at least for two or three days after
me- uecerebratien, because of shock.
D's/B.'T.' HVMAX, New York:. We used very little anes-
thesia, just enough to do a tracheotomy. So we feel that it
was''hbt' a factor. Sometimes the epinephrin injection, is not
made for two or three hours afterward. We are unable to
1101
keep the animals alive more than seven or eight hours. We
have never been able to keep an animal alive over night. The
English institutes can do that but we cannot, despite the
fact that we use as ideal conditions as possible. . A number
of things the speaker said are of extreme importance. I should
like to call attention to one point particularly. The relations
between the sympathetic and vagus are not clear. Most
-people have the conception that the systems are antagonistic..
For instance, if one gives small doses of atropin one may .
stimulate the vagus center; if large doses, one paralyzes, ,so
that one gets certain antagonistic effects. If one uses small
doses, one gets depressor effects; if large doses, pressor
effects. We have seen it in the same animal and converted
. the depressor effect to a pressor effect, so that one cannot
try to reach conclusions as to the effects of these drugs. The
dosage is not the same for the same animal at the same time,
or different times. In other words, there is an extreme vari-
ability in this whole business.. Then, of course, .different
animals have different tonus in regard to their vagus and
sympathetic systems'. As to a conclusion about the drug
reaction clinically, it is simply impossible to determine the
positive reaction of the drug. The tendency of the ehdo-
crinologist and the drug therapy salesmen is to attribute all
the things enumerated to upsets in the various hormones.
There is no proof of it. . :..,,',...
A NEW METHOD OF CLOSING THE
. EUSTACHIAN TUBE IN THE RAD-
ICAL MASTOID OPERATION '
NORVAL H. PIERCE, M.D.
CHICAGO
Failure to secure a dry ear, following ,the radical
mastoid operation, which has for its purpose the .cure
of suppurative ear disease, is due almost exclusively to
an open eustachian tube, the persistence of hyperplas-
ticunucosa and the presence of dead bone. Of these
factors the former is the most frequent cause of failure.
The matter may be stated in this way: With a patulous
tube, a permanently dry ear is impossible, no', matter
how successful we may be in removing the hyperplastic
mucosa and dead bone. Such failures are. estimated
by different writers at from 10 to 50 per cent. Various
methods to secure closure of the tube have been em-
ployed, but though the technic of any .of them may be
as closely followed as possible, the results', so far as
concerns closure of the tube, are always .uncertain.
It is the experience of competent operators that they
may follow precisely the same .technic in, say, three
cases, and in one there results a closed tube, while in
the others there remains a widely patulous. or only a
partially closed tube. , '
THE PROBLEM
The eustachian tube consists of two parts, a movable
and an immovable part. The movable part is composed
of cartilage and soft tissue, and is closed except when
certain movements of the pharynx and velum palati
cause it momentarily to open. When the muscular acts
which cause the tube to open cease, the tube is again
closed, with the result that the air which entered it
during the open phase is forcibly injected into the bony
or immovable portion and thence into the cavum. The
immovable portion is a bony canal and the point, at
which the two portions join is the most constricted
portion of the tube, called the isthmus. Surgical
attempts at closure of the movable portion are rendered
undependable because of its inaccessibility: fey'the.ordi-
nary methods, and because the. rather rapidly/tecu.rrent
physiologic movements of this portion of- --the tube