Pe aRe Aes yy

New York State Veterinary College

ITHACA, NEW YORK

 

 

Stoddard, James L,.

Torula infection in man.
 
     
   

LIBRARY
NEW YORK STATE VETERINARY COLLEGE
ITHACA, N. Y.

 

 

 
Cornell University Libra
 

 

 

 

LIBRARY
NEW YORK STATE VETERINARY COLLEGE
ITHACA, N. Y.

 

 

 

 

 
MONOGRAPH OF THE ROCKEFELLER INSTITUTE FOR MEDICAL RESEARCH, NO. 6.
JANUARY 31, 1916.

TORULA INFECTION IN MAN.

A Group oF CASES, CHARACTERIZED BY CHRONIC LESIONS OF THE
CENTRAL Nervous System, witH CLrmnicaL SympToms
SUGGESTIVE OF CEREBRAL TuMOoR, PRODUCED BY AN
ORGANISM BELONGING TO THE TORULA GROUP
(TorvLA HIsTotytica, N. Sp.).*

By JAMES L. STODDARD, M.D., anp ELLIOTT C. CUTLER, M.D.

(From the Pathological Laboratory and Surgical Service of the Peter Bent Brigham
Hospital, Boston.)

PLaTEs 1 To 9.

(Received for publication, June 14, 1915.)

TF, Introduction .oisis ie dada paces eens dans Saas Ree ee tadeg 2
Ti. Historical x. ssc sa yas steaaine o Gee cchsd ads aaa she’s old) ¢ nately oslo nee a4 4
1. Evidence that coccidioidal granuloma is distinct from the other

diseases called blastomycosis............. 0.00 cece ceceeeees 4
2. Previous attempts to classify the blastomycoses................. 5
3. Cases of systemic blastomycosis with brain lesions.............. 7
A. Abstracts-of ten cases..........000 00 cc ccc cece eee nee 7
B. Discussion of cases.......... 0000s cece eee eee e ene 14

a. Characteristics of six cases similar to those of the
usual form of systemic blastomycosis and cutaneous

blaStOMYCOSIS: miccsd ass aa ons HORNS Nea eS 14
b. Four cases distinct clinically, pathologically, and bac-
teriologically 04 ccc Muse ensued. dence oeele ewe 15
4, Cases of systemic blastomycosis without brain lesions.......... 18
ITI. Two cases of torula infection, with autopsies.................. eee ees 20
Te: Casé Licsicatucneos coe See eieraeurideaned noun de Sea een 20
A. Discussion of Case I... 0.00... cece cece eee eens 38
2. Case [ois r snes cea diy eared Gas seas Cao cea eea ane eee 40
A. Discussion of Case ID ......... 0. cece eee ene eet eeeenees 57
IV. Classification of the diseases formerly called blastomycosis.......... 59

 

*Aided by a grant from The Rockefeller Institute for Medical Research.
1
2 TORULA INFECTION IN MAN

V.. Experimental, 0.0... c000 0. che bee VeRO RES ee eee Ee eee en eS 62
1. Materials and methods.............. 0: eee e cece e eter eeeee 62
2. Experiments on dogs......... 2000.0 c cece cnet eee eee neee 62
3. Experiments on rabbits............ 0000 c cece eee eee e nee ee 63
4. Experiments on guinea pigs. ............ 0. cece eee eee eee eee 65
5. Experiments on mice.......... 0.000 cece eect eens 66
6. Experiments on fatsicccris sine tad ee en eee tees ale tee Dat 68
7. Agglutination experiments............ 0... e cece eee e eens 75
8. Cultural characteristics of torula..... side ecttek Sa ere bouts Cretan i 77

VI. Table of differential points between torula infection, oidiomycosis, and
coccidioidal granuloma........... 0.0. e cece eee eee eee aee 79
MID DISCUSSION sini eradv ns Geto S eer Se at hade te beetle ale Neem aca 82
VIL. Suniilaty ss gccg ig vor oscar Ge cages cede weenie cinta tesa PASS 89
IX. Bibliography... sion ces Sioa eee eee fans SEE Geese OKs eRe 93
XX. Explanation of platese cscs sees as sce sae soning eee waa wee RES Oa pe 96

I. INTRODUCTION.

Two cases from the clinic of Dr. Harvey Cushing, at the Peter
Bent Brigham Hospital, presented at autopsy unusual lesions in
the brain and meninges. The histories and physical examinations
included such signs of cerebral tumor as to indicate decompression
or exploratory operation, but the pathological examination in each
case proved the complete absence of tumor. Lesions were found,
however, which fully explained the clinical symptoms and physical
signs. Enormous numbers of organisms having many points of
resemblance to those of blastomycosis occurred in all of the lesions
in such a manner as to leave no doubt of their causal relations.
Certain differences from the usual descriptions of the organisms of
the blastomycosis group and their lesions made a careful study nec-
essary to determine the relations of our cases.

Two problems which have received increasing attention in late years,
without great progress toward their solution, were thus brought
to our notice by the study of the cases,—the problem of cerebral
pseudotumor, and the problem of the relationships of the lower
fungi forming the group called blastomycosis. It seemed probable
that our cases might throw light upon both these questions.

In the study of the first problem, that of pseudotumor cerebri,
the literature furnished a considerable number of cases in which
symptoms and signs of brain tumor existed for a short or long time,

 

 
JAMES L. STODDARD AND ELLIOTT C. CUTLER 3

with subsequent recovery, or with indefinite autopsy findings. The
cases were mysterious, but many reports by competent observers
left no doubt of their existence. No well known disease could ex-
plain them; the promise of their solution lay in the finding of similar
cases fully studied and made clear, or in the investigation of little
known disease capable of producing such syndromes. To show that
our cases and experiments suggest a solution is part of the object of
this paper.

In trying to solve the other problem, that of the relationships of
the organisms of the blastomycosis group, we studied the literature
and made animal experiments. We used in our experiments pure
cultures of three different organisms: one isolated from a human case
of cutaneous blastomycosis, one from a human case of coccidioidal
granuloma, and one from Dr. Frothingham’s case of torula infection
in a horse. Inoculations were made in various ways upon several
species of laboratory animals, and agglutination experiments done
upon the infected animals. We realized that a great deal of work
had been done upon the cultural characteristics of these organisms,
but hoped that the careful study of the histological changes and the
serological reactions would give more definite information as to the
similarity or identity of the diseases produced.

Wolbach says, in regard to the blastomycotic group of organisms:

For the present we wish to emphasize the necessity for careful studies upon
the organisms by means of animal experiments, for it is by this method only
that the more striking differences between the types may be demonstrated.
Cultural methods as applied to bacteria have not been of value to us.

It is difficult, and often impossible, to make fungi produce a
characteristic fructification. None has yet been discovered for the
group of organisms causing the cases of blastomycosis localized near
Chicago.

In our second case cultures of the ventricular fluid made in bouillon
were injected into mice intraperitoneally, and at autopsy a meningitis
was found with organisms like those in the human meninges. In
the first case no spinal fluid was obtained on account of the danger
of puncture during pressure symptoms, and the technique of formalin
injection of the brain before removal prevented cultures at autopsy.
4 TORULA INFECTION IN MAN

The lesions were so peculiar, however, that when we succeeded in
reproducing them in animals no doubt remained of their identity
with the experimental ones.

As the study of our cases and experimental results progressed, we
found that another problem of importance came into relation with
our work. It is recognized that lesions similar to those of tuber-
culosis occur in other diseases; coccidioidal granuloma, for instance,
has often very similar lesions, but the parasite is so large that
its recognition is not difficult; blastomycosis occasionally produces
tubercle-like nodules; other fungi are known to produce reactions
more or less closely similar to tuberculosis. We found in our cases
and in our experimental work lesions so closely resembling tuber-
culosis that a differential diagnosis would be impossible without
finding the parasites. The parasites are so small that they could
easily be overlooked, and in the later stages of the lesions they dis-
appear entirely, leaving as a result tubercle-like nodules with no trace
of their origin. The lesions have typical caseation or consist of
miliary nodules without caseation. A number of human cases with
similar lesions in which no tubercle bacilli could be found have come
to our attention in this hospital. It is possible that many cases
diagnosed as tuberculosis may be due to this organism.

Il. HISTORICAL.

An enormous mass of literature has grown up with reference to lesions in
human beings, produced by organisms which bud without producing mycelium
in the tissues, and by some that are roughly similar, but that do not bud in the
tissues. All of these have been loosely classified as cases of blastomycosis. As
many observers long ago realized, there is nothing distinctive about the bud-
ding type of growth, for many fungi higher than yeasts have a stage in which
they reproduce by budding.

1, Evidence That Coccidioidal Granuloma Is Distinct from the Other
Diseases Called Blastomycosis.

It seemed possible, therefore, that the name blastomycosis would eventu-
ally be applied to a group of diseases produced by various organisms. This
has proved to be the case, for at least two distinct types have been separated
by different observers. They are the coccidioidal granuloma and the blastomy-
cosis types. The difference is simple; the coccidioidal organism never buds in
JAMES L. STODDARD AND ELLIOTT C. CUTLER 5

tissue but sporulates; the blastomycotic organism buds but never sporulates.
It is obvious that coccidioidal granuloma should never have been confused with
blastomycosis. There are further differences. Thus the coccidioidal organism
varies more in size, having large forms up to 30 to 40 in diameter, which pro-
duce many small ascospores which escape from the capsule. The coccidioidal
organism, furthermore, produces lesions more nearly like tuberculosis, and the
infection more often spreads by the lymphatics as well as by the blood. The
disease is almost invariably fatal (Wolbach, however, reports a case with recovery)
and occurs practically always in males who have lived in the San Joaquin valley,
California. Cases of blastomycosis have a wider distribution, the systemic
cases recover in 10 per cent of the instances recorded, and cutaneous cases
frequently recover without internal lesions. The patients are benefited, as a
rule, by iodides, which have no effect on coccidioidal granuloma.

Among German observers, Buschke does not recognize a difference between
the coccidioidal and the blastomycotic type, and confuses coccidioidal granu-
loma with coccidiosis. Wright regards them as different manifestations of
the same disease. Ever since the first observations by Posadas and Wernicke,
and Rixford and Gilchrist, evidence has accumulated that the diseases are really
distinct. Wolbach accurately described the life cycle of the organism of der-
matitis coccidioides, and found it entirely different from that of blastomycosis;
MacNeal and Taylor studied the life cycle of the coccidioides organism, summarized
the known cases, and concluded that the two diseases were distinct clinically,
pathologically, and biologically. Other summaries of the literature by Ophiils,
Ryfkogel, and Hektoen lead to the same conclusion Innumerable studies of
the organism of blastomycosis have never revealed the methods of reproduction
by endosporulation characteristic of the coccidioidal type. A possible source
of confusion in the early accounts was the occurrence, in apposition, of small
forms in coccidioidal granuloma, which simulated buds. True budding is not
found in coccidioidal. granuloma, but is constant in blastomycosis. A recent
paper by Brown and Cummins again establishes the differences between the
two diseases and adds evidence from animal experiments.

The first study of our cases with the many budding forms showed that the
picture was entirely different from that of coccidioidal granuloma. Our experi-
ments substantiated the statements made by the other workers as to the dif-
ferences in the two diseases, and showed us that the brain lesions we produced
with Coccidioides immitis were different in type from those of our cases.

2. Previous Atiempts to Classify the Blastomycoses.

Of .the remaining group of true blastomycoses, many attempts by Ameri-
can workers to make divisions have resulted in indefinite conclusions. Ricketts,
in his extensive study of organisms from seventeen cases of cutaneous blastomy-
cosis, made a tentative division into blastomycetoid, or organisms showing a
predominating tendency to bud, oidiomycetoid, or those showing a tendency to
6 TORULA INFECTION IN MAN

bud or produce mycelium, and hyphomycetoid, or organisms tending to produce
aerial hyphe. The differences were somewhat inconstant and of degree rather
than of kind. Hamburger studied organisms from four cases of systemic infec-
tion, and found them practically identical. Montgomery and Ormsby have
asserted that all types hitherto described have been observed at different times
in the same strain. Stober states that in his study of eleven strains the chief
difference was in the size of mycelium and spores. In all the organisms studied
mycelium production has occurred sooner or later; it is favored by room tem-
perature, dryness of the medium, and transplantation, while budding occurs
chiefly when there is abundant moisture and a thermostat temperature.

Of German workers, Buschke divides the blastomycoses into diseases produced
by true yeasts, saccharomycoses, and those produced by organisms which bud
and produce mycelium, the oidiomycoses. Two cases of true yeast infection in
man are sufficiently well established to deserve attention.

When we turn to botanical literature we find that there is a distinction between
the true yeasts and the torule (or yeast-like organisms which do not produce
endospores) on the one hand, and the oidium group on the other hand, in which
both budding and hypha production occur. The organisms of ordinary blastomy-
cosis evidently belong to the oidium group.

In animal experiments with lower fungi, it was observed that the torule
had marked pathogenic powers for animals,—greater than those of yeasts. Rabin-
owitsch, in an investigation of forty species of yeast, found only eight patho-
genic. Klein found a pathogenic torula in milk, and produced lesions in animals
with a pure culture; Cohn worked with the same organisms and obtained simi-
lar results. Nichols, in his experiments upon budding organisms in relation to
cancer, used two strains of torula and easily produced lesions. Many other
workers have confirmed these statements. Often a tendency for the organisms
to produce brain lesions is noted. Frothingham found a torula naturally pro-
ducing lesions in a horse, and in animal experiments proved its marked patho-
genic powers. It was possible, then, that an organism pathogenic for animals
would sooner or later be found to produce disease in man. We could not find,
however, cases reported as torula infection.

In studying the organisms of the cases of blastomycosis, it seemed of value
to look up the literature, first from the point of view of brain lesions, and to
tabulate all the cases classified as blastomycosis which involved the brain, and
then to look for cases like ours and for atypical cases; secondly, to tabulate the
cases of systemic blastomycosis without brain lesions, and observe similarities
and differences. ;

The results of our tabulations show that the cases of systemic blastomycosis
without brain lesions are closely alike clinically and pathologically, but,there are

divisions to be made within this group, as will be explained in detail in the dis-
cussion of the cases.
JAMES L. STODDARD AND ELLIOTT C. CUTLER 7

The cases with brain lesions, on the contrary, are a much less homogeneous
group. A number of cases stand out from the rest as distinctly atypical, but
similar to each other.

3. Cases of Systemic Blastomycosis with Brain Lesions.

A. Abstracts of Ten Cases.

Case 1.—Reported by von Hansemann.

Patient—A laborer, 18 years old, with tuberculosis of the lungs (bacilli in
sputum).

Present Iliness—Onset with apathy. Double abducens paralysis, vertical
nystagmus, unequal pupils, choked disc, slow pulse (46). Spinal puncture gave
at first a watery, later a slightly cloudy fluid, in which were at first few, then
more numerous lymphocytes, but always peculiar large round bodies considered
to be corpora amylacea. They were in part singly, in part doubly contoured,
of very variable size, some larger, some smaller than an erythrocyte, were color-
less and moderately refractive. There were also biscuit forms, and longer forms
in three to four jointed figures that recalled myelin drops. Cultures did not grow.

Diagnosis —Tubercular meningitis.

Course.—Then followed vomiting, involuntary discharge of feces and urine,
delirium, and coma, and death 19 days after entrance.

Autopsy.—Tuberculosis of the lungs. The pia and arachnoid were saturated
and the ventricles filled with a slightly cloudy fluid containing bodies similar
to those described above. On the surface of the brain were about sixty small
cysts, the largest the size of a hemp-seed, only slightly projecting above the sur-
face, and on section emptying themselves partially, leaving slimy colloidal masses.
Section showed similar cysts, often confluent, especially numerous in the corpus
striatum and its neighborhood. The corpus striatum and part of the thalamus
bulged out into the lateral ventricle with a myxomatous-like mass. Cultures
did not grow.

Microscopical Examination Cysts and tumor-like masses consisted of enor-
mous collections of yeast-like bodies embedded in a colloid-like substance, and the
surrounding brain substance showed very little reaction. In many colonies were
numerous large phagocytic cells, but for the most part the organisms lay free.
In the pia was a slight increase in lymphocytes and leukocytes, especially the
former, but the numerous organisms called forth almost no reaction of the menin-
geal tissues.

Case 2.—Reported by Tiirck.

Patient.—A woman, 43 years old, servant, entered the hospital on Apr. 21, 1906.

Past History—Scarlet fever in childhood; epilepsy with general convulsions
since the age of 4 years; operation for purulent neck glands at 11; later an oper-
ation for eye trouble. In recent years much coughing, but no hemoptysis.
8 TORULA INFECTION IN MAN

Present Illness ——A sudden onset at the end of March, 1906, with headache,
vomiting, and a chill. There followed weakness, frequent nocturnal or early
morning vomiting, and increasing stiffness of the neck.

Examination Apr. 21. A slight, poorly nourished woman; temperature 38° to
38.2°C. Frontal and occipital headache; cranial tenderness, and tenderness of the
stiff cervical, thoracic, and lumbar spinal muscles; general hyperesthesia toward pin
pricks, but no sensitiveness of the abdominal or leg muscles; positive Kernig; nor-
mal knee jerk; throat normal;scars on neck; palpable glands in the neck and axilla;
lungs with dulness at the apices, with rales and bronchial breathing;no sputum;
urine with much nucleo-albumin and mucin, and a trace of serum albumin.

Course—No marked change. No cranial nerve involvement. Temperature
irregular, 37° to 38°C., pulse 80. Lumbar puncture on Apr. 25 gave a clear
serous fluid under increased pressure. At the end of 4 weeks the condition of the
patient was the same as at entrance. This caused doubt as to the diagnosis of
tubercular meningitis, which was made on entrance. A second lumbar puncture
on May 3 gave 5 cc. under high pressure. The fluid was slightly cloudy.

Microscopical Examination—Many typical yeasts of round or oval shape.
The extraordinary finding made a verification necessary and a second puncture
was done with especial care on May 5. The specific gravity of the fluid was
1,008. A slight clot formed on standing. No tubercle bacilli were found, but
there were enormous numbers of organisms often joined as are yeast cells, numer-
ous small lymphocytes, rare red cells, and groups of large phagocytic mononu-
clear cells. On May 8 examination showed great emaciation; otherwise no change.

Blood Examination.—Red cells 5,210,000; hemoglobin 14.49 per cent (Fleischer-
Miescher) ; white cells 7,000; increased blood platelets.

Differential Count.—Polymorphonuclears 91.5 per cent; lymphocytes 3.6
per cent; large mononuclears 4.9 per cent. :

On May 10 an increasing white coat over the throat was noticed. The general
condition grew worse. Lumbar punctures on May 13, 14, and 15 gave results
similar to the earlier ones. On May 15 the temperature rose to 40.1°C. and the
patient died.

Autopsy.—Dura thin and smooth; a soft brain with slightly cloudy hydro-
cephalus, and cloudy edema of the meninges of the Sylvian fissure. The mucous
membranes of the tongue, throat, soft palate, and esophagus thickened in increas-
ing degree to the cardia, with a crumbly, dry, yellowish white layer. The lung
apices were thick with caseous nodules and cavities. A few small caseous mesen-
teric glands. Liver capsule thickened. A group of enlarged glands near the aorta.

Microscopical Examination.—Organisms in the ventricular fluid, but none in
the brain substance, or in the ependyma or choroid plexus. Large numbers
of these in the meninges, a few within cells, but with no reaction of tissues, except
occasional collections of lymphocytes. No organisms were seen in the vessels
or vessel walls. The esophagus showed loss of epithelium, with a fibrinous
deposit; joined organisms penetrated even to the striated muscle beneath. No
JAMES L STODDARD AND ELLIOTT C. CUTLER 9

mycelium was found. Cultures from the throat gave organisms similar to those
from the meninges, with no mycelium formation.

Organisms.—The organisms in the lumbar puncture were found to be elliptical
or ovoid, and equal in size to a red blood cell or slightly smaller. They almost
always had typical yeast joinings to the number of two to four elements. The
long diameter varied from 3.33 to 8.33, the width from 2.2 to 6.66u. ‘The
small ones were usually ovoid; the large ones approached a spherical form, and
often had a double contour. One or two poorly marked eccentric oval nuclei
were present, and one to eight refractive droplets. Many giant forms of from
10 to 154 were found, which were more refractive, with larger oil droplets, a double
contour, frequent yeast joinings, and a Gram-negative capsule. The phagocytized
cells showed a clear capsule almost equal in width to the yeast cell.

Cultures—Mycelium formation was never found. The yeast grew least well
on bouillon, gelatin, and agar. Growth appeared in 4 to 5 days and then pro-'
ceeded slowly. No liquefaction of the gelatin took place. Glucose was not
fermented. The best growth was obtained on glucose-agar. No spore production
was noted.

The atrium of infection was considered to be the throat.

Case 3.—Reported by Eisendrath and Ormsby. Final report by Le Count and
Myers.

Patient.—A Polish laborer, 33 years old.

Illness.—Discomfort in the right chest for 6 months, then numerous cutane-
ous lesions, followed in 4 months by edema of the face and extremities, muscular
weakness, emaciation, pallor, and elevated temperature. Shortly before death
incontinence of urine and feces was frequent. Death occurred during a convul-
sion, after 30 months’ illness.

Autopsy.—Blastomycotic bronchopneumonia; blastomycosis of the peri-
bronchial lymph nodes, of the pleura, the subpleural and retropharyngeal. tissue,
the liver, kidneys, colon, spinal column, external spinal dura, cerebellum, left
elbow, both knee and ankle joints, skin, and subcutaneous tissues. Emaciation.

Cerebellum.—On horizontal section nearly the entire external half of the right
lobe was involved in coalescent areas of softening with wide margins of necrotic
tissue in which small nodules were present.

Microscopical Examination.—Small areas of necrosis surrounded by granu-
lation tissue and inflamed cerebellar tissue. The margins of the lesion were made
irregular by very minute abscesses, some no larger than a fat cell, containing
mono- and polymorphonuclear leukocytes and organisms multiplying by budding.
Giant cells containing organisms were found at the periphery of the larger lesions.
The granulation tissue often occurred in peculiar masses, containing many cells
of chronic inflammation, and very small non-budding blastomycetes. Several
large empty capsules were found, with numerous small forms near by. Intact
large forms contained several granules resembling nucleoli, with pale areas oc-
10 TORULA INFECTION IN MAN

casionally visible about them. The small forms each contained one granule.
These appearances to the author indicated endosporulation.

Cultures.—Cultures from the cutaneous lesions and the sputum gave spherical
and oval organisms, much fine and coarse mycelium, later conidia and aerial
hyphe. Guinea pigs inoculated with the material developed local lesions.

Case 4.—Reported by Krost, Stober, and Moes.

Patient.—A Pole, 42 years old, resident in the United States for 4 years.

Illness —Pulmonary symptoms, then skin lesions. No brain symptoms were
noted except moroseness and irritability toward the end. Blood cultures positive
for blastomycetes. Duration of illness, 6 months.

Autopsy.—Miliary and nodular blastomycosis of the lungs, kidneys, spleen,
cerebrum, pleura, and lymph nodes. Multiple blastomycotic abscesses of the
cerebrum, cerebellum, prostate, pleura, skin, and osseous, muscular, and cutane-
ous tissue. Parenchymatous nephritis. Fatty changes, adenoma, and angioma
of the liver. General lymphatic hyperplasia. Atrophy of the testicles.

Brain.—Weight 1,400 gm. No gross lesions externally. On section, an
abscess 2 mm. in diameter was found in the cortex near the middle of the parieto-
occipital sulcus. A small nodule was found in the right parietal lobe, one in the
right temporal lobe, and two in the occipital lobe; the nodules were in the cortex,
usually at the margin of the white matter. There was a nodule in each lobe of the
cerebellum.

Microscopical Examination—There was much necrosis. ‘Apparent bands of
fibrous tissue between adjacent lesions, due to pressure,’ and numerous “ bizarré”’
giant cells. Blastomycetes were present in the lesions.

Case 5.—Reported by Lewison and Jackson.

Patient.—An Italian, 17 years old, resident in the United States for 4 years.

Iilness.—1 year’s duration. No nervous symptoms noted.

Autopsy.—Indurated blastomycotic bronchopneumonia of the left lung,
blastomycosis of the bones, subcutaneous tissues, pons varolii, inguinal and
axillary lymph nodes; acute vegetative mitral endocarditis, fatty liver, parenchy-
matous degeneration of the kidneys, hyperplasia of the lymphoid tissue of the
ileum, edema of the lungs, hydropericardium, atrophy of the heart, pancreas,
and testes, emaciation, and anemia. There was one blastomycotic nodule in the
brain, a few mm. below the ventral surface of the pons, containing numerous
organisms, and apparently formed by the coalescence of small lesions.

No note as to histology.

Case 6.—Reported by Myers and Stober. *

Patient— American.

Illness.—The only symptoms referable to brain lesions were irritability toward
the end, with occasional refusal of food and medicine, and delirium a few days
before death.

Autopsy.— Healing and discharging blastomycotic abscesses and ulcers of
JAMES L. STODDARD AND ELLIOTT C. CUTLER 11

the skin; blastomycotic abscesses of the bones and muscles; blastomycosis of the
lungs, peribronchial lymph nodes, liver, spleen, pancreas, kidneys, cerebrum,
and cerebellum; serofibrinous and fibrous pleuritis; parenchymatous nephritis;
chronic splenitis; hyperplasia of the mesenteric lymph nodes, pigmentation of
Peyer’s patches; decubital ulcers; emaciation.” The brain lesions consisted of
abscesses, about some of which connective tissue walls were present.

Case 7.—Reported by Bechtel and Le Count.

Patient.—A Swede, 38 years old.

Iliness—8 months’ duration. No nervous symptoms noted.

Autopsy.—Ulcerative blastomycosis of the upper lobe of the left lung; dis-
seminated blastomycosis of the lungs, liver, spleen, kidneys, adrenals, brain, sub-
cutaneous tissues, and skin; blastomycotic caries of the left iliac and right parietal
bones; fibrinous and fibrous pleurisy; hyperplasia of the tracheobronchial, cervical,
and mesenteric lymph nodes; red marrow in the femur; emaciation; atrophy of
the liver; fibrous mural endocarditis.

Brain.—Fourteen small lesions in the cerebrum, most of them located at the
bottom of sulci or at the junction of gray and white matter, a few in the basal
ganglia and deeper parts, varying from 2 to 4 mm. in diameter. Two larger
lesions in the cerebellum, one 15 by 11 mm. in the white substance between the
dentate nuclei and slightly above them, and one 4 mm. posteriorly.

Microscopical Examination —The histological note states only that there was
but little tissue reaction about the lesions.

Case §.—Reported by Riley and Le Count.

Patient.—An Italian laborer, 31 years old.

Iliness.—After an illness of 7 months the first nervous symptoms were noted
a few days before death as neck rigidity, slight strabismus, exaggerated reflexes,
and a positive Babinski.

Autopsy—Chronic blastomycosis of the upper lobe of the left lung; erosion of
the third and fourth thoracic vertebre; blastomycotic abscesses of the root of the
right lung; disseminated miliary blastomycosis of the spleen and liver; blastomy-
cotic basilar meningitis; abscess of the prostate, peritonsillar tissue, epididymis,
and skin (with ulcers), and subcutaneous tissues; caries of the foot bones; multiple
intercostal subpleural abscesses; blastomycotic tracheobronchial lymphadenitis;
fibrinous and fibrous pleuritis; fibrous peritonitis; emaciation and anemia; brown
atrophy of the heart; atrophy of the liver; slight sclerosis of the aorta and coro-
naries; emphysema of the lungs; ossification of the thyroid cartilage.

Brain.—A thick gray pus or fibrinopurulent exudate covered the base of the
brain, thickest over the circle of Willis. Aggregated masses of small size were
found in the fundi of the sulci, especially on the right, at times forming marble-
sized lesions. No deep lesions were found.

No note as to histology.

Cultures.--Cultures from the cerebrospinal fluid gave a pure growth of blasto-
mycetes.
12 TORULA INFECTION IN MAN

Organisms in the last five cases were all described in a common cultural report,
a partial summary of which follows. In the tissues, discharges, and pus they
appeared in pairs or clumps as round or oval bodies, with frequent budding. The
size varied from 3 to 30u, with 20u as the average size. There was an outer re-
fractile capsule and a clear central portion, the capsule varying in thickness with
the size of the organism, and occasionally being invisible in the organisms in old
foci. The capsule rarely stained. The central portion was granular and took
basic stains, and often contained three to ten spherical basophilic granules. No
hyphz were found in the tissues, and endosporulation was suggested only in Case
3. Incultures there was first a proliferation by budding, then hypha production,
and finally a formation of aerial hyphe. Occasionally segmentation of the my-
celium into spores was seen. Another slightly different type had a very fine
mycelium and small spores.

Case 9.—Reported by Rusk.

Past History.—Obscure. Previous history of “rheumatism.”

Examination.—A confused and talkative patient, becoming exhausted, semi-
stuporous, and unintelligent. Pupils irregular and reactive; knee jerks, Achilles
jerks, and abdominal reflex absent; diminished pharyngeal reflex; muscular
weakness; general diminished sensibility to touch and pain with preservation of
temperature sense; some tenderness on pressure over nerve trunks; fine tremor of
tongue, coarse tremor of extremities. Temperature 98°F., pulse 108, respiration
26. Stupor.

Course.—Stupor increased, and after an attack of hematuria the patient died.
‘Duration of observed course about 30 days.

Diagnosis.—Senile dementia.

Autopsy. Brain.—Cerebrospinal fluid not cloudy. Frontal convolutions
moderately atrophied. The pia was diffusely hazy.

Microscopical Examination—A chronic inflammatory reaction in the meninges,
over the base, along the Sylvian fissure, over the cerebellum and spinal cord, with
infiltration of lymphoid, plasma, and large endothelial cells. Giant cells with
peripheral nuclei and a circumscribed border were found. Organisms were
frequently enclosed in giant cells or endothelioid cells. There were no areas of
caseation and no miliary abscesses. The neuroglia of the first layer of the cortex
showed a diffuse and general hyperplasia, with increased fibrils and cells. No
alterations were found in the nerve cells. In the cortex were two kinds of lesions:
first, extensions from the pial lesions; second, circumscribed areas in the basal
ganglia, about 1 cm. in diameter, in which the tissue appeared forced apart
and filled with gelatinous material. There was a scanty reaction about these
lesions of the same type as in the pia.

Lungs.—The left lung contained a group of cavities from the limits of visi-
bility to 2 cm. in diameter, filled with a sticky gelatinous material. Laterally
from them was a firm triangular area containing tiny pale yellow foci. Sections
from the gelatinous masses showed them to be composed of a spherical, doubly
JAMES L. STODDARD AND ELLIOTT C. CUTLER 13

contoured organism, with a sticky, jelly-like capsule of varying thickness, lying
in an amorphous matrix. The organism proliferated by budding. The walls of
the cavities were formed by fibrous tissue, apparently not newly formed, but the
remnant of bronchi or alveoli, which the organisms appeared to be in the proc-
ess of eroding; the lining cells were swollen, the protoplasm was finely vacuolated,
and the nuclei were pyknotic. Some little distance further in the tissue the first
evidence of inflammatory reaction occurred, consisting of a slight accumulation
of lymphoid and plasma cells, with a few multinucleated cells.

Sections from the firm tissue showed a diffuse chronic granulomatous process.
with large giant cells containing the organisms. No caseation or interstitial
abscess formation was present. Organisms were scattered in the tissue, in cells,
and free. Occasional small hemorrhages were present.

No lesions were found in other organs.

Organisms.—Organisms were present in the pia in giant cells, or free singly,
or in zoogleal masses. Spherical organisms with a gelatinous capsule, proliferat-
ing by budding, filled the lung cavities and were seen in giant cells in the granu-
lation tissue. No cultures were made.

Case 10.—Reported by Rusk.

Patient.—German, 57 years old.

Past History.—Positive for lues.

Illness.—Weakness, morning expectoration, painful muscles, and shortness of
breath, were followed by transitory hemiplegias and syncopal attacks, and a
temporary loss of speech. Later there were times of confusion and forgetfulness
of decencies of dress.

Examination—Frontal headache and abdominal pain were the complaints.
The man was depressed, agitated, perplexed, unable to concentrate his attention,
disoriented for time, place, and person; had impaired memory, lack of interest,
unstable emotions, poor enunciation with slurring and transpositions; he realized
that he was sick, and had no delusions or grandiose ideas. His pupils failed to
react to light, the knee and Achilles jerks were absent, the pharyngeal reflex was
active. There were ataxia, a positive Romberg sign, a coarse tremor of the face
and tongue, diminution in the acuteness of pain and touch over the entire surface
of the body with differentiation of temperature. Temperature 101.8°F., pulse
95, respiration 21.

Spinal Fluid.—Positive Noguchi reaction; marked lymphocytosis.

Course.—Increased weakness; urinary retention; death after 24 hours’ stupor.
Total illness 2 years’ duration; nervous symptoms for 10 months.

Clinical Diagnosis —General paresis, tabetic type.

Autopsy.—Pial haziness and adhesions; cloudy cerebrospinal fluid in the lower
part of the spinal canal; a few granulations in the fourth ventricle.

Brain.—Slightly atrophic; weight 1,226 gm.

Microscopical Examination —The reaction was of the same type as in the pre-
vious case with the addition of a few poorly defined miliary abscesses and rare
14 TORULA INFECTION IN MAN

areas with necrotic caseated centers. The meningitis was distributed over the
whole cortex. A few small arteries had a subintimal infiltration. Giant cells
of enormous size were noted. Organisms were found throughout the pia. There
were similar extensions into the cortex, and the same glial reaction. The lungs
showed a bronchopneumonia with occasional small bronchi containing parasites,
and small granulomatous masses growing from the alveolar walls contained the
organisms. Larger granulomatous masses had typical giant cells with the organ-
isms. There was no caseation. , Granulomatous lesions containing the organisms
were found in the kidney. No cultures were obtained. ;

Organisms of the last two cases were spherical, doubly contoured, varying in
size up to 20u, with a homogeneous viscid capsule outside the wall, embedded in a
homogeneous matrix; staining weakly, with no differentiation of internal struc-
tures; the capsule stained with hematoxylin; reproduction was by budding only.
Naked forms were seen, free and within cells. Star-like forms occurred after
Zenker mordanting.

B. Discussion of Cases.

a. Characteristics of Six Cases Similar to Those of the Usual Form
of Systemic Blastomycosis and Cutaneous Blastomycosis.

All but four of these cases had either skin or subcutaneous tissue
lesions and presented the usual picture of blastomycotic infection,
clinically and in regard to the pathology and the characteristics of
organisms in tissues and cultures. The brain involvement was part
of a general infection, and clinically, at least, an unimportant part,
for no symptoms were produced except in two cases shortly before
death,—in Case 3, where the patient died during a convulsion, and
in Case 8, in which signs of meningitis were manifested in the last
days. We have studied the original reports of all.other reported
cases of systemic blastomycosis, and have found that in all these there
is involvement of the skin or subcutaneous tissues. Stober states
that the most characteristic changes in systemic blastomycosis are
cutaneous ulcerations, deep and superficial abscesses, and tubercle-
like nodules in the viscera. In only three cases has the systemic
involvement been the evident result of a spread from cutaneous
lesions; in many cases infection in the bronchi and lungs constituted
the primary focus, from which dissemination of organisms in the
blood resulted in the skin and subcutaneous lesions. Thus a pre-
dilection is clear for the development of the blastomycetes in skin and
subcutaneous tissues.
JAMES L. STODDARD AND ELLIOTT C. CUTLER 15

b. Four Cases Distinct Clinically, Pathologically, and Bacteriologically.

The four cases without skin or subcutaneous tissue lesions all have
brain lesions of such a nature as to cause the predominating clinical
symptoms throughout the disease. In von Hansemann’s case (Case 1)
there were choked disc, slow pulse, unequal pupils, vertical nystagmus,
double abducens paralysis, and death following vomiting, involuntary
discharge of urine and feces, delirium, and coma. In Tiirck’s case
there were headache and frequent vomiting, stiffness of the neck,
sensory hyperesthesia, and a positive Kernig sign, the symptoms
continuing for nearly 2 months. Rusk’s first case had confusion,
semistupor, irregular pupils, absent knee jerks, and tremors, with
death during stupor, 30 days after the first observation. His second
case had headache, depression, perplexity, impaired memory, transient
hemiplegias, speech disturbance, Argyll Robertson pupils, absent
knee and ankle jerks, ataxia, a positive Romberg, and coarse tremor.
The diagnoses were as follows: Case 1, tubercular meningitis;
Case 2, tubercular meningitis—ruled out later on account of the
long duration; Case 9, senile dementia; Case 10, general paresis,
tabetic type.

The marked difference in the character of the clinical histories of
this group of cases suggests a careful study of the pathological findings
in comparison with those of cases of blastomycosis showing skin or
subcutaneous tissue lesions. In Case 1 we find the brain lesions
consisting of cysts composed of enormous collections of yeast-like
bodies embedded in a gelatinous matrix, with very little reaction
about them. Numerous large phagocytic cells were in many colonies.
In the meninges was an increase in lymphocytes and leukocytes.
In the second case the brain lesions showed edema of the meninges,
with large numbers of yeast-like bodies, a few of them within cells,
with little reaction of the tissues except occasional collections of
lymphocytes; the organisms in cells having a clear space about them
equal to their diameter; in Cases 9 and 10 there were lesions in the
brain consisting of enormous numbers of yeast-like cells with gelatin-
ous capsules, embedded in a homogeneous matrix, with little or no
reaction about them; naked forms occurred also; the meninges had a
chronic inflammatory reaction with lymphoid, plasma, large endothe-
16 TORULA INFECTION IN MAN

lioid cells, and giant cells. There was an increase in glia cells. In the
second case there were similar lesions but so extensive as to result
in areas of caseation. We have had an opportunity to see a section
of a brain lesion from one of these cases, and were struck by the fact
that the organisms did not produce the lesion by the pressure of their
growth, but evidently by a solution of the brain tissue in their immedi-
ate neighborhood.

These pictures have no resemblance to those of the brain lesions of
blastomycosis with skin lesions. Case 3 showed small areas of
necrosis surrounded by granulation tissue and inflamed cerebellar
tissue, with minute abscesses in the margins containing polynuclear
and mononuclear leukocytes; Case 6, abscesses in the cerebellum and
cerebrum, with connective tissue walls; Case 8, a thick purulent
exudate over the base of the brain. In the other cases histological
notes are very scanty and the assumption seems to be made that
the lesions were much like those elsewhere; that is, with acute exu-
date and granulation tissue. Occasionally the reaction is slight in
amount.

Thus the first group of cases is peculiar pathologically (1) in that in
lesions within the brain substance there is produced a gelatinous or
homogeneous substance in which the organisms are embedded, and
about which there is a very slight chronic reaction; and (2) in that
there are meningeal reactions of varying degrees of severity, but
always containing only cells of chronic inflammatory type. In the
cases of blastomycosis with skin or subcutaneous lesions, the brain
lesions are described as abscesses with varying amounts of granu-
lation tissue about them, or in one case as a purulent meningitis.

It is important to know whether lesions in other organs differed
also. In Case 1 there were lesions of tuberculosis in the lungs, but no
other lesions. Case 2 had a lesion in the esophagus with the same
organisms as in the brain lesions, and caseous nodules and cavities
in the lungs (due to tuberculosis?). There were no other lesions.
Case 9 showed lesions in the lungs similar to those in the brain, with
sticky gelatinous material and only a very slight chronic reaction;
also areas of a chronic, non-caseating granulomatous process with
large giant cells. Case 10 had a bronchopneumonia, and granulo-
matous lesions in the lungs and kidney like those in the previous case
JAMES L. STODDARD AND ELLIOTT C. CUTLER 17

Granulomatous lesions occur in ordinary blastomycosis, but the
lung lesion in Case 9 is distinct. The freedom from extensive lesions
in other organs in comparison with the usual cases of systemic blasto-
mycosis, and the limited distribution of the lesions, are striking.

In the special group of cases the organisms produced the gelatinous
material in three instances; in the second case there were no lesions
in the brain, but wide clear zones occurred about the organisms when
in cells. The organisms in Case 1 were not described fully; in Case 2
they were elliptical or ovoid, from 3.33 to 8.33y in length, from 2.2 to
6.66u in width, the large ones more nearly spherical, with a double
contour. The interior contained only one or two eccentric oval
masses and a few refractive droplets. Giant forms from 11 to 15y
were found. In Cases 9 and 10 the organisms were placed in a homo-
geneous matrix and had wide clear spaces or gelatinous capsules
about them, varied in size up to 20p, and had little or no differentiation
of internal structure. In every case multiplication was by budding.
No mycelium could be found in any of the cases, in tissue or in culture.
In Cases 9 and 10 radiating projections from the cell wall were
noted after certain stains. The walls of these organisms stained
easily. These descriptions are markedly different from those of the
other group of cases, in which the organism appears in tissue as a
sphere from 10 to 15y in diameter, with little or no space between it
and other cells, but with a ;pace between the cell wall and the cen-
tral protoplasmic mass, which is finely granular and stains well, as a
rule. The cell wall has poor staining qualities. No notes of gelat-
inous material in the brain lesions ever occur.

Cultures from the first case did not grow; from the second case
cultures yielded organisms which did not produce mycelium or endo-
spores even after long observations; from the ninth and tenth cases
cultures were not obtained. Cultures of blastomycotic organisms
sooner or later produce mycelium.

This group of cases then is distinct clinically, and pathologically
from the cases of blastomycosis producing skin or subcutaneous tis-
sue lesions.

In a search for other cases to be correlated with these we found the
case described by Frothingham, through whose kindness we have
seen sections and have procured tissues and cultures. Part of a
18 TORULA INFECTION IN MAN

lobe of the right lung of a horse was enlarged, pinkish yellow, and
gelatinous, microscopically showing a loose connective tissue network
with budding organisms embedded in a homogeneous gelatinous
matrix. The other organs of the horse were not examined. The
organisms had for the most part a homogeneous non-granular interior,
containing only a few fat droplets. The cellular reaction included
varying numbers of large mononuclear cells, numerous giant cells,
and some connective tissue. Pure cultures were obtained. They
grew in 5 to 7 days, produced a slight amount of gelatinous material,
multiplied only by budding, did not produce mycelium, or ferment
dextrose, lactose, or saccharose, and did not form spores, even after
observations of growth for 12 weeks on gypsum blocks at varying
temperatures. They often formed large resting cells, and were facul-
tative anaerobic. After subcutaneous inoculation they produced sub-
cutaneous tissue lesions of the same type as those from which they
were obtained. Thus this organism, which was thoroughly studied,
was proved to be a torula, distinct from the oidium-like organisms of
blastomycosis, and distinguished from true yeasts by the absence of
spore production under special conditions.

The organisms found by Tokishige in lymphangitis epizootica of
horses produced mycelium in culture; the disease resembled glanders,
involving the skin, lymphatics, and respiratory mucous membranes.
It has no relation to the case described by Frothingham.

The similarity of the sections of Frothingham’s case to the group
of cases described above was so great that a series of inoculations of
pure cultures of the torula organism into animals was made in an
attempt to produce brain lesions for comparison with those of the
cases. The results will be given in detail later, but it may be stated
here that lesions identical with the brain lesions of Cases 1, 2, 9, and
10 were produced in rats, thus adding to the evidence that these are
true cases of torula infection.

4. Cases of Systemic Blastomycosis without Brain Lesions.

The study of the other cases of systemic blastomycosis without
brain lesions led us to the conclusion that Buschke’s cases of the true
yeast infections formed a group distinct from either of the two just
discussed. It is a small group; in fact only two undoubted cases can
JAMES L. STODDARD AND ELLIOTT C. CUTLER 19

be found. Many cases reported as such, especially in dermatological
literature, are incompletely reported, and of doubtful nature, as
Buschke himself states. The case of Busse and Buschke was so
carefully observed by both, and the pathogenicity of the organism
proved so conclusively by inoculations of a pure culture of the organ-
ism on the patient’s skin, with the reproduction of the lesions, which
contained a pure culture, that it can hardly be doubted. The lesions
were in the subcutaneous and cutaneous tissues, tibia, left ulna,
and left sixth rib, with perirenal abscesses, and lesions in the lungs,
kidneys, and spleen. The organism had produced a purulent infiltra-
tion in the bones as in streptococcus lesions; in the skin there was
overgrowth and destruction of epithelium with many giant cells.
The lung contained abscesses bordered by fibrous tissue containing
nodular accumulations of small round cells, in which were parasites.
The parasites here were not often intracellular. In the kidney was
an abscess with acute interstitial inflammation. The whole picture
to Busse was that of a chronic pyemia. The organism often had an
adventitious capsule in tissues; in culture it fermented sugar and did
not produce mycelium, even after long observation under varying
conditions; it produced spores readily on gypsum blocks. The re-
production was by budding, with frequent formation of joined bands.
In rabbits intraperitoneal injections produced a fresh fibrinous peri-
tonitis, with peritoneal nodules. In some tissues the organism had an
adventitious capsule. In mice and rats brain lesions were produced,
but no capsule formation occurred. The pathological processes in
general were those of degeneration .and necrosis, with inflammatory
reaction, which varied with the virulence of the culture.

The organism in this case is in a way a transition from the oidium
type to the torula. It resembles the oidium type in that the principal
lesions it causes are cutaneous or subcutaneous, with internal lesions
in the bones, lungs, kidneys, and spleen. It has less attractive power
for polynuclear leukocytes, sometimes has an adventitious capsule,
and is known to produce brain lesions in animals, in these respects
showing a resemblance to the torula group. It differs from the torula
group in not having a predilection for the nervous system in man,
but in affecting especially the skin, and does not produce the gelati-
nous matrix. Of course it is distinct culturally in its spore production.
20 TORULA INFECTION IN MAN

The case of Hudelo, Duval, and Laederich, in which there were
subcutaneous and cutaneous lesions, was exactly similar to Busse’s,
as regards all the characteristics of the lesions and parasites, as
Buschke, who studied both, states.

In Curtis’ case, where there were multiple subcutaneous tumors of a
myxomatous appearance, with little proliferation of connective tis-
sue, and some acute reaction, the organism usually did not occur in
cells, measured 2 to 7u in diameter, and had a clear capsule, with thin
layers. In animals it grew in masses with an adventitious capsule,
producing little reaction. No mention is made of the presence or
absence of sporulation. Fermentation occurred. This case is anom-
alous. It does not exactly resemble either of the above groups; on the
whole, it seems better to leave it unclassified until more observations
are collected.

We defer a summary of the differential points of these three groups
of true yeast, torula, and oidium infection, into which cases of
systemic blastomycosis fall, until the cases to be presented in the
paper have added further details.

' In the remainder of the paper oidiomycosis will be used to designate
the group of cutaneous and systemic diseases produced by organisms
budding in tissue and producing mycelium in culture, especially noted
near Chicago. The term blastomycosis confuses relationships and
should be discarded.

)

Ill. TWO CASES OF TORULA INFECTION, WITH AUTOPSIES.

1. Case I.

A woman, aged 42 years, a native of Vermont, resident in Florida,
entered the Surgical Service of the Peter Bent Brigham Hospital on
Aug. 14,1914, on account of headaches, failing vision, and dizziness of
3 months’ duration, nausea and vomiting, diplopia, unsteady gait,
difficulty in finding words, and disorientation.

Family History.—No record of definite nervous diseases, or of other
significant troubles was obtained. Married for 18 years, with no
children or miscarriages.

Past History.—Only minor illnesses. Always troubled with nerv-
ous headaches accompanied by lacrimation. Several attacks of |
JAMES L. STODDARD AND ELLIOTT C. CUTLER 21

sore throat. Mild photophobia habitual. No history of cardio-
respiratory, gastro-intestinal, genito-urinary, or skin diseases.

Present Illness.—About May 15 the patient began to have a severe
headache, persistent and throbbing, at first frontal, but later occipital,
accompanied for the first 2 weeks by a temperature ranging be-
tween 98° and 102°F. The headache did not stop; its most recent
situation was in the back of the head and neck. Vomiting not pre-
ceded by nausea and not related to meals occurred twice, once 2
months before entrance and once a week before. After May 15 the
patient’s eyes ached and tired easily. Her vision, previously good,
deteriorated until only the coarser type in a newspaper could be made
out. Diplopia was definite in the 2 weeks before entrance. Dizzi-
ness and a staggering gait were present from the beginning of the
illness. It was noticed early that the patient at times dropped words
and found expression difficult. Faulty spelling and omissions
occurred in her letters. Mental dulness began a month before
admission, and 10 days before there was said to be complete dis-
orientation for time, place, and person.

Previous Examination.—A choked disc; greater knee jerk on the
right; negative Wassermann blood test; white count of 10,200;
differential count of polymorphonuclears 58 per cent; small mononu-
clears 20 per cent; large mononuclears 12 per cent; eosinophils 10
per cent.

On entrance the following data were obtained. The patient was
a fairly developed, rather poorly nourished woman, lying with closed
eyes, tossing about restlessly, frequently throwing her hands up to
the back of her neck and crying with pain in her neck, arms, and shoul-
ders. She was dull, muttered unintelligible words, was completely
disoriented for time and place, but apparently recognized her family.

Physical Examination—Negative except for a blowing systolic murmur,
loudest over the 2nd 1.i.s., and also heard at the apex, and a white sticky pharyn-
geal exudate and a heavily coated tongue.

Cranial Nerve Examination—A symmetrical head with marked suboccipital
tenderness. Pressure over the neck and shoulders caused pain. Nerve I: the
patient apparently did not recognize coffee. NerveII: fundus o.u. disc distinctly
obliterated; lamina cribrosa gone. Swelling of the cup estimated at 3 to4 D.
Partial and in places complete embedding of the large and tortuous veins. No
22 TORULA INFECTION IN MAN

definite perivascular streaking. Arteries partially embedded. Macular region
and peripheral fundus clear. Nerves III, IV, and VI: pupils vary in equality;
both react to light; a tendency to exophthalmus. No ptosis. Apparently a
slight weakness of the left external rectus. No definite nystagmus. Nerve V:
negative. Nerve VII: question of some weakness of the right side of the face.
Nerve VIII: slightly better hearing on the right. Nerve IX: definite dysarthria.
Nerve X: pulse regular, very slight vomiting. Nerves XI and XII: negative.

Cerebrum.—Frontal: memory—some past memory; practically no recent
memory. The patient knew where she was born and schooled, but did not know
whether she had had breakfast or not. Orientation: completely disoriented
for time and place, but not for person. Habits and disposition: marked change.
The patient had become very disagreeable. Phases of negativism brought out
during the examination were evidenced by poor cooperation, refusal of orders,
etc. Temporal: a suggestive but not definite history of aphasia. None made
out on examination, although a certain amount of dysarthria was present. No
uncinate gyrus attacks or dreamy states. No hemianopsia on rough test. Parie-
tal: negative for sensory and motor disturbances. Occipital: negative.

Cerebellum.—Romberg positive with eyes open, the patient tending to fall back-
ward and more toward the left, even on a wide base. Gait: very uncertain,
although the patient was able to walk, with staggering, especially to the left.
Ataxia:, negative. Tests: finger to nose test fairly well performed, right and left.
Heel to knee test not cooperated in. Vertigo: some on standing. Diadokokine-
sia: fairly well performed.

Reflexes.—Superficial: epigastric, abdominal, and plantar not elicited. Deep:
no biceps, triceps, patellar, tendo Achilles, ankle clonus, Babinski, Gordon, or
Oppenheim on either side. Sphincters: not disturbed.

Positive Findings—Objective: patient dull, muttering, disoriented
for.time and place, complaining of pain in the neck, arms, and
shoulders; with suboccipital tenderness, questionable anosmia, marked
choked disc, occasional inequality of pupils, possible weakness of
left abducens, marked dysarthria, impaired memory, changed dis-
position and habits, positive Romberg, deviation in gait to the left,
with uncertainty; and no obtainable superficial and deep reflexes,
Kernig negative. Tongue and pharynx heavily coated.

Course of the Case.—On Aug. 15 a considerable resistance to flexion
of the neck was noted. The left side of the face apparently moved
less well than the right. There seemed to be great pain in the back
and neck. No definite Kernig was found. Suboccipital tenderness
and some fine nystagmiform twitches were discovered, but there
was no outspoken nystagmus.
JAMES L. STODDARD AND ELLIOTT C. CUTLER 23

There was no marked extracranial dilatation of vessels, and no
visible lack of parallelism of globes, although diplopia was complained
of. The mental disturbances with rambling speech were striking
features. The diagnosis was thought to depend upon internal hydro-
‘cephalus or general pressure.

Operation.—On Aug. 15 a right subtemporal decompression was
done. The dura showed no abnormality other than increased ten-
sion. On incising the dura the brain appeared tense, and exuded
fluid freely. There was some excess of fluid in the subdural and
subarachnoid spaces. No fluid was obtained on attempted ventricular
puncture.

Aug. 18. X-ray examination of the head was negative. Eye
€xamination showed a disc elevation of 13 to 2 D with considerable
perivascular streaking about the disc. Venous engorgement and tortu-
osity were still present to a moderate degree, and a few fine punctate
hemorrhages in both discs, with partial embedding about the disc.

On Aug. 20 the left pupil was considerably wider than the right.
On Aug. 21 Cheyne-Stokes respiration set in. The decompression
wound was bulging and tense. There was marked carphology.
The face was puffed more to the left, and the left lower side seemed
weak. The head was constantly turned to the left, and the right
lez was moved much more often than the left. The plantar reflex
alone could be obtained. The temperature was 103°F.

On Aug. 27 examination of the chest showed dulness to percussion
over the lower half of the left back with high pitched tubular breath-
ing and many fine crackling rales. At the extreme base the note was
flat and the signs were distant. A diagnosis of lobar pneumonia was
made, with beginning pleurisy with effusion.

After a period of profound stupor, the patient began to respond
imperfectly to questions. The left facial paralysis became more
marked. The optic nerve head was 1} to 2 D higher, and little punc-
tate hemorrhages were visible in the left eye. The head was still
held to the left and resisted straightening. The left pupil was still
dilated. The arm and leg on the right were never used spontane-
ously, but the right arm was drawn back on pin prick. The right
knee jerk was elicited for the first time. The hands moved aimlessly.
There was a normal plantar reflex on the right.
24 TORULA INFECTION IN MAN

The patient became rapidly worse, with cyanosis and dyspnea,
and died on Aug. 27, at 7.30 p.m.

Clinical Pathology —Urine examination: specific gravity 1,011 to
1,022; albumin, trace. Sugar 0. Sediment: bacteria, squamous cells,
a few white cells, very rare granular casts.

Blood examination: white count, on Aug. 14, 11,000; Aug. 17,
16,200; Aug. 20, 34,300; Aug. 26, 25,200. Hemoglobin 90 per cent
(Talquist).

Temperature course (rectal) on entrance 99.5°; on Aug. 15, 101.5°;
on Aug. 17, 103.8°; then variations from 101.8° to 103.8° until 2 days
before death when it was 102°.

Autopsy.—Permission for a complete autopsy was obtained and the examina-
tion made on Aug. 28, 13 hours post mortem. The body was put in a refrigerator
immediately after death. The brain was hardened in situ by an injection with
10 per cent formalin through both carotid arteries.

Body.——The body is that of a slightly built, normally proportioned white
woman, 165 cm. long. The skin is smooth, white, and free from edema or pig-
mentation. There are no discharges from external orifices, and no palpable
glands. There is slight postmortem rigidity and lividity. The head shows a
slightly bulging area, the site of a right subtemporal: decompression operation.
The pupils are equal and measure 4mm. The chest is narrow and small. The
breasts are slightly developed. The abdomen is level. The extremities show no
abnormalities.

Primary Incision.—There is found to be a thin layer of abdominal fat and thin
musculature.

Peritoneal Cavity—The omentum is free from adhesions and contains a small
amount of fat. There are about 20 cc. of clear, very slightly blood-tinged fluid
in the pelvic cavity. The peritoneal surfaces are smooth, gray, and glistening,
and there are no adhesions. The mesenteric and retroperitoneal lymph nodes
are of normal size. The gastro-intestinal tract appears normal. The° liver
extends 4 cm. below the xyphoid and 3 cm. below the costal margin in the right
mammary line. The diaphragm ascends to the fifth space on the right and the
fourth space on the left.

Pericardial Cavity.—The pericardial sac contains about 10 cc. of clear yellow
fluid; the surfaces are smooth and the heart lies entirely free within the cavity.

Heart.—Tricuspid valve 10.5 cm.; pulmonary valve 6.5 cm.; mitral valve 9 cm.;
aortic valve 5.8 cm. Right ventricle 3 mm. thick; left ventricle 12.5 mm. thick.
Weight 250 gm. The foramen ovale is closed. The endocardium covering the
cavities is normal. Except for slight diffuse thickening of the edges of the tri-
cuspid valve and slightly more focal thickening of the edges of the mitral valve
with slight roughening of the endocardium, the valves appear normal. The
JAMES L. STODDARD AND ELLIOTT C. CUTLER 25

aorta shows a few small plaques of sclerosis, especially about the orifices of the
coronary arteries. The coronary arteries are open throughout their extent.
The heart muscle is pale and appears slightly yellowish, but is uniform through-
out.

Right Lung.—The right lung is crepitant and slightly more firm than normally.
The external surface shows a light deposit of carbon, and lividity at the base.
The cut surface shows the carbon in a slightly moist, pinkish gray surface with
distinct alveoli. At the tip of the apex is an area 0.5 cm. in diameter, apparently
composed of fibrous tissue. The middle lobe has a slightly paler and moister
external surface, but on section shows a reddish surface with scattered lighter
areas apparently connected with the bronchi, exuding a thin white pus on
pressure. The lower lobe is similar, but shows in addition slight congestion.
The bronchi have a reddened mucosa with much purulent matter. The bronchial
lymph nodes do not seem enlarged.

Left Lung.—The upper lobe is similar to the right upper lobe. The lower lobe
is dark purple externally, and more solid than any of the other lobes. It is deep
red and homogeneous on section. Pieces sink rapidly in water. The bronchi
contain little pus, and there are no areas of induration about them. The bronchial
lymph nodes are smooth and pale, with black streaks of carbon.

‘Liver—Weight 1,205 gm. The external surface appears normal. Section
shows greatly dilated and reddened central veins. The gall-bladder and bile
ducts appear normal.

Kidneys.—Right weighs 120 gm.; left 145 gm. The right appears small and
the capsule strips with some difficulty, leaving a finely granular surface in several
places. The tissue cuts with slightly increased resistance. The vessels are
congested. The glomeruli are visible. The left kidney is similar to the right
except for a larger size, smoother surface, and less adherent capsule.

Spleen.—Weight 125 gm. The external surface is normal. On section it is
pale with prominent Malpighian bodies.

Pancreas.—Appears normal.

Adrenals.—The medulla is soft,—almost liquefied.

Gastro-Intestinal Tract.—There is no sign of ulceration or inflammation.

Bladder.—Appears normal.

Genitalia —The vagina appears normal. The external os is extremely small
and leads into a small cavity into which the probe point of small enterotome
scissors can hardly enter. Just at the level of the internal os the uterine wall
contains a small nodule 1 cm. in diameter, whiter and harder than the rest of the
uterine tissue. The left ovary is almost entirely converted into a sac containing
bloody fluid. There is a slight amount of ovarian tissue surrounding the sac.
The wall of the cyst has a smooth gray internal surface, and is about 1 mm. thick.
The ovary is freely movable. The right ovary has a number of yellowish hard
areas; on section one of them is circular, placed near the outer surface, and 4 mm.
in diameter. The pelvic peritoneum covering the organs appears normal.

Aorta.—The aorta has a few sclerosed areas in the abdominal portion, especially
26 TORULA INFECTION IN MAN

about the orifices of the branches, but they are slight, usually not measuring
over 5 mm. in diameter, and little raised above the surrounding intima.

Lymph Nodes—A calcified mediastinal lymph node is found, but the bronchial,
mesenteric, and retroperitoneal nodes are free from signs of tuberculosis.

Head.—On removing the calvarium the dura is found to be free
from adhesions to the skull except about the margins of the subtem-
poral decompression site. The dura is grayish white. The internal
surface of the calvarium appears normal. When the dura is stripped
back a number of not very strong white adhesions (more than the
normal number) passing to the pia are found. The base of the skull
appears normal.

Brain.—The brain is of normal size. The pia is definitely thick-
ened, and more adherent than normally. On the right side of the
brain in the temporal region, at the site of the decompression, is a
hernial protrusion. The vessels and nerves at the base oi the brain
appear normal; there is no arteriosclerosis. On removing the meninges
from the frontal lobes the convolutions appear slightly atrophied, with
slight roughening of the surface by the presence of very small pits
which are barely visible. There is some flattening of the convolu-
tions over the whole brain. Asymmetry is evident, the right side
being broader, especially in the temporal region.

On section the lateral ventricles are found to be dilated, the right
more than the left. There seems to be no ependymal thickening, but
the choroid plexus appears slightly thickened. The aqueduct of
Sylvius is blocked in the posterior two-thirds by dense white tissue.

Serial sections of the whole brain, about 3 to 6 mm. thick, were
made in a frontal plane. Frontal lobe: gray matter 3.5 to 5 mm.
thick. Meninges in the depths of the sulci much thickened. The fol-
lowing lesions were found. In the left superior frontal gyrus, 2.3 cm.
from the anterior tip of the lobe, is an area in the gray matter, border-
ing on the meninges, 2.5 mm. in diameter, filled with colorless gelati-
nous matter amid which are fine white dots and threads. Some of the
threads are adherent to the edge, others pass across the middle. In
the same convolution, 4 mm. further back, are two similar lesions in
the gray matter at the border of the white matter; one 0.5 mm., the
other 0.25 mm. in diameter, separated by a distance of 0.125 mm.
In the same gyrus at the level of the tip of the caudate nucleus are
JAMES L. STODDARD AND ELLIOTT C. CUTLER 27

two similar lesions, 0.5 mm. from the upper surface of the gray matter,
measuring 0.33 and 0.25 mm. The right superior frontal gyrus
contains several similar lesions; one 0.5 mm. in diameter, just anterior
to the caudate nucleus, another 0.25 mm. in diameter, 0.25 mm. fur-
ther off. One at the tip of the caudate nucleus is 3 mm. in diameter.
At the level of the anterior tip of the temporal lobes a lesion 0.75 mm.
in diameter is found, 0.125 mm. from the upper surface of the cortex,
and a similar lesion in the white matter 1 mm. below the gray matter.
In the middle frontal gyrus is a lesion 0.75 mm. in diameter.

The right temporal lobe has an area 2 by 1.3 cm., extending mesially
1.5 cm. from the surface, and including the whole middle and part of
the superior temporal convolutions, where there is loss of substance
and granulation tissue (area of decompression). For 0.9 cm. back from
this are minute spots of hemorrhage in thegray and whitematter. Back
of this decompression area, in the inferior frontal gyrus, just above the
insula, is a lesion 1.6 by 1.5 cm., extending 1.6 cm. within the surface,
of similar character. The internal capsule of this side is very soft.

Basal Ganglia.—The superior part of the putamen of the lenticular
nucleus has many small lesions about 0.5 mm. in diameter, similar
to those in the frontal lobe. Several coalesce into a streak 4 mm.
long, Y-shaped.

Occipital Lobes.—Similar lesions in the precuneus, 4.8 cm. from the
tip of the lobe. One is 1 mm. in diameter, and extends from the gray
into the white matter; another is 2 by 1 mm.

Cerebellum.—iIn. the right lobe, on the upper border, is a sharply
circumscribed area 4 by 6 mm., of translucent rather mucoid appear-
ance, surrounded by a white zone.

Corpus Callosum.—On the left is an area where the corpus callosum
is swollen, softened, and apparently disintegrated. It is 7 mm. in
diameter here as compared with 5mm. on the other side. This is
evidently the track of the needle used in the ventricular puncture.

The perivascular spaces throughout the brain appear slightly
dilated, and often contain a small amount of gelatinous material.

Symmeiry—At the anterior end of the thalamus the greatest
width—measured to the midtemporal convolution—is 7.7 cm. The
left side at the same level is 6.1 cm. broad. The white matter on
the right side appears much wider. The lateral ventricles have
28 TORULA INFECTION IN MAN

abnormal shapes; the general alteration in angles is apparently due
to a combination of dilatation and drawing to the right which is the
result of the herniation.

The lesions in the right temporal lobe and the corpus callosum,
and the asymmetry, are evidently the result of operative procedures.

Anatomical Diagnoses.—Right subtemporal decompression, right
ventricular puncture. Internal hydrocephalus (slight). Occlusion
of the aqueduct of Sylvius. Subacute or chronic meningo-encepha-
litis of unknown origin, with multiple foci of infection in the cere-
bellum, cerebral cortex, and basal ganglia. Lobar pneumonia of ‘the
left lower lobe. Left pleurisy with effusion. Slight bronchopneu-
monia of the left upper and right middle and lower lobes. Subacute
mitral endocarditis. Calcified mediastinal node. Passive conges-
tion of liver and spleen. Slight ascites. Slight chronic interstitial
nephritis. Leiomyoma of uterus. Stenosis of cervical canal. Cystic
left ovary. Postmortem softening of adrenals.

Microscopical Examination.

In general, a chronic leptomeningitis, consisting of the accumu-
lation of lymphoid, large phagocytic mononuclear, giant, and rarely
polymorphonuclear cells, with formation of connective tissue, especi-
ally about vessels, and with occasional caseous areas, is found over the
cerebrum, cerebellum, and spinal cord. Enormous numbers of spheri-
cal organisms, of varying size, with a definite wall, intra- and extra-
cellular, are present everywhere in the lesions. There are areas of
necrosis, but no circumscribed tubercles. Foci of infection of two
kinds are seen within the brain. One consists of a perivascular lesion
resembling the meningeal lesions. The other presents itself as a
small, spherical space in the cerebral tissue, filled with a non-staining
matter in which are embedded singly large spherical dark staining
organisms, which are occasionally seen budding. Few reactive cells
are seen within or around the lesion. The only reaction consists
of a very slight increase in glia tissue close to the lesion, and a moder-
ate number of large epithelioid cells and lymphocytic cells within the
lesion. The cerebellar lesion is of this second type. The more general
reactions of the brain consist of a marked cortical gliosis, and a diffuse
slight degeneration of ganglion cells and myelin sheaths.
JAMES L. STODDARD AND ELLIOTT C. CUTLER 29

Meningeal Lesions —The meninges are thickened in varying degree,
with connective tissue infiltrated with large phagocytic mononuclear,
giant, lymphocytic, and plasma cells. The most extensive lesion is
adjacent to the hippocampus; a somewhat less advanced lesion is
in a section of the island of Reil. The lesions are more extensive
in the sulci; in some regions of the cortex there is but little cell increase.

The advanced lesions show areas of necrosis or caseation, resembling
that seen in tuberculosis. In detail, these areas include a caseous
center, staining pink with eosin, in which indistinct remains of endo-
thelial and lymphocytic cells, and organisms, can be seen. Often a
moderate amount of fibrin, in fine threads, is present in the caseation,
but is more apt to be seen at its border. Immediately surrounding
the caseous material is a layer of elongated nuclei radially arranged,
some of which have fibroglia fibrils along their periphery. Numerous
large phagocytic endothelial cells and a few lymphocytes are present
in this zone. Beyond isa thin band of connective tissue containing a
few giant cells., In other places vessels may be seen surrounded by
increased connective tissue, beyond which are caseous zones.

Between the areas of caseation the lesion consists of connective
tissue of varying density, but on the whole reticular, in the meshes
of which are included many plasma, giant, lymphoid, and large
phagocytic mononuclear cells.

This chronic inflammatory tissue has many small spaces, entirely
or partially filled with the organisms to be described later. These
spaces for the most part are formed by the solution of the protoplasm
of endothelioid or giant cells. Often in necrotic material a small
space about 10 to 15y in diameter is seen to contain an organism in
the center. Giant cells are numerous and occur in two forms: one
with eight to ten centrally located oval nuclei; the other with more
spherical nuclei, peripherally located, and often entirely surrounding
the central part of the cell. Organisms are at first peripheral in
both forms, and occupy only the central portion after the outer por-
tion has been destroyed or filled. The giant cells, as a rule, are not
especially associated with nodular thickenings, but they occur diffusely.
There are no areas of acute exudate. Polynuclear leukocytes are
extremely rare.

Vascular Changes—The most frequent vascular change in the
30 TORULA INFECTION IN MAN

meninges is a proliferation of the adventitia of the vessels. Some-
times the endothelium is raised by a few mononuclear cells, or is
swollen, with a deposit of brownish pigment back of it.

Distribution.—Over the greater part of the cortex the meningitis
has not progressed to the point of necrosis or caseation, and corre-
sponds to the lesion just described as occurring between the areas of
caseation. Where there is the least amount of meningitis, the menin-
ges show slight thickening, a good deal of edema, and comparatively
slight cellular infiltration. A greater or less degree of meningitis is
present in all parts of the cortex.

Organisms.—Besides the organisms to be described later no others
could be found after search in sections stained with methylene blue
and eosin, the tubercle bacillus stain, and the Levaditi stain.

Reaction of the Coriex.—Throughout the cerebral cortex there is
great peripheral gliosis, varying somewhat in intensity. This takes
the form of a dense cortical felt-work of fibers as much as 28u thick
in the sulci, and 8 to 104 on the convexity of the convolutions. In the
subcortical regions are large numbers of neuroglia spider cells, and
some increase in glia cells extends down to the ganglion cell layer.
The fibril formation is relatively more marked than the cellular
reaction, but the large cells in close relation to fibrils are very evident.
In the marginal gliosis no cells are seen.

Organisms in the Meningeal Lesions——The size varies from 1.25
to 94. The large forms are spherical and have a wall 1p thick; the
smaller forms, which occur most often, measure about 3.5u in diam-
eter, and have a wall about 0.25y thick; many are ovoid, the diam-
eters being 2.75 by 3.5u, or 3.75 by 4.254. Measurements of some
of the smallest forms are 1.5 by 2u, or 1.25 by 1.54; some appear to be
1u in diameter. The wall is so thin in these very small forms that it
cannot be made out definitely.

The organisms are refractive and of a round or oval shape; the
larger ones have a wall appearing as a double line with a deeper
staining enclosed space; the smaller ones have thinner walls, so that
those about 3u in diameter have a wall appearing as a single line of
definite thickness. As stated above it is difficult to make out the
presence or absence of a wall in the very smallest forms, but the reg-
ularity of shape and the refractility suggest that there is a defi-
JAMES L. STODDARD AND ELLIOTT C. CUTLER 31

nite membrane about the protoplasm. Sometimes the organisms
stand out prominently; at other times they are difficult to see without
special stains. With hematoxylin the inner line of the wall stains as
a definite, sharply defined line, slightly thicker than the extremely
thin line outlining the outer surface. Cresyl blue gives a similar
staining reaction. With both, as well as with methylene blue, the wall
stains diffusely, so that the double contoured part appears darker than
the central part. Partly degenerated organisms lose their staining
properties. Mallory’s aniline blue connective tissue stain colors the
walls of the organisms a faint blue, and they stand out prominently
in contrast to the red tinge of the surrounding tissue. Levaditi’s
stain colors them a yellowish brown, giving a strong contrast to the
light staining tissues. The very small organisms do not show evi-
dent coloration of the wall with any staining reagent tried; consequently
their presence might easily escape notice; but this absence of color-
ation makes it easy to distinguish them from nuclear detritus; while
their refractility makes a less easy distinction possible from products
of degeneration. A stain with iodine results in slight brown color-
ation of the outer part of the wall of the largest organisms; in the
smaller ones no staining can be seen.

Interior of Organisms.—Usually eccentrically placed, is a small
particle, about one-sixth the diameter of the organism, roughly
spherical, which takes nearly all stains slightly,—cresyl blue, Marchi,
methylene blue, and Scharlach R. It is present especially in the
smaller organisms. In the largest ones it is almost invariably
absent; and it is often absent in organisms of all sizes. In frozen
sections stained with cresyl blue the cell interior is best made
out,—and then it is found that besides the material just described,
there are varying numbers of particles about one-half its size. The
masses are sharply outlined, and vary in size and number without
relation to the size or budding of the organism. In formalin-fixed
material teased out and mounted in glycerine or in salt solution plus
a drop of 10 per cent sodium hydroxide, these masses appear more
refractive than the organism, but less refractive than fat; they have
the same refractility as the droplets usually present in fungi. The
organisms do not show a clear zone between the cell wall and the
cell protoplasm, as is usual in the organisms of blastomycosis. The
32 TORULA INFECTION IN MAN

study of the cell interior is unsatisfactory in the meningeal lesions
on account of the age of the lesions and the degeneration of most of
the organisms.

Variations from the Usual Forms.—Occasional organisms are irregular
in outline, appearing partially collapsed, or are broken in places, or are
open showing a cup-like interior. These broken forms, except in their
size, resemble red blood corpuscles. They also differ in often having a
jagged or pointed edge, and in having different staining properties.

Reproduction.—The organisms occur in enormous numbers in the
meninges, but evidence of a method of reproduction is at first difficult
to find; probably because the lesion is a very old one and not pro-
gressing. The empty capsules suggested endosporulation, but no
evidence of such a process could be found. Budding was more strongly
suggested by the frequent occurrence in apposition of a large form and
a small form. Many definite buds were found, the protoplasm of
the larger cell flowing out, then becoming constricted to form a new
cell one-third to one-half the diameter of the original one. In one
case a cell 3.75 by 4.254 was producing a bud 1.54 in diameter,
which was partially separated by constriction. Budding occurred
most frequently in the medium sized forms; it was made out definitely,
however, in the largest and the smallest forms. The buds have thinner
walls than the parent organisms;some have no visible wall.

Occurrence of Organisms.—The greater part of the organisms occurs
in giant cells. Sometimes one-half of a giant cell is represented by a
space in which are four or five organisms; one arrangement is a space
containing one organism about 3 to 4, in diameter, and three to four
organisms 1.5 to 2.5u in diameter. The organisms lie in the space
separated from each other, unlessthey are budding. In other cases the
organisms pack the giant cells full of spherules 3 to 4u in diameter,
the protoplasm and nuclei of the giant cell having entirely disappeared.
Sometimes the bodies occur diffusely through the outer portions of
the giant cell, with very slight spaces, or no spaces, about them.
These organisms usually show no central masses. The organisms
are often found in phagocytic mononuclear cells, having the same
relation to the cell as in the giant cells. Many organisms occur
extracellularly. These usually have a more or less spherical space
around them about two to two and a half times their diameter,
JAMES L. STODDARD AND ELLIOTT C. CUTLER 33

especially when the organisms are large or when they occur in ne-
crotic material. The spacing of the organisms in necrotic tissue gives
a honeycombed appearance.

The larger organisms often have fine threads connecting them, which
stain easily with methylene blue. The threads are a little larger
near the organisms, taper slightly to a place midway between them,
are a little irregular in outline, apparently are attached to the cell
wall, and cannot be made out to haveawall themselves. Occasionally.
they are apparently formed by the separation of budding cells, and
on the whole do not appear at all like mycelium. They suggest some
mucoid or gelatinous substance which is drawn out into threads as
reproduction and separation take place, or is shriveled into filaments
by the action of a fixative; in short, they represent some extracellular
substance about the organisms. These filaments are more prominent
in the intracerebral lesions than in the meninges.

Relation of the Organisms to the Cells —The phagocytic giant cells
show all stages of degeneration. There may be spaces like those’
just described, probably resulting from a solution of the substance
of the cell; the nuclei become pyknotic, the remainder of the pro-
toplasm becomes finely vacuolated and stains faintly; finally the
nuclei disappear; then the protoplasm vanishes, and a space which
is occupied by a few organisms or packed full of them remains, bor-
dered by the old edge of the cell. When the organisms occur without
spaces about them the giant cells do not show such degeneration;
it is probable that in this case the giant cell has taken up dead organ-
isms which have not been able to destroy it.

Intracerebral Lesions——In the cerebral cortex, in the cerebellum,
and in the basal ganglia are lesions peculiar in the mode of extension
and in the reaction.

The Cerebellar Lesion.—This lesion measures 0.45 cm. in diameter
and consists essentially of a solution of the cerebellar cortex and a
filling up of the space by a colony of organisms, each separately
placed in a gelatinous matrix. Strands of tissue are seen crossing
the cavity, consisting of remains of the granular and molecular layers,
in apparently good condition. No layer seems to be more susceptible
to the destructive influence than another, and the almost spherical
outline of the lesion shows that the periphery is being extended uni-
34 TORULA INFECTION IN MAN

formly without regard to the tissue. The extension is plainly by
solution of the tissue, and not by the pressure of the organized mass.
Small masses of organisms, or even individual organisms, can be seen
sinking into the molecular or granular layers. Numbers of hyaline
remnants of cells, some of which were apparently large phagocytic
mononuclear cells, others lymphocytes, float in the cavity, and in
one place form a layer at the periphery. The small organisms often
pack these cells. No polymorphonuclear, plasma, or red blood cells,
no newly formed connective tissue, and no bacteria can be found with-
in the cavity.

Organisms in the Cerebellar Lesion —The usual size is from 9 to 13y.
Smaller ones 6u in diameter are frequent; occasional organisms are
3.54 in diameter. Near the periphery of the lesion organisms 1.5
to 2u occur rarely.

The organisms are spherical, and thick walled. The wall stains
a deep blue with methylene blue. Perhaps on account of the thick-
ness of the cell wall, no differentiation of the cell interior can be made
out. The organisms are homogeneous throughout, with a certain
clearness quite different from the solidity of corpora amylacea, and
the frequent occurrence of broken forms shows them to be hollow
spheres with thick walls. Often the outline of the organism is uneven,
as if there had been crushing, or partial collapse from the process of
dehydration. The smaller forms appear like the organisms in the
meninges. Threads connect the organisms as in the meninges, but
they are thicker and more definite in this lesion. With a cresyl blue
stain it is seen that the lesion is nearly filled with a substance staining
faintly which surrounds the organisms. This is irregular in outline,
very variable in extent, and resembles a mucoid or gelatinous material
which has been formed as a result of the activity of the organisms
and has constricted during the processes of preparation, so that it
adheres to and surrounds the solid materials in the cavity. The
threads seen in the methylene blue stain are thickenings in this
material, formed by the drawing apart of the organisms or the shrink-
age of the material. With the cresyl blue stain radiating thicken-
ings often project from an organism in great numbers, giving it a
star-like appearance. Rusk has described similar forms and they
resemble the gelatinous deposit described by Klein, Cohn, Busse,
JAMES L. STODDARD AND ELLIOTT €. CUTLER 35

and Nichols in their experiments with torule, and seen by us in our
experimental lesions in animals. It results in holding the organisms
in their peculiar separate placing. Budding forms are rare in this
lesion. Sometimes there is an appearance as of successive buds,
the budding cell itself budding before it is separated. No appearances
at all suggestive of endospore formation are seen. These large
forms with thick walls and few evidences of reproduction seem like
involution forms or like resting cells. They suggest the large cells
found in old cultures of torulz. The conclusion is evident that the
lack of reaction is not to be explained by a postmortem invasion of
the organisms; these large thick walled forms with little evidence of
activity and the presence of the desquamated mononuclear cells
indicate the end-stage of an old process.

Reactions of the Cerebellar Tissue to the Lesion—On account of the
relations of the meninges in the cerebellum it is difficult to say what
reaction is due to the meningeal lesion and what to the internal lesion.
There is a slight but definite increase in the glia tissue of the cerebellum
near the lesion, most marked where the infected meninges are close;
and since it is also plainly visible in the strands of molecular layer
floating in the lesion, and indeed is more marked here than beyond
the periphery, it is probable that there is a slight reaction of the glia
to the internal lesion.

Degenerations in the Cerebellum—On one side of the lesion the
Purkinje cells appear slightly shrunken and elongated, the nucleus
is poorly marked, the Nissl bodies are not clearly cut, and, toward
the periphery of the cell, the cell protoplasm takes an abnormally
deep blue with methylene blue and hasasomewhat cloudy appearance.
This change is more marked near the lesion than at a distance from
it; but around a considerable part of the lesion no change is demon-
strable.

Other Lesions within the Brain —Lesions similar to the cerebellar
lesion in all respects except size are found in sections of the basal gan-
glia. There is the same slight invasion with the large phagocytic
mononuclear cells, the same slight reaction of the glia cells, the same
absence of all acute exudate even in the smallest lesions, the same
method of extension by solution of brain tissue with the formation
of new lesions, and the same spacing and form of organisms. The
36 TORULA INFECTION IN MAN

differences are that the organisms are, as a rule, smaller than in the
cerebellar lesion; the average size is 7 to 8u instead of 10 to 11y; the
largest is 9u instead of 134; a good many are 4.5 to Su, and they occur
as small as 2u. Many of the medium sized or smaller organisms are
seen to contain a protoplasm staining dark red, irregularly granular,
without definite nucleus. The protoplasm fills the cell. Budding
organisms are more frequent here than in the cerebellum.

The cerebral tissue adjacent to the lesion shows little or no change.
The pointed projections between the organisms show how these sink in-
dividually into the tissue. Often no gliosis can be made out; at other
times there is a slight increase in glia cells, more rarely in glia fibrils.

Stages occur from these comparatively non-reactive lesions to peri-
vascular lesions similar to the meningeal lesion. There is more and
more cellular infiltration and increase of connective tissue, and less
evidence of the peculiar extension by solution of tissue, the organisms
becoming more and more intracellular and smaller in size. Often the
perivascular spaces become considerably dilated.

Another type of cortical lesion consists of the thrombosis of a vessel
with many organisms in the thrombus, with dilatation of the vessel
wall, and extension through it, forming a lesion of. the first or second
type. It is not possible to say whether all the lesions in the cortex
arise in this way. It would not be hard for the minute forms of the
organisms to pass through the vessel walls, and in fact evidence of
this was seen in three cases, although on account of the hyaline char-
acter of the forms definite conclusions are impossible.

A fourth, and fairly frequent type of cortical lesion consists of the
thrombosis of a vessel, with fibrin and blood cells in the lumen and a
surrounding exudation of lymphoid, large mononuclear, and plasma
cells, with formation occasionally of connective tissue. In these
lesions organisms were never found. It is possible that they are the
result of the occlusion of the vessel further on by the organisms, or
the organisms may have been destroyed.

Distribution of the Brain Lesions.—As in the gross examination, the
greatest numbers of intracranial lesions are in the frontal and olfactory
lobes, and in the basal ganglia.

Degenerations—Many of the small pyramidal cells, and a less
number of the large ones, show evidence of slight degeneration;
JAMES L. STODDARD AND ELLIOTT C. CUTLER 37

the cells stain faintly, the Nissl bodies are not made out, often the
nucleus is faint or invisible or shrunken and pyknotic, irregular in
shape or elongated. The cell body at times appears shrunken, the
cytoplasm irregularly stained. In the large pyramidal cells there is
apt to be a clear zone around the nucleus, with irregular staining of
the periphery. The polymorphous cells appear normal. In the
medulla the ganglion cells appear more normal, but here the Nissl
bodies are usually not made out and the cell body is occasionally
shrunken. The ganglion cell changes are more marked in the frontal
region. Here especially ganglion cells are often seen with two to
four trabant cells about them. Marchi stains show a slight diffuse
deposit of osmic acid in the myelin sheaths throughout the brain.

Miscellaneous Lesions ——The third ventricle shows lesions in the
choroid plexus of the velum interpositum similar to those in the
meninges, except for the absence of necrotic areas, and a larger pro-
portion of phagocytic endothelioid cells. One foramen of Munro
is partially occluded with a perivascular lesion. Sections of the lateral
ventricles show similar conditions in the choroid plexus.

Distribution of Basal Ganglia Lesions ——In the gray matter of the
median thalamic nucleus are many small lesions, the largest about
0.1 mm. in diameter, for the most part of the non-reactive type. In
one section 5 by 8 mm. in size, twelve small lesions are found. The
vessel sheath spaces are often greatly dilated and contain plasma
cells or lymphocytes.

Peripheral Nerves —Organisms are packed beneath the nerve sheath
of the eighth cranial nerve and are in the capillaries of the same
cranial nerve.

Aqueduct of Sylvius——Sections of the occluded aqueduct show a
mass of chronic inflammatory tissue with much vessel formation,
similar in general character to the meningeal thickening, and contain-
ing many organisms, which completely fills the lumen. The wall of
the aqueduct is thickened with glia tissue.

Ventricles —About the ventricles there is a dense gliosis.

Spinal Cord.—There is slight meningitis of the same character as
in the cerebral meninges.

Lungs.—In most sections there is a typical acute bronchopneumonia
in which no torula organisms can be found. Section of the left lower
38 TORULA INFECTION IN MAN

lobe shows a pneumonia with alveoli filled with polymorphonuclear
leukocytes, red blood cells, lymphocytes, endothelioid cells, and
fibrin.

Liver —No lesions. A slight thickening of the portal connective
tissue.

Spleen.—There are many nodules the size of miliary tubercles,
composed of epithelioid cells with poorly staining nuclei and a few
small giant cells. Although there is no central caseation the nodules
closely resemble the more chronic type of miliary tubercles. There is
sometimes some central necrosis. The nodules are scattered through-
out the tissue without reference to the follicles. No organisms of
any kind can be found in these nodules. The arteries of the follicles
show hyaline degeneration, and there is slight hyaline in the reticulum.

Kidneys.—A chronic lesion, about 2 mm. in diameter, composed of
a diffuse interstitial infiltration with lymphoid and plasma cells,
without caseation, occurs near the pyramids. In giant cells and
free are organisms which stain faintly and are evidently partially
destroyed. Other lesions consist of small accumulations of lymphoid
and plasma cells, without visible organisms, in the renal cortex.
Degeneration of near-by tubules is evident. :

Heart—No lesion. Histological changes probably postmortem
in origin. Sections of the mitral valve show organized vegetations
and cicatricial connective tissue.

Adrenals.—No lesions. Postmortem changes only.

Bronchial Lymph Node.—A small amount of carbon deposit, a
diffuse increase in connective tissue, a somewhat thickened capsule,
and hypoplastic germinal centers.

Ovary.—Some areas of hyaline connective tissue occur and there
are collections of large pale cells.

A. Discussion of Case I.

Explanation of the Clinical History —Evidently the internal hydro-
cephalus, to be explained by the stoppage of the aqueduct of Sylvius
by chronic inflammatory tissue, together with the chronic meningitis,
is sufficient to explain the general pressure symptoms of long duration.
The effect of the long continued pressure explains in part the cerebral
symptoms; the more localizing symptoms in the frontal lobes, basal
JAMES L. STODDARD AND ELLIOTT C. CUTLER 39

ganglia, cerebellum, and cranial nerves are to be further explained
by the lesions in these regions found at autopsy. Lesions such as
these, with their chronic course and variety of situation, are evidently
capable of simulating brain tumors with definite localizations so
closely that from the symptoms alone a differential diagnosis would
be impossible.

That the organisms are the causal factor in the lesions is proved
by the peculiar character of the lesions, by the occurrence of the
organisms in all the lesions in enormous numbers, by their occurrence
nowhere else, and by the absence of any other demonstrable agent.
It is unfortunate that cultures could not be obtained and Koch’s
laws fulfilled, but experimental lesions have been produced by us in
animals by torula organisms, which are so exactly like those of this
parasite in morphology and in reaction that there can beno doubt that
the organism found in this brain is a torula. The morphology of the
parasite with the clear homogeneous appearance of the large ones,
the small number of differentiated droplets in the small ones, the
tendency to multiply in and dissolve cells, to produce solution of
brain tissue with only a slight chronic reaction; the formation of a
wide clear zone about the outer wall, demonstrated by special stains
to be caused by a gelatinous deposit in the lesion which keeps the
organisms far apart and becomes converted into threads connecting
the organisms, and the good staining properties of the cell wall, all
differentiate this organism distinctly from the oidium, which has a
finely granular content separated from the wall by a clear zone, a
faintly staining or non-staining cell wall, slight or no production of
gelatinous material so that organisms lie close together, and a tenden-
cy to attract polynuclear cells and cause a proliferation of fibroblasts.
This organism is distinct from the coccidioidal organism in the smaller
size, the presence of budding, the absence of endosporulation, and
in the failure to attract leukocytes. The case is one of torula infec-
tion and is closely similar clinically and pathologically to the cases
collected from the literature.

How can the absence of reaction in the intracerebral lesions of long
duration be explained? There is a reaction in the meninges, so that
the lack of reaction in the brain cannot be due to the peculiar nature
of the organism. In morphology the parasite is old and slowly grow-
40 TORULA INFECTION IN MAN

ing, so that the lesions could not possibly be explained by an invasion
near the time of death. Something prevents the reaction of the cere-
bral tissues, and the most probable substance which could do this is
the gelatinous substance peculiar to these lesions. Probably this
gelatinous deposit greatly hinders all attempts at destruction of the
parasite by the host. The general gliosis cannot be ascribed to the
action of the organisms, but is to be explained, for the most part at
any rate, as the result of the long continued pressure due to the in-
ternal hydrocephalus. The resulting interference with circulation
may also explain the degenerations found.

The solution of tissue confined to the immediate neighborhood of
the organisms suggests that the poisonous products are very slightly
diffusible or are neutralized immediately.

Whether the intracerebral lesions arose from the meningeal lesion
by the carrying of organisms along the perivascular sheaths, whether
the reverse occurred, or whether both occurred independently, it is
impossible to say. No direct connection between a meningeal lesion
and an intracerebral lesion was ever found, except in the case of the
cerebellar lesion. We can only say that probably in many cases
the infection extended by way of the perivascular spaces.

The resemblance of the meningeal lesions to tuberculosis is interest-
ing. The chief differences between these lesions and those of tuber-
culosis are the absence of perivascular infiltration, the diffuse distri-
bution of giant cells without reference to nodule formations, the
large number of plasma cells in the tissue, and the occurrence of spaces
in the giant cells and tissues filled completely or partially with organ-
isms.

2. Casell.

The second case was that of a man, 39 years old, a teacher living in
Boston, who entered the Surgical Service of the Peter Bent Brigham
Hospital on Nov. 8, 1914. The history was complicated, and the
diagnosis had been uncertain. The main symptoms were cerebral,
and included a right hemiplegia, dizziness, and drowsiness, and a com-
plex referable to increased intracranial pressure. The clinical record
follows.

Family History. Negative.
JAMES L. STODDARD AND ELLIOTT C. CUTLER 41

Past History.—A severe attack of scarlet fever at 3 years of age.
Frequent colds with cough, but no chronic bronchitis, or chronic
cough with raising of sputum. No history of hemoptysis. Syphilis
and gonorrhea were denied. The highest weight was 180 pounds,
14 years before entrance; at entrance it was 170 (average weight).
There had been no cardiac or gastro-intestinal symptoms. Nocturia
occurred one or two times. There had beennoedema. There was an
error of refraction, for which glasses had been prescribed 7 years
before entrance, without subsequent correction. The secondary
sexual characteristics largely failed to develop. In March, 1914, an
acute middle ear was opened and drained with good result.

Present Illness —In the latter part of September, 7 weeks before
entrance, pain in the right ear came on. The ear was opened
and drained and a small amount of pus was obtained. The pain
was relieved and for a week the patient felt well. 6 weeks before
entrance a frontal headache began, with a temperature of 102°, and
the patient went to bed. 3 days later, on awaking, he found that
he had a right hemiplegia, affecting the arm most of all, then the
face, and to a less degree the leg. The hemiplegia gradually cleared
up, except for a residual weakness of the right arm. During this
same period of 6 weeks drowsiness was a marked symptom, the
patient sleeping most of the time during the day. There was no loss
of vision.

The patient was at the Massachusetts General Hospital under the
observation of Dr. F. T. Lord, from Sept. 21 until his admission to the
Peter Bent Brigham Hospital. During his stay there two spinal
punctures were made. The first one showed 57 cells (lymphocytes)
perc. mm. The Wassermann test was negative, the Noguchi posi-
tive, the gold chloride test positive for tumor or tuberculosis. The
second puncture fluid had 21 cellsperc.mm. Here again the Noguchi
test was positive and the Wassermann negative, but the gold chloride
test was positive for syphilis. A Wassermann test on the blood
serum was again negative. Cultures of the spinal fluid were made
on blood serum, and no growth was observed within 48 hours. A
guinea pig was inoculated with the fluid, and later killed, with nega-
tive results.
42 TORULA INFECTION IN MAN

The eye grounds were negative on several examinations in Sep-
tember and the early part of October.

Salvarsan was given twice, first on Oct. 16, 0.1 gm., then on Oct.
23, 0.3 gm. Previous to the salvarsan, mercury inunctions were
used for about 3 weeks. The night before the second administra-
tion of salvarsan the patient complained of headache. After the
inoculation, fever, occipital and bitemporal headache, dizziness, and
vomiting came on. The temperature soon went down, but the head-
ache and dizziness persisted until entrance to the Peter Bent Brigham
Hospital, and vomiting occurred three times without nausea. On
Oct. 26 examination of the eye grounds showed an early choked disc

without measurable swelling.
An x-ray of the chest showed a diffuse shadow at the roots of both
lungs. The tibia had some thickening of the bone.

Physical Examination at Entrance to the Peter Bent Brigham Hospital.—A
right-handed man lying in bed with his eyes closed, apparently from photophobia,
complaining of pain in the eyes. There was evident weakness of the right face
and arm, and some puffiness under the eyes. The veins of the upper lids were
dilated and the globes were prominent. The head had no areas of tenderness or
change in percussion note.

Cranial Nerve Examination—Nerve I: normal. Nerve II: the ophthal-
moscope showed in the right eye obscured margins on the temporal side, new
tissue in the cup, and a disc raised 2 D. The left eye had a more advanced choked
disc. There was a height of 3 D, with embedded vessels, and one punctate
hemorrhage. The surrounding retina showed considerable edema; the visual
fields were practically normal. Nerves III, IV, and VI: the pupils were irregular,
small, and reacted sluggishly, especially on the left. No von Graefe’s sign, no
nystagmus. Movements of eyeballs not restricted. Slight exophthalmus, no
diplopia. Nerve V: no subjective disturbance. Masseters and temporals
equally strong. Pain, touch, and temperature well and equally recognized.
Nerve VII: the right corner of the mouth was weak, and the right nasolabial
fold smoothed out. The eyes closed and the forehead wrinkled equally well on
both sides. Nerve VIII: a watch could be heard at 3 feet on each side. History
of right hemiplegia. Air conduction was better than bone conduction on both
sides. Galton whistle was well heard. Weber’s test was heard, but not referred
to either side. Nerve IX: no history of difficulty in swallowing and speaking.
Nerve X: pulse regular, 64 to the minute. History of vomiting three times.
Palate symmetrical. No vocal cord disturbance. Nerve XI: sternocleido-
mastoid and trapezius equally strong on both sides. Nerve XII: tongue protruded
in median line. Movements normal; no apraxia. Except for the impairment
JAMES L. STODDARD AND ELLIOTT C. CUTLER . 43

of motor power on the right, there were no symptoms referable to the frontal,
temporal, parietal, or occipital regions. Dynamometer test: right 10 kilos;
left 70 kilos. All the muscle groups of the right arm were markedly weak. The
right leg was not greatly impaired. There were no sensory abnormalities; no
astereognosis. Cerebellar examination showed dizziness; no nystagmus; inability
to stand on account of weakness, but no history of unsteadiness; impossible
diadokokinesia on the right, normal on the left; finger to finger and heel to shin
tests fairly well performed, allowing for weakness of the right arm and leg.

Reflexes—The abdominal and plantar were absent on the right. The epi-
gastric was not elicited. The cremasteric, plantar, corneal, triceps, and biceps
were present on both sides. The knee jerks were active to exaggeration, especi-
ally on the left. The Achilles jerks were active on both sides. Clonus was
absent on the left, poorly sustained on the right. Babinski and Oppenheim were
absent.

Examination of the right ear showed a little clotted blood about the external
meatus, a dark blackish green membrane with no light reflex, and a small scar
at the center. The left drumhead was bulging a little and reddened around its
‘ margin, with dim reflex. X-ray of the head was negative. The urine had a specific
gravity of 1,750; albumin 0; negative sediment. The white count was 9,100;
hemoglobin 75 per cent (Talquist). The temperature was normal. Wassermann
reaction on the blood serum was negative.

Positive Findings, Subjective-—Pain in the right ear, two attacks,
in March and September, 1914. Impaired vision of 2 weeks’ dura-
tion. Headache and fever for a few days 6 weeks ago. Right
hemiplegia, beginning 6 weeks ago and clearing up partially by the
time of entrance. Dizziness of 2 weeks’ duration. Headache of
2 weeks’ duration, located in eyes. Vomiting three times in the last
2 weeks, following the administration of salvarsan. Drowsiness of
6 weeks’ duration.

Positive Findings, Objective-—Weakness of the right face, arm, and
leg. Exophthalmos. Dilated venules of eyelids. Choked disc,
more marked in the left eye. Sluggish pupils. Exaggerated deep
reflexes, especially on the right.

Wassermann reaction (blood serum) negative.

Progress of Case-—On Nov. 13 a left subtemporal decompression
operation was done to relieve the increased intracranial pressure. The
dura was found to be quite tense, and there was considerable fluid.
The arachnoid and brain surface appeared normal.

The wound healed quickly and well. At first the headache was less,
but in a few days it returned and frontal symptoms, such as dis-
44 TORULA INFECTION IN MAN

orientation and loss of memory, with failure to recognize his family,
became more and more evident. Suboccipital headache was then
complained of. Drowsiness continued. By Nov. 21 the suboccipital
headaches had become very severe, and disorientation and hallu-
cinations were marked. Incontinence of feces and urine at night with
great restlessness were noted by Nov. 25. The eye grounds showed
no further changes. On Nov. 27 the headache seemed to be mostly
frontal. Examination on this date showed a deviation of the jaw to
the left. The disc swelling was 4 D,and the decompression very tense.
Vomiting occurred occasionally. There was an inspiratory hiccough,
and deviation of the tongue to the right. There were wrist clonus
and ankle clonus on the right. On Nov. 30 some apraxia was noted.
On Dec. 1 spinal puncture gave 15 cc. of fluid, not under increased
pressure. There was 1 cell per c. mm. (lymphocyte), and about
60 red blood corpuscles. On the same day eye examination revealed
a swelling of the discs of 4 D with exudate and edema spreading far
over the retina. On the left were many flame-shaped hemorrhages.
The tentative diagnosis at this time included temporal lobe abscess,
unilateral hydrocephalus, rapidly growing glioma, or vascular lesions.

Operation.—On Dec. 4 an osteoplastic exploration was made. The
brain was incised to a depth of 3 cm.,in the posterior part of the field,
and a needle inserted through this opening, through which about
150 cc. of cerebrospinal fluid were obtained. There was definite im-
provement following operation, but for only a brief period. Pulse
and respiration became irregular. A ventricular puncture was made
through the former opening, and 175 cc. of slightly turbid fluid were
withdrawn, in which 1 cell was found perc. mm. A Wassermann re-
action on the spinal fluid on Dec. 4 was negative. On Dec. 11, 200 cc.
of ventricular fluid were obtained, and a Wassermann reaction on it
proved negative. Following the puncture came relief of the sub-
occipital headache.

Ventricular punctures were made, with the following results:

Dec. 17. 150 cc. of yellowish fluid, 60 red cells.

“cc 22. 30 rT “ spinal “ 4 cc ce
90 “ “ ventricular ““ 18 “ “
ce 27. 118 ce ce ce ce 73 té ce

jan, 2" “ 84 “ “3 white cells.
JAMES L. STODDARD AND ELLIOTT C. CUTLER 45

Examination of the fluid gave: albumin, 0.016 to 0.12; sugar,
0.0786 to 0.0972.

It is of interest that on Dec. 22 the spinal fluid soon ceased flowing,
while the ventricle, punctured at the same time, continued to give
forth fluid. This seemed to prove the absence of a free communi-
cation between the ventricle and the spinal subarachnoid space.

On Dec. 7 Cheyne-Stokes respirations were noted at times. The
patient became more stupid and refused nourishment except milk.
The pulse became irregular, there being a pause every 6 to 10 beats.
On Dec. 8 the irregularity of pulse and respirations entirely disap-
peared, but returned on Dec. 11. On Dec. 12 paralysis of the right
side was practically complete, and there was marked aphasia. On
Dec. 28 there was difficulty in breathing, with rapid, noisy respira-
tions. On examination of the lungs coarse rales were heard over
the trachea.

After the last puncture there was the usual temporary relief of
symptoms, and during the evening the patient seemed brighter than
usual. The pulse was good, the respiration regular. The patient
died during the early morning.

Autopsy.—The autopsy was performed 5 hours post mortem. The brain was
hardened im situ by an injection of 10 per cent formalin through the carotid
arteries.

Externally the body is that of a moderately well nourished man and shows no
abnormalities other than a herniation of the brain in the left parietal region. No
lymph nodes are palpable. There is no pigmentation of the skin. No scars
are visible. The testes are large and firm.

The peritoneal cavity appears normal.

In each pleural cavity, at the apices of the lungs, are found a few string-like
adhesions. The cavities are free from fluid.

The pericardial cavity appears normal.

Heart —Weight 350 gm. The foramen ovale is patent to a diameter ‘of about
4 mm., but the valve-like action of the folds of endocardium about it must have
made the opening functionally unimportant. The valve segments all appear
normal except for a very slight fibrous thickening of the edges of the mitral valve.
On the aorta are several spots of sclerosis about 2mm. in diameter. The coro-
nary arteries show a slight sclerosis, but the lumen is fully patent.

Lungs.—The pleural surface of the apex of the right lung is deeply puckered with
folds from 1 to 1.5 cm. deep. The upper lobe is shrunken and has a large area of
consolidation, which cuts like hard fibrous tissue, and is composed of small,
46 TORULA INFECTION IN MAN

firm grayish white nodules varying in size up to 2 mm., not circumscribed, and
set in a hard slate-gray tissue. The mass as a whole is irregular, with nodular
extensions into the surrounding tissue. It is dry and anemic looking. The
consolidation extends to the pleural surface and is surrounded by fibrous masses
extending into the lung. There is no calcification, nothing even suggesting
caseation, and no cavity formation. The bronchi pass into the fibrous area with
dilatation and are lost in it. In the lung elsewhere are scattered small miliary
nodules resembling those in the consolidated area, and on the pleural surface are
a number of small flat nodules, not elevated, extending in pointed processes into
the lung beneath. Some of these are in small masses.

The left lung shows a similar condition, but the consolidation is more extensive,
and occupies most of the upper lobe, even to the root of the lung. The puckering
of the surface is very marked.

The bronchial lymph nodes are enlarged, pigmented, indurated, but neither
caseated nor calcified. The mediastinal nodes are similar to the bronchial,
showing on section yellowish white areas.

Liver.—Weight 1,920 gm. The external surface and cut section appear normal.
The bile passages are open and appear normal.

Spleen.—Weight 280 gm. When cut it is found to be soft, scraping off easily
with the knife. The surface is deep red, with prominent Malpighian bodies.

Pancreas.—Appears normal.

Gastro-Intestinal Tract.—Appears normal.

Kidneys.—Weight of each 200 gm. The capsule strips easily, leaving a smooth
deep red surface. On section deep congestion is seen, with prominent markings.

Adrenals.—Slight postmortem degeneration.

Bladder, Prostate, Seminal Vesicles—Appear normal.

Aorta.—Slight diffuse sclerosis of the abdominal portion.

Head.—There is considerable adhesion about the site of the bone-
flap operation.

The calvarium, on removal, appears normal, as does the external
surface of the dura. When the removal of the brain is attempted, it
is found that there are very strong adhesions in both cerebellar fosse,
which prevent the removal of the cerebellum without tearing it.
There is no exudate here, however, or evidence of acute inflammation.
A piece of the dura with adherent cerebellum is put into Zenker’s
fluid at once. The middle ears are opened. The right appears nor-
mal, the left shows a slight amount of mucoid material.

Brain.—There is a large bulging mass on the left side at the site
of the decompression operation. The convolutions are flattened.
The dura, except in the immediate vicinity of the wound, is not
JAMES L. STODDARD AND ELLIOTT C. CUTLER 47

adherent. The pia is slightly thickened and cloudy, but hardly to
a noticeable extent. On the upper surface of the cerebellum, partic-
ularly on the right side, but to a certain extent elsewhere, there is a
very definite thickening of the pia arachnoid, which has stripped
smoothly from the dura, but is firmly adherent to the cerebellum.
The same thickening of the pia arachnoid with formation of adhesions
is found posteriorly, more marked on the right.

The brain is then cut into parallel frontal sections from 3 to 6 mm.
thick.

Section through the frontal lobe shows dilated ventricles and
normal cortex. In a section through the anterior commissure there
is found on the left side, just above the anterior commissure, in the
lower extremity of the internal capsule, a lesion 4 by 2 by 3-mm.
anteroposteriorly, yellow, soft, with loss of brain substance.

5 mm. further posteriorly, at the level of the amygdaloid nucleus
and the anterior tip of the caudate nucleus, is a lesion 6 by 3 mm.,
extending 6 mm. posteriorly, consisting of an area of induration with
a yellow soft spot in the center, situated in the globus pallidus and
lower part of the internal capsule on the left.

A section through the head of the caudate nucleus shows greatly
dilated ventricles. The dilatation is equal on both sides. The
horizontal diameter of the ventricles is 2.2 cm., the greatest vertical
diameter (measured diagonally) 3.3 cm.

At the level of the tips of the anterior horns of the ventricles the
cortex of the superior frontal convolution is 2.5 to 3.5 mm. thick, of
the midfrontal 2.5 mm., of the inferior frontal 3 to 3.5 mm., of the
uncinate gyrus 1.5 to 2 mm.

In the lenticular nucleus on the right, and extending very slightly
into the internal capsule, is an indurated pale area 4 by 2.5 mm. made
up of several spherical nodules 1 to 2 mm. in diameter. It extends
9 to 10 mm. anteroposteriorly.

The third ventricle, the foramen of Munro, and the aqueduct of
Sylvius are dilated. The brain stem appears normal. There is no
evidence of change in the posterior lobes.

The brain is softened in the vicinity of the operation.

Cerebellum.—On section, in the left upper part, posterior to the
dentate nucleus, is an area seemingly of purulent infiltration of the
48 TORULA INFECTION IN MAN

tissue, with a matting together of the cerebellar leaflets. The lesion
extends into the cerebellar tissue and resembles tuberculosis strongly,
but the definite caseation is distinctly absent. The lesion is more
diffuse than a tuberculous lesion. On further section this lesion is
found to extend posteriorly to the surface of the cerebellum. Another
similar but smaller soft mass is found in the right upper posterior
portion. It appears like a softening of the tissues, without a definite
line of demarcation. Even after hardening it is soft. It extends
posteriorly as does the other lesion, and in the posterior part cuts
with much resistance, and appears like a meningeal process with
extensions into the cerebellum.

No exudate can be seen on the base of the brain.

The spinal cord is removed, but is not observed to be abnormal in
gross.

Microscopical Examination.

Cerebellum.—Section through the lower surface with adherent
dura. The dura is greatly thickened by dense connective tissue, and
is separated from the cerebellar cortex by a wide mass of chronic
inflammatory tissue. On lower power observation it is seen that
this tissue has areas of irregular shape where there are few cells and
much. connective tissue; occasionally these areas have an almost
spherical form. Between the denser areas the tissue is thickly in-
filtrated with mononuclear cells. Some areas suggest tubercles; there
is a central necrotic or almost caseous mass, with dense connective
tissue about it. A prominent element in the tissue as a whole is
the large number of giant cells, which are scattered about diffusely,
but are more numerous in the denser areas. There are a few small
collections of polynuclear cells, slightly larger than giant cells. In
giant cells and outside of them can be seen clear spaces, in which small
organisms are barely visible.

The cerebellar cortex is partially necrotic and replaced by this
tissue, which extends into it in thin strands, so that the molecular
layer has a shredded appearance, while the granular layer appears
to be intact. High power observation shows that the necrotic areas
have in the center caseous cell detritus, in which, especially near its
edge, polymorphonuclear cell nuclear detritus and remains of the
JAMES L. STODDARD AND ELLIOTT C. CUTLER 49

organisms to be described later can be made out. Directly border-
ing the necrotic area is connective tissue arranged in general radially,
and containing occasional polynuclear, mononuclear, and plasma
cells; the mononuclear cells here also contain the bodies. Giant
cells are not especially numerous in this zone. Beyond is the main
mass of granulation tissue.

The major part of this tissue is made up of connective tissue which
forms a loose network in the meshes of which occur principally
plasma and giant cells; lymphocytes occur in much smaller numbers,
and polynuclear cells are still more rare, but are seen especially in
small collections about the size of giant cells. Plasma cells with
several nuclei are occasionally found. The giant cells are of two types.
One variety has clear oval or spherical nuclei arranged along the
regular definite border; the other has long spindle-shaped nuclei in
parallel fashion, and long prolongations of the cytoplasm. The most
striking feature of the giant cells is the spaces filled with the organisms.

Organisms.—In size they range from slightly over Iu to 7.5u. As

‘in the preceding case, the large forms are spherical, with a wall about
0.754 thick. The size of the most frequently occurring organisms
is 4.5 to 5.54 in the longest diameter; these forms are slightly ovoid,
the diameters of two typical organisms being 4 by 5y, and 3.5 by 5.54;
some forms are so ovoid that they measure 2.66 by 4.66u. The very
small forms are often much elongated, measuring 1.5 by 2.75u or
1.87 by 3.5u. As in the previous case, the wall varies in thickness
with the diameter of the organism, and it is impossible to make it out
in the smallest organisms. They have the same general refraction as
in the previous case; the wall of the large ones is outlined by a double
line, and stains in the same way.

The chief difference between the organisms in this case and the
first case is in the presence of a larger amount of staining material
within the cell; this is to be explained largely on account of the fact
that in the second case tissue was put into Zenker’s fluid only 5 hours
post mortem. In sections of the material preserved in formalin there
is the same internal structure as in the previous case; that is, a few
globules or droplets taking many stains slightly. In the Zenker
material stained with aniline blue connective tissue stain, irregular
red-staining masses or specks are seen. In the smallest organisms
50 TORULA INFECTION IN MAN

these masses are often elongated and slightly curved, and fill more
than half the cell space, giving a sickle-like appearance. Often there
are two or more separate masses, perhaps connected with a thin thread,
or perhaps merely four or five little specks; but no appearance was
ever traced out suggestive of a mitotic or amitotic division. In the
slightly larger forms the masses occupy a smaller proportion of cell
space and show much more variety in shape and arrangement. There
may be a circular form with thickenings in the outline; or a long
bar with curved cross bars, or a Y-shape or X-shape, or small specks.
Occasionally the mass is round or oval, with one or two darker points,
and apparently a membrane, and resembles a nucleus closely. Here
again no correlation can be made out of changes in the chromatic
material with the reproduction processes, except that when bud-
ding occurs the large organism sometimes contains the material in
small masses, and some of the smallest of these apparently pass out
into the bud. More often, a single large chromatic mass, containing
practically all the chromatin of the cell, is seen at the budding end.
As the bud forms the mass shows a concavity toward the cell interior,
and a prolongation of the mass passes out into the bud and then breaks
off as the bud separates. This corresponds in general with the changes
found by Kohl in torule. In the large sized organisms, as in the
previous case, chromatic material is slight or absent. The chromatic
material stains with hematoxylin and with methylene blue, but as
the latter stains the wall:the same color it is not so useful for the
study of the internal structure. It takes the Marchi stain, and the
Scharlach R stain slightly, as in the previous case. With formalin
tissue teased out in salt solution, with a drop of 10 per cent sodium
hydroxide, the organisms stand out strongly from the tissue elements.
Iodine cannot be made out to stain the cell wall.
Reproduction.—Definite buds are much more frequent than in the
other case. The medium sized cells are the most active; the process
consists of an extrusion of a part of the cell interior at one end, which,
when it attains a diameter of 2.5 to 3.54, becomes separated from the
parent cell by a constriction. The cell wall at first bulges out, then
the part enclosing the bud becomes thinner as the bud enlarges, and
often appears as a very delicate membrane. Sometimes very small
cells are formed, with no visible wall. When small organisms divide,
JAMES L. STODDARD AND ELIJOTT C. CUTLER 51

the bud is more nearly the size of the parent than in the other case.
Sometimes a multiplication of the very smallest organisms by a bud
the same size as the parent is suggested. The larger organisms bud
rarely, but when they do they either send out a protoplasmic mass
with an extremely thin membrane or bulge out the whole cell wall.
Measurements of budding cells are as follows: a cell 4.25 by 5.5u is
connected by a thin isthmus with a cell 2.25 by 3.75; a cell 4.75 by 6u
has just become separated from a cell 2.5 by 3.75u; a cell 4 by 5y is
connected by an isthmus 0.75 thick with a mass 1.5 by 2.5y.

Occurrence of Organisms.—More frequently than in the previous
case the organisms partially fill spaces in giant cells, endothelioid
cells, or tissue. Often one large organism is seen near the center
of a space, with many small ones about the periphery; probably the
giant cell took up one organism, which produced another cell by bud-
ding, and then by continued budding a small colony was produced,
with continued enlargement of the cavity. The original organism be-
comes large and thick walled, representing an involution form or rest-
ing cell. Earlier stages of this process are easily found; in one case a
medium sized organism in a giant cell surrounded by a thin space
was pushing a bud into the protoplasm of the cell. Occasionally
organisms lying in a space are connected by a thread exactly similar
to the filaments seen in the previous case, and evidently caused by a
drawing out of material about the cells as they separate.

Relations of the Organisms to the Cells——The organisms have the
same destructive effect upon the giant cells as in the previous case.
The frequency of budding within giant cells shows even less evidence
of ability of the giant cells to harm the organisms. Whether the
vacuole in which the organisms lie is a digestive vacuole or whether
it represents a lytic effect of the organisms upon the cell cannot be
determined definitely. As other tissues are definitely dissolved, and
as the vacuole enlarges until the cell disappears, it is possible that it
does represent histolysis of the giant cell by the organisms.

There is a definite lytic effect of the organisms upon the cerebellar
cortex. Organisms are seen in the outer parts of the molecular
layer, and the tissue about them becomes loose and full of spaces, in
which plasma cells and then fibroblasts appear.
52 TORULA INFECTION IN MAN

The cerebellar cortex reacts by the production of a definite gliosis,
with heavy glia fibers, which extends into the granular layer. The
Purkinje cells next to the lesion show marked chromatolysis and often
appear as oval bodies with fine blue granules scattered diffusely
through a coarse pink protoplasm, no nucleus being visible.

Sections of the Extensive Areas of Softening within the Cerebellar
Leaflets —There is necrosis of all layers of the cerebellum, with the
formation of large masses of necrotic or caseous material and loose
collections of lymphoid and large phagocytic mononuclear cells.
The latter have finely vacuolated, faintly staining cytoplasm and
small round eccentric nuclei, and usually contain organisms. The
necrosis often is in great masses, in which few nuclear remains and
many hyaline organisms can be made out. There is occasional
hemorrhage but no fibrin formation. Large collections of polynuclear
cells sometimes border regions of necrosis. Caseous or necrotic
areas sometimes touch seminecrotic cerebellar tissue without inter-
vening inflammatory tissue. In a few places, just outside of the
cerebellar border, a moderate number of large epithelioid cells are
seen. Rarely, next to the cerebellar tissue many necrotic polynuclear
cells occur. The cerebellar cortex, in undergoing destruction, be-
comes vacuolated, especially at the level of the Purkinje cells, the
nuclei become further and further apart, and the tissue is more and
more indefinite, until it can no longer be recognized as brain tissue.
Sometimes there is enormous enlargement of the molecular layer, with
separation of nuclei, without definite vacuolization. Mononuclear
cells often are present in the vessel walls, and about the vessels there
is often a thick plasma cell infiltration. In the midst of the caseous
areas vessels often have an intima and media greatly thickened from
cell proliferation. There is occasional slight proliferation of the
adventitia.

Formation of Large Mononuclear Cells —The glia cells in the molec-
ular layer become swollen, the cytoplasm faintly staining, and in
fine network formation. The cells show some irregularities in form
and in distribution, become more numerous near the outer part of the
molecular layer, and then crowd the tissue outside. Organisms are
often present within them and are apparently destroyed with them,
becoming faintly staining and scarcely visible.
JAMES L. STODDARD AND ELLIOTT C. CUTLER 53

Intracerebral Lesions —Sections from the border of the internal
capsule on the right show two lesions between white and gray matter,
extending into each, but chiefly into the gray matter. One lesion
has two areas of caseation similar to those in the meninges,
surrounded by tissue similar to the chronic inflammatory tissue of the
meningeal lesion. There is also a spherical accumulation of giant,
lymphoid, and connective tissue cells, without central necrosis,
containing many organisms in cells and spaces and surrounded
by dense connective tissue. The giant cells contain many organ-
isms which destroy their protoplasm, producing spaces which give
the dense tissue a vacuolated appearance. There is more dense
connective tissue in this lesion than is usual in the meningeal lesion.
Where it borders on the brain tissue the lesion is thickly infiltrated
with plasma cells and lymphoid cells. The brain tissue near the
lesion is either vacuolated or compressed, but shows little cell increase.
The other lesion is close to the first and consists of three partly
coalescent nodules without necrosis, of similar construction to those
just described. In both lesions there is a thick plasma cell layer
along the vessels. In neither is there any great infiltration with the
large phagocytic mononuclear cells. About both lesions is an in-
crease in glia cells with a slight formation of thick glia fibrils. The
ganglion cells show chromatolysis, with eccentrically placed nuclei,
and often are indented by glia cells. Occasional organisms can be
seen in the loose cerebral tissue about the lesion.

Sections from the left internal capsule also show two lesions sepa-
rated from each other by nearly normal brain tissue, situated chiefly
in the white matter of the internal capsule. The larger lesion has
ovoid accumulations, with necrotic polynuclear cells and organisms
in the center, and a wall similar to that of the nodules previously
described, containing, however, a rather greater number of organisms
and showing a more extensive necrosis. Here the organisms are
larger and more spherical than elsewhere, are more uniformly dis-
tributed throughout giant cells without definite space formation.
On the whole, they appear nearly identical with those in the meningeal
lesions of the first case. Often each organism has an eccentric red-
staining round dot. The giant cells in this nodule are almost entirely
converted into thin rims containing a little vacuolated protoplasm .
54 TORULA INFECTION IN MAN

between large numbers of organisms. The tissue about this lesion
and the nodule near it is like that previously described. Near the
lesion, in the white matter, are ill defined areas, where brain tissue is
lacking, and the space is filled with large mononuclear cells. No
organisms occur in these areas; they may be areas of degeneration
resulting from the lesions or areas in which the organisms have
disappeared. There is a slight gliosis about these lesions.

Sections of the cortex from the frontal, temporal, parietal, and
occipital regions, and from the uncinate gyrus show, as a rule, no
meningitis. There is a peripheral gliosis of moderate degree, very
-marked in the depths of the sulci. The increase in glia fibers extends
almost to the ganglion cell layer, but is marked only in the subpial
layer.

In sections of the occipital lobe there is a very marked meningeal
thickening in one sulcus. The character of the lesion is in general
like that in the cerebellum; but there are more minute collections of
polynuclear cells. On one side of the sulcus the inflammatory tissue
is making extensions into the brain tissue exactly as it does into the
cerebellar cortex, but on the other side there is a very thick periph-
eral layer of glia fibers, through which no progress is made.

Sections from the temporal lobe show a marked peripheral gliosis,
but no meningitis. The ganglion cells here appear slightly shrunken;
the Nissl bodies are indistinct, and often a phagocytic glia cell indents
the margin. This section also takes in the lateral border of the
lateral ventricle, which has a very marked peripheral gliosis consist-
ing of a dense felt of heavy fibers.

The anterior and posterior central regions on the right show edema
of the meninges with a slight increase in mononuclear cells, and
occasional small organisms. Gliosis and ganglion cell changes are
much the same as in the temporal region. The anterior and posterior
regions on the left are similar to those onthe right. The frontal lobes
also have some chronic thickening and edema of the meninges. Gliosis
and ganglion cell changes are as in other regions. The uncinate
gyrus shows the usual changes. The fourth ventricle and the aque-
duct of Sylvius show a heavy gliosis. The choroid plexus appears
ee The spinal cord shows'no meningitis. There is no peripheral
gliosis.
JAMES L. STODDARD AND ELLIOTT C. CUTLER 55

Weigert stains show interruption of the tracts of the internal
capsule on the left by the lesions, with degeneration of myelin sheaths
near the lesion, manifested by swollen and bulbous fibers. The
internal capsule on the right at the same levels appears normal.
The internal capsule lesion on the right is very slight, and interrupts
only a few fibers. Sections of the internal capsule at the level of the
posterior end of the thalamus show isolated areas of degeneration
or absence of myelin sheaths on the left side, the myelin sheaths being
replaced by glia cells and fibers. Sections of the spinal cord show a
distinct thinning with swelling and degeneration of fibers in the direct
pyramidal tract of one side and the crossed pyramidal tract of the
opposite side. Sections of the left optic and olfactory nerves appear
normal. Bordering the ventricles and in the cerebellum there is
degeneration of myelin sheaths, especially near the cerebellar lesions.

Marchi stains show marked deposit of osmic acid in the same areas
where the myelin sheath stain showed degeneration. There is also
much fat in and about the lesions.

Lungs.—There are large dense fibrous formations of hyaline con-
nective tissue with few nuclei, tending to arrange themselves in large
nodular whorls. No tendency is seen toward necrosis or caseation.
Bordering the areas are small nodules consisting of lymphoid and
endothelioid cell accumulations, with giant cells and connective tis-
sue proliferation, closely resembling tubercles, but lacking caseation.
Occasionally there is a slight deposit of brown pigment in the tissue.
The near alveoli are filled with plasma and lymphocytic cells, with
occasional large phagocytic endothelioid cells and giant cells diffusely
distributed. The capillaries are increased in number and size. The
giant cells are partially honeycombed with small round or oval spaces,
which sometimes coalesce and contain indefinite brown granules in
their centers. The appearance is what might be expected as an
end-result of an infection of the same character as that of the meninges,
but it is possible that it represents merely a form of degeneration.
Certain of the giant cells contain radiate or stellate masses lying in a
vacuole in the cell which are evidently of the same character as the
stellate bodies described by Wolbach in giant cells in the spleen.

Other sections show nodular connective tissue thickenings sur-
rounded by nearly normal alveoli. In these indurated areas are
56 TORULA INFECTION IN MAN

spherical formations where the tissue is loose and occupied by large
irregular giant cells and a few lymphocytes and plasma cells. A
later stage shows these nodules entirely converted into connective
tissue, with no caseation, but with a surrounding lymphocytic and
plasma cell proliferation. In these lesions are a few spherical bodies
4 to 6u in diameter, with walls 1u thick, and small central bodies con-
taining central dots. In size and in the character of the wall they
correspond with the torule found in the brain, but they differ in the
absence of the gelatinous capsule and all evidence of multiplication.
They probably represent organisms completely obsolete which have
become enclosed in the dense connective tissue of lesions which are
themselves obsolete. It was the presence of these bodies seen in a
frozen section of the lung which first led to the consideration of this
case as a possible torula infection.

Bronchial Lymph Node.—Similar connective tissue formations to
those in the lung occur in the lymph nodes. Small and large areas of
hyaline connective tissue of irregular shape are scattered throughout
the node. The first formation of connective tissue takes place about
the vessels and in the walls of the lymph sinuses. There are no col-
lections of endothelioid and plasma cells, and no giant cells.

Kidneys.—Slight acute degenerative lesions.

Laver —One nodular lesion the size of a miliary tubercle consists
of giant, lymphoid, and endothelioid cells, embedded in connective
tissue with lymphoid infiltration about the periphery.

Spleen.—There are nodular accumulations of endothelioid, lym-
phoid, and giant cells without caseation. Apparently later stages
show hyalinized connective tissue, sometimes slightly infiltrated with
lymphoid cells. These lesions usually occur in the follicles, and occa-
sionally can be seen to arise around vessels. In general there is
increased connective tissue about the vessels.

Adrenals, Pancreas, Myocardium, and Thyroid. Negative.

Testicles and Seminal Vesicles —Normal.

Cultures.—Cultures were made in bouillon of ventricular fluid re-.
moved during life. Smears showed round bodies considered to be
precipitated stain, or other indefinite material. Nevertheless, the
bouillon culture was inoculated into two white mice intraperitoneally
under aseptic precautions. About 4 weeks later the mice were
JAMES L. STODDARD AND ELLIOTT C. CUTLER 57

autopsied. Nothing was observed in gross. Microscopical examina-
tion of the tissues showed a meningitis consisting of a production of
large phagocytic mononuclear cells in which occurred large and small
organisms similar to those in the original case. The organisms were
multiplying by budding. Some large forms 10y in diameter occurred.
Small forms of 2.54 were seen. The organisms were nearly spherical,
and had a few vacuoles in an otherwise almost homogeneous interior.
The large organisms occurred surrounded by wide clear zones, in
which radiating lines could be seen in some cases, like those in the
first case and in Rusk’s cases. In several cases extension into the
cortex by solution of tissues without reaction was evident,—early
stages of lesions similar to those in the preceding case. A large part
of the meninges was edematous, with many organisms, some of them
thick walled, but with no cellular infiltration. This is a condition
like that of the second case (Rusk’s) in the literature. No lesions
occurred in other organs.

A. Discussion of Case IT.

The chief differences between this and the preceding case depend
upon the variations in the extent and activity of the process. In
this case the process is so extensive that more necrosis and caseation
result; it is so active that budding forms are frequent, and the organ-
isms have not produced the large resting cells or the peculiar brain
lesions especially associated in the first case with the presence of the
resting cells. The characteristic tendency to solution of tissue is
_present, the meningeal inflammatory tissue is like that of the preceding
case, and the absence of the peculiar intracerebral lesions is made up
for by their presence in the brain of the inoculated animal. The
difference between this case and those of coccidioidal granuloma or
ordinary blastomycosis is obvious; further evidence for its identity
with torula will be given under experimental results.

Explanation of the Clinical Course—Underlying the general pres-
sure symptoms of headache, vomiting, and impaired vision, with the
corresponding objective findings, is an internal hydrocephalus, as
in the other case. The mechanism here must have been partial
blockage of the exit of cerebrospinal fluid from the foramen of Magen-
die by the dense inflammatory tissue. The hemiplegia is well ex-
58 TORULA INFECTION IN MAN

plained by the lesions in the internal capsule, partly old and healed,
partly active, with the resulting degenerations. The relation of the
otitis media to the disease has not been discovered.

The lesions in the lungs, bronchial lymph nodes, liver, and spleen
are in all probability due to the action of the same organism. The
lesions are unusual, and bodies occur in the lung lesions closely re-
sembling the organisms. Animal experiments show all stages to the
production of the cicatricial lesions.

In this case again there is a close resemblance of the lesions with
caseation to tuberculosis. There are the same points of differenti-
ation; in this case the predominance of plasma cells is even more
marked.

In connection with the data of all the cases of torula infection, it
is interesting to observe additional points. Fever was noted in all
but the first of the cases in the literature, where its presence or ab-
sence is not mentioned, and in Rusk’s first case. In our two cases
fever occurred only near the time of onset and was moderate in
degree. In all cases where the white count was taken it was not
increased, but usually fever was not present at the time. However,
in Tiirck’s case the white count was 7,000 when an irregular temper-
ature was run. In ordinary systemic oidiomycosis there is usually
a marked leukocytosis, averaging 16,000, and occurring up to 30,000.
In our second case and in Rusk’s second case there was a positive
Noguchi reaction in the spinal fluid. Organisms were found in the
spinal fluid in von Hansemann’s case; in the spinal fluid and ventric-
ular fluid in Tiirck’s case; and they were evidently present in the
ventricular fluid in our second case. In Rusk’s cases and in our first
case no examination was made. In Tiirck’s case and in our second
case cultures did not succeed.

The best means of diagnosis, until some exact serum test is worked
out, will be cultures on agar or potato at room temperature, and
inoculation of white mice or rats intraperitoneally with spinal or
ventricular fluid or cultures, with microscopical examination of the
brain. Some ordinary laboratory animals, such as guinea pigs, are
practically insusceptible to the disease, and the usual technique of
growing cultures for 48 hours on blood serum at incubator tempera-
ture must result in many failures; the organism grows much more
JAMES L. STODDARD AND ELLIOTT C. CUTLER 59

surely on agar or potato at room temperature, and growth is often
slow, especially after the organism has been passed several times
through animals. Differentiation in smears from tissue elements
such as red cells is best effected, as in oidiomycosis, by examining in
salt solution or glycerine or with’ the addition of a drop or two of
sodium hydroxide. In the ordinary stained smears recognition might
be difficult.

The symptomatology of the cases resembles closely that of brain
tumor. The essential factor in the similarity is the occurrence of a
chronic, slowly progressing inflammatory process, which by being
situated in such a way as to interfere with the passage of cerebro-
spinal fluid causes an internal hydrocephalus, or results in the forma-
tion of masses of parasites in various parts of the cerebrum or cerebel-
lum, or causes a chronic meningitis with overproduction of fluid.
Involvement of special nerves may give false localizing symptoms.
The absence of cutaneous or recognizable systemic lesions adds to the
confusion. The pathological reports of other cases of pseudotumors
are so scanty that it is impossible to tell whether many of them may
not have the same or a similar explanation. Pseudotumors have
been one of the mysteries of brain surgery; an explanation of a few
cases now gives a definite line of attack for future work. Necessarily
there are also points of similarity with chronic diseases of the nervous
system, such as syphilis.

IV. CLASSIFICATION OF THE DISEASES FORMERLY CALLED
BLASTOMYCOSIS.

Botanically torule form a group of organisms similar to the yeasts
in the form and organization of the cell and the method of reproduction
by budding, but different in the constant absence of endospore pro-
duction and the frequent lack of power to ferment sugars. Other
points of difference are commonly present, but not invariably. From
the oidia they are distinguished by their absence of mycelium pro-
duction under all circumstances. The true yeasts are classed in most
systems as ascomycetes on account of the endospore production.
The real biological relationships of the yeasts and torule are not
yet determined. The type of organism budding in tissues and pro-
60 TORULA INFECTION IN MAN

ducing mycelium in cultures is botanically an oidium. The oidia
have no characteristic fructification and hence their systematic
position is also obscure.

Coccidioides immitis is definitely an ascomycete on account of its
endosporulation, and is seen to be in close biological relation to the
yeasts.

The various organisms belong to different groups and have differ-
ent appearances and pathological effects. Coccidioidal granuloma
is already established as a name for the disease produced by the
ascomycete with hyphe, and causes no confusion. The term blasto-
mycosis, however, which signifies a disease caused by a budding
organism, obscures the real differences in the various diseases which
have been included under its name, and should be discarded. Oidio-
mycosis, yeast infection, or torula infection should be substituted,
according to the case. Following is a summary of the differential
points in torula infection, oidiomycosis, and yeast infection.

Summary.—1. True yeast infection, produced by an organism which
reproduces by budding. It produces no true mycelium, forms endo-
spores under certain conditions, and usually ferments sugar. The
organism is rather feebly pathogenic for animals. There are two
authentic cases in man, the first being Busse’s. Both cases include
skin lesions. The pathological changes are characterized by necrosis,
stimulation of epithelial growth, some exudation of polynuclear cells,
tendency to giant cell formation, nodular accumulations of small
round cells, and abscess formation. The organism has an adventi-
tious capsule occasionally in human and animal lesions, but does not
produce a gelatinous matrix and does not have even a capsule in
brain lesions in animals.

2. Torula infection, produced by a yeast-like organism, distin-
guished from yeasts by its absence of endospore production under
all circumstances. It never produces mycelium, usually does not fer-
ment sugar, and reproduces by budding alone. The organism is more
pathogenic for animals than that of the preceding group. The first
spontaneous case reported was described by Frothingham as occur-
ring in a horse. Six cases are known in human beings. In locali-
zation the nervous system especially is affected, to a less extent other
organs, never the skin as part of the general infection. The symptoms
JAMES L. STODDARD AND ELLIOTT C. CUTLER _ 61

are chiefly caused by the brain lesions. The pathological changes in
the meninges are characterized by chronic inflammatory reaction,
with areas of caseation like tuberculosis, if the lesion is extensive; the
organisms usually occur in cells, bud freely in the large vacuole
enclosing them, and usually destroy the cells. The organism produces
peculiar intracerebral lesions, consisting of a lysis of the cerebral tissue,
with only a very chronic proliferative reaction which is often almost
lacking, and fills the lesion with a peculiar gelatinous material holding
the organisms separate, in which occasionally threads and star-like
processes form. In other organs it produces, as a rule, nodular les-
ions resembling miliary tubercles which finally become dense con-
nective tissue masses. The organism in tissues has a nearly homo-
geneous, non-granular, faintly staining interior except in the smaller
forms, varies in size from 1 to 13u, and often produces large resting
cells. The wall stains easily and diffusely. The organism increases
by budding. Small buds may be produced by organisms of any
size. When produced by an organism of small size they may equal
the size of the parent. The small forms have a good deal of chromatic
material in masses. In mice and rats pure cultures produce lesions
of the same character as those found in man.

3. Oidiomycosis is caused by an organism reproducing by budding
in tissue, and forming mycelium in cultures. There is no endospore
production. There are over thirty recorded cases of systemic involve-
ment, and more numerous cutaneous cases. In localization oidiomy-
cosis affects especially the skin and subcutaneous tissues, no reported
systemic cases being free from such involvement; it often involves
bones; it affects all internal organs, including the brain, but has not
yet produced lesions in the brain which have caused symptoms until
just before death from the general infection. The pathological
changes are characterized by necrosis and overgrowth of epithelium
with miliary epidermoid abscesses, forming characteristic skin lesions;
abscess production is present in deep tissues and in organs, also
tubercle-like nodules; there is a marked attraction for leukocytes (ex-
cept in occasional cases in the spleen and bone marrow); no lesions
have the peculiar gelatinous matrix (although occasionally, especially
in the bone marrow, an adventitious capsule is produced). The only
reported case of meningitis was a purulent one; the brain lesions are
62 TORULA INFECTION IN MAN

much like the other lesions with somewhat less reaction. The organ-
ism in tissues has a granular interior, usually with a separation of
the protoplasm from the wall by a distinct space, is spherical, and
reproduces by budding. The wall stains with difficulty or not at
all. It is from 3 to 30u in diameter, the average size being 16y.
In animals it produces lesions with difficulty; they resemble the
lesions in man.

V. EXPERIMENTAL.

1. Materials and Methods.

All inoculations were made with pure cultures suspended in sterile
salt solution. The organisms with mycelium were teased into as fine
particles as possible. The site of each inoculation was shaved, washed
with alcohol, and painted with iodine. We used the following
organisms: a culture of torula from Frothingham’s case of infection
in a horse, a culture of oidiomycosis from the human cutaneous case
teported by Wolbach, and a culture of Coccidioides immitis from a
human case of coccidioidal granuloma.

Since so much experimental work has been done on so called
blastomycetes and Coccidioides immitis, our results, which confirm
the differences in the two organisms, will be given with especial refer-
ence to the histological changes rather than to the morphology of the
organisms in the tissues.

2. Experiments on Dogs.

A thick suspension of each organism was injected into a dog intra-
venously to the amount of 5 to8 cc. Later a similar suspension was
injected into the lower bronchi through a rubber catheter introduced
into the trachea. The animals were killed in 3 to 6 weeks. The dogs
inoculated with oidiomycosis and coccidioidal organisms showed no
lesions. The animal inoculated with torula had no lesions in any
organs but the brain and kidney. The kidney showed a few minute
white dense spots, about 1 mm. in diameter, in the medulla. ‘On
serial section of the brain hardened in formalin several small white
areas 1 10 2 mm. in diameter were found in the cortex, white matter,
and basal ganglia.
JAMES L. STODDARD AND ELLIOTT C. CUTLER 63

Microscopical Examination. Kidney.—The lesion consists of a
diffuse collection of lymphoid and plasma cells with a few polynuclear
cells, obliterating and replacing tubules. Plasma cells predominate.
Other lesions consist of a diffuse connective tissue formation, with
areas of plasma cells. No definite organisms can be found in these
lesions. The lesions resemble closely those in the kidney in the
first case.

Brain.—The lesions consist of focal collections of mononuclear
cells with rare polynuclear cells. Some of the cells are plasma cells;
most of them have a large amount of cytoplasm and large round
centrally located nuclei, and appear to be arising from the glia cells
about the lesion. A few large mononuclear cells are seen. Poly-
nuclear cells are extremely rare. Some of the lesions are near vessels,
and about the vessels there are dense masses of lymphoid cells. A few
partially disintegrated organisms are found in these lesions.

These few experiments show that the dog must be regarded as a
relatively resistant animal to the three groups of organisms. It is
interesting that the only lesions in the series of dogs are brain and
kidney lesions from the torula injection, and of these the brain lesions
are the most numerous.

3. Experiments on Rabbits.

One series of rabbits was inoculated intraperitoneally with 2 cc. of
a thick suspension of each organism, another intravenously in the
ear vein, one subcutaneously, and one subdurally. With oidiomycosis
no lesions were produced. The subdural inoculation with the coc-
cidioidal organism resulted in an abscess at the site of inoculation
from which a pure culture of the Coccidioides was obtained. In the
rabbit inoculated intraperitoneally with the torula, lesions were
found in the kidney, brain, and meninges.

Rabbit 1.—Intraperitoneal inoculation with torula. Animal autopsied 3
weeks later. In gross no lesions were noted.

Microscopical Examination. Liver -——A large area is found nearly
the diameter of a low power field, with central caseation, surrounded
by epithelioid cells, then a zone of thick infiltration with lymphoid
64 TORULA INFECTION IN MAN

cells, containing many eosinophilic cells, with a slight surrounding
connective tissue band. No organisms are found in the lesion.

Brain.—A chronic meningitis in which definite torula organisms
are found. The cells consist chiefly of large mononuclear cells and
sometimes contain organisms. There are moderate numbers of plasma
cells, but no polynuclear cells. The organisms are scarce and show
much degeneration. The large phagocytic mononuclear cells are filled
with hyaline droplets or vacuoles. The cortex near the lesion has a
slight increase in glia tissue, with spider glia cells. In the cortex are
focal lesions consisting of accumulations of mononuclear, lymphoid,
and plasma cells, the lesions being about the diameter of a high dry
power field. Organisms occur in these lesions but are difficult to find.
The meningitis is not found in all sections.

Rabbit 2—Subcutaneous inoculation with Coccidioides immitis. Autopsy 7
weeks later. A nodule 1 cm. in diameter was found at the site of inoculation
open, with a thick purulent content. No internal lesions. Sections of the nodule
show diffuse connective tissue increase and many large irregular masses of poly-
nuclear cells, with little necrosis.

The intervening connective tissue is remarkably free from cellular infiltration.
The abscess contents consist practically entirely of polynuclear cells. The border
is sharp and made up of a band of denser connective tissue. Caseation occurs
near the borders of the abscesses, rather than in the contents. No giant cells
are present. The earliest lesions consist of small accumulations of polynuclear
cells with surrounding. connective tissue proliferation. The organisms occur in
the abscess and in the connective tissue. They are placed close to the cells
without intervening spaces.

Rabbit 3.—Subdural inoculation with Coccidioides immitis. At the site the
meninges are greatly thickened with increased connective tissue and abscess
formation. The lesion has extended into the cortex and is bordered there by a
zone of connective tissue thickly infiltrated with plasma cells and lymphocytes.
Outside of this connective tissue band polynuclear infiltration becomes more
marked and large abscesses are found similar to those in the subcutaneous nodule
just described, but more extensive, and with more necrosis and peripheral casea-
tion. Giant cells occur frequently at the borders of the abscesses. The organ- -
isms occur in giant cells and free, but they never have a clear zone about them.
They are seen more often outside than in the abscesses. Sporulating forms are
rare. One large abscess has several free pieces of cortex within it. Inthe series
of rabbits the tendency of the torula to infect the nervous system is evident.
In one case a meningitis is produced from intraperitoneal injection. The
coccidioidal organisms produce brain lesions only from subdural inoculations.
JAMES L. STODDARD AND ELLIOTT C. CUTLER 65

4. Experiments on Guinea Pigs.

Inoculations were made intraperitoneally and subdurally. No
lesions were produced with oidiomycosis. With torula the only
lesions produced were peritoneal nodules in the guinea pig inoculated
intraperitoneally. The surface of the peritoneum was slightly dull
and dotted with minute, raised, slightly whitish areas, appearing much
like a culture of streptococcus on agar. Microscopically the lesions
consisted of lymphoid and endothelioid cells in connective tissue with
a few mono- and polynuclear eosinophils. The large resting cell
forms of the organism occurred in the nodules singly, each organism
surrounded by a clear space, about which were endothelioid cells
which showed signs of fusion into giant cells. The muscle fiber
just underneath the nodules showed a loss of the cross-striation so
plain elsewhere.

Two of the guinea pigs inoculated with the coccidioidal organisms
had lesions; the one inoculated subdurally had a brain lesion.

Guinea Pig 1.—Inoculated intraperitoneally with Coccidioides immitis. At au-
topsy abscesses are found in the testes, epididymis, and liver, and nodules in the
peritoneum. There are no lesions in the central nervous system. The lesions
consist of abscesses, large and small, and collections of epithelioid cells, as in the
preceding case. The small circumscribed collections of polynuclear cells about
a few organisms are frequent. Caseation is always in the zone about large col-
lections of polynuclear cells. In the giant cells the organism enlarges until it
finally appears closely surrounded by a thin band of the protoplasm and nuclei
which appear unchanged. Organisms sporulate much more often than in the
rabbit, and the leukotactic influence of the young organisms is very plain.

Guinea Pig 2.—Inoculated intraperitoneally with Coccidioides immitis; killed
in 4 weeks. Lesions in the peritoneum, testes, epididymis, liver, spleen, and
lung. There are no brain lesions. Pure cultures of the coccidioidal organism
recovered from the testicular lesion. The lesions are similar histologically to
those in the previous animal.

Guinea Pig 3.—Inoculated subdurally with the coccidioidal organisms. At
autopsy an abscess is found at the site of the inoculation, from which a pure
culture of the. coccidioides was recovered. No lesions in the other organs.

Microscopical Examination —Large and small masses of polynuclear
cells, with surrounding connective tissue often infiltrated with poly-
nuclear cells, have greatly thickened the meninges inand abouta sulcus,
compressed, and in one place invaded the surrounding cortex. A
66 TORULA INFECTION IN MAN

single mass of polynuclear cells is one and one-third times the diam-
eter of a low power field. Organisms are numerous except in the
thick connective tissue. Giant cells are rarely seen. Some small
masses of polynuclear cells are surrounded by a zone of epithelioid
cells. Where the lesion has eroded the brain there is much new
vessel formation with exudation of polynuclear, plasma, and lymphoid
cells, and in the brain all about the lesion there are polynuclear, plasma,
and glia cells, sometimes forming thick masses. The meningitis is
localized to the neighborhood of the sulcus.

5. Experiments on Mice.

Lesions were produced with the coccidioidal and the torula organ-
isms, but not with that of oidiomycosis. The culture of oidiomycosis
had been used previously in animal experiments, but had probably
lost its virulence with time. The torula culture, which was just as
old, seemed to have retained its virulence extremely well, for general
lesions were easily produced in mice and rats. We were able, through
the kindness of Dr. S. B. Wolbach, to procure paraffin blocks of the
animals used in his experiments with oidia. The lesions found will
be described briefly.

Coccidioides immitis Lesions.

Mouse 1—Inoculated intraperitoneally with Coccidioides immitis. At autopsy
a pure culture of the organism was obtained from a nodule in the liver and from
a peritoneal nodule at the site of injection. Lesions were found in the mesentery,
peritoneum covering the liver and spleen, and in the lung and liver.

Microscopical Examination. Lung.—Nodules consisting of many
small organisms mingled with polynuclear cells. One mass consists
of large organisms nearly all of which are sporulating, surrounded by
a hemorrhagic zone containing a few polynuclear cells. Some lesions
show little reaction other than hemorrhage; others large numbers of
polynuclear cells and few organisms. Usually there is a beginning
invasion of polynuclear cells and formation of connective tissue.

Liver —There is a small collection of organisms with an early
invasion of polynuclear cells. The liver tissue about the colony is
compressed. Other larger lesions show diffuse infiltration with
polynuclear cells and a connective tissue capsule. The liver cells
JAMES L. STODDARD AND ELLIOTT C. CUTLER 67

immediately surrounding the colony appear normal except for com-
pression. Other lesions consist of small abscesses containing small
organisms and without surrounding connective tissue. Adherent to
the peritoneal surfaces of the liver, spleen, and pancreas are large and
small organisms with varying amounts of acute exudate. The
mesentery is thickened with a purulent exudate and many organisms.
There is a good deal of new vessel formation, and an infiltration in
these places with plasma cells. There is necrosis, almost caseation,
of organisms and cells in a diffuse manner. Peritoneal nodules
occur with polynuclear cells, especially about small organisms.

The chief peculiarity of the lesions is the greater size of the large
organisms, some of which measure 85yu in diameter, and the great
frequency of sporulation, some lesions consisting of numbers of large
sporulating cells producing masses of small organisms. The small
amount of reaction about some lesions in the liver and lung seems
to be due to the recent invasion of the tissue, for an acute reaction
with hemorrhage is always present to some extent. Most of the
lesions are fairly characteristic except for the small number of epithe-
lioid and giant cells. The coccidioidal organism is a virulent one,
and the infection evidently overwhelmed the animal.

Lesions with an Oidiomycosis Organism.

Lungs.—The bronchi contain a purulent exudate with organisms,
and the walls are necrotic. Lobules of the lung are solidified with
enormous numbers of oidia and a purulent exudate. It is diff-
cult in these areas to make out the alveolar walls, which frequently
appear to have been destroyed. Occasional small irregular areas of
caseation are seen immediately surrounded by the infiltrated tissue
and apparently the result of the crowding of the enormous numbers of
the organisms in the tissue. The organisms lie close to each other
or to the polynuclear cells, without intervening spaces. They are
occasionally seen budding. Large endothelial cells occur and con-
tain organisms, which distend the cells, but do not seem to injure
them otherwise than by this mechanical action. There are a few giant
cells in which organisms occur without causing solution of their pro-
toplasm. No connective tissue formation is evident. Other large
68 TORULA INFECTION IN MAN

areas, normal except for a few large endothelial cells, immediately
adjoin these lesions. About some of the vessels there is a plasma
cell infiltration.

Lesions with Torula Organisms.

Mouse 2.—Inoculated intraperitoneally with torula. The peritoneum contains
a slight amount of sticky exudate; the surface is dull, and small white thickenings
are visible on the surface. The omentum and mesentery are thickened. No
lesions can be found in the internal organs, except the brain. Pure cultures were
obtained from the peritoneal exudate.

Microscopical Examination—In the peritoneum are enormous
numbers of very minute organisms and a few larger ones, appearing
as empty shells which are often broken open. There is an infiltration
with a few mononuclear cells and a moderate number of eosinophils.
The organisms occur in spaces, some of which are fat spaces, others
formed from destroyed cells. These spaces give the tissue a honey-
combed appearance. In the omentum is a similar lesion with a
slightly greater reaction, consisting of numbers of lymphoid, plasma,
and large endothelioid cells. The brain shows a meningitis consisting
of a considerable accumulation of large mononuclear cells in which
no definite torula organisms can be found.

6. Experiments on Rats.

Inoculations were made intraperitoneally with the torula and
oidiomycosis organisms. No lesions were produced with the oidio-
mycosis, but with the torula a general infection with lesions in the
meninges, brain, and cerebellum was produced. Pure cultures of
the organism were recovered from the animals in nearly all cases.

Rat 1.—Inoculated intraperitoneally with 2 cc. of a thick suspension of torula
on Feb. 24, 1915. The animal died on Apr. 14, 1915.

Autopsy.—The peritoneal cavity contains no fluid, there are no adhesions, and
no nodules on the peritoneum. The surface seems slightly dull and sticky. The
abdominal organs and lymph nodes appear normal. The lungs are greatly dis-
tended, firm, pale grayish pink, with a slightly nodular appearance of the surface.
All lobes of both lungs are affected in equal degree. On section the surface is
whitish and sticky and slightly nodular. The tissue has a semitranslucent appear-
ance. The brain appears normal.

Smears from the peritoneal cavity and lung show only.torula organisms. In
the smear from the lung there is much homogeneous material adherent to the
JAMES L. STODDARD AND ELLIOTT C. CUTLER 69

organisms, staining faintly and obscuring the details. A culture from the peri-
toneal cavity gives a pure growth of torula. A lung culture gives a growth of
torula, contaminated with other organisms.

Microscopical Examination. Lung.—The alveoli are dilated and
often broken to form large spaces, which are filled with a gelatinous
material in which organisms are embedded. With material fixed in
Zenker’s fluid the gelatinous material stains a faint reddish blue and
is seen to be filled with fine granules taking a light red stain. There
are irregular thickenings which stain blue and often take the form of
threads joining the organisms. As a whole, the substance has shrunk-
en during fixation, so that irregular spaces exist in it. With formalin
fixation and hematoxylin staining the material is scarcely colored
at all, but occasionally stains slightly where it is thickest. Cresy]
blue after formalin fixation colors it intensely, however, and shows
fine radiating thickenings from the large organisms. The larger
organisms are spherical, 10 to 134 in diameter, with a definite wall
staining diffusely with methylene blue, which is often irregular in
outline as if somewhat collapsed. The contents are homogeneous
and stain faintly. The whole general appearance of the lesion and
organisms is identical with that of the peculiar cerebellar and cerebral
lesions of the first case. On close examination enormous numbers of
small organisms varying in size from 1 to 6y in diameter are seen.
These occur especially in spaces surrounded by fragments of the
destroyed cells of the alveolar walls. The method of reproduction is
always by budding; medium sized organisms give off small buds 1 to
2u in diameter, and organisms 3 to 4 give off the smallest forms.
Occasionally, the small forms appear to reproduce by buds the size
of the original organism. ‘These small forms are more oval than the
larger ones and appear exactly like those in the second case except
that they are not quite so thick walled and are not so frequently seen
budding. They show the same relations to cells, multiplying freely
in large vacuoles in giant cells, and finally destroying the cells. They
have clear zones about them. A cresyl blue stain colors the outer
surface of these organisms and shows that even the smallest has a thin
membrane or wall. With hematoxylin the wall of the small forms
scarcely stains, so that one sees principally the chromatic material,
and an impression is gained of extreme minuteness. In the spaces the
70 TORULA INFECTION IN MAN

organisms frequently occur as one large organism, and many small
ones, the latter frequently about the periphery of the space. In
spite of the enormous numbers of small organisms in contrast to the
fewer larger ones, no evidence of a process of endosporulation is
found. The only suggestion of it is the finding once of a large
cell with many small chromatin masses of varying size irregularly
distributed in the cell. Frequently the larger organisms are seen
giving off the minute forms as buds.

The reaction in the lung is very slight, and consists of a perivascular
exudate of plasma and lymphoid cells, with production: of large
mononuclear and giant cells containing organisms. Occasional
small hemorrhages are seen. In some areas there is a formation of »
dense connective tissue about the organisms, forming nodular masses,
infiltrated slightly with lymphoid and plasma cells. Other sections
show areas of diffuse production of connective tissue.

Spleen.—A lesion extends into the pulp from the surface. It
consists of a formation of dense connective tissue with a loose meshed
tissue on the peritoneal side enclosing spaces filled with organisms.
The organisms are nearly all of the large resting cell type. They
show signs of degeneration, and reproduction is not active. In
another place there is a formation of dense connective tissue on the
peritoneal surface of the spleen with a number of mononuclear
eosinophilic cells and a few barely recognizable organisms.

Kidneys.—A number of small irregular areas of dense connective
tissue contain a few thick walled organisms. Sometimes an area
encloses an atrophic glomerulus. One area of dense connective tissue
extends in irregularly from the surface. Honeycombed spaces in the
center contain hyaline organisms. In one place dilated tubules with
atrophic epithelium contain organisms, and nearby tubules on close
examination show small organisms in the epithelium, causing its
destruction. About the infected areas are a few lymphoid and plasma
cells.

Liver.—A lesion extends in from the surface, consisting of a caseous
center containing large organisms, then a layer of giant cells and
epithelioid cells containing organisms, beyond which is a thick wall
of connective tissue.

-Brain.—A chronic meningitis is found in all sections, varying some-
JAMES L. STODDARD AND ELLIOTT C. CUTLER 71

what from a slight cellular infiltration to a marked thickening. Large
numbers of small and fewer large organisms are present everywhere.
The cell reaction consists of lymphoid and plasma cells, and a few
giant cells, but principally of large phagocytic mononuclear cells.
Rare polynuclear cells occur. Connective tissue formation is begin-
ning.

The organisms always occur with clear zones about them, demon-
strated by special stains to consist of a gelatinous material. There
are extensions into the cortex forming lesions with solution of tissue
filled with gelatinous material, and absence of reaction, exactly like
the peculiar brain lesions in the first case. The only difference is in
the great number of small organisms present in the large phagocytic
mononuclear cells which have invaded the lesion. The small organisms
are seen in the substance of the cortex and the edge of the lesion,
causing its disintegration. In some of the lesions there is con-
siderable production of large phagocytic mononuclear cells which
are filled with the small organisms; in other lesions these cells are

‘few. Cresyl blue stains the gelatinous material in the lesions as in
the first case. There are several lesions in the cerebral cortex, and
in the cerebellum.

The small organisms occurring in large numbers are in contrast
to the lesions of the case described by Frothingham, from which the
organism was obtained. Evidently, as in the coccidioidal disease,
where enormous numbers of sporulating forms were found in the
lesions in mice, the small animals furnish a particularly favorable
ground for their multiplication.

Rat 2.—Inoculated Apr. 25, 1915, by an injection of 1 cc. of a salt solution
suspension of torula into the right pleural cavity; killed May 15. No external
lesions. The peritoneal cavity appears normal. A smear shows no organisms,
and cultures give no growth. Small white spots, 1 to 2 mm. indiameter, are found
in the liver and kidneys. The spleen and lymph nodes appear normal. Both
lungs are filled with gray nodules about 1 mm. in diameter. The brain appears
normal externally.

Microscopical Examination. Lung.—Scattered throughout sec-
tions of the lung are miliary nodules which often occur in groups of
two to ten, like miliary tubercles, the adjacent nodules often coales-
cing to form larger ones; these are composed of collections of
72 TORULA INFECTION IN MAN

epithelioid cells with a few lymphocytes and occasional giant cells.
About the periphery of the nodule there is slight connective tissue
formation, and there are often numbers of eosinophilic cells. The
alveoli next to the nodules appear normal. In some of the nodules
torula organisms can be found. They occur in the center, often with
a few eosinophilic cells, and show all stages of degeneration to com-
plete destruction. The majority of the nodules contain no intact
organisms; in some not even remains of organisms can be made out.
These nodules are indistinguishable from miliary tubercles, produced
by the tubercle bacillus, except for the presence of the organisms.
In some cases there is a slight central caseation, but usually none is
present. Giant cells vary much in numbers; sometimes six or seven
occur in a section of a nodule, in others there are none. Although
they often contain the organisms, their number does not seem to
be in relation to the numbers of the torulz.

Spleen.—Tubercles similar to those in the lung, but of larger size
and with central caseation, are found. In some nodules remains
of the small forms of the torule but no large forms can be seen.

Peritoneal Nodule—There is a diffuse chronic inflammatory tissue
very much like that of the meninges with lymphoid, plasma, and.
epithelioid cells. Eosinophilic cells are scarce as a rule, but are.
often numerous about vessels. Giant cells occur diffusely; a few
organisms, in a partially disintegrated condition, are seen.

There are large and small coalescent areas of necrosis with partial
caseation in which torule are numerous. The caseous material is
partially honeycombed with spaces, in the centers of each of which
one of the larger forms of the torule is seen. Remains of cells can
often be seen in the caseation, and fibrin is often present at its
periphery.

The whole picture is similar to an advance tuberculous node, except
that the caseation is not complete and there are often visible torula
organisms.

Kidney.—Miliary collections of epithelioid and giant cells as in
the lung.

Liver.—Perivascular collections of lymphoid, plasma, and many
eosinophilic cells, and a few miliary nodules similar to those described
above.
JAMES L. STODDARD AND ELLIOTT C. CUTLER 73

Brain.—A chronic meningitis in some of the large sulci with ex-
tension into the cortex. The whole picture is just like that in the
rat previously described, except that the organisms are undergoing
greater destruction and the lesion is being invaded by the chronic
inflammatory tissue from the meninges. This shows the chronic
recoverable character of the brain lesions caused by the torule.

Rat 3.—Inoculated Apr. 25, 1915, by an injection of 1 cc. of a salt solution sus-
pension into the heart. The culture was obtained from the peritoneal cavity of
Rat 1. On May 15 the animal was noted to be sluggish in reaction and to keep
in a crouching position with somewhat labored breathing. Gradually the symp-
toms became more marked and finally the animal no longer attempted to defend
itself when touched, and when rolled over righted itself with difficulty, and walked
slowly with a dragging gait. The hind legs seemed weak, and the animal could
not run.

On May 25, 4 weeks after inoculation, the animal was chloroformed and
autopsied. The peritoneal cavity appears normal. Many small gray nodules
are found in the kidney, from 0.33 to 1 mm. in diameter. A few very small gray
nodules in the spleen appear to be different from the Malpighian bodies. No
lesions in the liver. The retroperitoneal nodes appear normal. The lungs are
a little more firm than normally, and contain many nodules similar to those in the
kidney. In the mediastinum is a thickened fibrous mass of tissue in which
enlarged lymph nodes are found containing miliary lesions. The brain is con-
sidered to have a few minute nodules, but their presence is not certain.

Cultures on potato and dextrose agar from the meninges, and from the lung
and kidney lesions give pure growth of torula.

Microscopical Examination. Brain.—In five sections from five
different blocks of the cerebrum and cerebellum. forty-two lesions
are found in the brain substance, and many areas of infection of the
meninges. The lesions in the brain are perivascular or extensions
from the meninges. They are all ina stage of healing, and show a
high degree of destruction of the parasites. Sometimes in a lesion are
only one or two large collapsed organisms, or there may be a small
collection of the large non-granular spheres. The small forms so
conspicuous in the rat that died from the injection are almost entirely
absent. The method of extension of the brain lesions by a solution of
the tissue by the individual organisms is plain. The reaction in all
is of an extremely chronic character. There are accumulations of
plasma and lymphoid cells with a few large mononuclear cells in the
perivascular lesions. Almost all the reactive cells in the lesions with
74 TORULA INFECTION IN MAN

solution of tissue are the large mononuclear cells, probably glial in
origin. The meningeal reaction is similar to the perivascular. Many
lesions are present in the cerebellum, especially in the cortex. There
is a distinct production of thick glia fibers in the outer layer of the
cerebral cortex. The whole picture here is strikingly similar to our
first case. A lesion is found in the choroid plexus of the third ven-
tricle consisting of an ill defined accumulation of mononuclear cells.
The choroid plexus of the fourth ventricle contains an almost perfect
imitation of a miliary tubercle, without caseation.

Kidneys.—Numerous single and conglomerate tubercles are present,
some with a few hyaline or collapsed large torula forms, others in
which none can be made out. In several instances large thick walled
organisms are seen in glomeruli. The character of the tubercles is
the same asin Rat 2. There is occasional necrosis in the center, with
remains of organisms, the material staining a nearly uniform pink
and resembling caseation. Occasionally there is a diffuse infiltration
with lymphoid cells between the tubules.

Liver.—Many small lesions are seen, consisting of collections of
lymphoid cells about small masses of hyaline organisms in the peri-
portal tissue. Sometimes dense connective tissue in considerable
degree is formed.

Spleen.—Frequently in a large giant cell eccentrically placed in a
Malpighian nodule are numbers of small torule.

Lungs.—Numerous miliary nodules as in Rat 2. More often rec-
ognizable organisms can be seen.

Lymph Nodes.—(Mediastinal.) Numerous and large lesions like
those in the peritoneum in the preceding case. The reaction is al-
most entirely of epithelioid and giant cells with formation of con-
nective tissue. Often a ring of connective tissue encircles the clear
zone about an organism. There are also miliary lesions like those
previously described. Some of the lymph sinuses are distended with
organisms which have not yet excited a reaction.

Stains for tubercle bacilli were made, but no organisms found in
any of the tubercles.

Rats 4 and 5 —Inoculated intraperitoneally on Apr. 25, 1915, with a few drops
of a thin salt solution suspension of torula from the original culture. 2 weeks
later inoculated intraperitoneally with 2 cc. of a thick suspension of torula ob-
tained from Rat 1. No symptoms of illness. Killed May 25.
JAMES L. STODDARD AND ELLIOTT C. CUTLER 75

No lesions in gross except in the retroperitoneal lymph nodes, which are en-

larged, with miliary white areas, and in the peritoneum covering the spleen and
kidneys...
Cultures from the peritoneal cavity, heart’s blood, and brain give no growth.

Microscopical Examination.—The absence of lesions in the organs
is confirmed. The lesions in the retroperitoneal nodes are extensive
and of the type already described.

Rats 6 to 18.—Inoculated intracardially on June 22 with 2 cc. of a salt solution
suspension of torula recovered from Rat 1. Rat 6 died on the 2nd day, Rats 7
to 10 on the 5th day, Rat 11 on the 6th day, Rats 12 to 14 on the 7th day, Rat
15 on the 9th day, Rat 16 on the 10th day, Rat 17 on the 11th, and Rat 18 on the
12th day. Symptoms of illness consisting in lack of vigor and alertness preceded
death by 1 to 2 days. At autopsy pneumonia and pleurisy of the type already
described were found in all the rats except Nos.6and9. In gross the only other
lesions noted were enlargement of the spleen and lymph nodes.

Pure cultures of torula were recovered from the spleen and liver of Rat 6, from
the spleen of Rat 12, and from the spleen and meninges of all the other rats.

Microscopical Examination.—Brain lesions are seen in every case,
besides miliary lesions in other organs, which are sometimes exten-
sive. The type of reaction is that previously described. In no case
can an acute exudate be found. In the brain lesions reaction is
practically completely lacking, even though a considerable amount
of reactive tissue exists in the other organs. The brain lesions are
smaller than in the rats killed later, while the lesions in the other
organs are, as a rule, more extensive. Apparently the torula grows
faster, but excites more resistance in most organs, while in the brain
it grows slowly but keeps on for a longer time.

Control Examination.—Six uninoculated rats from the same lot
were autopsied and examined histologically to be sure that similar
diseases did not occur spontaneously in the animals. No lesions
were found.

7. Agglutination Experiments.

Agglutination tests were done on sera taken from all the inoculated
animals. In the first series blood was taken from the heart on Jan.
17, and the sera were kept in the refrigerator. On Jan. 18 a suspen-
sion of the torula organism was tested against the sera in dilutions of
1:20, 1:100, and 1:1,500. The tubes were put in the incubator and
76 TORULA INFECTION IN MAN

readings made in 4 hour and 24 hours; the tubes were then kept at
room temperature, and a third reading was made at the end of 12
hours. All tubes showed the same degree of clearing, with sédiment
of similar appearance. On Jan. 19 a torula suspension was tested
against the sera again in dilutions of 1:2, 1:10, 1:1,000, and 1:5,000,
and readings were made as before. All tests were negative.

On Jan. 22 oidiomycosis and coccidioidal organisms were similarly
tested with all the sera, and no agglutination was found in dilutions
of 1:2, 1:20, 1:100, and 1:500.

All tests were then repeated in dilutions of 1:2, 1:20, 1:100, and
1:500, and found negative. In all tests salt solution and sera of
normal rabbits and pigs were used as controls.

Of the animals tested, four were found at later autopsy to have
lesions produced by the torula; one rabbit, one dog, one guinea pig,
and one mouse. Of the animals inoculated with oidia, none had
lesions. Five animals had coccidioidal lesions,—three guinea pigs,
two rabbits, and a mouse.

In the second series macroscopic and microscopic agglutination
tests were done on the sera of the mice and rats infected with torula
and oidiomycosis. The rats infected with torula proved later to
have extensive lesions. First a suspension of the torula was tested
against the sera of two mice infected with torula and one rat infected
with oidiomycosis in dilutions of 1:20, 1:30, 1:90, 1:180, 1:540, and
1:620. The readings were made as before. No definite aggluti-
nation could be made out.

The microscopic tests were made in dilutions of 1:10, 1:30, 1:90,
1:180, 1:360, and 1:720, and were examined at intervals for 18 hours.
No agglutination occurred. The microscopic tests were repeated
with negative results.

Later it occurred to us that possibly the gelatinous secretion of the
torula interfered with the physical conditions necessary for the test,
as in the case of Friedlander’s bacillus and other encapsulated bacilli.
Consequently treatment with acid, according to the method of Porges
and Prantschoff, was tried. Dilutions were made of 1:2, 1:50, 1:100,
1: 200, and 1:500. After 2 hours in the incubator complete aggluti-
nation was found in the sera of one.mouse in dilution of 1:50, partial
in dilution of 1:100, a questionable slight clumping in dilution
JAMES L. STODDARD AND ELLIOTT C. CUTLER 77

of 1:150, and none in 1:200: This test occurred in a mouse
which was autopsied at the time blood was taken and found to have
a sticky peritoneal exudate from which a pure culture of torula was
obtained. The test was made about 3 weeks after inoculation.
The other mouse gave slighter agglutination. This mouse had been
inoculated only 3 days previously, but at autopsy at the time of
the experiments had a peritoneal exudate containing a pure culture
of torula. Careful control tests with normal rat blood, however,
showed practically the same degree of agglutination. The tests were
also carried out by this last technique on the blood of Rats 3, 4, and 5,
taken at the time of autopsy, and the same results obtained.

Conclusion.—No agglutination test of diagnostic value occurs
in an infected animal.

8. Cultural Characteristics of Torula.

We repeated and confirmed the observations previously reported
in regard to Frothingham’s torula. Observations were made on
cultures growing under varying conditions of temperature and
moisture on many media. Direct observations of growth were made
on agar slides and in hanging drops. Reproduction was always by
budding. In cultures fresh from animals the production of small
forms about 1.25 in diameter occurred.

Fermentation tests in 1 per cent lactose, saccharose, dextrose,
dextrin, and glucose, in Smith fermentation tubes, resulted in no gas
production.

No spore production was found in cultures or in our observations
of growth on gypsum blocks. Extensive observations of gypsum
cultures had already been made by Weis.

The growth at first was most abundant on carbohydrate media,—
potato and agar or dextrose agar,—and was extremely scanty on blood
serum. After animal inoculation growth occurred more vigorously
on blood serum, but never so abundantly as on the dextrose agar
or potato tubes. No growth or very slight growth occurred in anaer-
obic cultures. Growth first occurred in 12 hours to 4 days. It was
nearly as vigorous at room temperature as in the incubator. The
colonies are first white, then they acquire more and more of a yellow
tinge as they grow older. Colonies starting from a single organism
78 TORULA INFECTION IN MAN

become much heaped up, probably from the adhesive nature of the
capsule. In the usual tube inoculation a smooth, pasty, slightly
shiny, thick, slightly yellow layer is formed. No liquefaction of
media or growth into media or along stabs occurred. In bouillon,
after a week, there is slight cloudiness, but no surface growth. Most
of the growth in liquid media occurs as a fine white deposit at the
bottom of the tube. In bouillon cultures a white growth along the
glass above the surface of the media occurs in about a week.

Microscopical Examination.—The cultures show round cells from 1
to 6u in diameter, the average size being 3 to 4y.

Buds form from large cells or from the smaller cells, but most often
from the medium sized cells. The buds measure usually about
1 to 1.54 in diameter. They may attain a diameter of 2.54 before
separation. Sometimes the bud reaches nearly the diameter of the
parent cell.

As the bud begins to separate a deposit of gelatinous substance
forms about the neck of the bud, and after separation occurs it ap-
pears as a thick line at the area of separation. The substance stains
blue with methylene blue, a dark purple with Wright’s stain, and a red
color with Giemsa’s stain or fuchsin. When cells occur in masses,
this substance forms similar lines between adjacent cells, and the
cells often are flattened to form hexagons. If the cells become sepa-
rated the material is drawn out into fine threads connecting the cells,
similar to those in the cases. The torula tends to occur in masses in
cultures, probably on account of this secretion. When growing in
hanging drops it forms close groups.

The medium sized torula cell has a definite wall 0.5 to 1p thick,
staining easily with methylene blue or with Gram’s stain. The cell
interior, as a rule, cannot be made out to have a definite nucleus.
Examination of the organism from cultures is much less satisfactory
than in sections of animal lesions. In smears from young cultures
a stain with methylene blue shows one to six small, very dark stain-
ing masses, irregularly distributed in the cell. . In old organisms these
are not present. The whole interior of the cells in young cultures
usually takes a deep blue stain, in which one or more lighter staining
areas may be apparent. Rarely the interior appears coarsely gran-
ular. In older cultures, especially in the larger cells, the interior does
JAMES L. STODDARD AND ELLIOTT C. CUTLER 79

not stain so uniformly. There is a darker staining mass in a light
staining cell. The mass sometimes appears like a nucleus, and occa-
sionally is surrounded by a thin line like a membrane and may contain
avacuole. In some cases the vacuole appears to have distended the
mass, so that the dark staining material lies next to the cell wall.
Similar appearances are seen in the animal lesions. With Wright’s
stain a definite darker staining mass one-third to one-half the diame-
ter of the cell is usually present, eccentrically situated, in the
smallest organisms. In the larger ones the mass becomes more irreg-
ular in outline and position. In the process of budding part of the
chromatic material flows out into the bud and is separated by the
constriction of the bud. No nucleolus can be made out.

Torulz are widely distributed in nature. They occur in the earth,
on trees and fruits, in wasps’ and bees’ nests, and on these insects.
Classification of different varieties has been attempted, but is un-
satisfactory, on account of the slight and inconstant differences.
Weis, in an investigation of four torule, found great similarity.
None of them fermented sugars. The principal differences were as
to the presence or absence of close or open budding, whether they
formed top or bottom growth in liquid media, the presence of
growth on the glass of the tube, and the amount of gelatinous secre-
tion. These characteristics varied greatly until the organisms had
been under cultivation for months. Our torula shows close budding,
bottom growth with no growth on the surface, yeast ring after a
week’s growth, and distinct gelatinous secretion.

VI. TABLE OF DIFFERENTIAL POINTS BETWEEN TORULA INFECTION,
OIDIOMYCOSIS, AND COCCIDIOIDAL GRANULOMA.

 

Oidiomycosis

(usually termed blastomycosis). Coccidioidal granuloma.

Torula infection.

 

 

Cell wall.
Stains diffusely and eas- Does not stain, as a rule, Stains faintly with hem-
ily with methylene blue and | with methylene blue or | atoxylin and methylene
hematoxylin. hematoxylin. Occasionally | blue, but not diffusely; the

in deeply stained prepara- | inner and outer layers are
tions it partially takes a | principally stained.
faint color.

 

 

 
80 TORULA INFECTION IN MAN

TABLE OF DIFFERENTIAL POINTS—Continued.

 

Torula infection.

Oidiomycosis :
(usually termed blastomycosis).

Coccidioidal granuloma.

 

Protoplasm.

 

In large forms not evi-
dent. In medium sized
forms often shrunken into
an irregular shape, and
takes a diffuse red stain

Usually slightly shrunken
regularly from the wall.
Usually stains well and
appears uniformly granu-
lar, with occasional vacu-

Adheres to the capsule,
often forming a rim in-
side it. It is greatly varie-
gated with all the changes
attendant on the process of

 

 

 

 

with few differentiated | oles or droplets. It colors | endosporulation. Stains
droplets. In small forms | a reddish blue with eosin | well as a rule.
fills the organism and has | and methylene blue.
dark staining masses.
Size.
1 to 13. 3 to 4u to 20u. 5 to 85.
Reproduction.
By budding, often with By budding; usually the Never buds. (Buds may

the production of small
organisms which can bud
before enlarging.

bud is 3 to 3 the diameter
of the parent cell and
grows to the original size
before it reproduces.

be simulated by cells in
apposition.) Produces asco-
spores.

 

Occurrence.

 

Always with a clear
zone about it composed of
gelatinous material.

No clear zone except in
rare cases in the bone
marrow.

£

Ceil products.

No clear zone.

 

A gelatinous material
which often fills the lesion.

No gelatinous material.

 

No gelatinous material.

 

Action on tissues.

 

Destroys the cells it is
enclosed in and appears
in large vacuoles which
are probably due to de-
struction of the cell proto-
plasm.

 

Distends the cells it is
enclosed in, but does not
occur in large vacuoles.

 

Distends the cells it is
enclosed in, is closely sur-
rounded by the cell pro-
toplasm,- and often the cell
shows no evidence of in-
jury.
JAMES L. STODDARD AND ELLIOTT C. CUTLER 81

TABLE OF DIFFERENTIAL POINTS—Continued.

 

Torula infection.

Oidiomycosis
(usually termed blastomycosis).

Coccidioidal granuloma.

 

Character of lesions.

 

1. Lesions with solution
of tissue, filling with gela-
tinous material, slight
chronic reaction. «

2. Nodules with or with-
out caseation composed of
epithelioid cells, giant cells,
and lymphoid cells. Case-
ation occurs centrally and
apparently depends on the
action of the cell products.

No collections of poly-
nuclear cells.

No cutaneous lesions.

Does not attract poly-
nuclear leukocytes in any
stage.

No such lesions.

Nodules with or without
caseation. Caseation is
secondary to a crowding of
cells, apparently.

Abscesses deep and super-
ficial.

Miliary epidermoid ab-
scesses.

Usually attracts poly-
nuclear leukocytes.

No such lesions.

Nodules composed of
epithelioid cells with occa-
sional giant cells. Case-
ation is secondary to large
accumulations of cells and
is peripheral.

Abscesses deep and super-
ficial. *
Cutaneous ulcerations.

The smaller forms es-
pecially attract polynuclear
leukocytes.

 

Clinical course in man.

 

A chronic disease of the
nervous system, without
constant or great fever or
leukocytosis.

A chronic skin disease or
general infection with fever
and leukocytosis.

A chronic skin disease
or a general or brain in-
fection with fever and
leukocytosis.

 

Organs affected.

 

Brain and meninges,
lungs, liver, spleen, kid-
neys. Not skin or bones.

 

All organs, always the
skin, often the bones.

 

All organs, often the skin.

 

Not helped hy salvarsan.
Np data as to effect of
iodides.

Reaction to treatment.

Usually helped by iodides.

 

Not helped by iodides.
82 TORULA INFECTION IN MAN

TABLE OF DIFFERENTIAL POINTS—Concluded.

 

 

 

 

 

 

 

 

 

 

t ‘i Oidiomycosis dais
Torula infection. (usually farmed bestomyodela Coccidioidal granuloma.
Pathogenicity in animals.
Marked for mice and Slight or absent for all Marked for all animals
rats, slight for guinea pigs, | animals tried. tried.
rabbits, and dogs, where
brain lesions are the princi-
pal ones.
Organs affected in intraperitoneal inoculation.
Brain, lungs, liver, spleen, Peritoneum, occasionally Lungs, spleen, liver, kid-
kidneys. lungs. Experiments re- | neys, peritoneum.
ported in which miliary
abscesses or nodules were
produced in various organs
by intravenous inoculation.
None mentioned in the
brain. =.
Organism in culture.
Reproduces by budding. Always grows mycelium Always grows mycelium
Never produces mycelium. sooner or later. and aerial hyphe.

 

 

VII. DISCUSSION.

Historically there is great interest in the fact that torule were
proved years ago by several observers to have marked pathogenic
action in animals, with frequent production of brain lesions. It.
was also shown that torulz are widespread organisms in nature. It
would not have been too venturesome to have prophesied that the
organisms would be found at some future date producing nervous
disease in man. We have found that cases do occur. It will take
time to determine how common this type of infection is, but many
facts indicate the possibility of its being frequently present without
recognition. A number of factors work to conceal its nature. The
organism is not very pathogenic and the lesions are recoverable.
Thus, many infections may occur during life without causing notice-
able symptoms. At autopsy lesions may be found, but, if in the
healed stage, the organisms will be practically or absolutely indis-
JAMES L. STODDARD AND ELLIOTT C. CUTLER 83

tinguishable, and the picture that of a slightly atypical tuberculosis,
caseation being slight or absent. In animals we frequently produced
lesions in nearly all organs, some of which were indistinguishable
from miliary tubercles without caseation, or with slight central necro-
sis. In our human cases the slight lesions outside of the nervous sys-
tem produced no symptoms in the first case; in the second case, with
extensive lung lesions, only an indefinite history of lung symptoms is
given. The lesions closely resembled tuberculosis, and in them the
organisms had practically disappeared. Without brain examination
we could not have recognized the nature of the cases. In the litera-
ture are many cases of nodular lesions in internal organs which do
not seem to be tuberculous in origin, although the lesions resemble
tubercles. Wolbach reports several, and mentions peculiar crystal-
loid bodies in the giant cells, which we found in our second case. Other
cases in our recent hospital records are of the same character. Thus
the tendency toward recovery, the often slight involvement of organs,
the destruction of the parasite, and the resemblance to tuberculosis,
render it possible that the infection is common, but not recognized.

The probability of its recognition in brain examinations is greater,
but even here there are several sources of error. The gliosis and
thickened meninges, with slight atrophy of the convolutions, the
chronic character of the meningitis, with many plasma cells, and often
hyaline organisms, make confusion with syphilis easy. When the
lesions have progressed to caseation, the diagnosis of tuberculosis
might be made. There is no identity on careful examination; the
caseation is not typical, its character and distribution are different,
and only careful microscopical examination shows the organisms. The
perivascular lesions are often small and would escape discovery, unless
the brain were completely sectioned. Many cases would easily escape
recognition in the often careless routine brain examination.

The factors which will aid the recognition of torula infection are:
discovery of early lesions in internal organs before the parasite is
destroyed; realization of the finer points of difference from tuberculo-
sis; complete brain examination; cultures, especially on carbohydrate
media at room temperature; and injections of fluids and cultures into
white rats intraperitoneally, with microscopical examination, espe-
cially of the brain.
84 TORULA INFECTION IN MAN

Torula infection is essentially a chronic disease. In man the
symptoms are measured by months; in animals the lesions last weeks
or months. Its total duration as a general disease cannot be deter-
mined in the human cases, for the first organ lesions probably produce
no symptoms. Asa nervous disease it is clinically essentially chronic,
and the pathological reaction is always one of extreme chronicity.

The lesions in internal organs, outside of the nervous system, are
recoverable. In the human cases and in nearly all the animal
cases there is evident a strong tendency toward destruction of the
parasites, with the production of small nodules or large masses of
connective tissue. In our animal experiments we have seen the
various stages of this conversion. In one animal, however, which
died from the infection after 5 weeks, there was no tendency toward
recovery in the lung lesion, but some in the other lesions. Rusk’s
case and Frothingham’s case showed similar lung lesions. In the’
brain the tendency toward recovery is not so marked. Many of the
lesions in the human and animal cases, especially the intracerebral
lesions, show little evidence of defense by cell proliferation or de-
struction of the organisms. In other instances there is marked
phagocytosis by invading mononuclear cells with partial disappear-
ance of the organisms; and in some animals all the brain lesions are
seen in a healing stage. The meninges have a more effective defense
than the brain.

As to localization of lesions and organ resistance, the animal
experiments show a marked tendency to the production of a general
infection from intraperitoneal inoculations, with especial involve-
ment of the nervous system. Lesions were found in the brain,
meninges, lungs, spleen, liver, kidneys, and lymph nodes. The liver
showed the least extensive lesions, the spleen more involvement,
and the lung, kidney, and brain the greatest involvement. Sometimes
there was more involvement of the brain than of any other organ.
This was the case especially in the higher animals. In the dog there
was only one small lesion in the kidney; there were none in the other
organs, but many small nodules in the brain. The rabbit had one
liver lesion, but no other lesion except a meningitis of considerable
extent. The mouse inoculated intraperitoneally with the ventricular
fluid had only a meningeal lesion; a mouse inoculated with the torula
JAMES L. STODDARD AND ELLIOTT C. CUTLER 85

culture had only a peritoneal lesion, besides the meningitis. In all
rats there was a general involvement of many organs, but the brain
lesions in the later stages showed more evidence of activity than
those of other organs. The same distribution is evident in the
human cases; in our cases the organ lesions, as a tule, were insignifi-
cant with the exception of the lung lesions of the second case.
Histological examination shows a greater destruction of the organ-
isms in the spleen, kidney, and liver than in the lung, and in the lung
greater than in the brain. The brain, however, has some power of
resistance and recovery. The results all show the peculiar low resist-
ance of the nervous system to torula infection. In higher animals
where the resistance is more marked the difference between the
lesions in and outside of the nervous system becomes more striking,
for here the nervous lesions are the only ones which form or progress
in any degree.

The tendency toward the production of brain lesions is in sharp
contrast to the action of the other organisms studied, where intra-
peritoneal inoculation produced brain lesions in no case. Our experi-
ments again support the differences in the human cases, and show
that organ resistance in man is not different from that in animals.

The localization of the lesions in the nervous system is in the
meninges, in the perivascular spaces, and in the brain substance by
extension from these lesions. In the human cases and in animal
experiments lesions were also found in the choroid plexus, in one
human case in the aqueduct of Sylvius, and in another about the fora-
men of Magendie. Lesions in the basal ganglia, internal capsule,
frontal lobes, and cerebellum occurred. A perineuritis was seen in
one case. This tendency toward localization in critical points
obviously makes the production of even small lesions of great impor-
tance. In animals the same distribution is evident, involvement of
the cerebellum being especially noticeable.

Resulting from the chronicity and localization of the lesions are
the symptoms in man. Fever was evident only at the onset in the
cases and was moderate in degree, the white count was low in one case
when fever was present and in others at various periods. We have
already discussed the spinal fluid findings in the cases. The variabil-
ity of the localization will evidently cause no constant symptoma-
86 TORULA INFECTION IN MAN

tology. The tendency to involve the cerebrospinal fluid pathways
is of extreme importance as a method of production of internal
hydrocephalus which will cause confusion with cerebral tumor, es-
pecially in connection with the localizing symptoms of the other
lesions. The optic nerve may become involved, or choked disc may
be secondary to other lesions. The frequent occurrence of psychic
symptoms is in accord with the tendency toward involvement of the
frontal lobes and basal ganglia.

With the exception of syphilis there is little accurate knowledge of
recoverable chronic infections of the central nervous system. There
is clinical evidence in the reports of pseudotumors and other con-
ditions that such cases may not be uncommon, and the torula infec-
tion may have importance in this regard.

The Mechanism of the Disease —The mode of infection in the human
cases is uncertain. Of especial interest is the lesion in the esophagus
in Tiirck’s case, from which organisms were isolated similar to those
in the spinal fluid. However, yeast-like organisms are common in
the throat, and a similarity in cultures cannot be taken to mean
identity. In our second case a sticky pharyngeal exudate was
noted, but no examination made. In Rusk’s case and in our second
case there was an evident possibility of origin in an infection of the
lung. On the whole, the respiratory tract, as in oidiomycosis, seems
the most probable atrium. It is possible that infection may occur
together with a tubercular infection. Ascending infection through
the fallopian tubes is a possibility.

The path of distribution after infection occurs, in many cases at
least, is through the lymphatics to the blood stream. Our second
case, with the numerous lesions in the bronchial lymph nodes and the
miliary lesions in the spleen and liver, suggests this mode of spread.
_ In the animal experiments transport by lymphatics is plain. Lesions
in the retroperitoneal nodes after intraperitoneal inoculation were
marked. In an intrathoracic injection, mediastinal nodes were
involved. The miliary lesions in all organs are due to blood infection.

In all lesions engulfment of organisms by giant and large mono-
nuclear cells was a marked feature. The organisms continue to live
and multiply within these cells and after destroying them are set
free. Thus the methods of defense on the part of the host may spread
the infection.
JAMES L. STODDARD AND ELLIOTT C. CUTLER 87

In the brain lesions additional methods of spreading are evident.
Organisms are carried along the perivascular spaces of the vessels
and start new intracerebral lesions. Or there is direct extension
by solution of tissue. This extension by methods similar to those
of the ameba is not so evident in other organs, probably because the
resistance is so much greater that the organisms are quickly destroyed.
It did occur, however, in the lung of an animal with low resistance.
Nerve lesions are started by organisms carried into the sheath by the
fluid currents.

In the study of the relationship of the organism to its host histology
furnishes evidence of a method of attack by mechanical means, the
pressure of the growing mass of parasites, and by chemical means,
the destruction of the cells of the tissues. The latter factor is the
more important: Another means of offense is a weakening of the
host by the accumulation of its defensive cells in critical spots so as
to interfere with function. In this mode of attack the torula has the
great advantage of being able to produce lesions easily in the nervous
system, and in almost any part of the nervous system. In our cases
it was evident that a great deal of the disease picture was produced
by the interference with the passage of cerebrospinal fluid by focal
lesions; and the weakening of the host produced by the internal
hydrocephalus gave the organism a chance to multiply with greater
freedom.

In the older lesions the organism becomes fainter staining, or
collapsed, and finally disappears. In some cases only miliary lesions
exist. Old cultures of torula do not show disappearance of the
organisms, so that the destruction in the lesions is probably by the
action of the tissues. The destruction occurs in cells or out of
cells. In some cases, however, it is not evident. No production of
agglutinins was found in any case. A further advantage possessed
by the torula is the production of the large thick walled resting cells.
These are typical of torule in nature, which are highly resistant and
long enduring. Dried up cultures of torula several years old im-
mediately grow with rapidity when transplanted, and are pathogenic.
In one rat the histological study of the meninges showed only the
large, almost hyaline forms, but a pure culture was obtained with
ease. It is probable that the infection can remain dormant for a
long time, and then start up afresh. We have direct evidence of this
88 TORULA INFECTION IN MAN

in our second case, where the lung, lymph node, and liver lesions
were old, the lung lesions consisting of hyaline connective tissue masses,
with only a few thick walled forms, while the brain showed a very
active process with young forms predominant. The cerebellar lesion
in our first case was an old lesion, consisting almost entirely of the
resting cell forms. Here the struggle between the parasite and the
tissues had apparently come to a standstill.

The Mode of Multiplication of the Organism.—The small, actively
budding organisms found under favorable conditions of nutrition,
and the resistant spheres under unfavorable circumstances adapt the
parasite to most various conditions.

The histology of the lesions has been fully described, but the
relationship of the two principal types has not been explained. The
experiments give a plain solution of the question, and show part of
the mechanism of the lesions. Possibly the lesion starts by the
passage of a small torula into the tissue while in a phagocytic cell
from the blood stream. It multiplies within the cell and destroys
the cell, and then the organisms are liberated. A single organism
in an endothelial cell or a few small organisms in a giant cell have been
found as the early lesions. The organism then multiplies and pro-
duces a gelatinous material which surrounds it. Phagocytic mono-
nuclear cells gather and take up organisms, which multiply within
them, destroy the cell, and are set free. Giant cells form and undergo
a similar process. The surrounding tissue meanwhile is partly pushed
apart, partly dissolved. Strands of connective tissue often form about
the gelatinous capsule, giving rise to a honeycombed appearance,
the spaces each containing an organism. This is a stage common to
all types of lesion. The varying degrees of resistance of the animal
determine the further fate of the lesion. In a non-resistant animal
or organ, the ameba-like extension by solution of tissue occurs, with
a feeble defense by the production of mononuclear cells and slight
connective tissue. This type of lesion occurs especially in the brain
substance, but is seen in the lung and to a less extent in other organs.
It is a striking and characteristic lesion.

If the animal is comparatively resistant, there is more cell accumu-
lation and proliferation, with some destruction of the organisms.
Epithelioid and lymphoid cells gather, the central part of the lesion
undergoes necrosis and partial caseation, in which at first the organisms
JAMES L. STODDARD AND ELLIOTT C. CUTLER 89

can be seen in honeycombed material, and later almost disappear.
In lymph nodes this type of lesion is most extensive and furnishes a
resemblance to a scrofulous gland. If the destruction occurs promptly
the lesion is small and nodular, with slight central necrosis or case-
_ ation or none, and is like a miliary tubercle. Organisms may or may
not be recognizable. Lesions thus were found in all organs. If
infection occurs simultaneously, in many adjoining foci, there is a
diffuse chronic inflammatory tissue consisting of giant cells, lymph-
oid, epithelial, endothelial, and plasma cells, with connective tissue
formation, and torule enclosed in small spaces. Such lesions are
especially frequent in the meninges and correspond to diffuse tuber-
culous tissue. Early and slight diffuse lesions in the meninges and
brain call out only fluid and large phagocytic mononuclear cells.
When the organisms are overcome quickly, there is slight production
of gelatinous material, but gelatinous encapsulation is always plain.
Very old lesions become converted into fibrous tissue masses.

On account of the histolytic action so striking and characteristic
in early lesions and in brain lesions, it is suggested that the organism
be called Torula histolytica.

We wish to emphasize the fact that not only do the lesions resemble
those of tuberculosis, but they resemble them more closely than do the
lesions of any other disease. Coccidioidal granuloma, considered
by some authors to produce lesions indistinguishable from tuberculo-
sis, in our experiments showed a marked tendency toward miliary or
larger accumulations of polymorphonuclear leukocytes, especially
around sporulating organisms. Caseation was at the periphery of
large collections of polynuclear and epithelioid cells and did not
occur in the small epithelioid cell masses. The parasites were large
and easily seen. Oidiomycosis bears still less resemblance to tuber-
culosis. In torula infection the parasites are often hyalinized and,
being about the size of tissue cells, are almost impossible of recogni-
tion in advanced lesions.

VIII. SUMMARY.
One of the problems in our work was the relationship of the organ-

isms causing the diseases termed blastomycoses. We have shown
the confusion existing in text-books, where the various diseases are
90 TORULA INFECTION IN MAN

described as one disease, or as different manifestations of the action
of a single organism in different states. The study of the literature
convinced us that coccidioidal granuloma was a disease distinct
clinically, pathologically, and biologically from other diseases called
blastomycosis. The work of Wolbach, and MacNeal and Taylor,
who described the life cycle of the organism of dermatitis coccidioides,
never present in the other cases, makes the biological distinction evi-
dent; the summaries of Ophiils, Ryfkogel, Hektoen, and Brown and
Cummins, establish the clinical differences. We have not regarded
it necessary to repeat these summaries. Our experiments bear out
the former work. The lesions produced by Coccidioides immitis
are not to be easily confused with those of blastomycosis, or torula
infection. For the details of the differences between the diseases we
refer to the discussion in the review of literature and to the table.
We lay emphasis on the point, not because we do not consider that
other workers have not made it sufficiently clear, but because it is
not yet recognized in text-books, and because our experiments bear
out the former statements.

Having seen that coccidioidal granuloma was a distinct disease,
we turned our attention to the blastomycoses. We found in the
literature two cases of skin and general infection produced by a true
yeast, with endospores in culture. Both cases were observed by
Buschke, and appeared to be distinct from the American cutaneous
disease. Frothingham’s discovery of torula infection in a horse
indicated another type, but no such cases had been reported in human
beings.

Our cases were distinct from the larger part of the reported cases
of blastomycosis in their clinical histories and pathology. It did not
seem improbable that in the early study of blastomycosis such cases
had been described, but their nature not recognized. We studied
the original reports of all the cases of systemic blastomycosis and
found that nearly all the cases were similar to each other as far
as we could tell from the printed reports, except those involving the
brain. Among these there were obvious differences. First there were
six cases like the other systemic cases, but in which the brain became
involved as part of the general infection, which always included skin
manifestations and often bone lesions. The symptomatology was not
JAMES L. STODDARD AND ELLIOTT C. CUTLER 91

perceptibly influenced by the brain lesions. The pathology of the
brain lesions resembled that of the other lesions. Different from
these were four cases in which there were no skin lesions, but in
which a general infection occurred with brain lesions which caused the
predominating symptoms. Pathologically the lesions were distinct in
many ways; but principally in the extension by solution of tissue,
the always chronic reaction, and the production of a gelatinous
material in the lesions.

Our first case was evidently identical with this latter group. Our
second case was not fully identifiable by the study of the literature
alone, for the peculiar intracerebral lesions were not present, and
the parasite occurred in greater numbers of small forms. Such forms
occurred in the meninges of the first case, but not in the intracerebral
lesions, and were not described in the literature. In the experimental
meningitis in a mouse produced by the injection of a culture of the
ventricular fluid from the second case, however, large organisms were
produced, identical with those of the first case, and intracerebral
lesions of the same type were seen in process of formation. Thus our
two cases were proved to be alike in origin.

Frothingham’s case of torula infection was evidently the type of
infection of these cases. In our animal experiments with torula
we found both forms of parasites present in the lesions in varying
proportions according to the extent and activity of the process. In
a very active lesion enormous numbers of small organisms similar
to those of the second case occurred; these were seen especially in
the meningeal lesions. In older lesions, tending toward recovery,
or in those slowly progressing, and in the higher animals, the larger
forms predominated. In sections of the original horse lesions, small
formsare entirely absent. Our experiments resulted in the production
of all the variations in lesions and organisms seen in the cases. The
animal experiments thus provided the necessary steps for the clear
correlation of all the human cases as cases of torula infection.’

2 Doubt has occasionally been thrown on the possibility of distinguishing a true
yeast or a torula from an oidium or a degeneration form of some higher fungus
by mere examination of the tissues. In the case of certain organisms which do
not produce especially characteristic pathological effects, and are sufficiently
similar morphologically, this may be true, but in the case of the three organisms
92 TORULA INFECTION IN MAN

For all points of difference in the types of disease studied, we refer
to the summary on page 60 and to the table on page 79.

As we have shown (page 60), the term blastomycosis has resulted
in confusion of different diseases in the past and will continue to do so
if used in the future, on account of its insufficient biological signifi-
cance. Oidiomycosis is the proper name for the diseases occurring
near Chicago and caused by the organisms budding in tissues and pro-
ducing mycelium in cultures. Torula infection, coccidioidal granu-
loma, and yeast infection sufficiently designate the other diseases
studied.

We wish to express our thanks to Dr. W. T. Councilman, as the
instigator and constant helper and advisor in the work; to Dr. Harvey
Cushing, for permission to use the cases; to Dr. S. B. Wolbach,
for the cultures of the organisms and for many useful suggestions;
to Dr. L. Frothingham, for the use of slides and tissue from his
original case; to Dr. F. B. Mallory, for the use of slides; and to Dr.
Roland T. Thaxter, for his careful examination of the organisms.

we studied there were no lesions where confusion as to the cause could exist after
careful examination. Each variety of organism had a characteristic appearance
in the tissues. When the histology and the distribution of the lesions are also
considered, enough factors exist to make full identification possible. Lesions
(not described in this paper) were also produced with various oidia (Oidium
albicans and others, isolated from human throat infections), and no appearance
was seen which would be confused with any of our other lesions. Reported cases
of higher fungus infection in which budding forms occur in tissues are distinct
from our cases. If we had had no cultures from the cases and no culture of torula
from other sources for experimental purposes the nature of the organisms could
not have been stated positively. In future other forms of torule or yeasts may
be found which are not sufficiently characteristic in their effects to be distinguished
from budding forms of higher fungi by histological examination alone. The
cases described in this paper are probably a small part of those existing in nature
and not yet studied. Thus, Escomel’s recently reported cases of surface infection
with budding organisms occurring in Peru and Bolivia are apparently caused by
another variety of either yeast or torula. No mycelium is ever produced; the
presence or absence of ascospores is not noted, and no plates are given or details
of histology. The classification in this paper does not pretend to be complete,
but merely to prevent confusion and to make clear the distinctions possible at the
present time.
JAMES L. STODDARD AND ELLIOTT C. CUTLER 93

IX. BIBLIOGRAPHY.

Bassoe, P., Disseminated Blastomycosis, Jour. Infect. Dis., 1906, iii, 91.

Bechtel, R. E., and Le Count, E. R., A Case of Systemic Blastomycosis with Necropsy,
Arch. Int. Med., 1914, xiii, 609.

de Beurman, L., and Gougerot, H., Les nouvelles mycoses: exascoses (exblastomycoses),

_ oidiomycoses, sporotrichoses, botrytimycose, oosporoses hémisporose, Paris, 1912.
a ei T. H., and Clark, S. N., A Case of Blastomycosis, Arch. Int. Med., 1914, xiii,
94.

Boughton, T. H., and Stober, A. M., A Case of Systemic Blastomycosis with Recovery,
Arch. Int. Med., 1914, xiii, 599.

Bowen, J. T., and Wolbach, S. B., A Case of Blastomycosis: The Results of Culture and
Inoculation Experiments, Jour. Med. Research, 1906, xv, 167.

Brown, P. K., A Fatal Case of Coccidioidal Granuloma, Jour. Am. Med. Assn., 1913,
1xi, 770.

Brown, P. K., Coccidioidal Granuloma, Jour. Am. Med. Assn., 1907, xlviii, 743.

Brown, P. K., and Cummins, W. T.,A Differential Study of Coccidioidal Granuloma and
Blastomycosis, Arch. Int. Med., 1915, xv, 608.

Buschke, A., Die Sprosspilze, in Kolle, W., and von Wassermann, A., Handbuch der
pathogenen Mikroorganismen, Jena, 2nd edition, 1913, v, 155.

Busse, O., Uber Saccharomycosis Hominis, Virchows Arch. f. path. Anat., 1895, cxl, 23.

Busse, O., Experimentelle Untersuchungen iiber Saccharomycosis, Virchows Arch. f. path.
Anat., 1896, cxliv, 360.

Busse, O., Uber parasitire Zelleinschliisse und ihre Ziichtung, Centralbl. f. Bakteriol.,
1894, xvi, 175.

Carson, G. R., and Cummins, W. T., A Case of Coccidioidal Granuloma (California
Disease), Jour. Am. Med. Assn., 1913, lxi, 191.

Christensen, C., and Hektoen, L., Two Cases of Generalized Blastomycosis, Jour. Am.
Med. Assn., 1906, xIvii, 247.

Churchill, T., and Stober, A. M., A Case of Systemic Blastomycosis, Arch. Int. Med.,
1914, xiii, 568.

Cleary, J. H., A Case of Generalized Blastomycosis, Medicine, 1904, x, 818; Tr. Chicago
Path. Soc., 1903-06, vi, 105.

Coates, W. E., A Case of Blastomycotic Dermatitis: Clinically and Histologically an
Epithelioma, Medicine, 1900, vi, 100.

Cohn, E., Untersuchungen tiber eine neue tierpathogene Hefeart, Ceniralbl. f. Bakteriol.,
lie Abt., Orig., 1902, xxxi, 739.

Coley, W. B., and Tracy, M., Report of a Case of Oidiomycosis, Jowr. Med. Research,
1907, xvi, 237.

Curtis, F., Contribution 4 l’étude de la Saccharomycose humaine, Ann. de P Inst. Pasteur,
1896, x, 449.

Duggar, B.M., Fungus Diseases of Plants, with Chapters on Physiology, Culture Meth-
ods and Technique, Boston and London, 1909.

Fisendrath, D. N., and Ormsby, O. S., A Case of Systemic Blastomycosis, with Blasto-
mycetes in the Sputum, Jour. Am. Med. Assn., 1905, xlv, 1045.

Eisenstaedt, J. S., and Boughton, T. H., A Case of Systemic Blastomycosis, Arch. Int.
Med., 1914, xiii, 617.

Escomel, E., Sur la Blastomycose humaine au Pérou et en Bolivie, Bull. de la Soc. de
Path. exot., 1915, viii, 90.

uo
94 TORULA INFECTION IN MAN

Frothingham, L., A Tumor-Like Lesion in the Lung of a Horse Caused by a Blastomyces
(Torula), Jour. Med. Research, 1902, viii, 31.

Gilchrist, T. C., A Case of Blastomycetic Dermatitis in Man, Rep. Johns Hopkins Hosp.,
1896, i, 269.

Gilchrist, T. C., Some Additional Cases of Blastomycotic Dermatitis, Jour. Cutan. Dis.,
1904, ii, 107.

Gilchrist, T. C., and Stokes, W. R., A Case of Pseudo-Lupus Vulgaris Caused by a Blasto-
myces, i Exper. Med., 1898, ili, 53.

Gilchrist, T. C., and Stokes, W. R., The Presence of an Oidium in the Tissues of a Case of
Pseudo-Lupus Vulgaris, Bull. Johns Hopkins Hosp., 1896, vii, 129. | -

von Hansemann, D., Uber eine bisher nicht beobachtete Gehirnerkrankung durch Hefen,
Verhandl. d. deutsch. path. Gesellsch., 1906, ix, 21.

Hektoen, L., Systemic Blastomycosis and Coccidioidal Granuloma, Jour. Am. M. ed.
Assn., 1907, xlix, 1071.

Hektoen, L., The Organism in a Case of Blastomycetic Dermatitis, Jour. Exper. Med.,
1899, iv, 261.

Herrick, J. B., Generalized Blastomycosis, Jour. Am. Med. Assn., 1907, xlix, 328.

Heubner, O., Uber einen Fall von Soor-Allgemeininfektion, Deutsch. med. Wchnschr., 1903,
xxix, 581, 604.

Hildreth, E. R., and Sutton, A. C., Oidiomycosis in Porto Rico, Jour. Am. Med. Assn.,
1914, Ixiii, 2289.

Hill, H. P., and Dickson, E. C., Report of a Case of Systemic Blastomycosis, California
State Four. of Med., 1914, xii, 120.

Hyde, J. M., Hektoen, L., and Bevan, A. D., A Contribution to the Study of Blastomy-
cetic Dermatitis, Bri, Jour. Derm., 1899, xi, 261.

Hyde, J. M., and Montgomery, F. H., in Montgomery, F. H.,and Ormsby, O.S. Pree
Hinsiommyends Arch. Int. Med. , 1908, ii, 36.

Irons, E. E., in Montgomery, F. i, and Ormsby, O. S., Arch. Int. Med., 1908, ii, 36.

Irons, E. E., and Graham, E. A., Generalized Blastomycosis, Jour. Infect. Dis., 1906,
iii, 666.

Jackson, H., A Case of Systemic Blastomycosis, Arch. Int. Med., 1914, xiii, 607.

Klein, E., Pathogenic Microbes in Milk, Jour. Hyg., 1901, i, 78.

Klein, E., Weitere Untersuchungen iiber die Kleinsche tierpathogene Hefe, Ceniralbl. f.
Bakteriol., lie Abt., Orig., 1903, xxxiv, 224.

Kohl, F. G., Die Hefepilze, ihre Organisation, Physiologie, Biologie und Systematik,
sowie ihre Bedeutung als Gdrungsorganismen, Leipzig, 1908.

Krost, R. A., Moes, M. J., and Stober, A. M., A Case of Systemic Blastomycosis, J our.
Am. Med. Assn., 1908, 1, 184.

Le Count, E. R., Blanimaypestic Lesions of the Brain, Jour. Nero. and Ment. Dis, 1909,
xxxvi, 144. .

Le Count, E. R., Blastomycetic Meningitis, Tr. Chicago Path. Soc., 1906-09, vii, 268.

Le Count, E. R., and Myers, J., Systemic Blastomycosis, Tr. Chicago Path. Soc., 1906-09,
vii, 49; Jour. Infect. Dis., 1907, iv, 187. *

Lewison, ee , and Jackson, H., A Case of Systemic Blastomycosis, Arch. Int. Med., 1914,
xiii, 575.

Lindau, G., Die Pilze Sammlung Géschen, No. 574, Leipzig, 1912.
JAMES L. STODDARD AND ELLIOTT C. CUTLER 95

\

MacNeal, W. J., and Hjelm, C. E., Note on a Mold, Coccidioides immitis, Found in a
Case of Generalized Infection in Man, Jour. Am. Med. Assn., 1913, lxi, 2044.

MacNeal, W. J., and Taylor, R. M., Coccidioides immitis and Coccidioidal Granuloma,
Jour. Med. Research, 1914, xxx, 261.

Metschnikoff, E., Uber ein Sprosspilzkrankheit der Daphnein, Virchows Arch. f. path.
Anat., 1884, xcvi, 177.

Montgomery, F. H., A Brief Summary of the Clinical, Pathological, and Bacteriological
Features of Cutaneous Blastomycosis, Jour. Am. Med. Assn., 1902, xxxviii, 1486.

Montgomery, F. H., and Ormsby, O. S., Systemic Blastomycosis, Arch. Int. Med., 1908,
ii, 1.

Montgomery, F. H., and Ricketts, H. T., Three Cases of Blastomycetic Infection of
the Skin: One Case Limited to a Tumor of the Lower Lip, Jour. Cut. and Gen.-Urin.
Dis., 1901, xix, 26.

Morris, R. T., A Case of Systemic Blastomycosis, Jour. Am. Med. Assn., 1913, lxi, 2043.

Myers, H. J., and Stober, A. M., A Case of Systemic Blastomycosis, Arch. Int. Med.,
1914, xiii, 585.

Neumayer, J., Untersuchungen iiber die Wirkungen der verschiedenen Hefearten, welche
bei der Bereitung weingeistiger Getrinke vorkommen, auf den thierischen und
menschlichen Organismus, Arch. f. Hyg., 1891, xii, 1.

Nichols, E. H., Relationship of Blastomycetes to Cancer, Jour. Med. Research, 1902, vii,
312.

Nonne, M., Uber Fille von Symptomcomplex “tumor cerebri” mit Ausgang in Heilung,
Deutsch. Zischr. f. Nervenh., 1904, xxvii, 169.

Ophiils, W., Coccidioidal Granuloma, Jour. Am. Med. Assn., 1905, xlv, 1291.

Ophiils, W., Further Observations on a Pathogenic Mould Formerly Described as a
Protozoon, Jour. Exper. Med., 1901-05, vi, 443.

Ophiils, W., and Moffit, H. C., A New Pathogenic Mould, Philadelphia Med. Jour., 1900,
v, 1471.

Ormsby, O. S., in Montgomery, F. H., and Ormsby, O. S., Arch. Int. Med., 1908, ii, 35.

Ormsby, O. S., and Miller, H. M., Report of a Case of Systemic Blastomycosis, Jour.
Cut. Dis., 1903, xxi, 121.

Oswald, in Montgomery, F. H., and Ormsby, O. S., Arch. Int. Med., 1908, ii, 36.

Otis, F. J., and Evans, N., The Morphology and Biology of the Parasite from a Case of
Systemic Blastomycosis, Jour. Am. Med. Assn., 1903, xli, 1075.

Owens, J. E., Eisendrath, D. N., and Ready, C. F. W., Blastomycotic Dermatitis, Ann.
Surg., 1899, xxx, 545.

Paltauf, R., Die Agglutination, in Kolle, W., and von Wassermann, A., Handbuch der
Pathogenen Microorganismen, Jena, 2nd edition, 1913, ii, 504.

Pilger, R., Die Stimme des Pflanzenreichs, Sammlung Géschen, No. 485, Leipzig, 1910.

Rabinowitsch, L., Untersuchungen iiber pathogenen Hefearten, Zischr. f. Hyg. u. In-
fectionskrankh., 1896, xxi, 11.

Raum, J., Zur Morphologie und Biologie der Sprosspilze, Ztschr. f. Hyg. u. Infections-
krankh., 1891, x, 1. ,

Ricketts, H. T., An Organism from Cutaneous Oidiomycosis (Blastomycosis), Tr. Chicago
Path. Soc., 1903-06, vi, 113. :

Ricketts, H. T., Oidiomycosis of the Skin and Its Fungi, Jour. Med. Research, 1901, vi,
377.

Riley, F. B., and Le Count, E. R., A Case of Systemic Blastomycosis, Arch. Int. Med.,
1914, xiii, 614.
96 TORULA INFECTION IN MAN

Rixford, E., and Gilchrist, T. C., Two Cases of Protozoic (Coccidioidal) Infection of the
Skin and Other Organs, Rep. Johns Hopkins Hosp., 1896, i, 209.

Rusk, G. Y., Systemic Oidiomycosis, University of California Publications in Pathology,
1912, ii, 47.

Ryfkogel, H. A. L., Coccidioidal Meningitis with Secondary Internal Hydrocephalus
and Death (Anaphylactic?) Following a Secondary Injection of Flexner’s Serum,
Jour. Am. Med. Assn., 1910, lv, 1730.

Shaffner, P. F., A Case of Systemic Blastomycosis, Arch. Int. Med., 1914, xiii, 621.

Stober, A. M., Systemic Blastomycosis, Arch. Int. Med., 1914, xiii, 509.

Tokishige, H., Uber pathogene Blastomyceten, Centralbl. f. Bakteriol., Ist Abt., 1896, xix,
105.

Tiirck, W., Ein Fall von Hefeinfektion (Saccharomykose) der Meningen, Arch. f. klin. Med.,
1907, xc, 335.

Walker, J. W., and Montgomery, F. H., Further Report of a Previously Recorded Case
of Blastomycosis of the Skin; Systemic Infection with Blastomyces; Death; Autopsy,
Jour, Am. Med. Assn., 1902, xxxviii, 867.

Weis, J. D., Four Pathogenic Torule (Blastomycetes), Jour. Med. Research, 1902, vii,
280.

Wells, H. G., Preliminary Report of a Case of Blastomycotic Dermatitis, New York
Med. Jour., 1898, Ixvii, 427.

Wernicke, R., Uber einen Protozoenbefund bei Mycosis Fungoides (?), Centralbl. f. Bak-
teriol., 1892, xii, 859.

Whitman, R. C., A Contribution to the Botany of the Organism of Blastomycosis, Jour.
Infect. Dis., 1913, xiii, 85.

“Wolbach, S. B., A New Type of Cell Inclusion, Not Parasitic, Associated with Dissemi-
nated Granulomatous Lesions, Jour. Med. Research, 1911, xxiv, 243.

Wolbach, S. B., The Life Cycle of the Organism of “Dermatitis Coccidioides,” Jour.
Med. Research, 1904, xiii, 53.

Wolbach, S. B., Recovery from Coccidioidal Granuloma, Boston Med. and Surg. Jour.,
1915, clxxii, 94.

Wright, J. H., Oidiomycosis, in Osler, W., and McCrae, T., Modern Medicine, Phila-
delphia and New York, 2nd edition, 1913, i, 1050; Blastomycosis, 1054.

X. EXPLANATION OF PLATES.
Pate 1.

Fic. 1. Slight atrophy and pitting of convolutions of the frontal lobe of the first case.
Fic. 2. Lesion in the frontal lobe of the first case.
Fic. 3. Cerebellar lesion in the first case.

PLATE 2.

Fic. 4. Periphery of cerebellar lesion in the first case, showing the method of extension
by solution of tissue. Stained with eosin and methylene blue. > 150.

Fic. 5. A group of intracerebral perivascular lesions in the first case. Stained with
eosin and methylene blue.

Fic. 6. Single perivascular lesion in the first case. Stained with eosin and methylene
blue. xX 150.
JAMES L. STODDARD AND ELLIOTT C. CUTLER 97

PLATE 3.

Fic. 7. Small intracerebral lesion in the first case. Apparently the organisms arose
from the large organism in the center. The drawing out of the secretion into threads is
evident. Stained with eosin and methylene blue. > 2,000.

Fic. 8. Peripheral gliosis in the first case. Stained with phosphotungstic acid
hematoxylin. > 1,000.

Fic. 9. Organisms in giant cells in the meninges in the first case. Cresy] blue stain.
X 850.

PLaTE 4,

Fic. 10. Granulation tissue filling the aqueduct of Sylvius in the first case. > 60.

Fic. 11. Area of meninges in the first case where the pseudotuberculous process is
marked. Stained with eosin and methylene blue. > 100.

Fic. 12. Cerebellar lesions in the second case.

Prate 5.

Fic. 13. Edge of cerebellar cortex showing meningitis in the second case. Stained
with eosin and methylene blue.  X 100.

Fic. 14. Organisms in meninges in the second case. Note the budding organism.
Oil immersion. Stained with eosin and methylene blue. X 1,200.

Fic. 15. Lymph node in the second case. At the upper right hand corner is the edge
of a mass of dense connective tissue. Stained with eosin and methylene blue. > 100.

Fic. 16. Lung lesion in the second case. Stained with eosin and methylene blue.
X 100.

Fic. 17. Lesion in the internal capsule in the second case. Stained with hematoxylin
and eosin. X 50.

Fic. 18. At the left side is the necrotic center of the lesion in Fig. 5. Oil immersion.
Stained with hematoxylin and eosin. X 1,200.

Pirate 6.

Fic. 19. Giant cell containing organisms in the meninges in the second case.

Fic. 20. Organisms in a large vacuole in a meningeal giant cell of the second case.

Fic. 21. Meninges of a mouse infected intraperitoneally with a culture of ventricular
fluid of the second case. Stained with hematoxylin and eosin. X 250.

Fic. 22. Radiating threads in an organism from Fig. 3. Oil immersion. Stained
with hematoxylin and eosin. X 2,000.

Fic. 23. Radiating threads in organisms in cerebellar lesion in the first case. Cresyl
blue stain. XX 1,000.

Fic. 24. Original torula infection in the lung of a horse. Stained with hematoxylin
and eosin. XX 300.

Fic. 25. Intracerebral lesions in a rat infected intraperitoneally with torula.

Fic. 26. Torule in experimental lesion. Oil immersion. Stained with eosin and
methylene blue. X 1,000.

Fic. 27. Torule in an endothelial cell in the lung of a rat. Oilimmersion. Stained
with eosin and methylene blue. > 2,000.
98 TORULA INFECTION IN MAN.

PLate 7.

Fic. 28. Torula lesion in a rat infected intraperitoneally. Stage of healing. Stained
with eosin and methylene blue. X 150. :

Fics. 29, 30, 31. Torule in experimental lesions. Oil immersion. Note the apparent
nucleus in Fig. 31. XX 2,000.

Fic. 32. Budding torulz. Note the extremely small buds. Oilimmersion. Stained
with eosin and methylene blue. 1,000.

Fic. 33. Variations in the size of torula in an experimental eaion in a rat (lung).
Oil immersion. Stained with hematoxylin and eosin. X 2,000. ;

Fic. 34. Meningeal lesion in a rat infected intraperitoneally with torula. XX 2,000. .

Fic. 35. Pseudotuberculous lesion in a peritoneal nodule in a rat infected with torula.
Note organisms in spaces. Stained with eosin and methylene blue. X 50.

Fic. 36. Lesions like miliary tubercles in the lung of a rat infected with torula by heart
injection. Stained with eosin and methylene blue. X 50.

PLaTE 8.

Fic. 37. Organisms in a destroyed giant cell in the meninges in the second case. At
the upper left hand corner are two red blood corpuscles for comparison of size. Camera
lucida drawing. Oil immersion. Mallory’s aniline blue connective tissue stain.

Fic. 38. Beginning lesion in a meningeal giant cell in the second case. The organisms
are thinner walled than in Fig. 1. Camera lucida drawing. Oil immersion.

Fic. 39. Organisms in the meninges of a mouse infected intraperitoneally with a
culture of ventricular fluid of the second case. Note budding of the small organism.
Camera lucida drawing. Oil immersion.

PLATE 9.

Fic. 40. Organisms itka giant cell in the lung of a rat infected with torula. The
central part of the cell: contains the completely finished drawing. Camera lucida. Oil
immersion.

Fic. 41. Organisms in ihe lung of a rat infected with torula. Camera lucida. Oil
immersion. : ‘

Fic. 42. Very small torule in the cerebellar cortex of an infected rat. Camera lucida. :
Oil immersion.
PLATE 1.

MONOGRAPH NO. 6.

SSS

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<<

 

(Stoddard and Cutler: Torula lofection )
PLATE 2,

MONOGRAPH NO. 6,

 

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a Infection

ard and Cutler: Torul.

(Stodd
PLATE 3.

6.

MONOGRAPH NO.

 

jon )

Torula Infect

(Stoddard and Cutler
PLATE 4.

MONOGRAPH NO. 6.

 

Torula Infection.)

Stoddard and Cutler:

(
MONOGRAPH NO. 6.

PLATE 5.

 

(Stoddard and Cutler: Torula Intection.)
PLATE 6.

MONOGRAPH NO. 6.

 

(Stoddard and Cutler: Torula Infection.)
MONOGRAPH NO. 6. PLATE 7.

 

(Stoddard and Cutler: Torula Infection.)
PLATE 8.

MONOGRAPH NO. 6.

 

(Stoddard and Cutler: Torula Infection.)
MONOGRAPH NO. 6. PLATE 9.

 

(Stoddard and Cutler: Torula Infection.)