857
MUCORMYCOSIS
Report
of a Case
By Jerome S. Harris, M.D.*
S
CATTERED through medical literature arereports of a bizarre, fatal, invasive,
necrotizing process in which broad
non-septate hyphal strands can be seen on
his-tologic section. The etiologic agent has not
been cultured in any of the reported cases
because the diagnosis was not made prior
to the examination of tissues which had
been fixed. As non-septate broad hyphae are
ty pical of the Mucoraceae, the disease was
called mucormycosis by Paltauf’ who
de-scribed the first case in 1885. Baker2
re-viewed and summarized the problem as
follows : “Acutely fatal mycotic disease . .
may be confused with acute infectious
dis-ease of bacterial or viral nature. Two
mycoses are notable, namely,
mucormyco-sis and blastomycosis. Mucormycosis is the
most acutely fatal mycosis known. The
dura-tion of the disease has been brief, a matter
of days.” “Unfortunately Mucor fungi have
not been cultured in any of the reported
cases, because the tissues were fixed before
the need for cultures was realized. The
appearance of the fungus in microscopic
sections strongly suggests Mucor, for there
are large, branching hyphae with absent or
rare septa. The disease can develop,
appar-enthy, only in the presence of some factor
that reduces resistance to invasion of the
body by this fungus, because, of 6 autopsy
cases, all had diabetes mellitus.”
The present typical case in a diabetic
child is reported because it is the first to be
diagnosed during life. The diagnosis has
been established by biopsy; the organism
has been identified by culture; the patient
has recovered from the acute phase under
therapy and is now in fair health, 13 months
later.
From the Department of Pediatrics, Duke
Uni-versity School of Medicine.
0 ADDRESS: Departnlent of Pediatrics, Duke Uni-versity, Durllam, North Carolina.
History
CASE REPORT
Constance M., a 14-year-old colored girl,
was admitted to Duke Hospital on January 29,
1954. For a vague period of time (2 to 6
weeks), she had noted some polyuria, polydyp-sia, weakness and weight loss. It is uncertain
whether this started before or immediately
fol-lowing an episode, 3 weeks prior to admission,
diagnosed as mumps. However, she remained
essentially well until January 20 when she
de-veloped a nasopharyngitis with painful throat,
dysphagia and soreness of the roof of her
mouth. The next day she was seen by a
physi-cian who made a diagnosis of mild
nasopharn-gitis and prescribed symptomatic therapy. On
January 22, she complained of pain in the left
side of her head. The next day she developed
tachycardia, weakness and impending coma.
The patient was hospitalized and determination
of the blood sugar concentration showed it to be
500 mg./100 ml. The carbon dioxide
com-bining power was 24 volumes per cent.
Treat-ment of diabetic acidosis was begun witll salme
solution, insulin and potassium chloride. The
child improved somewhat, but on the next
day the left eye became injected, proptosed
and fixed. Her temperature rose to 103#{176}F.and
her leukocyte count to 18,000. Penicillin and
dihydrostreptomycin were prescribed. Despite
warm compresses the eye did not improve and
she developed paralysis of the heft side of the
face, weakness of the left side of the uvula,
slight weakness on swallowing and some
drool-ing from the left side of her mouth.
Roent-genograms on January 26 showed extensive
mottling of the lower left lung field which was
interpreted as bronchopneumonic infiltration.
From then until admission to Duke Hospital,
she was treated for diabetes with 35 units of
regular insulin 3 times daily and 95 units of
protamine zinc insulin daily. Althougil the
dia-betes was partly controlled, the ocular and
neurological difficulties did not improve.
Physical Findings
The patient was an acutely ill, thin girl,
coopera-858 HARRIS - MUCORvIYCOSIS
tive, who complained of severe pain in the left side of 11cr neck particularly n flexion. Tile
skin was warm, dry and had good turgor. The
left side of the face was generally swollen. The
left eye was proptosed and there was a
corn-plete internal and external ophthalmoplegia on
tilat side. The conjunctivae Oil the left were
edematous and injected. Cornea! clouding and
ulceration were present and there was some
gieenish yellow purulent exudate (Fig. 1). The
left fundus showed severe venous congestion but
no papilledema. The right eye was normal. The
right ear canal was clear and the right ear drum
slightly reddened. Tile left ear canal showed
maceration and the presence of white
cheesy-looking material. The left ear drum was white
and thickened, and the landmarks were
ob-scured. There ‘as no sinus or mastoid
tender-ness. The nasal turbinates on the left were
markedly swollen but the nasal septum was
in-tact. The breath was extremely foul. There was
atrophy and weakness of the left side of the
tongue. The left palate was also weak. At the
juilctiOn of the soft and hard palate on the left
side, there was a large ulceration (3 by 5 cm.)
\‘ilicll was partly covered by a brownish yellow cheesy material. In tile center of this ulcerated area, there was a perforation (1 by 1 cm.) of the
palate which revealed the nasal cavity. The
bare 1)terg0id plate on the lateral side of the
nasal cavity could also be seen through the
perforation. The entire area was covered with
a wilitish cheesy necrotic material and a
sero-sanguinous exudate oozed from the perfora-tiOll. On the left lateral aspect of tile tongue
there was a firm, white mass (0.5 b 0.5 cm.).
The neck was not remarkable save for
resist-ance and pain on passive movement,
particu-larhy flexion. The thorax, lungs, heart and
ab-domen were normal. The genitalia were
nor-mally developed but there was a moderate
amount of purulent vaginal discharge. Bones,
joints, and spine were not remarkable.
Neuro-logical examination showed a clear sensorium
with abnormal findings liniited to the cranial
nerves. There was almost complete blindness on
the heft. The left third, fourth and sixth nerves
were completely paralyzed. the left pupil was
moderately dilated and fixed. There was
corn-plete anesthesia of tile maxillary division of the
left fifth nerve aild partial anesthesia of its
orbital division with absent corneal sensation.
There was weakness of the left side of the face
but this might have been more apparent than
real because of swelling. Tile left side of the
tongue showed diffuse atrophy. The tongue
deviated to the left on protrusion and the
palate deviated to the right on gagging. Tile
jaw deviated to the left on opening and there
was weakness of tile muscles of mastication on
the left. Tile left sternocleidomastoid and
trape-zius muscles were weak. The deep reflexes in
tile extremities, the abdominal reflexes and tile
plalltar reflexes were normal.
Laboratory Findings
Oil admission, tile hemoglobin was 12.0 gnl. alld the leukocyte coullt was 17,100 with 80
per cent segmented forms, 5 per ceilt
unseg-mented, 2 per cent juveniles, 5 per cent small
lympllocytes, 5 per cent large lymphocytes, and
3 per cent monocytes. Sickle cells were not
present. Tile leukocyte count was 20,800 n
January 31 vith 70 per cent segmented forms.
OIl February 4, the count had dropped to
13,750 with a percentage distribution of 69
segmented, 4 unsegmented, 2 eosinophils, 1
juvenile, 11 small lymphocytes, 8 large lympho-cytes and 5 monocytes. Thereafter, throughout the remaining 4 months of the child’s
hospitali-zation. the leukocyte count varied between
7,000 and 10,700 with 59 to 77 per cent
seg-mented forms. Urine on admission showed
ke-tone bodies, a trace of protein, 3 plus sugar,
12 to 15 leukocytes, and rare erythrocytes.
Thereafter, the urinary sediment contained only
occasional leukocytes. The stool did not
con-tam blood, ova or parasites. On admission the
fasting blood sugar was 225 mg./100 ml.; the
carbon dioxide combining power, 66 volumes
per cent; the serum chloride, 95 mEq./l.; serum
sodium, 143 mEq./l. and serum potassium,
4.4 mEq./l. The total protein was 7.4 gm./100
ml. with Il A/G ratio of 1.0. Serologic tests
for syphilis were negative. Intradermal
tuber-culin skill test was negative in 1 : 1000 dilution.
The histoplasmin, Frei and coccidioidin skin
tests were negative but that for blastomycosis
showed a slight transient erythema. There was
a mildly positive reaction to intradermai Rhizo-IRIS vaccine ill 1:1000 dilution all(l a very in-tense, 3 plus, indurated reaction to the 1 :100
dilutioll.
On admission lumbar puncture revealed clear
spillal fluid under normal pressure. The spinal
fluid sugar was 92 mg./100 ml., the protein
40 mg./100 ml. and routine cultures were
nega-tive. There were 28 heukocytes, predominantly mononuclear cells, and 10 erythricytes/mm..
Another lumbar puncture on February 2 again
revealed normal spinal fluid pressure. Jugular
compression on either side caused a prompt rise
in spinal fluid pressure followed by a rapid
fall. The cell count on the fluid from the
see-ond lumbar puncture was 43 mononuclear and
8 polymorphonuclear leukocvtes/mm
A biopsy from the ulcerated lesion of the
palate on February 3 showed necrotic fatty
areolar tissues without nuclear stainillg but
with maintenance of tissue structure. Broad,
branching, non-septate hyphae, 4-14 micra in
thickness and up to 180 micra in lengtil,
oc-curred in the walls and humina of blood vessels,
perineural lymphatics, nerves and diffusely in
the tissues (Fig. 2). The hyphae were
histo-logically characteristic of the coenocytic
phy-comycetes. No bacteria were stainable deep in
the tissue though gram-positive cocci,
gram-positive and gram-negative bacilli and a yeast
suggestive of Candida were adherent to tile
surface. A biopsy on February 8 showed healthy
0 Intradermal tests with the 1:100 dilution of
vaccine were made on 8 normal individuals. Four
showed nlild reactions at 24 hours hut all were
negative after 48 hours.
FIG. 2. Hyphae of Rhizopus in tissue (H and E x 218). (Left) Hyphae present in wall and lumen of blood
860 HARRIS - MUCORMYCOSIS
granulation tissue free of organisms, but
with broad branching hyphae in the pus on the
surface. Cultures of these biopsied lesions
showed Rhizopus arrhizus. Cultures for
acid-fast organisms were negative. On March 11, the
nasal mucosa was biopsied. One fragment
showed lymphoid tissue covered on all sides
by stratified squamous epithelium. The other
was a fragment of skeletal muscle heavily
in-filtrated by acute inflammatory cells but without
fungi. On March 18, Rhizopus arrhizus was again cultured from the palatal lesion.
An electrocardiogram on January 30 was
within normal limits. An electroencephalogram
OIl March 12 showed waves of slow frequency
and irregular form, but not of enlarged
amphi-tude, almost continuously over the frontal and
temporal regions on both sides. Over the
parie-to-occipital areas the pattern was within
nor-mal limits. Overventilation had no significant
effect on the pattern. The findings were
inter-preted as being suggestive of a frontotemporal
dysfunction but not as evidence of any strictly localized cerebral disorder.
Roentgenograms of the chest on January 29,
showed an area of increased density in the
left lower lung field associated with some shift
of the heart to the left and elevation of the left
diaphragm, indicating atelectasis of segments
of tile left lower lobe. The heart was normal.
Roentgenograms of the skull, sinuses and orbits
showed cloudiness of all the sinuses on the
left side but no evidence of bone destruction.
The basilar foramina did not appear eroded.
On February 6, the lungs were normal. On
February 20, the sinuses on the left side still
appeared clouded without bone destruction.
Roentgenograms of the skull were normal. On
March 25, the left antrum, ethmoid and frontal
smuses were still markedly clouded. The
mas-toids and optic foramina were clear. Similar
dense clouding of the left sinuses and
thicken-ing of the membrane on the left side of the
sphenoidal sinus were noted on April 14. On
April 22 haziness but no definite bone
destruc-tion was found in the left mastoid cells. The pe-trous bones and mastoids were normal on the right.
Course
The admission diagnosis was diabetes
corn-plicated by either tumor or infection causing
bronchopneumonia and extensive involvement
of the left side of the head and face. The child
was thought to have left pansinusitis, cavernous
and left lateral sinus thrombosis with extension
to the jugular vein aIld inflammation around the
hypoglossal foramen. The diagnosis of
mucor-mycosis was suggested shortly after admission
and was verified by biopsy and culture.
Therapy was directed toward rigid control
of the diabetes, elimination of secondary
bac-terial contamination, symptomatic relief and the
possibility of specific action against the
invad-ing fungus. Numerous in-vitro sensitivity tests
were made but only disulfiram (Antabuse#{174})
was found to be slightly effective. It was not
tried since preliminary experiments indicated
an adverse effect on alloxan-diabetic rats.
Within 1 week after admission, the child
was taking a 1580 calorie diet (80 gm. protein,
65 gm. fat, and 150 gm. carbohydrate) and
in-sulin (60 units NPH and 30 units regular at
8:00 A.M., 15 units NPH and 10 units regular
at 5: 15 P.M.). At no time thereafter was sugar
present in any of the urine specimens and the
morning blood sugar concentration ranged from
51 to 114 mg./100 ml. (most often between
70 and 80 mg./100 ml.). For the first 2 weeks
of hospitalization, the child was given 1 gm.
oxytetracychine (Terramycin#{174}) and between
600,000 and 1,000,000 units of pencillin daily.
Therapy against the fungus consisted of iodides
and desensitization. A vaccine was made from
the rhizopus cultured from the pharyngeal
lesion. On February 22 0.1 ml. of a 1:10,000
dilution was given subcutaneously after
pre-liminary intradermal tests had shown the child to be sensitive to the 1 : 1000 dilution.
Increas-ing doses were given every other day until the
child was receiving 0.6 ml. of the 1: 10
dilu-tion at the time of discharge. At that time she
showed only a 1 plus reaction to undiluted
vac-cine. Saturated solution of potassium iodide was
started at 1 drop per day on March 23, after
a month of the desensitization regime. The
dose was slowly increased
(
1 drop per day)until 20 drops were taken 3 times daily. This
dose was maintained until discharge.
On this regimen, the child’s fever, which had
ranged above 39#{176}C.for the first 3 days of
hos-pitalization, gradually fell over the course of 7
weeks to levels between 37#{176}and 38#{176}C.After
March 16, the patient was essentially afebrile
save for 2 spikes to 39#{176}C.on March 28 and
April 4. A very marked improvement in general
condition occurred during the first week
prob-ably due to the control of the diabetes and
bac-terial infection. She was ambulatory after 10
dur-ing the remainder of her stay. There were no
complaints other than irregular but fairly severe
headaches which were referred to the left
ver-tex and left ear, occasionally with lancinating
pains deep in the left ear. These headaches
were fairly well controlled with acetylsalicylic
acid but required codeine on 5 occasions.
Shortly after admission, loss of vision in the
left eye progressed to complete blindness. The
conjunctivitis and corneal ulceration responded
rapidly to hot saline compresses and
medica-tion with chlortetracycline (Aureornycin#{174}) eye
drops and ointment. A left tarsorrhaphy was
done on February 13 because of the child’s
proptosis, corneal anesthesia and inability to
close the eye. The proptosis slowly receded
although exact measurements were impossible
because of the tarsorrhaphy. Towards the end
of the hospital stay, slight movement of the
eye-ball on attempted lateral gaze could be
de-tected. There was no light perception through
the closed lids.
The left ear canal was cleaned mechanically.
A left myringotomy was done on February 9
and a small amount of purulent material
ob-tamed. No organisms were seen on fresh or
stained preparations and cultures did not show
growth of fungi or bacteria. Thereafter
Aero-sponin#{174} otitic solution was used locally and
the myringotomy incision healed rapidly.
Another culture for fungi on April 3 was
negative. The otitis externa slowly subsided and
the canal was clear by April 16. At that time
the left drum appeared thick, edematous and
white, particularly in the inferior portions-an
appearance ascribed to chronic otitis media
(
fungal[P1).
There was no air or bone conduc-tion on the left.Treatment of the nose and mouth included
mechanical cleansing with cotton applicators
and suction, frequent warm saline gargles and
maintenance of an open airway on the left with
0.5 per cent Neo-Synephrine#{174} drops and
fre-quent warm saline douching. A solution of
sodium propionate and aqueous gentian violet
was applied 3 times daily to the ulceration and
perforation. Under this therapy, the white
cheesy necrotic material disappeared in 3
weeks-leaving an apparently healthy edge to
the ulceration. Thereafter the ulceration slowly
filled in from the periphery so that, by the end
of the hospitalization, it was only one-half the
size on admission. However, the perforation
in-to the left nasopharynx remained unchanged.
The medial pterygoid plate was exposed and the
structures distorted. Although the
roentgeno-grams of the sinuses remained cloudy, irrigation
of the antrum through the decalcified left
nasoantral wall yielded a clear return.
On admission there was marked swelling not
only of the left orbit but also of the left cheek
and the area in front of the left ear. The left
anterolateral aspect of the neck was also
swol-len with moderate tenderness along the course
of the left internal jugular vein. The latter
ap-peared firm and cordlike to palpation. As the
left sided facial swelling slowly subsided, two
small firm, non-tender subcutaneous nodules
(2 by 3 cm. and 1 by 1 cm. in size) could be
felt beneath the left eye. These nodules slowly
diminished in size except for a transient
in-crease during the early period of
desensitiza-tion to Rhizopus vaccine. They had disappeared
by the time of discharge. The swelling around
the left ear and in the neck likewise
dis-appeared but the left internal jugular vein
re-mained thickened to palpation.
Dysarthria, dysphagia and difficulty in
chew-ing quickly diminished but without clearing
of the underlying neurological defects.
Prob-ably the swelling and palatal perforation
ac-counted for part of the difficulties.
Improve-ment in the former and re-education may have
been responsible for the rapid clearing of the
difficulties in talking, chewing, and swallowing.
The left facial paresis improved but this may
have been only apparent and partly due to loss
of facial swelling. Weakness and atrophy of the
left tongue, palate and masseters remained
unchanged. However, there was a return of
sensation to portions of the left side of the
face. The complete anesthesia which originally
extended from forehead to jaw gradually
re-ceded so that, by discharge, the area extended
from the lower forehead to the upper lip and
from the front of the ear to the lateral side
of the nose.
At the time of discharge, June 2, 1954, the
child felt well and complained only rarely of
headaches. The ulcerated area on the palate
was healing but the perforation remained
changed. Many neurological abnormalities
per-sisted; blindness of the left eye,
ophthal-mophegia, deafness on left, left facial weakness,
left palatal weakness, atrophy and paresis of
the left side of the tongue, weakness of the
left mastication muscles, diminished to absent
sensation on the left side of the face and
weak-ness of the left trapezius. Roentgenograms
862 HARRIS - \IUCORIYCOSIS
FIG. 3. The patient 9 months after admission.
The left eyeiids remain sutured because of
per-sistent anesthesia on that side of the face. Note tile appearance of general well-being and the ab-sence of proptosis.
The child was seen on November 19, 1954,
at which time she was feeling well and going to
school (Fig. 3). The urine had been consistently
free from sugar on the same dose of insulin.
The exophthalmos of the left eye had
corn-pletely receded. External ophthalmoplegia was
still present. The area of anesthesia was
some-what smaller but extended from the lips to
the forehead on the left face. The perforation
of the palate was clean and less than one-half
of its original size. The patient was re-examined
on January 26, 1955, 1 year after admission.
She has continued to do well.
DISCUSSION
The true fungi (Eumycetes) are divided
illto 2 classes, those having septate
myce-ha and those having non-septate or
coeno-cytic mycehia.1 To the latter class
(Phycomy-cetes) belong members of the Family
Mucoraceae of which Mucor and Rhizopus
are representative genera. These genera,
which are only rarely pathogenic, cannot
be separated by their appearance in tissue
since cllaracteriStic sporulation is usually
not present. In cultures, both form asexual
spores (sporangiospores) in sporangia and
also tile larger, thick-walled sexual spores
(
zygospores). In contrast to Mucor, tilegenus Rilizopus is cilaracterized by the
pres-ence of groups (fascicles) of unbranched
sporangiOpiloreS which arise from nodes of
runners (stolons) opposite root-like hyphae
or rhizoids. The growth thus resembles the
familiar grasses which spread along the
ground by runners that give rise at intervals
both to clusters of blades and to roots.
Spe-cies within each genus are distinguisiled by
their sporangia, sporangiospores and
zygo-spores.
Rhizopus arrhizus gives dense, grey
brown colonies with some sterile aerial
mycelia on an asparagine, dextrose agar.
The sporangiophores are short and dark
brown, sometimes with fusiform intercalary
swellings. Sporangia are subspherical and
60 to 180 micra in diameter. The columehla
is broadly hemispherical, not decorated and
tends to collapse at maturity.
Sporangio-spores are spherical or ovoid, sharply angled
and visibly striate, 3 to 6 by 4 to 5 microns
in size. Tile rhizoids are short and somewhat corahloid. This species differs from Rhizopus
nigricans l)y the much smaller spores and
shorter sporangiopilores and from Rhizopus
oryzae by colony color and density as well
as by shorter sporangiopilores and smaller
spores.
The N”Iucoraceae are very abundant in
nature where they exist largely as
sapro-phytes in the soil, in manure, on fruits and
starchy foods (bread molds). They are
fre-quently encountered laboratory
contami-nants. Occasionally they became parasitic,
apparently more often in animals than in
man. The subject was thoroughly reviewed
in 1943 by Gregory et al., who mention
spontaneous infection in i)irds, dogs, pigs,
ilorses and cows.
Since tile Mucoraceae are ubiquitous,
care must be taken not to mistake them for
863
be mere contaminants or saprophytes. The
organisms should not be considered
patho-genie in tile absence of definite histologic
evidence of invasiveness. Similar difficulties
in deciding tile role of a fungus ill disease
are well known in tile case of Candida
which frequently can be isolated from
bronchial secretions alld the intestinal
tract when it does not play an etiologic role
in the disturbance.
Mucoraceae have been isolated from
iluman sources in several categories of
con-ditions. Tiley have been cultured from the
nose and tile gastrointestinal tract in normal individuals where they were prob-ably accidental and harmless contaminants.6
They have also been found in chronic
pul-monary disease (tuberculosis, sarcoma,
car-cinoma) where their role may have been
that of a secondary and probably
saprophy-tic invader.
Superficial infections in tile skin of the
external auditory canal and on the genitalia
have apparently been caused by the
Mucoraceae.7 Somewhat deeper lesions with
abscess formation were reported by
Suther-land-Campbell who described an unusual
epidemic of Mucor paronychia among
han-dlers of orange pulp.8 Mucoraceae were also
cultured from a 2-cm. size papillomatous
lesion on the face of a farmer by Wade and
Matthews.9 They speculated on the’
epidem-iologic significance of similar lesions on the
noses of several sheep wilich their patient
had tended.
Progressing to more serious infections,
Mucoraceae ilave been implicated as
causa-tive agents in some instances of bronchitis
and bronchopneumonia. Gukelbergerbo
noted non-septate hyphae in the sputum of
a mild diabetic but was unable to culture
the fungus. The patient ran a protracted
febrile course and eventually responded to
massive doses of iodides. Lucet and
Cos-tantin1’ cultured ‘sIucor from the sputum
of a patient with an atypical chronic hung
disease Wilicil also responded to iodides. In
such cases, where the exact pathology is not
known, tile role of the fungus is difficult to
determine.
FIG. 4. Photoniicrograph of culture of Rhizopus arrhizus showing the characteristic mode of growth
(
sporangiophores witll sporangia arising fronl stolons opposite rhizoids-see text). Note the ab-sence of septation in the broad hyphae.There have been several instances of
iso-lated organ infections which have healed
and become calcified. Murphy and
Born-stein’2 isolated Absidia italiania (closely
related to Mucor corymbifera) from a
calci-fled solitary mass removed from the lung
of a 40-year-old man who had chronic
cough, dyspnea and weight loss. Calcified
brain tumors have shown broad non-septate
hyphae in 2 instances13’14 but unfortunately
cultures were not made prior to fixation.
Wadsworth5 reported the presence of
simi-lar mycelial elements in the calcified
ret-inal lesion of a 10-year-old boy who showed
the clinical picture of Coats’ disease.
Finally there are the rare, fulminating,
fatal infections to which Baker2 refers (vide
supra). These may involve the
gastrointes-tinal tract, the lungs and the brain. Baker
and Severanc&6 reported briefly on an
acute lobular pneumonia in a 3-year-old
diabetic child and Lloyd et al.1T recorded
the presence of extensive mycosis of the
lungs and pleura in a 26-year-old pregnant
throm-864
HARRIS
- MUCORMYCOSIS1.1 a
a a 0 S S
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865
bus of “Mucor” infection in the left
pul-monary artery. A more extensive
involve-ment was noted by Moore et al.18 in a
37-year-old white female who had severe
ulcerative colitis. Necropsy showed mycotic
involvement of the bowel, peritoneum and
retropleural space. Unfortunately
permis-sion for examination of the brain had not
been granted. In none of these cases were
cultures made.
The most severe “Mucor” infections have
caused an acute, diffuse involvement of the
central nervous system. Prior to the present
case, 10 such instances have been reported.
They are summarized in Table I. Diabetes
had been the predisposing cause in 6,
diar-rhea in 3 while in 1, although no history was
available, the histology of the pancreas
sug-gested the diagnosis of diabetes. All ages
from 2% months to 75 years have been
af-fected and the sex ratio has favored males.
Four cases have occurred in Negroes.
Ex-cept for the first case to be reported, the
infection started in the vicinity of the nasal
cavity and spread to the brain with
exten-sive involvement of blood vessels. In all
reported cases, as in tile present one, the
histology of the lesions is strikingly similar.
The photomicrographs of LeCompte,19
Kur-rein,22 Martin,23 or Gregory3 also would
serve to illustrate many features in our
biopsy. The organism causes an intense
inflammatory reaction with a
polymorpho-nuclear response and extensive necrosis. Of
particular interest is the tendency of the
organism to invade blood vessels and cause
thrombosis. The hyphae penetrate and grow
in the walls of both arteries and veins,
breaking out in some sections through the
adventitia and in other parts rupturing the
intima. Thrombosis occurs and the
organ-isms can be seen together with many
leuko-cytes and fibnin strands in the clot. The
resulting infarction accounts for much of
the necrosis. The striking invasion of nerves
and perineural lymphatics which is seen in
this case may account in part for the
para-lyses and sensory loss. Involvement of the
cranial cavity may lead to a severe
lepto-meningitis with an outpouring of leukocytes.
Since the fungus grows in the walls of
vessels, a cavernous sinus or carotid artery
thrombosis may occur. Acute necrotizing
encephalitis is the result of extension of the
organism into the brain and of infarction
due to thrombosis of blood vessels. In
sum-mary, the gross pathology and clinical
pie-hire probably result from a combination of
(
a) the inflammatory and necrotizing actionof the organism, (b) vascular obstructions
and infarction due to the invasion of blood
vessels by the organisms, and (c) direct
neural and perineural penetration by
hyphae.
This disease has been called “Cerebral
Mucormycosis” or “Mucormycosis of the
Central Nervous System” even though the
nature of the infecting organism was not
established by culture. Our studies show the
etiologic agent in the present case to belong
to the genus Rhizopus rather than Mucor.
Nevertheless it is proposed that the original
name be retained because the term
“Mucor-mycosis” can refer to the family Mucoraceae
as well as to the genus Mucor.
It is remarkable that a saprophytic
organ-ism should suddenly become so invasive in
certain instances as to cause rapid death
through widespread inflammation,
thrombo-sis and necrosis. An increase in virulence
or a decrease in host resistance may account
for this change. The organism isolated in
the present patient did not differ culturally
from ordinary species of Rhizopus arrhizus.
More probably the disease arises because of
a breakdown in the host’s defensive
mecha-nism rather than because of any particular
quality of the invading organism. Most of
the reported cases have occurred in patients
who have suffered some type of metabolic
bankruptcy. Diabetes, sometimes associated
with hemochromatosis or pregnancy, has
been the precipitating factor in the majority
of cases but debilitation, uremia, diarrhea
and dehydration have also preceded the
disease. The organism invades via the nasal
cavity, the lung or possibly the
gastro-intestinal tract. In cases with involvement
of the central nervous system, the
866 HARRIS - MUCORMYCOSIS
orbit or sinuses with extension to the brain
either directly or by growth through the
vascular system or perineural lymphatics.
Clinically the typical story is that of a
middle-aged patient who is seriously ill and
semi-comatose with ullcofltrOlled diabetes.
Shortly thereafter, orbital cellulitis and
proptosis appear. Examination reveals
cvi-dence of central nervous system
involve-ment with cranial nerve dysfunction and
signs of meningeal irritation. All patients,
save the present case, have died in a very
short period of time with massive cerebral
involvement.
The present case, as is typical,
delnon-strated an extensive invasion of the fungus
in a debilitated individual with uncontrolled
diabetes mehhitus. The portal of invasion was
probably the nasal cavity or the accessory
nasal sinuses. The fungus then invaded the
palate where a perforation resulted.
Inva-sion of blood vessels, lymphatics and nerves
together with necrosis and inflammation
were demonstrated in biopsies. The dense
clouding of all the nasal sinuses on the left
side was probably due to mucosal invasion
by
hyphae as was seen in Stratemeier’s21 The organism extended from the
palate and sinuses directly through the
tis-sues and along the vessels and nerves. The
proptosis and ophthalmoplegia suggested
retro-orbital tissue inflammation and the
possibility of involvement of the nerves and
vessels entering or leaving the orbit. The
involvement of the fifth, seventh, ninth,
eleventh and twelfth nerves suggested an
extensive invasion along the left base of the
skull either directly or indirectly through
blood vessels so that ultimately the heft
posterior jugular outflow was involved. The
presence of a cord like thickening of the
left internal jugular indicated invasion and
thrombosis of that vein. At the same time,
the appearance of nodules in the cheek
swelling demonstrated local invasion,
ab-scess formation or infarcted foci. Similar
nodules have been noted by Paltauf and
others in the viscera.1
It is rather amazing, in the light of the
100 per cent mortality recorded in the
literature, that this child apparently
re-covered from the acute phase of her disease
and llO\V (1 year hater) seems to be well
except for the neurological residua and a
relatively clean palatal perforation.
Prob-ably the vascular thrombi have organized
and recanalized, the organisms have died
or are dormant, and necrotic tissue has
be-come fibrotic. Whether some illness or
exacerbation of tile diabetes will disturb
this balance and allow the disease to become
invasive again is a matter for conjecture and
concern.
In addition to precise control of the
diabetes, therapy was based on the use of
iodides and on desensitization. These
prin-ciphes of therapy are well known in other
systemic fungus diseases, particularly
bias-tomycosis wilere Smith2 has shown the
adverse effect of a hypersensitive state on
the course of tile disease, especially during
therapy with iodides. Naturally we cannot
determine the individual effectiveness of
these different therapies since the severity
of the disease demanded prompt application
of all agents likely to do any good. On the
negative side of therapy, prolonged use of
antibiotics was avoided because of their
tendency to favor growth of certain fungi,
either by a direct stimulation or by
interfer-ing with the balance between bacteria,
fungi and host.
SUMMARY
Tile present report is tilat of a child with
the typical symptomatology of
Mucormyco-sis of the central nervous system. The diag.
nosis was established during life by biopsy
and culture. Tile organism was identified
as Rhizopus arrhizus, a member of the
family Mucoraceae. The patient recovered
on therapy which consisted of rigid control
of the diabetes, desensitization against the
fungus and the administration of iodides.
The literature on “Mucor” infections in
humans has been reviewed with particular
reference to the rare instances of
involve-ment of the nervous system. The typical
story is that of a poorly controlled diabetic
or nasal infection and dies in a few days
with signs of invasion of the central nervous
system. Examination reveals a necrotizing,
inflammatory and vascular occlusive process
in which broad non-septate hyphae may be
seen. Until the present case, diagnosis has
not been made during life, the infecting
fungus has not been cultured or identified
an(l no patient has survived.
ACKNOWLEDGMENTS
Dr. N. F. Conant cultured the fungus and
Dr. Roger D. Baker interpreted the
pathol-ogy of the lesion and prepared the
photomi-crographs of the biopsy sections. The
organ-ism was identified by Dr. Victor M. Cutter
of the Department of Biology of the
Wom-an’s College of the University of North
Carolina at Greensboro, North Carolina. Dr.
D. T. Smith gave invaluable advice in the
clinical management of the patient.
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