ETIOCHOLANOLONE FEVER
bilirubin could not be determined because of hemolysis.
Soon after admission the patient received
500 cc of whole blood. Intravenous 5%
dcx-trose in water containing bicarbonate to
alka-linize the urine was given during the first 48
hours of hospitalization. Pain was relieved by
meperidine. Urinary output was watched
closely and 50011 stabilized at about 75 cc per
hour. Twenty-four hours after admission the
hemoglobin was 9.5 gm/100 ml and the white
count 55,400, still with a left shift. The
jaun-dice cleared promptly, and the tenderness of
the skin improved during the next several
day’s. The urine became normally colored
with-in 3 days and negative for protein on the
fourth day, but the Gregersen test remained
positive until the day of discharge. A
circum-scnibed ecchvmotic area 1 .5 by 3 cm developed
around the site of the bite.
The patient was discharged nine days after
admission. There was slight tenderness around
the bite lesion. The liver was palpable 2 cm
below the costal border, and the spleen tip was
palpable; these were not tender. He was seen
as an outpatient 19 days after the bite. At this
time the area surrounding the bite showed
sup-erficial necrosis.
SUMMARY AND COMMENT
A 7-year-old boy developed a severe
hemo-lvtic reaction following a bite by a spider. A
hemorrhagic and necrotic lesion developed at
the bite. Although the arachnid responsible was
not available for identification, the syndrome is
typical of bites by spiders of the genus
Loxo-sceles and quite different from that associated
with bites or stings of other arthropods of this
geographic region. A specimen of Loxosceles
reclusa was later collected in the patient’s
house.
The mechanism of hemolysis and indeed the
entire mode of action of Loxosceles venom is
very little understood. Regarding a case they
observed, Weiner and associates5 conclude, “It
seems likely that the hemolytic system did not
require participation of the patient’s tissues in
the production of antibodies.” The Coombs test
was negative in their patient but was positive
Ill one case as reported by Nance.1 It was not
done in the case reported here. Atkins et al.
could not reproduce the massive hemolysis
syn-drome with Loxosceles venom in rabbits and
guinea pigs, although intestinal and muscle
hemorrhages were seen. The local necrotic
lesions are readily produced in experimental
animals. While reactions similar to the one
re-ported here occur in onl’ a small percentage
of Loxoscles bites, they represent a potentially
fatal complication. Therapy in this case was
symptomatic and supportive except for
ad-ministration of ACTH and prednisone before
admission. These agents had no discernible
effect on the course of the envenomation.
SHERMAN A. MINTON, JR., M.D.
Department of Microbiology’ Indiana University Medical Center 1 100 West Michigan Street,
indianapolis 7, Indiana
CHARLOTTE OLSON, M .D.
Department of Pediatrics
University of Oklahoma Medical Center Oklahoma City, Oklahoma
We wish to express our thanks to Dr. Willis
J.
Gertsch, Department of Entomology, The
Amen-can Museum of Natural History, for identification of spiders collected in the patient’s home and for
comments on the genus Loxosceles. NI. \V.
Sander-son kindly made available recent records of these
spiders in Illinois and adjoining states. REFERENCES
1. Nance, W. E. : Necrotic arachnidism. Amer. J.
Med., 31:801, 1961.
2. Lessenden, C. NI., and Zimmer, L. K. : Brown
spider bites. J. Kans. Med. Soc., 61:379, 1960.
3. Atkins, J. A., et al.: Necrotic arachnidism. Amer. J. Trop. Med. Hyg., 7:165, 1958.
4. Elliott, F. R.: The araneology of Indiana. Proc.
Indiana Acad. Sci., 62:299, 1953. 5. Weiner, R. G., et al.: Massive intravascular
hemolysis. J. Kans. Med. Soc., 61:206, 1960.
Etiocholanolone
Fever
REPORT OF A CASE IN CHILDHOOD WITH PER!.
ODIC PERITONITIS ASSOCIATED WITH ELEVATED
SERUM ETIOCHOLANOLONE
A clinical syndrome of benign but recurrent
episodes of fever and serous membrane
in-flammation has been variously described as
periodic disease, recurrent polvserositis,
fa-milial Mediterranean fever, and benign paroxys-mal peritonitis. The subject has been
repeat-edly reviewedi and recently a series of affected
children was 2
In 1958, Bondy and co-workers, in a study
of two patients with periodic disease, noted
ele-vated plasma levels of free etiocholanolone, a
EXPERIENCE AND REASON-BRIEFLY RECORDED 285
C01 steroids.3 This finding was present only
during the febnile episodes in these patients and
was not noted in patients with familial
Mcdi-terranean fever or fever of known cause. Sub-sequent studies have confirmed these findings in 14 additional patients including the girl re-ported here. The syndrome has been called “Etiocholanolone Fever.”
CASE REPORT
RB. was first seen at the Babies Hospital in
1956 at the age of 11 years for evaluation of recurrent fever and abdominal pain. From 2 months of age and thereafter at 1- to 4-week
intervals, the patient had fever, pulled up her
legs, screamed, and sometimes had a grand mal
seizure; all sy’mptoms subsided overnight. At
8 months of age and again when 2 years old,
she was admitted to hospitals but no diagnosis
was established. Trials of digitalis and
quin-idine, various diets, and psychiatric therapy
failed to relieve her symptoms. As she grew
older, the pattern of attacks became more
clearly defined. They were characterized by a decrease in appetite for 24 hours followed by a nocturnal rise in temperature to 103#{176}to 104#{176}
F. and severe generalized abdominal pain.
Oc-casionally there was chest or joint pain and
often headache. The attacks subsided in less than 48 hours and occurred as often as once a week.
Family history revealed that the
grandpar-cots had emigrated from Poland, Lithuania, and Russia. The father had required a
gast-rectomy for duodenai ulcers which were first
found in childhood and the mother apparently had migraine headaches as a child. The only previous pregnancy of the mother had resulted
in an infant who died on the first day of life,
possibly of congenital heart disease. Two
sub-sequent pregnancies had resulted in a healthy
boy and girl.
Physical examination of the patient was within normal limits as were the complete blood count, urinalysis, nonprotein nitrogen, and skull x-ray. An electroencephalogram
dem-onstrated abnormal features compatible with but not diagnostic of a convulsive disorder. Because of this, the patient was given a trial on diphenvihydantoin and phenobarbital with-out noticeable response.
In July, 1957, at the age of 12 years, she
was admitted to Babies Hospital for study; at
that time retrograde py’elograms and
cysto-scopic study of the urine for porphvnins was negative. The patient was discharged only to
be readmitted 10 days later, 24 hours after the
onset of another attack. Within 3 hours, her
temperature and physical findings were
nor-mal. Gastrointestinal and gall bladder x-ray series revealed no abnormalities. A complete
blood count and urinalysis were normal. Blood
chemistry studies, including sugar, nonprotein nitrogen, sodium, potassium, chloride, and
car-bon dioxide combining power were within
nor-mal limits. Cephalin flocculation, thvmol
tur-biditv, Shigella agglutination, and Mazzini
tests were negative. Electrophoretic study of
hemoglobin and serum proteins was
unreveai-ing. The only abnormal laboratory determina-tion was an elevated erythrocyte
sedimenta-tion rate of 41 mm in 1 hour (Westergren). In
view of the clinical and laboratory findings, a
diagnosis of periodic peritonitis was made.
On August 24, 1957, the child was
ad-mitted to the Babies Hospital in an effort to observe her throughout an attack. The admis-sion blood count was normal. On the afternoon of August 26, she began to have mild
ab-dominal pain. The WBC was 8,000 with polys
60, lymphs 37, monos 2. At 2:30 AM. on
August 27, her temperature had risen to 101.8#{176}
F. (38.2#{176}C) and physical examination
re-vealed spasm of abdominal muscles with
non-localized rebound tenderness and reduced
bowel sounds. The WBC was now 14,500 with
polys 84, lvmphs 16. Exploratory laparotomy
revealed thickened, edematous, and injected
abdominal serosal surfaces and a small amount
of cloudy serous fluid. The only other abnor-mality noted was apparent replacement of the right ovary by a unilocular lutein c’st which
was removed along with the appendix and a biopsy specimen of peritoneum. Pathological
examination revealed the pertioneum to be
thickened by fibrous tissue in which
polymor-phonuclear leucocytes were numerous. No lymphocytes, plasma cells, or organisms were found, but a very large number of mast cells
were noted in the peritoneum and appendix.
Culture of the peritoneal fluid was sterile. On
September 3, she had another mild attack with
some wound disruption but otherwise her
post-operative course was benign.
at-36.0 14.2 1.6
<0.5-i .2 <0.5-1.2 <0.5-0.8
A 16-year-old girl with the clinical syndrome
TABLE I
UNCONJUGATED PLASMA KETOSTEROID VALUES
Deliydroepi-androsterone
It ioholanolone Androsterone
Patient RB. Normal
during Attack Range (/Jg/100 ml)
attacks at weekly intervals, she claimed they
were milder and less bothersome. She
con-tinued on this regimen for a period of months l)IIt decided that the benefits derived from the
prednisone ‘ere not sufficient to warrant the
annoyance caused b’ the increased appetite and weight gain which were associated with the medication; accordingly this treatment was discontinued. Over a 3-month period, she took
an estimated 150 mgm of prednisone per
month, an inadequate trial for assessing its
usefulness.
In the spring of 1959, 150 cc of whole
blood was collected during an acute attack and
the serum was subsequently sent to Dr. George
Cohn at Yale University for determination
of plasma-free unconjugated 17-ketosteroids
(Table 1). The plasma level of
dehydroepi-androsterone was 36 micrograms per 100 ml,
of androsterone 1.6, and of etiocholanolone 14.2 micrograms per ml of plasma. These
levels were all elevated, the level of
etiochol-anolone being more than thirty times the mean
normal value for adult men and women.5
At the time of a follow-up examination in
March, 1963, the patient, at 17, was in her
second ‘ear of college and doing well. Attacks
were continuing at intervals varying from 1
to 3 weeks and were severe for only one day,
during which she took codeine and analgesics
which enabled her to attend school. Physical findings remained within normal limits. Routine laboratory studies were negative except for the ervthrocyte sedimentation rate, which re-mained persistently elevated (32 mm in 1
hour, Westergren). She seems to have adapted
well to her disease.
COMMENT
This patient has had recurrent episodes of fever and abdominal pain with signs of
pen-toneal irritation since infancy; arthralgia and
pleural discomfort have been minor manifesta-lions. Biopsy of the peritoneum showed gross
and microscopic evidence of inflammation
dur-ing an acute attack. No cause had been
eluci-dated despite extensive study in several
mcdi-cal centers. She has matured normally, appears
healthy and excels in her schoolwook. Various
therapeutic regimens including diet and
rela-tively small doses of corticosteroids have not significantly altered the course of her disease. Small doses of aspirin and codeine when
nec-essary have given symptomatic relief.
She and the patients reported by Bondy
et al. differ from the majority of patients with
periodic disease in that the’ have elevated
un-conjugated etiocholanolone in their plasma
dur-ing acute attacks and are of European Jewish
background (Ashkenazic Jews) rather than of
Mediterranean origin. Otherwise their pattern is indistinguishable from that of the over-all group of patients with periodic peritonitis.
Kappas et al.6 fortuitously discovered that
injections of etiocholanolone into normal
sub-jects caused fever, abdominal pain, and
leu-cocytosis. At about the same time, Conzales
and Gardner described a patient with the
ad-renogenital syndrome who had elevated plasma
ketosteroids during episodes of paroxysmal
fever and abdominal pain.7 Bondy et
were the first to recognize the clinical
syn-drome associated with elevated levels of free
etiocholanolone. The concentration of free
de-hvdroepiandrosterone in the plasma of our
pa-tient was exceedingly’ high; however, this
ster-oid is not pyrogenic.
Studies of etiocholanolone production and
excretion in these patients have so far failed
to reveal abnormalities which would explain
this syndrome. The association with liver
dis-ease8 and congenital adrenal 79 in
two instances suggests that there may be more
than one cause. Any postulated defect must
explain the periodic appearance of free
etio-cholanolone in the serum, and the inability of
this “febrile serum” to cause fever when trans-fused back into the patient or into normal sub-jects. It may be that the etiocholanolone is merely a mediator or by-product resulting from various disturbances in steroid
metabo-lism.8
EXPERIENCE AND REASON-BRIEFLY RECORDED 287
of periodic peritonitis since early infancy was
found to have elevated serum levels of un-conjugated etiocholanolone during an acute attack. Biopsy of 11cr peritoneum at that time
revealed peritonitis and an abundance of mast
cells. The recently described entity of Etio-cholanoione Fever was briefly reviewed.
J
ERRY C. JACOBS, M.D.Department of Pediatrics,
Co-lumbia University College of
Physicians and Surgeons, the
Babies Hospital, and the
Ed-ward Daniels Faulkner Arthritis Clinic of the Presbyterian Hos-pital.
New York, N.Y.
REFERENCES
1. Ehrenfeld, E. N., Eliakim, M., and
Rachmiie-witz, NI. : Recurrent polyserositis (familial
Mediterranean Fever; periodic disease). A
report of fifty-five cases. Amer. J. Med., 31:107, 1961.
2. Shapiro, T. R., and Ehrenfeld, E. N. :
Recur-rent polyserositis ( “periodic disease,”
“fami-hal Mediterranean Fever”) in children.
Pam’-ATRIC5, 30:443, 1962.
3. Bondy, P. K., Cohn, G. L., Herrmann, W. and Crispell, K. R. : The possible relationship of etiocholanolone to periodic fever. Yale J. Biol. & Med., 30:395, 1958.
4. Bondy, P. K., Cohn, C. L. and Castiglione, C.: Etiocholanolone fever: A clinical entity.
Trans. Asso. Amer. Phys., 73: 186, 1960. 5. Cohn, G. L., Bondy, P. K., and Castiglione, C.:
Studies on pyrogenic steroids. I. Separation, identification, and measurement of unconju-gated dehydroepiandrosterone,
etiocholano-lone, and androstenone in human plasma. J. Clin. Invest., 40:400, 1961.
6. Kappas, A., Hellman, L., Fukushima, D., and Gallagher, T. F. : The pyrogenic effect of
etiocholanolone. J. Clin. Endocnin., 17:451, 1957.
7. Gonzales, R. F., and Gardner, L. I. :
Con-genital adrenal hyperplasia with associated episodes resembling histamine poisoning.
PEDIATRICS, 17:524, 1956.
8. Schenker, S., Wilson, H., and Spickand, A.: Periodic fever associated with increased plasma unconjugated etiocholanolone and
granulomatous liver disease: Case report and
studies in etiocholanolone and cortisol
con-jugation. J. Clin. Endocrin. & Metab., 23:95, 1963.
9. Cara, J., Beas, F., Spach, C., and Gardner,
L. I.: Increased urinary’ and plasma etio-cholanolone and related steroids in a boy with vinilizing adrenal hyperplasia and
pen-odic fever. J. Pediat., 62:521, 1963.
Acknowledgment is made to Dr. Nicholas P.
Christy, Dr. Melvin M. Grumbach, and Dr. George L. Cohn for their helpful suggestions.
The Use of Gastrostomy
in Feeding
Premature
Infants
Various methods have been employed to reduce the problem of feeding small, pre-mature infants. The variety of techniques in-eludes intermittent gavage feeding, use of an indwelling nasogastric tube, and less corn-monly use of a medicine dropper or Breck feeder. Because each of these methods pre-sents distinct drawbacks, the practicality of
the gastrostomy in nourishing weak premature
infants was explored. METHODS
The Stamm technique for gastrostomy was
employed with the tube brought out either
through the laparotorny incision or through a
separate left upper quadrant stab wound.l
The feeding reservoir was connected to the
gastrostomy tube by a Murphy Drip-Bulb con-taming a blow-off 2 The procedure was
performed under procaine infiltration anes-thesia; to avoid administration of a toxic dose,
care was taken not to exceed 3 to 4 ml of
0.5% procaine. Operating room temperature
was maintained at approximately 80#{176}Fand
infants were not removed from the incubators
until this temperature was achieved. A
warm-ing blanket was placed under the infant at the
time of operation, and a constant reading
rectal thermometer was kept in place.
Feed-ings were begun from 1 to 12 hours following
operation. The initial feedings were either
lactose water or plain water; thereafter, until
bottle feedings were instituted, they were
composed of a proprietary formula which does
not form curds (Nutramigen) plus supplemen-tary Karo syrup. Because curd formation tends
to plug the tubing, a non-curd forming
for-mula was employed. The drip was so
regu-lated that individual feedings lasted abaut 45
minutes. Residual formula, if present, was
