January 1964 Leading Articles
production of a triple response due to histamine release. In
bone they may be osteolytic or sclerotic. A variety of asso-
ciated phenomena have been described in some cases of
mastocytosis which suggests a general release of histamine.
A third of these patients develop flushing attacks and tachy-
cardia; headaches also occur, and there may be vomiting and
diarrhoea. The symptoms thus resemble those of the
carcinoid syndrome, but the skin lesions in mastocytosis are a
characteristic diagnostic feature and occur in nearly all
patients. Histamine and its metabolites imidazolacetic acid
and especially 1,4-methyl imidazole acetic acid may be
found in the urine, while the excretory product of carcinoid,
5-hydroxyindole acetic acid, has not been found.
D. J. Demis' administered "GC-labelled histamine and
histidine to some patients with mastocytosis in an attempt to
discover the mechanism producing the excess histamine. No
evidence of a block in histamine breakdown was found and the
indications were that the increased excretion of histamine was
the result of overproduction.
There is no satisfactory treatment of this disorder, but anti-
histamines may diminish the effects of histamine release.
External Shock Therapy For Atrial
Fibrillation
The indications for applying electric-shock therapy to the
heart have recently been extended by improvements in
technique.' At first this treatment was reserved for
ventricular fibrillation, the electrodes being applied direct to
the exposed heart. Later the development of methods of
delivering the shock externally through the intact chest wall
allowed this treatment to be given to patients with serious
refractory tachycarditis.' The most recent technical improve-
ments introduced by Lown and his colleagues' are the
substitution of direct current for alternating current and the
delivery of the shock in a preselected " safe " period during
the cardiac cycle, when the heart is not susceptible to
electrically induced ventricular fibrillation. The latter point
is of great importance, since electric shock, though used to
terminate fibrillation, may itself also sometimes initiate it.
The time of delivery of the shock is selected by the use of
a synchronizer triggered by the electrocardiogram.
Only after a technique has been shown to be entirely safe
and also therapeutically successful in a high proportion of
cases could it be reasonably applied to the treatment of so
relatively benign a condition as atrial fibrillation. The
greatest hazard of atrial fibrillation is systemic or pulmonary
embolism from the development of thrombi within the atria.
In addition cardiac output is reduced by atrial fibrillation in
the presence of underlying heart disease such as mitral
stenosis.4 The patient simply with atrial fibrillation may
experience few or no symptoms.5
Lown and his co-workers report the successful conversion
of atrial fibrillation to sinus rhythm in 45 out of 50 patients,
the only complication being splenic embolism in one patient.
The great majority of their patients were suffering from
l Lown, B. Periroth, M. G., Kaidbey, S., Tadaaky, A., and Harken,
D. E., New Engl. 7. Med., 1963, 269, 325.
2 Beck, C. S., Weckesser, E. C., and Barry, F. M., 7. Amer. med. Ass.,
1956, 161, 434.
'
Zoll, P. M., and Linenthal, A. J., Circulation, 1962, 25, 596.
' Oram, S., Davies, J. P. H., Weinbren, I., Taggart, P., and Kitchen,
L. D., Lancet, 1963, 2, 159.
5 Evans, W., and Swann, P., Brit. Heart Y., 1954, 16, 189.
BRITISH 7
rheumatic heart disease and had been treated by mitral
valvotomy. Previous attempts to convert fibrillation to sinus
rhythm by the use of quinidine in full doses had been success-
ful in only 4 out of 23 patients: thus conversion by electric
shock attained a 90 0% immediate success rate compared with
a success rate of only 17%, by the use of quinidine.
The patient was given a general anaesthetic (intravenous
thiopentone) during the administration of the shocks. In
most cases one shock of 100 watt-seconds was sufficient, but
in some up to five shocks of increasing energy were required.
Lown and his colleagues suggest that the selection of patients
for atrial defibrillation should be based on the same principles
as have previously determined the use of quinidine in
converting atrial fibrillation to sinus rhythm. They
recommend giving anticoagulants beforehand to reduce the
possibility of embolism during conversion to sinus rhythm and
later maintenance therapy with quinidine as a prophylactic
measure against subsequent recurrence of atrial fibrillation
to sinus rhythm after mitral valvotomy by this method may
well help to produce the best post-operative results, especially
when the onset of fibrillation is recent, the heart is small, and
the valvotomy is technically fully successful.
The introduction of direct-current shock, delivered at a
period in the cardiac cycle when the ventricle is not vulnerable
to electrically induced fibrillation, is a considerable advance
in the therapy of cardiac arrhythmias. Its practical value as
a method of restoring atrial fibrillation to sinus rhythm must
be judged by the lasting success achieved in maintaining sinus
rhythm in patients whose hearts are apt to be rhythmically
unstable as a result of the underlying cardiac disease.
Neonatal Jaundice From Sepsis
Recent years have seen great advances in our knowledge of
the physiology of the formation and excretion of bilirubin' 2
and hence of the various forms of jaundice which may affect
the young infant. The non-obstructive group, which includes
the hyperbilirubinaemia of prematurity and of blood-group
incompatibility, has received particular attention because of
the dreaded complication of kernicterus. As a consequence
kernicterus to-day has become relatively rare in Great Britain.
On the other hand the various causes of obstructive jaundice
in the newborn such as biliary atresia, the so-called neonatal
" hepatitis," viral hepatitis from cytomegalic inclusion disease
or herpes simplex viraemia, and toxoplasmosis, though well
recognized and often correctly diagnosed during life,
frequently resist cure. An earlier generation of paediatricians
rightly regarded bacterial sepsis as an important cause of
jaundice in the newborn. While the most common causal
organism is Escherichia coli, the problems of staphylococcal
sepsis have tended to divert attention from the coliform
infections in recent years. At present, however, infections
due to E. coli seem to be becoming commoner in nurseries
for the newborn. It is therefore opportune that J. R. Hamilton
and A. Sass-Kortsak,' from Toronto, have again focused
attention on neonatal jaundice due to bacterial sepsis,
particularly as efficacious drugs are available provided the
correct diagnosis is reached early enough.
As in all neonatal infections, the diagnosis may be difficult
because focal signs are so frequently absent or minimal. The
1 Billing, B. H., and Lathe, G. H., Amer. 7. Med., 1958, 24, 11.
'
Sherlock, S., Brit. med. 7., 1962, 1, 1359.
3 Hamilton, J. R., and Sass-Kortsak, A., 7. Pediat., 1963, 63, 121.
8 4 January 1964 Leading Articles
commonest presenting symptom is the sudden appearance of
jaundice in an infant who often does not look ill. There may
be additional symptoms such as vomiting, diarrhoea, cough,
or otorrhoea, but hepatomegaly need not be present and
splenomegaly is never great. An obvious focus of infection
such as a septic umbilicus, pneumonia, or otitis media is
infrequent but should be diligently sought. A white-cell count
in the blood of over 12,000 per c.mm. suggests the presence
of infection, but tests of liver function are of little help.
Frank pyuria was noted in 16 of Hamilton and Sass-Kortsak's
24 cases and it is a strong indication at this age of pyaemia
due to Gram-negative organisms. A blood culture should be
carried out on every infant with unexplained jaundice,
irrespective of the body temperature. Pathogens were isolated
in 18 of Hamilton and Sass-Kortsak's cases.
The results of treatment depend on two factors-early
diagnosis and the age of onset. In Hamilton and Sass-
Kortsak's 24 cases, 8 infants developed jaundice in the first
week of life, with 7 deaths, while only 4 died of the 16 infants
in whom jaundice appeared after this time. The choice of
antibiotic will depend on the causal organism when this can
be isolated from the blood, urine, or elsewhere, and on its
sensitivity to antibiotics. Gram-negative organisms other than
E. coli which have been found to cause jaundice include
Aerobacter aerogenes, Paracolobactrum coliforme, Shigella
sonnei, and Pseudomonas pyocyanea. The jaundice itself
seems to be due to a combination of excess destruction of red
cells and hepatocellular dysfunction. Intrahepatic biliary
stasis may also contribute to it. There is, however, often
remarkably little evidence of actual infection of the liver tissue,
with formation of abscess, vasculitis, or cholangitis.
Mental Illness and Pregnancy
Few adequate epidemiological studies have been made of the
incidence of mental disorders in relation to child-bearing.
A recent paper by Thomas Pugh and his colleagues at Harvard
is therefore welcome.' They enumerated the married women
aged 15-44 admitted to psychiatric hospitals in
Massachusetts during 1950 who were either pregnant or had
been delivered within the previous 9 months. They compared
this figure with the number that would have been expected
if there were no relationship between admission and child-
bearing. The number observed was significantly in excess
of the number expected, which could be entirely accounted for
by patients with a diagnosis of psychosis, particularly mania
and depression. The greatest risk was to the youngest and
the oldest women, least to those in the middle of the child-
bearing period. The time-relationships with delivery were
interesting. There was an actual deficit of admissions during
pregnancy and almost all the excess occurred during the first
three post-partum months, though a slighter excess continued
to 9 months post partum.
There are several questions for further investigation. Are
psychiatrists less inclined to diagnose schizophrenia at such
times ? Does pregnancy have an ameliorating effect on
psychotic illnesses, thus reducing the likelihood of admission,
or are married psychotic women less fertile, or do psychiatrists
tend to delay admission until after delivery ? The high risk
1 Pugh, T. F., Jerath, B. K., Schmidt, W. M., and Reed, R. B., New
Engl. 7. Med., 1963, 268, 1224.
MEDICAL JOURNAL
of admission after delivery remains significant even if it is
assumed that the deficit during pregnancy is due solely to
delay in admission. The authors' cautious conclusion that
there is, indeed, an added risk of admission for psychosis
during the post-partum period can therefore be accepted.
They did not collect data about single women, and their
material does not allow comment on such specific problems
as whether pregnancy or delivery exacerbates an already
established psychosis, or whether termination of pregnancy
also carries a higher risk.
Biochemistry of Some Neural
Tumours
Neuroblastomas, ganglioneuromas, and sympathoblastomas all
arise from the ectoderm of the neural crest. These tumours
of similar histological appearance vary greatly in their
biochemical activity with respect to the production of catechol
amines and their metabolites. Dopamine, epinephrine, and
norepinephrine act as hormones, but since the amounts found
in the urine are small their measurement has been technically
difficult. Recently methods have been developed for measuring
their metabolites, since these are present in urine in greater
quantity. The determination of 3-methoxy-4-hydroxy-
mandelic acid (V.M.A.) is probably the most popular.'
In 1962 M. L. Voorhess and L. I. Gardner2 suggested that
neural tumours might be classified according to the patient's
urinary excretion of catechol amines and their metabolites.
Recently a group working in Bethesda3 has extended this
work. The catechol amines, their precursors, and their
metabolites were determined in the urine of twenty-one
children with tumours of the sympathetic nervous system.
The patients were aged from 1 month to 15 years, and apart
from diarrhoea in two cases the presenting symptoms were
all related to the tumour itself. Urine from fifteen children
without tumours served as controls. In a high proportion
of the patients with tumours increased amounts of the
following compounds were found: dopa, dopamine,
norepinephrine, normetanephrine, homovanillic acid, and
vanilmandelic acid. The pattern of excretion varied very
much between different patients. In four of them the levels
of norepinephrine, normetanephrine, homovanillic acid, and
vanilmandelic acid decreased after surgical removal of the
tumour, but this was not true of the levels of dopamine or
dopa except in one patient, in whom excretion of dopa
returned to normal. Only six patients were still alive at
least six months after the study.
Though the authors considered that the estimation of
vanilmandelic acid or normetanephrine was a particularly
reliable test for the diagnosis of neuroblastoma, this is not
usually in much doubt. These determinations probably have
greater use in following the progression of the disease and
the effects of therapy. Further study of the metabolism of
catechol amines by these tumours is worth while because
it may open up a way to treatment, particularly
since a malignant neuroblastoma may occasionally regress
spontaneously to a more benign tumour.
I
Pisano, J. J., Crout, J. R., and Abraham, D., Clin. chim. Acta, 1962,
7, 285.
2I Voorhess, M. L., and Gardner. L. I., 7. clin. Endocr., 1962, 22, 126.
Studnitz, W. von, Kdser, H., and Sjoerdsma, A., New Engl. 7. Med.,
1963, 269, 232.