REVIEW ARTICLE
902
ENCEPHALOMYOCARDITIS
VIRUS
INFECTION
IN CHILDHOOD
By D. Carleton Gajdusek, M.D.*
C
URRENT opinion is divided as to the roleof the encephalomyocarditis (EMC)
group of viruses in human disease. In the
serologic survey of Tarahumara Indians
re-ported elsewhere in this issue’ it has been
shown that antibody neutralizing significant
amounts (namely, 20, 80, 1000, and 6000
LD,0, respectively) of the AMS strain of
EMC virus was found in 4 of the 56 serum
specimens studied. This finding serves to
focus attention again on the scattered
ne-ports suggesting the EMC virus as an
etiologic agent in human disease.
History of the Discovery of EMC Viruses
J
ungeblut and Sanders2 isolated fromcotton rats inoculated with Yale-SK strain
of poliomyehitis virus, a virus different from
that which they had inoculated. They
desig-nated this new agent “Columbia-SK.” Later
Jungeblut and Dalldorf’ isolated an agent
they called MM-virus from hamsters
inocu-hated with central nervous system (CNS)
tissue of a fatal case of undiagnosed
paraly-sis suspected of being poliomyehitis. Many
workers have assumed that these first
isola-tions were of viruses latent in the laboratory
rodents. Helwig and Schmidt obtained
encephalomyocarditis (EMC) virus from a
captive chimpanzee with myocarditis and
hydrothorax in Florida; and Dick, Best,
Haddow, and 56 obtained
so-called Mengo encepilahomyehitis virus in
Uganda from a paralyzed rhesus monkey,
later from mosquitoes (Taeniorrhynehus
fuseopennatus), and from a wild mongoose
caught near the monkey compound in
Entebbe, Uganda. Accidental infection of a
From the Department of Virus and Rickettsial Diseases, Army Medical Service Graduate School.
0 ADDRESS: \Valter Reed Arm Medical Center,
Washington 12, D.C.
laboratory worker in Entebbe with Mengo
VifllS demonstrated the pathogenicity of this
agent for lllafl.5’ Tile worker developed an
encephalitic illness and the virus was
iso-hated from his serum. In the convalescent
serum of this patient and ill sera from 2
na-tives of Uganda, neutralizing antibody to
Mengo virus was found. An epidemic of mild
febnile illness with evidence of meningeal
involvement, called “three-day fever” in U.S.
troops in Manila in 1945-46, produced
neu-tralizing antibodies to EMC and MM strains
in sena of many of the patients during
con-Warren, Smadel, and Russ8 demonstrated
that the ENIC, Columbia-SK, MM and
Mengo strains of virus are indistinguishable
by
cross-immunity, cross-neutralization andcross-complement-fixation techniques and
by analysis of their physical and pathogenic
properties. Since their work, these diverse
agents have been considered strains of a
single virus, designated
“encephalomyo-carditis.” All strains of EMC have high
in-feetivity titers in mice following
intracere-bral, and also intnapenitoneal and
intra-muscular inoculation. They possess
hemag-glutmnating activity in centrifuged
suspen-sions of virulent mouse brain for sheep
erythrocytes and human type 0
erythro-cytes, and their infectivity and hemaggluti-nating capacities are specifically neutralized
by hypenimmune serum to any one of the
strains.
Sera of an appreciable number of 442
wild rats trapped in several widely
sepa-rated areas of the United States were found
to contain neutralizing antibodies to the
EMC group of viruses. For example: 13
per cent of 100 rats collected in California
had EMC antibodies; 7 (or 30 per cent) of
and 87 per cent of 49 rats from Mississippi were found to be positive.9
Recently Kissling and Vanella9 have
re-ported the isolation in 1952 of EMC virus
from CNS tissue of a mandrill baboon which
died after a brief febnile illness in the
anthro-poid Ape Research Foundation Colony in
Dania, Florida. This ape had been in
cap-tivity in Florida for 4 years. In 1953 they
isolated EMC virus again from a monkey
which died at the same colony, and the
following year this virus was isolated from
a sick squirrel which had bitten a child
near Palm Beach, Florida.9” This last is the
first reported isolation of this agent from a
native American wild rodent.
Recent Reports Incriminating EMC Virus as
the Cause of CNS Disease in Childhood
Since 1949 several reports have appeared
from Germany of the isolation of new
strains of EMC virus from young patients
suffering from aseptic meningitis,
polio-myehitis-like disease, and Guillain-Barr#{233}
syndrome. Better and Keller1#{176} isolated the
virus strain designated Li32 from the
cere-brospinal fluid (CSF) of a 6-year-old child
suffering from a polyradiculitis of the
Guillain-Barr#{233} type with clean-cut
ahbumino-cytological dissociation in the CSF. Bieling
and Koch in 12 observed a small
outbreak of acute aseptic meningitis caused
by
the EMC virus. The illness was ofsudden onset with 2 to 4 days of fever and
a CSF lymphocytosis. It was frequently
as-sociated with bronchitis and otitis. They
iso-hated EMC viruses from 3 clinical cases of
this CNS disease from the blood, CSF,
feces, and from washings of infected ears.
In 1 child they demonstrated the
develop-ment of specific neutralizing antibodies to
their F strain of EMC. Vivell and Mauer13
report 6 isolations of EMC viruses, all from
children with myehitis or encephalitis, in
Freibung. Stool suspensions have frequently
been the source of the isolated viruses.
Verlinde and van Tongeren’4 in the
Netherlands recently reported the isolation
of 3 viruses specifically neutralized by
Co-lumbia-SK monkey antiserum and
produc-ing encephalomyehitis in the experimental
animals. They obtained these agents by
independent intracerebral inoculation of
suckling mice, older mice and cynomolgus
monkeys with stool suspensions of 3
chit-dren (age 1 to 2 years) suffering from
non-fatal illnesses diagnosed respectively as
aseptic meningitis, paralytic potiomyelitis
and eneephalomyelitis. The agent was
iso-lated from throat washings of the third
patient as well as from the stools. To
estab-lish that these agents did not originate in
the animals used for inoculation, they
re-isolated 2 of the agents from the original
stool specimens a second and third time;
furthermore, they have used both the
mon-key and the mouse for isolation and had
found no virus when control, noninfectious
materials were used for inoculation.
Ex-amination of paired sena from the 2 latter
patients (but not from the first) revealed
development of neutralizing antibodies to
the patient’s own virus. One patient showed
log neutralizing indices of 0.8, 2.2 and 2.4
on the tenth, twenty-ninth and forty-third
days from onset, while the other showed log
neutralizing indices of 1.0 and 2.2 on the
tenth and twenty-fifth days, respectively. This significant rise in neutralizing antibody
during convalescence is convincing
evi-dence that the virus isolated was the cause
of active infection in the patient. The
pan-ents and 2 siblings of the former patient
had no specific antibody to Columbia-SK
virus in their sena while the father of the
latter had a log neutralization index of 3.2.
He had suffered from a mild diarrheal
ill-ness shortly before his child’s disease.
Although the EMC viruses have now
been isolated from many types of CNS
disease in children, no case of myocanditis
in man has been definitely attributed to
these agents. There are clinical and
patho-logical reports of fatal encephalitic disease
in young children with associated
myo-canditis wherein the authors have suggested
EMC virus as the possible etiologic
done on such cases and thus the suggestion
remains unsupported. It is true, however,
that cynomohgus and the cercopithecus
monkeys develop myocardial involvement
when infected with this agent.’7
Serologic Evidence for EMC Infections in
Man
Surveys in Germany, Sweden, and the
United States have demonstrated specific
neutralizing as well as
hemagglutination-inhibiting antibodies to the EMC group in
normal people and in subjects recently
re-covered from a variety of nonbactenial
cen-tral nervous system infections.1823
Junge-blut’9 has reported 21 pen cent of sera
collected from pohiomyelitis cases contained
neutralizing antibodies to EMC, while 15
pen cent of his “normal” control sena had
such antibody. Where the
hemagglutina-lion-inhibition technique was used, 0.7 per
cent to 4.5 pen cent of the sera from healthy
individuals have been reported positive.
These same surveys have shown 12 to 16
per cent of sera collected from cases
diag-nosed as paralytic and nonpanalytic
polio-myelitis, aseptic meningitis, myelitis and
encephalitis positive for EMC
hemagghu-tination-inhibiting antibody.
Gard and Helter’8 have pointed out that
a number of the strongly
hemagglutination-inhibiting human sera which they tested for
virus neutralizing power against
Columbia-5K failed to show any virus neutralization. Others have found similar inconsistencies
between the 2 types of tests’#{176}but, on the
other hand, Jungeblut and Bautista” have
reported better agreement between results
obtained by the hemagglutination-inhibition
and neutralization procedures. These
work-ers report 30 pen cent of 77 human sena
drawn from pohiomyehitis cases, their
con-tacts, or healthy individuals in the small
rural village of Gonospe (35 miles east of
Puebla in Mexico) neutralized 500 on more
LD,0 of Columbia-SK virus, whereas only
5 per cent of a group of 54 similar sera
collected from city dwellers in Puebla
con-tamed neutralizing antibodies of such titer.
These authors also found 3 positive
speci-mens among 19 wild rat sena collected in
Mexico City. Furthermore, they reported a
high neutralizing antibody titer of
Co-lumbia-SK in 1 of 5 sera from children
ne-covering from paralytic poliomyehitis in
Sautillo, Mexico.
An early confusion of these agents with
poliomyehitis viruses resulted from the
pe-cuhian circumstance of their first isolation
in the course of investigations on pohiomye-hitis. Today the situation is cleaner: the EMC
agents are a distinct group of viruses
unre-hated serologicahly and probably
epi-demiologically to the poliomyelitis viruses.
However, a higher percentage of positive
sena has been found regularly among sena
of patients who have recovered from
polio-myelitis-like illnesses and other central
nervous system infections than in the
gen-enal populace. The term “panapohiomyehitis”
has thus been used in much recent European
literature to replace “encephahomyocarditis” for this group of agents.
Probable Occurrence of EMC Infections in
American Children
The observation that 3 or 4 of the 56
sena from young Indians possessed
neu-trahizing antibody to EMC virus suggests
that infection with this agent occurs with
significant frequency among the
Tara-humara (5 to 7 per cent) and that most
in-fections occur before adolescence.’ In spite
of persisting confusion as to the role of the
EMC group of viruses in human disease,
the following facts now force the attention
of physicians in this country to these
agents: 1) the presence of EMC neutralizing
and hemagglutinating antibodies in the sera
of normal persons in the United States,
Mexico (especially in the Tarahumara,
whose homeland is not far south of the
United States border), the Netherlands,
Germany, Sweden and in Africa; 2) the
knowledge that wild rats are probably
harboring the virus throughout the United
States,9 and 3) the recent reliable
re-ports of isolations of EMC virus from young
children in Europe with a variety of CNS
pleocytosis in the cenebrospinal fluid. These findings provide sufficient grounds to pre-dict that cases of EMC virus infection in childhood may be found in this country if sufficiently sought for. The pediatrician
must now consider this virus among the
other possible etiologic in
chil-dren suffering from the syndrome of aseptic
meningitis (lymphocytic meningitis on
Wallgnen’s syndrome), and it might be well
to suspect this group of viruses in cases of
Guillain-Banr#{233} syndrome on polyradiculitis
and other paralytic and nonpanalytic,
non-bacterial CNS infections. Virus isolation
at-tempts should be made on blood,
cerebro-spinal fluid, stool specimens and
naso-pharyngeal washings of such patients early
in the illness. Paired, acute and
convales-cent sterile serum specimens should be
col-hected for virus neutralization tests and for
study for the presence of specific
hemag-glutination-inhibiting antibody or
comple-ment-fixing antibody. Only repeated
con-trotted isolations, which exclude the
possibility of the isolation of an agent latent
in the laboratory animals, should be
con-sidened adequate proof that the virus
originated from the patient. Thus, a portion
of the infectious materials collected from
the patient for inoculation should be
pre-served at -70#{176}C. (dry ice). In serologic diagnosis it is not sufficient to demonstrate
the presence of specific neutralizing
anti-bodies in convalescent serum-a significant
rise in antibody titer between acute phase
and convalescent serum specimens should
be shown. Such a demonstration of
increas-ing antibody is particularly important when
we are dealing with an agent which may
be enzootic in the laboratory animals.
Thus, the problem of establishing the note
of this confusing group of viral agents in
human disease remains a challenging
pnob-lem for the pediatrician. The latter alone
can provide the virologist with carefully
selected specimens, study of which will
mdi-eate whether a portion of the currently
undiagnosed cases of nonbactenial CNS
in-fections of childhood are caused by the
EMC viruses.
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