EMERGING INFECTIOUS DISEASES
Volume 1, Number 4, October-December 1995

DISPATCH

(Pages 152-3)

Lymphocytic Choriomeningitis Virus: An Unrecognized Teratogenic
Pathogen

Lymphocytic choriomeningitis virus (LCMV), the first member of
the arenavirus family to be isolated, is the causative agent of a
zoonosis acquired from chronically viremic mice or hamsters (1).
The clinical spectrum of acquired human LCMV infection ranges
from inapparent and asymptomatic to, in rare instances, severely
symptomatic, systemic, and fatal central nervous system (CNS)
disease. Intrauterine LCMV infection has resulted in fetal or
neonatal death, as well as hydrocephalus and chorioretinitis in
infants (2-6). We have diagnosed congenital LCMV infection in
three infants (7) and have collated published and unpublished
data on three additional affected infants (8, G.R. Istre, pers.
comm.). This report briefly summarizes the salient features of
the infection in five of these six American infants and outlines
the similarities between these and features observed earlier in
Europe. We suggest that LCMV is a more frequent cause of CNS
disease in newborns than previously recognized.

Congenital LCMV infection was first recognized in Great Britain
in an infant who died at 12 days of age (3). Subsequently, fetal
infection with spontaneous abortion (2) and congenital infection
in liveborn infants with hydrocephalus and chorioretinitis were
documented in Germany (4), France (6), and Lithuania (5). We have
recently documented congenital LCMV infection in three infants
from Arizona (7) and have obtained information regarding three
additional neonates from Arizona, Nebraska (8), and Texas (G.R.
Istre, pers. comm.). Detailed clinical and laboratory data are
available for five of the six infants. All displayed
nonobstructive hydrocephalus with periventricular calcifications,
chorioretinitis, and psychomotor retardation. One of the five
infants had sensorineural deafness. None of the infants had
cardiac abnormalities. Two infants have had follow-up
ophthalmologic and audiologic examinations which have shown
neither the progression of chorioretinitis nor the development of
new auditory deficits. Toxoplasma gondii, cytomegalovirus, Herpes
simplex virus, rubella, enterovirus, and Treponema pallidum
infections were excluded by culture or serology in all infants.
The diagnosis of congenital LCMV infection was confirmed in all
infants by immunofluorescence antibody (IFA) and enzyme-linked
immunosorbent assays (ELISAs). In addition, serum, CSF, urine,
and throat wash specimens from two infants were injected into
Vero cell monolayers. Neither cytopathic effect nor LCMV antigens
were detected after incubation. Because virus isolation was only
attempted after the disease was first diagnosed when the children
were 10 months of age, failure to isolate LCMV was not
unanticipated.

Laboratory diagnosis of LCMV infection is generally made by
serologic techniques. IFA is a more sensitive diagnostic method
than either complement fixation or neutralizing antibody
techniques (9,10). The newer ELISAs are now being used to
evaluate congenitally infected infants. Testing the child's serum
and CSF and a simultaneously obtained serum specimen from the
mother yields the maximum information if done as soon after birth
as possible.

The mothers of four of the five infants in this report had a
history of febrile illness during pregnancy, in contrast to a
minority of mothers of affected infants previously reported.
Typical LCMV infection in adults is a biphasic disease with
fever, malaise, myalgias, anorexia, nausea, vomiting,
pharyngitis, cough, and adenopathy followed by defervescence and
a second phase of CNS disease. However, CNS symptoms may appear
without any prodrome or may never develop. Meningitis and
meningoencephalitis are the most frequent neurologic
manifestations of disease, although myelitis, Guillain-Barr‚
syndrome, and sensorineural deafness have been reported (11).
Between 1941 and 1958, 8% to 11% of viral CNS syndromes in
hospitalized patients in a Washington, D.C., medical center were
etiologically associated with LCMV (12). Arthritis, parotitis,
orchitis, myocarditis, and rash have also been noted (13).
Clinical interest in LCMV, however, has not been maintained, and
the disease is rarely considered despite improved serodiagnostic
methods.

Although a history of contact with rodents and their excreta is
of diagnostic utility, it is not universally present. A maternal
history of rodent exposure was elicited for three of our five
infants. Wild mice (Mus musculus) and hamsters infected in utero
with LCMV during maternal viremia develop both persistent viremia
and viruria. The virus is transmitted to humans by direct animal
contact; by contact with infected rodent saliva, nasal
secretions, urine, feces, semen, and milk; and by infectious
aerosols (1). Human-to-human transmission has not been
documented. The distribution of LCMV is highly variable within
mouse populations. Seasonal, annual, and cyclical variations in
rodent density and infection have been postulated but remain
inadequately studied (14). LCMV spreads to humans in rural
settings or when human habitats are substandard. Infected
laboratory and pet rodents have also been associated with disease
in humans (1). Serologic surveys and clinical studies have
documented both epidemic and endemic human infection in Europe
and the Americas. In Baltimore, 9.0% of house mice and 4.7% of
residents have had measurable LCMV antibody (15,16).

We hypothesize that congenital LCMV infection is generally
undiagnosed and may account for unexplained hydrocephalus with
microcephaly or macrocephaly, deafness, blindness, and mental
retardation (three of the five infants in this report were
referred for infectious disease consultation by pediatric
geneticists, and two were referred by pediatric neurologists). No
accurate data are available regarding the prevalence and
persistence of LCMV antibodies in unselected infants, children,
and adults in diverse geographic locales or in children with
unexplained visual and/or auditory deficits, microcephaly, and
retardation. Increased recreational activities in rural
environments, rehabilitation of and habitation in older
rodent-infected domiciles, and acquisition of unscreened rodents
for pets or laboratory use pose as yet undefined risks for LCMV
infection to the fetus, child, and adult. The need for further
research to define the frequency of LCMV infection in human and
animal populations is clear. LCMV infection can best be prevented
by educating the public and medical professionals on the hazards
of contact with infected rodents.

Leslie L. Barton, M.D.,* C.J. Peters, M.D.,+  T.G. Ksiazek,
D.V.M., Ph.D.+
*University of Arizona Health Sciences Center, Department of
Pediatrics and Steele Memorial Childrens Research Center, Tucson,
Arizona, USA; +National Center for Infectious Diseases, Centers
for Disease Control and Prevention, Atlanta, Georgia, USA

Acknowledgments
We thank Drs. Jane Wilson, Gregory Istre, Stephen Chartrand, and
Laurie Seaver for patients' information; Dr. Matafija Seinbergas
for his enthusiastic support; and Ms. Amy Sites for technical
support.

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