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Boppana et al. 1992, 1997; Perlman and Argyle 1992; Anderson et al. 1996). In
almost all cases, infected infants resolve the infection but can be left with sequelae
in organ systems with low regenerative capacity such as the brain and auditory sys-
tem (Boppana et al. 1992, 1997; Dahle 2000). Brain damage and hearing loss can
occur in up to 5%-20% of infants with congenital CMV (Fowler et al. 1992;
Boppana et al. 1997, 1999; Dahle 2000; Noyola et al. 2001). Hearing loss is the
most common long-term sequelae of infants with congenital HCMV infection and
in the US and northern Europe may rank second only to familial or genetic causes
of hearing loss (Harris et al. 1984; Hicks et al. 1993). Similarly, severe brain damage
can result from intrauterine HCMV infection with loss of normal cortical architecture,
intracranial calcium deposits following loss of the integrity of the endothelium, and
loss of cognitive function (Becroft 1981; Perlman and Argyle 1992; Barkovich and
Lindan 1994; Boppana et al. 1997).
Two histopathologic types have been described: a focal infection characterized by
microglial nodules and more widespread involvement described as ventriculoencephalitis
(Becroft 1981). In the former and more common presentation, virus is assumed to
infect the parenchyma of the brain following viremic spread, whereas in infants with
more severe disease characterized with ventriculoencephalitis, virus is thought to
infect the ventricular epithelium and spread through the periventricular epithelium,
possibly through the cerebrospinal fluid (Becroft 1981; Arribas et al. 1996).
The pathogenesis of brain damage following congenital HCMV infection is
unknown, but several lines of evidence have suggested that it follows fetal infection
early in gestation, and that the symmetry of involvement suggests that it is related to
the infection and disruption of the microvasculature of the developing brain and/or
disruption of the neuronal migration from the periventricular gray area (Becroft 1981;
Perlman and Argyle 1992; Barkovich and Lindan 1994). Mechanisms of cell loss
such as virus-induced apoptosis of neuronal stem cells have been suggested based on
animal model systems, but only very limited information is available to support this
mechanism. At this time, it is unknown whether cell death and/or cell dysfunction is
a direct effect of virus infection or secondary to damage to supporting cells and struc-
tures from the associated inflammation. Animals models have provided only limited
information, and to date, the rhesus macaque fetal model appears to most closely
model human disease, although this model requires direct inoculation of the fetus
with rhesus CMV (Tarantal et al. 1998). Findings from this model system indicate
that gestational age of the fetus at the time of infection appears to determine the extent
and severity of disease, a result consistent with the correlation between early gesta-
tional maternal seroconversion and central nervous system disease in congenital
HCMV infections (Perlman and Argyle 1992; Barkovich and Lindan 1994; Stagno
and Britt 2006). Once the fetus is infected, the CMV immune status of the mother
appears to have only a limited role in the outcome of the fetal infection. Congenitally
infected infants with evidence of end-organ disease and long-term sequelae have
higher levels of replicating virus as well as a higher virus burden measured in periph-
eral blood (Fig. 2) (Stagno et al. 1975; Boppana et al. 2005; Stagno and Britt 2006).
Interestingly, the strongest correlation between high viral burden in peripheral blood
is the presence of hepatitis and in some infants with severe CNS involvement, the
