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Arenaviruses a neurological problem at any age.

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Arenaviruses: A
Neurological Problem
at Any Age
Two studies in this issue of Annals of Neurology remind us that arenaviruses can cause serious neurological disease. Arenaviruses take their name from their
sandy (Latin, arenosus), granular appearance on ultrastructural examination. These RNA viruses are less
well known to neurologists as a cause of serious neurological disease than are herpesviruses and retroviruses. Several arenaviruses cause severe hemorrhagic
fever in humans, whereas others are nonpathogenic.
In South America, the Junin and Machupo arenaviruses cause Argentine and Bolivian hemorrhagic fever,
respectively. In West Africa, Lassa fever virus kills approximately 5,000 people per year.1 In the United
States, lymphocytic choriomeningitis virus (LCMV) is
the most common arenavirus that affects humans.
LCMV causes chronic but asymptomatic infections of
rodents, and it is not surprising that numerous outbreaks of infection and disease have been described in
laboratory workers exposed to virus excreted by infected mice and hamsters.2 Early clinical features include cough, malaise, and fever, whereas later symptoms are characterized by headache, fever, and stiff
neck. Although most cases are self-limiting, LCMV
infection can be fatal.3 Disease often occurs in early
winter, when infected mice come indoors. Pet hamsters are also a source of human infection.4 Other
clinical clues to the diagnosis of LCM include: (1) a
high cerebrospinal fluid (CSF) cell count, often exceeding 1,0005; (2) a lymphocytic pleocytosis in CSF
that may persist for more than 1 month6; (3) oligoclonal bands in CSF7; and (4) hypoglycorrhachia,8 often profound.7 These same CSF abnormalities may
also be seen in patients with mumps virus meningoencephalitis. LCMV, like mumps virus, can also produce orchitis and parotitis.9 There is a single report of
LCM preceded by rash and a circulating anticoagulant.10
LCMV was first isolated from laboratory mice more
than 70 years ago. Based on Traub’s studies of LCMV
infection in mice, Burnet11 espoused his concept of acquired immunological tolerance, for which he and Medawar received the Nobel Prize in Medicine in 1960.
There are two types of LCMV-mediated immunopathologies. The first is antibody mediated (immune
complex disease). Mice infected at birth do not develop
acute disease; rather, they become persistently infected
carriers, with virus present in every organ, including
blood. Persistently infected mice produce antibodies
against all the major structural proteins of LCMV, and
virus circulates in serum as infectious immune complexes, as demonstrated by a reduction in infectious titer after incubation of serum from LCMV carrier mice
with antibodies directed against mouse immunoglobulin.12 High-molecular-weight virus-antibody immune
complexes fail to exit renal glomeruli and accumulate
between glomerular epithelial cells and the glomerular
basement membrane underneath the capillary endothelium. LCMV-antibody complexes fix complement and
attract proinflammatory cytokines, which, in turn, attract leukocytes to the periglomerular space, culminating in chronic fatal glomerulonephritis.
The second immunopathology, most relevant for
neurologists, is T-cell–mediated acute LCM. Intracerebral injection of LCMV in adult mice induces an acute
lethal choriomeningitis approximately 7 days after inoculation. Death is heralded by a seizure and characterized by inflammation of the meninges, ependyma,
and choroid plexus, but sparing the cerebral parenchyma. Virus is detected in those lining structures, but
not in the brain of mice dying of acute LCM. Anticonvulsant therapy prolongs life but does not reverse
the pathological or virological changes.13 Rowe’s14
demonstration that acute LCM could be prevented by
irradiation provided the first evidence that acute lethal
choriomeningitis was immune mediated. Proof that
acute LCM in mice is immunopathological came from
analyses showing that cyclophosphamide treatment of
mice injected intracerebrally with LCMV abrogated
disease and induced an LCMV carrier state,15 and that
adoptive transfer of LCMV-sensitized immunocytes to
these syngeneic-immunosuppressed LCMV carriers
produced acute LCM in brain.16 LCMV-sensitized
CD8 lymphocytes were later shown to mediate acute
choriomeningitis in mice. Zinkernagel and Doherty17
quickly used the LCMV model to show that cytotoxic
T cells are restricted by class I major histocompatibility
complex antigens, work for which they were awarded
the Nobel Prize in Medicine in 1996.
Cell-mediated immunopathology produced by
LCMV is not restricted to the lining structures of the
brain. In newborn rats, LCMV produces cerebellar hypoplasia after intracerebral inoculation,18 which is prevented by treatment with antilymphoid serum,19 and
higher virus titers are found in the brain of immunosuppressed virus-infected rats than in nonimmunosuppressed virus-infected rats. Furthermore, intracerebral
inoculation of neonatal mice with Tamiami virus, an
arenavirus that does not infect humans, produces an
acute meningoencephalitis, and cerebellar heterotopia
© 2007 American Neurological Association
Published by Wiley-Liss, Inc., through Wiley Subscription Services
is a prominent pathological feature in mice that survive
acute disease.20 Neonatal thymectomy prevents both
acute central nervous system disease and the resultant
cerebellar heterotopia in Tamiami virus–infected mice,
despite equivalent titers of virus and viral antigen in
the brains of both thymectomized and nonthymectomized mice.21 Although the cerebellar heterotopia produced by Tamiami virus differs from the frank cerebellar necrosis produced by LCMV, both lesions are
The cell-mediated immunopathology produced by
LCMV extends to the liver and has important parallels
with hepatitis caused by LCMV. In mice, CD8 cells
mediate disease produced by hepatotropic strains of
LCMV.22 In humans, acute hepatitis produced by hepatitis B virus appears to be the most important viral
disease of humans that is immune mediated. The evidence is as follows: after primary infection with hepatitis B virus, most individuals clear virus and become
immune.23 Importantly, when primary infection results
in hepatitis, infection is also cleared at the same time
that liver disease peaks. This suggests that virus alone
does not cause disease, and that hepatitis might be
caused by a cell-mediated immunopathological response to hepatitis B virus. Interestingly, after primary
infection in 2 to 10% of humans, hepatitis does not
develop even though virus is not cleared, presumably
because of a lack of a good cell-mediated immune response, after which virus persists for years in the face of
a strong antibody response. The presence of high titers
of virus in the absence of hepatitis contrasted with the
development of acute hepatitis in patients who clear
their virus suggests the disease is not due to virus alone
but rather the immune response to the virus. Experimental evidence for immunopathology in acute hepatitis induced by hepatitis B virus comes from the demonstration that mice transgenically expressing the major
hepatitis B virus structural proteins in liver cells develop acute hepatitis when injected with syngeneic
CD8 lymphocytes directed against hepatitis B envelope
Not only does LCMV cause meningoencephalitis in
humans of any age, but various developmental disorders of the brain and retina in children also have been
attributed to LCMV based on seroconversion associated with clinical disease. For example, antibody to
LCMV was detected in 9 of 28 children with congenital hydrocephalus and, at moderate titers, in 6 mothers
of these seropositive children, suggesting that LCMV
infection of the fetus in utero played a role in the
pathogenesis of congenital hydrocephalus.25
In this issue of Annals, Bonthius and colleagues26 report their study of 20 children with serologically confirmed congenital LCMV infection, all of whom un-
Annals of Neurology
Vol 62
No 4
October 2007
derwent neuroimaging studies and were followed for
up to 11 years. Multiple imaging abnormalities were
found, including microencephaly, periventricular calcification, ventriculomegaly, pachygria, cerebellar hypoplasia, porencephalic and periventricular cysts, and
hydrocephalus. Many of the children had profound
mental retardation, epilepsy, and motor disorders.
Some children had isolated cerebellar hypoplasia with
clinical features of jitteriness and ataxia. Thus, congenital LCMV infection appears to be a far more serious
problem than acute LCMV meningoencephalitis in
adults, who do not usually suffer a permanent neurological deficit. In a companion article,27 the same investigators show that the development of microencephaly, cerebellar hypoplasia, encephalomalacia, cyst
formation, migrational disturbances, and chorioretinitis
in young rats experimentally infected with LCMV depends on the time of congenital infection. These findings confirm and extend earlier studies by Monjan and
colleagues,28 who demonstrated that cerebellar hypoplasia after infection of neonatal rats is age dependent.
Overall, the arenaviruses appear to be an important
cause of congenital neurological disease. Many of the
clinical and imaging abnormalities had previously been
attributed to genetic abnormalities. Whether any or all
of the protean neurological problems produced by
LCMV infection in utero are immunopathological remains to be determined. Pediatricians and pediatric
neurologists can be grateful to Bonthius and colleagues
for their careful clinical and pathological correlations
both in humans and in rats experimentally infected
with LCMV. In an era of molecular virology and sophisticated imaging technology, the arenaviruses provide a model that can be exploited to understand and
hopefully prevent serious disease of the nervous system.
Donald H. Gilden, MD
Departments of Neurology and Microbiology
University of Colorado Health Sciences Center
Denver, CO
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DOI: 10.1002/ana.21276
Pharmacoresistant Epilepsy:
If at First You Don’t
Succeed. . .
For many epilepsy patients and their physicians, the
persistence of seizures despite treatment remains a
seemingly insurmountable obstacle. There is ample
evidence that even rare seizures have a significant impact on physical and psychosocial functioning, and
may be associated with increased mortality. The few
prospective studies examining long-term outcomes
have demonstrated that, unfortunately, this problem
is highly prevalent; 14 to 34% of patients will suffer
from treatment-resistant epilepsy.1–3 The last 14 years
have seen the addition of nine new antiepileptic drugs
(AEDs) to the US market. Although there is a sense
that some of the new drugs have an overall better
side-effect profile than the more traditional AEDs, it
is unclear whether these new medications have decreased the proportion of treatment-resistant cases. A
recent review of the published open-label trials of
eight of the new AEDs examined the percentage of
patients who achieved a 6-month period of seizure
freedom. The authors were able to extrapolate results
for only three of the eight drugs and found that 4.7
to 16.1% of patients achieved a 6-month period of
Lowenstein and Shih: Pharmacoresistant Epilepsy
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problems, arenaviruses, neurological, age
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