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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. 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. 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. Disease often occurs in early winter, when infected mice come indoors. Pet hamsters are also a source of human infection. Other clinical clues to the diagnosis of LCM include: (1) a high cerebrospinal fluid (CSF) cell count, often exceeding 1,000; (2) a lymphocytic pleocytosis in CSF that may persist for more than 1 month; (3) oligoclonal bands in CSF; and (4) hypoglycorrhachia, often profound. These same CSF abnormalities may also be seen in patients with mumps virus meningoencephalitis. LCMV, like mumps virus, can also produce orchitis and parotitis. There is a single report of LCM preceded by rash and a circulating anticoagulant. LCMV was first isolated from laboratory mice more than 70 years ago. Based on Traub’s studies of LCMV infection in mice, Burnet 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. 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. Rowe’s 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, and that adoptive transfer of LCMV-sensitized immunocytes to these syngeneic-immunosuppressed LCMV carriers produced acute LCM in brain. LCMV-sensitized CD8 lymphocytes were later shown to mediate acute choriomeningitis in mice. Zinkernagel and Doherty 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, which is prevented by treatment with antilymphoid serum, 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