Lymphocytic choriomeningitis virus (LCMV) is a single-stranded RNA virus classified in the family Arenaviridae, genus Mammarenavirus. It was first isolated in 1933 by Armstrong and Lillie from the cerebrospinal fluid of a patient during an investigation of a St. Louis encephalitis epidemic 1). In 1935, Traub identified the house mouse (Mus musculus) as its natural host 1).
Soon after its discovery, LCMV was recognized as one of the major causative viruses of aseptic meningitis. In a US survey from 1953 to 1958, LCMV was detected in 58 of 713 cases of neuroinvasive disease 1). Subsequently, large outbreaks occurred in Germany (1968–1971, 47 cases) and the United States (1973–1974, 181 cases) 1).
In recent years, the frequency of reported clinical cases has decreased, but the possibility of missed cases has been pointed out. A Finnish survey (2013–2014) detected LCMV IgG antibodies in 5.0% of patients with neuroinvasive disease 1). A survey in southern Iraq (2012–2013) identified LCMV RNA in 5.1% of cerebrospinal fluid samples 1). The seroprevalence in the general population varies widely by region, ranging from 0.2% to 37.5% 1).
Congenital LCMV infection was first reported in the United Kingdom in 1955, and more than 82 cases have been documented worldwide 1). The three major findings are hydrocephalus, periventricular calcification, and chorioretinitis, making it an important differential diagnosis in TORCH syndrome.
The seroprevalence in the general population is reported to range from 0.2% to 37.5% depending on the survey region. Many infections are asymptomatic or mild and thus go unnoticed, so the actual number of infections is estimated to far exceed the reported number.
Symptoms differ greatly between acquired and congenital infections.
Approximately one-third of infections are asymptomatic 1). When symptoms occur, they appear 6–20 days after exposure and typically follow a biphasic course 1).
Caron et al. (2023) reported a case of percutaneous exposure to the LCMV Armstrong strain. From 7 days after exposure, headache, severe eye pain, dizziness, nausea, and numbness in the legs appeared and persisted for about 10 days. Fever and vomiting were not observed 3).
The entire clinical course usually resolves within 1 to 3 weeks.
Neurological and ophthalmic symptoms are prominent. It presents with microcephaly, macrocephaly, ventricular enlargement, seizures, psychomotor developmental delay, and chorioretinitis.
Acquired Infection
Cerebrospinal fluid findings: Marked pleocytosis (more severe than other viral meningitis). Accompanied by decreased CSF glucose and mildly elevated protein 1).
Blood test abnormalities: In the early phase, leukopenia, thrombocytopenia, and mild elevation of liver enzymes are observed1)2).
Imaging tests: MRI often shows no abnormalities2)3).
Congenital infection
Fundus findings: Chorioretinal scars in the periphery and macula. May be accompanied by optic atrophy.
Head CT/MRI: Periventricular calcification, hydrocephalus, ventricular enlargement, cerebellar hypoplasia, corpus callosum agenesis, brain atrophy, etc.1).
Associated findings: Nystagmus, strabismus, microphthalmia, and cataracts have also been reported.
The triad of hydrocephalus, periventricular calcification, and chorioretinitis is seen in 87.5% of congenital LCMV infections 1).
The main findings are chorioretinal scars in the periphery and macula. Optic atrophy, nystagmus, and strabismus may be present, and microphthalmia and cataracts have been reported rarely. Optic atrophy and strabismus are seen only in patients with chorioretinal scars.
The natural host of LCMV is the house mouse (Mus musculus). Mice infected in utero acquire immune tolerance and continue to shed the virus asymptomatically in saliva, urine, feces, semen, and breast milk throughout life 1).
The main routes of transmission to humans are as follows:
Pet hamsters and guinea pigs can also be sources of infection. Most infections occur in autumn and winter when mice move indoors.
| Risk factors | Details |
|---|---|
| Rodent breeding | Hamsters, mice |
| Rural residence | Rodents gather at feed storage sites |
| Working in research facilities | Handling laboratory animals |
Among employees at rodent breeding facilities in the United States, 8–47% were seropositive for LCMV1).
Pet hamsters can be a source of infection. Several outbreaks have been reported in association with hamster exposure. Pregnant women in particular should be cautious.
Serological testing is the most widely used method for confirming LCMV diagnosis. IgM and IgG antibodies are detected using ELISA and indirect immunofluorescence assay (IFA) 1).
LCMV RNA is detected in blood and cerebrospinal fluid by RT-PCR. It is effective in the acute phase of the disease and targets the GPC and N genes1). The detection limit is 1 to 10 PFU/mL depending on the virus strain1).
Pankovics et al. (2023) tested cerebrospinal fluid from 74 cases of CNS infection over 12 years in Hungary and detected LCMV RNA by RT-PCR in 2 cases (2.7%). These were the first molecularly confirmed cases in Hungary2).
It can be cultured in BHK-21 cells, Vero cells, etc. Intracerebral inoculation in newborn mice induces characteristic convulsive disease within 5 to 7 days1).
At birth, the virus has often already been eliminated. It is necessary to measure both IgM and IgG in maternal and neonatal sera. Consider the influence of maternal IgG transferred transplacentally 1).
The following TORCH pathogens are important for the differential diagnosis of congenital LCMV.
| Differential Diagnosis | Differences from LCMV |
|---|---|
| Cytomegalovirus | Hepatosplenomegaly is common (rare in LCMV) |
| Toxoplasma | Scattered intracerebral calcifications (LCMV is periventricular) |
| Rubella | Heart disease, cataract, salt-and-pepper retinopathy |
Congenital toxoplasmosis shows diffuse intracranial calcification, whereas LCMV is characterized by periventricular calcification 1). In cytomegalovirus infection, hepatosplenomegaly is prominent, but in LCMV, systemic signs of infection are scarce and neurological findings are predominant 1).
No established antiviral drugs exist 1)2). Treatment is mainly symptomatic, and most immunocompetent individuals recover without sequelae within 1 to 3 weeks 1). Mortality is less than 1% 1).
LCMV infection after transplantation has an extremely high mortality rate of 71% 1). Survival has been reported with a combination of intravenous ribavirin and reduction of immunosuppressive drugs 1). However, there are cases of survival without ribavirin, and evidence for its efficacy is limited 1).
There is no established treatment for congenital LCMV. Long-term follow-up with a multidisciplinary team including ophthalmologists, neurologists, physical therapists, and occupational therapists is necessary.
LCMV is an enveloped virus with a diameter of 110–130 nm, possessing a genome consisting of two ambisense RNA segments (S and L) 1). The S segment encodes the nucleoprotein (NP) and the envelope glycoprotein precursor (GPC), while the L segment encodes the matrix zinc-binding protein (Z) and the RNA-dependent RNA polymerase (RdRp) 1). The presence of sand-like ribosomal granules inside the viral particle is the origin of the name “arena” (meaning sand) 1).
The virus is inhaled as an aerosol, deposited in the lung parenchyma, and then spreads throughout the body via the bloodstream. LCMV shows affinity for neuroblasts and proliferates in the meninges, choroid plexus, and ventricular ependyma. Tissue damage is primarily caused by inflammation due to the host’s T-cell-mediated immune response, rather than direct viral cytopathology.
The virus is transmitted transplacentally from the mother to the fetus via maternal viremia 1). The periventricular region of the fetal brain contains abundant actively dividing neuroblasts, to which LCMV has a strong affinity. This explains the distribution of periventricular calcifications 1). Furthermore, LCMV infection impairs neuronal migration, leading to gyral abnormalities 1).
Macrocephaly is caused by obstruction of the ventricular system due to inflammation of the cerebral aqueduct, while microcephaly results from immune-mediated and virus-mediated destruction of brain tissue.
Based on phylogenetic analysis, LCMV is classified into four genetic lineages (lineages I–IV)1). Lineage I includes the classic Armstrong and WE strains from the United States, as well as strains from France, Germany, and Slovakia. Lineage II consists solely of European strains1). Two strains detected in Hungary in 2020 belong to lineages I and II, respectively, ruling out a common source of infection2).
Lineages I–III have all been associated with severe human disease. The Armstrong strain and the Clone-13 variant differ by only five nucleotides (three amino acids) yet produce completely different disease courses—acute versus chronic infection1).
Currently, repurposing of several existing drugs is being studied1).
Favipiravir (T-705) is an RdRp inhibitor that showed excellent efficacy against acute disseminated LCMV infection in a mouse model. Early administration to NZB mice infected with low-dose LCMV-Clone 13 resulted in 0% mortality, and virus levels were below the detection limit in most organs1).
Umifenovir (Arbidol) is an indolecarboxylic acid used as an influenza treatment that inhibited the replication of several arenaviruses, including LCMV, in vitro1).
Wan et al. (2020) screened 63 FDA-approved drugs and confirmed LCMV inhibitory effects of five drugs: benidipine hydrochloride (entry inhibition), mycophenolic acid, lapatinib, dabrafenib (replication inhibition), and clofazimine (both mechanisms)1).
Some Lassa virus-specific human monoclonal antibodies have been shown to cross-react with the LCMV glycoprotein complex in vitro. Based on findings that demonstrated 100% protective efficacy against Lassa fever in a monkey model, the development of LCMV-specific antibody therapy is anticipated1).
Genetically engineered recombinant LCMV (rLCMV) is being studied as a candidate vaccine vector. A non-replicating rLCMV vector derived from Clone 13 safely induced multifunctional CD8+ T cells in immunodeficient mice and was cleared within 7 days1). Additionally, an LCMV-based therapeutic cancer vaccine expressing HPV-16 tumor proteins E7E6 showed tumor control effects in a mouse model1).
