Congenital Lymphocytic Choriomeningitis Virus Research Articles

Lymphocytic choriomeningitis virus injures the developing brain: effects and mechanisms.

Lymphocytic choriomeningitis virus (LCMV) is a prevalent pathogen, whose natural host and reservoir is the wild mouse. Humans can be infected when they contact the secretions of mice. Most infections of postnatal humans result in mild illness. However, the consequences can be severe when the infection occurs during pregnancy, as the virus crosses the placenta to infect the fetus. LCMV infection of the human fetus can lead to severe neuropathologic effects, including microencephaly, hydrocephalus, focal destructive lesions, and cerebellar hypoplasia. Outcomes among children with congenital LCMV are variable, but most are permanently and severely disabled. The neonatal rat inoculated with LCMV models human prenatal infection. The rat model has demonstrated that effects of LCMV depend on host age at the time of infection. Some effects, including encephalomalacia and neuronal migration disturbances, are immune-mediated and depend on the actions of T-lymphocytes. Other effects, including cerebellar hypoplasia, are virus-mediated and do not depend on T-lymphocytes. Cerebellar neuronal migration disturbances are caused by immune-mediated corruption of Bergmann glia structure. The rat pup inoculated with LCMV is a superb animal model for human congenital infection. All neuropathologic effects observed in human congenital LCMV infection can be recapitulated in the rat model. IMPACT: Lymphocytic choriomeningitis virus (LCMV) is a prevalent human pathogen that can cause serious neurologic birth defects when the infection occurs during pregnancy. The effects of the virus on the developing brain depend strongly on the age of the host at the time of infection. Some of the pathologic effects of LCMV are immune-mediated and are driven by T-lymphocytes, while other pathologic effects are due to the virus itself.

Transmission, seroprevalence, and maternal-fetal impact of lymphocytic choriomeningitis virus.

Congenital infections can have devastating short- and long-term impacts on the developing fetus. Lymphocytic choriomeningitis virus (LCMV) is a zoonotic pathogen of concern that causes a severe congenital syndrome but is under-recognized and under-studied. Herein we review data on the natural animal reservoirs of LCMV, modes of transmission to humans, seroprevalence of LCMV worldwide in both pregnant and non-pregnant individuals, mechanisms of viral dissemination to placenta and fetus, and impact of climate change on viral transmission. We highlight opportunities to enhance awareness of congenital LCMV and provide recommendations for prevention and monitoring among at-risk pregnant people. IMPACT: Key message of the article: LCMV is a zoonotic virus that poses a major threat to maternal-fetal health. Adds to the existing literature: We comprehensively address transmission of LCMV from the natural reservoir to the pregnant individual, placenta, and fetus. Impact: Available data call for enhanced patient and provider awareness about congenital LCMV during pregnancy, as well as a need for efforts to better define the seroprevalence and impact of congenital LCMV worldwide.

Lymphocytic choriomeningitis virus: An under-recognized congenital teratogen.

BACKGROUNDLymphocytic choriomeningitis virus (LCMV) is a neglected rodent-borne arenavirus associated with transplacental transmission and fetal infection. AIMTo summarize the epidemiological, clinical, and diagnostic features of reported patients with congenital LCMV infection.METHODSA literature search was conducted in PubMed, Medline, Google Scholar, and ResearchGate. The keywords used were ‘congenital lymphocytic choriomeningitis virus,’ and 48 studies were included. In addition, we conducted a relevant search by Reference Citation Analysis (RCA) (https://www.referencecitationanalysis.com).RESULTSThe results have shown 27 reports of congenital LCMV infection in 86 patients, with 52.73% of them being males. Patients presented with chorioretinitis (83.53%), hydrocephalus (54.12%), and psychomotor retardation or developmental delay (54.12%). Computed tomography and/or magnetic resonance imaging most often demonstrated ventriculomegaly (74.07%), periventricular calcifications (66.67%), and microcephaly (40%). Most mothers of congenitally infected infants were exposed to rodents during pregnancy, predominantly mice, with flu-like symptoms mainly occurring during the first two trimesters of gestation. Mortality in congenitally infected children was 16.47%. The diagnosis of congenital LCMV infection was confirmed serologically in most patients (86.67%).CONCLUSIONLCMV is still an insufficiently recognized fetal teratogen that often leads to long-term neurologic sequelae. Clinicians need to be familiar with LCMV and its potential teratogenic effect and as well as to effectively differentiate LCMV from other TORCH (T: Toxoplasma gondii, O: Other pathogens, R: Rubella virus, C: Cytomegalovirus, H: Herpes simplex virus) pathogens.

Congenital lymphocytic choriomeningitis virus: A review.

Lymphocytic choriomeningitis virus (LCMV) uses rodents such as mice and hamsters as its principal reservoir. When women acquire LCMV during pregnancy because of contact with rodents, it can lead to congenital LCMV infection, which is associated with high mortality and morbidity. Although the number of cases reported in the literature is increasing, LCMV is rarely mentioned because a history of exposure to rodents is uncommon and mostly unknown. The main objective of this article was to summarize all morphological, antenatal, and postnatal abnormalities that may suggest a congenital LCMV infection. We reviewed PubMed case reports and case series where an antenatal and/or a postnatal description of at least one case of congenital LCMV infection was documented. We found 70 cases of congenital LCMV infection, 68 of which had antenatal or postnatal brain abnormalities, which were mainly chorioretinitis (59/70), hydrocephaly (37/70), microcephaly (22/70), ventriculomegaly (11/70) and periventricular calcifications (11/70). Antenatal and postnatal extracerebral abnormalities were mainly small for gestational age, ascites, cardiomegaly or anemia. Other organ damage was rare, but could include skin abnormalities, hydrops or hepatosplenomegaly. Seventy percent (49/70) of cases had major cerebral abnormalities that could have been detected by antenatal ultrasound examination. Congenital LCMV infection is associated with a significant mortality rate (30%) and survivors often have severe neurologic sequelae. LCMV is a rare congenital infection, but awareness of the various prenatal ultrasound morphological abnormalities should be improved, and LCMV should be considered when first-line etiological explorations are negative, especially when the mother's medical history indicates exposure to rodents.

Echoencephalography of encephalopathy due to congenital lymphocytic choriomeningitis virus.

AbstractCongenital lymphocytic choriomeningitis virus (LCMV) infection is a transient intrauterine viral infection with selective teratogenicity depending on the timing of the primary maternal infection. LCMV is cleared from the body of the fetus after the acute phase of illness and, in most cases, has lost its virulence at the time of birth. LCMV competes with extracellular matrix proteins for its tropism toward heavily glycosylated alpha‐dystroglycan. In the first trimester, while tropism toward heart myoblasts is high, intrauterine infection (IUI) can lead to miscarriage or fetal demise. Later in pregnancy, LCMV becomes neurotropic with tropism toward retina and brain. Most often systemic symptoms are subtle or absent at the time of birth. The timing of the IUI determines the neuroteratogenic phenotypes of congenital LCMV infection. IUI that occurs early during gestation can lead to isolated cerebellar dysgenesis and hypoplasia. When IUI occurs during neural radial migration, echoencephalography shows defective cerebral opercularization, intracranial calcifications at the gray‐white matter junction, enlarged extra‐axial subarachnoid space, and cortical dysplasia. When IUI occurs after the completion of insular opercularization (late second trimester), echoencephalography shows extensive cystic periventricular leukomalacia with bi‐occipital porencephaly and mild defects in gyrogenesis. A late gestation IUI induces aseptic LCMV meningitis with occlusion of the aqueduct of Sylvius, leading to congenital obstructive hydrocephalus. Congenital LCMV remains underdiagnosed as clinical manifestations are predominantly neurologic. As echoencephalography remains the preferred screening strategy for detecting neonatal central nervous system pathology, prior knowledge of echoencephalography of congenital LCMV may facilitate its recognition, prompting a serological evaluation.

Lymphocytic Choriomeningitis-Emerging Trends of a Neglected Virus: A Narrative Review.

Lymphocytic choriomeningitis virus (LCMV) is a neglected rodent-borne zoonotic virus distributed worldwide. Since serologic assays are limited to several laboratories, the disease has been underreported, often making it difficult to determine incidence and seroprevalence rates. Although human clinical cases are rarely recorded, LCMV remains an important cause of meningitis in humans. In addition, a fatal donor-derived LCMV infection in several clusters of solid organ transplant recipients further highlighted a pathogenic potential and clinical significance of this virus. In the transplant populations, abnormalities of the central nervous system were also found, but were overshadowed by the systemic illness resembling the Lassa hemorrhagic fever. LCMV is also an emerging fetal teratogen. Hydrocephalus, periventricular calcifications and chorioretinitis are the predominant characteristics of congenital LCMV infection, occurring in 87.5% of cases. Mortality in congenitally infected children is about 35%, while 70% of them show long-term neurologic sequelae. Clinicians should be aware of the risks posed by LCMV and should consider the virus in the differential diagnosis of aseptic meningitis, especially in patients who reported contact with rodents. Furthermore, LCMV should be considered in infants and children with unexplained hydrocephalus, intracerebral calcifications and chorioretinitis. Despite intensive interdisciplinary research efforts, efficient antiviral therapy for LCMV infection is still not available.

Congenital lymphocytic choriomeningitis virus—an underdiagnosed fetal teratogen

Congenital lymphocytic choriomeningitis virus (LCMV) infection is associated with high mortality and morbidity. Although the number of cases reported in the literature has been increasing, it might still be clinically an underdiagnosed human fetal teratogen. We report 2 more cases of serologically proven congenital LCMV infection. One case presented with Aicardi-like syndrome features. Since congenital LCMV infection may mimic Aicardi syndrome, serologic testing should be considered in the workup of patients with Aicardi syndrome to rule out LCMV infection.

Congenital Lymphocytic Choriomeningitis Virus in a Member of a Twin Pregnancy

AbstractWe report a male infant, twin A of a dichorionic pregnancy, with a fetal ultrasound and subsequent MRI at 29 weeks of gestation revealing a small cranium (26 cm, < 3rd percentile for gestation) and marked ex vacuo ventriculomegaly. Twin B had normal ultrasound and brain MRI. Newborn exam was unremarkable and his weight and head circumference were both at 5th percentile. Placental pathology findings included focal acute vasculitis and chronic villitis. Postnatal brain MRI showed significant cerebral volume loss with extensive large cystic parietal encephalomalacia and diffuse cerebral cortical dysplasia (polymicrogyria). Common congenital infectious diseases investigation on maternal serum was normal. Twin A was admitted for bronchiolitis and possible seizure at 3 months of age. At this time, he had microcephaly and was not tracking light. Ophthalmology exam showed markedly abnormal macula with diffuse pigment changes and scarring that extended between the full arcades bilaterally. Congenital lymphocytic choriomeningitis virus (LCMV) infection was confirmed with negative IgM titer and highly positive IgG titer of greater than 1:256. Serologic tests for LCMV should be considered in infants who have central nervous system and retinal involvement but negative TORCH studies.

T-Cells Underlie Some but Not All of the Cerebellar Pathology in a Neonatal Rat Model of Congenital Lymphocytic Choriomeningitis Virus Infection.

Lymphocytic choriomeningitis virus (LCMV) infection during pregnancy injures the human fetal brain. Neonatal rats inoculated with LCMV are an excellent model of congenital LCMV infection because they develop cerebellar injuries similar to those in humans. To evaluate the role of T-lymphocytes in LCMV-induced cerebellar pathology, congenitally athymic rats, deficient in T-lymphocytes were compared with euthymic rats. Peak viral titers and cellular targets of infection were similar, but viral clearance from astrocytes was impaired in the athymic rats. Cytokines and chemokines rose to higher levels and for a greater duration in the euthymic rats than in their athymic counterparts. The euthymic rats developed an intense lymphocytic infiltration, accompanied by destructive lesions of the cerebellum and a neuronal migration defect because of T-cell-mediated alteration of Bergmann glia. These pathologic changes were absent in the athymic rats but were restored by adoptive transfer of lymphocytes. Athymic rats were not free of pathologic effects, however, as the virus induced cerebellar hypoplasia. Thus, T-lymphocytes play key roles in LCMV clearance, cytokine/chemokine responses, and pathogenesis of destructive lesions and neuronal migration disturbances but not all pathology is T-lymphocyte-dependent. Cerebellar hypoplasia from LCMV occurs even in the absence of T-lymphocytes and is likely due to the viral infection itself.

9. Congenital Lymphocytic Choriomeningitis Virus: A Neuropathological Study

Lymphocytic choriomeningitis virus (LCMV) carried and secreted by mice, infects great numbers of people. LCMV infection acquired during childhood or adulthood is usually moderately symptomatic with a full recovery. When the infection occurs prenatally, it results in a wide spectrum of severe brain lesions described mainly on imaging. Neuropathological data have never been reported.We present 2 fetuses with a prenatal diagnosis of microcephaly with ventriculomegaly, abnormal gyration, and ponto-cerebellar hypoplasia in one case. Parents elected to terminate the pregnancy. A complete autopsy demonstrated no dysmorphic features, no visceral or skeletal malformation. Histological examination of viscera did not show any significant lesion.Neuropathological examination confirmed microcephaly and ventriculomegaly with a thick yellowish band surrounding the ventricles. Identical histological lesions were observed in both cases associating a polymicrogyria and a diffuse necrosis of parenchyma with massive calcifications all around the ventricles. The most characteristic feature was the unusual aspect of necrosis, distinct from that observed in other infections, characterized by a finely granular appearance looking like sand. Small lymphocytic infiltrates were observed in the leptomeninges and in the choroid but not in the retina. The congenital LCMV infection was confirmed by serologic testing.This study confirms the strong neurotropism of LCMV and demonstrates that prenatal infection has some particular features such as absent systemic signs, and distinct appearance of the necrosis that allow to distinguish it from other congenital infections and other non infectious conditions.

Congenitally acquired persistent lymphocytic choriomeningitis viral infection reduces neuronal progenitor pools in the adult hippocampus and subventricular zone.

Lymphocytic choriomeningitis virus (LCMV) can be transmitted through congenital infection, leading to persistent infection of numerous organ systems including the central nervous system (CNS). Adult mice persistently infected with LCMV (LCMV-cgPi mice) exhibit learning deficits, such as poor performance in spatial discrimination tests. Given that deficits in spatial learning have been linked to defects in adult neurogenesis, we investigated the impact of congenital LCMV infection on generation of neuroblasts from neural progenitor cells within neurogenic zones of adult mice. In LCMV-cgPi mice, QPCR and immunohistochemistry detected presence of LCMV glycoprotein-coding RNA and nucleoprotein in the hippocampal dentate gyrus and subventricular zone (SVZ), sites of neurogenesis that harbor populations of neuroblasts. Numbers of neuroblasts were reduced in LCMV-cgPi mice, as determined by IHC quantification, and analysis of BrdU incorporation by flow cytometry revealed lower numbers of BrdU-labeled neuroblasts. Additionally, TUNEL assays performed in situ showed increased numbers of apoptotic cells in the two neurogenic regions. Next, neurosphere cultures were infected in vitro with LCMV and differentiated to create a population of cells that consisted of both transit amplifying cells and neuroblasts. Immunocytochemical and TUNEL assays revealed increased numbers of TUNEL-positive cells that express nestin, suggesting that the drop in numbers of neuroblasts was due to a combination of impaired proliferation and apoptosis of progenitor cells. LCMV-cgPi mice exhibited transcriptional up-regulation several cytokines and chemokines, including gamma-interferon inducible chemokines CXCL9 and CXCL10. Chronic up-regulation of these chemokines can facilitate a pro-inflammatory niche that may contribute to defects in neurogenesis.

Congenital Lymphocytic Choriomeningitis Virus

Lymphocytic choriomeningitis virus is a rodent-borne arenavirus that can cause congenital infection affecting the developing central nervous system. When the infection occurs during pregnancy, the virus targets the fetal brain and retina, potentially causing ventriculomegaly, hydrocephalus, chorioretinitis, and neurodevelopmental abnormalities. It has been previously suggested that lymphocytic choriomeningitis virus be added to the list of congenital infections currently included in the TORCH acronym (toxoplasmosis, rubella, cytomegalovirus, herpes, and syphilis). We present 2 neonates with antenatally known ventriculomegaly that were diagnosed with congenital lymphocytic choriomeningitis virus infection after birth. In addition to ventriculomegaly, one had nonimmune hydrops fetalis and the other had intracranial hemorrhage. In view of the seroprevalence of lymphocytic choriomeningitis virus (4.7%-10%), our findings suggest that screening for congenital lymphocytic choriomeningitis virus infection should be considered in fetuses and newborns with ventriculomegaly as well as other abnormal neuroimaging findings such as intracranial hemorrhage.

Exposure to Lymphocytic Choriomeningitis Virus, New York, USA

To the Editor: Lymphocytic choriomeningitis virus (LCMV) is an arenavirus carried by the house mouse, Mus musculus. Human infections can range from mild febrile illness to severe encephalitis and disseminated disease (1). Infection during pregnancy is associated with teratogenic effects, including congenital hydrocephalus and chorioretinitis (2). The overall occurrence of human exposure to LCMV is not known. Two large US serosurveys suggest that 3%–5% of persons tested had previous LCMV exposure as measured by immunoglobulin (Ig) G (3,4). In 2002, LCMV-associated congenital subependymal calcifications, hydrocephalus, and chorioretinitis were confirmed for 2 children in central Syracuse, Onondaga County, New York, USA. In 2009, the Centers for Disease Control and Prevention confirmed another case of LCMV-associated congenital hydrocephalus and chorioretinitis in a child from the same neighborhood. For each of the 3 cases, the mother’s history included exposure to mice during pregnancy. One mother also had a pet guinea pig, which had negative results for LCMV by serologic testing and reverse transcription PCR of kidney tissue (5). Congenital LCMV is rarely reported to public health departments or in the literature. Therefore, to better understand the magnitude of LCMV exposure in the general population of Onondaga County, we conducted a serosurvey. The American Red Cross provided the Wadsworth Center of the New York State Department of Health with blood or serum samples collected from persons >16 years of age at blood drives during August 2009. Information about date of birth, sex, and county and ZIP code of residence was provided. A subset of samples from blood donors residing in Onondaga County were tested at the Centers for Disease and Prevention by ELISA for LCMV IgM and IgG as described (4). State and federal institutional review board approval was obtained for this study. Samples from 562 blood donors were tested. Mean age of donors was 48 years (median 50 ± 15 SD, range 17–79 years). LCMV IgG was detected in 2 (0.4%) samples (titer >400) and was undetectable in all other samples. LCMV IgM was not detected in any samples. Of the 25 donors who reported residing in 1 of the 2 ZIP codes as the case-patients with congenital LCMV, none had positive test results. Given our findings, little evidence supports a high level of human exposure to LCMV in Onondaga County. Compared with previously reported seroprevalences of 3%–5%, the proportion of persons exposed to LCMV was lower than expected (3,4). The same serologic assay was used in this study and the 2 previous US serosurveys, suggesting that the different results are not an artifact of different assays. Additionally, persons tested in the current survey were older than those tested in previous serosurveys (median 50 vs. 23 [3] and 40 years [4], respectively). Because IgG against LCMV can persist for years, seroprevalence would be expected to be higher for an older population as a result of more chances for exposure. Also, a serosurvey of >1,000 hospitalized persons from upstate New York in the 1970s detected no positive antibody titers (6), consistent with our findings. Our serosurvey had a few limitations. Blood samples from an entire county cannot detect potential household- or neighborhood-scale areas of increased risk for LCMV exposure, which may be related to focal distribution of populations of LCMV-infected house mice. Serosurveys of house mice have previously shown evidence for clustering of LCMV-infected individuals (7); however, the prevalence of LCMV in house mice in Onondaga County is unknown. Additionally, because blood donors were volunteers, the population sampled did not necessarily reflect the population at risk for LCMV exposure. Despite these considerations, the low prevalence of LCMV antibodies suggests low occurrence of LCMV exposure in this population. Although little is known about frequency of human exposure and infection, LCMV seems to be rare with a propensity for inducing severe disease. LCMV infection has been associated with high incidence of clinical disease, including a pet hamster–associated outbreak in 1973–1974 that resulted in at least 181 cases and 46 hospitalizations in 12 states (8). LCMV-related disease is reportable in only 3 states (Wisconsin, Massachusetts, Arizona) and 1 city (New York, New York) and is considered to be widely undertested and underdiagnosed. A recent survey of health care providers in Connecticut found that LCMV diagnostic tests were not requested for all patients suspected to have LCMV infection (9); thus, missed diagnoses are possible. Additional studies are needed to understand the incidence of LCMV-related disease and LCMV seroprevalence in the general population (10).

Human Infection with Lymphocytic Choriomeningitis Virus

To the Editor: I read with great interest the article regarding lymphocytic choriomeningitis virus (LCMV) meningitis in a New York City resident (1). The authors’ conclusion that there is a need to ascertain the true incidence of LCMV infection is worthy of underscoring. Nearly 15 years ago, in this same journal, we described congenital LCMV as an unrecognized teratogen and recommended further “research to define the frequency of LCMV” (2). Five years later, we reiterated that recommendation when reporting acquired LCMV meningoencephalitis in an adolescent from Tucson, Arizona (3). Despite, or because of, the lack of prospective studies, the fact that this author has accrued data regarding >60 congenitally infected infants from all geographic areas in the United States during the past 15 years reinforces the concept that LCMV is a neglected pathogen whose time for more extensive study has indeed come.

A case of congenital lymphocytic choriomeningitis virus (LCMV) infection revealed by hydrops fetalis

Prenatal DiagnosisVolume 29, Issue 6 p. 626-627 Research Letter A case of congenital lymphocytic choriomeningitis virus (LCMV) infection revealed by hydrops fetalis J. F. Meritet, Corresponding Author J. F. Meritet jean-francois.meritet@svp.aphp.fr Service de Virologie, Hôpital Cochin—Saint Vincent de Paul APHP, Paris, FranceService de Virologie, Hôpital Cochin—Saint Vincent de Paul, 82 Avenue Denfert-Rochereau, 75674 Paris Cedex 14, France.Search for more papers by this authorA. Krivine, A. Krivine Service de Virologie, Hôpital Cochin—Saint Vincent de Paul APHP, Paris, FranceSearch for more papers by this authorF. Lewin, F. Lewin Service d'Obstétrique, Hôpital Cochin—Saint Vincent de Paul APHP, Paris, FranceSearch for more papers by this authorM. H. Poissonnier, M. H. Poissonnier Service d'Obstétrique, Hôpital Cochin—Saint Vincent de Paul APHP, Paris, FranceSearch for more papers by this authorR. Poizat, R. Poizat Service d'Obstétrique, Clinique du Tertre rouge, le Mans, FranceSearch for more papers by this authorP. Loget, P. Loget Service d'Anatomie Pathologique—Centre Hospitalier, le Mans, FranceSearch for more papers by this authorF. Rozenberg, F. Rozenberg Service de Virologie, Hôpital Cochin—Saint Vincent de Paul APHP, Paris, France Service d'Obstétrique, Hôpital Cochin—Saint Vincent de Paul APHP, Paris, France Service d'Obstétrique, Clinique du Tertre rouge, le Mans, France Service d'Anatomie Pathologique—Centre Hospitalier, le Mans, France Faculté de Médecine Descartes et Université Paris Descartes, Paris, FranceSearch for more papers by this authorP. Lebon, P. Lebon Service de Virologie, Hôpital Cochin—Saint Vincent de Paul APHP, Paris, France Service d'Obstétrique, Hôpital Cochin—Saint Vincent de Paul APHP, Paris, France Service d'Obstétrique, Clinique du Tertre rouge, le Mans, France Service d'Anatomie Pathologique—Centre Hospitalier, le Mans, France Faculté de Médecine Descartes et Université Paris Descartes, Paris, FranceSearch for more papers by this author J. F. Meritet, Corresponding Author J. F. Meritet jean-francois.meritet@svp.aphp.fr Service de Virologie, Hôpital Cochin—Saint Vincent de Paul APHP, Paris, FranceService de Virologie, Hôpital Cochin—Saint Vincent de Paul, 82 Avenue Denfert-Rochereau, 75674 Paris Cedex 14, France.Search for more papers by this authorA. Krivine, A. Krivine Service de Virologie, Hôpital Cochin—Saint Vincent de Paul APHP, Paris, FranceSearch for more papers by this authorF. Lewin, F. Lewin Service d'Obstétrique, Hôpital Cochin—Saint Vincent de Paul APHP, Paris, FranceSearch for more papers by this authorM. H. Poissonnier, M. H. Poissonnier Service d'Obstétrique, Hôpital Cochin—Saint Vincent de Paul APHP, Paris, FranceSearch for more papers by this authorR. Poizat, R. Poizat Service d'Obstétrique, Clinique du Tertre rouge, le Mans, FranceSearch for more papers by this authorP. Loget, P. Loget Service d'Anatomie Pathologique—Centre Hospitalier, le Mans, FranceSearch for more papers by this authorF. Rozenberg, F. Rozenberg Service de Virologie, Hôpital Cochin—Saint Vincent de Paul APHP, Paris, France Service d'Obstétrique, Hôpital Cochin—Saint Vincent de Paul APHP, Paris, France Service d'Obstétrique, Clinique du Tertre rouge, le Mans, France Service d'Anatomie Pathologique—Centre Hospitalier, le Mans, France Faculté de Médecine Descartes et Université Paris Descartes, Paris, FranceSearch for more papers by this authorP. Lebon, P. Lebon Service de Virologie, Hôpital Cochin—Saint Vincent de Paul APHP, Paris, France Service d'Obstétrique, Hôpital Cochin—Saint Vincent de Paul APHP, Paris, France Service d'Obstétrique, Clinique du Tertre rouge, le Mans, France Service d'Anatomie Pathologique—Centre Hospitalier, le Mans, France Faculté de Médecine Descartes et Université Paris Descartes, Paris, FranceSearch for more papers by this author First published: 27 February 2009 https://doi.org/10.1002/pd.2240Citations: 20AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat No abstract is available for this article.Citing Literature Volume29, Issue6June 2009Pages 626-627 RelatedInformation

Genetic mimics of congenital lymphocytic choriomeningitis virus encephalitis

Genetic mimics of congenital lymphocytic choriomeningitis virus encephalitis

Congenital Viral Infections of the Brain: Lessons Learned from Lymphocytic Choriomeningitis Virus in the Neonatal Rat

The fetal brain is highly vulnerable to teratogens, including many infectious agents. As a consequence of prenatal infection, many children suffer severe and permanent brain injury and dysfunction. Because most animal models of congenital brain infection do not strongly mirror human disease, the models are highly limited in their abilities to shed light on the pathogenesis of these diseases. The animal model for congenital lymphocytic choriomeningitis virus (LCMV) infection, however, does not suffer from this limitation. LCMV is a well-known human pathogen. When the infection occurs during pregnancy, the virus can infect the fetus, and the developing brain is particularly vulnerable. Children with congenital LCMV infection often have substantial neurological deficits. The neonatal rat inoculated with LCMV is a superb model system of human congenital LCMV infection. Virtually all of the neuropathologic changes observed in humans congenitally infected with LCMV, including microencephaly, encephalomalacia, chorioretinitis, porencephalic cysts, neuronal migration disturbances, periventricular infection, and cerebellar hypoplasia, are reproduced in the rat model. Within the developing rat brain, LCMV selectively targets mitotically active neuronal precursors. Thus, the targets of infection and sites of pathology depend on host age at the time of infection. The rat model has further shown that the pathogenic changes induced by LCMV infection are both virus-mediated and immune-mediated. Furthermore, different brain regions simultaneously infected with LCMV can undergo widely different pathologic changes, reflecting different brain region–virus–immune system interactions. Because the neonatal rat inoculated with LCMV so faithfully reproduces the diverse neuropathology observed in the human counterpart, the rat model system is a highly valuable tool for the study of congenital LCMV infection and of all prenatal brain infections In addition, because LCMV induces delayed-onset neuronal loss after the virus has been cleared, the neonatal rat infected with LCMV may be an excellent model system to study neurodegenerative or psychiatric diseases whose etiologies are hypothesized to be virus-induced, such as autism, schizophrenia, and temporal lobe epilepsy.

Congenital lymphocytic choriomeningitis virus infection: spectrum of disease

Lymphocytic choriomeningitis virus (LCMV) is a human pathogen and an emerging neuroteratogen. When the infection occurs during pregnancy, the virus can target and damage the fetal brain and retina. We examined the spectrum of clinical presentations, neuroimaging findings, and clinical outcomes of children with congenital LCMV infection. Twenty children with serologically confirmed congenital LCMV infection were identified. The children underwent neuroimaging studies and were followed prospectively for up to 11 years. All children with congenital LCMV infection had chorioretinitis and structural brain anomalies. However, the presenting clinical signs, severity of vision disturbance, nature and location of neuropathology, and character and severity of brain dysfunction varied substantially among cases. Neuroimaging abnormalities included microencephaly, periventricular calcifications, ventriculomegaly, pachygyria, cerebellar hypoplasia, porencephalic cysts, periventricular cysts, and hydrocephalus. The combination of microencephaly and periventricular calcifications was the most common neuroimaging abnormality, and all children with this combination had profound mental retardation, epilepsy, and cerebral palsy. However, others had less severe neuroimaging abnormalities and better outcomes. Some children had isolated cerebellar hypoplasia, with jitteriness as their presenting sign and ataxia as their principal long-term neurological dysfunction. Congenital LCMV infection can have diverse presenting signs, neuroimaging abnormalities, and clinical outcomes. In the companion article to this study, we utilize an animal model to show that the clinical and pathological diversity in congenital LCMV infection is likely due to differences in the gestational timing of infection.

Lymphocytic choriomeningitis virus infection of the developing brain: critical role of host age

Lymphocytic choriomeningitis virus (LCMV) is a common human pathogen that causes substantial injury to the developing brain when the infection occurs during pregnancy. However, among children with congenital LCMV infection, there is considerable variability in the site, nature, and severity of neuropathology and in the clinical outcome. We hypothesize that the variability in neuropathology and outcome is due to differences in the gestational timing of LCMV infection. We utilized an animal model of human congenital LCMV infection, in which developing rat pups were inoculated with LCMV at a series of postnatal ages, including postnatal days 1, 4, 6, 10, 21, 30, and 60. Cellular targets of infection were determined immunohistochemically, viral titers were determined by plaque assay, and pathology was determined by histological analysis, neuronal quantification, and immunostaining for lymphocytic subclasses. Host age at the time of infection profoundly affected the cellular targets of infection, maximal viral titers, immune response to the viral infection, and the severity, nature, and location of the neuropathology. All of the pathological changes observed in children with congenital LCMV infection were reproduced in the rat model by infecting the rat pups at different ages. The effect of LCMV infection on the developing brain strongly depends on host age at the time of infection. Much of the variability in neuropathology and outcome among children with congenital LCMV infection probably depends on the gestational age at which the infection occurs.

Lymphocytic choriomeningitis virus: An emerging obstetric pathogen?

A report in May 2005 from the Centers for Disease Control and Prevention describing a cluster of lymphocytic choriomeningitis virus (LCMV) infections among 4 solid organ recipients has increased awareness of and clinical interest in this pathogen. Human infection with LCMV results from direct or indirect contact with rodents. LCMV has particular relevance to obstetrics, as it is likely an under-recognized abortifacient and fetal teratogen. There have been 54 cases of congenital LCMV reported since 1955, with 34 of the cases diagnosed since 1993. Chorioretinitis and hydrocephalus are the predominant characteristics among children diagnosed with congenital LCMV infection. Obstetricians should educate their pregnant patients about the risks of exposure to laboratory, pet, and wild rodents.