Seroprevalence of lymphocytic choriomeningitis virus and Ljungan virus in Finnish patients with suspected neurological infections.

Directly-transmitted rodent-borne zoonotic viruses, such as lymphocytic choriomeningitis virus (LCMV) can cause nervous system infections. Rodent-borne Ljungan virus (LV) is considered potentially zoonotic possibly causing neurological symptoms. Our objective was to understand the role of these two viruses compared to other pathogens in causing neurological infections in Finnish patients. Routine screening data were available for 400 patients aged 5-50 years, collected from December 2013 to December 2014 with suspected neurological infection. Depending on symptoms, patients were variously tested for herpesviruses, enteroviruses, varicella zoster virus, and Mycoplasma pneumoniae, while those suspected of tick bite were further tested for Borrelia spp. and tick-borne encephalitis virus using antibody and/or nucleic acid tests. For 380 patients, we also screened the RNA and antibody prevalence of LCMV and LV in order to test if either of these viruses were the causative agent. Data collected indicated that the causative microbial agent was confirmed in only 15.5% of all Finnish patients with neurological symptoms, with M. pneumoniae (26 cases) being the most common causative agent found in sera, whereas Borrelia spp. (15), herpes simplex viruses (7), and enteroviruses (5) were the most common agents confirmed in the CSF. The seroprevalences for LV and LCMV were 33.8% and 5.0%, respectively, but no samples were PCR-positive. In this study, M. pneumoniae and Borrelia spp. were the most common causative agents of neurological infections in Finland. No LCMV or LV infections were detected. We conclude there was no association of LV with neurological diseases in this patient cohort.

Lymphocytic choriomeningitis virus meningitis, New York, NY, USA, 2009.

We describe a case of lymphocytic choriomeningitis virus (LCMV) meningitis in a New York, NY, resident who had no apparent risk factors. Clues leading to the diagnosis included aseptic meningitis during winter and the finding of hypoglycorrachia and lymphocytosis in the cerebrospinal fluid. LCMV continues to be an underdiagnosed zoonotic disease.

Recurrent lymphocytic meningitis positive for herpes simplex virus type 2.

We found the prevalence of recurrent lymphocytic meningitis associated with herpes simplex virus type 2 (HSV-2) was 2.2/100,000 population in Finland during 1996-2006, higher than previous estimates. PCR was most sensitive in detecting HSV-2 DNA from cerebrospinal fluid if the sample was taken 2-5 days after symptom onset.

Cryptococcus and lymphocytic meningitis in Botswana.

We retrospectively reviewed microbiological data from a tertiary care hospital in Botswana, and found that Cryptococcus neoformans was cultured from 15% (193/1307) of all cerebrospinal fluid (CSF) specimens submitted for analysis, making it the most common diagnosed cause of meningitis in this population. Moreover, almost 70% of CSF samples with significant lymphocytosis did not yield a pathogen, suggesting that many causes of lymphocytic meningitis go undiagnosed.

Opposing effects of CXCR3 and CCR5 deficiency on CD8+ T cell-mediated inflammation in the central nervous system of virus-infected mice.

T cells play a key role in the control of viral infection in the CNS but may also contribute to immune-mediated cell damage. To study the redundancy of the chemokine receptors CXCR3 and CCR5 in regulating virus-induced CD8+ T cell-mediated inflammation in the brain, CXCR3/CCR5 double-deficient mice were generated and infected intracerebrally with noncytolytic lymphocytic choriomeningitis virus. Because these chemokine receptors are mostly expressed by overlapping subsets of activated CD8+ T cells, it was expected that absence of both receptors would synergistically impair effector T cell invasion and therefore protect mice against the otherwise fatal CD8+ T cell-mediated immune attack. Contrary to expectations, the accumulation of mononuclear cells in cerebrospinal fluid was only slightly delayed compared with mice with normal expression of both receptors. Even more surprising, CXCR3/CCR5 double-deficient mice were more susceptible to intracerebral infection than CXCR3-deficient mice. Analysis of effector T cell generation revealed an accelerated antiviral CD8+ T cell response in CXCR3/CCR5 double-deficient mice. Furthermore, while the accumulation of CD8+ T cells in the neural parenchyma was significantly delayed in both CXCR3- and CXCR3/CCR5-deficient mice, more CD8+ T cells were found in the parenchyma of double-deficient mice when these were analyzed around the time when the difference in clinical outcome becomes manifest. Taken together, these results indicate that while CXCR3 plays an important role in controlling CNS inflammation, other receptors but not CCR5 also contribute significantly. Additionally, our results suggest that CCR5 primarily functions as a negative regulator of the antiviral CD8+ T cell response.

Recurrent lymphocytic meningitis: the role of herpesviruses.

BACKGROUND: Herpes simplex virus 2 (HSV-2) and HSV-1 have been recognized as causes of recurrent aseptic lymphocytic meningitis (RALM). However, the role of other herpesviruses has not been systematically assessed. OBJECTIVES: To evaluate the cause of RALM by using polymerase chain reaction (PCR) tests detecting varicella-zoster virus (VZV), cytomegalovirus (CMV), or human herpesvirus 6 (HHV-6), in addition to HSV, on cerebrospinal fluid (CSF) samples; and to assess the utility of PCR and antibody analyses in consecutive episodes of RALM. DESIGN: The PCR and antibody results for herpesviruses were analyzed from 14 patients having 48 episodes of RALM. RESULTS: The CSF PCR results for VZV, CMV, and HHV-6 were negative in 12, 10, and 11 patients investigated, respectively, and antibodies against VZV, CMV, and HHV-6 showed only old immunity. Herpes simplex virus 2 was detected from the CSF in 10 patients, and HSV-1 in 1 patient. In 6 of these 11 patients, the HSV PCR result was positive in more than one disease episode. A significant increase of serum antibodies for HSV was seen in only 1 of 15 episodes examined. An intrathecal antibody response to HSV was not recognized in 9 episodes investigated in these 11 patients. CONCLUSIONS: We could not find evidence of VZV, CMV, or HHV-6 in the pathogenesis of RALM, although most patients were previously infected by those viruses. Herpes simplex virus 2 was detected from the CSF in most patients, and often repeatedly, which further confirms the role of this virus in RALM. The causative diagnosis was obtained only by PCR, whereas antibody analysis was not clinically useful.

CCR2+ and CCR5+ CD8+ T cells increase during viral infection and migrate to sites of infection.

Chemokines and their receptors play a critical role in the selective recruitment of various leukocyte subsets. In this study, we correlated the expression of multiple chemokine and CC chemokine receptor (CCR) genes during the course of intracerebral (i.c.) infection with lymphocytic choriomeningitis virus (LCMV) and vesicular stomatitis virus (VSV), which are prototypic of a noncytopathic and a cytopathic virus, respectively. Infection of mice with either virus resulted in rapid activation and overlapping cerebral expression of a number of chemokine genes. Infection with VSV i.c. causes a rapidly lethal, T cell-independent encephalitis, and infection resulted in a dramatic early up-regulation of chemokine gene expression. Similar marked up-regulation of chemokine expression was not seen until late after LCMV infection and required the presence of activated T cells. Cerebral CCR gene expression was dominated by CCR1, CCR2 and CCR5. However, despite a stronger initial chemokine signal in VSV-infected mice, only LCMV-induced T cell-dependent inflammation was found to be associated with substantially increased expression of CCR genes. Virus-activated CD8+ T cells were found to express CCR2 and CCR5, whereas activated monocytes/macrophages expressed CCR1 in addition to CCR2 and CCR5. Together, these CCR profiles readily account for the CCR profile prominent during CD8+-dependent CNS inflammation.

[Herpes simplex and lymphocytic choriomeningitis viruses in infections of the central nervous system--clinical and cerebrospinal fluid characteristics]. / Virusi herpesa simpleks i limfocitarnog horiomeningitisa u infekcijama centralnog nervnog sistema--klinicke i likvorske karakteristike.

INTRODUCTION: A great number of various viruses are stated as the cause of acute infections and damages of the central nervous system. In most cases these are minor damages which exhibit as meningeal syndrome and a specific finding in the cerebrospinal fluid. According to the dominant location, central nervous system infections can take a form of meningitis, encephalitis or myelitis. Since the inflammatory process of the meninges can not be separated from the inflammatory process of the brain, we usually speak of meningoencephalitis. The etiological diagnosis of meningitis and encephalitis is established by isolating the virus from the cerebrospinal fluid and by finding the presence of the specific antibodies in the blood and in the cerebrospinal fluid. The most common causes of the viral meningitis are Enteroviruses, the Mumps virus, Arthropode borne viruses, the Herpes viruses, Adeno viruses and the Lymphocytic choriomeningitis virus. The aim of our study was to establish the correlation between the clinical features and immunological and cerebrospinal fluid changes and the degree of the damage to the blood-brain barrier during the infections of the central nervous system, caused by the Herpes Simplex virus and the Lymphocytic choriomeningitis virus. MATERIAL AND METHODS: From a group of 103 patients, who had been treated for viral meningitis and meningoencephalitis, a group of 27 patients with established specific viral etiology--Herpes Simplex virus and Lymphocytic choriomeningitis virus, had been taken into the account. Herpes Simplex infection had been proven by the complement binding reaction and the neutralisation test of the even samples of serum. The diagnosis of Lymphocytic choriomeningitis was confirmed by the immunofluorescence test of the pharynx swabs and cerebrospinal fluid. The clinical features, such as body temperature, encephalitic signs, and electroencephalographic findings had been followed and compared. RESULTS: Herpes Simplex infection had been found in 20 patients, Lymphocytic choriomeningitis had been proven in 7 patients. All the patients had increased body temperature. Only four of the patients exhibited encephalitic signs, all infected by the Herpes Simplex virus. Patients from the Herpes Simplex group showed various degrees of consciousness disturbances, ranging from somnolence to coma, while the Lymphocytic choriomeningitis patients exhibited none. Higher pleocytosis and protein level had been found in the Lymphocytic choriomeningitis group. DISCUSSION: Viral diseases of the central nervous system are the result of the direct damage of the brain and meninges by the virus and immunological processes. Herpes Simplex meningitis usually has a good prognosis. Lymphocytic choriomeningitis has longer course of the disease and exhibits more severe clinical features. CONCLUSION: In cases of the central nervous system infections, caused by Herpes Simplex virus or Lymphocytic choriomeningitis virus, the correlation between the severeness of clinical features and the degree of damage of the blood-brain barrier, the level of pleocytosis and the increase of the cerebrospinal fluid proteins had been established.

Development of a reverse transcription-polymerase chain reaction assay for diagnosis of lymphocytic choriomeningitis virus infection and its use in a prospective surveillance study.

Lymphocytic choriomeningitis virus (LCMV), which is one of several arenaviruses that are pathogenic for humans, causes encephalitis and meningitis in man. In this study, single-stage and nested reverse transcription-polymerase chain reaction (RT-PCR) assays were developed that targeted the GPC and N genes of LCMV. Both assays detected < 1 TCID50 unit of LCMV. These assays were used to measure the incidence of LCMV infection by testing cerebrospinal fluid (CSF) samples with > or = 10 leukocytes/microl collected over 1 year from patients undergoing lumbar puncture for diagnostic reasons at two Birmingham hospitals. Samples were tested for the presence of LCMV RNA by using the RT- PCR assay and for LCMV-specific IgM antibody by using an ELISA assay. None of the specimens collected from 813 patients was positive by either assay. Although no cases of acute infection were detected, 4% (11/272) of serum collected from a subset of patients was positive for LCMV-specific IgG. A significantly greater rate of seropositivity was found among subjects over 60 years of age (9.4%; P < 0.025) than was found in younger subjects (2.4% at 30-59 years of age; 0% at < 30 years of age). These data suggest that serious central nervous system disease due to LCMV infection is not common in this population. The high rate of seropositivity in those over 60 years of age suggest that infection was once more common.

[Acid-base balance and electrolytes in cerebrospinal fluid of patients with bacterial and lymphocytic meningitis]. / Równowaga kwasowo-zasadowa i elektrolity plynu mózgowo-rdzeniowego u chorych na ropne i limfocytarne zapalenie opon mózgowo-rdzeniowych.

Acid-base balance and electrolytes concentration in cerebrospinal fluid (CSF) of patients with bacterial and lymphocytic meningitis were assessed. Inflammatory process causing the damage of blood-brain barrier and brains hypoxia leads to statistically significant changes of pH, pO2, bicarbonates and K+ concentrations in CSF of patients with bacterial meningitis, which in lymphocytic meningitis were not observed. Patients with fatal; outcome of bacterial meningitis showed higher CSF's acidosis and lover bicarbonates with higher K+ concentrations, which suggest deeper damage of brain hemostasis regulating mechanisms in those patients.

Dissection of an inflammatory process induced by CD8+ T cells.

A massive delayed type hypersensitivity (DTH) reaction occurs in the cerebrospinal fluid (CSF) of mice with lymphocytic choriomeningitis (LCM). In this article, Peter Doherty and colleagues analyze this reaction together with the population dynamics of the regional lymph node to give a comprehensive picture of the events underlying this CD8+ T-cell-mediated immunopathological disease. Their findings are of general relevance to the understanding of inflammation.

Tumor necrosis factor alpha in cerebrospinal fluid during bacterial, but not viral, meningitis. Evaluation in murine model infections and in patients.

To evaluate the potential role of cachectin/TNF-alpha in the pathogenesis of bacterial and viral meningitis, concentrations and kinetics of TNF-alpha were determined in cerebrospinal fluid (CSF). After intracerebral, but not systemic, infection with Listeria monocytogenes in mice, TNF-alpha was detected as early as 3 h after infection reaching maximum titers after 24 h. However, TNF-alpha was not found in serum during the course of Listeria infection. In contrast to bacterial meningitis, no TNF-alpha was detected at any time in CSF of mice suffering from severe lymphocytic choriomeningitis induced by intracerebral infection with lymphocytic choriomeningitis virus. This difference is striking since both model infections led to a massive infiltration of polymorphonuclear and mononuclear leukocytes into the meninges and CSF. The results found for the two model infections were paralleled by findings in humans; CSF from three out of three patients with bacterial meningitis examined during the first day of hospitalization showed significant levels of TNF-alpha; none of the CSF obtained later than 3 d after hospitalization was positive. In addition, similarly to what was found in mice with viral meningitis, zero out of seven patients with viral meningitis had detectable TNF-alpha in CSF.

Cerebrospinal fluid immunoglobulins and virus-specific antibodies in disorders affecting the facial nerve.

Sixty-two patients with acute idiopathic peripheral facial nerve palsy (AIPFP) and 31 patients with lymphocytic meningoradiculitis (Garin-Bujadoux or Bannwarth's syndrome) are described. Results of cerebrospinal fluid (CSF) analysis, including the measurement of immunoglobulins (Ig) G, A, and M, indicate that pleocytosis and/or disturbance of the blood-CSF barrier (BCB) and/or local immunoglobulin synthesis within the central nervous system (CNS) do occur in about 25% of patients with AIPFP. The commonest finding is a slight to moderate breakdown of BCB function without evidence of intrathecal immunoglobulin synthesis. In only about 10% of patients, further support for an inflammatory process within the CNS is found by intrathecal synthesis of oligoclonal IgG and/or localized synthesis of IgG and/or IgA. The majority of cases (75%) do not show any signs of an inflammatory process within the CNS. In contrast, lymphocytic meningopolyradiculitis (LMR) has a characteristic CSF profile with early impairment of BCB permeability as well as with rapid and predominant intrathecal IgM synthesis, which helps to distinguish monosymptomatic LMR from AIPFP. By applying a sensitive enzyme-linked immunosorbent assay to identical concentrations of IgG in serum and CSF, evidence of intrathecal synthesis of virus-specific antibodies was found only in 2 of 13 patients with AIPFP. In contrast, all 4 patients with herpes zoster oticus and peripheral facial palsy (Ramsay Hunt syndrome) showed an intrathecal IgG synthesis to varicella zoster virus lasting for up to 4 months after onset of disease.

The acute inflammatory process in murine lymphocytic choriomeningitis is dependent on Lyt-2+ immune T cells.

Virus-immune spleen cells induce fatal immunopathology following adoptive transfer into adult C57B1/6J mice that have been infected with lymphocytic choriomeningitis virus (LCMV) and immunosuppressed with cyclophosphamide. This is accompanied by the development of potent cytotoxic T-lymphocyte (CTL) activity of donor origin in the recipient spleen. Both the capacity to trigger the acute meningitis observed at 72 hr and to generate CTL effectors in lymphoid tissue are completely abrogated by the removal of Lyt-2+ cells from the donor population. However a lower level of inflammatory process in the central nervous system may emerge, in the absence of significant CTL function in recipient spleen, by 5 days after transfer of the Lyt-2-depleted cell population. Treatment of the transferred cells with antibody to the L3T4 marker does not reduce either the severity of inflammation or the level of CTL effector function in the recipient. Thus Lyt-2+ cells are required for the acute, fatal immunopathology characteristic of LCM, but it is not clear that in a more chronic situation, they are the sole effectors capable of triggering inflammatory process in this disease.

Phenotypic analysis of the inflammatory exudate in murine lymphocytic choriomeningitis.

The massive inflammation of the cerebrospinal fluid (CSF) which occurs in adult mice injected with lymphocytic choriomeningitis virus (LCMV) has been analyzed by flow microfluorometry (FMF). The great majority of the T cells detected by direct examination of freshly obtained CSF were found to be Lyt-2+, with an almost total absence of L3T4+ lymphocytes. The Lyt-2/L3T4 ratio of lymphocytes in blood was within normal limits. Predominance of the Lyt-2+ subset was confirmed by culturing the CSF cells after mitogenic stimulation. In addition, the T lymphocytes in CSF of cyclophosphamide-suppressed, virus-infected recipients that had been injected 4 d previously with LCMV-immune spleen cells were almost entirely donor Lyt-2+ cells, while the nonlymphoid elements were exclusively of host origin. However this pattern of donor and host T cell distribution was reversed when the LCMV-infected recipients were not immunosuppressed. The frequency of LCMV-specific CTL precursors in CSF taken immediately before the development of symptoms was as low as 1:3,000 cells. Thus most of the T lymphocytes extravasating into the CSF of mice with LCM are passive participants recruited as a consequence of the function of relatively few LCMV-specific effector T cells. The dominance of the Lyt-2+ T cell subset in the CSF of mice with LCM is intriguing.

Expression of Pgp-1 (or Ly24) by subpopulations of mouse thymocytes and activated peripheral T lymphocytes.

The expression of Pgp-1 (Ly24) by subpopulations of thymocytes was investigated and a subpopulation of Lyt-2-/L3T4-/J11d- thymocytes was identified which contained significant numbers (80%) of Pgp-1+ cells. Among freshly isolated lymph node T cells but not cortisone-resistant thymocytes, Pgp-1 expression was heterogeneous. Stimulation of T lymphocytes with either concanavalin A or the combination of phorbol myristate acetate plus calcium ionophore resulted in increased Pgp-1 expression which was found to be regulated independently of DNA synthesis and interleukin 2 receptor expression. T cells in the cerebrospinal fluid exudate of mice infected with lymphocytic choriomeningitis virus were also found to be Pgp-1+.

Oligoclonal immunoglobulin bands in cerebrospinal fluid of a patient with lymphocytic choriomeningitis.

We describe a patient with meningitis caused by lymphocytic choriomeningitis virus. Oligoclonal IgG bands were found in the patient's cerebrospinal fluid during acute and convalescent stages of the illness, and results of liver function tests were abnormal. Acute attacks of lymphocytic choriomeningitis virus infection in humans can be added to the list of diseases associated with cerebrospinal fluid oligoclonal IgG.

[Incidence and features of neuroinfections induced by lymphocytic choriomeningitis virus]. / Chastota i osobennosti neiroinfektsii, vyzyvaemykh virusom limfotsitarnogo khoriomeningita.

A follow-up examination of blood sera and cerebrospinal fluid was carried out in 413 patients with various neuroinfections and related diseases. The modern immunological methods were employed: the complement fixation test, the fluorescent antibody test as well as immuno-enzymic and radioimmunoassays. It was established that 8.5% of serous meningitides and 12% of encephalitides were induced by lymphocytic choriomeningitis (LCM) virus. The verified diseases were subjected to a clinical analysis. It is emphasized that the immunological examination of the cerebrospinal fluid in patients with LCM infection contributes to a more detailed study of the pathogenesis of the disease.