Viral Infections Of Nervous System Research Articles

Caspase-3 activation is required for reovirus-induced encephalitisin vivo

Reovirus infection of neonatal mice provides a classic experimental system for understanding the molecular pathogenesis of central nervous system (CNS) viral infection. CNS tissue injury, caused by many human neurotropic viruses, including herpes viruses and West Nile virus, is associated with caspase-dependent apoptotic neuronal cell death. We have previously shown that reovirus-induced CNS tissue injury results from apoptosis and is associated with activation of both death-receptor and mitochondrial apoptotic pathways culminating in the activation of the downstream effector caspase, caspase-3. In order to directly investigate the role of caspase-3 in virus-induced neuronal death and CNS tissue injury during encephalitis, we have compared the pathogenesis of reovirus CNS infection in mice lacking the caspase-3 gene (caspase-3 (-/-)) to syngeneic wild-type mice. Prior studies of antiapoptotic treatments for reovirus-infected mice have indicated that protection from reovirus-induced neuronal injury can occur without altering the viral titer in the brains of infected mice. We now show that reovirus infection of caspase-3 (-/-) mice was associated with dramatic reduction in severity of CNS tissue injury, decreased viral antigen and titer in the brain, and enhanced survival of infected mice. Following intracerebral inoculation, the authors also show that virus spread from the brain to the eyes in reovirus-infected caspase-3 (-/-) mice, indicating that viral spread was intact in these mice. Examination of brains of long-term survivors of reovirus infection among caspase-3 (-/-) mice showed that these mice eventually clear their CNS viral infection, and do not manifest residual or delayed CNS tissue injury.

Neuroimmunology of central nervous system viral infections: the cells, molecules and mechanisms involved

Viral infections of the central nervous system (CNS) necessitate rapid, yet tightly controlled responses to contain viral spread while limiting tissue damage. All CNS resident cell types are equipped with pattern recognition receptors (PRRs) to respond to viruses. The resulting activation of IFN-alpha/beta, pro-inflammatory cytokines and chemokines is dependent on the virus replication strategy, tropism and PRR distribution. Although IFN-alpha/beta induced antiviral mediators are essential to restrict initial viral spread, adaptive immunity promoted by chemokines, cytokines and metalloproteinases is equally crucial in lowering viral burden. Recognition of viral antigen presented by MHC molecules is crucial for T cell retention and function. Non-lytic clearance mechanisms mediated by IFN-gamma and antibodies prevail in providing protection. Targeted intervention can be achieved by PRR stimulation, chemokine-receptor blockade and immune modulation of T cell function. However, owing to the extensive positive and negative feedback signaling cascades linking innate and adaptive immune responses, enhanced anti-viral functions will have to be counterbalanced to avoid pathology.

Chronic Bacterial and Viral Infections in Neurodegenerative and Neurobehavioral Diseases

Often, patients with neurodegenerative or neurobehavioral diseases have chronic, neuropathic infections that could be important in disease inception, disease progression, or increasing the types or severities of signs and symptoms. Although controversial, the majority of patients with various neurodegenerative or neurobehavioral conditions, such as amyotrophic lateral sclerosis, multiple sclerosis, Alzheimer’s disease, Parkinson’s disease, and autistic spectrum disorders, show evidence of central nervous system or systemic bacterial and viral infections. For example, using serology or polymerase chain reaction evidence of Chlamydia pneumoniae, Borrelia burgdorferi, Mycoplasma species, human herpesvirus-1 and -6, and other bacterial and viral infections revealed high infection rates that were not found in control subjects. Although chronic infections were not found in some studies, and the specific role of chronic infections in neurological disease pathogenesis has not been determined or is inconclusive, the data suggest that chronic bacterial or viral infections could be common features of progressive neurodegenerative and neurobehavioral diseases.

NKG2D contributes to efficient clearance of picornavirus from the acutely infected murine brain

Activated murine cytotoxic T cells express the NKG2D natural cytotoxicity receptor. This receptor recognizes major histocompatibility complex (MHC) class I-like molecules expressed on the surface of infected cells and serves to augment T cell-mediated cytotoxicity. The role of NKG2D-mediated augmentation in the clearance of central nervous system viral infections has not been explored. Using the Theiler’s murine encephalomyelitis virus model, the authors found that NKG2D-positive CD8+ cytotoxic T cells enter the brain, that NKG2D ligands are expressed in the brain during acute infection, and that interruption of NKG2D ligand recognition via treatment with a function-blocking antibody attenuates the efficacy of viral clearance from the central nervous system.

Optic Chiasm Involvement Secondary to Herpetic Encephalitis

Herpes simplex (HSV) encephalitis is one of the most common central nervous system (CNS) viral infections in adults. Early diagnosis is essential for treatment. We describe the case of a 70-year-old man who reported sudden bilateral reduction of visus. Four days after admission the patient showed high fever, followed the next day by a generalised convulsive crisis and coma. A first magnetic resonance imaging (MRI) showed no alterations, whereas the second showed the usual patterns of HSV encephalitis. With a clinical suspicion of herpetic encephalitis an intravenous therapy with acyclovir was established. The diagnosis of herpetic encephalitis was confirmed by cerebrospinal fluid (CSF) detection of herpes simplex DNA sequences. A further ten days later we performed a third MRI, demonstrating the typical pattern of HSV encephalitis and an increase in size and signal of the optic chiasm.

Outcome of Hematopoietic Stem Cell Transplantation in Severe Combined Immune Deficiency With Central Nervous System Viral Infection

Patients with severe combined immunodeficiency and preexisting viral pneumonitis formally had a poor outcome from hematopoietic stem cell transplantation. With inhaled steroid and antitumor necrosis factor alpha antibody treatment, results improved. The poor outcome of patients with viral central nervous system infection prompted this retrospective single center review. Eight of 71 patients with severe combined immunodeficiency transplanted since 1987 were identified with viral central nervous system infection (adenovirus [1], cytomegalovirus [2], Epstein-Barr virus [2], parvovirus [1], varicella zoster virus [1], human herpesvirus 6 [1]). Nonspecific neurologic symptoms included drowsiness, irritability, head lag, fisting and floppiness. Later symptoms included unresponsiveness, apnea, posturing, hypotonia, hyperreflexia and seizures. All had neuroradiologic investigations. Only one had an initially normal computed tomography scan. Magnetic resonance image abnormalities included cerebral atrophy, basal ganglia changes, diffuse leukoencephalopathy, and multifocal mass lesions. Five patients had virus identified from cerebrospinal fluid by polymerase chain reaction and brain tissue examination from 3 patients identified human herpesvirus 6, adenovirus type 41 and varicella zoster virus. Three children remain alive, 2 received replete marrow and one remains untransplanted. Others who received T cell depleted marrow died of neurologic sequelae. Outcome of viral central nervous system infection after hematopoietic stem cell transplantation for severe combined immunodeficiency is poor, particularly associated with T cell depleted marrow.

Novel molecular methods for understanding the viral aetiology of encephalitis

Polymerase chain reaction (PCR) analysis of cerebrospinal fluid (CSF) has revolutionized the diagnosis of nervous system viral infections, particularly those caused by human herpesviruses (HHV). The PCR technique allows the detection of minute quantities of DNA or RNA in body fluids and tissues. Both fresh-frozen and formalin-fixed tissues may be utilized for PCR assays, with the latter making archival studies possible. CSF PCR has now replaced brain biopsy as the gold standard for the diagnosis of herpes simplex virus (HSV) encephalitis. PCR analysis of both CSF and nervous system tissues has also broadened our understanding of the spectrum of disease caused by HSV-1 and -2, cytomegalovirus (CMV), Epstein–Barr virus (EBV), varicella zoster virus (VZV) and HHV-6. PCR results obtained from tissue specimens must be interpreted cautiously, since this highly sensitive technique may detect portions of viral genomic material that may be present even in the absence of active viral infection. Tissue PCR results in particular must be corroborated with clinical and neuropathologic evidence of central nervous system (CNS) infection. In several neurological diseases, negative PCR results have provided evidence against a role for herpesviruses as the causative agents. This review summarizes the role of CSF PCR in the diagnosis and therapeutic management of herpesvirus infections of the nervous system, particularly those caused by HSV and VZV.

High susceptibility of a human oligodendroglial cell line to herpes simplex type 1 infection

More than 20 infectious agents, ranging from retroviruses to mycobacteria, have been associated with multiple sclerosis onset or relapses in which oligodendrocytes, the myelin-forming cells of the central nervous system, are the initial target of the pathogenic status. In this work, the nature of the susceptibility of the human precursor oligodendroglial KG-1C cell line to herpes simplex virus type 1 (HSV-1) was investigated. Infection of KG-1C cells was characterized by a high level of virus production and a notable progression of the cytopathic effect. After infection, there was a significant shut-off of host mRNA translation, which was correlated with evident synthesis of viral proteins. An examination by electron microscopy of the infected cells revealed the presence of large clusters of mitochondria located in the proximity of intracellular HSV-1 particle groups. In addition, transmission electron microscopy and nuclear fluorescence analysis showed neither signs of chromatin condensation nor of apoptotic bodies. Furthermore, procaspase-3 remained uncleaved, suggesting that apoptosis does not take place, at least in this system. Finally, expression and localization of MAL2, a subpopulation of detergent-insoluble lipid raft protein, was studied. Detection of MAL2 significantly increased after infection and it was colocalized with HSV-1 proteins. From these findings the authors conclude that human oligodendrocyte-like cells are highly susceptible to HSV-1 infection. The implications of this for central nervous system viral infection are discussed.

Chronic restraint stress during early Theiler's virus infection exacerbates the subsequent demyelinating disease in SJL mice

Chronic restraint stress, administered during early infection with Theiler's virus, was found to exacerbate the acute central nervous system (CNS) viral infection and the subsequent demyelinating phase of disease (an animal model of Multiple Sclerosis (MS)) in SJL male and female mice. During early infection, stressed mice displayed decreased body weights and spontaneous activity; while increased behavioral signs of illness and plasma corticosterone (CORT) levels. During the subsequent chronic demyelinating phase of disease, previously stressed mice had greater behavioral signs of the chronic phase, worsened rotarod performance, and increased inflammatory lesions of the spinal cord. In addition, mice developed autoantibodies to myelin basic protein (MBP), proteolipid protein peptide (PLP139-151), and myelin oligodendrocyte glycoprotein peptide (MOG33-55).

Molecular mechanisms of axonal damage in inflammatory central nervous system diseases.

Axonal dysfunction and damage is an early pathological sign of autoimmune central nervous system disease, viral and bacterial infections, and brain trauma. Axonal injury has attracted considerable interest during the past few years because the degree of axonal damage appears to determine long-term clinical outcome. Advanced magnetic resonance spectroscopic imaging techniques have suggested that axonal loss and dysfunction is responsible for the persistent neurological deficits that occur in patients with multiple sclerosis. Histopathological methods have shown that axonal damage is defined primarily by dysfunction of axonal transport, and finally by complete transection and degeneration of axons. Recent studies have demonstrated that the extent of axonal damage in the primary demyelinating lesion of multiple sclerosis patients is associated with the number of activated microglia/macrophages and cytotoxic CD8+ T lymphocytes. In addition, diffuse axonal dysfunction independent of demyelination develops in normal appearing white matter, possibly due to indirect effects of inflammation. The fact that axonal damage in response to overt inflammatory reactions may occur gradually, leaving a window for therapeutical intervention, has important clinical implications. Determination of the exact molecular mechanism might help in finding new therapies for inflammatory axonal damage.

Newer Antimicrobials for Neurosurgery

Learning Objectives: After reading this article, the participant should be able to: 1. Describe treatment guidelines for acute bacterial meningitis, bacterial brain abscess, and spinal epidural abscess. 2. Describe the treatment guidelines for osteomyelitis and surgical wound infections. 3. Describe the treatment guidelines for central nervous system viral and fungal infections.

Acute central nervous system complications in varicella zoster virus infections

In a previous multicenter study on central nervous system (CNS) viral infections varicella zoster virus (VZV) appeared the most frequent etiologic agent and appeared often without rash. To evaluate the appearance and diagnostics of VZV in CNS more thoroughly, we studied the cases systematically by using sensitive and specific methods to learn the best diagnostic approach in order to start specific therapy. We analyzed all serum and cerebrospinal fluid samples of 174 patients, 88 females and 86 males, with acute CNS symptoms associated with VZV infection diagnosed in the multicenter study on viral CNS infections. About 38 patients (22%) had chickenpox, 59 (34%) had shingles, and 77 (44%) had no cutaneous symptoms at all. The mean age of chickenpox patients was 8.6 years, of the others 46.6 and 41.4 years. VZV-specific nucleic acid was detected in the CSF in one fourth of the patients in all groups, primarily during the first week of illness. In serum specimens, specific IgM was present in two thirds of the patients with chickenpox, whereas in the others in one third of the cases. In CSF, specific IgM was present in 15-17% of patients with skin manifestations, compared with 6% of those without rash. The role of VZV infections in CNS complications seems remarkable, often presenting without rash. Even these cases should be promptly recognized in order to conduct proper antiviral therapy. In children, a combination of PCR and IgM tests is the best approach. In adults, PCR, together with the measurement of intrathecal antibody production yields best results.

Use of PCR for the diagnosis of herpesvirus infections of the central nervous system.

Polymerase chain reaction (PCR) analysis of cerebrospinal fluid (CSF) has revolutionized the diagnosis of nervous system viral infections, particularly those caused by human herpesviruses (HHV). The PCR technique allows the detection of minute quantities of DNA or RNA in body fluids and tissues. Both fresh-frozen and formalin-fixed tissues may be utilized for PCR assays, with the latter making archival studies possible. CSF PCR has now replaced brain biopsy as the gold standard for the diagnosis of herpes simplex virus (HSV) encephalitis. PCR analysis of both CSF and nervous system tissues has also broadened our understanding of the spectrum of disease caused by HSV-1 and -2, cytomegalovirus (CMV), Epstein-Barr virus (EBV), varicella zoster virus (VZV) and HHV-6. PCR results obtained from tissue specimens must be interpreted cautiously, since this highly sensitive technique may detect portions of viral genomic material that may be present even in the absence of active viral infection. Tissue PCR results in particular must be corroborated with clinical and neuropathologic evidence of central nervous system (CNS) infection. In several neurological diseases, negative PCR results have provided evidence against a role for herpesviruses as the causative agents. This review summarizes the role of CSF PCR in the diagnosis and therapeutic management of herpesvirus infections of the nervous system, particularly those caused by HSV and VZV.

Polymerase chain reaction as a diagnostic adjunct in herpesvirus infections of the nervous system.

Polymerase chain reaction (PCR) is a powerful technique that allows detection of minute quantities of DNA or RNA in cerebrospinal fluid (CSF), vesicle and endoneurial fluids, blood, fresh-frozen, and even formalin-fixed tissues. Various infectious agents can be detected with high specificity and sensitivity, including bacteria, parasites, rickettsia and viruses. PCR analysis of CSF has revolutionized the diagnosis of nervous system viral infections, particularly those caused by human herpesviruses (HHV), and has now replaced brain biopsy as the gold standard for diagnosis of herpes simplex virus (HSV) encephalitis. PCR analysis of both CSF and nervous system tissues has also broadened our understanding of the spectrum of disease caused by HSV-1 and -2, cytomegalovirus (CMV), Epstein-Barr virus (EBV), varicella zoster virus (VZV), and HHV-6. Nonetheless, positive tissue PCR results must be interpreted cautiously, especially in cases that lack corroborating clinical and neuropathologic evidence of infection. Moreover, positive PCR results from tissues do not distinguish latent from productive (lytic) viral infections. In several neurological diseases, negative PCR results have provided strong evidence against a role for herpesviruses as the causative agents. This review focuses on the use of PCR tests to diagnose HSV and VZV infections of the nervous system.

Regulation of t cell responses during central nervous system viral infection

Publisher SummaryThis chapter focuses on the contribution of T cells to the pathogenesis of neurologic disease and discusses specific examples of how individual T cell effector functions can be regulated during central nervous system's (CNS) viral infections. T cells can serve a variety of functions as part of the host immune response during CNS viral infection. They can participate directly in viral clearance from the brain, or they can promote the survival of the host without exerting any direct effect on virus replication. Only a small number of T cells infiltrate the brain under normal circumstances. This paucity of immune surveillance of baseline is one of several reasons why the CNS has often been characterized as an “immunologically privileged” site. T cell-mediated lysis of infected cells has been demonstrated to be an important mechanism of viral clearance from tissues other than the CNS. In several well-characterized animal models of CNS viral infection, part of the elicited T cell response actually contributes to the pathology and adverse outcome of disease. Neurotropic lymphocytic choriomeningitis virus infection of adult mice is the premier example of this phenomenon.

Resistance of interleukin-1beta-deficient mice to fatal Sindbis virus encephalitis.

Interleukin-1beta (IL-1beta) concentrations are frequently elevated in central nervous system (CNS) viral infections, but the pathophysiologic significance of such elevations is not known. To examine the role of IL-1beta in CNS viral pathogenesis, we compared the natural histories of IL-1beta-deficient and wild-type 129 SV(ev) mice infected with a neurovirulent viral strain, neuroadapted Sindbis virus (NSV). We found that the incidence of severe paralysis and death was markedly decreased in NSV-infected IL-1beta-/- mice compared to NSV-infected wild-type mice (4 versus 88%, P < 0.001). Despite this marked difference in clinical outcome, no differences in numbers of apoptotic cells or presence of histopathologic lesions in the brains of moribund wild-type mice and those of clinically healthy IL-1beta-/- mice could be detected. These results suggest that IL-1beta deficiency is protective against fatal Sindbis virus infection by a mechanism that does not involve resistance to CNS virus-induced apoptosis or histopathology.

多発性脳神経症状を呈したヘルペス感染症例

We experienced a case of multiple cranial nerve palsy due to varicella-zoster virus (VZV) infection. The patient was a 52-year-old man who complained of sudden onset of symptoms including left hearing impairment, sore throat and hoarseness. Physical examination and findings included sensorineural deafness, palatoplegia and recurrent laryngeal nerve palsy on the left side. No other abnormal neurological findings were noted. No vesicles were noted in the ear, oral cavity or pharynx, and there was no facial palsy. Brain CT and MRI revealed no abnormal findings. The cerebrospinal fluid, however, showed pleocytosis. A diagnosis was a suspected central nervous system viral infection. The patient was treated with an anti-viral agent (Acyclovir). Remission of all symptoms occurred gradually after approximately one month of treatment. The serum and CSF antibody titers for VZV were elevated. Localized brainstem encephalitis due to VZV was the final diagnosis. In cases of 8th, 9th and 10th cranial nerve involvement with unknown etiology, the serum and CSF antibody titers for VZV should be evaluated.

A persistent biochemical marker for partially treated meningitis/ventriculitis.

Regulation of circulating iron is important in bacterial, yeast, and fungal infections. In the present study, cerebrospinal fluid levels of ferritin, an iron-binding protein, were determined in controls and in patients with central nervous system pyogenic and viral infections. Among 441 controls, cerebrospinal fluid ferritin level was higher than 18 ng/mL in two relapsed patients with central nervous system leukemia, 12 with bacteremia or pneumonia, and one with hemorrhagic herpes simplex encephalitis. Cerebrospinal fluid ferritin levels were more than 18 ng/mL in 13 of 63 patients diagnosed with nonhemorrhagic aseptic meningitis/ventriculitis, when defined solely by negative cerebrospinal fluid culture. Conversely, cerebrospinal fluid ferritin exceeded 18 ng/mL in culture-proven meningitis (46 of 47 cases) and ventriculitis (five of five cases). Cases of indolent cryptococcus and tuberculous meningitis showed modest increases despite traditional cerebrospinal fluid markers, at times, being normal. Cerebrospinal fluid ferritin levels did not correlate with cerebrospinal fluid neutrophil count, cerebrospinal fluid protein concentration, serum ferritin level, or patient age. In 16 of 19 cases monitored sequentially during ongoing antibiotic treatment, levels remained over 18 ng/mL (average, 15.0 days; range, 1 to 54 days). This observation suggests that obtaining cerebrospinal fluid ferritin levels is helpful whenever traditional laboratory benchmarks normalize, as during acute or chronic antibiotic therapy, or create confusion with positive cultures stemming from sample contamination.

Early Diagnosis of Central Nervous System (CNS) Viral Infections in the Neonatal Period and Early Infancy

Early Diagnosis of Central Nervous System (CNS) Viral Infections in the Neonatal Period and Early Infancy

Role of the virology laboratory in diagnosis and management of patients with central nervous system disease.

A number of viruses cause acute central nervous system disease. The two major clinical presentations are aseptic meningitis and the less common meningoencephalitis. Clinical virology laboratories are now more widely available than a decade ago; they can be operated on a modest scale and can be tailored to the needs of the patients they serve. Most laboratories can provide diagnostic information on diseases caused by enteroviruses, herpesviruses, and human immunodeficiency virus. Antiviral therapy for herpes simplex virus is now available. By providing a rapid diagnostic test or isolation of the virus or both, the virology laboratory plays a direct role in guiding antiviral therapy for patients with herpes simplex encephalitis. Although there is no specific drug available for enteroviruses, attention needs to be paid to these viruses since they are the most common cause of nonbacterial meningitis and the most common pathogens causing hospitalization for suspected sepsis in young infants in the United States during the warm months of the year. When the virology laboratory maximizes the speed of viral detection or isolation, it can make a significant impact on management of these patients. Early viral diagnosis benefits patients with enteroviral meningitis, most of whom are hospitalized and treated for bacterial sepsis or meningitis or both; these patients have the advantage of early withdrawal of antibiotics and intravenous therapy, early hospital discharge, and avoidance of the risks and costs of unnecessary tests and treatment. Enteroviral infection in young infants also is a risk factor for possible long-term sequelae. For compromised patients, the diagnostic information helps in selecting specific immunoglobulin therapy. Good communication between the physician and the laboratory will result in the most benefit to patients with central nervous system viral infection.