Viral Infections Of Central Nervous System Research Articles

Epidemiological Characteristics of Neuro-Specific Antibodies Following Viral Infections.

This study aims to explore the epidemiological characteristics of neuro-specific antibodies (ns-Ab) induced by different viral infections within the central nervous system (CNS). Additionally, it seeks to compare the autoimmune effects following several typical viral infections in CNS. We conduct a retrospective study to compare and analyze the prevalence trends of ns-Ab in patients with different viral infections. Additionally, evaluate the intensity of CNS inflammatory responses postviral infection by correlating clinical characteristics and laboratory findings, and briefly demonstrate the immune effects in CNS following various viral infections. This study retrospectively collected data from 1037 patients hospitalized with suspected CNS infections. A total of 654 patients (63.1%) were included in the final analysis. A higher proportion of patients with pathogens present in their cerebrospinal fluid (CSF) (114 out of 332, 34.3%) tested positive for ns-Ab compared to those without pathogens (70 out of 322, 21.7%) (p = 0.0004). Specifically, the screening rate for ns-Ab in patients with CNS viral infections (83 out of 165, 50.3%) and the prevalence of ns-Ab (27 out of 83, 32.5%) were significantly higher than in those with other pathogen infections (p < 0.0001 and p = 0.016, respectively). Among these, human herpesvirus 7 (HHV7) patients had the highest detection rate of ns-Ab during the disease course (11 out of 26, 42.3%), but exhibited infection characteristics distinctly different from those of herpes simplex virus 1 (HSV1). Viral infections significantly promote the development of autoimmune responses in CNS. The production of ns-Ab and the subsequent autoimmune response vary across different viral infections. There is a strong statistical correlation between HHV7 and the presence of ns-Ab, suggesting that HHV7 may serve as an early indicator of secondary autoimmune response following CNS infections.

Soluble Proteoglycans and Proteoglycan Fragments as Biomarkers of Pathological Extracellular Matrix Remodeling

ABSTRACTProteoglycans and their proteolytic fragments diffuse into biological fluids such as plasma, serum, urine, or synovial fluid, where they can be detected by antibodies or mass‐spectrometry. Neopeptides generated by the proteolysis of proteoglycans are recognized by specific neoepitope antibodies and can act as a proxy for the activity of certain proteases. Proteoglycan and proteoglycan fragments can be potentially used as prognostic, diagnostic, or theragnostic biomarkers for several diseases characterized by dysregulated extracellular matrix remodeling such as osteoarthritis, rheumatoid arthritis, atherosclerosis, thoracic aortic aneurysms, central nervous system disorders, viral infections, and cancer. Here, we review the main mechanisms accounting for the presence of soluble proteoglycans and their fragments in biological fluids, their potential application as diagnostic, prognostic, or theragnostic biomarkers, and highlight challenges and opportunities ahead of their clinical translation.

Early Diagnosis of CNS Virus Infections from Neurological Autoimmune Diseases: A Cross-Sectional Study from China in ER Setting.

It is challenging to differentiate between central nervous system (CNS) virus infections and neurological autoimmune diseases in the emergency department. Considering their different pathogenesis, we assume they differ in neuropsychiatric symptoms and laboratory results. A total of 80 patients were included in this study, 50 with CNS virus infections and 30 with CNS autoimmune diseases, confirmed by a polymerase chain reaction (PCR) of cerebrospinal fluid (CSF). A binary logistic regression model and receiver operating characteristic (ROC) curve were employed to examine the discrimination between the two types of diseases based on neuropsychiatric symptoms and laboratory results. Compared to patients with neurological autoimmune diseases, patients with CNS virus infections had a higher incidence of abnormal behavior (p = 0.026) and abnormal sensation/thought (p = 0.029); higher total (p = 0.005), direct (p = 0.004), and indirect bilirubin (p = 0.004); and increased CSF cell (p = 0.01) and CSF white cell counts (p = 0.01). Patients with disturbance of consciousness and abnormal sensation/thought were 7.79-fold and 5.07-fold more likely to be diagnosed with CNS virus infections (OR = 7.79, p = 0.008; OR = 5.07, p = 0.032). Each unit increase in blood indirect bilirubin concentration and CSF white cell counts increased the risk of developing CNS virus infections by 1.25-fold and 1.01-fold (OR = 1.25, p = 0.016; OR = 1.01, p = 0.011). ROC analysis showed that the area under the curve was 88.0% (p < 0.001). Our study found that patients with CNS viral infections tend to have higher blood indirect bilirubin concentration, CSF leukocyte count, frequency of disorders of consciousness, and abnormal sensation and thought, which may help differentiate them from those with neurological autoimmune diseases.

The EBV connection: a severe case of GFAP-A with central hypoventilation unresponsive to IVIG and literature review

PurposeGlial fibrillary acidic protein astrocytopathy (GFAP-A) pathogenesis remains uncertain, with potential viral involvement. More clinical cases are needed to deepen our understanding of this disease, along with the exploration of more effective treatment options to provide clinicians with additional choices.MethodsWe report a severe case of GFAP-A secondary to EBV infection, characterized predominantly by central respiratory failure. Additionally, we conducted a literature review summarizing the characteristics of GFAP-IgG-positive patients associated with EBV infection.ResultsAmong the 13 patients identified, fever (92.3%) and headache (84.6%) were the most common initial symptoms, while urinary dysfunction was universally present in all patients. Over half of the patients with altered consciousness required endotracheal intubation (7/11, 63.6%), with only one individual experiencing complete resolution without any residual sequela. Only two patients (16.7%) displayed the classic feature of periventricular enhancement on neuroimaging, whereas T2-FLAIR hyperintensities were more prevalent. All patients tested positive for GFAP-IgG in CSF, and 91.7% (11/12) had detectable serum GFAP-IgG antibodies. Three patients (23.1%) achieved full recovery solely through antiviral therapy. In patients receiving various immunotherapies, 60% (6/10) still had residual sequelae.ConclusionEBV infection may contribute to the pathogenesis of GFAP-A. GFAP antibody testing is recommended for diagnostic evaluation in cases of central nervous system viral infections presenting with respiratory insufficiency. For severe GFAP-A patients, Protein A immunoadsorption (Protein A IA).

LC-MS metabolomics and lipidomics in cerebrospinal fluid from viral and bacterial CNS infections: a review.

There is compelling evidence that a dysregulated immune inflammatory response in neuroinfectious diseases results in modifications in metabolic processes and altered metabolites, directly or indirectly influencing lipid metabolism within the central nervous system (CNS). The challenges in differential diagnosis and the provision of effective treatment in many neuroinfectious diseases are, in part, due to limited understanding of the pathophysiology underlying the disease. Although there are numerous metabolomics studies, there remains a deficit in neurolipidomics research to provide a comprehensive understanding of the connection between altered metabolites and changes in lipid metabolism. The brain is an inherently high-lipid organ; hence, understanding neurolipidomics is the key to future breakthroughs. This review aims to provide an integrative summary of altered cerebrospinal fluid (CSF) metabolites associated with neurolipid metabolism in bacterial and viral CNS infections, with a particular focus on studies that used liquid chromatography-mass spectrometry (LC-MS). Lipid components (phospholipids) and metabolites (carnitine and tryptophan) appear to be the most significant indicators in both bacterial and viral infections. On the basis of our analysis of the literature, we recommend employing neurolipidomics in conjunction with existing neurometabolomics data as a prospective method to enhance our understanding of the cross link between dysregulated metabolites and lipid metabolism in neuroinfectious diseases.

Targeted metabolomics identifies accurate CSF metabolite biomarkers for the differentiation between COVID-19 with neurological involvement and CNS infections with neurotropic viral pathogens

BackgroundCOVID-19 is primarily considered a respiratory tract infection, but it can also affect the central nervous system (CNS), which can result in long-term sequelae. In contrast to CNS infections by classic neurotropic viruses, SARS-CoV-2 is usually not detected in cerebrospinal fluid (CSF) from patients with COVID-19 with neurological involvement (neuro-COVID), suggesting fundamental differences in pathogenesis.MethodsTo assess differences in CNS metabolism in neuro-COVID compared to CNS infections with classic neurotropic viruses, we applied a targeted metabolomic analysis of 630 metabolites to CSF from patients with (i) COVID-19 with neurological involvement [n = 16, comprising acute (n = 13) and post-COVID-19 (n = 3)], (ii) viral meningitis, encephalitis, or myelitis (n = 10) due to herpes simplex virus (n = 2), varicella zoster virus (n = 6), enterovirus (n = 1) and tick-borne encephalitis virus (n = 1), and (iii) aseptic neuroinflammation (meningitis, encephalitis, or myelitis) of unknown etiology (n = 21) as additional disease controls.ResultsStandard CSF parameters indicated absent or low neuroinflammation in neuro-COVID. Indeed, CSF cell count was low in neuro-COVID (median 1 cell/µL, range 0–12) and discriminated it accurately from viral CNS infections (AUC = 0.99) and aseptic neuroinflammation (AUC = 0.98). 32 CSF metabolites passed quality assessment and were included in the analysis. Concentrations of differentially abundant (fold change ≥|1.5|, FDR ≤ 0.05) metabolites were both higher (9 and 5 metabolites) and lower (2 metabolites) in neuro-COVID than in the other two groups. Concentrations of citrulline, ceramide (d18:1/18:0), and methionine were most significantly elevated in neuro-COVID. Remarkably, triglyceride TG(20:1_32:3) was much lower (mean fold change = 0.09 and 0.11) in neuro-COVID than in all viral CNS infections and most aseptic neuroinflammation samples, identifying it as highly accurate biomarker with AUC = 1 and 0.93, respectively. Across all samples, TG(20:1_32:3) concentration correlated only moderately with CSF cell count (ρ = 0.65), protein concentration (ρ = 0.64), and Q-albumin (ρ = 0.48), suggesting that its low levels in neuro-COVID CSF are only partially explained by less pronounced neuroinflammation.ConclusionsThe results suggest that CNS metabolite responses in neuro-COVID differ fundamentally from viral CNS infections and aseptic neuroinflammation and may be used to discover accurate diagnostic biomarkers in CSF and to gain insights into differences in pathophysiology between neuro-COVID, viral CNS infections and aseptic neuroinflammation.

Subacute sclerosing panencephalitis with a fulminant course: Case series

ABSTRACT Subacute sclerosing panencephalitis (SSPE) is a life-threatening and delayed complication of measles. It may rarely follow a fulminant course, with rapid progression to a vegetative state. There have been case reports of this challenging and aggressive form of SSPE in previously immunised children. The cause of the rapid progression in many patients is unknown. However, it is postulated that genetically determined immune dysfunction can prevent cell-mediated immune clearance of the measles virus. This was a retrospective study of five patients who presented with clinical features and laboratory investigations suggestive of fulminant SSPE over the previous year. The diagnosis of SSPE was established using Radermecker’s complexes in electroencephalogram, encephalitis on brain magnetic resonance imaging and elevated titres of immunoglobulin (Ig) M and IgG measles antibodies in the serum and cerebrospinal fluid. Treatment included isoprinosine, intravenous Igs, sodium valproate, levetiracetam and clobazam. The outcome was dismal in all patients, with progression to a bedridden state despite timely intervention. In our series of five cases, the diagnosis of SSPE was often missed because the children were immunised and healthy before the onset of symptoms. However, after excluding other central nervous system viral infections, the clinical presentation and laboratory findings corroborated the fulminant course of SSPE. This article captures the presentation and outcomes of five patients and emphasises the importance of clinicians’ awareness of this condition.

Role of inflammatory cytokine burst in neuro-invasion of Japanese Encephalitis virus infection: an immunotherapeutic approaches.

Japanese Encephalitis remains a significant global health concern, contributing to millions of deaths annually worldwide. Microglial cells, as key innate immune cells within the central nervous system (CNS), exhibit intricate cellular structures and possess molecular phenotypic plasticity, playing pivotal roles in immune responses during CNS viral infections. Particularly under viral inflammatory conditions, microglial cells orchestrate innate and adaptive immune responses to mitigate viral invasion and dampen inflammatory reactions. This review article comprehensively summarizes the pathophysiology of viral invasion into the CNS and the cellular interactions involved, elucidating the roles of various immune mediators, including pro-inflammatory cytokines, in neuroinflammation. Leveraging this knowledge, strategies for modulating inflammatory responses and attenuating hyperactivation of glial cells to mitigate viral replication within the brain are discussed. Furthermore, current chemotherapeutic and antiviral drugs are examined, elucidating their mechanisms of action against viral replication. This review aims to provide insights into therapeutic interventions for Japanese Encephalitis and related viral infections, ultimately contributing to improved outcomes for affected individuals.

Astrocytic RIPK3 exerts protective anti-inflammatory activity during viral encephalitis via induction of serpin protease inhibitors.

Flaviviruses pose a significant threat to public health due to their ability to infect the central nervous system (CNS) and cause severe neurologic disease. Astrocytes play a crucial role in the pathogenesis of flavivirus encephalitis through their maintenance of blood-brain barrier (BBB) integrity and their modulation of immune cell recruitment and activation within the CNS. We have previously shown that receptor interacting protein kinase-3 (RIPK3) is a central coordinator of neuroinflammation during CNS viral infection, a function that occurs independently of its canonical function in inducing necroptotic cell death. To date, however, roles for necroptosis-independent RIPK3 signaling in astrocytes are poorly understood. Here, we use mouse genetic tools to induce astrocyte-specific deletion, overexpression, and chemogenetic activation of RIPK3 to demonstrate an unexpected anti-inflammatory function for astrocytic RIPK3. RIPK3 activation in astrocytes was required for host survival in multiple models of flavivirus encephalitis, where it restricted neuropathogenesis by limiting immune cell recruitment to the CNS. Transcriptomic analysis revealed that, despite inducing a traditional pro-inflammatory transcriptional program, astrocytic RIPK3 paradoxically promoted neuroprotection through the upregulation of serpins, endogenous protease inhibitors with broad immunomodulatory activity. Notably, intracerebroventricular administration of SerpinA3N in infected mice preserved BBB integrity, reduced leukocyte infiltration, and improved survival outcomes in mice lacking astrocytic RIPK3. These findings highlight a previously unappreciated role for astrocytic RIPK3 in suppressing pathologic neuroinflammation and suggests new therapeutic targets for the treatment of flavivirus encephalitis.

Resiquimod Induces C-C Motif Chemokine Ligand 2 Via Nuclear Factor-Kappa B in SH-SY5Y Human Neuroblastoma Cells.

Toll-like receptor (TLR) 7 plays an important role in recognizing virus-derived nucleic acids. TLR7 signaling in astrocytes and microglia is critical for activating immune responses against neurotrophic viruses. Neurons express TLR7, similar to glial cells; however, the role of neuronal TLR7 has not yet been fully elucidated. This study sought to determine whether resiquimod, the TLR7/8 agonist, induces the expression of inflammatory chemokines in SH-SY5Y human neuroblastoma cells. Immunofluorescence microscopy revealed that TLR7 was constitutively expressed in SH-SY5Y cells. Stimulation with resiquimod induced C-C motif chemokine ligand 2 (CCL2) expression, accompanied by the activation of nuclear factor-kappa B (NF-κB) in SH-SY5Y cells. Resiquimod increased mRNA levels of C-X-C motif chemokine ligand 8 (CXCL8) and CXCL10, while the increase was slight at the protein level. Knockdown of NF-κB p65 eliminated resiquimod-induced CCL2 production. This study provides novel evidence that resiquimod has promising therapeutic potential against central nervous system viral infections through its immunostimulatory effects on neurons.

CNS Viral Infections-What to Consider for Improving Drug Treatment: A Plea for Using Mathematical Modeling Approaches.

Neurotropic viruses may cause meningitis, myelitis, encephalitis, or meningoencephalitis. These inflammatory conditions of the central nervous system (CNS) may have serious and devastating consequences if not treated adequately. In this review, we first summarize how neurotropic viruses can enter the CNS by (1) crossing the blood-brain barrier or blood-cerebrospinal fluid barrier; (2) invading the nose via the olfactory route; or (3) invading the peripheral nervous system. Neurotropic viruses may then enter the intracellular space of brain cells via endocytosis and/or membrane fusion. Antiviral drugs are currently used for different viral CNS infections, even though their use and dosing regimens within the CNS, with the exception of acyclovir, are minimally supported by clinical evidence. We therefore provide considerations to optimize drug treatment(s) for these neurotropic viruses. Antiviral drugs should cross the blood-brain barrier/blood cerebrospinal fluid barrier and pass the brain cellular membrane to inhibit these viruses inside the brain cells. Some antiviral drugs may also require intracellular conversion into their active metabolite(s). This illustrates the need to better understand these mechanisms because these processes dictate drug exposure within the CNS that ultimately determine the success of antiviral drugs for CNS infections. Finally, we discuss mathematical model-based approaches for optimizing antiviral treatments. Thereby emphasizing the potential of CNS physiologically based pharmacokinetic models because direct measurement of brain intracellular exposure in living humans faces ethical restrictions. Existing physiologically based pharmacokinetic models combined with in vitro pharmacokinetic/pharmacodynamic information can be used to predict drug exposure and evaluate efficacy of antiviral drugs within the CNS, to ultimately optimize the treatments of CNS viral infections.

Slc43a2+ T cell metastasis from spleen to brain in RGNNV infected teleost.

The origin of T cells in the teleost's brain is unclear. While viewing the central nervous system (CNS) as immune privileged has been widely accepted, previous studies suggest that T cells residing in the thymus but not in the spleen of the teleost play an essential role in communicating with the peripheral organs. Here, we identified nine T cell subpopulations in the thymus and spleen of orange-spotted grouper (Epinephelus coioices) through single-cell RNA-sequencing analysis. After viral CNS infection with red-spotted grouper nervous necrosis virus (RGNNV), the number of slc43a2+ T cells synchronously increased in the spleen and brain. During the infection tests in asplenic zebrafish (tlx1▲ zebrafish model), no increase in the number of slc43a2+ T cells was observed in the brain. Single-cell transcriptomic analysis indicated that slc43a2+ T cells mature and functionally differentiate within the spleen and then migrate into the brain to trigger an immune response. This study suggests a novel route for T cell migration from the spleen to the brain during viral infection in fish.

The Contribution of Microglia and Brain-Infiltrating Macrophages to the Pathogenesis of Neuroinflammatory and Neurodegenerative Diseases during TMEV Infection of the Central Nervous System.

The infection of the central nervous system (CNS) with neurotropic viruses induces neuroinflammation and is associated with the development of neuroinflammatory and neurodegenerative diseases, including multiple sclerosis and epilepsy. The activation of the innate and adaptive immune response, including microglial, macrophages, and T and B cells, while required for efficient viral control within the CNS, is also associated with neuropathology. Under healthy conditions, resident microglia play a pivotal role in maintaining CNS homeostasis. However, during pathological events, such as CNS viral infection, microglia become reactive, and immune cells from the periphery infiltrate into the brain, disrupting CNS homeostasis and contributing to disease development. Theiler's murine encephalomyelitis virus (TMEV), a neurotropic picornavirus, is used in two distinct mouse models: TMEV-induced demyelination disease (TMEV-IDD) and TMEV-induced seizures, representing mouse models of multiple sclerosis and epilepsy, respectively. These murine models have contributed substantially to our understanding of the pathophysiology of MS and seizures/epilepsy following viral infection, serving as critical tools for identifying pharmacological targetable pathways to modulate disease development. This review aims to discuss the host-pathogen interaction during a neurotropic picornavirus infection and to shed light on our current understanding of the multifaceted roles played by microglia and macrophages in the context of these two complexes viral-induced disease.

Diagnostic accuracy of clinical and laboratory characteristics in suspected non-surgical nosocomial central nervous system infections

BackgroundThe diagnosis of meningitis in nonsurgical hospitalised patients is often difficult and diagnostic accuracy of clinical, laboratory, and radiological characteristics is unknown. MethodsIn a prospective multi-centre cohort study in the Netherlands with adults suspected of central nervous system (CNS) infections, we included consecutive patients who underwent a lumbar puncture for the suspicion of a nonsurgical nosocomial CNS infection. All episodes were categorized into five final clinical diagnosis categories, as reference standard: CNS infection, CNS inflammatory disease, systemic infection, other neurological disease, or non-systemic, non-neurological disease. Diagnostic accuracy of clinical characteristics, the index test, was assessed by determining sensitivity, specificity, and positive and negative predictive values (PPV; NPV). ResultsBetween 2012-2022, 114 of 1275 (9%) patients included in the cohort had suspected nonsurgical nosocomial CNS infection. Sixteen (14%) patients had a confirmed diagnosis of nonsurgical nosocomial CNS infection, including 4 (25%) with bacterial meningitis, 9 (56%) with viral CNS infections, 2 (13%) fungal meningitis and 1 (6%) parasitic meningitis. Diagnostic accuracy of individual clinical characteristics was generally low. Elevated CSF leukocyte count had the highest sensitivity (81%; 95% CI 54-96) and NPV (96%; 95% CI 90-99). When combining the presence of abnormalities in neurological or CSF examination, sensitivity for diagnosing a CNS infection was 100% (95% CI 79-100) and NPV 100% (95% CI 78-100). CSF examination changed clinical management in 47% of patients. ConclusionOf patients suspected of nonsurgical nosocomial CNS infections, 14% were diagnosed with such infections. Diagnostic accuracy for individual clinical characteristics was low, with elevated CSF leukocyte count having the highest sensitivity and NPV.

Contribution of microglia/macrophage to the pathogenesis of TMEV infection in the central nervous system.

The infection of the central nervous system (CNS) with neurotropic viruses induces neuroinflammation and an immune response, which is associated with the development of neuroinflammatory and neurodegenerative diseases, including multiple sclerosis (MS). The activation of both innate and adaptive immune responses, involving microglia, macrophages, and T and B cells, while required for efficient viral control within the CNS, is also associated with neuropathology. Under pathological events, such as CNS viral infection, microglia/macrophage undergo a reactive response, leading to the infiltration of immune cells from the periphery into the brain, disrupting CNS homeostasis and contributing to the pathogenesis of disease. The Theiler's murine encephalomyelitis virus (TMEV)-induced demyelination disease (TMEV-IDD), which serves as a mouse model of MS. This murine model made significant contributions to our understanding of the pathophysiology of MS following subsequent to infection. Microglia/macrophages could be activated into two different states, classic activated state (M1 state) and alternative activated state (M2 state) during TMEV infection. M1 possesses the capacity to initiate inflammatory response and secretes pro-inflammatory cytokines, and M2-liked microglia/macrophages are anti-inflammatory characterized by the secretion of anti-inflammatory cytokines. This review aims to discuss the roles of microglia/macrophages M1/M2-liked polarization during TMEV infection, and explore the potential therapeutic effect of balancing M1/M2-liked polarization of microglia/macrophages on MS.

Meningitis a Listeria monocytogenes in a young, immunocompetent male

Listeria Monocytogenes (LM) is a gram-positive intracellular pathogen usually transmitted to humans by ingesting contaminated food. It typically infects immunocompromised individuals, such as pregnant women, newborns, alcoholics, and the elderly. LM is a rare cause of meningitis in immunocompetent, healthy adults. However, its clinical presentation is similar to that of other viral or bacterial central nervous system infections and its course can be rapid and aggressive. Physicians should therefore always consider LM as a possible etiologic agent of meningitis, especially in cases that do not respond to first-line empiric antibiotic therapy. We report a case of Listeria Monocytogenes meningitis in a previously healthy 16-year-old.

The Role of Varicella Zoster Virus (VZV) in Central Nervous System Infectious Syndromes

Background: We describe the proportion of VZV infection in central nervous system (CNS) infectious syndromes in a single Israeli medical center.Methods: An observational cohort study was conducted in Kaplan Medical Center (a secondary hospital, Israel) between July 1, 2014, and March 31, 2019. Included were adult patients (≥ 16 years old) with CNS infection with an aseptic CSF profile that were subjected to molecular tests for herpes viruses, HSV either 1 or 2, VZV, enteroviruses, and IgM for West Nile virus (WNV).Results: Clinical presentation suggestive of CNS infection led to lumbar puncture and CSF analysis in 1500 patients yielding 178 cases with aseptic CSF profile. For 62/109 (55.9%) cases of meningitis, the etiology remained unknown, enterovirus accounted for 21 cases (18.9%), VZV for 16 (14.4%), and HSV 1 for 7 (6.3%). One case each of bacterial, fungal, and parainfluenza virus accounted for the other 3 cases. For 30/63 (47.6%) cases of encephalitis, the etiology remained unknown, HSV accounted for 11 cases (17.5%), VZV for 8 (12.7%), and WNV for 10 (15.9%); in two cases, enterovirus was identified and one case of influenza A and one of mycoplasma, accounted for the rest. In six patients with myelitis VZV was identified in 4 (66.7%). Notably, a typical herpetic rash was identified in only 11/28 (39.28%) of cases of VZV CNS infection.Conclusions: VZV is a significant cause of viral CNS infections. In the majority of patients with neurologic syndrome and evident VZV there is no association with a typical herpetic rash. These results apply to Israeli population and likely to other populations with similar background of VZV past infections.

Metagenomic next-generation sequencing of cell-free DNA for the identification of viruses causing central nervous system infections.

This study provides significant new data on the application of metagenomic next-generation sequencing (mNGS) to clinical diagnostics of central nervous system (CNS) viral infections, which can have high mortality rates and severe sequelae. Conventional diagnostic procedures for identifying viruses can be inefficient and rely on preconceived assumptions about the pathogen, making mNGS an appealing alternative. However, the effectiveness of mNGS is affected by the presence of human DNA contamination, which can be minimized by using cell-free DNA (cfDNA) instead of whole-cell DNA (wcDNA). This multi-center retrospective study of patients with suspected viral CNS infection found that mNGS using cfDNA had a significantly lower proportion of human DNA and higher sensitivity for detecting viruses than mNGS using wcDNA. Herpesviruses, particularly VZV, were found to be the most common DNA viruses in these patients. Overall, mNGS using cfDNA is a promising complementary diagnostic method for detecting CNS viral infections.

Laboratory diagnosis of CNS infections in children due to emerging and re-emerging neurotropic viruses.

Recent decades have witnessed the emergence and re-emergence of numerous medically important viruses that cause central nervous system (CNS) infections in children, e.g., Zika, West Nile, and enterovirus/parechovirus. Children with immature immune defenses and blood-brain barrier are more vulnerable to viral CNS infections and meningitis than adults. Viral invasion into the CNS causes meningitis, encephalitis, brain imaging abnormalities, and long-term neurodevelopmental sequelae. Rapid and accurate detection of neurotropic viral infections is essential for diagnosing CNS diseases and setting up an appropriate patient management plan. The addition of new molecular assays and next-generation sequencing has broadened diagnostic capabilities for identifying infectious meningitis/encephalitis. However, the expansion of test menu has led to new challenges in selecting appropriate tests and making accurate interpretation of test results. There are unmet gaps in development of rapid, sensitive and specific molecular assays for a growing list of emerging and re-emerging neurotropic viruses. Herein we will discuss the advances and challenges in the laboratory diagnosis of viral CNS infections in children. This review not only sheds light on selection and interpretation of a suitable diagnostic test for emerging/re-emerging neurotropic viruses, but also calls for more research on development and clinical utility study of novel molecular assays. IMPACT: Children with immature immune defenses and blood-brain barrier, especially neonates and infants, are more vulnerable to viral central nervous system infections and meningitis than adults. The addition of new molecular assays and next-generation sequencing has broadened diagnostic capabilities for identifying infectious meningitis and encephalitis. There are unmet gaps in the development of rapid, sensitive and specific molecular assays for a growing list of emerging and re-emerging neurotropic viruses.

Central nervous system infection in a pediatric population in West Java.

Central nervous system (CNS) viral infections are critical causes of morbidity and mortality in children; however, comprehensive data on etiology is lacking in developing countries such as Indonesia. To study the etiology of CNS infections in a pediatric population, 50 children admitted to two hospitals in Bandung, West Java, during 2017-2018 were enrolled in a CNS infection study. Cerebrospinal fluid and serum specimens were tested using molecular, serological, and virus isolation platforms for a number of viral and bacteriological agents. Causal pathogens were identified in 10 out of 50 (20%) and included cytomegalovirus (n = 4), Streptococcus pneumoniae (n = 2), tuberculosis (n = 2), Salmonella serotype Typhi (n = 1) and dengue virus (n = 1). Our study highlights the importance of using a wide range of molecular and serological detection methods to identify CNS pathogens, as well as the challenges of establishing the etiology of CNS infections in pediatric populations of countries with limited laboratory capacity.