Lipid droplets in Zika neuroinfection: Potential targets for intervention?

Lipid droplets (LD) are evolutionarily conserved lipid-enriched organelles with a diverse array of cell- and stimulus-regulated proteins. Accumulating evidence demonstrates that intracellular pathogens exploit LD as energy sources, replication sites, and part of the mechanisms of immune evasion. Nevertheless, LD can also favor the host as part of the immune and inflammatory response to pathogens. The functions of LD in the central nervous system have gained great interest due to their presence in various cell types in the brain and for their suggested involvement in neurodevelopment and neurodegenerative diseases. Only recently have the roles of LD in neuroinfections begun to be explored. Recent findings reveal that lipid remodelling and increased LD biogenesis play important roles for Zika virus (ZIKV) replication and pathogenesis in neural cells. Moreover, blocking LD formation by targeting DGAT-1 in vivo inhibited virus replication and inflammation in the brain. Therefore, targeting lipid metabolism and LD biogenesis may represent potential strategies for anti-ZIKV treatment development. Here, we review the progress in understanding LD functions in the central nervous system in the context of the host response to Zika infection.

An In Vivo Model of Echovirus-Induced Meningitis Defines the Differential Roles of Type I and Type III Interferon Signaling in Central Nervous System Infection.

Echoviruses are among the most common worldwide causes of aseptic meningitis, which can cause long-term sequelae and death, particularly in neonates. However, the mechanisms by which these viruses induce meningeal inflammation are poorly understood, owing at least in part to the lack of in vivo models that recapitulate this aspect of echovirus pathogenesis. Here, we developed an in vivo neonatal mouse model that recapitulates key aspects of echovirus-induced meningitis. We show that expression of the human homologue of the primary echovirus receptor, the neonatal Fc receptor (FcRn), is not sufficient for infection of the brains of neonatal mice. However, ablation of type I, but not III, interferon (IFN) signaling in mice expressing human FcRn permitted high levels of echovirus replication in the brain, with corresponding clinical symptoms, including delayed motor skills and hind-limb weakness. Using this model, we defined the immunological response of the brain to echovirus infection and identified key cytokines, such as granulocyte colony-stimulating factor (G-CSF) and interleukin 6 (IL-6), that were induced by this infection. Lastly, we showed that echoviruses specifically replicate in the leptomeninges, where they induce profound inflammation and cell death. Together, this work establishes an in vivo model of aseptic meningitis associated with echovirus infections that delineates the differential roles of type I and type III IFNs in echovirus-associated neuronal disease and defines the specificity of echoviral infections within the meninges. IMPORTANCE Echoviruses are among the most common worldwide causes of aseptic meningitis, which can cause long-term sequelae or even death. The mechanisms by which echoviruses infect the brain are poorly understood, largely owing to the lack of robust in vivo models that recapitulate this aspect of echovirus pathogenesis. Here, we establish a neonatal mouse model of echovirus-induced aseptic meningitis and show that expression of the human homologue of the FcRn, the primary receptor for echoviruses, and ablation of type I IFN signaling are required to recapitulate echovirus-induced meningitis and clinical disease. These findings provide key insights into the host factors that control echovirus-induced meningitis and a model that could be used to test anti-echovirus therapeutics.

Non-cell autonomous astrocyte-mediated neuronal toxicity in prion diseases.

Under normal conditions, astrocytes perform a number of important physiological functions centered around neuronal support and synapse maintenance. In neurodegenerative diseases including Alzheimer's, Parkinson's and prion diseases, astrocytes acquire reactive phenotypes, which are sustained throughout the disease progression. It is not known whether in the reactive states associated with prion diseases, astrocytes lose their ability to perform physiological functions and whether the reactive states are neurotoxic or, on the contrary, neuroprotective. The current work addresses these questions by testing the effects of reactive astrocytes isolated from prion-infected C57BL/6J mice on primary neuronal cultures. We found that astrocytes isolated at the clinical stage of the disease exhibited reactive, pro-inflammatory phenotype, which also showed downregulation of genes involved in neurogenic and synaptogenic functions. In astrocyte-neuron co-cultures, astrocytes from prion-infected animals impaired neuronal growth, dendritic spine development and synapse maturation. Toward examining the role of factors secreted by reactive astrocytes, astrocyte-conditioned media was found to have detrimental effects on neuronal viability and synaptogenic functions via impairing synapse integrity, and by reducing spine size and density. Reactive microglia isolated from prion-infected animals were found to induce phenotypic changes in primary astrocytes reminiscent to those observed in prion-infected mice. In particular, astrocytes cultured with reactive microglia-conditioned media displayed hypertrophic morphology and a downregulation of genes involved in neurogenic and synaptogenic functions. In summary, the current study provided experimental support toward the non-cell autonomous mechanisms behind neurotoxicity in prion diseases and demonstrated that the astrocyte reactive phenotype associated with prion diseases is synaptotoxic.

Cerebral protothecosis mimicking high-grade glioma.

Prototheca wickerhamii is a common, indolent alga that seldom causes central nervous system infections in humans. We report the first UK case of cerebral protothecosis in an immunocompetent 56-year-old woman who presented with a 5-month history of intermittent fatigue followed by a 2-week history of symptoms, including right arm and leg weakness, a loss of fine motor coordination, worsening gait, right facial tingling, diplopia and a metallic oral taste. MRI scans revealed a multifocal abnormality suggestive of high-grade glioma. Given the clinical presentation, absence of immunodeficiency and characteristic MRI features, a diagnosis of high-grade glioma was deemed most likely by the multidisciplinary team. Surgical biopsy provided material for histopathological and microbiological diagnosis. She underwent a 2-year course of antimicrobials with surveillance MRI scans. The patient made a good functional recovery but still retains mild neurological sequelae.

Nontraumatic coma in the pediatric intensive care unit: etiology, clinical characteristics and outcome

Background/aim: The purpose of this study was to evaluate the etiology, clinical characteristics, and outcome of nontraumatic coma (NTC) among children admitted to a pediatric intensive care unit (PICU). Materials and methods: A total of 159 children with NTC were included in the study. The modified Glasgow coma scale (GCS) was used to assess consciousness. Patients were classified with regard to etiology. For each patient, demographic and clinical characteristics, survival and degree of disability at PICU discharge were recorded. Results: Median age was 55 months (IQR: 17.0 - 109.0). The most common cause of NTC was neuroinfection (31.4%) followed by toxic- metabolic conditions (25.8%) and epileptic disorder (15.1%). There was no significant relationship between the level of encephalopathy at admission and NTC etiology. A total of 13 patients died (8.2%). Among the survivors, 61.6% were discharged without any neurologic deficit, 2.8% had severe neurologic disability, and 3.4% were in a vegetative state. Complete neurological recovery was significantly more common in patients with toxic metabolic disease, whereas neurological deficits were more frequent in patients with tuberculous meningo-encephalitis (P = 0.01 and P = 0.04, respectively). Higher pediatric risk of mortality III (PRISM III) score at PICU admission (Odds ratio: 1.51, 95% CI: 1.19 - 1.92; P < 0.001) was the only variable that was independently associated with mortality. The length of stay (LOS) at hospital (Odds ratio: 0.73, 95% CI: 0.58-0.91; P = 0.006) was associated with improved odds of survival. Conclusions: Although results obtained from this single-center study cannot be generalized to the pediatric population, the contribution to the literature in terms of the relationships between NTC etiology, and outcome can be crucial for clinical decision-making. We report neuroinfection as the most common cause of NTC, and the only factor that was closely associated with mortality was PRISM III score. Length of hospital stay was inversely correlated to patient mortality.

Severe acute respiratory syndrome coronavirus 2 may be an underappreciated pathogen of the central nervous system.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes a highly contagious respiratory disease referred to as COVID-19. However, emerging evidence indicates that a small but growing number of COVID-19 patients also manifest neurological symptoms, suggesting that SARS-CoV-2 may infect the nervous system under some circumstances. SARS-CoV-2 primarily enters the body through the epithelial lining of the respiratory and gastrointestinal tracts, but under certain conditions this pleiotropic virus may also infect peripheral nerves and gain entry into the central nervous system (CNS). The brain is shielded by various anatomical and physiological barriers, most notably the blood-brain barrier (BBB) which functions to prevent harmful substances, including pathogens and pro-inflammatory mediators, from entering the brain. The BBB is composed of highly specialized endothelial cells, pericytes, mast cells and astrocytes that form the neurovascular unit, which regulates BBB permeability and maintains the integrity of the CNS. In this review, potential routes of viral entry and the possible mechanisms utilized by SARS-CoV-2 to penetrate the CNS, either by disrupting the BBB or infecting the peripheral nerves and using the neuronal network to initiate neuroinflammation, are briefly discussed. Furthermore, the long-term effects of SARS-CoV-2 infection on the brain and in the progression of neurodegenerative diseases known to be associated with other human coronaviruses are considered. Although the mechanisms of SARS-CoV-2 entry into the CNS and neurovirulence are currently unknown, the potential pathways described here might pave the way for future research in this area and enable the development of better therapeutic strategies.

Clinical time course of COVID-19, its neurological manifestation and some thoughts on its management.

Coronavirus disease-2019 (COVID-19) has become a global pandemic. COVID-19 runs its course in two phases, the initial incubation phase and later clinical symptomatic phase. Patients in the initial incubation phase often have insidious clinical symptoms, but they are still highly contagious. At the later clinical symptomatic phase, the immune system is fully activated and the disease may enter the severe infection stage in this phase. Although many patients are known for their respiratory symptoms, they had neurological symptoms in their first 1-2 days of clinical symptomatic phase, and ischaemic stroke occurred 2 weeks after the onset of the clinical symptomatic phase. The key is to prevent a patient from progressing to this severe infection from mild infection. We are sharing our experience on prevention and management of COVID-19.

Consensus for prevention and management of coronavirus disease 2019 (COVID-19) for neurologists.

Coronavirus disease 2019 (COVID-19) has become a pandemic disease globally. Although COVID-19 directly invades lungs, it also involves the nervous system. Therefore, patients with nervous system involvement as the presenting symptoms in the early stage of infection may easily be misdiagnosed and their treatment delayed. They become silent contagious sources or 'virus spreaders'. In order to help neurologists to better understand the occurrence, development and prognosis, we have developed this consensus of prevention and management of COVID-19. It can also assist other healthcare providers to be familiar with and recognise COVID-19 in their evaluation of patients in the clinic and hospital environment.

CNS Infections in Immunoincompetent Patients : Neuroradiological and Clinical Features.

In patients with immunodeficiency the pathogen spectrum of central nervous system (CNS) infections is broader and different from that of immunocompetent patients. Numerous opportunistic infections are characterized by a high prevalence of viral, bacterial and parasitic pathogens, and depend on the type of impaired immune defense, for example impaired T­cell or monocyte function, monoclonal antibody treatment, and impaired granulocyte function. Neuroradiological features as well as laboratory findings are often different and versatile in comparison to immunocompetent individuals and pathognomonic imaging findings do not exist; however, knowledge of possible pathways of pathogens in the CNS and preferred tissue affection may help in narrowing down differential diagnoses. Therefore, knowledge of the type of patient and the performed immunomodulatory therapy is essential for the neuroradiological assessment and the differential diagnostic considerations. Moreover, parenchymal reactions in the sense of an immune reconstitution inflammatory syndrome (IRIS) can occur when immunocompetence is restored. This review focus on the most common pathologies in immunocompromised patients, and an overview of imaging features but also of pathology and clinical aspects is given. The synopsis of anamnestic information, clinical findings and structured analysis of the lesion pattern, its spread and short-term follow-up may increase the correct diagnostic classification; however, the gold standard is still determination of the pathogen in the cerebrospinal fluid (CSF), blood cultures or biopsies.

Parkinsonism in autoimmune diseases.

Parkinsonism can be manifested and complicate either systemic or organ-specific autoimmune diseases. Even though it is a rare co-morbidity, it merits attention from clinicians as it affects the quality of life of patients. In systemic autoimmune diseases such as systemic lupus erythematosus, antiphospholipid syndrome and Sjogren's syndrome reported cases of parkinsonism are attributed to the underlying disease and its mechanisms, whether this is brain vasculitis or immune complexes. Regarding antibody-mediated autoimmune neurological disorders, parkinsonism is, in most cases, a manifestation within the spectrum of each disorder and is attributed to the action of humoral and cellular immunity in brain regions such as the basal ganglia. Depending on the pathophysiology, immunotherapy can be effective, while Parkinson's specific therapies are usually less effective.

Mechanisms of Pathogen Invasion into the Central Nervous System.

CNS infections continue to rise in incidence in conjunction with increases in immunocompromised populations or conditions that contribute to the emergence of pathogens, such as global travel, climate change, and human encroachment on animal territories. The severity and complexity of these diseases is impacted by the diversity of etiologic agents and their routes of neuroinvasion. In this review, we present historical, clinical, and molecular concepts regarding the mechanisms of pathogen invasion of the CNS. We also discuss the structural components of CNS compartments that influence pathogen entry and recent discoveries of the pathways exploited by pathogens to facilitate CNS infections. Advances in our understanding of the CNS invasion mechanisms of different neurotropic pathogens may enable the development of strategies to control their entry and deliver drugs to mitigate established infections.

Infectious causes of peripheral facial nerve palsy in children-a retrospective cohort study with long-term follow-up.

The aim of this study was to analyze the clinical and laboratory characteristics of children with peripheral facial nerve palsy (pFP) with a focus on identifying infectious etiology and long-term outcome. We conducted an ICD-10-based retrospective chart review on children hospitalized with pFP between January 1, 2006, and December 31, 2016. Furthermore, a telephone-based follow-up survey was performed. A total of 158 patients were identified, with a median age of 10.9 years (interquartile range 6.4-13.7). An infectious disease was associated with pFP in 82 patients (51.9%); 73 cases were classified as idiopathic pFP (46.2%). Three cases occurred postoperatively or due to a peripheral tumor. Among the infectious diseases, we identified 33 cases of neuroborreliosis and 12 viral infections of the central nervous system (CNS), caused by the varicella-zoster virus, human herpesvirus 6, herpes simplex virus, enterovirus, and Epstein-Barr virus. Other infections were mainly respiratory tract infections (RTIs; 37 cases). Children with an associated CNS infection had more often headache and nuchal rigidity, a higher cerebrospinal fluid cell count, and a longer length of hospital stay. Long-term follow-up revealed an associated lower risk of relapse in CNS infection-associated pFP. Among all groups, permanent sequelae were associated with female sex, a shorter length of hospitalization, and a lower white blood cell count at presentation. pFP is frequently caused by an CNS infection or is associated with concurrent RTIs, with a potential impact on the short- and long-term clinical course.

Blood and cerebrospinal fluid characteristics in neonates with a suspected central nervous system infection.

Clinical signs and symptoms of central nervous system (CNS) infections in neonates are often nonspecific. Therefore, cerebrospinal fluid (CSF) analysis is performed to diagnose CNS infections. Data on combined microbiological results and their correlation with biochemical characteristics in CSF and blood in infants younger than 90 days are limited. This study provides an overview of microbiological test results, CSF- and hematological characteristics among infants with a clinically suspected CNS infection.This retrospective study included infants younger than 90 days, with a clinically suspected CNS infection who underwent a diagnostic lumbar puncture between January 2012 and January 2014. Data on the presence of microbiological pathogens in CSF, CSF inflammation markers (white blood cell [WBC] counts, protein levels and glucose CSF/serum ratio) and blood inflammatory responses (WBC count, C-reactive protein [CRP], neutrophil percentage) were collected by reviewing patient files.We included data from 576 infants (median age 12.5 days, interquartile range, 6-27 days) of whom 383 (66.5%) were born prematurely. In total, 16 bacterial pathogens (3.0%) and 21 viruses (5.5%) were detected in CSF. Escherichia coli was detected in 5 cases (1.0%), Enterovirus was detected in 12 cases (3.1%). Leucocytosis in CSF was associated with identification of a pathogen in CSF. Increased CRP was associated with the identification of a bacterial pathogen in CSF.Bacterial or viral pathogens were only identified in a small proportion of infants with a clinically suspected CNS infection. Leucocytosis in CSF was associated with CNS infection in infants. An increased CRP was indicative of bacterial meningitis.

Research advancements in the neurological presentation of flaviviruses.

Owing to the large-scale epidemic of Zika virus disease and its association with microcephaly, properties that allow flaviviruses to cause nervous system diseases are an important area of investigation. At present, although potential pathogenic mechanisms of flaviviruses in the nervous system have been examined, they have not been completely elucidated. In this paper, we review the possible mechanisms of blood-brain barrier penetration, the pathological effects on neurons, and the association between virus mutations and neurotoxicity. A hypothesis on neurotoxicity caused by the Zika virus is presented. Clarifying the mechanisms of virulence of flaviviruses will be helpful in finding better antiviral drugs and optimizing the treatment of symptoms.

Differences between central nervous system infection and neuropsychiatric systemic lupus erythematosus in patients with systemic lupus erythematosus.

Objective Neuropsychiatric systemic lupus erythematosus (NPSLE) is a manifestation of systemic lupus erythematosus (SLE). Central nervous system (CNS) infection is a consequence of intensive immunosuppressive therapy that patients with SLE might undergo. This study aimed to compare the differences between NPSLE and CNS infections in patients with SLE. Methods Patients with SLE and NPSLE or CNS infections were retrospectively reviewed. Clinical manifestations, laboratory test results, and prognoses were recorded. The independent sample t-test or chi-square test was used to compare data. Results Patients with CNS infections (n = 20) had more serious headache, high fever (>39.0°C), and vomiting compared with patients with NPSLE (n = 48). Patients with CNS infections also had a larger prednisone dose at the time of symptom onset, larger cumulative dosages over the preceding year, lower SLE Disease Activity Index (SLEDAI) scores, higher rate of nephritis, lower albumin levels, higher C-reactive protein (CRP) levels, higher 24-h-urine protein levels, higher cerebrospinal fluid (CSF) white blood cell levels, and lower protein and glucose levels than those with NPSLE. Conclusions For patients with SLE presenting with CNS symptoms, serious headache, high fever, a high dose of corticosteroids, low SLEDAI scores, and abnormal CSF are more important indicators for CNS infections than NPSLE.

Molecular mechanisms of bacterial infections of the central nervous system.

Central nervous system (CNS) infections may involve the meninges, brain and/or spinal cord. The most common etiologic agents are Streptococcus pneumoniae, group B Streptococci, Neisseria meningitidis, Haemophilus influenzae, and Listeria monocytogenes. CNS is characterized by specific structure and function. Despite a unique system of brain barriers and autonomous immune system, CNS is very susceptible to microorganisms which may invade directly, via the blood, or less frequently by reverse axonal transport. The complex process of bacteria and activated polymorphonuclear leukocyte transfer to the subarachnoid space, which is devoid of natural immune defence mechanisms, initiates an inflammatory response that subsequently spreads to the brain tissue. Consequences of these changes include damage to the blood-brain barrier, development of vasogenic cerebral oedema, and intracranial pressurevolume disturbances leading to impaired CNS perfusion.

The clinical significance of neutrophilic pleocytosis in cerebrospinal fluid in patients with viral central nervous system infections.

BACKGROUND: Viral central nervous system (CNS) infections are typically characterized by a cerebrospinal fluid (CSF) lymphocytic pleocytosis. A CSF neutrophilic pleocytosis presentation has been described, but its prognostic and clinical significance is unknown. The objectives of this study were to (1) compare the clinical and laboratory characteristics of viral CNS infections with a CSF neutrophilic pleocytosis to those with a lymphocytic pleocytosis, and (2) evaluate factors associated with an adverse clinical outcome. METHODS: A retrospective study of patients with confirmed viral CNS infections was conducted. The patients were divided into those with CSF neutrophilic pleocytosis and those with CSF lymphocytic pleocytosis. Clinical findings and outcomes were compared between the two groups. RESULTS: Of the 182 patients included in the study, 45 (24.7%) had CSF neutrophilic pleocytosis. Enterovirus infections were the cause of 64% of neutrophil-predominant CSF and 33% of lymphocyte-predominant CSF (p<0.001), while herpes infections were the cause of 46% of lymphocytic pleocytosis and 20% of neutrophilic pleocytosis (p=0.003). Moreover, neutrophilic pleocytosis was seen more commonly in younger patients (p=0.001), patients with respiratory symptoms (p=0.04), and patients with higher CSF white cell counts (p=0.004). Twenty-nine patients had an adverse clinical outcome (15.9%); the only predictor independently associated with an adverse clinical outcome on multivariable logistic regression analysis was an encephalitis presentation (p=0.01). CONCLUSIONS: The results of a study exploring the association between CSF neutrophilic pleocytosis and clinical and prognostic significance are presented here. This study suggests that CSF neutrophilic pleocytosis is not associated with higher adverse clinical outcomes.