Severe Central Nervous System Infection Research Articles

Frequency of Meningococcal Meningitis Susceptibility Associated TLR4 +896 A/G (rs4986790) Allele in the Saudi Population

Meningococcal meningitis (MM) is a severe central nervous system (CNS) infection that occurs primarily in children. MM can damage brain areas associated with hearing, learning, reasoning, focus, and memory. Genetic changes, including single nucleotide polymorphisms (SNPs), which compromise pathogen recognition increase the risk and severity of MM. There is little data on how the variation in the frequency of the rs4986790 polymorphism in the Toll-like receptor 4 (TLR4) gene may affect the population of Saudi Arabia. This study sought to determine the allelic frequency and distribution of the TLR4 rs4986790 A/G polymorphism in the Saudi population and compare the data to other global populations. Data from epidemiological studies conducted in various ethnic groups were extracted using PUBMED (Medline) and similar web databases. An estimated 5.88% of the Saudi population harbors the TLR4 rs4986790 G variant allele. This differed significantly from the frequencies in populations in China (p=0.0002), Japan (p=0.0001), Korea (p=0.0001), and Mexico (p=0.01). The TLR4 rs4986790 polymorphism variant allele has a unique pattern in the Saudi population, which may be the result of racial differences. These findings could assist in the risk assessment of people harboring the TLR4 +896 GG genotype susceptible to MM in the Saudi population.

Understanding global changes of the mouse brain proteome after vaginal infection with HSV-2 using a label-free shotgun approach.

Herpes simplex virus type 2 (HSV-2) is a common human pathogen that establishes lifelong latency in neurons of the nervous system. The number of severe central nervous system infections caused by the virus has increased recently. However, the pathogenesis of HSV-2 infection in the nervous system is not fully understood. Here, we demonstrated global proteomic changes in the brain tissue in BALB/c mice vaginally infected with HSV-2. Data are available via ProteomeXchange with identifier PXD034186. A total of 249 differentially expressed proteins were identified in infected brain tissue. The GO and KEGG enrichment analysis of these proteins indicated that they were mainly involved in the regulation of synapse formation and synaptic excitability. In addition, genes affecting autophagy, the development of other neurodegenerative diseases, and signaling pathways relevant to other neurologic diseases were identified. Additional experiments, comparing the brain tissue of asymptomatic and symptomatic mice showed a differential expression of proteins involved in synapse formation and synaptic transmission. Others were involved in autophagy, addiction, and signaling pathways of other neurologic diseases. These results suggest that changes in synaptic structure and function, as well as autophagy, may be related to the development of neurologic abnormalities that follow HSV-2 infection. We also identified a protein GluN2A encoded by Grin2a was continuously expressed at high levels after infection. We propose that GluN2A may be a key molecule in the pathogenesis of HSV-2-induced neurologic diseases.

Isolation and characterization of phage display-derived scFv antibodies against human parechovirus 1 VP0 protein

Human parechoviruses (PeVs) are common viruses that are associated with a variety of diseases from mild gastrointestinal and respiratory symptoms to severe central nervous system infections. Until now there has not been antibodies for visualizing parechovirus infection. We used E. coli recombinant PeV-A1-VP0 protein as a target in phage display single chain variable fragment (scFv) antibody library panning. Three rounds of panning allowed identification and isolation of several candidate scFv clones, which tested positive in enzyme-linked immunosorbent assay (ELISA) against VP0. Three scFv clones (scFv-55, -59 and -71) with different CDR-3 sequences were further purified and tested in ELISA, Western blot and immunofluorescence microscopy (IFA) against a set of PeV-A1 isolates and a few isolates representing PeV types 2–6. In IFA, all three scFv binders recognized twenty PeV-A1 isolates. ScFv-55 and -71 also recognized clinical representatives of PeV types 1–6 both in IFA and in capture ELISA, while scFv-59 only recognized PeV-A1, -A2 and -A6. PeV-A1-VP0 (Harris strain) sequence was used to generate a peptide library, which allowed identification of a putative unique conformational antibody epitope with fully conserved flanking regions and a more variable core VVTYDSKL, shared between the scFv antibodies. Sequencing of the VP0 region of virus samples and sequence comparisons against parechoviral sequences in GenBank revealed 107 PeV-A1, -A3, -A8, -A17, -A (untyped) sequences with this exact epitope core sequence, which was most dominant among PeV-A1 isolates. These data suggest the first-time isolation of broad range phage display antibodies against human parechoviruses that may be used in diagnostic antibody development.

Augmented Renal Clearance in Severe Infections-An Important Consideration in Vancomycin Dosing: A Narrative Review.

Vancomycin is a hydrophilic antibiotic widely used in severe infections, including bacteremia and central nervous system (CNS) infections caused by Gram-positive bacteria such as methicillin-resistant Staphylococcus aureus (MRSA), coagulase-negative staphylococci and enterococci. Appropriate antimicrobial dosage regimens can help achieve the target exposure and improve clinical outcomes. However, vancomycin exposure in serum and cerebrospinal fluid (CSF) is challenging to predict due to rapidly changing pathophysiological processes and patient-specific factors. Vancomycin concentrations may be decreased for peripheral infections due to augmented renal clearance (ARC) and increased distribution caused by systemic inflammatory response syndrome (SIRS), increased capillary permeability, and aggressive fluid resuscitation. Additionally, few studies on vancomycin’s pharmacokinetics (PK) in CSF for CNS infections. The relationship between exposure and clinical response is unclear, challenging for adequate antimicrobial therapy. Accurate prediction of vancomycin pharmacokinetics/pharmacodynamics (PK/PD) in patients with high interindividual variation is critical to increase the likelihood of achieving therapeutic targets. In this review, we describe the interaction between ARC and vancomycin PK/PD, patient-specific factors that influence the achievement of target exposure, and recent advances in optimizing vancomycin dosing schedules for severe infective patients with ARC.

Polymicrobial Anaerobic Meningitis Detected by Next-Generation Sequencing: Case Report and Review of the Literature

BackgroundAnaerobic meningitis is a severe central nervous system infection associated with significant neurological sequelae and high mortality. However, the precise detection of causative pathogen(s) remains difficult because anaerobic bacteria are difficult to culture. Next-generation sequencing is a technology that was developed recently and has been applied in many fields. To the best of our knowledge, the use of next-generation sequencing for cerebrospinal fluid analysis in the diagnosis of anaerobic meningitis has been rarely reported.Case presentationHere, we report a case of polymicrobial anaerobic meningitis diagnosed using next-generation sequencing of cerebrospinal fluid in a 16-year-old girl. Five species of anaerobic bacteria (Porphyromonas gingivalis, Prevotella enoeca, Campylobacter rectus, Fusobacterium uncleatum, and Actinomyces israelii) were detected by next-generation sequencing and treated with antibacterial agents (ceftriaxone, vancomycin, and metronidazole). The patient responded well to antibacterial treatment. Further inspection revealed bone destruction at the base of the skull, which further confirmed that these bacteria had originated from the oral cavity. One month later, the patient's condition improved significantly. At the same time, we performed a literature review on anaerobic meningitis using studies published in the last 20 years.ConclusionsThis case emphasizes the importance of applying metagenomic next-generation sequencing to clinch the clinical diagnosis for patients with central nervous system infection. Metagenomic next-generation sequencing has been reported to be an important diagnostic modality for identifying uncommon pathogens.

Does Tigecycline Have a Place in Therapy for Rickettsial Infection of the Central Nervous System?

This brief report documents the safety and efficacy of high-dose tigecycline as a salvage-therapy in in a case series of five patients with serious central nervous system (CNS) rocky mountain spotted fever (RMSF). These severily ill patients were unable to take any oral drug therapy, parenteral doxycycline was unavailable and absorption of oral doxycycline was a concern in these critically ill patients. As far as we know, we report the successfull use of tigecycline for the treatment of rickettsial meningitis for the first time in Italy. We suggest more studies on tigecycline in severe CNS infections from Rickettsia species and multi-drug resistant bacteria, especially the use of tigecycline at higher than standard doses in these life-threathening infectious diseases.

Parechovirus infection in infants: Evidence-based parental counselling for paediatricians.

Human parechovirus (HPeV) is an increasingly recognised cause of severe illness and central nervous system infection in infants. Medium- to long-term neurodevelopmental outcomes post-HPeV infection remain unknown. This study aims to assess neurodevelopmental outcomes for children hospitalised as infants with HPeV infection in their second and third years of life. This prospective cohort study followed children hospitalised with HPeV in Brisbane, Queensland during the 2017/2018 outbreak. Serial application of Ages and Stages Questionnaire (ASQ) was used to assess developmental progress in the second and third years of life. Data from clinical follow-up, audiology and neuroradiology were included. In the second year of life, 63% (n= 29) of children showed some or significant concerns for developmental delay. This had largely been ameliorated by the third year of life when only 30% (n= 14) reported developmental concerns. Prematurity and apnoeas were associated with developmental concerns at 27-36 months of age. Communication was the most common domain of concern. The majority of infants hospitalised with HPeV infection in 2017-2018 showed normalisation of developmental progress by 27-36 months of age. Further investigation into more subtle neurological impairments in later childhood is required. These results can help guide clinicians in counselling parents during the acute illness and in planning appropriate follow-up.

Effect of surgical treatment on prognosis in preterm infants with obstructive hydrocephalus.

To study the effect of surgical treatment on prognosis in preterm infants with obstructive hydrocephalus. A retrospective analysis was performed on the medical data of 49 preterm infants with obstructive hydrocephalus. According to the treatment regimen, they were divided into two groups: surgical treatment (n=12) and conservative treatment (n=37). The drainage methods, drainage complications, and eventual shunt outcome were analyzed in the surgical treatment group. The two groups were compared in terms of the etiology of hydrocephalus and prognosis. Among the 49 preterm infants with obstructive hydrocephalus, severe intracranial hemorrhage (37 cases; 76%) and central nervous system infection (10 cases, 20%) were the main causes of hydrocephalus. There was no significant difference in the composition of etiology between the two groups (P>0.05). In the surgical treatment group, 4 infants were treated with ventriculosubgaleal shunt and 8 were treated with Ommaya reservoir. One infant had secondary infection and 8 infants eventually underwent ventriculoperitoneal shunt. The surgical treatment group had a significantly higher survival rate than the conservative treatment group (P<0.05). As for the 37 preterm infants with severe intracranial hemorrhage, the surgical treatment group had a significantly higher proportion of infants with normal neurodevelopment than the conservative treatment group (P<0.05). As for the 10 preterm infants with central nervous system infection, neurodevelopmental abnormalities were observed in each of the two groups. Surgical treatment can improve the survival rate of preterm infants with obstructive hydrocephalus and the prognosis of preterm infants with severe intracranial hemorrhage.

Molecular Docking of SP40 Peptide towards Cellular Receptors for Enterovirus 71 (EV-A71).

Enterovirus 71 (EV-A71) is one of the predominant etiological agents of hand, foot and mouth disease (HMFD), which can cause severe central nervous system infections in young children. There is no clinically approved vaccine or antiviral agent against HFMD. The SP40 peptide, derived from the VP1 capsid of EV-A71, was reported to be a promising antiviral peptide that targeted the host receptor(s) involved in viral attachment or entry. So far, the mechanism of action of SP40 peptide is unknown. In this study, interactions between ten reported cell receptors of EV-A71 and the antiviral SP40 peptide were evaluated through molecular docking simulations, followed by in vitro receptor blocking with specific antibodies. The preferable binding region of each receptor to SP40 was predicted by global docking using HPEPDOCK and the cell receptor-SP40 peptide complexes were refined using FlexPepDock. Local molecular docking using GOLD (Genetic Optimization for Ligand Docking) showed that the SP40 peptide had the highest binding score to nucleolin followed by annexin A2, SCARB2 and human tryptophanyl-tRNA synthetase. The average GoldScore for 5 top-scoring models of human cyclophilin, fibronectin, human galectin, DC-SIGN and vimentin were almost similar. Analysis of the nucleolin-SP40 peptide complex showed that SP40 peptide binds to the RNA binding domains (RBDs) of nucleolin. Furthermore, receptor blocking by specific monoclonal antibody was performed for seven cell receptors of EV-A71 and the results showed that the blocking of nucleolin by anti-nucleolin alone conferred a 93% reduction in viral infectivity. Maximum viral inhibition (99.5%) occurred when SCARB2 was concurrently blocked with anti-SCARB2 and the SP40 peptide. This is the first report to reveal the mechanism of action of SP40 peptide in silico through molecular docking analysis. This study provides information on the possible binding site of SP40 peptide to EV-A71 cellular receptors. Such information could be useful to further validate the interaction of the SP40 peptide with nucleolin by site-directed mutagenesis of the nucleolin binding site.

Endogenous α7 nAChR Agonist SLURP1 Facilitates Escherichia coli K1 Crossing the Blood-Brain Barrier.

Alpha 7 nicotinic acetylcholine receptor (α7 nAChR) is critical for the pathogenesis of Escherichia coli (E. coli) K1 meningitis, a severe central nervous system infection of the neonates. However, little is known about how E. coli K1 manipulates α7 nAChR signaling. Here, through employing immortalized cell lines, animal models, and human transcriptional analysis, we showed that E. coli K1 infection triggers releasing of secreted Ly6/Plaur domain containing 1 (SLURP1), an endogenous α7 nAChR ligand. Exogenous supplement of SLURP1, combined with SLURP1 knockdown or overexpression cell lines, showed that SLURP1 is required for E. coli K1 invasion and neutrophils migrating across the blood-brain barrier (BBB). Furthermore, we found that SLURP1 is required for E. coli K1-induced α7 nAChR activation. Finally, the promoting effects of SLURP1 on the pathogenesis of E. coli K1 meningitis was significantly abolished in the α7 nAChR knockout mice. These results reveal that E. coli K1 exploits SLURP1 to activate α7 nAChR and facilitate its pathogenesis, and blocking SLURP1-α7 nAChR interaction might represent a novel therapeutic strategy for E. coli K1 meningitis.

Central Nervous System Involvement in Trichinellosis: A Systematic Review.

We reviewed the evidence on features of central nervous system (CNS) involvement in trichinellosis, systematically searching five databases (to January 2021). We categorized clinical features based on their diagnostic value as warning signs for severe CNS infection (with outcome death) or non-specific signs (outcome improvement). They were suggestive of severe infection if they substantially raised death probability. The review included 87 papers published from 1906 through 2019, with data on 168 patients. Mydriasis, paraparesis, dysphagia, psychomotor seizures, or delirium present a 30–45% increased death likelihood. The best poor prognosis predictor is mydriasis (positive likelihood ratio 9.08). Slow/absent light reflex, diminished/absent knee reflexes, globally decreased tendon reflexes present a moderate increase (20–25%) of death risk. Anisocoria, acalculia, or seizures could also indicate an increased death risk. We provided a detailed presentation of clinical and paraclinical signs that alert physicians of a possible neurotrichinellosis, emphasizing signs that might indicate a poor prognosis.

Monoclonal antibody against VP0 recognizes a broad range of human parechoviruses

Parechoviruses (PeVs) are common viruses that cause mild gastrointestinal or respiratory symptoms to severe central nervous system infections. In infants, parechovirus infection is one of the leading causes of life-threatening viral disease. High-quality antibodies with broad binding specificities are essential to improve accurate parechovirus diagnosis in diagnostic laboratories. Such antibodies have potential in the development of rapid antigen detection assay against PeVs. In the present study, VP4 and VP2 genes from human parechovirus A1 (PeV-A1) were cloned and VP0 fusion protein produced to develop monoclonal antibodies against PeVs. Two pan-parechovirus antibodies, one IgG and one IgM isotype, were isolated. The properties of IgG1/κ monoclonal (designated as Mab-PAR-1) was studied further. Mab-PAR-1 was shown to be functional in western blot against denatured recombinant protein and viral particles. In immunofluorescence assay, the antibody tested positive for nineteen PeV-A1 isolates while showing no cross-reactivity to fourteen entero- and rhinovirus types. In addition, Mab-PAR-1 showed positive reactivity against five other cultivable parechovirus types 2−6. A unique Mab-PAR-1 epitope located in the junction of the three capsid proteins VP0, VP1, and VP3 was identified using a peptide library screen. This study demonstrates that PeV-A1-VP0 protein is functional antigen for developing monoclonal antibody for diagnosis of broad range of parechovirus infections.

Hyperbaric oxygen treatment: Results in seven patients with severe bacterial postoperative central nervous system infections and refractory mucormycosis

Resistant bacterial infections following brain and spine surgery and spontaneous mucormycosis with central nervous system (CNS) involvement represent a serious treatment challenge and more efficient therapeutic approaches ought to be considered. Hyperbaric oxygen treatment (HBOT) has shown promise as a complementary therapy. This case series evaluated whether HBOT contributed to infection resolution in seven patients with refractory CNS infectious conditions. Clinical results for seven patients referred for HBOT between 2010 to 2018 to treat refractory postoperative brain and spine infections or spontaneously developing mucormycosis were retrospectively analysed. The patients' clinical files and follow-up consultations were reviewed to assess evolution and outcome. Seven patients were referred with a median age of 56 years. The median follow-up was 20 months. Four patients had postoperative infections and three had rhino-orbital-cerebral mucormycosis (ROCM). HBOT was used as an adjunctive treatment to antimicrobial therapy in all patients. Prior to HBOT, all patients had undergone an average of four operations due to infection refractoriness and had completed an average of five months of antimicrobial therapy. After HBOT, infection resolution was obtained in six patients without additional operations, while one patient with ROCM stopped HBOT after the third session due to intolerance. Three patients stopped antimicrobial therapy while four were maintained on prophylactic treatment. Infection resolution was reached in the six patients that completed HBOT as prescribed. HBOT may serve as an effective complementary treatment in CNS refractory postoperative and spontaneous infections.

Point-of-Care Approaches for Meningitis Diagnosis in a Low-Resource Setting (Southwestern Uganda): Observational Cohort Study Protocol of the "PI-POC" Trial.

BackgroundA timely differential diagnostic is essential to identify the etiology of central nervous system (CNS) infections in children, in order to facilitate targeted treatment, manage patients, and improve clinical outcome.ObjectiveThe Pediatric Infection-Point-of-Care (PI-POC) trial is investigating novel methods to improve and strengthen the differential diagnostics of suspected childhood CNS infections in low-income health systems such as those in Southwestern Uganda. This will be achieved by evaluating (1) a novel DNA-based diagnostic assay for CNS infections, (2) a commercially available multiplex PCR-based meningitis/encephalitis (ME) panel for clinical use in a facility-limited laboratory setting, (3) proteomics profiling of blood from children with severe CNS infection as compared to outpatient controls with fever yet not severely ill, and (4) Myxovirus resistance protein A (MxA) as a biomarker in blood for viral CNS infection. Further changes in the etiology of childhood CNS infections after the introduction of the pneumococcal conjugate vaccine against Streptococcus pneumoniae will be investigated. In addition, the carriage and invasive rate of Neisseria meningitidis will be recorded and serotyped, and the expression of its major virulence factor (polysaccharide capsule) will be investigated.MethodsThe PI-POC trial is a prospective observational study of children including newborns up to 12 years of age with clinical features of CNS infection, and age-/sex-matched outpatient controls with fever yet not severely ill. Participants are recruited at 2 Pediatric clinics in Mbarara, Uganda. Cerebrospinal fluid (for cases only), blood, and nasopharyngeal (NP) swabs (for both cases and controls) sampled at both clinics are analyzed at the Epicentre Research Laboratory through gold-standard methods for CNS infection diagnosis (microscopy, biochemistry, and culture) and a commercially available ME panel for multiplex PCR analyses of the cerebrospinal fluid. An additional blood sample from cases is collected on day 3 after admission. After initial clinical analyses in Mbarara, samples will be transported to Stockholm, Sweden for (1) validation analyses of a novel nucleic acid–based POC test, (2) biomarker research, and (3) serotyping and molecular characterization of S. pneumoniae and N. meningitidis.ResultsA pilot study was performed from January to April 2019. The PI-POC trial enrollment of patients begun in April 2019 and will continue until September 2020, to include up to 300 cases and controls. Preliminary results from the PI-POC study are expected by the end of 2020.ConclusionsThe findings from the PI-POC study can potentially facilitate rapid etiological diagnosis of CNS infections in low-resource settings and allow for novel methods for determination of the severity of CNS infection in such environment.Trial RegistrationClinicalTrials.gov NCT03900091; https://clinicaltrials.gov/ct2/show/NCT03900091International Registered Report Identifier (IRRID)DERR1-10.2196/21430

Imaging appearance of acute disseminated encephalomyelitis: a study of 22 cases

L'Encéphalomyélite aiguë disséminée (ADEM) est une cause rare d'encéphalite de l'adulte, caractérisée par des lésions inflammatoires de la substance blanche du système nerveux central (SNC). Le tableau clinique initial peut mimer un tableau sévère d'infection du SNC avec fièvre, encéphalopathie, crises convulsives, ou un tableau de sclérose en plaque. Le but de notre travail est de rapporter les caractéristiques épidémiologiques, cliniques, radiologiques, thérapeutiques et évolutives de l'ADEM, aussi évaluer l'apport des séquences IRM dans le diagnostic, le suivi et le pronostic de la maladie. Il s'agit d'une étude rétrospective des dossiers cliniques et radiologiques d'ADEM sur 11 ans (janvier 2006-janvier 2017) portant sur 22 cas suivis au service de neurologie et explorés au niveau du service d'imagerie médicale de l'Hôpital Militaire d'Instruction Mohammed V de Rabat. L'âge moyen des patients était de 35 ans [12-57ans]. Une notion d'infection récente était retrouvée dans 31%, une vaccination récente dans 4%. La symptomatologie était dominée par un déficit neurologique focal avec un pourcentage de 72%. La TDM était normale dans 78%. L'IRM a montré un hyper signal FLAIR de la SB sus et sous tentoriel dans 70%, sans restriction de la diffusion dans la totalité des cas, avec rehaussement des lésions dans 27%, l'atteinte de la moelle cervicale estimait à 68%. L'évolution clinique et radiologique était favorable dans la totalité des cas.

Nörolojik tutulumu olmayan brusellozlu çocuk ve ergenlerin depresyon açısından değerlendirilmesi

Purpose: Brucella infection may appear with varying clinical manifestations, from subclinical infection to severe bacteremia or central nervous system infections. The aim of this study was to compare depression rates in brucellosis cases without neurobrucellosis with a non-brucellosis control group.Materials and Methods: One hundred and twenty children and adolescents, 60 with brucellosis and 60 controls, were included in the study. All subjects were administered the Kiddie Schedule for Affective Disorders and Schizophrenia for School-Age Children -Present and Lifetime Version-Turkish Version (K-SADS-PL-T), and psychiatric evaluation was performed on the basis of DSM-5 diagnostic criteria. Subjects were also assessed with the administration of the Children's Depression Inventory (CDI) and a detailed information form.Results:Depression was diagnosed in 16 (26.7%) of the patients with brucellosis, and in 3 (5%) of the control group, the incidence being significantly higher in the case group (p=0.002). CDI scores were also higher in the case group than in the control group (p&amp;lt; 0.001).Conclusion:The higher rate of depression in children and adolescents with brucellosis, even in the absence of neurological involvement, suggests the importance of these cases being evaluated in psychological terms.

Induced Pluripotent Stem Cell-Derived Brain Endothelial Cells as a Cellular Model to Study Neisseria meningitidis Infection.

Meningococcal meningitis is a severe central nervous system infection that occurs when Neisseria meningitidis (Nm) penetrates brain endothelial cells (BECs) of the meningeal blood-cerebrospinal fluid barrier. As a human-specific pathogen, in vivo models are greatly limited and pose a significant challenge. In vitro cell models have been developed, however, most lack critical BEC phenotypes limiting their usefulness. Human BECs generated from induced pluripotent stem cells (iPSCs) retain BEC properties and offer the prospect of modeling the human-specific Nm interaction with BECs. Here, we exploit iPSC-BECs as a novel cellular model to study Nm host-pathogen interactions, and provide an overview of host responses to Nm infection. Using iPSC-BECs, we first confirmed that multiple Nm strains and mutants follow similar phenotypes to previously described models. The recruitment of the recently published pilus adhesin receptor CD147 underneath meningococcal microcolonies could be verified in iPSC-BECs. Nm was also observed to significantly increase the expression of pro-inflammatory and neutrophil-specific chemokines IL6, CXCL1, CXCL2, CXCL8, and CCL20, and the secretion of IFN-γ and RANTES. For the first time, we directly observe that Nm disrupts the three tight junction proteins ZO-1, Occludin, and Claudin-5, which become frayed and/or discontinuous in BECs upon Nm challenge. In accordance with tight junction loss, a sharp loss in trans-endothelial electrical resistance, and an increase in sodium fluorescein permeability and in bacterial transmigration, was observed. Finally, we established RNA-Seq of sorted, infected iPSC-BECs, providing expression data of Nm-responsive host genes. Altogether, this model provides novel insights into Nm pathogenesis, including an impact of Nm on barrier properties and tight junction complexes, and suggests that the paracellular route may contribute to Nm traversal of BECs.

Enterovirus A71 VP1 Variation A289T Decreases the Central Nervous System Infectivity via Attenuation of Interactions between VP1 and Vimentin In Vitro and In Vivo.

Vimentin (VIM) is a surface receptor for enterovirus-A71, mediating the initial binding and subsequent increase in EV-A71 infectivity. The caspid protein VP1 variation, A289T, is reportedly closely associated with less severe central nervous system (CNS) infections in humans. However, it is unclear whether VIM is associated with a reduction in CNS infections of EV-A71 in the presence of A289T. We investigated whether VIM served as a receptor for EV-A71 in the presence of an A298T substitution in VP1. EV-A71-289A and EV-A71-289T were used to infect human rhabdomyosarcoma cells, control human brain microvascular endothelial cells (HBMECs), and VIM-knockout (KO) HBMECs and inoculated BALB/c mice, SV129 mice, and VIM-KO SV129 mice. Furthermore, we cloned VP1-289A-Flag and VP1-289T-Flag proteins for co-immunoprecipitation analysis. Analysis of viral function revealed that the capacity of viral attachment, replication, and protein synthesis and secretion decreased in HBMECs during an EV-A71-289A infection, the infectivity being higher than that of EV-A71-289T upon VIM-KO. Histopathological and immunohistochemical analyses of brain tissue revealed that cerebral cortical damage was more extensive in EV-A71-289A than in EV-A71-289T infections in control SV129 mice; however, no significant difference was observed upon VIM-KO. Co-immunoprecipitation analysis revealed an interaction between VP1 and VIM, which was attenuated in VP1 harboring A289T; however, this attenuation was reversed by VIM (1-58) peptide. The A289T variation of VP1 specifically decreased the virulence of EV-A71 in HBMECs, and the attenuated interaction between VP1 harboring the A289T variation and VIM essentially decreased the CNS infectivity of EV-A71 in vitro and vivo.

Profile of Childhood Epilepsies and Syndromes Seen in an Electrophysiology Laboratory in Southeast Nigeria

Background: Epilepsy and other seizure disorders are highly prevalent in resource-poor countries. Electroencephalogram (EEG) plays an invaluable role in differentiating seizure types, epilepsy syndromes and choice of appropriate anti-epileptic drugs. This is critical for effective management of epilepsies including their prognostication. The profile of childhood epilepsies in our locality is unknown. This study was therefore carried out to ascertain the prevalent electro-clinical syndromes and epilepsy types, etiological factors and co-morbid conditions in children who had EEG in Owerri, Southeast Nigeria. Methods: The clinical data including the Basic Data Sheet and EEG records of all children with epilepsy seen between January 2017 and December 2018 at the EEG Unit/Child Neurology Clinic of Mother Healthcare Diagnostics & Hospital, Owerri were retrospectively reviewed. Relevant data from each patien t’s clinical history, physical examination, investigation findings and EEG diagnosis of seizure type and epilepsy syndrome were extracted and recorded. Results: Out of 97 children with epilepsy, 57 were males and 40 were females giving an male/female (M/F) ratio of 1.4:1. Focal epilepsy (31%) was the most frequent epilepsy type, while benign rolandic epilepsy (BRE) (14%) was the most common epilepsy syndrome seen. West syndrome was the second most prevalent epilepsy syndrome. Epilepsy was of genetic etiology in 48 (50%) and 22 (23%) had a history of severe perinatal asphyxia. No co-morbidity was detected in 70 (72%) patients but among those with co-morbidity, communication disorder (12.4%) was the most frequent. Conclusions: Focal epilepsies and syndromes of genetic etiology were the more prevalent epilepsy types and syndromes in our locality. Majority of the children had no co-morbid conditions but most of those with co-morbidity would require speech therapy. Epileptic encephalopathies were also frequent and this underscores the need to prevent severe perinatal asphyxia and central nervous system (CNS) infections. Int J Clin Pediatr. 2019;8(2):32-36 doi: https://doi.org/10.14740/ijcp344

Ataxia telangiectasia. A prototype of neurological involvement in primary immune deficiencies

The number of primary immune deficiencies exceeds 350, approximately a quarter of them having neurological implications. Severe central nervous system infections may occur in an even higher proportion. Beyond listing in a table of all diseases with a neurological impact, the author gives detailed analysis of one typical disorder. Ataxia telangiectasia is caused by biallelic mutation of the ATM gene resulting in genomic instability, increased cancer risk, immune deficiency and a predominantly cerebellar neurodegeneration. The most common classic form is characterized by gait and limb ataxia, oculomotor apraxia, choreoathetosis, disturbance of speech and swallowing, less often by other movement disorders. There is no remarkable cognitive deficit. Telangiectasia of the conjunctivae and skin usually appears after 6 years of age. Frequent, especially severe sino-pulmonary infections may indicate the immune deficiency present in 60 to 80% of patients, who are also prone to malignancies. The clinical course is sometimes atypical or has a late onset which results in diagnostic difficulties. Serum alpha-fetoprotein level is elevated in nearly all patients. Brain MRI shows progressive cerebellar atrophy starting at the age of 7-8 years. DNA testing of the ATM gene is necessary for the diagnosis. The detected biallelic pathogenic variants provide help for family planning and for possible gene therapies in the future. Ataxia telangiectasia has to be differentiated from a number of other disorders, some of which also belong to primary immune deficiencies. The disorder has no causal treatment at present, the patients live until their young adult ages. Orv Hetil. 2018; 159(49): 2057-2064.