Aseptic meningitis and leptomeningeal enhancement associated with anti-MOG antibodies: A review.

BACKGROUND: Aseptic meningitis can be caused by autoimmune diseases, such as lupus and sarcoidosis. Aseptic meningitis with leptomeningeal enhancement can be the initial presentation of a neuroinflammatory syndrome associated with antibodies to myelin oligodendrocyte glycoprotein (MOG-abs). MOG-abs is a serum biomarker for MOG-associated disorder (MOG-AD), an acquired demyelinating syndrome that includes features of neuromyelitis optica, multiple sclerosis, optic neuritis, and acute disseminated encephalomyelitis. The purpose of this study is to review cases of aseptic meningitis and leptomeningeal enhancement associated with MOG-abs. METHODS: Systematic review using PubMed, Embase, Ovid MEDLINE, Web of Science Core Collection, and Google Scholar up to December 2020 was performed. Cases of MOG-AD were included if they met the following criteria: 1) Initial clinical presentation of aseptic meningitis; 2) positive leptomeningeal enhancement and 3) MOG-Ab seropositivity. Descriptive statistics were used. This analysis was limited to the cases available in the literature. RESULTS: 11 total cases of aseptic meningitis and leptomeningeal enhancement in setting of MOG-ab were identified. Demyelinating type T2 lesions were also present at time of presentation in 6/11; however, 5/11 of patients had leptomeningeal enhancement alone without demyelinating lesions. All 5 patients required immunotherapy for improvement, including one patient with symptoms for 28 days, with 4/5 receiving steroids and 1/5 receiving intravenous immunoglobulin (IVIG). CONCLUSIONS: Aseptic meningitis with leptomeningeal enhancement can be the initial presenting symptom of MOG-AD. MOG-ab testing should be considered in a patient presenting with aseptic meningitis and leptomeningeal enhancement of unknown etiology.

Prolonged Fever: An Atypical Presentation in MOG Antibody-Associated Disorders.

BACKGROUND: Myelin oligodendrocyte glycoprotein (MOG) antibody-associated demyelinating disorders (MOGAD) are increasingly being recognized in the pediatric age group. Over time, unusual presentations have expanded the clinical presentation. We report 12 cases of MOGAD where prolonged fever (PF) was an important part of the symptom complex during the course of the illness. METHODS: After initial recognition of this atypical clinical presentation, more patients were recruited over 2 years and followed up prospectively. RESULTS: Eight of twelve patients had no clinical/imaging evidence of demyelination until much later in the course. Three clinical presentations recognized were fever of unknown origin (4 of 12), aseptic meningitis (4 of 12), and PF seen concurrently with established acute demyelination syndrome (4 of 12). Leukocytosis, raised inflammatory markers, and cerebrospinal fluid pleocytosis were almost universal. The first two presentations frequently caused diagnostic confusion, as MOGAD was not considered until several weeks after disease onset. The third group was more a therapeutic conundrum on how to manage the PF. Early seizures without encephalopathy were not uncommon and were probably independent of the later-appearing demyelination. CONCLUSIONS: This case series highlights PF as an important component of the pediatric MOGAD symptom complex. MOGAD could be considered in the differential diagnosis of these clinical presentations.

Clinical Prediction Rule for Distinguishing Bacterial From Aseptic Meningitis.

BACKGROUND: New biomarkers like procalcitonin and C-reactive protein may help design an accurate decision support tool used to identify children with pleocytosis at low or high risk of bacterial meningitis. Our objective was to develop and validate a score (that we call the meningitis score for emergencies [MSE]) to distinguish bacterial meningitis from aseptic meningitis in children with pleocytosis when initially evaluated at the emergency department. METHODS: We included children between 29 days and 14 years old with meningitis admitted to 25 Spanish emergency departments. A retrospective cohort from between 2011 and 2016 was used as the derivation set and a prospective cohort recruited during 2017 and 2018 was used as the validation set. RESULTS: Among the 1009 patients included, there were 917 cases of aseptic meningitis and 92 of bacterial meningitis. Using multivariable logistic regression analysis, we identified the following predictors of bacterial meningitis from the derivation set: procalcitonin >1.2 ng/mL, cerebrospinal fluid (CSF) protein >80 mg/dL, CSF absolute neutrophil count >1000 cells per mm3, and C-reactive protein >40 mg/L. Using the derivation set, we developed the MSE, assigning 3 points for procalcitonin, 2 points for CSF protein, and 1 point for each of the other variables. An MSE ≥1 predicted bacterial meningitis with a sensitivity of 100% (95% confidence interval [CI]: 95.0%-100%), a specificity of 83.2 (95% CI: 80.6-85.5), and a negative predictive value of 100% (95% CI 99.4-100.) CONCLUSIONS: The MSE accurately distinguishes bacterial from aseptic meningitis in children with CSF pleocytosis.

A Case of Cerebral Venous Thrombosis and Deep Venous Thrombosis Due to Hyperthyroidism with Increased Factor VIII Activity.

A 48-year-old woman was admitted to our hospital because of headache and fever. She was diagnosed with aseptic meningitis. Five days later, she had a seizure and developed left hemiparesis. Magnetic resonance imaging showed hyperintensity in the right parietal area on fluid attenuated inversion recovery imaging. She was diagnosed as having cerebral venous thrombosis (CVT) because the suprasagittal sinus was invisible on the venographic studies. Moreover, deep venous thrombosis (DVT) was detected in her left lower extremity. Laboratory findings showed hyperthyroidism and markedly increased factor VIII activity. This is a rare case of concomitant CVT and DVT induced by high factor VIII activity due to hyperthyroidism under the presence of meningitis, an additional risk factor for thrombosis.

MOG antibody seropositive aseptic meningitis: A new clinical phenotype.

The spectrum of myelin oligodendrocyte glycoprotein antibody (MOG-Ab) associated demyelination is evolving. Our case report describes a unique clinical presentation of aseptic meningitis with demyelinating lesions of the brain resembling acute disseminated encephalomyelitis and MOG-Ab seropositivity. A 22-year-old lady presented with history of fever of one week duration followed by headache, vomiting and neck stiffness. She had bilateral papilledema and signs of meningeal irritation. Neuroimaging revealed T2 and FLAIR hyperintense lesions in the right caudate, temporal lobe and left insula with enhancement on gadolinium contrast along with leptomeningeal enhancement. An extensive search for infectious and inflammatory etiology was negative while serum was positive for MOG-Abs tested twice at an interval of 12 days. She showed remarkable clinical-radiological resolution with steroids and has remained symptom free on follow up.

The value of serum procalcitonin in acute meningitis in children.

Early diagnosis and initial therapy are important to reduce the complications of bacterial meningitis. We aimed to evaluate the diagnostic value of serum procalcitonin in children with acute meningitis. We included 40 children (4 months-14 years) suspected to have acute meningitis in our study. Based on the clinical scenario, physical examination and complete analysis of cerebrospinal fluid, patients were assigned into two groups: bacterial meningitis group (24 patients) and aseptic meningitis group (16 patients). Twenty-five apparently healthy children of matched age and sex served as a control group. Procalcitonin, C-reactive protein, and leukocyte count were measured initially at the time of admission and again after 72 h. Initially, patients with bacterial meningitis showed statistically significant higher values of serum procalcitonin than both patients with aseptic meningitis and the control groups (p < 0.001). After 72 h of treatment, patients of bacterial meningitis group showed statistically significant lower values of serum procalcitonin than their initial values (P < 0.05). The cutoff point of procalcitonin needed for early diagnosis of bacterial meningitis was >10 ng/ml at the time of admission. However, values of procalcitonin >2 ng/ml had 100% sensitivity. Whereas, the specificity, negative predictive value and positive predictive value of procalcitonin were 63%, 100%, and 67% respectively. Serum Procalcitonin can be used as an early diagnostic marker of acute bacterial meningitis and its differentiation from aseptic meningitis. In acute bacterial meningitis, it can be used to follow the response to antibiotic therapy.

Serum interleukin-6 levels as an indicator of aseptic meningitis among children with enterovirus 71-induced hand, foot and mouth disease.

OBJECTIVES: The enterovirus EV71 is a major pathogen of hand, foot, and mouth disease (HFMD) in children. Aseptic meningitis is the most common neurologic complication of EV71-induced HFMD. Lumbar puncture is a crucial procedure in the diagnosis of aseptic meningitis. It is often performed based on physicians' clinical suspicion. A diagnostic method that can aid in deciding whether this procedure should be performed is necessary. Cytokines are speculated to be associated with neurologic complications. In this study, we aimed to find an indicator of the presence of aseptic meningitis in children with EV71-induced HFMD. METHODS: This cross-sectional study included children with EV71-induced HFMD. The children underwent lumbar puncture due to suspected aseptic meningitis. They were categorized into an aseptic meningitis complicated group (n = 54) and uncomplicated group (n = 47) based on the results of cerebrospinal fluid examination. Healthy children were included as controls (n = 51). The sample serum levels of tumor necrosis factor-α, interferon-γ, interleukin (IL)-1ß, IL-2, IL-6, IL-8, IL-10, and IL-13 were detected using multiplexed fluorescent bead-based immunoassays. RESULTS: The levels of all cytokines were significantly higher in children with EV71-induced HFMD complicated with aseptic meningitis than in children with uncomplicated EV71-induced HFMD and controls (p < 0.001). Binary logistic regression analysis demonstrated that IL-6 had the strongest association with aseptic meningitis of all cytokines examined. According to receiver operating characteristic analysis, the optimal cutoff value for IL-6 was 66 pg/mL with maximum sensitivity and specificity. CONCLUSIONS: The results of this study suggest the association between higher production of cytokine and aseptic meningitis among children with EV71-induced HFMD. IL-6 was also suggested as an indicator of aseptic meningitis. Rapid measurement of IL-6 could be useful in deciding whether physicians should perform lumbar puncture on children.

Association of anti-triosephosphate isomerase antibodies with aseptic meningitis in patients with neuropsychiatric systemic lupus erythematosus.

Autoantibodies to triosephosphate isomerase (TPI), which is an important glycolytic enzyme in red blood cells and neuronal cells, have been reported to be associated with neuropsychiatric systemic lupus erythematosus (NPSLE) pathogenesis. However, the clinical features regarding anti-TPI antibody (anti-TPI)-positive NPSLE are not yet known. The aim of this study is to investigate the clinical features of anti-TPI-positive NPSLE patients using anti-TPI index values determined by enzyme-linked immunosorbent assay (ELISA). Thirty-one NPSLE patients treated in our department were included in this study. Serum samples were collected, and serum anti-TPI titers were measured by ELISA. The anti-TPI index values were defined as follows: (OD405 of samples - OD405 of negative control)/(OD405 of positive control - OD405 of negative control) × 100. Anti-TPI index values greater than 2 standard deviations above the mean of healthy controls were regarded as positive. The clinical features of anti-TPI-positive and anti-TPI-negative NPSLE were compared. Ten of the 31 NPSLE patients had anti-TPI positivity (32.3%). The clinical features of anti-TPI-positive NPSLE were comparable with those of anti-TPI-negative NPSLE, except for a higher frequency of aseptic meningitis (p = 0.027) and a lower frequency of acute confusional state (P = 0.026). Laboratory data in patients with anti-TPI-positive NPSLE showed significantly higher serum IgG levels. Furthermore, anti-TPI index values positively correlated with serum IgG levels. Our study indicates that serum anti-TPI increases in the presence of elevated IgG levels and can be associated with the pathogenesis of aseptic meningitis in NPSLE.

Blood-CSF-barrier dysfunction is a marker for encephalitic involvement in patients with aseptic meningitis/meningoencephalitis.

BACKGROUND: The term "aseptic meningitis" encompasses cases of meningitis with negative bacterial CSF culture, which predominantly are of viral etiology. While the clinical course is usually benign, complications such as encephalitic involvement resulting in a more severe clinical course may occur. Dysfunction of the blood-brain-barrier (BBB), which is a prerequisite for viral entry into the brain parenchyma, can be approximated using the CSF/serum albumin ratio, readily obtainable in routine CSF analysis. OBJECITVES: Analysis of CSF patterns in patients with aseptic meningitis/meningoencephalitis with a focus on BBB dysfunction as a marker for encephalitic involvement. STUDY DESIGN: Retrospective chart review of patients admitted to our hospital between 2004 and 2016 with a diagnosis of aseptic meningitis/meningoencephalitis. RESULTS: Patients with aseptic meningitis displaying clinical, MR-tomographic or electroencephalographic signs of encephalitic involvement were significantly older than patients without these features (47.4 vs. 35.5 yrs., p=0.002). In patients with meningoencephalitis, CSF analysis revealed a more severe disruption of BBB, approximated by the CSF/serum albumin ratio (p=0.002). Compromised BBB function correlated positively with length of hospitalization (p=0.007), indicative of a more severe clinical course. The number of CSF lymphocytes was found to predict the severity of the BBB disruption, which additionally was more frequently observed when herpesviridae were identified as infectious agents. CONCLUSIONS: We suggest that the CSF/serum albumin ratio as an estimate for BBB function should be attended to in the evaluation of patients with aseptic meningitis. Severe BBB dysfunction, older age and infection with herpesviridae appear to raise the risk for encephalitic involvement.

IL-6 and IFNγ are elevated in severe mumps cases: a study of 960 mumps patients in China.

INTRODUCTION: Mumps is a common infectious disease. Epidemics of mumps are reported globally every year and represent a threat to public health, especially in China and other developing countries. METHODOLOGY: Clinical and laboratory findings of 960 mumps patients admitted to Beijing You'an Hospital, China, between January 2010 and December 2012 were collected and analyzed. Patients with isolated complication were selected and grouped as aseptic meningitis/encephalitis (AME) patients (n = 156) and Orchitis patients (n = 72). One hundred and fifty patients without complication were grouped as control. Levels of T cell subtypes and 8 serum cytokines were also tested. RESULTS: Majority of mumps patients were male (76.3%) and younger than 17 years old (76.2%). AME was complicated in 41.6% of mumps cases, and orchitis was in 21.3% (64.7% were left-sided). Unvacinated patients had more chance to have AME or orchitis (p = 0.034 and 0.027). The rates of AME and orchitis in mumps patients rapidly increased during the last three years. No laboratory findings were associated with AME or orchitis (all p > 0.05). Serum IL-10 level was elevated in almost all patients. IL-6 and IFNγ levels were correlated with AME (p = 0.025 and p = 0.018). Their levels peaked at day one after admission, and started to decline thereafter. CONCLUSIONS: This study suggests that the incidence of serious complications has become more common in recent years, moreover IL-6 and IFNγ may possibly be used as early serum markers for identifying patients with risk of developing complications in mumps.

Cerebrospinal fluid/blood glucose ratio as an indicator for bacterial meningitis.

BACKGROUND: Bacterial meningitis is an emergent disease requiring prompt diagnosis and treatment with appropriate antimicrobials. Although the lumbar puncture is widely used as a diagnostic tool for bacterial meningitis, it remains unclear which value in cerebrospinal fluid (CSF) analysis in emergency laboratory tests precisely predicts the presence of bacterial meningitis. METHODS: This is a single-center, retrospective review of medical records to determine which emergency laboratory CSF test results are useful for predicting bacterial meningitis. The diagnosis of meningitis is made when the white blood cell count in CSF exceeds 5 cells/µL, while the diagnosis of bacterial meningitis additionally requires the growth of a pathogen from a CSF culture or the identification of a pathogen in Gram staining of CSF specimen. RESULTS: We identified 15 patients with bacterial meningitis and 129 patients with aseptic meningitis. While neutrophil-predominant pleocytosis and a decreased glucose level in CSF can predict the presence of bacterial meningitis, the CSF/blood glucose ratio is more precise (optimal cut-off=0.36, sensitivity=92.9%, specificity=92.9%, area under the curve=.97) even after administration of antimicrobials prior to examination in the emergency department. CONCLUSION: This study suggests that the CSF/blood glucose ratio may be a better single indicator for bacterial meningitis. Since the CSF glucose and blood glucose values are promptly and easily obtained from a lumbar puncture, the CSF/blood glucose ratio should be considered as a timely diagnostic indicator of bacterial meningitis. It may also help exclude the diagnosis of bacterial meningitis especially in cases in which no microorganisms can be cultured.

Serum procalcitonin in septic meningitis.

OBJECTIVE: To evaluate the role of serum procalcitonin (PCT) in diagnosis of septic meningitis in children and its efficacy in differential diagnosis. METHODS: The study included 40 children of septic meningitis admitted in pediatric ward with fever, headache, vomiting and seizure, up to 14 y of age. The diagnosis of septic meningitis was based on clinical features; physical examination, blood and cerebrospinal fluid (CSF) cytochemical findings, gram's stain and bacterial culture. Fifteen cases of aseptic meningitis admitted during same period were also included in the study, and 15 children with normal CSF were taken as control. Serum PCT was measured by ELISA Kit. RESULTS: Serum PCT level was significantly higher in children with septic meningitis than those with aseptic meningitis or in controls (p < 0.001). In culture and gram's stain positive 7 cases, serum procalcitonin was significantly elevated (24,768.21 ± 6,567.45 pg/mL) than aseptic meningitis(14,451.24 ± 4,266.15 pg/mL) (p < 0.001). Further its level was found significantly elevated in partially treated septic meningitis as compared to aseptic meningitis cases (p < 0.001). At optimum cut off value of ≥ 5,000 pg/mL, based on area under ROC curve, PCT showed sensitivity, specificity, positive predictive value and negative predictive value of 98.5 %, 93.5 %, 98.6 % and 93.3 % respectively. Serum PCT with cut off level of 15,000 pg/ml showed sensitivity, specificity, PPV and NPV of 92 %, 67 %, 91.4 % and 71.4 % respectively for the differentiation of septic from aseptic meningitis. CONCLUSIONS: Serum PCT may be used as diagnostic marker for septic meningitis and its differentiation from aseptic meningitis.

Evidence of an autochthonous Toscana virus strain in Croatia.

BACKGROUND: Phleboviruses are large and widespread group of viruses that are transmitted by arthropods and they have been reported to circulate in endemic regions of Mediterranean Basin, including Croatia. OBJECTIVES: To investigate the role of Toscana virus, as a cause of the aseptic meningitis, in summer months in Croatia. STUDY DESIGN: Samples from 30 patients with aseptic meningitis were retrospectively tested by serology and RT-PCR for TOSV. RESULTS: TOSV RNA was detected in 2/30 and TOSV IgM antibodies were found in 4/30 of patients. Phylogenetic analysis of partial L and S segments suggests that TOSV from Croatia represents an autochthonous strain. CONCLUSIONS: The study has confirmed the role of TOSV as an agent that causes aseptic meningitis in Croatia, therefore it should be considered by physicians when encountering meningitis or febrile illness among indigenous population or travellers during the summer months.

Prevalence of Lyme meningitis in children with aseptic meningitis in a Lyme disease-endemic region.

This study determined the prevalence of Lyme meningitis in children with undifferentiated aseptic meningitis from April to December in a Lyme disease-endemic region. Of the 60 children, 8 were seropositive (prevalence 13.3%; 95% confidence interval: 6.3-25.1%), with another probable case having high cerebrospinal fluid antibody titers. Clinicians in endemic regions should evaluate children with undifferentiated aseptic meningitis for Lyme meningitis in appropriate seasons.

Coxsackieviral infections involved in aseptic meningitis: a study in Slovakia from 2005 to 2009.

A wide range of diseases is associated with enteroviruses.They are reported to be responsible for viral meningitis, especially in children, but also in adults.This study analysed infection with eight selected coxsackievirus serotypes as the cause of aseptic meningitis in 480 patients in Slovakia from 2005 to 2009,using a quantitative assay for the detection of intrathecal antibodies. Intrathecal production of antibodies against selected coxsackieviruses was proved in 21%of these patients. A significant decrease from 35% in 2005 to 8,5% in 2009 (p=0.004) in the proportion of patients with proven intrathecal production of virus specific antibodies was observed during the study period. We conclude that coxsackievirus B4 was the endemic serotype in Slovakia and was responsible for most cases of coxsackieviral meningitis in the study period.

Concentration gradient of CXCL10 and CXCL11 between the cerebrospinal fluid and plasma in children with enteroviral aseptic meningitis.

BACKGROUND: Lymphocyte migration from the blood into the CNS is mediated by chemokines and chemokine receptors. Chemokines CXCL10 and CXCL11 are important for the recruitment of CXCR3-expressing Th1 lymphocytes to the site of inflammation. AIMS: To determine the concentrations of CXCL10 and CXCL11 in the CSF and plasma of children with enteroviral aseptic meningitis (EV AM) and controls and the contribution of these chemokines to the chemokine concentration gradient between the periphery and the CNS. METHODS: The study included 26 pediatric patients with EV AM and 16 controls in whom CNS infection is excluded by negative CSF examination. Chemokines were quantified by using enzyme immunoassay. Etiological diagnosis of EV AM was based on the detection of enteroviral RNA in the CSF using real-time PCR. RESULTS: CXCL10 (median 12 725 pg/ml) and CXCL11 (median 187 pg/ml) concentrations in CSF of patients with meningitis were significantly higher compared to plasma (median 173 pg/ml and median 110 pg/ml; p < 0.001, p = 0.026 respectively). CXCL10 concentrations in the CSF (median 198 pg/ml) and plasma of controls (median 124 pg/ml) were not significantly different (p = 0.642). CXCL11 concentrations in the CSF of controls (median 89 pg/ml) were significantly lower compared with plasma (median 139 pg/ml, p = 0.004). Chemokine concentration gradient was not influenced by pleocytosis, nor dependent on cytologic CSF formula or the presence of proteinorrachia. CONCLUSION: CXCL10 and CXCL11 concentration gradient between the CSF and plasma in children with EV AM suggests an important role of these chemokines in the T-cells recruitment into the CNS and local immunoreaction.

Diagnostic value of serum procalcitonin levels in children with meningitis: a comparison with blood leukocyte count and C-reactive protein.

OBJECTIVES: To determine the level of serum procalcitonin, blood leukocyte count (TLC) and C-reactive protein (CRP) in children with bacterial and non bacterial meningitis and document their efficacy in differential diagnosis. Also described are procalcitonin levels variation during treatment. METHODS: From March 2005 to February 2008, we evaluated 38 clinically suspected meningitis patients in the paediatric departments, Al-Jedaany Hospital, Jeddah, KSA, for Serum procalcitonin, CRP, TLC and Lumbar punctures and CSF analysis. Patients were classified into bacterial meningitis group I (18) and non bacterial meningitis group II (20). RESULTS: Serum PCT levels were significantly higher in bacterial meningitis (BM) {mean 4.8 +/- 3.85 ng/ml (2.9-11.6)} compared with non bacterial meningitis (NBM) {mean 0.38 +/- 0.25 ng/ml (0.31-0.61)} {P < 0.001}. Mean of all CSF parameters, TLC {15,000 +/- 2,900 cell/ml(BM) & 9500 +/- 1105 cell/ml (NBM)} and CRP {20 +/- 6.8 mg/l (BM) & 12.5 +/- 12.0 mg/l (NBM)} showed a zone of overlapping between the two groups. There is a positive correlation between serum PCT, TLC and CRP in bacterial and non bacterial meningitis cases but this relation becomes highly significant with bacterial meningitis positive group. Day 3 and day 6 treatment serum PCT was less than on admission levels (P < 0.001). CONCLUSION: PCT can be used in the early diagnosis of bacterial meningitis and may be a useful adjunct in differentiating bacterial and non bacterial meningitis than CRP or TLC and diminishing the value of lumbar puncture performed 48-72 hours after admission to assess treatment efficacy.

IL-17 is elevated in cerebrospinal fluids in bacterial meningitis in children.

Bacterial meningitis has a poor prognosis and neurologic complications. The present study aimed to investigate the cytokine/chemokine network in cerebrospinal fluid (CSF) from children with bacterial meningitis and aseptic meningitis. Interleukin (IL)-1beta, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12, IL-13, IL-17, interferon-gamma, tumor necrosis factor-alpha, granulocyte colony-stimulating factor, granulocyte monocyte colony-stimulating factor, monocyte chemoattractant protein-1 and macrophage inflammatory protein-1beta, were measured simultaneously in CSF supernatants. We found that, IL-17 was significantly elevated in CSF with bacterial meningitis. We believe that IL-17 plays a key role in neutrophil infiltration into CSF and neuronal protection in bacterial meningitis.