Meningitis patients with Angiostrongylus cantonensis may present without eosinophilia in the cerebrospinal fluid in northern Vietnam

BackgroundEosinophilic meningitis (EM) is a rare clinical syndrome caused by both infectious and noninfectious diseases. In tropical pacific countries, Angiostrongylus cantonensis is the most common cause. However, the EM definition varies in the literature, and its relation to parasitic meningitis (PM) remains unclear.Methodology/Principal findingsAdult and adolescent patients of 13 years old or above with suspected central nervous system (CNS) infections with abnormal CSF findings were prospectively enrolled at a tertiary referral hospital in Hanoi, Vietnam from June 2012 to May 2014. Patients with EM or suspected PM (EM/PM) were defined by the presence of either ≥10% eosinophils or an absolute eosinophil cell counts of ≥10/mm³ in the CSF or blood eosinophilia (>16% of WBCs) without CSF eosinophils. In total 679 patients were enrolled: 7 (1.03%) had ≥10% CSF eosinophilia, 20 (2.95%) had ≥10/mm³ CSF eosinophilia, and 7 (1.03%) had >16% blood eosinophilia. The patients with ≥10% CSF eosinophilia were significantly younger (p = 0.017), had a lower body temperature (p = 0.036) than patients with ≥10/mm³ CSF eosinophilia among whom bacterial pathogens were detected in 72.2% (13/18) of those who were tested by culture and/or PCR. In contrast, the characteristics of the patients with >16% blood eosinophilia resembled those of patients with ≥10% CSF eosinophilia. We further conducted serological tests and real-time PCR to identify A. cantonensis. Serology or real-time PCR was positive in 3 (42.8%) patients with ≥10% CSF eosinophilia and 6 (85.7%) patients with >16% blood eosinophilia without CSF eosinophils but none of patients with ≥10/mm³ CSF eosinophilia.ConclusionsThe etiology of PM in northern Vietnam is A. cantonensis. The eosinophil percentage is a more reliable predictor of parasitic EM than absolute eosinophil count in the CSF. Patients with PM may present with a high percentage of eosinophils in the peripheral blood but not in the CSF.     

Cerebrospinal fluid eotaxin and eotaxin-2 levels in human eosinophilic meningitis associated with angiostrongyliasis

Eosinophilic meningitis associated angiostrongyliasis (EOMA) is a harmful disease of the brain and spinal cord caused by a parasitic helminth, Angiostrongylus cantonensis, presenting with severe headaches and cerebrospinal fluid (CSF) eosinophilia. However, the immunologic pathophysiology especially in relation to the eosinophilic inflammation is still unknown. We measured the CSF concentrations of eotaxin and eotaxin-2 of 30 patients and 10 controls. The CSF eotaxin and eotaxin-2 levels of the EOMA patients were significantly higher than those of the controls (p<0.001). The positive detection values were 83.3% (25/30) and 93.3% (28/30) for eotaxin and eotaxin-2, respectively. CSF eotaxin-2 levels also correlated with CSF eosinophilia (p=0.002). These results might indicate that the recruitment of eosinophils to the brain and spinal cord in EOMA patients could be related to elevated eotaxin-2 levels.     

Carcinomatous meningitis as the initial manifestation of breast cancer

Report is made of an elderly woman in whom carcinomatous meningitis was the initial manifestation of breast cancer. The patient presented with nonfocal neurologic symptoms. Cytologic examination of cerebrospinal fluid (CSF) revealed malignant cells arranged either in loose clusters or as isolated single cells. The morphology of the cells, some of which had a signet-ring configuration with a crescent-shaped nucleus as well as prominent round nucleoli, suggested a breast primary, which was proven by subsequent histologic study.     

Isolated intracranial hypertension: a rare presentation of neurobrucellosis

Brucella melitensis infection is endemic in the eastern and south-eastern Anatolia regions of Turkey. We report an unusual case of brucella meningitis presenting with bilateral papilla stasis, diplopia and absence of other neurological involvement. Diagnosis was made by positive culture of Brucella spp. with a BACTEC 9120 system with inoculation of the patient's cerebrospinal fluid (CSF). This is the first report of isolation of Brucella spp. from CSF on a BACTEC 9120 system for diagnosis of meningitis. This case demonstrated that brucella meningitis may present with very slight symptoms, and inoculation of CSF into BACTEC bottle besides conventional cultures improves the detection of Brucella in endemic areas such as Turkey.     

Eosinophilia in the cerebrospinal fluid of children with shunts implanted for the treatment of internal hydrocephalus

Cerebrospinal fluid (CSF) eosinophilia was observed in 26 of 404 children after the implantation of shunts for the treatment of internal hydrocephalus. High levels of 65% and 78% were recorded in two cases, which are reported in detail. In the remaining 24 cases, CSF eosinophilia ranging between 1% and 3% was found. None of the cases with CSF eosinophilia had blood eosinophilia. The cases indicate that a reaction to the material used for the shunt should be considered along with possible parasitic infestations in patients with such findings.     

Infectious Causes of Eosinophilic Meningitis in Korean Patients: A Single-Institution Retrospective Chart Review from 2004 to 2018

Eosinophilic meningitis is defined as the presence of more than 10 eosinophils per μl in the cerebrospinal fluid (CSF), or eosinophils accounting for more than 10% of CSF leukocytes in patients with acute meningitis. Parasites are the most common cause of eosinophilic meningitis worldwide, but there is limited research on patients in Korea. Patients diagnosed with eosinophilic meningitis between January 2004 and June 2018 at a tertiary hospital in Seoul, Korea were retrospectively reviewed. The etiology and clinical characteristics of each patient were identified. Of the 22 patients included in the study, 11 (50%) had parasitic causes, of whom 8 (36%) were diagnosed as neurocysticercosis and 3 (14%) as Toxocara meningitis. Four (18%) patients were diagnosed with fungal meningitis, and underlying immunodeficiency was found in 2 of these patients. The etiology of another 4 (18%) patients was suspected to be tuberculosis, which is endemic in Korea. Viral and bacterial meningitis were relatively rare causes of eosinophilic meningitis, accounting for 2 (9%) and 1 (5%) patients, respectively. One patient with neurocysticercosis and 1 patient with fungal meningitis died, and 5 (23%) had neurologic sequelae. Parasite infections, especially neurocysticercosis and toxocariasis, were the most common cause of eosinophilic meningitis in Korean patients. Fungal meningitis, while relatively rare, is often aggressive and must be considered when searching for the cause of eosinophilic meningitis.     

C-reactive proteins, immunoglobulin profile and mycobacterial antigens in cerebrospinal fluid of patients with pyogenic and tuberculous meningitis.

Cerebrospinal fluid (CSF) samples were collected from 12 patients with pyogenic meningitis (PM), 19 with tuberculous meningitis (TBM), 20 with clinically suspected but not definitely proved cases of tuberculous meningitis (STBM) and 12 normal controls. C-reactive proteins, immunoglobulins G, A, M and mycobacterial antigens were estimated in the CSF samples. Seven out of 51 (13.7%) samples obtained from the patient groups were positive for CRP. Immunoglobulins M and A were significantly raised in the PM group. When the TBM and STBM groups were compared with the controls a highly significant increase was obtained for all immunoglobulins. Mycobacterial antigens/epitopes were identified in 36.8% samples with TBAGB1 and TB68-H monoclonals and in 26.3% with WTB72-A2. In case of patients with suspected TBM, 6.6% were positive with TBAGB1 and WTB72-A2 and 13.3% with TB68-H. However, non-tuberculous patients also reacted with WTB72-A2 (10.5%) and TB68-H (21.0%). This is, to the authors' knowledge, the first report on the presence of CRP in the CSF. Technique for immunoglobulins in CSF is also updated in this paper. We infer that the monoclonal antibody TBAGB1 and immunoglobulins G and A may be safely considered as diagnostic markers of TBM. Estimation of CRP in CSF samples may be made to give a preliminary or additional diagnosis of meningitis regardless of its aetiology.     

Using PCR-based detection and genotyping to trace Streptococcus salivarius meningitis outbreak strain to oral flora of radiology physician assistant

We recently investigated three cases of bacterial meningitis that were reported from a midwestern radiology clinic where facemasks were not worn during spinal injection of contrast agent during myelography procedures. Using pulsed field gel electrophoresis we linked a case strain of S. salivarius to an oral specimen of a radiology physician assistant (RPA). We also used a real-time PCR assay to detect S. salivarius DNA within a culture-negative cerebrospinal fluid (CSF) specimen. Here we extend this investigation through using a nested PCR/sequencing strategy to link the culture-negative CSF specimen to the case strain. We also provide validation of the real-time PCR assay used, demonstrating that it is not solely specific for Streptococcus salivarius, but is also highly sensitive for detection of the closely related oral species Streptococcus vestibularis. Through using multilocus sequence typing and 16S rDNA sequencing we further strengthen the link between the CSF case isolate and the RPA carriage isolate. We also demonstrate that the newly characterized strains from this study are distinct from previously characterized S. salivarius strains associated with carriage and meningitis.     

Scrub Typhus Meningitis in South India — A Retrospective Study

Background

Scrub typhus is prevalent in India although definite statistics are not available. There has been only one study on scrub typhus meningitis 20 years ago. Most reports of meningitis/meningoencephalitis in scrub typhus are case reports

Methods

A retrospective study done in Pondicherry to extract cases of scrub typhus admitted to hospital between February 2011 and January 2012. Diagnosis was by a combination of any one of the following in a patient with an acute febrile illness- a positive scrub IgM ELISA, Weil-Felix test, and an eschar. Lumbar puncture was performed in patients with headache, nuchal rigidity, altered sensorium or cranial nerve deficits.

Results

Sixty five cases of scrub typhus were found, and 17 (17/65) had meningitis. There were 33 males and 32 females. Thirteen had an eschar. Median cerebrospinal fluid (CSF) cell count, lymphocyte percentage, CSF protein, CSF glucose/blood glucose, CSF ADA were 54 cells/µL, 98%, 88 mg/dL, 0.622 and 3.5 U/mL respectively. Computed tomography was normal in patients with altered sensorium and cranial nerve deficits. Patients with meningitis had lesser respiratory symptoms and signs and higher urea levels. All patients had received doxycycline except one who additionally received chloramphenicol.

Conclusion

Meningitis in scrub typhus is mild with quick and complete recovery. Clinical features and CSF findings can mimic tuberculous meningitis, except for ADA levels. In the Indian context where both scrub typhus and tuberculosis are endemic, ADA and scrub IgM may be helpful in identifying patients with scrub meningitis and in avoiding prolonged empirical antituberculous therapy in cases of lymphocytic meningitis.     

Leukocyte Attraction by CCL20 and Its Receptor CCR6 in Humans and Mice with Pneumococcal Meningitis

We previously identified CCL20 as an early chemokine in the cerebrospinal fluid (CSF) of patients with pneumococcal meningitis but its functional relevance was unknown. Here we studied the role of CCL20 and its receptor CCR6 in pneumococcal meningitis. In a prospective nationwide study, CCL20 levels were significantly elevated in the CSF of patients with pneumococcal meningitis and correlated with CSF leukocyte counts. CCR6-deficient mice with pneumococcal meningitis and WT mice with pneumococcal meningitis treated with anti-CCL20 antibodies both had reduced CSF white blood cell counts. The reduction in CSF pleocytosis was also accompanied by an increase in brain bacterial titers. Additional in vitro experiments showed direct chemoattractant activity of CCL20 for granulocytes. In summary, our results identify the CCL20-CCR6 axis as an essential component of the innate immune defense against pneumococcal meningitis, controlling granulocyte recruitment.     

布氏杆菌脑膜炎病例报道2例及文献复习

目的:目前布氏杆菌性脑膜炎在国内只是偶见报道,本文报道2例布氏杆菌性脑膜炎,对其诊断及治疗进行探讨,并对布氏杆菌脑膜炎进行文献回顾.方法:我们近期连续通过检查脑脊液内布氏杆菌抗体的办法诊断了2例布氏杆菌性脑膜炎,并通过给予四环素、利福霉素及链霉素治疗1个月并通过随访.结果:半年后脑脊液内布氏杆菌抗体恢复阴性,临床症状完全消失.结论:通过我们的观察应用上述3联药物综合治疗1月对布氏杆菌性脑膜炎是有效的.     

Correlation between culture of Mycobacterium tuberculosis and antimycobacterial antibody in lumbar, ventricular and cisternal cerebrospinal fluids of patients with tuberculous meningitis.

In this study positive culture for M. tuberculosis were obtained, 20% in lumbar cerebrospinal fluid (CSF), 75% in ventricular CSF and 87.5% in cisternal CSFs of patients with tuberculous meningitis. Low culture positivity in lumbar CSF is due to the low density of circulating tubercle bacilli in lumbar CSF than in cisternal or ventricular CSFs. However antimycobacterial antibody in lumbar, cisternal and ventricular CSFs circulate in significant titres and are not statistically different from one another. Since specimens of CSF can not be obtained from cisternal or ventricular routes for the routine bacteriological investigations in patients with tuberculous meningitis, detection of antimycobacterial antibody of M. tuberculosis antigen 5 in lumbar CSF by an indirect ELISA may be considered as an aid for the diagnosis of tuberculous meningitis, particularly when repeated CSF cultures are negative for M. tuberculosis.     

Gram-negative bacillary community acquired meningitis is not a rare entity in last two decades

The aim of this short note is to assess gram-negative bacillary community acquired meningitis (CBM) and nosocomial meningitis (NM) within 17 years nationwide survey. All cases of gram-negative bacillary CBM within 1990-2007 were assessed in national database of 372 patients with bacterial meningitis: 69 of gram-negative cases were nosocomial and 24 of gram-negative meningitis cases were CBM. Those 24 cases were compared with all CBM (201 cases) for risk factors and outcome. Among nosocomial gram-negative pathogens, A. baumannii in 23 cases, Ps. aeruginosa in 15 cases and Enterobacteriaceae in 31 cases were isolated. Among CBM, in 13 cases Enterobacteriaceae (Escherichia coli 6, Klebsiella pneumoniae 3, Proteus mirabilis 2, Enterobacter cloacae 2), in 5 cases Ps. aeruginosa and in 6 cases Acinetobacter baumannii were isolated from cerebrospinal fluid (CSF). The only significant risk factor for CBM due to gram-negative bacilli was neonatal age (12.5% vs. 3.5%, p=0.04) as underlying disease. However, mortality among gram-negative bacillary meningitis was significantly higher (12.4% vs. 37.5%, p=0.001) in comparison to other meningitis.     

Bronchioloalveolar carcinoma presenting with meningeal carcinomatosis. Cytologic diagnosis in cerebrospinal fluid

The cytologic findings in a 35-year-old patient with bronchioloalveolar carcinoma who initially presented with central nervous system involvement are reported. Following the cytologic diagnosis of carcinomatous meningitis (metastatic adenocarcinoma), an open lung biopsy was performed, which confirmed the presence of a primary pulmonary neoplasm (bronchioloalveolar carcinoma). This case illustrates the importance of the cytologic diagnosis of a clinically unsuspected primary neoplasm. Further, together with three earlier reported cases, it indicates that, in young patients, tumor cells shedding into the cerebrospinal fluid can be the first indication of bronchioloalveolar carcinoma.     

系统性红斑狼疮并发隐球菌性脑膜炎:1例报告并文献复习

目的探讨系统性红斑狼疮(SLE)合并隐球菌性脑膜炎的诊断及鉴别诊断。方法对1例SLE并发隐球菌性脑膜炎患者的临床及实验室检查特点进行分析,并结合文献复习进行讨论。结果患者出现中枢感染前长期使用泼尼松治疗,曾误诊为狼疮脑病应用激素冲击治疗无效;治疗过程中出现狼疮活动,激素加量后症状缓解。结论 SLE并发隐球菌性脑膜炎患者的临床表现缺乏特异性,感染相关症状与SLE表现部分重叠,腰穿脑脊液墨汁染色找隐球菌和隐球菌抗原乳胶凝集试验是诊断的主要手段。及时诊断和有效抗真菌治疗可改善患者的预后。     

A Multi-Target Real-Time PCR Assay for Rapid Identification of Meningitis-Associated Microorganisms

A central nervous system (CNS) infection, such as meningitis, is a serious and life-threatening condition. Bacterial meningitis can be severe and may result in brain damage, disability or even death. Rapid diagnosis of CNS infections and identification of the pathogenic microorganisms are needed to improve the patient outcome. Bacterial culture of a patient??s cerebrospinal fluid (CSF) is currently considered the ??gold standard?? for diagnosing bacterial meningitis. From the CSF cultures researchers can assess the in vitro susceptibility of the causative microorganism to determine the best antibiotic treatment. However, many of the culture assays, such as microscopy and the latex agglutination test are not sensitive. To enhance pathogen detection in CSF samples we developed a multi-target real-time PCR assay that can rapidly identify six different microorganisms: Streptococcus pneumoniae, Neisseria meningitidis, Haemophilus influenzae, Streptococcus agalactiae, Listeria monocytogenes and Cryptococcus neoformans. In this study we applied this PCR analysis to 296 CSF samples from patients who were suspected of having meningitis. Of the 296 samples that were examined, 59 samples were positive according to the CSF culture and/or molecular assays. Forty-six CSF samples were positive for both the CSF culture and our real-time PCR assay, while 13 samples were positive for the real-time PCR but negative for the traditional assays. This discrepancy may have been caused by the fact that these samples were collected from 23 patients who were treated with antimicrobials before CSF sampling.     

Mediators and biomarkers of inflammation in meningitis: Cytokine and peptidome profiling of cerebrospinal fluid

Differential diagnosis of bacterial and viral meningitis is an urgent problem of the modern clinical medicine. Early and accurate detection of meningitis etiology largely determines the strategy of its treatment and significantly increases the likelihood of a favorable outcome for the patient. In the present work, we analyzed the peptidome and cytokine profiles of cerebrospinal fluid (CSF) of 17 patients with meningitis of bacterial and viral etiology and of 20 neurologically healthy controls. In addition to the identified peptides (potential biomarkers), we found significant differences in the cytokine status of the CSF of the patients. We found that cut-off of 100 pg/ml of IL-1β, TNF, and GM-CSF levels discriminates bacterial and viral meningitis with 100% specificity and selectivity. We demonstrated for the first time the reduction in the level of two cytokines, IL-13 and GM-CSF, in the CSF of patients with viral meningitis in comparison with the controls. The decrease in GM-CSF level in the CSF of patients with viral meningitis can be explained by a disproportionate increase in the levels of cytokines IL-10, IFN-γ, and IL-4, which inhibit the GM-CSF expression, whereas IL-1, IL-6, and TNF activate it. These observations suggest an additional approach for differential diagnosis of bacterial and viral meningitis based on the normalized ratio IL-10/IL-1β and IL-10/TNF > 1, as well as on the ratio IFN-γ/IL-1β and IFN-γ/ TNF < 0.1. Our findings extend the panel of promising clinical and diagnostic biomarkers of viral and bacterial meningitis and reveal opposite changes in the cytokine expression in meningitis due to compensatory action of proand antiinflammatory factors.     

Interferon in the Cerebrospinal Fluid of Children with Central Nervous System Disorders

Interferon was detected in the cerebrospinal fluid (CSF) of 26 of 51 children with aseptic meningitis, two of 44 with bacterial meningitis, and four of 118 with miscellaneous conditions including encephalitis, convulsive disorders and leukemia with neurological involvement. The geometric mean titre of interferon in mumps meningitis was seven to eight times higher than that in enteroviral meningitis; however, levels of interferon were not related to the concentration of leukocytes in CSF from these patients. Interferon titres were relatively greater at the height of the febrile response in children with mumps meningitis or enteroviral meningitis. There was no association between the presence of interferon in the CSF and the isolation of mumps virus or an enterovirus from the same specimen. Patients frequently developed homologous antibody one to three days after signs of aseptic meningitis, obscuring the relationship of interferon production to clinical improvement.     

IgG antibody to Mycobacterium tuberculosis antigen-5 in cerebrospinal fluid and its diagnostic application in tuberculous meningitis

IgG antibody to M. tuberculosis antigen-5 was detected by non-competitive ELISA in cerebrospinal fluid specimens (CSF), from 40 patients with clinical diagnosis of tuberculous meningitis and in 42 patients of non-tuberculous neurological diseases. The geometric mean antibody titer in CSF specimen for tuberculous and non-tuberculous groups were 156 and 8 respectively. The antibody titer in CSF specimens showed no correlation to IgG levels, tuberculin reactor status and duration of chemotherapy in patients with tuberculous meningitis. At a dilution end-point 1:40, the assay had a sensitivity of 84% and specificity of 92%. However at dilution end-point 1:80, the specificity of the assay could be increased to 100% but sensitivity of the assay decreased to 75%. IgG antibody detection against M. tuberculosis antigen-5 by non-competitive ELISA, described in this communication has potential application in the laboratory diagnosis of tuberculous meningitis, particularly in developing countries where the incidence and prevalence of tuberculous meningitis is still high. In culture-negative cases of tuberculous meningitis, non-competitive ELISA could be applied as an alternative diagnostic tool.     

Direct PCR assay for detection ofNeisseria meningitidis in human cerebrospinal fluid

A PCR amplification was performed to detectNeisseria meningitidis insertion sequence1106 (IS-1106) in the humancerebrospinalfluid (CSF) in cases of meningitis. The study included 27 CSF samples from suspected meningitis patients. Although the inflammatory response in most of the samples was slightly increased, the results showed that 7 (26%) and 8 (30%) CSF samples were diagnosed as meningococcal meningitis by Gram staining and by culture, respectively. The primers of theIS-1106 were used for direct diagnosis ofN. meningitidis in the human spinal fluid after a minor treatment of the CSF samples. The sample was diagnosed as meningococcal meningitis, if a DNA band of about 600 bp was detected in the ethidium bromide-stained agarose gel. The 27 CSF samples were analyzed in a random manner. Of these, 18 samples including the Gram staining- and culture-positive samples were also positive in PCR amplification. However, a CSF sample, which was diagnosed to be meningococcal meningitis in culture was negative in both Gram staining and PCR analysis. The specificity of theIS-1106 primers was determined to be 95%, with 100% sensitivity in comparison to Gram staining and culture. The primers were sensitive to 10 pg or more of meningococcal DNA. In addition, the PCR amplification showed high predictive values (89 and 100%) in diagnosing meningitis in patients that were negative and positive responders when tested by culture and by Gram staining. In conclusion, the PCR amplification ofIS-1106 ofN. meningitidis is specific and sensitive to both culture-positive and-negative meningococcal meningitis. Hence, PCR assay is highly recommended for use in a rapid diagnosis of suspected meningitis patients.