Amoxicillin-induced aseptic meningitis: clinical features, diagnosis and management.

OBJECTIVES: The clinical features of aseptic meningitis associated with amoxicillin are unknown. The main objective of this study was to investigate the clinical characteristics of amoxicillin-induced aseptic meningitis (AIAM) and provide a reference for clinical diagnosis and treatment. METHODS: AIAM-related studies were collected by searching the relevant databases from inception to October 31, 2022. RESULTS: AIAM usually occurred 3 h to 7 days after amoxicillin administration in 13 males and 9 females. Twenty-one patients (95.5%) had recurrent AIAM with a total of 62 episodes. Fever (19 cases, 86.4%) and headache (18 cases, 81.8%) were the most common symptoms. Typical cerebrospinal fluid (CSF) findings were leukocytosis (100%) with lymphocytic predominance (14 cases, 63.6%), elevated protein (20 cases, 90.1%), normal glucose (21 cases, 95.5%) and negative culture (21 cases, 100%). Brain magnetic resonance imaging showed mild meningeal enhancement in one patient. The symptoms resolved mainly within 1-4 days after drug discontinuation in all patients. CONCLUSION: Clinical attention should be given to the adverse effects of AIAM. The medication history of patients with suspected meningitis should be investigated to avoid unnecessary examination and antibiotic treatment.

Pathological Characteristics of Echovirus 30 Infection in a Mouse Model.

Echovirus 30 (E30), a member of species B enterovirus, is associated with outbreaks of aseptic meningitis and has become a global health emergency. However, the pathogenesis of E30 remains poorly understood due to the lack of appropriate animal models. In this study, we established a mouse infection model to explore the pathogenicity of E30. The 2-day-old IFNAR-/- mice infected with E30 strain WZ16 showed lethargy and paralysis, and some died. Obvious pathological changes were observed in the skeletal muscle, brain tissue, and other tissues, with the highest viral load in the skeletal muscles. Transcriptome analysis of brain and skeletal muscle tissues from infected mice showed that significant differentially expressed genes were enriched in complement response and neuropathy-related pathways. Using immunofluorescence assay, we found that the viral double-stranded RNA (dsRNA) was detected in the mouse brain region and could infect human glioma (U251) cells. These results indicated that E30 affects the nervous system, and they provide a theoretical basis for understanding its pathogenesis. IMPORTANCE Echovirus 30 (E30) infection causes a wide spectrum of diseases with mild symptoms, such as hand, foot, and mouth disease (HFMD), acute flaccid paralysis, and aseptic meningitis and other diseases, especially one of the most common pathogens causing aseptic meningitis outbreaks. We established a novel mouse model of E30 infection by inoculating neonatal mice with clinical isolates of E30 and observed the pathological changes induced by E30. Using the E30 infection model, we found complement responses and neuropathy-related genes in the mice tissues at the transcriptome level. Moreover, we found that the viral dsRNA localized in the mouse brain and could replicate in human glioma cell line U251 rather than in the neuroblastoma cell line, SK-N-SH.

Pathological Features of Echovirus-11-Associated Brain Damage in Mice Based on RNA-Seq Analysis.

Echovirus 11 (E11) is a neurotropic virus that occasionally causes fatal neurological diseases in infected children. However, the molecular mechanism underlying the disease and pathological spectrum of E11 infection remains unclear. Therefore, we modelled E11 infection in 2-day-old type I interferon receptor knockout (IFNAR-/-) mice, which are susceptible to enteroviruses, with E11, and identified symptoms consistent with the clinical signs observed in human cases. All organs of infected suckling mice were found to show viral replication and pathological changes; the muscle tissue showed the highest viral replication, whereas the brain and muscle tissues showed the most obvious pathological changes. Brain tissues showed oedema and a large number of dead nerve cells; RNA-Seq analysis of the brain and hindlimb muscle tissues revealed differentially expressed genes to be abundantly enriched in immune response-related pathways, with changes in the Guanylate-binding protein (GBP) and MHC class genes, causing aseptic meningitis-related symptoms. Furthermore, human glioma U251 cell was identified as sensitive target cells for E11 infection. Overall, these results provide new insights into the pathogenesis and progress of aseptic meningitis caused by E11.

Multifocal Gorham-Stout disease associated with Chiari I malformation and recurrent aseptic meningitis: Case report and review of literature.

Gorham-Stout disease is a rare condition of uncertain aetiology characterised by lymphatic proliferation within osseous structures and subsequent massive osteolysis. This report describes the index case of a patient with multifocal Gorham-Stout disease involving the skull base with Chiari I malformation and recurrent aseptic meningitis without fistula. A five-year-old male presented following decompression of a Chiari I malformation with headaches, vomiting, and stiff neck and cerebrospinal fluid pleocytosis without growth of a pathogenic organism. Ongoing symptoms prompted a further three presentations over several months revealing persistent aseptic cerebrospinal fluid monocytic pleocytosis. Further investigation revealed multifocal osseous cystic disease and subsequent bone biopsy suggested Gorham-Stout disease. Suboccipital decompression was not repeated despite craniocervical junction re-stenosis. A literature review demonstrated the extreme rarity of Gorham-Stout disease associated with Chiari I malformation and meningitis. Potential mechanisms of these entities occurring in concert are discussed. Consideration of Gorham-Stout disease as a secondary cause for Chiari I malformation is important amid local bone changes or cerebrospinal fluid leakage prior to pursuing suboccipital decompression considering the poor outcomes reported.

Eosinopenia as a marker of diagnosis and prognostic to distinguish bacterial from aseptic meningitis in pediatrics.

Procalcitonin (PCT) has proven its efficacy to distinguish bacterial from aseptic meningitis in children. Nevertheless, its use in routine is limited by its cost and availability, especially in low- and middle-income countries. It is now acknowledged that eosinopenia is a marker of infection and/or severity of the systemic inflammatory response. Although no study ever demonstrated that eosinopenia could differentiate bacterial from viral infection, we decided to conduct a study concerning meningitis in children. This bicentric and retrospective study was conducted between January 2012 and October 2018, in children hospitalized for meningitis. The white blood cell was systematically gathered at the admission to evaluate the eosinophil count. Characteristic data were compared between 2 groups: documented bacterial meningitis (DBP) and aseptic meningitis which includes documented viral meningitis (DVM) and non-documented meningitis (ND). Among 190 patients admitted for meningitis, 151 were analyzed, including DBM (n = 45), DVM (n = 73), and ND (n = 33) meningitis. Groups were comparable. Mean age was 33 ± 48 months with a sex ratio of 1.6. Mean of eosinophil count was 15 ± 34/mm3 in the DBM group versus 132 ± 167/mm3 for the aseptic meningitis group (p < 0.0001). Best threshold for the diagnosis of bacterial meningitis was an eosinophil count < 5/mm3 with a sensitivity of 80% and specificity of 73% and a likelihood ratio of 2.9. Eosinopenia seems to be a reliable and non-invasive marker of bacterial meningitis in pediatrics. The absence of extra cost makes it very interesting in low- and middle-income countries or when usual biomarkers such as PCT are unavailable.

A Rare Manifestation of a Rare Disease: Mantle Cell Lymphoma Presenting With Aseptic Meningitis.

Mantle cell lymphoma (MCL) is a rare form of non-Hodgkin lymphoma characterized by clonal proliferation of follicular mantle zone B lymphocytes. It is caused by abnormal chromosomal translocation t(11;14) resulting in aberrant expression of cyclin D1. This leads to activation of anti-apoptotic pathways and abnormal proliferation of MCL cells. Patients can present with an indolent course or a fulminant disease with short overall survival. The disease frequently involves extranodal organs, but rarely manifests with neurological symptoms. We report a rare case of aberrant CD5-negative MCL presenting with aseptic meningitis.

[Aseptic meningitis associated to mumps during an epidemic outbreak]. / Meningitis aséptica en pacientes con parotiditis viral durante un brote epidémico.

We report two cases of acute aseptic meningitis associated to mumps in middle-aged women, one pregnant. Both presented shortly after parotid gland enlargement. Neurological complications were suspected by headache, fever and meningeal signs and confirmed by CSF findings (mononuclear predominant pleocytosis) with negative results for alternative causes. Mumps were confirmed by positive IgM and IgG serology. Both patients were discharged with a favorable evolution and complete disappearance of symptoms. Cases were concurrent with a regional mumps outbreak. Conclusions: Aseptic meningitis is a rare mumps-associated neurological complication. Its diagnostic can be achieved by precedent parotid enlargement, mononuclear pleocytosis in the CSF and positive IgM and IgG serology or viral detection by PCR in urine or salivary samples. This complication would be more probably observed during mumps outbreaks.

Outbreak of aseptic meningitis caused by echovirus 30 in Kushiro, Japan in 2017.

BACKGROUND: Echovirus 30 (E30) is one of the most common causative agents for aseptic meningitis. OBJECTIVES: In the autumn of 2017, there was an outbreak caused by E30 in Kushiro, Hokkaido, Japan. The aim of this study was to characterize this outbreak. STUDY DESIGN: Fifty-nine patients were admitted to the Department of Pediatrics, Kushiro Red Cross Hospital (KRCH) with clinical diagnosis of aseptic meningitis. Among those, 36 patients were finally diagnosed as E30-associated aseptic meningitis by the detection of viral RNA using reverse transcription-polymerase chain reaction (RT-PCR) and/or the evidence of more than four-fold rise in neutralizing antibody (NA) titers in the convalescent phase relative to those in the acute phase. We investigated these 36 confirmed cases. RESULTS: The median age was 6 years (range: 6 months-14 years). The positive signs and symptoms were as follows: fever (100%), headache (94%), vomiting (92%), jolt accentuation (77%), neck stiffness (74%), Kernig sign (29%), and abdominal pain (28%). The median cerebrospinal fluid (CSF) white cell count, neutrophil count, and lymphocyte count were 222/µL (range: 3-1434/µL), 144/µL (range: 1-1269/µL), and 85/µL (range: 2-354/µL), respectively. Although the detected viral genes demonstrated same cluster, they were different from E30 strains observed in Japan between 2010 and 2014. CONCLUSION: We mainly showed clinical and virological features of the E30-associated aseptic meningitis outbreak that occurred in Kushiro. To prevent further spread of E30 infection, continuous surveillance of enterovirus (EV) circulation and standard precautions are considered essential.

Meningitis aséptica en pacientes con parotiditis viral durante un brote epidémico / Aseptic meningitis associated to mumps during an epidemic outbreak

Resumen Comunicamos dos casos de meningitis aséptica asociadas a parotiditis viral en mujeres de edad mediana, una de ellas embarazada. Ambas se presentaron pocos días después del aumento de volumen parotídeo, con cefalea, fiebre y signos meníngeos, pleocitosis de predominio mononuclear en el LCR y resultados negativos para otras causas. La parotiditis fue confirmada por serología IgG e IgM positiva. Las pacientes tuvieron una evolución favorable con desaparición total de sus síntomas. Ambos casos ocurrieron durante un brote regional de parotiditis. La meningitis aséptica es una complicación frecuente de las parotiditis. Su diagnóstico puede lograrse por el aumento de volumen glandular precedente, la pleocitosis de predominio mononuclear en el LCR y una serología IgM e IgG positiva o detección genómica por RPC en muestra urinaria o salival. Esta complicación es más probable que sea observada durante brotes de parotiditis viral.

We report two cases of acute aseptic meningitis associated to mumps in middle-aged women, one pregnant. Both presented shortly after parotid gland enlargement. Neurological complications were suspected by headache, fever and meningeal signs and confirmed by CSF findings (mononuclear predominant pleocytosis) with negative results for alternative causes. Mumps were confirmed by positive IgM and IgG serology. Both patients were discharged with a favorable evolution and complete disappearance of symptoms. Cases were concurrent with a regional mumps outbreak. Conclusions: Aseptic meningitis is a rare mumps-associated neurological complication. Its diagnostic can be achieved by precedent parotid enlargement, mononuclear pleocytosis in the CSF and positive IgM and IgG serology or viral detection by PCR in urine or salivary samples. This complication would be more probably observed during mumps outbreaks.

Direct vascular channels connect skull bone marrow and the brain surface enabling myeloid cell migration.

Innate immune cells recruited to inflammatory sites have short life spans and originate from the marrow, which is distributed throughout the long and flat bones. While bone marrow production and release of leukocyte increases after stroke, it is currently unknown whether its activity rises homogeneously throughout the entire hematopoietic system. To address this question, we employed spectrally resolved in vivo cell labeling in the murine skull and tibia. We show that in murine models of stroke and aseptic meningitis, skull bone marrow-derived neutrophils are more likely to migrate to the adjacent brain tissue than cells that reside in the tibia. Confocal microscopy of the skull-dura interface revealed myeloid cell migration through microscopic vascular channels crossing the inner skull cortex. These observations point to a direct local interaction between the brain and the skull bone marrow through the meninges.

Vaccine-associated paralytic poliomyelitis in a patient with acute lymphocytic leukemia.

We report a case of vaccine-associated paralytic poliomyelitis (VAPP) in an immunocompromised patient with acute lymphocytic leukemia who was initially diagnosed with aseptic meningitis. Isolation of Sabin-like type 1 poliovirus from the patient's cerebrospinal fluid made this a case of vaccine-related poliovirus (VRPV) infection. The patient developed paralysis and respiratory distress and deceased a few months after onset of paralysis with respiratory failure. This tragic case report highlights the emergence of VAPP and indicates the importance of timely diagnosis of VRPV infections to improve clinical management of VRPV-infected patients and to prevent the devastating consequences of silent introduction of VRPVs in treatment wards and eventually in the society.

Fatal Meningitis in Swine after Intrathecal Administration of Adeno-associated Virus Expressing Syngeneic Interleukin-10.

Interleukin-10 (IL-10) delivered by intrathecal (i.t.) gene vectors is a candidate investigational new drug (IND) for several chronic neurological disorders such as neuropathic pain. We performed a preclinical safety study of IL-10. A syngeneic large animal model was used delivering porcine IL-10 (pIL-10) to the i.t. space in swine by adeno-associated virus serotype 8 (AAV8), a gene vector that was previously found to be nontoxic in the i.t. space. Unexpectedly, animals became ill, developing ataxia, seizures, and an inability to feed and drink, and required euthanasia. Necropsy demonstrated lymphocytic meningitis without evidence of infection in the presence of normal laboratory findings for body fluids and normal histopathology of peripheral organs. Results were replicated in a second animal cohort by a team of independent experimenters. An extensive infectious disease and neuropathology workup consisting of comprehensive testing of tissues and body fluids in a specialized research veterinary pathology environment did not identify a pathogen. These observations raise the concern that i.t. IL-10 therapy may not be benign, that previously used xenogeneic models testing the human homolog of IL-10 may not have been sensitive enough to detect toxicity, and that additional preclinical studies may be needed before clinical testing of IL-10 can be considered.

Enterovirus-D68 in the Cerebrospinal Fluid of Two Children with Aseptic Meningitis.

This case report describes two previously healthy children with aseptic meningitis whose cerebrospinal fluid was positive for enterovirus-D68, which indicates direct involvement of this infectious agent in the development of this neurologic disease.

Cerebrospinal fluid white cell count: discriminatory or otherwise for enteroviral meningitis in infants and young children?

Non-polio enteroviruses (EV) are the most common viruses causing aseptic meningitis in children. We aim to evaluate the cerebrospinal fluid (CSF) characteristics of neonates and children with EV meningitis with a view to determine whether it could be discriminatory or otherwise in making a positive diagnosis. We performed a 3-year (July 2008-July 2011) retrospective study of children ≤16 years, treated at a tertiary children's hospital, with positive CSF EV polymerase chain reaction (PCR) and negative blood and CSF bacterial cultures. A total of 206 children were studied. The median CSF white cell count was 79 cells/mm(3) (range 0-4608 cells/mm(3)). CSF pleocytosis was observed in 99/150 (66%) aged ≤90 days, 3/4 (75%) aged 90 days-1 year, and 49/52 (94%) children ≥3 years. There was a huge variability in CSF pleocytosis in infants ≤90 days, where 34% of them had no pleocytosis, while in 66%, a wide range of pleocytosis that might even suggest bacterial meningitis was noted. CSF red cells were low, and protein or sugar values were not discriminatory. CSF pleocytosis in relation to increasing age was found to be statistically significant (p < 0.001). Early lumbar puncture within 48 h of symptoms and absence of CSF pleocytosis was also statistically significant (p = 0.039). CSF pleocytosis in EV meningitis is commoner in older children. As there was a huge variability in CSF pleocytosis in infants ≤90 days particularly, CSF analysis including EV PCR could avoid unnecessary antibiotic therapy.

Etiology of aseptic meningitis and clinical characteristics in immune-competent adults.

Viral meningitis is the most common cause of aseptic meningitis. Use of the polymerase chain reaction (PCR) has increased the ability to determine the etiology of viral meningitis. This study used PCR analysis to evaluate the etiology of aseptic meningitis in 177 previously healthy adults over a 5-year period, as well as analyzing the clinical characteristics, cerebrospinal fluid (CSF) findings, and prognosis according to each etiology. The most frequent cause of aseptic meningitis was enterovirus (EV), followed by varicella zoster virus (VZV). Patients with EV meningitis were significantly younger than those with VZV meningitis. The percentage of lymphocytes in white blood cell counts and protein concentrations in the CSF differed significantly among patients with EV, VZV and meningitis of undetermined etiology. Younger age and lower percentage of lymphocyte and protein level in CSF analysis may be suggestive of EV meningitis. Further prospective studies are warranted to identify the correlations between the clinical characteristics and the etiologies of meningitis.

Incidence and natural history of intravenous immunoglobulin-induced aseptic meningitis: a retrospective review at a single tertiary care center.

BACKGROUND: Aseptic meningitis is a rare but significant complication of intravenous immunoglobulin (IVIG) therapy. The majority of literature is limited to case reports, so the true incidence of this complication is uncertain. STUDY DESIGN AND METHODS: A retrospective review of all cases of IVIG-associated adverse transfusion reactions was performed at London Health Sciences Centre (LHSC) from January 1, 2008, to December 31, 2013. All reported transfusion reactions were evaluated to identify cases of aseptic meningitis due to IVIG. All documented IVIG infusions and lumbar punctures performed during the study period were reviewed; patients with both interventions were identified and further chart review was performed to identify aseptic meningitis. RESULTS: During our study period, 1324 unique patients received a total of 11,907 IVIG infusions (554,566 g) for various conditions. Eight cases of aseptic meningitis were identified, suggesting an overall incidence of 0.60% for all patients and 0.067% for all IVIG infusions. Patients presented with symptoms within 24 to 48 hours of the infusion and were treated with antibiotics initially. The reactions were self-limited, as symptoms self-resolved within 5 to 7 days. Treatment was supportive, with subsequent IVIG infusions likely requiring preinfusion medication or possibly a switch in product formulation. CONCLUSION: This review of IVIG-induced aseptic meningitis over a 6-year period identifies a more robust estimate of incidence and risk of 0.60% and 0.067% for all patients and infusions, respectively. Given that this complication can mimic infectious meningitis and cause considerable morbidity, physicians need to be aware of this rare but important condition.