Impacto de la implantación de la reacción en cadena de la polimerasa a enterovirus en el manejo de la meningitis aséptica / Impact of introducing an enterovirus polymerase chain reaction in the management of aseptic meningitis

INTRODUCCIÓN: El diagnóstico de meningitis aséptica basado en la reacción en cadena de la polimerasa (PCR) frente a enterovirus en líquido cefalorraquídeo es un método rápido y sensible. OBJETIVO: Valorar la influencia de la implantación de la PCR a enterovirus en el uso de antibióticos y la estancia hospitalaria en meningitis aséptica. MATERIAL Y MÉTODOS: Estudio prospectivo de ni˜nos con meningitis aséptica durante un a˜no, utilizando como grupo control a pacientes previos a la implantación de la técnica. RESULTADOS: La realización de la PCR se asoció a un menor uso de antibióticos respecto al grupo control (16,2% vs. 41,4%; p = 0,029), a un menor tiempo de administración (0,54 vs. 2 días; p = 0,014) y a una disminución no significativa de la duración del ingreso (3,57 vs. 4,21 días; p = 0,376). CONCLUSIÓN: La implantación de la PCR a enterovirus disminuye la utilización de antibióticos y la estancia hospitalaria

INTRODUCTION: The diagnosis of aseptic meningitis, based on an enterovirus PCR (EV-PCR) in cerebrospinal fluid, is a rapid and sensitive test. OBJECTIVE: To assess the impact of introducing EV-PCR on the use of antibiotics and hospital length of stay in aseptic meningitis. MATERIAL AND METHODS: A prospective study that included children with aseptic meningitis during one year. The patients prior to the introduction of the test formed the control group. RESULTS: The performance of the PCR test was associated with less use of antibiotics compared to the control group (16.2% vs 41.4%, P = .029) and with fewer days of administration (.54 vs. 2 days, P=.014). A non-significant decrease in length of stay (3.57 vs. 4.21 days, P=.376) was also observed in the study group. CONCLUSION: The introduction of the EV-PCR test decreases the use of antibiotics and hospital length of stay

Poly(ADP-ribose) polymerase-1 inhibition in brain endothelium protects the blood-brain barrier under physiologic and neuroinflammatory conditions.

Blood-brain barrier (BBB) dysfunction seen in neuroinflammation contributes to mortality and morbidity in multiple sclerosis, encephalitis, traumatic brain injury, and stroke. Identification of molecular targets maintaining barrier function is of clinical relevance. We used a novel in vivo model of localized aseptic meningitis where tumor necrosis factor alpha (TNFα) was introduced intracerebrally and surveyed cerebral vascular changes and leukocyte-endothelium interactions by intravital videomicroscopy. Poly(ADP-ribose) polymerase-1 (PARP) inhibition significantly reduced leukocyte adhesion to and migration across brain endothelium in cortical microvessels. PARP inactivation diminished BBB permeability in an in vivo model of systemic inflammation. PARP suppression in primary human brain microvascular endothelial cells (BMVEC), an in vitro model of BBB, enhanced barrier integrity and augmented expression of tight junction proteins. PARP inhibition in BMVEC diminished human monocyte adhesion to TNFα-activated BMVEC (up to 65%) and migration (80-100%) across BBB models. PARP suppression decreased expression of adhesion molecules and decreased activity of GTPases (controlling BBB integrity and monocyte migration across the BBB). PARP inhibitors down-regulated expression of inflammatory genes and dampened secretion of pro-inflammatory factors increased by TNFα in BMVEC. These results point to PARP suppression as a novel approach to BBB protection in the setting of endothelial dysfunction caused by inflammation.

Role of cerebrospinal fluid IL-8 as a marker for differentiation between acute bacterial and aseptic meningitis.

No doubt, the distinguishing between bacterial and aseptic meningitis in the emergency department could help to limit unnecessary antibiotic use and hospital admissions. This study evaluated the role of cerebrospinal fluid IL-8 in differentiating acute bacterial meningitis (ABM) from aseptic meningitis (AM). A total of 80 hospitalized patients with clinical presentations of suspected acute meningitis were subjected to estimation of IL-8 CSF concentrations. The results showed that CSF IL-8 levels were higher in acute bacterial meningitis than in aseptic ones (p < 0.05). The best cut-off value of CSF IL8 for early diagnosis of bacterial meningitis was 3.6 ng/ml with a sensitivity of 82.5% and a specificity of 85.0%.

Complete factor I deficiency due to dysfunctional factor I with recurrent aseptic meningo-encephalitis.

PURPOSE: Complement regulators control the activated complement system. Defects in this homeostasis can result in tissue damage and autoimmune diseases with a heterogeneity in clinical presentation. Complement factor I (FI), a serine protease, is an important regulator of alternative pathway activation. We report a diagnostic work-up of a patient with relapsing inflammatory mediated meningo-encephalitis. Our work-up revealed a rare genetic factor I (FI) deficiency. So far, all cases of reported complete factor I deficiency have absent serum levels of FI. We present here a unique case of a complete factor I deficiency based on a functional FI defect. METHODS: Complement assays and measurement of FI activity were performed in the patient, her family, factor H-deficient patients, a patient with C3-nephritic factor and 11 healthy controls. Genetic sequencing of the FI coding regions in the patient and her parents was performed. RESULTS: The patient had absent alternative pathway activity with low levels of C3 and normal serum level of FI. The patient's plasma FI did not degrade C3b, with normalisation of C3b degradation after adding purified FI. Mutation analysis of the complement factor I gene revealed two heterozygous mutations (I322T and D506V). CONCLUSION: To our knowledge, this paper describes a complete FI deficiency caused by a defect of FI activity for the first time. Normal FI concentration does not exclude a complete FI defect, additional functional analysis of FI is required in any patient with a defect of complement activation. Recurrent aseptic meningo-encephalitis is a rare clinical presentation of complete FI deficiency.

Recurrent chemical meningitis in craniopharyngioma without reduction in size of cyst: case report of two cases and review of the literature.

Chemical meningitis is a rare phenomenon due to rupture of a craniopharyngioma cyst; it develops because of presence of cholesterol crystals in cyst fluid secreted by the squamous epithelium lining of the cyst. Spontaneous rupture of the cyst may present with or without meningitis, depending upon the cholesterol contents of cystic fluid of tumor. A decrease in the size of cyst may or may not be noted. Here we report two cases of craniopharyngioma, one which had a recurrent episode of chemical meningitis after surgery due to leak from residual component of the craniopharyngioma without evidence of recurrence of lesion, or decrease in the size of the cyst. Another case presented with initial symptoms and signs of meningitis, with no change in the size of the lesion after the second episode of chemical meningitis.

Adenine nucleotide hydrolysis in patients with aseptic and bacterial meningitis.

The meningitis is a disease with high mortality rates capable to cause neurologic sequelae. The adenosine (the final product of ATP hydrolysis by ectonucleotidases), have a recognized neuroprotective actions in the central nervous system (CNS) in pathological conditions. The aim of the present study was evaluate the adenine nucleotides hydrolysis for to verify one possible role of ATP, ADP and AMP hydrolysis in inflammatory process such as meningitis. The hydrolysis was verified in cerebrospinal fluid (CSF) from human patients with aseptic and bacterial meningitis. Our results showed that the ATP hydrolysis was reduced 12.28% (P < 0.05) in bacterial meningitis and 22% (P < 0.05) in aseptic meningitis. ADP and AMP hydrolysis increased 79.13% (P < 0.05) and 26.37% (P < 0.05) in bacterial meningitis, respectively, and 57.39% (P < 0.05) and 42.64% (P < 0.05) in aseptic meningitis, respectively. This may be an important protective mechanism in order to increase adenosine production.

A pilot study to detect high mobility group box 1 and heat shock protein 72 in cerebrospinal fluid of pediatric patients with meningitis.

OBJECTIVE: To determine whether cerebrospinal fluid (CSF) levels of high mobility group box 1 (HMGB1) or heat shock protein 72 (Hsp72) are elevated in patients with meningitis. DESIGN: Prospective study of four cohorts of patients. SETTING: Intensive care unit and infectious disease clinic of pediatrics at the Xiangya Hospital. PATIENTS: A total of 104 children (13 with bacterial meningitis, 38 with aseptic meningitis, 7 with tuberculous meningitis, and 46 without meningitis). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: At the time of admission, CSF samples were obtained from 104 patients with suspected meningitis and examined for the presence of invading pathogens, changes in CSF white blood cell counts, and protein and/or glucose concentrations. Based on CSF parameters, 13, 38, and 7 patients were diagnosed as having bacterial, aseptic, and tuberculous meningitis, respectively. All CSF samples were assayed for HMGB1 or Hsp72 using semiquantitative Western blot analysis. CSF levels of HMGB1 were elevated in patients with bacterial meningitis or aseptic meningitis but were four times higher in patients with bacterial meningitis vs. aseptic meningitis. There was a significant correlation between CSF HMGB1 levels and CSF white blood cell counts and glucose levels in patients with bacterial meningitis. Similarly, CSF levels of Hsp72 were significantly elevated in patients with bacterial meningitis or tuberculous meningitis and correlated well with CSF white blood cell counts in patients with bacterial meningitis or tuberculous meningitis. CONCLUSIONS: CSF levels of HMGB1 and Hsp72 were significantly higher in patients with bacterial meningitis than those with aseptic meningitis and correlated well with CSF white blood cell counts in patients with bacterial (but not aseptic) meningitis.

Thrombopoietin in the cerebrospinal fluid of patients with aseptic and bacterial meningitis.

Despite the recent evidence of the localization of thrombopoietin (TPO) and its receptor in the central nervous system (CNS), TPO protein concentrations in the cerebrospinal fluid (CSF) remained to be clarified. We previously reported that serum TPO is increased in children with meningitis. To determine changes in TPO concentrations in the CSF by meningitis and to explore the relationship between serum and CSF TPO concentrations, we measured TPO concentrations in 110 CSF samples and 33 serum/CSF pairs from 11 bacterial meningitis, 49 aseptic meningitis, and 50 nonmeningitis children. In only 12% (13 of 110) of CSF samples (0 bacterial meningitis, 8 aseptic meningitis, and 5 controls), TPO concentrations could be determined (24.1 +/- 29.0 pg/ml). CSF TPO concentrations did not significantly differ among the three groups and did not correlate with age. TPO concentrations in all serum samples were detectable, and mean concentrations in bacterial meningitis (510.6 +/- 237.0 pg/ml) were significantly higher than those in aseptic meningitis (136.6 +/- 71.6, p < 0.01) and controls (181.3 +/- 88.3, p < 0.01). These findings suggest that TPO is not produced in the CNS of patients with meningitis and that TPO did not cross the blood-brain barrier even during meningeal infection.

Free radicals in inflammatory neurological disease: increased lipid peroxidation and haptoglobin levels in Guillain Barré syndrome.

Oxidative damage in three inflammatory neurological disorders; Guillain Barré syndrome (GBS), multiple sclerosis and aseptic meningitis, were assessed by measuring the peroxidation of lipids in body fluids. The results were compared to a control group consisting of patients with either migraine, chronic/tension headaches, benign intracranial hypertension or psychological disorders. Antioxidant status was assessed by the measurement of the extracellular proteins, haptoglobin, albumin, caeruloplasmin and transferrin. The results of the study suggested that firstly, haptoglobin levels might be a useful, easily obtainable marker to aid the diagnosis of GBS. Secondly, free radical damage may be implicated in the pathology of GBS and therefore appropriate free radical scavenging might have beneficial effects.

Changes in cerebrospinal fluid and cerebrovascular endothelin concentrations during hypotension and hypertension in newborn piglets with induced sterile meningitis.

The effects of sterile meningitis on endothelin-1 (ET-1) and big ET-1 concentrations during hypotension and hypertension were studied in the cerebrospinal fluid and plasma of newborn piglets. Cerebrospinal fluid was obtained via cisterna magna puncture, and blood was obtained from the sagittal sinus vein and left subclavian artery. The study group consisted of 14 newborn piglets injected with 0.5 mL heat-killed group B streptococcus (GBS) (10(9) colony forming unit (cfu) equivalents), into the right cerebral lateral ventricle; the control group consisted of 10 newborn piglets injected with sterile normal saline, in a similar fashion. Hypotension (mean arterial blood pressure (MABP) 20-59 mmHg; 1 mmHg = 133.3 Pa) and hypertension (MABP 110-140 mmHg) were induced 1.5-2 h apart in random sequence in each animal, by inflating balloon-tipped catheters placed at the aortic root and descending aorta, respectively. Cerebral blood flow (CBF) was measured using radiolabeled microspheres, 15 min before and after injection of GBS or saline (normotension), during the hypotension and hypertension episodes, and during recovery normotension, immediately prior to cerebrospinal fluid and blood sampling. ET-1 and big ET-1 concentrations (pg/mL) were measured using radioimmunoassay kits. The combined effect of induced sterile meningitis and induced hypotension resulted in a significant rise in the concentration of cerebrospinal fluid ET-1 (control, 5.1 +/- 0.1; GBS, 9.3 +/- 0.2 pg/mL; p < 0.01), cerebrospinal fluid big ET-1 (control, 0; GBS, 18.1 +/- 2.7 pg/mL; p < 0.01), and sagittal sinus (cerebrovascular) big ET-1 (control, 15.5 +/- 4.2; GBS, 47.5 +/- 9.6 pg/mL; p < 0.01). In contrast, the combined effect of induced sterile meningitis and induced hypertension resulted in a marked elevation in cerebrovascular ET-1 concentrations (control, 9.5 +/- 0.9; GBS, 28.5 +/- 6.1 pg/mL; p < 0.01), with no significant change in cerebrospinal fluid concentrations. In addition, cerebrovascular production of ET-1 increased dramatically during hypertension in the GBS group (control, 0; GBS, 161.7 +/- 13.2 pg.min-1.100 g-1; p < 0.001), and was maintained during the recovery period (133.7 +/- 10.8 pg.min-1.100 g-1). Cerebrovascular ET-1 concentrations correlated significantly with total CBF and MABP in both groups of animals (control, r = 0.49, p < 0.002; GBS, r = 0.64, p < 0.0001), but the response was of a much greater magnitude in the GBS group. There was an inverse relationship between cerebrovascular big ET-1 concentrations and total CBF (r = -0.53, p < 0.0001) and MABP (r = -0.71, p < 0.0001) in the GBS group. In the MABP range of 60-110 mmHg a positive relationship was observed between cerebrovascular ET-1 concentrations and cerebral vascular resistance, in the control group only (r = 0.59, p < 0.002). The combined insult of induced sterile meningitis and induced hypotension or hypertension may be associated with increased cerebrovascular ET-1 and (or) big ET-1 concentrations. Changes in these vasoactive agents may contribute to pressure passivity of CBF in the newborn with meningitis.

Elevated biopterin and homovanillic acid levels in cerebrospinal fluid from children with aseptic meningitis.

To examine biopterin fractions and biogenic amine metabolites in cerebrospinal fluid in aseptic meningitis, the concentrations of homovanillic acid, 5-hydroxyindoleacetic acid, and the total, the oxidized form, and the reduced form of biopterin were determined in cerebrospinal fluid specimens from 15 children with aseptic meningitis in the acute phase, 15 children with aseptic meningitis in the recovery phase, and six other children as controls. The concentration of each substance was significantly higher in the acute phase than in the recovery phase. Homovanillic acid in the acute phase was significantly increased compared to that in the control group. The concentrations of the total, the oxidized form, and the reduced form of biopterin, and 5-hydroxyindoleacetic acid were higher in the acute phase than those in the controls; however, the differences were not significant. The concentration of each substance in the recovery phase was not significantly different from that in the controls. There was no difference in the 5-hydroxyindoleacetic acid/homovanillic acid ratio or in the reduced form/total biopterin ratio among the patients in acute and recovery phases and the controls. These results suggested that levels of biopterin and biogenic amine metabolites in cerebrospinal fluid are increased in the acute phase of aseptic meningitis and return to normal during the recovery phase. This is the first report of increased concentrations of biopterin fractions and biogenic amine metabolites in aseptic meningitis.

Synthesis of the complement factors C3 and C4 within the central nervous system over the course of aseptic meningitis.

The concentrations of complement factors C3 and C4 were quantified by single radial immunodiffusion in unconcentrated cerebrospinal fluid (CSF) and in serum from 38 patients up to 2 months after onset of acute aseptic meningitigs (AM). Elevated absolute concentrations were found in CSF in 26 and 35 patients, respectively, and in serum in 8 and 31, respectively. Elevation of the CSF C3 index, equal to (CSF/serum C3):(CSF/serum albumin), and of the corresponding CSF C4 index were found in 16 and 7 patients, respectively, as evidence of intrathecal synthesis. Only minor differences of the frequencies of elevated CSF C3 and C4 indices were encountered over the course of AM up to 2 months after onset. The occurrence of intrathecal C3 and C4 synthesis in AM is proposed as reflecting activation of hitherto unknown significance within the central nervous system.

Viral antibodies in oligoclonal and polyclonal IgG synthesized within the central nervous system over the course of mumps meningitis.

The occurrence of viral antibodies in relation to IgG separated by thin-layer polyacrylamide gel isoelectric focusing was studied in CSF and serum from 24 patients with mumps meningitis by immunofixation with viral antigens and autoradiography. Eleven of the patients displayed on the autoradiograms evidence of locally in the central nervous system synthesized mumps virus antibodies which were related to oligoclonal IgG bands in all 5 patients who displayed this CSF abnormality, otherwise to polyclonal IgG bands. Local synthesis of mumps virus antibodies was detectable in 43% of specimens obtained 1-13 days after onset, and in 75% obtained 27-47 days after onset. Only one patient displayed local synthesis of antibodies to other viruses (measles and herpes simplex) which could then be traced to polyclonal IgG bands.

Immunoglobulin-producing cells in CSF and blood from patients with multiple sclerosis and other inflammatory neurological diseases enumerated by protein-A plaque assay.

Using the Protein-A plaque assay, numbers of IgG + IgA + IgM producing cells determined in patients with multiple sclerosis (MS) were 0.1-5% in CSF and 0.1-0.7% in peripheral blood; interestingly, 7 of 11 MS patients had IgM producing cells in CSF. In patients with aseptic meningitis (AM), the corresponding values were 0.04-7.5% in CSF and 0.4-2.4% in peripheral blood. There were more Ig producing cells in peripheral blood from patients with AM and MS than in healthy subjects. A correlation between numbers of IgG producing cells in CSF and the concentrations of intrathecally produced IgG (CSF IgG index) was registered in patients with AM; the same was the true for IgA. The Protein-A plaque method, adopted for 20 X 10(3) lymphocytes, makes possible enumeration of Ig-producing cells in CSF and discrimination among cells secreting different Ig classes, thereby being a powerful tool for studying immune reactions in the CNS-CSF compartment.