Association of inflammatory cytokines expression in cerebrospinal fluid with the severity and prognosis of spontaneous intracerebral hemorrhage.

OBJECTIVE: To investigate the potential diagnostic and prognostic implications of inflammatory cytokine levels in the cerebrospinal fluid (CSF) of patients with spontaneous intracerebral hemorrhage (SICH) upon their initial hospital admission. METHODS: Our cohort included 100 patients diagnosed with acute SICH, presenting to the Department of Neurosurgery. Additionally, we recruited 50 individuals without central nervous system (CNS) pathology, treated concurrently at our facility, as controls. CSF samples, collected upon hospital entry, were quantitatively assessed for 10 inflammatory cytokines using the Mesoscale Discovery Platform (MSD, Rockville, MD, USA) electrochemiluminescence technology, followed by validation through enzyme-linked immunosorbent assay (ELISA). RESULTS: We observed a marked elevation of IL-6, IL-8, IL-10, and TNF-α in the CSF of the SICH subgroup compared to controls. Higher Glasgow Coma Scale (GCS) scores in SICH patients corresponded with lower CSF concentrations of IL-6, IL-8, IL-10, and TNF-α, indicating an inverse relationship. Notably, CSF inflammatory cytokine levels were consistently higher in SICH patients with hydrocephalus than in those without. Increases in IL-6, IL-8, IL-10, and TNF-α in the CSF were notably more pronounced in the poor prognosis group (Glasgow Outcome Scale, GOS 1-3) compared to those with a favorable prognosis (GOS 4-5). The AUC values for these cytokines in predicting SICH prognosis were 0.750, 0.728, 0.717, and 0.743, respectively. CONCLUSIONS: Initial CSF levels of IL-6, IL-8, IL-10, and TNF-α upon admission provide significant insights into the severity of neural damage and are robust indicators for prognosis in SICH patients.

Cytokine profile in patients with acute bacterial meningitis.

BACKGROUND: Bacterial meningitis is a life-threatening disease with high mortality and common long-term sequelae. The inflammatory response in the subarachnoid space, modulated by different cytokines, plays a major role in the pathogenesis of acute central nervous system infections. We aimed to examine correlations of interleukin (IL)-6, IL-8, IL-10, IL-12(p40), and tumor necrosis factor (TNF)-α levels with disease severity, complications, and outcome in patients with acute bacterial meningitis. METHODS: The study involved 30 patients with bacterial meningitis/meningoencephalitis admitted to the University Hospital St. George, Plovdiv over a period of 4 years. Patients were selected based on clinical presentation and laboratory abnormalities, consistent with a neuroinfection. Enzyme-linked immunosorbent assay was used to measure the studied cytokines in both cerebrospinal fluid (CSF) and serum in parallel. For microbiological diagnosis multiplex, polymerase chain reaction, and CSF culture were used. RESULTS: In patients with acute bacterial meningitis CSF levels of IL-6, IL-8, IL-10, and TNF-α are significantly increased than in serum. CSF TNF-α, CSF IL-8, and CSF IL-10 had a moderate negative correlation to CSF glucose. It was found that serum IL-8 is significantly elevated in patients who experienced neurological complications, have severe clinical course, and in deceased patients. CSF IL-10 is increased only in patients with severe acute bacterial meningitis. CONCLUSION: Among patients with acute bacterial meningitis serum IL-8 could delineate these with increased risk of neurological complications, severe clinical course, and fatal outcome. Serum IL-8 and CSF IL-10 could be used as indicators of disease severity.

CCL2/MCP-1, interleukin-8, and fractalkine/CXC3CL1: Potential biomarkers of epileptogenesis and pharmacoresistance in childhood epilepsy.

OBJECTIVE: The pathophysiological processes leading to epileptogenesis and pharmacoresistance in epilepsy have been the subject of extensive preclinical and clinical research. The main impact on clinical practice is the development of new targeted therapies for epilepsy. We studied the importance of neuroinflammation in the development of epileptogenesis and pharmacoresistance in childhood epilepsy patients. METHODS: A cross-sectional study conducted at two epilepsy centers in the Czech Republic compared 22 pharmacoresistant patients and 4 pharmacodependent patients to 9 controls. We analyzed the ProcartaPlex™ 9-Plex immunoassay panel consisting of interleukin (IL)-6, IL-8, IL-10, IL-18, CXCL10/IP-10, monocyte chemoattractant protein 1 (CCL2/MCP-1), B lymphocyte chemoattractant (BLC), tumor necrosis factor-alpha (TNF-α), and chemokine (C-X3-X motif) ligand 1 (fractalkine/CXC3CL1) to determine their alterations in cerebrospinal fluid (CSF) and blood plasma, concurrently. RESULTS: The analysis of 21 paired CSF and plasma samples in pharmacoresistant patients compared to controls revealed a significant elevation of CCL2/MCP-1 in CSF (p < 0.000512) and plasma (p < 0.00.017). Higher levels of fractalkine/CXC3CL1 were revealed in the plasma of pharmacoresistant patients than in controls (p < 0.0704), and we determined an upward trend in CSF IL-8 levels (p < 0.08). No significant differences in CSF and plasma levels were detected between pharmacodependent patients and controls. CONCLUSION: Elevated CCL2/MCP-1 in CSF and plasma, elevated levels of fractalkine/CXC3CL1 in CSF, and a trend toward elevated IL-8 in the CSF of patients with pharmacoresistant epilepsy indicate these cytokines as potential biomarkers of epileptogenesis and pharmacoresistance. CCL2/MCP-1was detected in blood plasma; this assessment may be easily achieved in clinical practice without the invasiveness of a spinal tap. However, due to the complexity of neuroinflammation in epilepsy, further studies are warranted to confirm our findings.

Doublecortin and Glypican-2 concentrations in the cerebrospinal fluid from infants are developmentally downregulated.

OBJECTIVE: Doublecortin (DCX) and glypican-2 (GPC2) are neurodevelopmental proteins involved in the differentiation of neural stem/progenitor cells (NSPCs) to neurons, and are developmentally downregulated in neurons after birth. In this study, we investigated whether the concentrations of DCX and GPC2 in the cerebrospinal fluid (CSF) from human pediatric patients reflect this developmental process or are associated with cerebral damage or inflammatory markers. METHODS: CSF was collected from pediatric patients requiring neurosurgical treatment. The concentrations of DCX, GPC2, neuron-specific enolase (NSE), S100 calcium-binding protein B (S100B), and cytokines (IL-1ß, IL-2, IL-4, IL-6, IL-8, IL-10, IL-13, IFN-γ, and TNF-⍺) were measured using immunoassays. RESULTS: From March 2013 until October 2018, 63 CSF samples were collected from 38 pediatric patients (20 females; 17 patients with repeated measurements); the median term born-adjusted age was 3.27 years [Q1: 0.31, Q3: 7.72]. The median concentration of DCX was 329 pg/ml [Q1: 192.5, Q3: 1179.6] and that of GPC2 was 26 pg/ml [Q1: 13.25, Q3: 149.25]. DCX and GPC2 concentrations independently significantly associated with age, and their concentration declined with advancing age, reaching undetectable levels at 0.3 years for DCX, and plateauing at 1.5 years for GPC2. Both DCX and GPC2 associated with hydrocephalus, NSE, IL-1ß, IL-2, IL-8, IL-13. No relationship was found between sex, acute infection, S100B, IL-4, IL-6, IL-10, IFN-γ, TNF-α and DCX or GPC2, respectively. CONCLUSIONS: Concentrations of DCX and GPC2 in the CSF from pediatric patients are developmentally downregulated, with the highest concentrations measured at the earliest adjusted age, and reflect a neurodevelopmental stage rather than a particular disease state.

TGF-ß1 in plasma and cerebrospinal fluid can be used as a biological indicator of chronic pain in patients with osteoarthritis.

INTRODUCTION: Previous studies have demonstrated that cytokines, transforming growth factor (TGF-ß1), and brain-derived neurotrophic factor (BDNF) can impact the intensity of pain in rodents. However, the roles of cytokines, TGF-ß1 and BDNF in humans with chronic pain in osteoarthritis remains unclear, and no comparison between plasma and central cerebral spinal fluid (CSF) has been conducted. METHODS: Patients with osteoarthritis who were scheduled to receive spinal anesthesia were enrolled. The intensity of pain was evaluated with a visual analogue scale (VAS). In addition, patients with genitourinary system (GU) diseases and without obvious pain (VAS 0-1) were included as a comparison (control) group. The levels of TGF-ß1, BDNF, tumor necrosis factor-α (TNF-α), and interleukin (IL)-8 within the CSF and plasma were collected and evaluated before surgery. RESULTS: The plasma and CSF TGF-ß1 levels were significantly lower in the osteoarthritis patients with pain (VAS ≥ 3) than in the GU control patients. Downregulation of plasma BDNF was also found in osteoarthritis patients with pain. The Spearman correlation analysis showed that the VAS pain scores were significantly negatively correlated with the levels of TGF-ß1 in the CSF of patients with osteoarthritis. However, there was no significant correlations between the pain scores and the levels of BDNF, TNF-α, and IL-8 in either the CSF or plasma. CONCLUSIONS: TGF-ß1 but not BDNF, TNF-α, or IL-8 may be an important biological indicator in the CSF of osteoarthritis patients with chronic pain.

Immunological investigations of the cerebrospinal fluid in patients with recent onset psychotic disorders: A study protocol.

BACKGROUND: Though many previous studies have indicated immunological alterations in psychotic disorders, the role and prevalence of neuroinflammation is still unknown. Studies previously investigating immune related biomarkers in the cerebrospinal fluid (CSF) of these patients are mainly small studies on few markers, and many have not compared patients to healthy controls. METHODS: We will conduct a large case-control study including at least 100 patients with recent onset psychotic disorders and 100 sex- and age matched healthy controls. The cases will include patients diagnosed with a psychotic disorder according to ICD-10 (F20/F22-29) within a year prior to inclusion. We will collect both CSF, blood and fecal samples, to gain insight into possible immunological alterations. The psychopathology of all participants will thoroughly be evaluated using the SCAN interview, and multiple rating scales covering different symptom groups. All participants will partake in a detailed neurological examination, including the Neurological Evaluation Scale assessing neurological soft signs. Additionally, we will assess cognitive functioning, evaluate quality of life and level of functioning, and collect data on a broad array of possible confounders. Our primary outcomes will include CSF leucocytes, CSF/serum albumin ratio, CSF total protein, IgG index, CSF levels of IL-6 and IL-8, and presence of antineuronal autoantibodies in CSF and blood. For our secondary outcomes, exploratory analyses will be performed on a broader panel of neuroimmunological markers. All participants will be invited for a follow-up visit to assess longitudinal changes. The current study is part of a larger CSF biobank build-up for severe mental disorders (PSYCH-FLAME). DISCUSSION: This study will represent the largest investigation of CSF in patients with psychotic disorders compared to healthy controls to date. We expect the study to contribute with new, important knowledge on pathophysiological mechanisms, and to help pave the way for future investigations of individualized treatment options. TRIAL REGISTRATION: The study is approved by The Regional Committee on Health Research Ethics (Capital Region, j.no: H-16030985) and The Danish Data Protection Agency (j.no: RHP-2016-020, I-Suite no.: 04945).

Early Inflammatory Cytokine Expression in Cerebrospinal Fluid of Patients with Spontaneous Intraventricular Hemorrhage.

We investigated cerebrospinal fluid (CSF) expression of inflammatory cytokines and their relationship with spontaneous intracerebral and intraventricular hemorrhage (ICH, IVH) and perihematomal edema (PHE) volumes in patients with acute IVH. Twenty-eight adults with IVH requiring external ventricular drainage for obstructive hydrocephalus had cerebrospinal fluid (CSF) collected for up to 10 days and had levels of interleukin-1α (IL-1α), IL-1ß, IL-6, IL-8, IL-10, tumor necrosis factor-α (TNFα), and C-C motif chemokine ligand CCL2 measured using enzyme-linked immunosorbent assay. Median [IQR] ICH and IVH volumes at baseline (T0) were 19.8 [5.8-48.8] and 14.3 [5.3-38] mL respectively. Mean levels of IL-1ß, IL-6, IL-10, TNF-α, and CCL2 peaked early compared to day 9-10 (p < 0.05) and decreased across subsequent time periods. Levels of IL-1ß, IL-6, IL-8, IL-10, and CCL2 had positive correlations with IVH volume at days 3-8 whereas positive correlations with ICH volume occurred earlier at day 1-2. Significant correlations were found with PHE volume for IL-6, IL-10 and CCL2 at day 1-2 and with relative PHE at days 7-8 or 9-10 for IL-1ß, IL-6, IL-8, and IL-10. Time trends of CSF cytokines support experimental data suggesting association of cerebral inflammatory responses with ICH/IVH severity. Pro-inflammatory markers are potential targets for injury reduction.

Cerebrospinal fluid and serum interleukins 6 and 8 during the acute and recovery phase in COVID-19 neuropathy patients.

This case series describes three patients affected by severe acute respiratory syndrome coronavirus 2, who developed polyradiculoneuritis as a probable neurological complication of coronavirus disease 2019 (COVID-19). A diagnosis of Guillain Barré syndrome was made on the basis of clinical symptoms, cerebrospinal fluid analysis, and electroneurography. In all of them, the therapeutic approach included the administration of intravenous immunoglobulin (0.4 gr/kg for 5 days), which resulted in the improvement of neurological symptoms. Clinical neurophysiology revealed the presence of conduction block, absence of F waves, and in two cases, a significant decrease in amplitude of compound motor action potential cMAP. Due to the potential role of inflammation on symptoms development and prognosis, interleukin-6 (IL-6) and IL-8 levels were measured in serum and cerebrospinal fluid during the acute phase, while only serum was tested after recovery. Both IL-6 and IL-8 were found increased during the acute phase, both in the serum and cerebrospinal fluid, whereas 4 months after admission (at complete recovery), only IL-8 remained elevated in the serum. These results confirm the inflammatory response that might be linked to peripheral nervous system complications and encourage the use of IL-6 and IL-8 as prognostic biomarkers in COVID-19.

The effect of pre-analytical handling on the stability of fractalkine, monocyte chemoattractant protein 1 (MCP1), interleukin 6 and interleukin 8 in samples of human cerebrospinal fluid.

Cytokine networks in cerebrospinal fluid (CSF) are important to our understanding of several neuroinflammatory diseases. Knowledge about optimal handling of samples is limited but important to minimize bias and reduce costs in CSF biomarker studies. The aim of this study was to examine the effect of storage temperature and time delay from CSF sample collection until freezing on the concentration of 11 different cytokines thought to be associated with chronic pain. CSF samples from 21 individuals undergoing hip or knee arthroplasty under spinal anesthesia were divided between two tubes. One tube was stored and centrifuged (within 30 min) at room temperature, and one tube was stored in ice water and centrifuged (within 30 min) at 4 °C. Each tube was split into six vials that were frozen at -80 °C, 0.5, 1, 2, 3, 4, or 5 h after collection. Cytokines were analyzed using a multiplex panel. A random effect panel data regression was conducted for each biomarker including the variables of storage temperature until freezing and time delay. Four cytokines had detectable levels: Fractalkine, monocyte chemoattractant protein 1(MCP-1), interleukine 6 (IL-6), and interleukine 8 (IL-8). There was no significant effect of storage temperature and time delay on MCP-1, IL-6, or IL-8 concentrations. Fractalkine concentration showed no clear trend. No concentration differences were observed between samples kept in ice water and those at room temperature except at the 3-h time point, and there was no overall significant effect of time delay on fractalkine concentration. We found no clear effect of storage temperature and time delay up to five hours from sample collection until freezing on the CSF concentrations of fractalkine, MCP-1, IL-6, or IL-8.

Mesenchymal stem cell-derived neural progenitors in progressive MS: Two-year follow-up of a phase I study.

OBJECTIVE: To determine the long-term safety and efficacy of repeated intrathecal (IT) administration of autologous mesenchymal stem cell-derived neural progenitors (MSC-NPs) in patients with progressive MS by evaluating subjects 2 years after treatment. METHODS: Twenty subjects were enrolled as part of a phase I, open-label single-arm study of 3 IT injections of MSC-NPs spaced 3 months apart. Subjects were evaluated for adverse events and disability outcomes including the Expanded Disability Status Scale (EDSS) and the timed 25-foot walk (T25FW). Long-term evaluation was conducted 2 years after the third treatment. CSF was collected before and 3 months after treatment. RESULTS: Eighteen of the 20 study participants completed the full 2-year follow-up protocol. There were no long-term adverse events associated with repeated IT-MSC-NP treatment. Seven subjects showed sustained improvement in EDSS after 2 years, although the degree of improvement was not maintained in 5 of the subjects. Three of the 10 ambulatory subjects showed sustained improvement in the T25FW after 2 years. CSF biomarker analysis revealed a decrease in C-C motif chemokine ligand 2 (CCL2) and an increase in interleukin 8, hepatocyte growth factor, and C-X-C motif chemokine ligand 12 (CXCL12) after treatment. CONCLUSIONS: Safety and efficacy of repeated IT-MSC-NP treatment was sustained for 2 years; however, the degree of disability reversal was not sustained in a subset of patients. CSF biomarkers altered in response to IT-MSC-NP treatment may reflect specific immunoregulatory and trophic mechanisms of therapeutic response in MS. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that for patients with progressive MS, IT administration of MSC-NPs is safe and effective. The study is rated Class IV because of the absence of a non-IT-MSC-NP-treated control group. CLINICALTRIALSGOV IDENTIFIER: NCT01933802.

Steroid-Responsive Encephalitis in Coronavirus Disease 2019.

Coronavirus disease 2019 (COVID-19) infection has the potential for targeting the central nervous system, and several neurological symptoms have been described in patients with severe respiratory distress. Here, we described the case of a 60-year-old patient with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection but only mild respiratory abnormalities who developed an akinetic mutism attributable to encephalitis. Magnetic resonance imaging was negative, whereas electroencephalography showed generalized theta slowing. Cerebrospinal fluid analyses during the acute stage were negative for SARS-CoV-2, positive for pleocytosis and hyperproteinorrachia, and showed increased interleukin-8 and tumor necrosis factor-α concentrations. Other infectious or autoimmune disorders were excluded. A progressive clinical improvement along with a reduction of cerebrospinal fluid parameters was observed after high-dose steroid treatment, thus arguing for an inflammatory-mediated brain involvement related to COVID-19. ANN NEUROL 2020;88:423-427.

Cytokines in narcolepsy: A systematic review and meta-analysis.

BACKGROUND: Narcolepsy is a sleep disorder characterized by a loss of hypocretin neurons in the hypothalamus. Inflammation is proposed as a mechanism for neurodegeneration in narcolepsy. Numerous studies have investigated peripheral cytokine measures in narcoleptic patients, though the results are not conclusive. The current systematic review and meta-analysis aims to address the question of how do serum/plasma cytokine levels change in narcolepsy. METHODS: A systematic search of the literature to July 2019, was conducted to identify studies that measured cytokine levels in patients with narcolepsy, compared with those in controls without narcolepsy. RESULTS: Twelve studies were included in the meta-analysis: ten for interleukin (IL)-6, five for IL-8, three for IL-10, and ten for tumor necrosis factor alpha (TNF-α). Compared with controls, patients with narcolepsy had higher plasma levels of IL-6 (95% CI [0.22, 3.74]; P = 0.03) and TNF-α (95% CI [0.53, 4.18]; P = 0.01), while did not significantly differ in plasma IL-8 (95% CI [-1.64, 2.08]; P = 0.82) and IL-10 (95% CI [-1.29, 0.72]; P = 0.57) as well as serum IL-6 (95% CI [-1.48, 0.32], P = 0.21) and TNF-α (95% CI [-3.14, 0.19], P = 0.08) and CSF IL-8 (95% CI [-1.16, 0.41]; P = 0.35) levels. Patients with narcolepsy exhibited lower CSF IL-6 (95% CI [-0.66, 0.06]; P = 0.02) levels comparing with controls. CONCLUSIONS: Patients with narcolepsy had elevated plasma levels of IL-6 and TNF-α and lower levels of CSF IL-6 than non-narcoleptic controls. Our results support the role of inflammation in the pathophysiology of narcolepsy. However, plasma levels of IL-8 and IL-10, serum levels of IL-6 and TNF-α and CSF IL-8 did not significantly differ between patients and controls.

Cerebrospinal Fluid Levels of Interleukin-8 in Delirium, Dementia, and Cognitively Healthy Patients.

BACKGROUND: Delirium is a common and serious complication in geriatric patients. The pathophysiology of delirium is not known. OBJECTIVE: The objective of the current study was to test the hypothesis that cerebrospinal fluid (CSF) levels of inflammatory markers at the time of spinal anesthesia for hip surgery are associated with delirium. METHODS: In total 133 hip fracture patients and 125 cognitively healthy controls undergoing elective surgery, together with 73 Alzheimer's disease (AD) dementia patients, were recruited at Oslo University Hospital and Diakonhjemmet Hospital, Oslo, Norway. Delirium was evaluated daily in hip fracture patients by the Confusion Assessment Method (CAM). Depression was evaluated by Cornell Scale for Depression in Dementia (CSDD). Tumor necrosis factor alpha (TNF-α), interleukin-1beta (IL-1ß), and interleukin-8 (IL-8) levels were measured in CSF using a Mesoscale Discovery (MSD) immunoassay. RESULTS: Hip fracture patients had significantly higher IL-8 levels (p < 0.001) compared to cognitively healthy controls or patients with stable AD dementia. Furthermore, preoperative IL-8 levels were significantly higher (p = 0.013) in hip fracture patients who developed delirium (incident delirium) after surgery as compared to patients with no delirium. However, subgroup analyses showed that IL-8 levels were only significantly higher in delirium patients without dementia (p = 0.006). In contrast, depression subgroup analysis showed that IL-8 concentration was significantly higher (p = 0.002) in delirium patients with depression. Both TNF-α and IL-1ß were undetected in most patients. CONCLUSIONS: Our study suggests that IL-8 levels are associated with delirium onset and that underlying depression or dementia influences IL-8 levels.

Lipid Peroxidation and Antioxidant Consumption as Early Markers of Neurosurgery-Related Brain Injury in Children.

BACKGROUND AND AIMS: Lipid peroxidation represents a marker of secondary brain injury both in traumatic and in non-traumatic conditions-as in major neurosurgical procedures-eventually leading to brain edema amplification and further brain damage. Malondialdehyde (MDA), a lipid peroxidation marker, and ascorbate, a marker of antioxidant status, can represent early indicators of this process within the cerebrospinal fluid (CSF). We hypothesized that changes in cerebral lipid peroxidation can be measured ex vivo following neurosurgery in children. METHODS: Thirty-six children (M:F = 19/17, median age 32.9 months; IQR 17.6-74.6) undergoing neurosurgery for brain tumor removal were admitted to the pediatric intensive care unit (PICU) in the postoperative period with an indwelling intraventricular catheter for intracranial pressure monitoring and CSF drainage. Plasma and CSF samples were obtained for serial measurement of MDA, ascorbate, and cytokines. RESULTS: An early brain-limited increase in lipid peroxidation was measured, with a significant increase from baseline of MDA in CSF (p = 0.007) but not in plasma. In parallel, ascorbate in CSF decreased (p = 0.05). Systemic inflammatory response following brain surgery was evidenced by plasma IL-6/IL-8 increase (p 0.0022 and 0.0106, respectively). No correlation was found between oxidative response and tumor site or histology (according to World Health Organization grading). Similarly, lipid peroxidation was unrelated to the length of surgery (mean 321 ± 73 min), or intraoperative blood loss (mean 20.9 ± 16.8% of preoperative volemia, 44% given hemotransfusions). Median PICU stay was 3.5 days (IQL range 2-5.5 d.), and postoperative ventilation need was 24 h (IQL range 20-61.5 h). The elevation in postoperative MDA in CSF compared with preoperative values correlated significantly with postoperative ventilation need (P = 0.05, r2 0168), while no difference in PICU stay was recorded. CONCLUSIONS: Our results indicate that lipid peroxidation increases consistently following brain surgery, and it is accompanied by a decrease in antioxidant defences; intraventricular catheterization offers a unique chance of oxidative process monitoring. Further studies are needed to evaluate whether monitoring post-neurosurgical oxidative stress in CSF is of prognostic utility.

Characterization of inflammatory cytokine profiles in cerebrospinal fluid of hand, foot, and mouth disease children with enterovirus 71-related encephalitis in Hangzhou, Zhejiang, China.

Enterovirus 71 (EV71) is an important etiological agent of hand, foot, and mouth disease (HFMD), which can also lead to severe neurological complications (eg, encephalitis) in young children. Although a series of reports on EV71 infection have been published, the pathogenic mechanism of EV71 infection is still not fully understood.We evaluated the cerebrospinal fluid (CSF) levels of the inflammatory cytokines interleukin (IL)-8, IL-1ß, IL-6, IL-10, tumor necrosis factor (TNF)-α, and IL-12p70 in 88 children with EV71-related encephalitis and 19 children with febrile convulsion (FC) with the use of commercial cytometric bead array kits.The levels of IL-8, IL-1ß, IL-6, and IL-10 in CSF were significantly higher in encephalitis group when compared with those observed in FC group, while no significant changes were noted in the levels of TNF-α and IL-12p70. In addition, significant and positive correlations among CSF IL-8, IL-1ß, IL-6, and IL-10 were observed in encephalitis group. Furthermore, receiver operator characteristic analysis determined a cut-off value of 10.62 pg/mL for IL-6 to discriminate encephalitis patients from FCs with the sensitivity and specificity of 89.8% and 84.2%, respectively. Moreover, logistic regression analyses revealed that IL-6 was an independent predictor of EV71-related encephalitis (odds ratio = 23.241, P < .001).Our results indicate that 4 inflammatory cytokines (IL-8, IL-1ß, IL-6, and IL-10) play important roles in the pathogenesis of EV71 infection. IL-6 may be used for the evaluation of EV71-related encephalitis and as a potential therapy candidate for EV71 infection.

Utility of chemokines CCL2, CXCL8, 10 and 13 and interleukin 6 in the pediatric cohort for the recognition of neuroinflammation and in the context of traditional cerebrospinal fluid neuroinflammatory biomarkers.

BACKGROUND: The recognition of active inflammation in the central nervous system (CNS) in the absence of infectious agents is challenging. The present study aimed to determine the diagnostic relevance of five selected chemo/cytokines in the recognition of CNS inflammation and in the context of traditional cerebrospinal fluid (CSF) biomarkers (white blood cell [WBC] counts, oligoclonal bands, protein levels, CSF/serum albumin ratios) and clinical diagnoses. METHODS: C-C and C-X-C motif ligands (CCL2, CXCL8, 10 and 13) and interleukin (IL) 6 levels in the CSF and serum from 37 control and 87 symptomatic children with ten different (mostly noninfectious) inflammatory CNS disorders (16 of which had follow-up samples after recovery) were determined using Luminex multiple bead technology and software. Nonparametric tests were used; p < 0.05 was considered statistically significant. Receiver operating characteristic curves were constructed to analyze controls and 1) all symptomatic samples or 2) symptomatic samples without CSF pleocytosis. RESULTS: Compared with the control CSF samples, levels of all investigated chemo/cytokines were increased in symptomatic CSF samples, and only IL-6 remained elevated in recovery samples (p ≤ 0.001). CSF CXCL-13 levels (> 10.9 pg/mL) were the best individual discriminatory criterion to differentiate neuroinflammation (specificity/sensitivity: 97/72% and 97/61% for samples without pleocytosis), followed by CSF WBC counts (specificity/sensitivity: 97/62%). The clinical utility of the remaining CSF chemo/cytokine levels was determined in descending order of sensitivities corresponding to thresholds that ensured 97% specificity for neuroinflammation in samples without pleocytosis (pg/mL; sensitivity %): IL-6 (3.8; 34), CXCL8 (32; 26), CXCL10 (317; 24) and CCL2 (387; 10). Different diagnosis-related patterns of CSF chemo/cytokines were observed. CONCLUSIONS: The increased CSF level of CXCL13 was the marker with the greatest predictive utility for the general recognition of neuroinflammation among all of the individually investigated biomarkers. The potential clinical utility of chemo/cytokines in the differential diagnosis of neuroinflammatory diseases was identified.

Interleukin-8 as a therapeutic target for chronic low back pain: Upregulation in human cerebrospinal fluid and pre-clinical validation with chronic reparixin in the SPARC-null mouse model.

BACKGROUND: Low back pain (LBP) is the leading global cause of disability and is associated with intervertebral disc degeneration (DD) in some individuals. However, many adults have DD without LBP. Understanding why DD is painful in some and not others may unmask novel therapies for chronic LBP. The objectives of this study were to a) identify factors in human cerebrospinal fluid (CSF) associated with chronic LBP and b) examine their therapeutic utility in a proof-of-concept pre-clinical study. METHODS: Pain-free human subjects without DD, pain-free human subjects with DD, and patients with chronic LBP linked to DD were recruited and lumbar MRIs, pain and disability levels were obtained. CSF was collected and analyzed by multiplex cytokine assay. Interleukin-8 (IL-8) expression was confirmed by ELISA in CSF and in intervertebral discs. The SPARC-null mouse model of progressive, age-dependent DD and chronic LBP was used for pre-clinical validation. Male SPARC-null and control mice received systemic Reparixin, a CXCR1/2 (receptors for IL-8 and murine analogues) inhibitor, for 8 weeks. Behavioral signs of axial discomfort and radiating pain were assessed. Following completion of the study, discs were excised and cultured, and conditioned media was evaluated with a protein array. FINDINGS: IL-8 was elevated in CSF of chronic LBP patients with DD compared to pain-free subjects with or without DD. Chronic inhibition with reparixin alleviated low back pain behaviors and attenuated disc inflammation in SPARC-null mice. INTERPRETATION: These studies suggest that the IL-8 signaling pathway is a viable therapy for chronic LBP. FUND: Supported by NIH, MMF, CIHR and FRQS.

IL-8 as a potential biomarker in Guillain-Barre Syndrome.

This pilot study was designed to compare the levels of interleukin-8 (IL-8), a pro-inflammatory chemokine, in the cerebrospinal fluid (CSF) of patients with Guillain-Barre syndrome (GBS), chronic inflammatory demyelinating polyneuropathy (CIDP), non-inflammatory polyneuropathy (PNP), and other non-inflammatory neurological diseases (functional syndrome or migraine). The results show elevated CSF IL-8 levels in GBS compared to the other groups (p < 0.05). IL-8 could be considered a potential biomarker to differentiate GBS from CIDP. This distinction could be relevant in terms of therapeutic decisions and functional prognosis.

The combination of cerebrospinal fluid procalcitonin, lactate, interleukin-8 and interleukin-10 concentrations for the diagnosis of postneurosurgical bacterial meningitis: A prospective study.

BACKGROUND: The differential diagnosis between postneurosurgical bacterial meningitis and aseptic meningitis remains challenging both for the clinician and the laboratory. Combinations of markers, as opposed to single ones, may improve diagnosis and thereby survival. METHODS: This prospective cohort study included patients with suspected bacterial meningitis after neurosurgery. The patients were divided into two groups according to the diagnostic criteria of meningitis involving a postneurosurgical bacterial meningitis group and a postneurosurgical aseptic meningitis group. Four biomarkers, including cerebrospinal fluid procalcitonin, lactate, interleukin-8 and interleukin-10 were assayed separately, and three algorithms were constructed using a linear combination. The area under the receiver operating characteristic curve was used to compare their performances. RESULTS: A cohort of 112 patients was enrolled in our study. Forty-three patients were diagnosed with postneurosurgical bacterial meningitis, and the cerebrospinal fluid values of their biomarkers were higher in patients with postneurosurgical bacterial meningitis than with postneurosurgical aseptic meningitis. The area under the receiver operating characteristic curves for the detection of postneurosurgical bacterial meningitis were 0.803 (95% confidence interval [CI], 0.724-0.883) for procalcitonin; 0.936 (95% CI, 0.895-0.977) for lactate; 0.771 (95% CI, 0.683-0.860) for interleukin-8; 0.860 (95% CI, 0.797-0.929) for interleukin-10; 0.937 (95% CI, 0.897-0.977) for the composite two-marker test; 0.945 (95% CI, 0.908-0.982) for the composite three-marker test and 0.954 (95% CI, 0.922-0.989) for the composite of all tests. The area under the receiver operating characteristic curves of the combination tests were greater than those of the single markers. CONCLUSIONS: Combining information from several markers improved the diagnostic accuracy in detecting postneurosurgical bacterial meningitis.