Is increased activator protein 1 in cerebrospinal fluid as a potential biomarker that distinguishes idiopathic intracranial hypertension from multiple sclerosis?

OBJECTIVES: To distinguish whether idiopathic intracranial hypertension (IIH) is a condition predisposing to multiple sclerosis (MS) or an isolated disease, the current gene transcription factor Activator Protein-1 (AP-1) was evaluated with its potential to differentiate both diseases. BACKGROUND: The aim of this study was to investigate the use of AP-1 as biomarkers for the discrimination of IIH and MS. METHODS: AP-1, TNF-α, and IL-6 protein values in the CSF of the cases were evaluated by the ELISA method. The numerical measures of the groups and the ability of AP-1 to distinguish the groups were analyzed with the ROC curve. RESULTS: There was no difference between the groups in CSF TNF-α, IL-6, CSF, and serum biochemistry analyses. However, it was determined that the AP-1 concentration (pg/ml) was significantly higher in the IIH group, the sensitivity of AP-1 in separating those with IIH was 75%, and the specificity in separating those with MS was 60% in those with an AP-1 concentration of 606.5 and above. CONCLUSION: According to our results, the fact that CSF TNF-α and IL-6 values did not differ in IIH compared to MS revealed that IIH could not methodologically control MS, and AP-1 was a supportive parameter in differentiating both diseases (Tab. 2, Fig. 1, Ref. 31).

Increased IL-22 in cerebrospinal fluid of neuro-behçet's disease patients.

Remitting-Relapsing Multiple Sclerosis (RRMS) and Neuro-Behçet Disease (NBD) are two chronic neuro-inflammatory disorders leading to brain damage and disability in young adults. Herein, we investigated in these patients the cytokine response by beads-based multiplex assays during the early stages of these disorders. Cytokine investigations were carried out on treatment-naive patients suffering from RRMS and NBD recruited at the first episode of clinical relapse. Our findings demonstrate that Cerebrospinal Fluid (CSF) cells from NBD patients, but not RRMS, secrete significant high levels of IL-22 which is associated with elevated IL-22 mRNA expression. We also observed an increase in IL-22 levels in the definite NBD subgroup as compared to the probable NBD one, indicating a clear relationship between elevated IL-22 levels and diagnostic certainty. Interestingly, we found no correlation of IL-22 secretion between CSF and serum arguing about intrathecal release of IL-22 in the CNS of NBD patients. Moreover, we showed by correlogram analysis that this cytokine doesn't correlate with IL-17A, IL-17F and IL-21 suggesting that this cytokine is secreted by Th22 cells and not by Th17 cells in the CSF of NBD patients. Finally, we found elevated levels of IL-6 and a positive correlation between IL and 6 and IL-22 in the CSF of NBD. In conclusion, these results suggest that IL-6 contributes to the production of IL-22 by T cells leading to the exacerbation of inflammation and damage within the CNS of NBD patients.

Diagnostic, monitoring, and prognostic value of combined detection of cerebrospinal fluid heparin-binding protein, interleukin-6, interleukin-10, and procalcitonin for post-neurosurgical intracranial infection.

OBJECTIVE: Intracranial infection is a common complication after neurosurgery and can increase the length of hospital stay, affect patient prognosis, and increase mortality. We aimed to investigate the value of the combined detection of cerebrospinal fluid (CSF) heparin-binding protein (HBP), interleukin-6 (IL-6), interleukin-10 (IL-10), and procalcitonin (PCT) for post-neurosurgical intracranial infection. METHODS: This study assessed the diagnostic values of CSF HBP, IL-6, IL-10, PCT levels, and combined assays for post-neurosurgical intracranial infection with the area under the receiver operating characteristic (ROC) curve by retrospectively analysing biomarkers of post-neurosurgical patients. RESULTS: The CSF HBP, IL-6, IL-10, and PCT levels were significantly higher in the infected group than the uninfected group and the control group (P < 0.001). The indicators in the groups with severe intracranial infections were significantly higher than those in the groups with mild intracranial infections (P < 0.001), and the groups with poor prognoses had significantly higher indexes than the groups with good prognoses. According to the ROC curve display, the AUC values of CSF HBP, IL-6, IL-10, and PCT were 0.977 (95 % CI 0.952-1.000), 0.973 (95 % CI 0.949-0.998), 0.884 (95 % CI 0.823-0.946), and 0.819 (95 % CI 0.733-0.904), respectively. The AUC of the combined test was 0.996 (95 % CI 0.989-1.000), which was higher than those of the four indicators alone. CONCLUSION: The combined detection can be an important indicator for the diagnosis and disease monitoring of post-neurosurgical intracranial infection.

Lifetime Stressful Events Associated with Alzheimer's Pathologies, Neuroinflammation and Brain Structure in a Risk Enriched Cohort.

OBJECTIVE: Along with the known effects of stress on brain structure and inflammatory processes, increasing evidence suggest a role of chronic stress in the pathogenesis of Alzheimer's disease (AD). We investigated the association of accumulated stressful life events (SLEs) with AD pathologies, neuroinflammation, and gray matter (GM) volume among cognitively unimpaired (CU) individuals at heightened risk of AD. METHODS: This cross-sectional cohort study included 1,290 CU participants (aged 48-77) from the ALFA cohort with SLE, lumbar puncture (n = 393), and/or structural magnetic resonance imaging (n = 1,234) assessments. Using multiple regression analyses, we examined the associations of total SLEs with cerebrospinal fluid (1) phosphorylated (p)-tau181 and Aß1-42/1-40 ratio, (2) interleukin 6 (IL-6), and (3) GM volumes voxel-wise. Further, we performed stratified and interaction analyses with sex, history of psychiatric disease, and evaluated SLEs during specific life periods. RESULTS: Within the whole sample, only childhood and midlife SLEs, but not total SLEs, were associated with AD pathophysiology and neuroinflammation. Among those with a history of psychiatric disease SLEs were associated with higher p-tau181 and IL-6. Participants with history of psychiatric disease and men, showed lower Aß1-42/1-40 with higher SLEs. Participants with history of psychiatric disease and women showed reduced GM volumes in somatic regions and prefrontal and limbic regions, respectively. INTERPRETATION: We did not find evidence supporting the association of total SLEs with AD, neuroinflammation, and atrophy pathways. Instead, the associations appear to be contingent on events occurring during early and midlife, sex and history of psychiatric disease. ANN NEUROL 2024;95:1058-1068.

COVID-19-associated serum and cerebrospinal fluid cytokines in post- versus para-infectious SARS-CoV-2-related Guillain-Barré syndrome.

INTRODUCTION: Guillain-Barré syndrome associated with Coronavirus-2-related severe acute respiratory syndrome (COV-GBS) occurs as para- or post-infectious forms, depending on the timing of disease onset. In these two forms, we aimed to compare the cerebrospinal fluid (CSF) and serum proinflammatory cytokine profiles to evaluate differences that could possibly have co-pathogenic relevance. MATERIALS AND METHODS: We studied a retrospective cohort of 26 patients with either post-COV-GBS (n = 15), with disease onset occurring > 7 days after SARS-CoV-2 infection, or para-COV-GBS (n = 11), with disease onset 7 days or less. TNF-α, IL-6, and IL-8 were measured in the serum with SimplePlex™ Ella™ immunoassay. In addition to the para-/post-COV-GBS patients, serum levels of these cytokines were determined in those with non-COVID-associated-GBS (NC-GBS; n = 43), paucisymptomatic SARS-CoV-2 infection without GBS (COVID, n = 20), and in healthy volunteers (HV; n = 12). CSF cytokine levels were measured in patients with para-/post-COV-GBS, in those with NC-GBS (n = 29), or with Alzheimer's disease (AD; n = 24). RESULTS: Serum/CSF cytokine levels did not differ in para- vs post-COV-GBS. We found that SARS-CoV-2 infection raises the serum levels of TNF-α, IL-6, and IL-8, as well as an increase of IL-6 (in serum and CSF) and IL-8 (in CSF) in either NC-GBS or COV-GBS than controls. CSF and serum cytokine levels resulted independent one with another. CONCLUSIONS: The change of cytokines linked to SARS-CoV-2 in COV-GBS appears to be driven by viral infection, although it has unique characteristics in GBS as such and does not account for cases with para- or post-infectious onset.

Effects of IL-6/IL-6R axis alterations in serum, plasma and cerebrospinal fluid with the schizophrenia: an updated review and meta-analysis of 58 studies.

Studies investigating the association between IL-6/IL-6R axis and schizophrenia (SZ) susceptibility found inconsistent data. To reconcile the results, a systematic review followed by a meta-analysis was performed to assess the associations. This study followed the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. A comprehensive search of the literature was carried out in July 2022 using electronic databases PubMed, EBSCO, Science Direct, PsychInfo, and Scopus. Study quality was assessed by the Newcastle-Ottawa scale. Pooled standard mean difference (SMD) with 95% confidence interval (CI) was calculated by fixed-effect or random-effect model analysis. Fifty-eight studies were identified, including 4,200 SZ patients and 4,531 controls. Our meta-analysis results showed an increase of IL-6 levels in plasma, serum, or CSF and decreased IL-6R levels in serum in patients under treatment. Further studies are needed to better elucidate the correlation between the IL-6/IL-6R axis and the schizophrenia.

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.

Elevated brain derived neurotrophic factor in plasma and interleukin-6 levels in cerebrospinal fluid in meningitis compared to cerebral malaria.

Neurological infections, such as Cerebral malaria (CM) and meningitis are associated with high mortality and in survivors, particularly young children, persistent neurologic deficits often remain. As brain inflammation plays a role in the development of these neurological sequelae, multiplex assays were used to assess a select set of immune mediators in both plasma and cerebrospinal fluid (CSF) from Zambian children with neurological infections. Both CM and meningitis patients showed high levels of markers for vascular inflammation, such as soluble ICAM-1 and angiopoietins. Although high levels of angiopoietin 1 and angiopoietin 2 were found in the meningitis group, their levels in the CSF were low and did not differ. As expected, there were high levels of cytokines and notably a significantly elevated IL-6 level in the CSF of the meningitis group. Interestingly, although elevated levels BDNF were found, BDNF levels were significantly higher in plasma of the meningitis group but similar in the CSF. The striking differences in plasma BDNF and IL-6 levels in the CSF point to markedly different neuro-pathological processes. Therefore, further investigations in the role of both IL-6 and BDNF in the neurological outcomes are needed.

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.

Interleukin-6 as a prognostic biomarker of clinical outcomes after traumatic brain injury: a systematic review.

Traumatic brain injury (TBI) is a major cause of mortality and morbidity worldwide. There are currently no early biomarkers for prognosis in routine clinical use. Interleukin-6 (IL-6) is a potential biomarker in the context of the established role of neuroinflammation in TBI recovery. Therefore, a systematic review of the literature was performed to assess and summarise the evidence for IL-6 secretion representing a useful biomarker for clinical outcomes. A multi-database literature search between January 1946 and July 2021 was performed. Studies were included if they reported adult TBI patients with IL-6 concentration in serum, cerebrospinal fluid (CSF) and/or brain parenchyma analysed with respect to functional outcome and/or mortality. A synthesis without meta-analysis is reported. Fifteen studies were included, reporting 699 patients. Most patients were male (71.7%), and the pooled mean age was 40.8 years; 78.1% sustained severe TBI. Eleven studies reported IL-6 levels in serum, six in CSF and one in the parenchyma. Five studies on serum demonstrated higher IL-6 concentrations were associated with poorer outcomes, and five showed no signification association. In CSF studies, one found higher IL-6 levels were associated with poorer outcomes, one found them to predict better outcomes and three found no association. Greater parenchymal IL-6 was associated with better outcomes. Despite some inconsistency in findings, it appears that exaggerated IL-6 secretion predicts poor outcomes after TBI. Future efforts require standardisation of IL-6 measurement practices as well as assessment of the importance of IL-6 concentration dynamics with respect to clinical outcomes, ideally within large prospective studies. Prospero registration number: CRD42021271200.

Systemic and central nervous system neuroinflammatory signatures of neuropsychiatric symptoms and related cognitive decline in older people.

BACKGROUND: Neuroinflammation may contribute to psychiatric symptoms in older people, in particular in the context of Alzheimer's disease (AD). We sought to identify systemic and central nervous system (CNS) inflammatory alterations associated with neuropsychiatric symptoms (NPS); and to investigate their relationships with AD pathology and clinical disease progression. METHODS: We quantified a panel of 38 neuroinflammation and vascular injury markers in paired serum and cerebrospinal fluid (CSF) samples in a cohort of cognitively normal and impaired older subjects. We performed neuropsychiatric and cognitive evaluations and measured CSF biomarkers of AD pathology. Multivariate analysis determined serum and CSF neuroinflammatory alterations associated with NPS, considering cognitive status, AD pathology, and cognitive decline at follow-up visits. RESULTS: NPS were associated with distinct inflammatory profiles in serum, involving eotaxin-3, interleukin (IL)-6 and C-reactive protein (CRP); and in CSF, including soluble intracellular cell adhesion molecule-1 (sICAM-1), IL-8, 10-kDa interferon-γ-induced protein, and CRP. AD pathology interacted with CSF sICAM-1 in association with NPS. Presenting NPS was associated with subsequent cognitive decline which was mediated by CSF sICAM-1. CONCLUSIONS: Distinct systemic and CNS inflammatory processes are involved in the pathophysiology of NPS in older people. Neuroinflammation may explain the link between NPS and more rapid clinical disease progression.

Kappa Free Light Chains, Soluble Interleukin-2 Receptor, and Interleukin-6 Help Explore Patients Presenting With Brain White Matter Hyperintensities.

Introduction: Many patients are referred to multiple sclerosis (MS) tertiary centers to manage brain white matter hyperintensities (WMH). Multiple diagnoses can match in such situations, and we lack proper tools to diagnose complex cases. Objective: This study aimed to prospectively analyze and correlate with the final diagnosis, cerebrospinal fluid (CSF) interleukin (IL)-1ß, soluble IL-2 receptor (CD25), IL-6, IL-10, and kappa free light chains (KFLC) concentrations in patients presenting with brain WMH. Methods: All patients over 18 years addressed to our MS tertiary center for the diagnostic workup of brain WMH were included from June 1, 2020, to June 1, 2021. Patients were separated into three groups-MS and related disorder (MSARD), other inflammatory neurological disorder (OIND), and non-inflammatory neurological disorder (NIND) groups-according to clinical presentation, MRI characteristics, and biological workup. Results: A total of 176 patients (129 women, mean age 45.8 ± 14.7 years) were included. The diagnosis was MSARD (n = 88), OIND (n = 35), and NIND (n = 53). Median CSF KFLC index and KFLC intrathecal fraction (IF) were higher in MSARD than in the OIND and NIND groups; p < 0.001 for all comparisons. CSF CD25 and IL-6 concentrations were higher in the OIND group than in both the MSARD and NIND groups; p < 0.001 for all comparisons. KFLC index could rule in MSARD when compared to NIND (sensitivity, 0.76; specificity, 0.91) or OIND (sensitivity, 0.73; specificity, 0.76). These results were similar to those with oligoclonal bands (sensitivity, 0.59; specificity, 0.98 compared to NIND; sensitivity, 0.59; specificity, 0.88 compared to OIND). In contrast, elevated CSF CD25 and IL-6 could rule out MSARD when compared to OIND (sensitivity, 0.58 and 0.88; specificity, 0.95 and 0.74, respectively). Discussion: Our results show that, as OCBs, KFLC biomarkers are helpful tools to rule in MSARD, whereas elevated CSF CD25 and IL-6 rule out MSARD. Interestingly, CSF IL-6 concentration could help identify neuromyelitis optica spectrum disorder, myelin oligodendrocyte glycoprotein antibody-associated disease, and central nervous system (CNS) vasculitis. These results need to be confirmed within more extensive and multicentric studies. Still, they sustain that KFLC, CSF CD25, and CSF IL-6 could be reliable biomarkers in brain WMH diagnostic workup for differentiating MSARD from other brain inflammatory MS mimickers.

Association between pro-inflammatory cytokines in cerebrospinal fluid and headache in patients with aneurysmal subarachnoid hemorrhage.

OBJECTIVE: To investigate the relationship between the dynamic changes of pro-inflammatory cytokines in cerebrospinal fluid (CSF) and headache in patients with aneurysmal subarachnoid hemorrhage (aSAH)at hospital admission. METHODS: CSF was collected from patients with aSAH at four time points (days 1, 3, 5, and 7; n = 216) from January 2017 to August 2017 at the Department of Neurosurgery of the First Affiliated Hospital of Wannan Medical College. We measured CSF levels ofinterleukin-1ß (IL-1ß), IL-6, IL-8, and tumor necrosis factor-alpha (TNF-α) levels using an enzyme-linked immunosorbent assay. Results were statistically analyzed to determine the relationship between the dynamic changes of pro-inflammatory cytokines in CSF and headache after aSAH. RESULTS: The concentrations of IL-1ß, IL-6, IL-8, and TNF-α in CSF showed dynamic changes after aSAH. Spearman correlation coefficient analysis revealed that high Hunt-hess grade and modified Fisher scale were associated with a worse headache after aSAH on days 1 and 7 (all P < 0.05). High values of intracranial pressure (ICP) and high levels of CSF pro-inflammatory cytokines were associated with a worse headache after aSAH at four time points (all P < 0.05). However, no significant associations were found between headache and sex, and age. After multiple regression analysis, the Hunt-hess grade, the levels of IL-6 and the levels of TNF-α were associated with headache severity at day 1 (all P < 0.05). The ICP, the levels of IL-1ß and the levels of TNF-α were associated with headache severity on day 3, 5 and 7 (all P < 0.05). CONCLUSIONS: Pro-inflammatory cytokines in CSF are closely associated with a headache after aSAH, and therefore may be a therapeutic target in the future.

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.

SARS-CoV-2-related Progressive Brain White Matter Lesion Associated with an Increased Cerebrospinal Fluid Level of IL-6.

We herein report a 49-year-old man with a fever, diagnosed with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. After two weeks of hospitalization, he suddenly mentioned visual field impairment. Computed tomography and magnetic resonance imaging revealed white matter damage and vasogenic edema. Cerebrospinal fluid showed increased levels of interleukin (IL)-6. His symptoms and white matter lesion deteriorated. After treatment with intravenous methylprednisolone therapy and plasmapheresis, his symptoms and white matter lesion improved gradually. We suspect that our patient was affected by a secondary hyperinflammatory syndrome related to cytokines, alone or in combination with direct viral injury through endothelial cell damage. The IL-6 levels were elevated only in the cerebrospinal fluid, suggesting focal central nervous system inflammation.

Interleukin-6 Levels in Serum, Plasma, and Cerebral Spinal Fluid in Individuals with Suicide Behavior: Systematic Review and Meta-Analysis with Meta-Regression.

Evidence suggests that interleukin-6 (IL-6) concentrations have an important role in suicide behavior (SB) as they are usually increased in these individuals, although no conclusive outcomes have been attained. The purpose of this study was to evaluate the IL-6 levels in plasma, serum, and cerebral spinal fluid (CSF) to determine through a meta-analysis if these levels are increased in individuals with SB in comparison to a group. We calculated the standardized mean difference and 95% confidence intervals (95% CIs). In the systematic review, 21 studies were included, while in the meta-analysis, we included nine studies. The results of our meta-analysis indicated that individuals with SB had reduced levels of IL-6 in plasma (d - 0.189, 95% CI: -0.274 to -0.103, Z, P (Q) = 0.339, I2= 7.478), but increased levels of IL-6 in serum (d - 1.14, 95% CI: 0.658 to 1.630, Z, P (Q) = 0.26, I2= 7.47) and CSF (d 0.64, 95% CI: 0.245 to 1.035, Z, P (Q) = 0.163, I2= 44.80). The meta-regression analysis showed an association between males and high IL-6 levels in plasma (P = 0.003) and serum (P = 0.010), but not the central nervous system (CNS), while age was not associated with IL-6 levels in any of the samples evaluated (plasma, serum, or CNS). The present meta-analysis indicates that serum and CNS IL-6 levels are increased in individuals with SB, while plasma IL-6 levels are decreased, highlighting the importance of the biological sample at the moment of selecting IL-6 as biomarker. However, we need more studies performed in different populations that measure IL-6 and also consider gender when these measures are performed.

Meningoencephalitis in relapsing polychondritis: A case report.

RATIONALE: Aseptic meningoencephalitis is a rare central nervous system complication of relapsing polychondritis (RP). PATIENT: We report a 61-year-old Japanese male patient with spiking fever and impaired consciousness. Neurological examination revealed meningealirritation, and cerebrospinal fluid (CSF) examination showed lymphocytic pleocytosis with elevated protein (199 mg/dL) and interleukin-6 (3810 pg/mL). Serological analysis showed high levels of anti-type II collagen antibodies, and the result of auricular biopsy was consistent with the diagnosis of RP showing cartilage degeneration surrounded by inflammatory cell infiltrations. DIAGNOSIS: A clinical diagnosis of RP was made according to the diagnostic criteria established by MacAdams et al. INTERVENTION: Steroid pulse therapy (methylprednisolone 1000 mg, consecutive 3 days) followed by oral prednisolone (60 mg/day) resolved the patient's high fever and disturbance of consciousness. OUTCOMES: The patient rapidly improved after steroid treatments and has a normal quality of life under the maintenance dose of steroid plus methotrexate (4 mg/week). LESSONS: RP-associated meningoencephalitis is a rare complication with significant morbidity and mortality. It should be considered and differentiated in patients with RP with unexplained spiking fever and impaired consciousness. In addition, the assessment of cerebrospinal fluid interleukin-6 levels may be useful to investigate the disease activity of RP-related meningoencephalitis. Further prospective studies are required to confirm this result.

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.