Elevated levels of several chemokines in the cerebrospinal fluid of patients with subarachnoid hemorrhage are associated with worse clinical outcome.

BACKGROUND: Chemokines are small cytokines that exert chemotactic actions on immune cells and are involved in many inflammatory processes. The present study aims to provide insight in the role of this relatively unexplored family of proteins in the inflammatory pathophysiology of subarachnoid hemorrhage (SAH). MATERIALS AND METHODS: Cerebrospinal fluid of 29 patients (17 female; mean age 57 years) was collected at days 1, 4 and 10 after SAH, centrifuged and frozen at -70°C. Analysis of 92 inflammation-related proteins was performed using Target 96 Inflammation ® assay (Olink Proteomics, Uppsala, Sweden) based on Proximity Extension Assay technology. The panel included 20 chemokines (CCL2 (or MCP-1), CCL3, CCL4, CCL7 (or MCP-3), CCL8 (or MCP-2), CCL11 (or Eotaxin), CCL13 (or MCP-4), CCL19, CCL20, CCL23, CCL25, CCL28, CXCL1, CXCL5, CXCL6, CXCL8 (or IL-8), CXCL9, CXCL10, CXCL11 and CX3CL1 (or Fractalkine)) that were analyzed for their temporal patterns of expression and compared in dichotomized clinical groups based on World Federation of Neurosurgical Societies (WFNS) admission score and amount of blood on admission CT based on Fisher scale; presence of delayed cerebral ischemia(DCI)/delayed ischemic neurological deficit (DIND); and clinical outcome based on Glasgow Outcome Scale. Protein expression levels were provided in output unit Normalized Protein Expression (NPX). ANOVA models were used for statistical analyses. RESULTS: Four temporal patterns of expression were observed (i.e., early, middle, late peak and no peak). Significantly higher day 10 mean NPX values were observed in patients with poor outcome (GOS 1-3) for chemokines CCL2, CCL4, CCL7, CCL11, CCL13, CCL19, CCL20, CXCL1, CXCL5, CXCL6 and CXCL8. In the WFNS 4-5 group, CCL11 showed significantly higher day 4 and day 10 mean NPX values and CCL25 significantly higher day 4 values. In patients with SAH Fisher 4, CCL11 showed significantly higher mean NPX values on days 1, 4 and 10. Finally, patients with DCI/DIND had significantly higher day 4 mean NPX values of CXCL5. CONCLUSION: Higher levels of multiple chemokines at the late stage of SAH seemed to correlate with worse clinical outcome. A few chemokines correlated with WFNS score, Fisher score and occurrence of DCI/DIND. Chemokines may be useful as biomarkers for describing the pathophysiology and prognosis of SAH. Further studies are needed to better understand their exact mechanism of action in the inflammatory cascade.

Dura Management Strategies in the Surgical Treatment of Adult Chiari Type I Malformation: A Retrospective, Multicenter, Population-Based Parallel Cohort Case Series.

BACKGROUND: Symptomatic Chiari I malformation is treated with suboccipital decompression and C1 laminectomy. However, whether the dura should be opened (durotomy) or enlarged with a graft (duraplasty) remains unclear. OBJECTIVE: To compare outcomes in adult Chiari I malformation patients treated with duraplasty, durotomy, or without dural opening ("mini-decompression"). METHODS: A retrospective, multicenter, population-based cohort study was performed of all adult patients surgically treated for a Chiari I malformation at 3 regional neurosurgical centers between 2005 and 2017. Three different dura management strategies were favored by the participating hospitals, with data stratified accordingly. The primary outcome was measured using the Chicago Chiari Outcome Scale (CCOS), dichotomized into favorable (CCOS ≥13) or unfavorable (CCOS ≤12). Propensity score matching was used to adjust for potential confounders in outcome comparisons. RESULTS: In total, 318 patients were included, of whom 52% were treated with duraplasty, 37% with durotomy, and 11% with mini-decompression. In total, 285 (90%) showed a favorable surgical outcome (CCOS ≥13). Duraplasty was associated with more favorable CCOS and shorter hospital stay compared with durotomy, both in unadjusted (93% vs 84%. P = .018 and 6.0 vs 8.0 days, P < .001) and adjusted analyses (92% vs 84%, P = .044 and 6.0 vs 8.0 days, P < .001). Mini-decompression was excluded from the adjusted analyses because of its small sample size. CONCLUSION: In this study of adult Chiari I malformation, posterior fossa decompression with duraplasty was associated with more favorable postoperative outcome, as determined by the CCOS, compared with posterior fossa decompression with durotomy alone.

Temporal patterns of inflammation-related proteins measured in the cerebrospinal fluid of patients with aneurysmal subarachnoid hemorrhage using multiplex Proximity Extension Assay technology.

BACKGROUND: The complexity of the inflammatory response post subarachnoid hemorrhage (SAH) may require temporal analysis of multiple protein biomarkers simultaneously to be more accurately described. METHODS: Ventricular cerebrospinal fluid was collected at days 1, 4 and 10 after SAH in 29 patients. Levels of 92 inflammation-related proteins were simultaneously measured using Target 96 Inflammation ® assay (Olink Proteomics, Uppsala, Sweden) based on Proximity Extension Assay (PEA) technology. Twenty-eight proteins were excluded from further analysis due to lack of >50% of measurable values. Temporal patterns of the remaining 64 proteins were analyzed. Repeated measures ANOVA and its nonparametric equivalent Friedman's ANOVA were used for comparisons of means between time points. RESULTS: Four different patterns (Groups A-D) were visually observed with an early peak and gradually decreasing trend (11 proteins), a middle peak (10 proteins), a late peak after a gradually increasing trend (30 proteins) and no specific pattern (13 proteins). Statistically significant early peaks defined as Day 1 > Day 4 values were noticed in 4 proteins; no significant decreasing trends defined as Day 1 > Day 4 > Day 10 values were observed. Two proteins showed significant middle peaks (i.e. Day 1 < Day 4 > Day 10 values). Statistically significant late peaks (i.e. Day 4 < Day 10 values) and increasing trends (i.e. Day 1 < Day 4 < Day 10 values) were observed in 14 and 10 proteins, respectively. Four of Group D proteins showed biphasic peaks and the rest showed stable levels during the observation period. CONCLUSION: The comprehensive data set provided in this explorative study may act as an illustration of an inflammatory profile of the acute phase of SAH showing groups of potential protein biomarkers with similar temporal patterns of activation, thus facilitating further research on their role in the pathophysiology of the disease.

Interleukin-6 Levels in Cerebrospinal Fluid and Plasma in Patients with Severe Spontaneous Subarachnoid Hemorrhage.

BACKGROUND: Inflammatory processes play a key role in the pathophysiology of subarachnoid hemorrhage (SAH). This study evaluated whether different temporal patterns of intrathecal and systemic inflammation could be identified in the acute phase after SAH. The intensity of the inflammation was also assessed in clinical subgroups. METHODS: Cerebrospinal fluid (CSF) and blood samples were collected at days 1, 4, and 10 after ictus in 44 patients with severe SAH. Interleukin-6 (IL-6) was analyzed by a routine monoclonal antibody-based method. Median IL-6 values for each day were calculated. Day 4 IL-6 values were compared in dichotomized groups (age, sex, World Federation of Neurosurgical Societies [WFNS] grade, Fisher scale grade, outcome, vasospasm, central nervous system infection and systemic infections). RESULTS: CSF IL-6 levels were significantly elevated from day 1 to days 4 and 10, whereas plasma IL-6 showed a different trend at lower levels. Median CSF IL-6 concentrations for days 1, 4, and 10 were 876.5, 3361, and 1567 ng/L, whereas plasma was 26, 27.5, and 15.9 ng/L, respectively. No significant differences in CSF concentrations were observed between the subgroups, with the most prominent one being in day 4 IL-6 in the WFNS subgroups (grades 1-3 vs. 4-5, 1158.5 vs. 5538 ng/L; P = 0.056). Patients with systemic infection had significantly higher plasma IL-6 concentrations than patients without infection (31 vs. 16.05 ng/L, respectively; P = 0.028). CONCLUSIONS: Distinctly different inflammatory patterns could be seen intrathecally compared with the systemic circulation. In plasma, a significant difference in the intensity of the inflammation was seen in cases with systemic infection. No other subgroup showed statistically significant differences.

Hypofractionated high-energy proton-beam irradiation is an alternative treatment for WHO grade I meningiomas.

BACKGROUND: Radiation treatment is commonly employed in the treatment of meningiomas. The aim of this study was to evaluate the effectiveness and safety of hypofractionated high-energy proton therapy as adjuvant or primary treatment for WHO grade I meningiomas. METHOD: A total of 170 patients who received irradiation with protons for grade I meningiomas between 1994 and 2007 were included in the study. The majority of the tumours were located at the skull base (n = 155). Eighty-four patients were treated post subtotal resection, 42 at tumour relapse and 44 with upfront radiotherapy after diagnosis based on the typical radiological image. Irradiation was given in a hypofractionated fashion (3-8 fractions, usually 5 or 6 Gy) with a mean dose of 21.9 Gy (range, 14-46 Gy). All patients were planned for follow-up with clinical controls and magnetic resonance imaging scans at 6 months and 1, 2, 3, 5, 7 and 10 years after treatment. The median follow-up time was 84 months. Age, gender, tumour location, Simpson resection grade and target volume were assessed as possible prognostic factors for post-irradiation tumour progression and radiation related complications. RESULTS: The actuarial 5- and 10-year progression-free survival rates were 93% and 85% respectively. Overall mortality rate was 13.5%, while disease-specific mortality was 1.7% (3/170 patients). Older patients and patients with tumours located in the middle cranial fossa had a lower risk for tumour progression. Radiation-related complications were seen in 16 patients (9.4%), with pituitary insufficiency being the most common. Tumour location in the anterior cranial fossa was the only factor that significantly increased the risk of complications. CONCLUSIONS: Hypofractionated proton-beam radiation therapy may be used particularly in the treatment of larger World Health Organisation grade I meningiomas not amenable to total surgical resection. Treatment is associated with high rates of long-term tumour growth control and acceptable risk for complications.