Modeling prognostic factors for poor neurological outcome in conservatively treated patients with intracerebral hemorrhage: A focus on TNF-α

Rendevski, Vladimir; Aleksovski, Boris; Stojanov, Dragan; Rendevska, Ana Mihajlovska; Aleksovski, Vasko; Gjorgoski, Icko

doi:10.1016/j.clineuro.2018.06.027

Cited by 8 publications

(3 citation statements)

References 36 publications

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“…Hence, aiming at prevention of formation of large edema volumes in patients after ICH, several studies up to now focused on its prediction. Most of these studies point out to the primary role of inflammatory mechanisms in the formation of large edema volumes; for instance, our previous work stressed the importance of TNF‐α, a pro‐inflammatory cytokine, in the formation of the brain edema [ 7 ], as well as its role in prediction of the 3‐month functional outcome [ 8 ]. Nevertheless, the data concerning the role of other cytokines in brain edema formation and functional outcome after ICH is scarce.…”

Section: Introductionmentioning

confidence: 99%

Inflammatory and oxidative stress markers in intracerebral hemorrhage: Relevance as prognostic markers for quantification of the edema volume

et al. 2022

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We aimed to analyze the inflammatory and oxidative stress (OS) markers after intracerebral hemorrhage (ICH) and their temporal changes, interaction effects, and prognostic values as biomarkers for the prediction of the edema volume. Our prospective, longitudinal study included a cohort group of 73 conservatively treated patients with ICH, without hematoma expansion or intraventricular bleeding, which were initialized with the same treatment and provided with the same in-hospital care during the disease course. Study procedures included multilevel comprehensive analyses of clinical and neuroimaging data, aligned with the exploration of 19 inflammatory and five OS markers. White blood cells (WBC), C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), neutrophilia, and lymphopenia peaked 3 days post-ICH, and they showed much stronger correlations with clinical and neuroimaging variables, when compared to the admission values. An intricate interplay among inflammatory (WBC, CRP, neutrophils, neutrophil-to-lymphocyte ratio [NLR], interleukin (IL)-6, and IL-10) and OS mechanisms (catalase activity and advanced oxidation protein products [AOPP]) was detected operating 3-days post-ICH, being assessed as relevant for prediction of the edema. The overall results suggested complex pathology of formation of post-ICH edema, via: (A) Not additive, but statistically significant synergistic interactions between CRP-ESR, neutrophils-CRP, and neutrophils-IL-6 as drivers for the edema formation; (B) Significant antagonistic effect of high protein oxidation on the CRP-edema dependence, suggesting a mechanism of potential OS-CRP negative feedback loop and redox inactivation of CRP. The final multiple regression model separated the third-day variables NLR, CRP Â AOPP, and WBC, as significant prognostic biomarkers for the prediction of the edema volume, with NLR being associated with the highest effect size. Our developed mathematical equation with 3D modeling for prediction and quantification of the edema volume might be beneficial for taking timely adequate strategies for prevention of delayed neurological deteriorations.

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Section: Introductionmentioning

confidence: 99%

Inflammatory and oxidative stress markers in intracerebral hemorrhage: Relevance as prognostic markers for quantification of the edema volume

et al. 2022

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“…Cytokines/chemokines. Two proinflammatory cytokines were included in meta-analyses; IL-6 29 , 33 , 72 , 86 , 93 , 101 , 106 and TNFα 29 , 33 , 86 , 93 , 101 , 107 . Four studies 29 , 72 , 86 , 93 of 303 participants reporting on IL-6 and 90-day mRS were meta-analysed, two of which included a multivariable analysis 72 , 86 .…”

Section: Resultsmentioning

confidence: 99%

Association between circulating inflammatory biomarkers and functional outcome or perihaematomal oedema after ICH: a systematic review & meta-analysis

Kirby,

Barrington,

Sondag

et al. 2023

Wellcome Open Res

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Background Currently, there are no specific medical treatments for intracerebral haemorrhage (ICH), but the inflammatory response may provide a potential route to treatment. Given the known effects of acute brain injury on peripheral immunity, we hypothesised that inflammatory biomarkers in peripheral blood may be associated with clinical outcome following ICH, as well as perihaematomal oedema (PHO), which is an imaging marker of the neuroinflammatory response. Methods We searched OVID Medline and EMBASE on 07 April 2021 for studies of humans with ICH measuring an inflammatory biomarker in peripheral blood and PHO or clinical outcome. Risk of bias was assessed both by using a scale comprising features of the Newcastle-Ottawa Assessment Scale, STROBE-ME and REMARK guidelines, and for studies included in meta-analysis, also by the QUIPS tool.We used random effects meta-analysis to pool standardised mean differences (SMD) if ≥1 study quantified the association between identical biomarkers and measures of PHO or functional outcome. Results Of 8,615 publications, 16 examined associations between 21 inflammatory biomarkers and PHO (n=1,299 participants), and 93 studies examined associations between ≥1 biomarker and clinical outcome (n=17,702 participants). Overall, 20 studies of nine biomarkers (n=3,199) met criteria for meta-analysis of associations between inflammatory biomarkers and clinical outcome. Death or dependency (modified Rankin Scale (mRS) 3‒6) 90 days after ICH was associated with higher levels of fibrinogen (SMD 0.32; 95%CI [0.04, 0.61]; p=0.025), and high mobility group box protein 1 (HMGB1) (SMD 1.67; 95%CI [0.05, 3.30]; p=0.04). Higher WBC was associated with death or dependency at 90 days (pooled SMD 0.27; 95% CI [0.11, 0.44]; p=0.001; but the association was no longer significant when the analysis was restricted to studies with a low risk of bias (pooled SMD 0.22; 95% CI -0.04-0.48). Higher CRP seemed to be associated with death or dependency at 90 days (pooled SMD 0.80; 95% CI [0.44, 1.17]; p<0.0001) but this association was no longer significant when adjusted OR were pooled (OR 0.99 (95% CI 0.98-1.01)). Conclusions Higher circulating levels of, fibrinogen and HMGB1 are associated with poorer outcomes after ICH. This study highlights the clinical importance of the inflammatory response to ICH and identifies additional research needs in determining if these associations are mediated via PHO and are potential therapeutic targets. Registration PROSPERO (CRD42019132628; 28/05/2019).

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“…TNF-α was elevated in ICH patients and increased peri-hematoma. TNF-α expression contributed to edema development after ICH in rodents (Rendevski et al, 2018). The expression levels of TNF-α peaked 3 d after ICH, and this increase aggravated secondary neurological impairment after ICH (Zhang et al, 2019).…”

Section: Discussionmentioning

confidence: 99%

Glymphatic Drainage Blocking Aggravates Brain Edema, Neuroinflammation via Modulating TNF-α, IL-10, and AQP4 After Intracerebral Hemorrhage in Rats

Liu

Tang

et al. 2021

Front. Cell. Neurosci.

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Objective: The “Glymphatic” system, a network of perivascular tunnels wrapped by astrocyte endfeet, was reported to be closely associated with the diseases of the central nervous system. Here, we investigated the role of the glymphatic system in intracerebral hemorrhage (ICH) and its protective mechanism.Method: Experimental ICH model was induced by type IV collagenase in rats. Cerebral lymphatic blockage was induced by ligation and removal of cervical lymph nodes. The experimental rats were divided into sham-operated (SO) group, ICH group, and cerebral lymphatic blocking and ICH (ICH + CLB) group. Neurological scores were measured using the Garcia scoring system on the third and seventh day after ICH. Active caspase-3 was immunostained to evaluate neuronal apoptosis. Brain water content was calculated using the dry-wet specific gravity method. The expression of inflammatory factors TNF-α, IL-1β, and IL-10 were detected using ELISA. Aquaporins-4 (AQP-4) and glial fibrillary acidic protein (GFAP) were detected using western blot analysis.Results: The neurological scores of rats in the CLB + ICH group were significantly lower than those in the in ICH group. The number of active caspase-3 neurons was significantly higher in the CLB + ICH group compared to the ICH group. CLB significantly aggravated ICH-induced brain edema 3 d after ICH. There was an increase in the expression of TNF-α, IL-1β, IL-10, AQP-4, GFAP after ICH. The expression of TNF-α was significantly higher in the CLB + ICH group compared to ICH group 3 d after ICH while there was no difference 7 d after ICH. There was no statistical difference in the expression of IL-1β between the ICH group and CLB + ICH group. However, the expression of IL-10 in the CLB + ICH group was significantly lower than that in the ICH group. Lastly, AQP-4 expression was significantly lower in the CLB + ICH group compared to the ICH group while the expression of GFAP was higher in the CLB + ICH group compared to the ICH group.Conclusion: CLB exacerbated cerebral edema, neuroinflammation, neuronal apoptosis and caused neurological deficits in rats with ICH via down-regulating AQP-4, up-regulating inflammatory TNF-α and inhibiting IL-10 expression. The glymphatic drainage system protects against neurologic injury after ICH induction in rats under normal physiological conditions.

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Modeling prognostic factors for poor neurological outcome in conservatively treated patients with intracerebral hemorrhage: A focus on TNF-α

Cited by 8 publications

References 36 publications

Inflammatory and oxidative stress markers in intracerebral hemorrhage: Relevance as prognostic markers for quantification of the edema volume

Inflammatory and oxidative stress markers in intracerebral hemorrhage: Relevance as prognostic markers for quantification of the edema volume

Association between circulating inflammatory biomarkers and functional outcome or perihaematomal oedema after ICH: a systematic review & meta-analysis

Glymphatic Drainage Blocking Aggravates Brain Edema, Neuroinflammation via Modulating TNF-α, IL-10, and AQP4 After Intracerebral Hemorrhage in Rats

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