Soluble ST2 Is Associated With New Epileptiform Abnormalities Following Nontraumatic Subarachnoid Hemorrhage

Abstract

Background and Purpose— We evaluated the association between 2 types of predictors of delayed cerebral ischemia after nontraumatic subarachnoid hemorrhage, including biomarkers of the innate immune response and neurophysiologic changes on continuous electroencephalography. Methods— We studied subarachnoid hemorrhage patients that had at least 72 hours of continuous electroencephalography and blood samples collected within the first 5 days of symptom onset. We measured inflammatory biomarkers previously associated with delayed cerebral ischemia and functional outcome, including soluble ST2 (sST2), IL-6 (interleukin-6), and CRP (C-reactive protein). Serial plasma samples and cerebrospinal fluid sST2 levels were available in a subgroup of patients. Neurophysiologic changes were categorized into new or worsening epileptiform abnormalities (EAs) or new background deterioration. The association of biomarkers with neurophysiologic changes were evaluated using the Wilcoxon rank-sum test. Plasma and cerebrospinal fluid sST2 were further examined longitudinally using repeated measures mixed-effects models. Results— Forty-six patients met inclusion criteria. Seventeen (37%) patients developed new or worsening EAs, 21 (46%) developed new background deterioration, and 8 (17%) developed neither. Early (day, 0–5) plasma sST2 levels were higher among patients with new or worsening EAs (median 115 ng/mL [interquartile range, 73.8–197]) versus those without (74.7 ng/mL [interquartile range, 44.8–102]; P =0.024). Plasma sST2 levels were similar between patients with or without new background deterioration. Repeated measures mixed-effects modeling that adjusted for admission risk factors showed that the association with new or worsening EAs remained independent for both plasma sST2 (β=0.41 [95% CI, 0.09–0.73]; P =0.01) and cerebrospinal fluid sST2 (β=0.97 [95% CI, 0.14–1.8]; P =0.021). IL-6 and CRP were not associated with new background deterioration or with new or worsening EAs. Conclusions— In patients admitted with subarachnoid hemorrhage, sST2 level was associated with new or worsening EAs but not new background deterioration. This association may identify a link between a specific innate immune response pathway and continuous electroencephalography abnormalities in the pathogenesis of secondary brain injury after subarachnoid hemorrhage.

Therapeutic Opportunities of Interleukin-33 in the Central Nervous System

“…In SAH patients, plasma sST2 levels are higher among patients with new or worsening epileptiform abnormalities than those of patients without (103), implying that IL-33, which can be decoyed by sST2, is associated with reduced odds of epileptiform abnormalities. In a rat model of recurrent neonatal seizure (RNS), IL-33 administration restores the reduced IL-33 in the cortex induced by RNS, improves RNSinduced behavioral deficits, promotes body weight gain, and ameliorates spatial learning and memory ability by impeding NF-kB-mediated neuroinflammation (104,105).…”

Biomarkers Utility: At the Borderline between Cardiology and Neurology

“…Increased levels of sST2 in patients with subarachnoid hemorrhage were associated with a shift towards a more pro-inflammatory immune cell population, which had a negative impact on the outcome [106]. As a prognostic marker, it was noticed that sST2 levels were associated with neurophysiologic changes on continuous electroencephalography, such as new or worsening epileptiform abnormalities after an episode of subarachnoid hemorrhage [107].…”

Challenges and Opportunities in Multimodal Monitoring and Data Analytics in Traumatic Brain Injury

“…Physiologic data is increasingly being curated in conjunction with metabolomic or genomic data. For example, the genotype of SIRT-1 has been associated with ICP trajectory [ 25 ], and inflammatory markers have been associated with seizures [ 26 ] as well as worsening epileptiform abnormalities [ 27 ]. As with the types of data mentioned above, the process of linking MMM data with -omics data requires pre-processing.…”