Nonconvulsive seizures in subarachnoid hemorrhage link inflammation and outcome

Abstract

Objective: Nonconvulsive seizures (NCSz) are frequent following acute brain injury and have been implicated as a cause of secondary brain injury, but mechanisms that cause NCSz are controversial. Proinflammatory states are common after many brain injuries, and inflammation-mediated changes in blood-brain barrier permeability have been experimentally linked to seizures.

Methods: In this prospective observational study of aneurysmal subarachnoid hemorrhage (SAH) patients, we explored the link between the inflammatory response following SAH and in-hospital NCSz studying clinical (systemic inflammatory response syndrome [SIRS]) and laboratory (tumor necrosis factor receptor 1 [TNF-R1], high-sensitivity C-reactive protein [hsCRP]) markers of inflammation. Logistic regression, Cox proportional hazards regression, and mediation analyses were performed to investigate temporal and causal relationships.

Results: Among 479 SAH patients, 53 (11%) had in-hospital NCSz. Patients with in-hospital NCSz had a more pronounced SIRS response (odds ratio [OR]=1.9 per point increase in SIRS, 95% confidence interval [CI]=1.3-2.9), inflammatory surges were more likely immediately preceding NCSz onset, and the negative impact of SIRS on functional outcome at 3 months was mediated in part through in-hospital NCSz. In a subset with inflammatory serum biomarkers, we confirmed these findings linking higher serum TNF-R1 and hsCRP to in-hospital NCSz (OR=1.2 per 20-point hsCRP increase, 95% CI=1.1-1.4; OR=2.5 per 100-point TNF-R1 increase, 95% CI=2.1-2.9). The association of inflammatory biomarkers with poor outcome was mediated in part through NCSz.

Interpretation: In-hospital NCSz were independently associated with a proinflammatory state following SAH as reflected in clinical symptoms and serum biomarkers of inflammation. Our findings suggest that inflammation following SAH is associated with poor outcome and that this effect is at least in part mediated through in-hospital NCSz.

Keywords: brain metabolism; continuous EEG monitoring; electrographic seizures; inflammation; nonconvulsive seizures; subarachnoid hemorrhage.

Figure 1

Daily mean SIRS score for SAH patients with and without in-hospital seizures.

Figure 2

Measures of inflammation of those with (grey boxes) and without NCSz (white boxes) stratified by EEG background attenuation (none-mild vs moderate-severe background attenuation). Higher hsCRP measurements and hsCRP/TTR ratios are seen for those with moderate to severe EEG background attenuation and those with NCSz. Interestingly, there was no clear difference between patients with and without NCSz amongst those with moderate to severe EEG background attenuation. This observation was true at post SAH days 4 to 7 (phase 2) as well as 8 to 10 (phase 3). hsCRP, high sensitivity C reactive protein; SAH, subarachnoid hemorrhage; TTR, transthyretin (also known as prealbumin. * P<0.05; ** P<0.001

Figure 3

TNF-R1 measurements for those with (grey boxes) and without NCSz (white boxes) during days 4 to 7 (left panel) and days 8 to 10 after SAH (right panel). TNF-R1, tumor necrosis factor TNF receptor 1* P<0.05; ** P<0.001

Figure 4

Mediation analyses indicating that SIRS, hsCRP and TNF-R1 significantly predict 3 months functional outcome independently and via NCSz. Moreover, we found that NCSz significantly predict outcome while controlling for SIRS, hsCRP and TNF-R1 (bolded in figure), suggesting that NCSz mediate the relationship between inflammatory markers and poor functional outcome. Data reported as b; P-values (95%-CI). The strongest effect is bolded.