Clearance of Early Complement Protein From CSF After Aneurysmal Subarachnoid Hemorrhage and Influence on Neurologic Outcome.
Aneurysmal subarachnoid hemorrhage (aSAH) triggers a robust inflammatory response, which has been associated with brain injury and poor outcome. The complement system is an integral part of the innate immune system activated after acute brain injury. The early complement proteins C1q and C3 have roles in glial-neuronal interactions and synaptic pruning. The objective of this study was to determine whether changes in CSF complement proteins over time after aSAH are associated with neurologic outcome.
We performed an exploratory retrospective case-control study investigating the association of CSF levels and clearance of C1q and C3 with outcome in patients with aSAH and compared with controls with normal CSF. Clearance was defined as the percent change of complement protein levels between 2 time points corresponding to peaks of early (<72 hours) and delayed (5-7 days) brain injury after aSAH. The primary endpoint was functional outcome, assessed by Glasgow Outcome Scale (GOS; range 1-5 with higher scores denoting better outcome), at the time of discharge. Good functional outcome was defined as GOS 4-5. Complement protein clearance was adjusted by baseline differences, and receiver operating characteristic analysis was performed.
Early after aSAH, there was a robust increase in C1q (median 89.10 vs 6.42 ng/mL, p < 0.0001) and C3 (78.00 vs 8.72 µg/mL, p = 0.0001) in CSF of 20 patients with aSAH compared with 11 controls. Between early and late time points, both C1q (97.38 vs 47.85 ng/mL, p = 0.0326) and C3 (85.23 vs 23.10 µg/mL, p = 0.0004) decreased in those with good outcome. Percent clearance of C3 from CSF was larger in those with good vs poor neurologic outcome (median 74.85% vs 11.43% reduction over time, p = 0.0159). C3 clearance, particularly when adjusted by baseline Glasgow coma scale on admission, was a highly sensitive and specific marker of neurologic outcome after aSAH (area under curve = 0.990, 95% confidence interval 0.958-1.000, sensitivity 90.9%, specificity 100.0%).
Increased CSF clearance of C3 within the first week after aSAH appears to be associated with improved neurologic outcome. Future strategies to promote clearance of inflammatory mediators such as early complement proteins from CSF may, therefore, improve outcomes after aSAH.
We performed an exploratory retrospective case-control study investigating the association of CSF levels and clearance of C1q and C3 with outcome in patients with aSAH and compared with controls with normal CSF. Clearance was defined as the percent change of complement protein levels between 2 time points corresponding to peaks of early (<72 hours) and delayed (5-7 days) brain injury after aSAH. The primary endpoint was functional outcome, assessed by Glasgow Outcome Scale (GOS; range 1-5 with higher scores denoting better outcome), at the time of discharge. Good functional outcome was defined as GOS 4-5. Complement protein clearance was adjusted by baseline differences, and receiver operating characteristic analysis was performed.
Early after aSAH, there was a robust increase in C1q (median 89.10 vs 6.42 ng/mL, p < 0.0001) and C3 (78.00 vs 8.72 µg/mL, p = 0.0001) in CSF of 20 patients with aSAH compared with 11 controls. Between early and late time points, both C1q (97.38 vs 47.85 ng/mL, p = 0.0326) and C3 (85.23 vs 23.10 µg/mL, p = 0.0004) decreased in those with good outcome. Percent clearance of C3 from CSF was larger in those with good vs poor neurologic outcome (median 74.85% vs 11.43% reduction over time, p = 0.0159). C3 clearance, particularly when adjusted by baseline Glasgow coma scale on admission, was a highly sensitive and specific marker of neurologic outcome after aSAH (area under curve = 0.990, 95% confidence interval 0.958-1.000, sensitivity 90.9%, specificity 100.0%).
Increased CSF clearance of C3 within the first week after aSAH appears to be associated with improved neurologic outcome. Future strategies to promote clearance of inflammatory mediators such as early complement proteins from CSF may, therefore, improve outcomes after aSAH.