Discussion
TNF-a, SAH, aSAH, fungal drain-related meningitis, infection, cerebral edema, hemolysis, platelet aggregation
ATYPICAL HEMOLYTIC-UREMIC SYNDROME, PAROXYSMAL NOCTURNAL HEMOGLOBINURIA, THROMBOTIC MICROANGIOPATHY, NEUROMYELITIS OPTICA, FUNGAL INFECTIONS, ACUTE DISEASE, INFECTION, CEREBRAL EDEMA, HEMOLYSIS
In this study, we found no evidence of a ⩾55% decrease in CSF C5a concentration in aSAH patients on day 3 after the first dose of eculizumab. However, with our high dose eculizumab administration thrice in the first week after aSAH onset, we found a profound reduction in serum C5a concentration and complement activity, which confirms the pharmacological efficacy of this regimen in serum. We found no increase in infection rate with this eculizumab dosing regimen in combination with infection monitoring by performing surveillance cultures and a prophylactic regimen. There were no other safety concerns, except for a fungal drain-related meningitis in one patient prior to antifungal monitoring and treatment.Eculizumab, a humanized monoclonal antibody directed against complement component C5, was first approved as treatment for paroxysmal nocturnal hemoglobinuria and atypical hemolytic-uremic syndrome, because it reduced complement-mediated intravascular hemolysis and thrombotic microangiopathy.The CLASH trial is the first in-human study on short-term treatment with eculizumab in an acute disease. Therefore, we based the high dose eculizumab and repeated drug administration on the results of a previous study, in which we found that the CSF C5a concentration in aSAH patients is increased >1400 times on day 1 after ictus compared to the CSF C5a concentration in control patients and slowly decreased until day 10 after ictus.CSF eculizumab concentration varied substantially between patients after one dose of eculizumab, possibly due to differences in blood-CSF barrier disturbances among aSAH patients and thereby eculizumab penetration. In patients with neuromyelitis optica, treatment with eculizumab resulted in a decrease in CSF free C5 concentration of more than 55%, while CSF eculizumab concentrations were lower than in our study.Various neuroinflammatory parameters, such as complement components, interleukin-6, and TNF-a have been associated with poor functional outcome after SAH and are therefore a target for intervention.Eculizumab can increase susceptibility to fungal infections.SAH patients are often treated with anti-inflammatory drugs such as aspirin or steroids. Aspirin or other types of platelet aggregation inhibitors are often used after coiling or placement of a flow-diverting stent, while steroids may be given (in the absence of evidence) for reducing cerebral edema after SAH. No contra-indication exists for treatment with eculizumab in patients already treated with aspirin, other platelet aggregation inhibitors or steroids.Several limitations need to be mentioned. First, CSF samples were obtained either by lumbar puncture or from an external ventricular CSF drain. In the post hoc analysis, C5a concentration in lumbar CSF samples and in CSF samples from an external ventricular drain differed between the intervention and control group. Future studies should preferably use only one method of CSF sampling. Second, sampling, processing and storage conditions can influence C5a measurements.In conclusion, treatment with eculizumab did not decrease CSF C5a concentration with ⩾55% on day 3 after one dose of eculizumab. Safety findings showed no other safety concerns than in previous studies, except for a 