Nonconvulsive seizures in subarachnoid hemorrhage link inflammation and outcome
Corresponding Author
Jan Claassen MD, PhD
Division of Critical Care Neurology, Department of Neurology, College of Physicians and Surgeons, New York, NY
Comprehensive Epilepsy Center, Department of Neurology, College of Physicians and Surgeons, New York, NY
Department of Neurosurgery, College of Physicians and Surgeons, New York, NY
Address correspondence to Dr Claassen, Division of Critical Care Neurology and Comprehensive Epilepsy Center, Neurological Institute, Columbia University, 177 Fort Washington Avenue, MHB 8 Center, Room 300, New York, NY 10032. E-mail: [email protected]Search for more papers by this authorDavid Albers PhD
Department of Biomedical Informatics, College of Physicians and Surgeons, New York, NY
Search for more papers by this authorJ. Michael Schmidt PhD
Division of Critical Care Neurology, Department of Neurology, College of Physicians and Surgeons, New York, NY
Search for more papers by this authorGian Marco De Marchis MD
Division of Critical Care Neurology, Department of Neurology, College of Physicians and Surgeons, New York, NY
Search for more papers by this authorDeborah Pugin MD
Division of Critical Care Neurology, Department of Neurology, College of Physicians and Surgeons, New York, NY
Search for more papers by this authorChristina Maria Falo PhD
Division of Critical Care Neurology, Department of Neurology, College of Physicians and Surgeons, New York, NY
Search for more papers by this authorStephan A. Mayer MD
Division of Critical Care Neurology, Department of Neurology, College of Physicians and Surgeons, New York, NY
Department of Neurosurgery, College of Physicians and Surgeons, New York, NY
Search for more papers by this authorSerge Cremers PhD
Biomarkers Core Laboratory of the Irving Institute, College of Physicians and Surgeons, New York, NY
Search for more papers by this authorSachin Agarwal MD
Division of Critical Care Neurology, Department of Neurology, College of Physicians and Surgeons, New York, NY
Department of Neurosurgery, College of Physicians and Surgeons, New York, NY
Search for more papers by this authorMitchell S. V. Elkind MD, MS
Department of Epidemiology, Mailman School of Public Health, College of Physicians and Surgeons, New York, NY
Division of Stroke, Department of Neurology, Columbia University, College of Physicians and Surgeons, New York, NY
Search for more papers by this authorE. Sander Connolly MD
Department of Neurosurgery, College of Physicians and Surgeons, New York, NY
Search for more papers by this authorVanja Dukic PhD
Department of Applied Mathematics, University of Colorado-Boulder, Boulder, CO
Search for more papers by this authorGeorge Hripcsak MD
Department of Biomedical Informatics, College of Physicians and Surgeons, New York, NY
Search for more papers by this authorNeeraj Badjatia MD
Division of Critical Care Neurology, Department of Neurology, College of Physicians and Surgeons, New York, NY
Department of Neurosurgery, College of Physicians and Surgeons, New York, NY
Search for more papers by this authorCorresponding Author
Jan Claassen MD, PhD
Division of Critical Care Neurology, Department of Neurology, College of Physicians and Surgeons, New York, NY
Comprehensive Epilepsy Center, Department of Neurology, College of Physicians and Surgeons, New York, NY
Department of Neurosurgery, College of Physicians and Surgeons, New York, NY
Address correspondence to Dr Claassen, Division of Critical Care Neurology and Comprehensive Epilepsy Center, Neurological Institute, Columbia University, 177 Fort Washington Avenue, MHB 8 Center, Room 300, New York, NY 10032. E-mail: [email protected]Search for more papers by this authorDavid Albers PhD
Department of Biomedical Informatics, College of Physicians and Surgeons, New York, NY
Search for more papers by this authorJ. Michael Schmidt PhD
Division of Critical Care Neurology, Department of Neurology, College of Physicians and Surgeons, New York, NY
Search for more papers by this authorGian Marco De Marchis MD
Division of Critical Care Neurology, Department of Neurology, College of Physicians and Surgeons, New York, NY
Search for more papers by this authorDeborah Pugin MD
Division of Critical Care Neurology, Department of Neurology, College of Physicians and Surgeons, New York, NY
Search for more papers by this authorChristina Maria Falo PhD
Division of Critical Care Neurology, Department of Neurology, College of Physicians and Surgeons, New York, NY
Search for more papers by this authorStephan A. Mayer MD
Division of Critical Care Neurology, Department of Neurology, College of Physicians and Surgeons, New York, NY
Department of Neurosurgery, College of Physicians and Surgeons, New York, NY
Search for more papers by this authorSerge Cremers PhD
Biomarkers Core Laboratory of the Irving Institute, College of Physicians and Surgeons, New York, NY
Search for more papers by this authorSachin Agarwal MD
Division of Critical Care Neurology, Department of Neurology, College of Physicians and Surgeons, New York, NY
Department of Neurosurgery, College of Physicians and Surgeons, New York, NY
Search for more papers by this authorMitchell S. V. Elkind MD, MS
Department of Epidemiology, Mailman School of Public Health, College of Physicians and Surgeons, New York, NY
Division of Stroke, Department of Neurology, Columbia University, College of Physicians and Surgeons, New York, NY
Search for more papers by this authorE. Sander Connolly MD
Department of Neurosurgery, College of Physicians and Surgeons, New York, NY
Search for more papers by this authorVanja Dukic PhD
Department of Applied Mathematics, University of Colorado-Boulder, Boulder, CO
Search for more papers by this authorGeorge Hripcsak MD
Department of Biomedical Informatics, College of Physicians and Surgeons, New York, NY
Search for more papers by this authorNeeraj Badjatia MD
Division of Critical Care Neurology, Department of Neurology, College of Physicians and Surgeons, New York, NY
Department of Neurosurgery, College of Physicians and Surgeons, New York, NY
Search for more papers by this authorAbstract
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. Ann Neurol 2014;75:771–781
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