Abstract
Nonconvulsive Seizures in Subarachnoid Hemorrhage Link Inflammation and Outcome.
Claassen J, Albers D, Schmidt JM, De Marchis GM, Pugin D, Falo CM, Mayer SA, Cremers S, Agarwal S, Elkind MSV, Connolly ES, Dukic V, Hripcsak G, Badjatia N. Ann Neurol 2014;75(5):771–781.
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
Commentary
Nonconvulsive seizures occur commonly after acute brain injury, including subarachnoid and other forms of intracranial hemorrhage, and may be associated with worse ultimate clinical outcome (1, 2). What remains unclear, though, is whether such seizures are merely a reflection of the severity of the underlying injury, or whether they further contribute negatively to the outcome and thus should be aggressively treated (3, 4). What is also not known is the mechanism by which subarachnoid hemorrhage (SAH), for example, leads to nonconvulsive seizures; such a mechanism could potentially be targeted for prophylactic purposes given that there is often a delay of many days before such seizures arise.
Claassen et al. report on some aspects of a large observational study of aneurysmal SAH in which patients were, on average, monitored on continuous video-EEG between days 4 and 9 post-SAH and were given phenytoin prophylaxis for the first week post-SAH; a subset also had serum markers of inflammation measured on multiple occasions. First, some general observations regarding their cohort are worthwhile. Among their 479 patients total, the average age was 56 years old, about two-thirds were women, the median Hunt-Hess score on admission was 3 (indicating drowsiness/confusion or mild focal neurologic deficit), and about half had aneurysm clipping performed. Overall, 11% of the patients had in-hospital nonconvulsive seizures at some point, and the median time of seizure onset was on day 8.5 following SAH. Between 8% and 22% of the SAH patient cohort developed infectious complications (sepsis, pneumonia, urinary tract infections), and 20% developed delayed cerebral ischemia from SAH-associated vasospasm. The median modified Rankin score at 3-month follow-up was 2 (slight disability).
The core of the authors’ findings is that patients with inhospital nonconvulsive seizures had higher measures of the systemic inflammatory response syndrome (SIRS), particularly in the period immediately preceding seizure onset, and the negative impact of SIRS on functional outcome was at least partly mediated through the nonconvulsive seizures, according to statistical mediation analyses estimating causal connections between SIRS, seizures, and outcome. Similarly, patients with nonconvulsive seizures had higher levels of serum inflammatory biomarkers (including tumor necrosis factor receptor 1 [TNF-R1] and high-sensitivity C-reactive protein [hsCRP]), and mediation analysis suggested that the negative impact of these markers on functional outcome was also partly mediated through the nonconvulsive seizures.
The data in this article provide an additional piece of the puzzle for clinicians caring for patients with nonconvulsive seizures related to SAH. The authors suggest that nonconvulsive seizures may be a “mechanism” through which SAH-associated inflammation leads to an ultimately worse neurologic outcome. While this does not directly address whether treating this sequence or cascade would actually be beneficial to patients, if the casual relationship is true then it would make theoretical sense to target the inflammation directly, rather than merely attempt to suppress the nonconvulsive seizures, especially since nonconvulsive seizures can be refractory to antiepileptic drug (AED) administration in this setting. (The authors do not report on the success rates of seizure control in their cohort.) This line of thinking could set the stage for further studies exploring these links.
There are some limitations to consider. The clinical and serum measures of inflammation are all quite crude. SIRS is an intentionally broad set of physical signs and blood results characteristic of systemic inflammation (elevated heart rate, elevated respiratory rate, high or low body temperature, and high or low serum white blood cell count), and the serum markers reported here (hsCRP, TNF-R1, and transthyretin) are fairly nonspecific. One would like to see some more brain-specific biomarkers of central nervous system inflammation, though both MRI and CSF analysis would have their limits and potentially be impractical in this setting. The association between serum inflammatory biomarkers and nonconvulsive seizures appears primarily in those with mild or no EEG background attenuation, for reasons that are not entirely clear. Could this be the result of a decreased ability to diagnose such seizures accurately in the setting of a very flat EEG, or could the variability in the serum markers be “overwhelmed” by other non–seizure-related factors in the most critically ill patients?
It is important to consider these results in light of the existing literature on post-SAH seizures (2, 5). We know that clinically evident seizures occur not infrequently after SAH (in 4–26% of patients) and that continuous EEG monitoring allows for the detection of nonconvulsive seizures after SAH, which may also occur in a significant fraction of cases (11% here, and 18% in a prior study [6]). Some, but not all studies, have shown that the occurrence of in-hospital post-SAH seizures is independently associated with a poor outcome, though the possibility that such a correlation is simply reflective somehow of the severity of hemorrhage is still debated. The use of AED prophylaxis after SAH varies widely in practice, and since there are no clear data about its efficacy, most recommendations come from studies of AED prophylaxis in traumatic brain injury or brain tumors. In the meantime, there are data suggesting that the use of AEDs post-SAH is associated with worse recovery [5], though again whether this merely reflects differential usage of AEDs in patients with more severe hemorrhages is not entirely clear.
With this current state of knowledge, then, any data on mechanisms that might casually link SAH and subsequent nonconvulsive seizures, particularly mechanisms that might ultimately suggest a potential intervention besides standard AEDs, are welcome. While the article here does not answer any of the key clinical questions faced by those caring for SAH patients, it does offer a tantalizing link that may bring us closer toward understanding the neurologic consequences of this serious condition.