Mortality after primary intracerebral hemorrhage in relation to post-stroke seizures

Intracerebral hemorrhage (ICH) accounts for roughly 10–20% of all strokes, and has a 10-year survival of only 24% [1‐4]. Furthermore, survivors of an ICH have a 10% risk to develop seizures [5, 6]. These seizures may develop within seven days (i.e., early, acute symptomatic seizures), or later (i.e., late, remote symptomatic seizures) [7]. The development of seizures may inflict additional cerebral damage, and hence increase mortality risks after ICH. However, seizure development might also coincide with important risk factors for mortality (e.g., old age, stroke severity, cortical involvement, and alcohol consumption) [6, 8, 9].

Previous studies showed conflicting findings with regard to the relation between early and late seizures, and mortality, mostly based on differences in follow-up, definition of seizures, number of included patients, and inhomogeneous patient populations [6, 10, 12‐18]. Furthermore, early, late, and recurrent seizures differ in pathogenesis and might also have a different relation with mortality [10, 11]. Because of the inconclusive evidence, we aimed at defining the long-term mortality risk after ICH in a large population, and relate this to post-stroke seizures. We hypothesized that the development of seizures negatively influences the survival of patients after ICH.

The present study is conducted in accordance with the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE statement) [19].

Our study underlines that seizures after ICH do not independently relate to higher late mortality risks after follow-up up to 10 years. Mortality was associated with higher age, male gender, peripheral vascular disease, higher NIHSS scores, and anticoagulant/antiplatelet drug use. Mortality in the long term (i.e., 10 years) was also determined by diabetes mellitus. Overall, we found that 10-year survival after ICH was 37% in our population, which was not significantly influenced by development of early or late seizures.

These results are in line with most [6, 10 13–15, 18], but not all [12, 16, 17] studies. These studies showed an increased or decreased risk of mortality in patients with seizures. Take note that these study populations were composed of both ischaemic stroke (IS) and ICH patients, and extrapolation should be done carefully though no differences between IS and ICH were mentioned. However, these previous studies did have significantly shorter periods of follow-up, and none of these studies found seizures to be an independent risk factor of mortality in multivariable analyses [12, 16, 18]. The one study that did indicate a significant independent relation, and showed a higher mortality rate in the seizure group, assessed a heterogeneous study population of supposedly vascular events (including ischemic stroke, transient ischemic attack and ICH) at a young age. However, authors did not specifically include ICH patients, and they did not exclude patients not surviving the first seven days after stroke [17]. Up and till now, studies with a long-term follow-up, specifically for ICH patients, are lacking to the best of our knowledge. Therefore, our study in ICH patients with a large sample size, long-term follow-up, and a selection process designed to study the long-term relation between seizures and mortality adds significantly to the existing reports. Our finding that mortality is not influenced by seizure development, but is mostly determined by age, stroke severity, and vascular risk factors might imply that patients may benefit more from management of these factors, than from management of the seizures.

AED use did correlate, independently from seizure frequency, with lower mortality risks in patients with late seizures 7.5 years after hemorrhage. This correlation weakened in the 10-year interval and disappeared in the full follow-up, probably due to the limited number of patients that already reached that time point. This might suggest that AED therapy improves long-term survival after ICH, though not likely due to lowered seizures frequencies. There are, however, some caveats, such as the small number of patients with late seizures that did not receive AED therapy (n = 5). Also, discrepancies in patient treatment may play a role in this as patients with worse clinical conditions might not have been treated equally, or even have not been treated at all. Though, Gilad et al. found a better neurological outcome after treatment with valproate in patients surviving an ICH, which, in combination with our findings, suggests a (weakly) positive effect of AED on recovery and prognosis after ICH [25]. This finding suggests that survival rates might benefit from AED therapy, but further research is needed to provide sufficient evidence.

Our study has some limitations. First, despite our large population, only 14% of participants developed seizures, which somewhat limits the power of this study. Also, there is bias due to the retrospective design, though efforts have been made to reduce the impact: we minimized the amount of missing data using diagnosis codes and hospital stroke registries. Furthermore, defining seizures retrospectively are another possible source of bias. Patients may underreport focal seizures or may not seek medical attention or overreport, for example, syncopes as seizures. Furthermore, subclinical seizures are missed because EEG monitoring was not routinely performed, which might lead to underestimation of the frequency of seizure development. As a consequence of the retrospective design, only survival status could be monitored in the period of follow-up after hospital discharge. Details on seizure severity and post-hospitalization comorbidities, which could underlie the association between AED therapy and decreased mortality, are not known. Furthermore, patients with worse prognosis might not have been treated at all. As all of these data are not available, these results have to be interpreted with caution.

Notwithstanding these limitations, the strengths of our study remain the large sample size allowing enough patients to develop early or late seizures, combined with the follow-up allowing sufficient time to develop late seizures and determine the long-term survival rates. Also, exclusion of patients who deceased during the first seven days allows to draw conclusions concerning the mortality risk based on seizure development, without interference of mortality risks primarily due to the hemorrhage itself.

In conclusion, seizure development does not relate to the mortality risk after ICH in our population. However, mortality mostly relates to age, stroke severity and vascular comorbidities and anticoagulant/antiplatelet use, and therefore, these prognostic factors are of value when discussing treatment and prognosis after ICH.