Delayed seizures after intracerebral haemorrhage

Abstract

Late seizures after intracerebral haemorrhage occur after the initial acute haemorrhagic insult subsides, and represent one of its most feared long-term sequelae. Both susceptibility to late seizures and their functional impact remain poorly characterized. We sought to: (i) compare patients with new-onset late seizures (i.e. delayed seizures), with those who experienced a recurrent late seizure following an immediately post-haemorrhagic seizure; and (ii) investigate the effect of late seizures on long-term functional performance after intracerebral haemorrhage. We performed prospective longitudinal follow-up of consecutive intracerebral haemorrhage survivors presenting to a single tertiary care centre. We tested for association with seizures the following neuroimaging and genetic markers of cerebral small vessel disease: APOE variants ε2/ε4, computer tomography-defined white matter disease, magnetic resonance imaging-defined white matter hyperintensities volume and cerebral microbleeds. Cognitive performance was measured using the Modified Telephone Interview for Cognitive Status, and functional performance using structured questionnaires obtained every 6 months. We performed time-to-event analysis using separate Cox models for risk to develop delayed and recurrent seizures, as well as for functional decline risk (mortality, incident dementia, and loss of functional independence) after intracerebral haemorrhage. A total of 872 survivors of intracerebral haemorrhage were enrolled and followed for a median of 3.9 years. Early seizure developed in 86 patients, 42 of whom went on to experience recurrent seizures. Admission Glasgow Coma Scale, increasing haematoma volume and cortical involvement were associated with recurrent seizure risk (all P < 0.01). Recurrent seizures were not associated with long-term functional outcome (P = 0.67). Delayed seizures occurred in 37 patients, corresponding to an estimated incidence of 0.8% per year (95% confidence interval 0.5-1.2%). Factors associated with delayed seizures included cortical involvement on index haemorrhage (hazard ratio 1.63, P = 0.036), pre-haemorrhage dementia (hazard ratio 1.36, P = 0.044), history of multiple prior lobar haemorrhages (hazard ratio 2.50, P = 0.038), exclusively lobar microbleeds (hazard ratio 2.22, P = 0.008) and presence of ≥ 1 APOE ε4 copies (hazard ratio 1.95, P = 0.020). Delayed seizures were associated with worse long-term functional outcome (hazard ratio 1.83, P = 0.005), but the association was removed by adjusting for neuroimaging and genetic markers of cerebral small vessel disease. Delayed seizures after intracerebral haemorrhage are associated with different risk factors, when compared to recurrent seizures. They are also associated with worse functional outcome, but this finding appears to be related to underlying small vessel disease. Further investigations into the connections between small vessel disease and delayed seizures are warranted.

Keywords: epilepsy; intracerebral haemorrhage; seizure.

The factors that predispose to delayed seizures after intracerebral haemorrhage are unclear. Biffi et al. demonstrate that delayed seizures are associated with different risk factors compared to early and recurring seizures. The former are also associated with poorer functional outcomes, but this is attributable to underlying cerebral small vessel disease.

Figure 1

Participants’ enrolment and eligibility criteria flow chart. Flow-chart summarizing sequential application of eligibility/exclusion criteria leading to definition of final study population. Solid bordered boxes in the centre report number of patients fulfilling eligibility criteria at each stage, thus being evaluated further for study inclusion. Double-lined bordered boxes at the bottom indicate participants selected for analyses mentioned in the ‘Results’ section. Criteria for eligibility at each stage are listed in grey background boxes on the right. Dashed lines connect to dashed boxes listing criteria for exclusion from analysis and number of participants excluded as a result.

Figure 2

Post-ICH seizure diagnosis incidence over time. The incidence of newly-diagnosed seizure disorders at different time points following ICH. The dashed vertical line identifies the cut-off for definition of early versus late seizure (i.e. within or beyond 7 days from onset of ICH symptoms).

Figure 3

Cumulative incidence of functional deterioration after ICH-based on seizure diagnosis. Graph illustrates cumulative incidence of combined functional decline endpoint (mortality, incident dementia or incident functional dependence) over time after ICH, separated based on presence/nature of post-ICH seizures. The number inside each bar represents percentage of overall study population. Number of patients remaining in follow-up at each time point is reported in the box below each set of values. At each time point subjects are assigned to a group based on current diagnostic status (no seizure history/early seizure history/delayed seizure history).