Abstract
Delayed Seizures after Intracerebral Haemorrhage
Biffi A, Rattani A, Anderson CD, Ayres AM, Gurol EM, Greenberg SM, Rosand J, and Viswanathan A. Brain 2016;139;2694–2705.
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.
Commentary
Seizures after intracranial hemorrhage (ICH) are relatively unusual, but not rare events. In general, seizures are generally subdivided into early (depending on definition, as early as <7 days but generally accepted to be <30 days) and late. These two types of seizures were thought to have differing etiologies, the former due to acute brain injury (1), and the latter associated with microbleeds (2).
Biffi et al. present evidence from their large single center longitudinal study that there is a significant difference in risk factors between patients who have had late seizures after experiencing early seizures (recurrent seizures), and patients who develop de novo late seizures (delayed seizures). Specifically, risk factors for recurrent seizures are those associated with the actual “mechanical” effects of the hemorrhage, such as ICH volume and admission Glasgow Coma Scale (GCS). Risk factors for delayed seizures are more insidious, and include pre-ICH dementia, ≥ copies of APOE ε4 and CT/MRI evidence of cerebral small vessel disease and microbleeds, in addition to cortical ICH involvement and prior lobar ICH bleeds prior to the index event. Indeed, they found that this method of subdividing patients resulted in better prediction of late seizures than previously published scoring criteria that just accounted for age, ICH volume, cortical involvement, and early seizures. More ominously, delayed seizures were associated with an increased risk of functional decline (death, dementia, functional dependence) where early seizures were not, but this association was entirely due to the underlying small vessel risk factors rather than seizures themselves.
There are multiple strengths of this study that make the results particularly convincing. As a single-center study, data acquisition is uniform and remarkably complete, given the large number of patients. In particular, the clinical and functional outcome data are meticulously obtained and all efforts are made to account for missing or incomplete data. The availability of genetic data adds a unique and probably underappreciated risk factor in such cohorts. Their results are significant even though a portion of the recurrent seizure group likely consists of patients who may have developed delayed seizures but had early seizures due to mechanical factors. Their biological interpretation of the heterogeneity post-ICH seizures is straightforward, logically sound, and of substantial clinical significance. This study lists support from multiple NIH (R01) grants; the benefits from such a well-funded infrastructure are clear in this skillfully conducted study.
In the context of its multiple strengths, it is quite unfortunate that this study did not directly involve an epileptologist, and this omission is reflected in the paper. The actual determination of seizures is the most critical data element of the study, and its validity is of some concern. The study relies on electrographic evidence of seizure on EEG, witnessed clinical events characterized by a neurologist, or unwitnessed clinical events characterized by an epileptologist. Determination of an ictal event on EEG can be challenging, as the rich spectrum of EEG abnormalities includes patterns on the ictal-interictal continuum. The vast majority of late seizures (73–81%) were diagnosed by observation of clinical symptoms alone. This method of evaluating seizures has been criticized as unreliable; particularly for identifying complex partial seizures that likely were prevalent in this group (3). Adjudication by an epileptologist would have brought more credibility to this very subjective area. A subgroup analysis of patients who had clearly defined seizures (e.g., convulsions or definite interictal electrographic events accompanying the suspicions clinical events) would have made the results more convincing to the epilepsy community.
In addition, the study does not substantially address the potential influence of antiseizure drug (ASD) use. Past studies prevaricate as to whether ASDs have an effect on clinical and functional outcome in these patients. Some groups had not found any relationship between ASD use and outcome (4, 5) though others have (6). A recent study demonstrated increasing prophylactic ASD use in these patients (7) despite prevailing guidelines against this practice (8). Certainly, given this controversy, an analysis of ASD use from this cohort would be welcome, particularly because the data presumably are likely readily available. The ASD usage and dosage likely differed significantly between patients with recurrent versus delayed seizures; it was noted that most patients with recurrent seizures were on ASDs, and that patients with delayed seizures were placed on ASDs after their first seizures. It would have been of particular interest to see how many patients with delayed seizures were exposed to ASDs prior to the late seizure the event. This should be further explored, particularly because the only randomized clinical trial of ASD use in ICH revealed an intriguing though not yet replicated finding of a lower NIH stroke scale after 12 months in patients who had received a month of prophylactic valproic acid (9).
Despite the study providing some intriguing insights into the biological mechanism of late seizures, and though it provides data to counsel patients and families regarding prognosis, this study leaves many questions of interest unanswered. Is the total seizure burden or specific types of seizures (e.g., status epilepticus) potentially more harmful in long-term outcomes as has been suggested in patients with other conditions (10)? Which of these seizure types are truly disabling? Can these late seizures be prevented by ASDs? All of these issues point to the continued need for further similarly high-quality studies in this field.