The STatus Epilepticus Prognosis Study

Treatment guidelines and predictive markers of neurologic recovery in status epilepticus (SE) and refractory SE are inadequate, which makes prognostication of neurological outcome a substantial clinical challenge. Given that SE is the second most common neurological emergency, there is an urgent need for novel biomarkers to predict outcome of patients admitted in the ICU. Given this limited data, evidence of CNS injury and inflammation may serve as biomarkers of SE severity and prognosis.

The etiology of seizures, patient age and extent of epileptiform activity are thought to be related to long neurocognitive impairments in survivors of SE/RSE. However, measures of outcome are often dichotomized as "good" and "poor", and the extent of cognitive dysfunction and the specific cognitive processes that are impaired stand to be elucidated. Additionally, the literature characterizing cognitive function after SE is heterogenous, with variability in the assessment tools and time points for neurocognitive function which leads to limited understanding of the true incidence, severity, and long-term implications of cognitive impairment.

In recent years, there has been an expansion of available cognitive assessment tools that can be self-administered remotely, overcoming the previous barriers to patient assessment. One such tool is the Creyos platform, a web-based neurocognitive battery consisting of 12 cognitive tasks (designed as online games) assessing cognitive function across various domains, including concentration, memory, verbal skills, and reasoning. The Creyos tests have the advantage of allowing for remote self-administration, which means that patients from a broader geographic area can complete outcome measures without having to travel for assessment. Including more patients in this way will undoubtedly improve research generalizability. In a recent pilot study, the Creyos battery was used in a cohort of ICU patients and showed that it is both feasible and able to identify cognitive impairment in several domains. These results demonstrate that web-based studies of cognition are not only possible but provide a novel opportunity for evaluating neurocognitive impairments in an accessible manner that would not be feasible using traditional methods.

Persistent epileptiform activity is thought to contribute to neuronal death following RSE ultimately resulting in progressive brain atrophy. Previous literature suggests that duration of anesthetic therapy and length of hospital stay are related to loss of parenchymal volume, and hippocampal and diffuse cerebral atrophy on MRI are more likely to be associated with worse functional outcomes. In people with epilepsy, neuroimaging techniques such as volumetric analysis of the hippocampus and associated cortices have shown evidence of volumetric changes that are predictive of reduced cognitive abilities. However, the vast majority of the current literature consists of retrospective analyses, and there are no known studies that have directly assessed the relationship between cerebral damage following RSE and functional/cognitive outcomes.

Functional and diffusion tensor imaging (fMRI/DTI) are two sophisticated neuroimaging methods that can be used to accurately measure the functional and structural integrity of the brain, respectively, with high precision and accuracy. These methods have been used in the past to image people with epilepsy, and several studies have shown large-scale functional network reorganization in this patient group (for review, see Gonen, 2020). Interestingly, correlations to disease duration and severity (e.g., drug resistance) have also been found in these studies. Characterizing functional and structural changes in survivors of RSE provides a unique opportunity for investigating the anatomical and functional correlates that may underlie impaired cognition and reduced quality of life, and will likely lead to an in-depth understanding of how acute epileptiform activity can alter the structural and functional mechanics of the brain.

The overall goal of this study is to comprehensively evaluate the acute and long-term effects of Status Epilepticus on the brain. The overarching research question is: do acute markers of neural degeneration that can be detected in blood plasma predict the long-term outcome of patients with Status Epilepticus? And, do these markers relate to cognitive and functional outcomes? The investigators hypothesize that patients who have higher levels of markers of neuronal degeneration in their blood samples from the ICU will have poor clinical outcomes, as indexed by their scores on the Creyos cognitive battery. The investigators also hypothesize that refractory status patients who have higher levels of markers of neuronal degeneration in their bloodstream in the ICU will have greater structural and functional alterations in their brain at ~1 and ~6 months post-seizure onset.