Antiseizure Medication Treatment and Outcomes in Patients with Subarachnoid Hemorrhage Undergoing Continuous EEG Monitoring

Abstract

Background: Patients with aneurysmal subarachnoid hemorrhage (aSAH) with electroencephalographic epileptiform activity (seizures, periodic and rhythmic patterns, and sporadic discharges) are frequently treated with antiseizure medications (ASMs). However, the safety and effectiveness of ASM treatment for epileptiform activity has not been established. We used observational data to investigate the effectiveness of ASM treatment in patients with aSAH undergoing continuous electroencephalography (cEEG) to develop a causal hypothesis for testing in prospective trials.

Methods: This was a retrospective single-center cohort study of patients with aSAH admitted between 2011 and 2016. Patients underwent ≥ 24 h of cEEG within 4 days of admission. All patients received primary ASM prophylaxis until aneurysm treatment (typically within 24 h of admission). Treatment exposure was defined as reinitiation of ASMs after aneurysm treatment and cEEG initiation. We excluded patients with non-cEEG indications for ASMs (e.g., epilepsy, acute symptomatic seizures). Outcomes measures were 90-day mortality and good functional outcome (modified Rankin Scale scores 0-3). Propensity scores were used to adjust for baseline covariates and disease severity.

Results: Ninety-four patients were eligible (40 continued ASM treatment; 54 received prophylaxis only). ASM continuation was not significantly associated with higher 90-day mortality (propensity-adjusted hazard ratio [HR] = 2.01 [95% confidence interval (CI) 0.57-7.02]). ASM continuation was associated with lower likelihood for 90-day good functional outcome (propensity-adjusted HR = 0.39 [95% CI 0.18-0.81]). In a secondary analysis, low-intensity treatment (low-dose single ASM) was not significantly associated with mortality (propensity-adjusted HR = 0.60 [95% CI 0.10-3.59]), although it was associated with a lower likelihood of good outcome (propensity-adjusted HR = 0.37 [95% CI 0.15-0.91]), compared with prophylaxis. High-intensity treatment (high-dose single ASM, multiple ASMs, or anesthetics) was associated with higher mortality (propensity-adjusted HR = 6.80 [95% CI 1.67-27.65]) and lower likelihood for good outcomes (propensity-adjusted HR = 0.30 [95% CI 0.10-0.94]) compared with prophylaxis only.

Conclusions: Our findings suggest the testable hypothesis that continuing ASMs in patients with aSAH with cEEG abnormalities does not improve functional outcomes. This hypothesis should be tested in prospective randomized studies.

Keywords: Anticonvulsants; Electroencephalography; Outcome assessment; Seizures; Subarachnoid hemorrhage.

Figure 1.. Patient selection process

A graphical description of the inclusion and exclusion criteria and exposed and unexposed groups is provided. aSAH: aneurysmal subarachnoid hemorrhage; ASM: anti-seizure medication; cEEG: continuous electroencephalopgraphy

Figure 2.. EEG and Treatment exposure windows

All cEEGs were performed within 4 days of admission and were at-least 24 hours in duration. Treatment exposure window: 24-hrs post EEG to up to day 10 of admission Unexposed group: ASM prophylaxis only Exposed group: ASM continuation or re-initiation for > 48 hours

1. Low intensity treatment: Monotherapy with: levetiracetam at a dose of <2000mg/day (<1000mg/day in impaired renal function), phenytoin at ≤ 300mg/day or mean level < 15mcg/mL, valproic acid at ≤ 15mg/kg/day or mean level < 75mcg/mL, or lacosamide at ≤ 200mg/day

2. High intensity treatment: >48 hours of levetiracetam at doses of ≥ 2000mg/day (≥ 1000mg/day in impaired renal function), phenytoin at >300mg/day or mean level ≥ 15mcg/mL, Valproic acid at >15mg/kg/day or mean level ≥ 75mcg/mL, lacosamide > 200mg/day, use of 2 or more ASMs, or initiation of anesthetics for treatment of epileptiform activity.

ASM: anti-seizure medications; cEEG: continuous electroencephalography

Figure 3.. 90-day mortality and functional outcomes

1. Kaplan-Meier curves for time to death comparing ASM treatment (low + high intensity) vs. prophylaxis only.

2. Propensity score adjusted survival curves for time to death comparing ASM treatment (low + high intensity) vs. prophylaxis only.

3. Kaplan-Meier curves for time to good functional outcome (mRS 0–3) comparing ASM treatment (low+ high intensity) vs. prophylaxis only.

4. Propensity score adjusted survival curves for time to good functional outcome (mRS 0–3) comparing ASM treatment (low+ high intensity) vs. prophylaxis only.

ASM: anti-seizure medications

Figure 4.. Conceptual diagram contrasting ASM treatment strategies in aSAH patients

Comparison of risks and benefits of ASM treatment at different intensities, and in combination with treatment modalities aimed at improving cerebral perfusion are shown. We hypothesize that treatment of cEEG epileptiform activity with low to moderate dose ASMs in conjunction with treatments aimed at augmenting cerebral perfusion, and guided by biomarkers of brain metabolism and oxygenation, can improve survival and functional outcomes in aSAH patients. Future randomized studies utilizing cEEG are indicated to test this hypothesis. * Hazard ratio and confidence interval for mortality and good functional outcomes comparing low intensity treatment with ASM prophylaxis only ** Hazard ratio and confidence interval for mortality and good functional outcomes comparing high intensity treatment with ASM prophylaxis only aSAH: aneurysmal subarachnoid hemorrhage; ASM: anti-seizure medication; DCI: delayed cerebral ischemia; cEEG: continuous electroencephalography