Continuous electroencephalography predicts delayed cerebral ischemia after subarachnoid hemorrhage: A prospective study of diagnostic accuracy

Abstract

Objective: Delayed cerebral ischemia (DCI) is a common, disabling complication of subarachnoid hemorrhage (SAH). Preventing DCI is a key focus of neurocritical care, but interventions carry risk and cannot be applied indiscriminately. Although retrospective studies have identified continuous electroencephalographic (cEEG) measures associated with DCI, no study has characterized the accuracy of cEEG with sufficient rigor to justify using it to triage patients to interventions or clinical trials. We therefore prospectively assessed the accuracy of cEEG for predicting DCI, following the Standards for Reporting Diagnostic Accuracy Studies.

Methods: We prospectively performed cEEG in nontraumatic, high-grade SAH patients at a single institution. The index test consisted of clinical neurophysiologists prospectively reporting prespecified EEG alarms: (1) decreasing relative alpha variability, (2) decreasing alpha-delta ratio, (3) worsening focal slowing, or (4) late appearing epileptiform abnormalities. The diagnostic reference standard was DCI determined by blinded, adjudicated review. Primary outcome measures were sensitivity and specificity of cEEG for subsequent DCI, determined by multistate survival analysis, adjusted for baseline risk.

Results: One hundred three of 227 consecutive patients were eligible and underwent cEEG monitoring (7.7-day mean duration). EEG alarms occurred in 96.2% of patients with and 19.6% without subsequent DCI (1.9-day median latency, interquartile range = 0.9-4.1). Among alarm subtypes, late onset epileptiform abnormalities had the highest predictive value. Prespecified EEG findings predicted DCI among patients with low (91% sensitivity, 83% specificity) and high (95% sensitivity, 77% specificity) baseline risk.

Interpretation: cEEG accurately predicts DCI following SAH and may help target therapies to patients at highest risk of secondary brain injury. Ann Neurol 2018;83:958-969.

Figure 1. Flow diagram of study (STARD diagram)

After the index test results, results are sorted based on the reference standard (consensus criteria for the blinded determination of DCI). HH = Hunt and Hess grade. F = Fisher group. cEEG = continuous EEG monitoring. DCI = delayed cerebral ischemia. For the 124 excluded patients, we list only the primary reason for exclusion in the order of exclusion.

Figure 2. Time-to-event data

(A) In the multistate survival analysis, patients occupy one of three possible states at any given time. Permissible transitions are indicated by arrows. (B) State occupancy versus time for 103 SAH patients, starting from the time of hemorrhage (t=0), continuing up to 20 days post-hemorrhage. Green bars indicate the baseline state (no EEG alarm or DCI thus far); yellow, the alarm state; and red, the DCI state. White dots indicate when EEG monitoring began, and black dots indicate when EEG monitoring ended.

Figure 3. Delayed cerebral ischemia (DCI) probability as a function of postbleed time for patients with low (A,D), medium (B,E) and high (C,F) baseline risk

(A–C) Multi-state survival model used to quantify the time-dependent risk of transitioning 1) from the baseline state, without DCI and without a cEEG warning (green), to the alarm state, in which there has been a cEEG warning but no DCI (yellow); 2) from the alarm state to DCI following a cEEG warning (pink), thus becoming a true positive case; or 3) from the baseline state to DCI without a preceding cEEG warning (red), thus becoming a false negative case. From the stacked probability plots one can calculate that cEEG has a positive predictive value ranging from 76% in patients with low baseline risk to 94% in patients with high baseline risk. (D–F) Examples of individualized risk curves, derived from the multistate survival model. The probability of subsequent DCI decreases each day following SAH, starting from a point that depends on the composite admission risk score (green curve). Patients for whom the clinical neurophysiologist detects a cEEG alarm are at increased risk for DCI, and move to the yellow probability curve which reflects a higher probability of DCI. Subfigure (d) illustrates a case with no alarm and no DCI in a low risk patient (true positive); (e), a case in a medium-risk patient with an alarm on day 6 but ultimately no DCI (false positive); and (f) a case in a high-risk patient with an alarm on day 6, followed by a DCI on day 8 (true positive). SAH = subarachnoid hemorrhage. DCI = delayed cerebral ischemia. cEEG = continuous EEG monitoring.

Figure 4. Latency from EEG alarm to diagnosis of DCI

The histogram shows the proportion of the 50 true positive cases (y-axis) occurring within each time latency interval (x-axis) from EEG alarm to DCI. The 2 false negative DCI cases had no EEG alarm and are not shown. The median duration from EEG alarm to DCI was 1.9 days (minimum 30 min, maximum 9.1 days). 41 [82%] of 50 true positive cases had a lead time longer than 12-hours. cEEG = continuous EEG monitoring. DCI = delayed cerebral ischemia.

Figure 5. EEG changes reported before a clinical diagnosis of DCI

EEG alarms for the 50 true positive predictions of DCI are divided by clinical presentation with (A) focal motor deficits (n=27), (B) decreased level of consciousness (n=22), (C) new infarct on CT or MRI (n=6), or (D) aphasia (n=5). Black bars indicate the percentage of cases with focal EEG abnormalities, including decreases in relative alpha variability (RAV-F) or alpha-delta ratio (ADR-F), new or increased focal slowing (SLO-F), focal sporadic epileptiform spikes or sharp waves (SS-F), and new or worsening lateralized periodic discharges (LPD) or lateralized rhythmic delta activity (LRDA). Gray bars indicate the percentage of cases with cEEG worsening in a bilaterally symmetric distribution, including symmetric decreases in relative alpha variability (RAV-B) or alpha-delta ratio (ADR-B), new or increased generalized slowing (SLO-B), bilaterally synchronous (usually frontally predominant) sporadic epileptiform spikes or sharp waves (SS-B), and new or worsening generalized periodic discharges (GPD). Numbers above the bars indicate the number of DCI subtype events preceded by a given EEG finding. Note that alarms may include multiple EEG abnormalities, thus the numbers above the black and gray bars do not add up to the total number of DCI events with a given presenting sign. Moreover, some DCI events presented with more than one clinical finding, thus the total number of presenting signs is larger than 50.