Association Between EEG Patterns and Serum Neurofilament Light After Cardiac Arrest: A Post Hoc Analysis of the TTM Trial

Abstract

Background and objectives: EEG is widely used for prediction of neurologic outcome after cardiac arrest. To better understand the relationship between EEG and neuronal injury, we explored the association between EEG and neurofilament light (NfL) as a marker of neuroaxonal injury, evaluated whether highly malignant EEG patterns are reflected by high NfL levels, and explored the association of EEG backgrounds and EEG discharges with NfL.

Methods: We performed a post hoc analysis of the Target Temperature Management After Out-of-Hospital Cardiac Arrest trial. Routine EEGs were prospectively performed after the temperature intervention ≥36 hours postarrest. Patients who awoke or died prior to 36 hours postarrest were excluded. EEG experts blinded to clinical information classified EEG background, amount of discharges, and highly malignant EEG patterns according to the standardized American Clinical Neurophysiology Society terminology. Prospectively collected serum samples were analyzed for NfL after trial completion. The highest available concentration at 48 or 72 hours postarrest was used.

Results: A total of 262/939 patients with EEG and NfL data were included. Patients with highly malignant EEG patterns had 2.9 times higher NfL levels than patients with malignant patterns and NfL levels were 13 times higher in patients with malignant patterns than those with benign patterns (95% CI 1.4-6.1 and 6.5-26.2, respectively; effect size 0.47; p < 0.001). Both background and the amount of discharges were independently strongly associated with NfL levels (p < 0.001). The EEG background had a stronger association with NfL levels than EEG discharges (R2 = 0.30 and R2 = 0.10, respectively). NfL levels in patients with a continuous background were lower than for any other background (95% CI for discontinuous, burst-suppression, and suppression, respectively: 2.26-18.06, 3.91-41.71, and 5.74-41.74; effect size 0.30; p < 0.001 for all). NfL levels did not differ between suppression and burst suppression. Superimposed discharges were only associated with higher NfL levels if the EEG background was continuous.

Discussion: Benign, malignant, and highly malignant EEG patterns reflect the extent of brain injury as measured by NfL in serum. The extent of brain injury is more strongly related to the EEG background than superimposed discharges. Combining EEG and NfL may be useful to better identify patients misclassified by single methods.

Trial registration information: ClinicalTrials.gov NCT01020916.

Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.

Figures

Figure 1. Flow Chart of Patient Inclusion

The modified intention-to-treat population in the Target Temperature Management After Out-of-Hospital Cardiac Arrest trial (TTM-trial) consisted of 939 patients. Nine study sites were excluded due to technical issues in providing EEGs for export in sufficient quality required for centralized evaluation. EEG: routine EEG performed after rewarming but

Figure 2. Highly Malignant, Malignant, and Benign EEG Patterns and Serum NfL

Boxplot demonstrating logarithmic peak neurofilament light (NfL) levels (highest serum neurofilament levels at either 48 or 72 hours postarrest) for EEG patterns as defined by Westhall et al.: “highly malignant”: burst-suppression or suppression with or without discharges; “malignant”: discontinuous, reversed anterio-posterior gradient or low-voltage background, abundant rhythmic or periodic discharges or unequivocal seizures; “benign”: continuous background without malignant features. Neurologic outcome for each patient is indicated through “X” (poor outcome, Cerebral Performance Category [CPC] 3–5) or “O” (good outcome, CPC 1–2) at 6 months’ follow-up. Peak NfL was increasingly higher in more malignant EEG patterns (p < 0.001).

Figure 3. EEG Background, Discharges, and Serum NfL

Boxplots demonstrating logarithmic peak neurofilament light (NfL) according to EEG background (A) or the presence of discharges (B). Neurologic outcome for each patient is indicated through “X” (poor outcome, Cerebral Performance Category [CPC] 3–5) or “O” (good outcome, CPC 1–2) at 6 months’ follow-up. The highest peak NfL levels were seen in patients with burst-suppression or suppression. In patients with a continuous background, patients with poor outcome had higher NfL levels than did patients with good outcome (median 60.7 [interquartile range (IQR) 32.8–118.7] pg/mL vs median 998.3 [IQR 366.0–3,449.7] pg/mL; p < 0.005). Peak NfL was higher in patients with an abundant amount of discharges than in patients without discharges (p < 0.001). In patients without discharges, NfL levels were higher in patients with poor outcome than in patients with good outcome (median 60.7 [IQR 32.9–128.4] pg/mL vs median 5,305.5 [IQR 1,064.8–12,926.6] pg/mL; p < 0.005).

Figure 4. EEG Background, Superimposed Discharges, and Serum NfL

Boxplot demonstrating logarithmic peak neurofilament light (NfL) in patients with continuous, discontinuous, burst-suppression, and suppressed EEG background and the presence of superimposed discharges. Neurologic outcome for each patient is indicated through “X” (poor outcome, Cerebral Performance Category [CPC] 3–5) or “O” (good outcome, CPC 1–2) at 6 months’ follow-up. In patients with a continuous background, NfL levels were higher in patients with an intermediate or abundant amount of discharges than in patients without discharges (p < 0.001). No other differences could be found between noncontinuous backgrounds and the presence of discharges.