Biomarkers of brain injury in neonatal encephalopathy treated with hypothermia

Abstract

Objective: To determine if early serum S100B and neuron-specific enolase (NSE) levels are associated with neuroradiographic and clinical evidence of brain injury in newborns with encephalopathy.

Study design: Patients who received therapeutic whole-body hypothermia were prospectively enrolled in this observational study. Serum specimens were collected at 0, 12, 24, and 72 hours of cooling. S100B and NSE levels were measured by enzyme linked immunosorbent assay. Magnetic resonance imaging was performed in surviving infants at 7-10 days of life. Standardized neurologic examination was performed by a child neurologist at 14 days of life. Multiple linear regression analyses were performed to evaluate the association between S100B and NSE levels and unfavorable outcome (death or severe magnetic resonance imaging injury/significant neurologic deficit). Cutoff values were determined by receiver operating curve analysis.

Results: Newborns with moderate to severe encephalopathy were enrolled (n = 75). Median pH at presentation was 6.9 (range, 6.5-7.35), and median Apgar scores of 1 at 1 minute, 3 at 5 minutes, and 5 at 10 minutes. NSE and S100B levels were higher in patients with unfavorable outcomes across all time points. These results remained statistically significant after controlling for covariables, including encephalopathy grade at presentation, Apgar score at 5 minutes of life, initial pH, and clinical seizures.

Conclusion: Elevated serum S100B and NSE levels measured during hypothermia were associated with neuroradiographic and clinical evidence of brain injury in encephalopathic newborns. These brain-specific proteins may be useful immediate biomarkers of cerebral injury severity.

Figure 1

Biomarker levels (A and B, S100B; C and D, NSE) by outcome category (death or severe MRI-detected injury and death or neurologic deficit). Regression fit lines for biomarker levels from infants with unfavorable (dashed line) and favorable (solid line) outcome are presented. Raw (unadjusted) data are shown in the overlying scatterplot. Error bars represent 95% CIs.

Figure 2

ROC curves for A and B, S100 and C and D, NSE (C, D) and prediction of outcome. Each time point has a representative curve. Biomarker levels at 0 hours of cooling are the best discriminators of death or severe MRI-detected injury, and levels at 72 hours of cooling are the best discriminators of death or significant neurologic deficit. TPR, true-positive rate; FPR, false-positive rate.