What is the clinical significance of an elevated neuron‑specific enolase level?

Clinical Significance of Elevated Neuron-Specific Enolase

Elevated NSE is a biomarker of neuronal injury that serves primarily as a confirmatory prognostic tool in post-cardiac arrest patients when measured at 48-72 hours and combined with other tests—never use it alone to predict outcomes or guide withdrawal of life support. 1, 2

Primary Clinical Context: Post-Cardiac Arrest Prognostication

NSE is released following neuronal injury and correlates with the extent of anoxic-ischemic brain damage, making it most clinically relevant for predicting neurological outcomes after cardiac arrest. 1, 3

Prognostic Thresholds and Timing

The threshold values for predicting poor neurological outcome vary substantially based on timing and whether targeted temperature management (TTM) was used:

• In non-TTM patients: NSE >33 μg/L at days 1-3 predicts poor outcome, though other studies report thresholds of 47.6 μg/L at 24h, 65.0 μg/L at 48h, and 90.9 μg/L at 72h 1, 3
• In TTM-treated patients: Thresholds range from 25-151.5 μg/L at 48 hours and 49.6-151.4 μg/L at 24 hours, reflecting greater variability 1, 3
• Optimal measurement timing: 48-72 hours post-return of spontaneous circulation (ROSC) provides significantly higher discriminative value than 24-hour measurements 1, 3

Serial Measurements Are Superior

Rising NSE values over time are more predictive than single measurements—an increase between any two time points (24h, 48h, 72h) strongly associates with poor neurological outcome. 1, 3, 2

• The NSE ratio (48h:24h) ≥1.7 demonstrated 100% specificity for poor outcome in one study, with good outcome patients showing decreasing NSE (median decrease 3.0 μg/L) versus poor outcome patients showing increasing NSE (median increase 13.4 μg/L) 4
• This ratio approach eliminates the need for absolute threshold values and accounts for individual baseline variations 4

Mandatory Multimodal Integration

NSE must never be used as a standalone predictor due to high false-positive rates—it should only be incorporated at ≥72 hours post-arrest alongside bilateral absence of N20 SSEP waves, EEG findings, brain imaging, and clinical examination. 1, 2

The American Heart Association explicitly classifies using NSE alone as Class III: Harm, meaning it can cause patient harm through premature withdrawal of life support 1, 2

Critical Limitations and Pitfalls

Hemolysis: The Most Common Error

Hemolysis releases NSE from erythrocytes and produces false elevations—verify sample quality before interpreting any NSE result. 1, 3, 2

• NSE is highly sensitive to hemolysis, making careful blood draw technique essential 1, 3
• Always check for hemolysis markers when NSE is unexpectedly elevated 2

Laboratory and Technical Variability

• Measurement standards vary dramatically between analyzers and centers, making absolute value comparisons unreliable 1, 3
• Use institution-specific reference ranges and trends rather than published absolute thresholds 3, 2

Extra-Neuronal Sources

NSE can be elevated from non-neurological sources including neuroendocrine tumors, small cell lung cancer, and other APUD-series tumors. 1, 5

• Small cell carcinoma cells contain much higher NSE levels than other lung cancers 6
• In cancer patients, NSE elevation may reflect tumor burden rather than neurological injury 5, 7

Secondary Clinical Applications

Traumatic Brain Injury

• CSF NSE levels correlate with TBI severity and mortality in moderate-to-severe TBI 3, 2
• The same limitations apply—never use NSE alone for prognostication 2

Neuroendocrine Tumors

• NSE is elevated in 38% of neuroendocrine tumor patients, but chromogranin A is more sensitive (59%) and should be the preferred general marker 7
• Elevated NSE in neuroendocrine tumors associates exclusively with poor tumor differentiation 7

Practical Clinical Algorithm

When encountering elevated NSE:

1. Verify sample quality: Rule out hemolysis immediately 1, 3, 2
2. Establish clinical context: Post-cardiac arrest, TBI, or known malignancy 3, 2, 5
3. Check timing: If post-cardiac arrest, wait until 48-72 hours for optimal discrimination 1, 3, 2
4. Obtain serial measurements: Single values are insufficient—assess trends over 24-48 hour intervals 1, 3, 2, 4
5. Integrate with other modalities: Combine with SSEP, EEG, neuroimaging, and clinical examination before making prognostic decisions 1, 2
6. Never use NSE alone: This is explicitly contraindicated and can lead to premature withdrawal of life support 1, 2