What does an elevated neuron-specific enolase (NSE) level indicate?

Elevated Neuron-Specific Enolase (NSE): Clinical Significance

Elevated NSE levels indicate neuronal injury and cell death, serving as a quantitative biomarker of brain damage severity across multiple clinical contexts including post-cardiac arrest, traumatic brain injury, seizures, neurodegenerative diseases, and neuroendocrine tumors. 1

Primary Clinical Applications

Post-Cardiac Arrest Prognostication (Most Critical Use)

NSE levels >33 μg/L measured at 48-72 hours after cardiac arrest predict poor neurological outcome and should be used alongside other prognostic tests, never in isolation. 1

Key thresholds and timing considerations:

• In non-TTM-treated patients: NSE thresholds for 0% false-positive rate ranged from 33 mcg/L to 90.9 mcg/L depending on timing (24-72 hours) 2
• In TTM-treated patients: Thresholds varied more widely, from 25-151.5 mcg/L at 48 hours 2
• Optimal measurement timing: 48-72 hours post-ROSC provides higher discriminative value than 24-hour measurements 2, 1
• Serial measurements: Increasing NSE values between any two time points (24h, 48h, 72h) strongly associate with poor outcome 2, 1

Neurological Injury and Disease States

NSE elevation reflects active neuronal damage across multiple conditions:

• Seizures and status epilepticus: NSE levels correlate directly with seizure frequency and duration, with highest levels in complex partial SE (mean 23.88 ng/mL) and subclinical SE (mean 37.83 ng/mL) 3, 4
• Traumatic brain injury: CSF NSE levels are proportional to TBI severity and correlate with mortality in moderate-to-severe cases 1, 5
• Alzheimer's disease: Elevated CSF-NSE (mean 18.12 ng/mL vs 8.46 ng/mL in controls) reflects altered neuronal metabolism, with high diagnostic accuracy when combined with tau proteins 6
• Stroke and hemorrhage: Provides quantitative measures of brain damage extent and improves outcome evaluation 7

Neuroendocrine Tumor Marker

NSE serves as the most reliable tumor marker for small cell lung cancer (SCLC), correlating with tumor burden, metastatic sites, and treatment response. 7

Additional malignancies with NSE elevation include:

• Neuroblastoma (especially metastatic disease) 7
• Gastroenteropancreatic neuroendocrine tumors 7
• Melanoma, seminoma, carcinoid tumors, and pheochromocytoma 7

Critical Limitations and Pitfalls

Never use NSE alone for prognostication due to significant false-positive potential and measurement variability. 1, 5

Technical Limitations

• Hemolysis sensitivity: NSE is highly susceptible to hemolysis-induced false elevations, as erythrocytes contain NSE 1, 7
• Laboratory variability: Measurement standards vary between centers and analyzers, making absolute value comparisons unreliable 2, 1
• Extra-neuronal sources: Neuroendocrine tumors and hemolyzed samples produce non-neurological NSE elevation 2, 1

Clinical Interpretation Caveats

• Threshold inconsistency: The 0% false-positive rate threshold varies dramatically (33-151.5 mcg/L) based on timing, temperature management, and measurement technique 2
• Incomplete kinetics knowledge: The exact temporal profile of NSE release and clearance post-injury remains incompletely characterized 2
• Dual biological role: NSE may paradoxically promote both neuroinflammation (via inflammatory pathway activation) and neuroprotection (via PI3K/MAPK signaling) depending on microenvironment 8

Practical Clinical Algorithm

For post-cardiac arrest patients (highest-yield application):

1. Draw NSE at 48 and 72 hours post-ROSC (not 24 hours alone) 2, 1
2. Ensure hemolysis-free samples by careful phlebotomy technique 1
3. Interpret values >33 μg/L as concerning but never definitive 1
4. Look for rising trend between serial measurements 2, 1
5. Combine with other prognostic indicators: absent EEG reactivity, absent pupillary/corneal reflexes, brain imaging findings 2
6. Account for hypothermia treatment which decreases NSE levels over time 1

For seizure-related neuronal injury assessment:

• Measure NSE within 24 hours of last seizure 3
• Higher levels correlate with seizure frequency and prolonged ICU stays 3
• Use to support aggressive seizure management decisions 3