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

What is Neuron-Specific Enolase (NSE)?

Neuron-specific enolase is a glycolytic enzyme that is highly enriched in neuronal cell bodies and peripheral neuroendocrine cells, making it a reliable biochemical marker of neuronal damage when released into blood or cerebrospinal fluid. 1, 2

Biochemical Characteristics

• NSE is one of three enolase isoenzymes in vertebrates: enolase α (ubiquitous), enolase β (muscle-specific), and enolase γ (neuron-specific) 3
• NSE exists as γγ- and αγ-dimers and its expression is a late event in neural differentiation, making it useful for assessing neural maturation 3
• The enzyme is present almost exclusively in neurons and neuroendocrine cells, providing high tissue specificity 4, 5

Clinical Applications

Neurological Injury Assessment

NSE is most valuable for prognosticating outcomes after cardiac arrest, where elevated levels at 48-72 hours correlate with the extent of anoxic-ischemic brain injury and predict poor neurological outcomes. 1, 2

• In post-cardiac arrest patients treated with targeted temperature management (TTM), NSE thresholds for predicting poor outcome with 0% false-positive rate vary: 49.6-151.4 mcg/L at 24 hours, 25-151.5 mcg/L at 48 hours, and 57.2-78.9 mcg/L at 72 hours 1
• The discriminative value of NSE levels at 48-72 hours is superior to 24-hour measurements 1, 2
• Serial measurements showing persistently high or increasing NSE values over time provide more reliable prognostic information than single measurements 2
• NSE levels in cerebrospinal fluid are proportional to traumatic brain injury severity and associated with increased mortality in moderate or severe TBI 2

Neuroendocrine Tumor Detection

• NSE is the most reliable tumor marker for small cell lung cancer (SCLC) diagnosis, prognosis, and follow-up, with levels correlating with tumor burden and number of metastatic sites 3
• Large amounts of NSE (mean 1626 ng/mg protein) are found in neuroendocrine neoplasias (APUDomas) including islet-cell tumors, pheochromocytomas, medullary thyroid carcinomas, and carcinoid tumors, while non-endocrine tumors contain less than 15 ng/mg protein 6
• NSE is useful for diagnosis and staging of neuroblastoma, with higher incidence of elevated concentrations in widespread and metastatic disease 3

Other Neurological Conditions

• Elevated NSE levels occur in ischemic stroke, intracerebral hemorrhage, seizures, and traumatic brain injury, providing quantitative measures of brain damage 3
• NSE is significantly higher in critically ill neurology patients with seizures compared to those without seizures, with close correlation between NSE levels and seizure frequency 7
• Patients with lower Glasgow Outcome Scale scores have higher cerebrospinal fluid NSE levels than those with favorable outcomes 4

Causes of Elevated NSE

Neuronal Injury

• Anoxic-ischemic brain injury following cardiac arrest 1, 2
• Traumatic brain injury 2, 3
• Ischemic and hemorrhagic stroke 3
• Status epilepticus and seizures 3, 7
• Encephalitis 4

Neoplastic Conditions

• Small cell and non-small cell lung cancer 3
• Neuroblastoma 3
• Gastroenteropancreatic neuroendocrine tumors 3
• Melanoma, seminoma, renal cell carcinoma, Merkel cell tumor, pheochromocytoma 3

Other Conditions

• Creutzfeldt-Jakob disease 3
• Guillain-Barré syndrome 3

Critical Limitations and Pitfalls

NSE should never be used alone to predict neurological outcomes due to significant methodological limitations and potential for false-positive results. 2

• Laboratory standards for NSE measurement vary substantially between centers and analyzers, making comparison of absolute values difficult and explaining the wide variation in reported thresholds 1, 2
• NSE is highly sensitive to hemolysis, which is a major source of false-positive results—blood samples must be drawn carefully to avoid hemolysis 2
• Extra-neuronal sources of NSE include hemolysis, erythrocytes, and neuroendocrine tumors, limiting specificity 1, 2
• Serum NSE is not sensitive enough to detect neuronal damage reliably, whereas cerebrospinal fluid NSE appears more reliable for assessing significant neurological insult 4

Best Practice Recommendations

When evaluating post-cardiac arrest patients, use high serum NSE values at 48-72 hours after cardiac arrest to support prognosis of poor neurological outcome, but only in combination with other prognostic tests including clinical examination, EEG, and neuroimaging. 2

• Obtain serial NSE measurements at 24,48, and 72 hours rather than relying on a single value 2
• Use NSE as a confirmatory test rather than a primary method for estimating prognosis 2
• Ensure proper blood collection technique to minimize hemolysis 2
• Consider the incomplete knowledge of NSE kinetics in the first few days after return of spontaneous circulation when interpreting results 1