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Neuron-specific Enolase in Comatose Survivors of Cardiac Arrest After Therapeutic Hypothermia
Abstract & Commentary
By John J. Caronna, MD, Professor of Clinical Neurology, Weill Cornell Medical College. Dr. Caronna reports no financial relationships relevant to this field of study.
Synopsis: Therapeutic hypothermia after cardiac arrest makes prediction of prognosis more difficult, and neuron-specific enolase measurements add an additional objective test to help determine outcome.
Sources: Cronberg T, et al. Neuron-specific enolase correlates with other prognostic markers after cardiac arrest. Neurology 2011;77:623-630. Mayer SA. Outcome prediction after cardiac arrest: New game, new rules. Neurology 2011;77:614-615.
In 2006, the American Academy of Neurology established a practice parameter that identified accurate predictors of poor neurologic outcome after cardiac arrest.1 The indicators of poor prognosis in comatose survivors were derived from patients not treated with induced hypothermia. In 2010, Fugate et al confirmed that the clinical examination of brain stem reflexes and motor response and the presence of myoclonus at day 3 after cardiac arrest remain accurate predictors of outcome even after therapeutic hypothermia.2 Also significantly associated with poor outcome were "malignant" EEG patterns, global cerebral edema on head CT, and neuron-specific enolase (NSE) levels greater than 33 mcg/L. At days 1–3 after resuscitation, NSE levels had a false-positive rate of 29%, which limited their usefulness.
In the current study, Cronberg et al describe the pattern of commonly used prognostic markers in 34 cardiac arrest patients treated with hypothermia who were comatose at 3 days after rewarming (4.5 days after cardiac arrest).
All 17 patients with peak NSE levels > 33 mcg/L failed to recover consciousness. In this group, patients who underwent MRI (10) or autopsy (6) had evidence of extensive, severe hypoxic-ischemic brain injury.
Seventeen other patients with peak NSE levels < 33 mcg/L had a somewhat better outcome, but only six recovered the ability to follow commands. In this group, there were 11 patients with electrographic status epilepticus (ESE) and only one recovered "with a severe neurologic handicap."
The authors found that a high NSE correlated with other measures of global ischemia: the clinical neurological exam, cortical sensory-evoked potentials, DWI signal changes on MRI, and postmortem histologic analysis. Comatose patients with a low motor score on the Glasgow Coma Scale and a normal or only modestly elevated NSE were in ESE.
In his accompanying editorial, Mayer offers an explanation for the worse than expected outcome in low NSE patients. He speculates that ESE might be "the missing link" that explains why some patients with milder biomarker evidence of tissue injury do not recover. It may be that ESE causes secondary neuronal injury. If so, patients with post-anoxic ESE might benefit from more aggressive antiepileptic treatment.
The reports of false predictions in this and other studies2 indicate that the NSE level cannot be used clinically as an independent predictor of outcome in comatose patients. NSE is an enzyme that is a biomarker for cell death and at levels > 33 mcg/L predicts a poor outcome after cardiac arrest.
The poor specificity of NSE in some studies may be due to the relatively short biological half-life of NSE, which means that the peak time for measuring levels of the biomarker may vary from one patient to another. It could be that some patients have an NSE peak above a given threshold before 48 hours and then partially "recover" lower levels thereafter.3
At present, the clinical prognosticators are absence of pupillary light response and corneal reflexes, an extensor or absent motor response at day 3, and myoclonic status remain accurate predictors of poor outcome after cardiac arrest even in those comatose patients treated with hypothermia. In this same population, a motor response better than reflex at day 3, and EEG reactivity are general indicators of a better prognosis.
The need still exists for a multicenter study of cardiac arrest patients in coma after therapeutic hypothermia. The study should define the clinical role of imaging, electrophysiologic testing, and biomarkers. In addition, the study should increase our understanding of the neurophysiology of coma and determine whether ESE is the cause of secondary neuronal damage or the effect of an initial severe anoxic-ischemic episode.
1. Wijdicks EF, et al. Practice parameter: Prediction of outcome in comatose survivors after cardiopulmonary resuscitation (an evidence-based review): Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 2006;67:203-210.
2. Fugate JE, et al. Predictors of neurologic outcome in hypothermia after cardiac arrest. Ann Neurol 2010;68:907-914.
3. Rossetti A. Quoted in Neurology Today 2011;11:17.