Written by Jenny ChuPresented by Philippa Holdaway

Wellington SCL

NEURON-SPECIFIC ENOLASE:

An Introduction

“In a dark place we find ourselves,

and a little more knowledge lights our

way.”

-Yoda (George Lucas)

OVERVIEW

What is NSE?

NSE and Neuroendocrine Tumours

NSE levels and OOHCA

Issues w/ establishing appropriate

thresholds

Future Avenues of Research?

WHAT IS NSE?

WHAT IS NSE?

Isoform of the enzyme enolase

Involved in glycolysis

Biological half-life = 24 hours

Glucose

Glucose-6-Phosphate

Fructose-6-Phosphate

Fructose-1,6-biphosphate

Glyceraldehyde-3-Phosphate

Glucose-6-phosphate Isomerase

Phosphofructokinase-1

Fructose-biphosphate aldolase

1,3-Biphospho-glycerate

3-Biphospho-glycerate

2-Phospho-glycerate

Phosphoenol-pyruvate

Pyruvate

Phosphoglycerate Kinase

Phosphoglycerate Mutase

Pyruvate Kinase

(Neuron-specific) Enolase

WHAT IS NSE? NSE IS VERY ORGAN-SPECIFIC. Located in:

Neurons

Specialised cells making up nervous system. Highly metabolically active.

Neuroendocrine cells

Receive neuronal input and in response release message molecules into

blood

RBCs and Platelets = pre-analytical interference

When these cells are injured e.g. traumatic brain injury:

NSE leaks out of the cell = Higher NSE levels measured in serum

APPLICATIONS

NSE AS A TUMOUR MARKER

Neuroendocrine cells synthesise NSE.

Tumours derived of neuroendocrine cells retain the ability to produce NSE

Malignant proliferation of neuroendocrine cells leads to increased NSE levels in serum.

Valuable for diagnosis, staging, and treatment of neuroendocrine tumours (NETS) e.g. small cell lung cancer (correlates with tumour burden, number of metastatic sites, recurrences and response to treatment)

OTHER PROPOSED USES

• Neuronal:• Traumatic Brain Injury

• Creutzfeldt-Jakob disease

• Neurodegenerative diseases? – Dubious on this point

• Stroke

• Neuronal damage secondary to other disease states e.g.

sepsis, metastatic cancer (e.g. breast cancer study)

• Severe hypoxic ischaemic encephalopathy

• Other neuroendocrine malignancies:• Pheochromocytoma (cells of adrenal medulla)

NSE: POST CARDIAC ARREST

SUDDEN CARDIAC ARREST

• Leading cause of mortality, and neurologicdisability in survivors.

• Cardiac arrest > cerebral blood flow stops > hypoxicischaemic brain injury

• Range from mild cognitive deficits to persistentvegetative state.

• Current prognostic variables

• EEG, Somatosensory-evoked potentials (SSEP),imaging techniques (CT, MRI), Glasgow outcomescore

TIME COURSE OF NSE

But when is the right time to measure?

• Schoerkhuber et al. (1999) determined NSE concentration measured 72-hours post-ROSC (return of spontaneous circulation) = best predictor of neurological outcome. Found significant differences in serial NSE measurements in those with poor vs. Good outcome

• Vondrakova et al. (2017): ‘The highest associations of NSE with outcomes were observed on day 4 and day 3 after cardiac arrest.’ Significant association with prognosis was also found for changes in NSE at different time points.

TIME COURSE OF NSE

• But production and secretion of NSE is a dynamic process!

• Could be more value in assessing NSE changes over time (serial measurements).

TIME COURSE OF NSE

Schoerkhuber W, Kittler H, Sterz F, Behringer W, Holzer M, Frossard M, Spitzauer S, Laggner AN. Time course of serum neuron-specific enolase: a predictor of neurological outcome in patients resuscitated from cardiac arrest. Stroke. 1999 Aug;30(8):1598-603.

Results of a

Multi-Centre

Study on 1053

Patients.

Kaspar et al.

Suggested NSE

equal to or >90 ug/L

as a threshold that

reliably predicts

poor prognosis

NSE equal to or <17

ug/L reliably

predicted good

prognosis.

Streitberger KJ, Leithner C, Wattenberg M, Tonner

P, Hasslacher J, Joannidis M, Pellis T, Di Luca

E, Födisch M, Krannich A, Ploner CJ. Neuron-specific

enolase predicts poor outcome after cardiac arrest and

targeted temperature management: a multicenter study

on 1,053 patients. Critical care medicine. 2017 Jul

1;45(7):1145-51.

NSE MEASUREMENT

Roche Immunoassay

Sandwich electrochemiluminescence

Fully automated (18 min)

Must be measured with serum indices.

Measuring range: 0.05 - 370 ug/L

Non-invasive, rapid, not limited by sedation, easy to interpret

CARDIAC ARREST

CASE 1:

51 y/o male admitted to ICU, post-OOHCA, collapsed at home. CPR performed on the scene. ROSC after 31 minutes.

Serum NSE level 57.4 ug/L (Above High Normal)

Taken off life support following discussions with family.

CARDIAC ARREST

CASE 2:

53 y/o male admitted to ICU, post-OOHC, collapsed at the gym. AED used on the scene. ROSC after 20 - 25 minutes.

Serum NSE level 50.3 ug/L (Above High Normal)

Failure to wake after 72 hours. Patient was extubated and referred to palliative care. Deceased.

CARDIAC ARREST

CASE 3:

28 year-old male, collapsed at home

Assisted by paramedics crew who performed CPR & 2x shocks before achieving ROSC 20 mins post-CA

Day 1-2: variable neurology, biting, thrashing

Day 4: significant neurological improvement. GCS: E4V1M6 (all 4 limbs). Head CT normal.

NSE = 20.7 ug/L (ref. < 17.1 ug/L)

CARDIAC ARREST

CASE 3 cont’d

Day 10: patient discharged. Diagnosed with BrugadaSyndrome

Brugada Syndrome – genetic disorder where electrical activity of the heart is abnormal. Increases risk of abnormal heart rhythms and sudden cardiac death.

> No cure. Implantable Cardioverter Defibrillator can be used in higher risk patients.

AN ETHICAL DILEMMA

AN ETHICAL DILEMMA

To prevent falsely suggesting a poor prognosis in

these patients:

• Thresholds must be set in a manner that aims

to predict poor prognosis with high

specificity, at the cost of optimal sensitivity.

• WSCL ICU Trial Thresholds:

• <17.1 ng/mL: suggests good outcome

• >90 ng/mL: suggestive of poor prognosis

POTENTIAL AREAS TO EXPLORE

Investigate optimal time of

collection and serial

measurements

South Africa – use in

penitentiaries

SUMMARY

NSE levels correlate with disease states

involving neuronal/neuroendocrine damage incl.

hypoxic ischaemic encephalopathy

Limitations exist – dynamic process, one

measurement = just a snapshot in time!

Consider serial measurements?

Ethics – life support should not be terminated on

the basis of a single biomarker level. Consider:

Dynamic approach to NSE and…

Comprehensive multimodal prognostication

protocol

ACKNOWLEDGEMENTS

Max Reed, HoD Biochem WSCL

Dr Carol Siu, Chem Path WSCL

Dr Melissa Yssel, Chem Path WSCL

REFERENCES Streitberger KJ, Leithner C, Wattenberg M, Tonner P, Hasslacher J, Joannidis M, Pellis T,

Di Luca E, Födisch M, Krannich A, Ploner CJ. Neuron-specific enolase predicts pooroutcome after cardiac arrest and targeted temperature management: a multicenter study on1,053 patients. Critical care medicine. 2017 Jul 1;45(7):1145-51.

Schoerkhuber W, Kittler H, Sterz F, Behringer W, Holzer M, Frossard M, Spitzauer S,Laggner AN. Time course of serum neuron-specific enolase: a predictor of neurologicaloutcome in patients resuscitated from cardiac arrest. Stroke. 1999 Aug;30(8):1598-603.

Petzinka VN, Endisch C, Streitberger KJ, Salih F, Ploner CJ, Storm C, Nee J, Leithner C.Unresponsive wakefulness or coma after cardiac arrest—A long-term follow-up study.Resuscitation. 2018 Oct 1;131:121-7.

Harding M, McAllister J, Hulks G, Vernon D, Monie R, Paul J, Kaye SB. Neurone specificenolase (NSE) in small cell lung cancer: a tumour marker of prognostic significance?.British journal of cancer. 1990 Apr;61(4):605.

Georgantzi K, Sköldenberg EG, Stridsberg M, Kogner P, Jakobson Å, Janson ET,Christofferson RH. Chromogranin A and neuron-specific enolase in neuroblastoma:Correlation to stage and prognostic factors. Pediatric hematology and oncology. 2018 Apr28:1-0.

Sekhon MS, Ainslie PN, Griesdale DE. Clinical pathophysiology of hypoxic ischemic braininjury after cardiac arrest: a “two-hit” model. Critical Care. 2017 Dec;21(1):90.

REFERENCES CONT’D Huntgeburth M, Adler C, Rosenkranz S, Zobel C, Haupt WF, Dohmen C, Reuter H. Changes in

neuron-specific enolase are more suitable than its absolute serum levels for the prediction ofneurologic outcome in hypothermia-treated patients with out-of-hospital cardiac arrest.Neurocritical care. 2014 Jun 1;20(3):358-66.

Tiainen M, Roine RO, Pettila V, Takkunen O. Serum neuron-specific enolase and S-100Bprotein in cardiac arrest patients treated with hypothermia. Stroke. 2003 Dec 1;34(12):2881-6.

Cheng F, Yuan Q, Yang J, Wang W, Liu H. The prognostic value of serum neuron-specificenolase in traumatic brain injury: systematic review and meta-analysis. PLoS One. 2014 Sep4;9(9):e106680.

Rech TH, Vieira SR, Nagel F, Brauner JS, Scalco R. Serum neuron-specific enolase as earlypredictor of outcome after in-hospital cardiac arrest: a cohort study. Critical care. 2006Oct;10(5):R133.

Sandroni C, Cavallaro F, Callaway CW, Sanna T, D’Arrigo S, Kuiper M, Della Marca G, NolanJP. Predictors of poor neurological outcome in adult comatose survivors of cardiac arrest: asystematic review and meta-analysis. Part 1: patients not treated with therapeutic hypothermia.Resuscitation. 2013 Oct 1;84(10):1310-23.

Sandroni C, Cavallaro F, Callaway CW, D’Arrigo S, Sanna T, Kuiper MA, Biancone M, DellaMarca G, Farcomeni A, Nolan JP. Predictors of poor neurological outcome in adult comatosesurvivors of cardiac arrest: a systematic review and meta-analysis. Part 2: patients treated withtherapeutic hypothermia. Resuscitation. 2013 Oct 1;84(10):1324-38.

REFERENCES CONT’D Sandroni C, Cavallaro F, Callaway CW, D’Arrigo S, Sanna T, Kuiper MA, Biancone M,

Della Marca G, Farcomeni A, Nolan JP. Predictors of poor neurological outcome in adultcomatose survivors of cardiac arrest: a systematic review and meta-analysis. Part 2: patientstreated with therapeutic hypothermia. Resuscitation. 2013 Oct 1;84(10):1324-38.

Rundgren M, Cronberg T, Friberg H, Isaksson A. Serum neuron specific enolase–impact ofstorage and measuring method. BMC research notes. 2014 Dec;7(1):726.