Article Figures & Tables
Figures
- Figure 1
Flow diagram for the selection of studies. NSE = neuron-specific enolase, TBI = traumatic brain injury.
- Figure 2
Risk of bias and applicability concerns of included studies.
- Figure 3
Mean differences of neuron-specific enolase blood levels in patients with moderate or severe traumatic brain injury, by mortality. A mean difference above zero indicates an increased risk of death. CI = confidence interval, IV = inverse variance, NSE = neuron-specific enolase, SD = standard deviation.
- Figure 4
Mean differences of neuron-specific enolase blood levels in patients with moderate or severe traumatic brain injury, by neurologic outcome (defined by the Glasgow Outcome Scale Score). A mean difference above zero indicates an increased risk of poor neurologic outcome. CI = confidence interval, GOS = Glasgow outcome scale, IV = inverse variance, NSE = neuron-specific enolase, SD = standard deviation.
Tables
- Table 1: Characteristics of the included studies Table 1: Characteristics of the included studies
Studies N* Inclusion criteria Age, yr No. of patients
(F/M)Severity scales Assay Main outcome Al Nimer et al.30 182 Patients with NF-L sample
in Traumatic Brain Injury Database of Karolinska InstituteMedian (range)
55 (15-79)45/137 Mean ± SD GCS 7 ± 4;
Median (IQR) ISS 25 (19-29)IRMA, Liaison (DiaSorin) GOS at 6 and 12 mo
1-3 unfavourable
4-5 favourableBaker et al.31 64 GCS ≤ 8; coma or loss of consciousness because of isolated blunt TBI Mean (range) 41.4 (18.3-87.9) 23/41 Mean ± SD GCS
5.7 ± 2.7Mortality, GOSE and GOS at hospital discharge (or 30 d)
1-3 unfavourable
4-5 favourableBöhmer et al.32 20 GCS ≤ 8 with abnormal brain CT scan on admission;
ventriculostomy installedMean ± SD
29 ± 132/18 NR Elecsys
(Roche Diagnostics)Mortality Chabok et al.33 28 GCS ≤ 8;
Severe diffuse axonal injury (exclusion of intra- and extracranial hematoma on CT); age ≥ 16 yr; no severe systemic injury; no intoxication; no pre-existing diseaseMean ± SD
31 ± 192/26 Mean admission ± SD
GCS 6.7 ± 1.3ELISA
(Can Ag Diagnostics)Dauberschmidt et al.34 9 Cerebral coma after severe head trauma Mean ± SD
39.7 ± 16.91/8 NR RIA Mortality at 1 mo Di Battista et al.35 85 GCS < 13; on-head abbreviated injury score (AIS) ≤ 2 Mean ± SD
45.8 ± 21.919/66 Median (range) GCS 5 (3-8);
Mean ± SD ISS 23.6 ± 11;
Mean ± SD AISh 4.2 ± 1.1ELISA, SECTOR Imager (Meso Scale Diagnostics) Mortality and GOS at 6 mo1-3 unfavourable
4-5 favourableGatson et al.36 18 GCS ≤ 8; ventriculostomy installed Mean ± SD
32.1 ± 12.37/11 Mean ± SD GCS 3.75 ± 1.2 ELISA (USCN Life Science) GOSE1-4 unfavourable
5-8 favourableGradisek et al.37 84 GCS ≤ 8 after reanimation or deterioration to GCS < 8 after the first 24 hr; isolated TBI (no extracranial injury with AIS ≥ 3); no neurologic disease Mean ± SD
46 ± 2111/73 Median (IQR) GCS 6 (4-8);
Median (IQR) ISS 24 (16-25)ELISA, Liaison (Sangtec Medical) All-cause mortality and GOS at 12 mo
1-3 unfavourable
4-5 favourableGuan et al.38 41 Admission within 6 hr after injury; closed TBI; no history of disease of vital organs such as heart, kidney and brain Mean (range)
44 (5-92)NR NR NR GOS at 6 mo
1-3 unfavourable
4-5 favourableKuroiwa et al.39 47 NR Mean 35.1 12/35 NR RIA Mortality and GOS Li et al.40 40 GCS ≤ 8; no severe systemic injury; no heart or renal failure; no severe CNS infection NR NR NR RIA (Sangtec Medical) GOS at 6 mo
1-3 unfavourable
4-5 favourableLuo et al.41 24 TBI NR NR GCS ≥ 13 = 9; GCS 9-12 = 17;
GCS ≤ 8 = 24Custom GOS
1-3 unfavourable
4-5 favourableMcKeating et al.42 21 TBI admitted to ICU Median (range) 35 (17-69) 4/17 Median (range) GCS 6 (3-13); Median (range) ISS 25 (9-38) RIA (Sangtec Medical) GOS at 6 mo
1-3 unfavourable
4-5 favourableMeissner et al.43 20 NR NR NR NR NR Mortality Meric et al.44 40 ≥ 18 yr of age; presenting to ED within 24 hr after trauma Median (range)
31 (18-88)28/12 GCS ≤ 13 ECLIA (Roche Diagnostics) Mortality and GOS at 1 mo Olivecrona et al.45 48 GCS ≤ 8; 15-70 yr of age; first recorded CPP > 10 mm Hg; arrival < 24 hr after TBI Median (range)
31 (15-63)17/31 Median (range) ISS 29 (9-50);
Median (range) APACHE II 21 (12-32)LIA (DiaSorin Diagnostica) GOS at 3 and 12 mo
1-3 unfavourable
4-5 favourablePersson et al.46 4 NR NR NR NR Custom GOS at hospital discharge
1-3 unfavourable
4-5 favourablePleines et al.47 13 GCS ≤ 8 admission; isolated TBI Mean (range)
36 (16-67)NR NR ELISA (Wallac Sverige AB) GOS between 3 and 6 mo Raabe et al.48 44 Severe head injury Median (range) 41 (16-83) 11/33 Median (range) GCS 5 (3-8) RIA (Sangtec Medical) GOS at 6 mo
1-3 unfavourable
4-5 favourableRaabe et al.49 82 GCS ≤ 8 postresuscitation; admitted neurosurgical ICU Median (range) 38 (16-85) 16/66 NR RIA (Sangtec Medical) GOS at 6 mo
1-3 unfavourable
4-5 favourableRoss et al.50 9 Admitted to ICU ≤ 24 h after TBI Median (range) 21.5 (4-70) 2/7 Median (range) GCS 6 (3-9) RIA Mortality at ICU discharge
GOSSawauchi et al.51 41 Consecutive TBI NR NR GCS > 8 = 30; GCS ≤ 9 = 11 NR GOS at 3 mo
1-3 unfavourable
4-5 favourableStein et al.52 24 Age > 17 yr; admission within the first 6 hr after injury; GCS score < 9 on admission; isolated TBI (no extracranial injury with AIS ≥ 4); placement of a clinically indicated ICP monitor performed Mean ± SD
30.7 ± 12.3;
Range 19-643/21 Mean ± SD GCS 5.8 ± 3.4 ELISA (Biovendor Candor) GOSE at 3, 6 and 12 mo
1-4 unfavourable
5-8 favourableVos et al.53 78 GCS ≤ 8 postresuscitation admitted ≤ 36 hr after injury; closed TBI; blood sample taken; long-term follow-up Median (range) 32 (15-81) 24/61 Median (range) GCS 4 (3-8);
Median (range) ISS 29 (9-75)LIA (Sangtec Medical) Mortality and GOS at
6 mo
1-3 unfavourable
4-5 favourableWang et al.54 34 Admitted to neurosurgery < 24 hr after injury Range 15-73 15/19 NR ECLIA (Roche Diagnostics) GOS at 3 mo
1-3 unfavourable
4-5 favourableWoertgen et al.55 30 GCS ≤ 8; admitted between 1 and 6 hr after injury; no spinal cord injury; no history of neurologic disease; no resuscitation or shock Mean (range)
32 (17-73)7/23 NR ELISA (Wallac Sverige AB) GOS at hospital discharge
1-3 unfavourable
4-5 favourableYamazaki et al.56 17 No severe hypoxia or systemic hypotension Mean (range)
45 (14-91)5/20 GCS < 8 = 9; GCS ≥ 8 = 16 NR Mortality at hospital discharge (mean 22 d) Yan et al.57 42 GCS ≤ 8; extraventricular drain Median (range)
29 (16-23)10/32 Median (range) GCS 5 (3-10);
Median (IQR) ISS 36 (27-43)ELISA (CanAg Diagnostics) GOSE at 6 mo
1-4 unfavourable
5-8 favourableZhan et al.58 30 GCS ≤ 8 admission; no severe systemic injury; no severe cardiac ischemia; no renal failure; no severe CNS infection Range 26-64 12/18 NR NR GOS at 1 mo
1-3 unfavourable
4-5 favourableZhang et al.59 102 Isolated head trauma; postresuscitation GCS ≤ 8; age ≥ 18 yr; admission time > 6 hr Mean ± SD
40.5 ± 15.334/68 Median (range) GCS 5 (3-8) ELISA (Phoenix Pharmaceuticals) GOSE at 6 mo
1-4 unfavourable
5-8 favourableNote: AIS = abbreviated injury score, AISh = abbreviated injury score head, APACHE II = acute physiology and chronic health evaluation II, CNS = central nervous system, CPP = cerebral perfusion pressure, CT = computed tomography, ED = emergency department, ECLIA = electrochemiluminescence immunoassay, ELISA = enzyme-linked immunosorbent assay, GCS = Glasgow Coma Scale, GOS = Glasgow Outcome Scale, GOSE = Glasgow Outcome Scale-Extended, ICP = intracranial pressure, ICU = intensive care unit, IQR = interquartile range, IRMA = immunoradiometric assay, ISS = injury severity score, LIA = luminescence immunoassay, NF-L = neurofilament light, NR = not reported, RIA = radioimmunoassay, SD = standard deviation, TBI = traumatic brain injury.
*Number of patients included in the analysis (may be different from the number of patients included in the study when data specific to our population of interest could be extracted).
Outcome No. of studies No. of patients Mean difference (95% CI) I2 Mortality Evaluation time ICU 0 - - - 1 mo 3 66 33.09 (9.67 to 56.51) 73 3 mo 0 - - - 6 mo 2 80 - - 12 mo 2 132 - - Unclear 3 84 22.71 (14.45 to 30.97) 0 Sampling time, hr Up to 12 5 336 15.11 (6.29 to 23.93) 83 Up to 24 5 138 22.86 (9.66 to 36.06) 56 Type of sample Venous 5 253 25.53 (6.54 to 44.53) 84 Blood NS 5 221 16.13 (7.63 to 24.62) 65 Biochemical analysis RIA 4 83 23.89 (16.22 to 31.05) 0 LIA 1 48 - - ELISA 3 271 6.12 (4.15 to 8.09) 0 ECLIA 0 - - - Other 2 72 - - Minimal TBI severity Mild 2 49 - - Moderate 2 125 - - Severe 6 268 13.30 (5.92 to 20.67) 79 Isolated TBI Isolated 3 235 17.07 (0.29 to 33.85) 88 Nonisolated 5 198 24.35 (9.70 to 39.00) 81 Unclear 2 41 - - GOS or GOSE Evaluation time ICU 1 30 - - 1 mo 2 70 - - 3 mo 2 75 - - 6 mo 4 268 17.19 (4.82 to 29.55) 87 12 mo 1 48 - - Unclear 4 113 16.54 (7.85 to 25.22) 52 Sampling time, hr Up to 12 8 400 17.49 (9.76 to 25.22) 85 Up to 24 6 204 14.97 (5.80 to 24.14) 71 Type of sample Venous 7 372 16.18 (8.41 to 23.95) 87 Blood NS 7 232 16.13 (9.00 to 23.26) 47 Biochemical analysis RIA 3 97 17.91 (12.59 to 23.23) 0 LIA 1 48 - - ELISA 5 282 6.26 (4.31 to 8.20) 79 ECLIA 1 34 - - Other 4 143 15.22 (10.74 to 19.70) 83 Minimal TBI severity Mild 4 148 11.61 (4.99 to 18.32) 46 Moderate 2 125 - - Severe 8 322 14.57 (7.36 to 21.77) 83 Isolated TBI Isolated 6 346 13.80 (6.67 to 20.93) 84 Nonisolated 7 226 22.42 (11.15 to 33.68) 72 Unclear 1 32 - - Note: CI = confidence interval, CSF = cerebrospinal fluid, ECLIA = electrochemiluminescence immunoassay, ELISA = enzyme-linked immunosorbent assay, GOS = Glasgow Outcome Scale, GOSE = Glasgow Outcome Scale-Extended, ICU = intensive care unit, LIA = luminescence immunoassay, NS = not specified, RIA = radioimmunoassay, TBI = traumatic brain injury.
- Table 3: Sensitivity analyses of studies reporting neuron-specific enolase serum concentration (excluding plasma concentration), by outcome
Outcome No. of studies No. of patients Mean difference (95% CI) I2 Mortality Overall 9 372 21.49 (12.57 to 30.41) 70 Evaluation time 6 mo 1 85 - - Sampling time Up to 12 hr 4 234 21.00 (6.67 to 35.32) 80 Type of sample Venous 4 151 32.31 (13.76 to 50.85) 59 Biochemical analysis ELISA 2 169 - - Minimal TBI severity Severe 5 166 15.99 (7.59 to 24.39) 63 Isolated TBI Isolated 2 133 - - GOS or GOSE Overall 13 501 18.21 (12.95 to 23.47) 63 Evaluation time 6 mo 3 166 20.49 (14.27 to 26.72) 0 Sampling time Up to 12 hr 7 298 19.39 (15.59 to 23.20) 0 Type of sample Venous 6 270 18.35 (10.68 to 26.02) 72 Biochemical analysis ELISA 4 180 23.34 (14.89 to 31.79) 0 Minimal TBI severity Severe 7 229 18.01 (14.08 to 21.94) 6 Isolated TBI Isolated 5 244 16.55 (12.47 to 20.63) 11 Note: CI = confidence interval, ELISA = enzyme-linked immunosorbent assay, GOS = Glasgow Outcome Scale, GOSE = Glasgow Outcome Scale-Extended, TBI = traumatic brain injury.
- Table 4: Neuron-specific enolase serum level cut-off values, sensitivity and specificity from included studies, by outcome
Outcome Cut-off values
(µg/L)Sensitivity (%) Specificity (%) Mortality Yamazaki et al.56 20 100 73 Vos et al.53 21.7 85 48 Olivecrona et al.45 11.6 100 45 Chabok et al.33 51.8 100 100 Zhang et al.59 17.6 93 62 Glasgow Outcome Scale ≤ 3 Raabe et al.48 100 9 96 Guan et al.38 60 54 96 Zhan et al.58 30 67 83 Li et al.40 30 67 77 Vos et al.53 21.7 80 55 Olivecrona et al.45 9.5 87 36 Meric et al.44 20.5 87 82 Zhang et al.59 16.4 87 82
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