Monitoring biomarkers of cellular injury and death in acute brain injury.

Neurocrit Care DOI 10.1007/s12028-014-0039-z

ORIGINAL ARTICLE

Monitoring Biomarkers of Cellular Injury and Death in Acute Brain Injury Sherry H-Y. Chou • Claudia S. Robertson • and the Participants in the International Multi-disciplinary Consensus Conference on the Multimodality Monitoring

Springer Science+Business Media New York 2014

Abstract Background Molecular biomarkers have revolutionalized diagnosis and treatment of many diseases, such as troponin use in myocardial infarction. Urgent need for high-fidelity biomarkers in neurocritical care has resulted in numerous studies reporting potential candidate biomarkers. Methods We performed an electronic literature search and systematic review of English language articles on cellular/molecular biomarkers associated with outcome and with disease-specific secondary complications in adult patients with acute ischemic stroke (AIS), intracerebral hemorrhage (ICH), subarachnoid hemorrhage (SAH), traumatic brain injury (TBI), and post-cardiac arrest hypoxic ischemic encephalopathic injuries (HIE). Results A total of 135 articles were included. Though a wide variety of potential biomarkers have been identified, only neuron-specific enolase has been validated in large cohorts and shows 100 % specificity for poor outcome prediction in HIE patients not treated with therapeutic hypothermia. There are many promising candidate blood and CSF biomarkers in SAH, AIS, ICH, and TBI, but none yet meets criteria for routine clinical use.

The Participants in the International Multi-disciplinary Consensus Conference on the Multimodality Monitoring are listed in ‘‘Appendix’’. S. H-Y. Chou (&) Department of Neurology, Brigham and Women’s Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA e-mail: [email protected] C. S. Robertson Department of Neurosurgery, Baylor College of Medicine, Houston, TX, USA

Conclusion Current studies vary significantly in patient selection, biosample collection/processing, and biomarker measurement protocols, thereby limiting the generalizability of overall results. Future large prospective studies with standardized treatment, biosample collection, and biomarker measurement and validation protocols are necessary to identify high-fidelity biomarkers in neurocritical care. Keywords Biomarker Traumatic brain injury Subarachnoid hemorrhage Stroke Intracerebral hemorrhage Cardiac arrest Outcome

Introduction Cellular and molecular biomarkers play important roles in critical care—they may help monitor disease progression, probe underlying physiology, and improve prognostic accuracy. The presence of the blood brain barrier (BBB) and its injury introduce the following unique complexities in the interpretation and the use of molecular biomarkers in neurocritical care: (1) (2)

(3)

Biomarker origin—whether it is primarily synthesized in the central nervous system (CNS) or elsewhere. The anatomical source of the biosample—whether it is serum, plasma, CSF, urine, or other. Molecular biomarkers have significantly different concentrations, biological half-lives, and time-course variations in different anatomical compartments. The timing of biomarker measurement relative to disease onset—The sensitivity and specificity of biomarkers vary depending on measurement time relative to disease onset.

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(4)

Association with potential injury mechanisms— Whether a molecule is part of a pathogenic pathway or a final result of cellular injury (reversible or irreversible) affects the clinical interpretation of this molecule as a biomarker of disease.

Here, we review current acute brain injury (ABI) biomarker data in light of these special considerations.

to the GRADE system. We included 28 studies for HIE following cardiac arrest (Tables 1, 2), 25 for SAH (Table 3), 25 for AIS (Table 4), 29 for ICH (Table 5), and 28 for TBI (Table 6). Available biomarkers that predict overall prognosis and secondary complications in ABI patients were reviewed to address specific endpoints. Review End-Points 1.

Methods Search Criteria This systematic review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. Using the PICO approach, we searched PubMed database for English language articles from January 1990 to August 2013 based on the following criteria: Patient population Adult patients C18 years of age with acute ischemic stroke (AIS), intracerebral hemorrhage (ICH), spontaneous subarachnoid hemorrhage (SAH), traumatic brain injury (TBI), and post-cardiac arrest (CA) hypoxic ischemic encephalopathic injuries (HIE). b. Intervention Cellular/molecular biomarkers from biological fluids such as serum, plasma, cerebrospinal fluid (CSF), and urine. c. Controls Patients without ABI. d. Outcome endpoints Primary outcomes of interest are mortality and long-term neurological outcome. Secondary outcomes of interest are prediction of diseasespecific secondary deteriorations and complications such as hemorrhagic transformation of AIS and delayed cerebral ischemia (DCI) and vasospasm following SAH.

2.

3.

4.

a.

Study Selection and Data Collection We excluded unpublished data or congress presentations/ abstracts, review articles, case reports or case series, studies with sample size B10 patients for CSF biomarkers and studies with sample size B30 for blood biomarkers, pediatric ICU studies, studies not conducted on ICU patients, and studies dealing with brain death. We also excluded microbiological markers of infection, biomarkers from microdialysis, and metabolites. One hundred and thirty-five studies were included. Both authors using predefined criteria systematically extracted data from the included studies, and the levels of evidence were classified and practical recommendations were developed according

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5.

(a) Are there cellular/molecular biomarkers that help predict long-term neurological prognosis in comatose cardiac arrest patients either treated or not treated with therapeutic hypothermia (TH)? Are there cellular/molecular biomarkers that help predict (a) long-term outcome and (b) development of vasospasm and/or DCI after SAH? Are there cellular/molecular biomarkers that help predict (a) long-term outcome and (b) incidence of malignant cerebral edema or hemorrhagic transformation following AIS? Are there cellular/molecular biomarkers that help predict (a) long-term outcome and (b) hematoma expansion and cerebral edema following ICH? Are there cellular/molecular biomarkers that help predict (a) long-term outcome and (b) cerebral edema and intracranial pressure (ICP) elevation after TBI?

Literature Summary Cardiac Arrest HIE: Without TH We found 20 prospective observational studies specific to these patients (Table 1). Outcome measures examined include regaining consciousness and Cerebral Performance Category (CPC) at 3 or 6 months after cardiac arrest. Molecules of CNS Origin The most extensively studied biomarkers in this population are s100b and neuron-specific enolase (NSE); both primarily originate from the central nervous system (CNS). The largest prospective study (n = 407) found serum NSE >33 lg/L at 24, 48, or 72 h after CA had 0 % false positive rate (FPR) for poor outcome (death or persistent unconsciousness) at 1 month [1]. Serum NSE >33 lg/L at 24–72 h post CA predicts death or persisting unconsciousness after 1 month with 100 % specificity in these patients. Several other studies with sample sizes between 56 and 110 supported serum NSE as a prognostic biomarker for HIE though optimal NSE cutoff values differed (20–65 lg/L) [2–6]. Additional confounds arise from the poor reproducibility of NSE assays used [7]. Studies with

Post cardiac arrest within 12 h of ROSC, survived >48 h

Out-of-hospital cardiac arrest

Non-traumatic out-of-hospital cardiac arrest

Post cardiac arrest, unconscious and 64 ventilated for >24 h

Post cardiac arrest

Non-traumatic out-of-hospital cardiac arrest

Pfeifer/2005/[2]

Rosen/2001/[6]

Bottiger/2001/[8]

Martens/1998/[4]

Hachimi-Idrissi/2002/[9]

Schoerkhuber/1999/[5]

Post cardiac arrest

Kasai/2011/[12]

357 Ammonia

Age >17 years, out-of-hospital 401 BNP cardiac arrest of presumed cardiac origin

NSE

s100b

NSE, s100b

s100b

s100b, NSE

NSE, s100b

Nagao/2004/[10]

56

58

66

66

97

110 NSE

Post cardiac arrest, comatose post CPR

Meynaar/2003/[3]

Molecules of non-CNS origin

Bio-marker

407 NSE, s100b

N

Post cardiac arrest, unconscious >24 h after CPR

Population

Zandbergen/2006/[1]

Molecules of CNS origin

Authors/year/Ref

Blood

Blood

Serum

Serum

Serum

Serum

Serum

Serum

Serum

Serum

Sample source

• 61 patients were treated with TH

• Ammonia >192.5 lg/dL had 100 % NPV for good outcome at discharge

• Elevated ammonia on ER arrival is associated with decreased odds for good outcome at hospital discharge (OR = 0.98 [0.96–0.99])

• BNP >100 pg/mL predicted lack of survival until hospital discharge (83 % sensitivity; 96 % NPV)

• Rate of survival to hospital discharge decreased in dose-dependent fashion with increasing quartiles of BNP on admission

• NSE >27.3 lg/L at any time predicted poor outcome (100 % specificity)

• NSE cutoffs for poor outcome were as follows: NSE > 38.5 lg/L at 12 h, NSE > 40 lg/ L at 24 h, NSE >25.1 lg/L at 48 h, and NSE >16.4 lg/L at 72 h (100 % specificity)

• NSE was significantly higher in patients who had poor 6-month outcome at 12, 24, 48, and 72 h after ROSC

• s100b >0.7 lg/L at admission predicted not regaining consciousness (85 % specificity; 66.6 % sensitivity; 84 % PPV; 78 % NPV; 77.6 % accuracy)

• NSE >20 lg/L predicted poor outcome (51 % sensitivity; 89 % specificity)

• s100b >0.7 lg/L is a predictor of not regaining consciousness after cardiac arrest (95 % PPV; 96 % specificity)

• s100b and NSE were significantly higher in patients who did not regain consciousness compared to those who did

• s100b >1.10 lg/L at 48 h post cardiac arrest predicted brain damage (100 % specificity)

• Significant differences in s100b level between survivors and non-survivors after cardiac arrest were observed from 30 min to 7 days post cardiac arrest

• s100b >0.217 lg/L and NSE >23.2 lg/L at 2 days post cardiac arrest predicted poor 1-year outcome (100 % PPV)

• s100b >1.5 lg/L predicts poor outcome (96 % PPV)

• NSE >65 lg/L predicted increased risk of death and persistent vegetative state at 28 days post CPR (97 % PPV)

• No one with NSE >25 lg/L at any time regained consciousness (100 % specificity)

• Performance of clinical tests was inferior to SSEP and NSE in predicting outcome • NSE at 24 and 48 h after CPR was significantly higher in patients who did not regain consciousness vs. those who did

• s100b >0.7 lg/L at 24–72 h post cardiac arrest predicts poor outcome (47 % PPV; 2 % FPR)

• 100 % of patients with NSE >33 lg/L at any time had a poor outcome (40 % PPV; 0 % FPR)

Findings

Table 1 Biomarkers for outcome following cardiac arrest without therapeutic hypothermia treatment

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123

Post cardiac arrest, unconscious and 34 ventilated for >48 h

Post cardiac arrest, survive >12 days post ROSC

VF or asystolic arrest

Out-of-hospital cardiac arrest of presumed cardiac

Martens/1998/[4]

Rosen/2004/[19]

Karkela/1993/[16]

Oda/2012/[14]

14

20

22

Comatose cardiac arrest patients with 52 SSEP studies

Sherman/2000/[17]

67

Out-of hospital VF arrest who survived >24 h

Roine/1989/[13]

CSF biomarkers

Non-traumatic out-of hospital cardiac 98 arrest with ROSC

Shinozaki/2011/[13]

Bio-marker

HMGB1, s100b

CKBB, NSE

NFL

NSE, s100b

CKBB

NSE, CKBB

Ammonia, Lactate

155 BNP

Post cardiac arrest, comatose

Sodeck/2007/[11]

N

Population

Authors/year/Ref

Table 1 continued

CSF

CSF

CSF

CSF

CSF

CSF

Blood

Blood

Sample source

• HMGB1 and s100b were significantly higher in poor outcome group compared to good outcome group and to normal controls

• CSF sampled at 48 h after ROSC

• Elevated CKBB at 4 and 28 h, and elevated NSE at 28 and 76 h after cardiac arrest were associated with not regaining consciousness

• CSF collected at 4, 28, and 76 h after resuscitation

• Case controlled

• NFL >18,668 lg/L predicted dependency in ADL at 1 year (100 % specificity; 46 % sensitivity)

• CSF sampled at 12–30 days after cardiac arrest

• CSF sampling time is not standardized

• NSE >50 lg/L (89 % sensitivity; 83 % specificity) and s100b >6 lg/L (93 % sensitivity; 60 % specificity) predicted death or vegetative state

• s100b and NSE were both significantly higher in patients who did not regain consciousness compared to those who did

• CSF sampling time not standardized

• CKBB >205 U/L predicted non-awakening (49 % sensitivity; 100 % specificity)

• CKBB >17 lg/L predicted poor outcome (52 % sensitivity; 98 % specificity)

• All patients with NSE > 24 lg/L remained unconscious or died at 3 months (74 % sensitivity; 100 % specificity)

• NSE and CKBB at 20–26 h post CPR were elevated in patients who did not regain consciousness compared with those who did

• Lactate >12 mmol/L predicted poor outcome (90 % sensitivity; 52 % specificity)

• Ammonia >170 lg/dL predicted poor outcome (90 % sensitivity; 58 % specificity).

• Elevated ammonia and lactate on admission were associated with poor outcome

• BNP >230 pg/mL predicts unfavorable neurological outcome (OR = 2.25 [1.05–4.81]) and death at 6 months (OR = 4.7 [1.27–17.35])

• Highest quartile BNP on admission is associated with poor outcome as compared to lowest quartile

Findings

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All studies are prospective observational unless otherwise noted

NPV negative predictive value, PPV positive predictive value, FPR false positive rate, OR odds ratio, ROSC return of spontaneous circulation, SSEP somatosensory evoked potential, TH therapeutic hypothermia, VF ventricular fibrillation

• Only 9 patients with CKBB >50U/L awakened and none regained independent ADLs

• CKBB >205 U/L predicted non-awakening at hospital discharge (100 % specificity; 48 % sensitivity).

• CSF sampling time not standardized

• Retrospective study CSF

Post cardiac arrest with CSF CKBB 351 CKBB measured Tirschwell/1997/[18]

Table 1 continued

N Population Authors/year/Ref

Bio-marker

Sample source

Findings

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serial biomarker measurements over time found that serum NSE increased over the first 72 h following CA, reaching maximal between-group difference at 24–72 h, while serum s100b had maximal between-group difference immediately after CA and then levels decreased over time [2, 4, 8]. Though elevated serum s100b also predicts poor outcome [4, 6, 8, 9], it never achieved 100 % specificity in any study and appears to be inferior to somatosensory evoked potentials (SSEP) and serum NSE to predict CA outcome [1]. Molecules of Non-CNS Origin Four prospective studies examined biomarkers from the first blood sample taken upon hospital arrival in CA patients, and found that elevated brain natriuretic peptide (BNP), ammonia, and lactate are associated with in-hospital mortality [10] and with poor 6-month outcome in comatose survivors [11–13]. These biomarkers lack replication and well-defined cutoff values. CSF Biomarkers There are few prospective studies on CSF biomarkers in CA; the largest sample size has 67 subjects. These studies suggest that elevation of CSF s100b [4, 14], NSE [15], creatinine kinase brain isoenzyme (CKBB) [15–18], and neurofilament (NFL) [19] are associated with non-awakening and poor outcome following CA. There was no standardized timing of CSF collection in these studies, and sampling time in these studies ranged from 4 h to 30 days post CA. Cardiac Arrest HIE: With TH (Table 2) Many of the clinical, electrophysiological, and molecular predictors of poor outcome following CA have decreased accuracy in patients treated with TH [20–22]. Several studies that either in part [23–25] or entirely [20, 26–28] examined TH-treated cardiac arrest patients showed that TH is associated with lower serum NSE levels and that it no longer predicts poor outcome after CA with 100 % specificity after TH [27]. Eight prospective observational studies examined this patient population. The largest studies consisted of 97–111 subjects and found that all patients with NSE >28–97 lg/L at 48 h post CA had poor outcome [24, 25, 29] and had MRI evidence of extensive brain injury [29]. Several other studies supported that higher serum s100b and NSE are associated with poor outcome, but none found 100 % specificity [23, 27, 28]. The latest prospective cohort study (n = 66) showed that 5 out of 28 CA survivors had NSE >33 lg/L at 24–48 h post CA, including 3 subjects who survived with good

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123

RCT

Pro

Tiainen/2003/[27]

Cronberg/2011/[29]

In- or out-of-hospital cardiac arrest, comatose >48 h

Daubin/2011/[24]

NSE, s100b

Bio-marker

Post cardiac arrest

Pro

Pro Pro

Stammet/2013/[28]

Rossetti/2012/[21] Mortberg/2011/[30]

NSE NSE, s100b, BDNF, GFAP

NSE, s100b

NSE, s100b

NSE

Serum Serum

Serum

Serum

Serum

Serum

Serum

Serum

Sample source

• s100b >1.0 lg/L at 2 h (93 % specificity), and s100b >0.18 lg/L at 24 h (100 % specificity) post- cardiac arrest predicted poor outcome

• NSE >4.97 lg/L at 48 h and NSE >3.22 lg/L at 96 h post cardiac arrest predicted poor outcome at 6 months (93 % specificity)

• 5 cardiac arrest survivors, including 3 with good outcome, had NSE >33 lg/L • No association between BDNF and GFAP levels and outcome

• Adding s100b to Bispectral index improved predictive value for poor outcome

• Elevated s100b and NSE levels are associated with poor outcome at 6 months

• s100b cutoff for poor outcome are as follows: s100b >1.41 lg/L at admission, s100b >0.21 lg/L at 6 h, and s100b >0.05 lg/L at 24 h post cardiac arrest (100 % specificity)

• s100b and NSE are both elevated in poor outcome group. s100b had better predictive performance than NSE

• NSE >97 lg/L predicted poor outcome (100 % PPV)

• NSE >47 lg/L predicted poor 3-month outcome (84 % specificity; 72 % sensitivity)

• Elevated NSE correlated with worse outcome at 3 months.

• s100b >0.51 lg/L at 24 h predicted poor 6-month outcome (96 % specificity; 62 % sensitivity)

• NSE >28 lg/L at 48 h predicted poor 6-month outcome (100 % specificity; 67 % sensitivity).

• NSE >27 lg/L predicted poor outcome at 6 months (100 % specificity)

• All patients with NSE >33 lg/L at 48 h died without regaining consciousness

• Elevated NSE was associated with worse outcome, DWI changes on MRI, and worse neuropathology

• TH: s100b >0.21 lg/L at 24 h (100 % specificity), s100b >0.21 lg/L at 36 h, and s100b >0.23 lg/L at 48 h (96 % specificity) predicted poor outcome

• Normothermia: NSE >13.3 lg/L at 24 h, >12.6 lg/L at 36 h, and >8.8 lg/L at 48 h had 100 % specificity for poor outcome

• TH: NSE >31.2 lg/L at 24 h, >26 lg/L at 36 h, and >25 lg/L at 48 h predicted poor outcome (96 % specificity)

• NSE did not reach 100 % specificity in TH, whereas it does in normothermia

• NSE levels were lower in TH compared to normothermia

Findings

PPV positive predictive value, Pro prospective observational, RCT randomized controlled trial, ROSC return of spontaneous circulation, TH therapeutic hypothermia, VF ventricular fibrillation, VT ventricular tachycardia

Post cardiac arrest, comatose 61 Post cardiac arrest, 31 SBP >80 mmHg x > 5 min, GCS B7, 20 min, with GCS B8

97

107 NSE, s100b

111 NSE

70

N

Shinozaki/2009/[23] Pro

Pro

In- or out-of-hospital cardiac arrest, GCS B7

Rundgren/2009/[25] Pro

Post cardiac arrest with GCS 94.5 nmol/L was independently associated with increased odds for poor outcome at 3 months (OR 1.1–9.8)

• Adding pGSN improved predictive performance of WFNS and Fisher scores for functional outcome but not for mortality

• pGSN was an independent predictor of poor functional outcome (OR = 0.957) and death (OR = 0.953) at 6 months

• pGSN were lower in SAH compared with controls

• CKBB >40l/L is associated with poor outcome at hospital discharge (100 % specificity)

• s100b is lower in patients with vasospasm (by transcranial doppler)

• NSE had no association with outcome

• all patients with s100b >1.0 lg/L had unfavorable outcome

• s100b during first 3 days of SAH is higher in those who died compared to survivors

• s100b decreased after EVD insertion

• s100b correlates positively with HH and Fisher scores

• Admission s100b >0.3 lg/L predicted unfavorable outcome and is an independent predictor of short-term survival (HR 2.2) (77.8 % sensitivity; 76 % specificity)

• higher s100b in the first week after SAH correlate with worse 6 month outcome

• Higher s100b levels correlate with worse HH grade.

• s100b is higher at 24 h, 3 and 7 days post SAH compared to controls

Findings

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123

123

Pro

Pro

Pro

Pro

Retro

Retro

Chou/2012/[50]

Chou/2011/[64]

Fassbender/2001/[52]

Mathiesen/1997/[53]

Weir/1989/[43]

Niikawa/1997/[39]

Case control

Case control

Case control

Case control

Case Control

Meta-analysis

Pro

Pro

Niskakangas/2001/[79]

Juvela/ 2009/[76]

Lanterna/2005/[78]

Leung/2002/[77]

Kay/2003/[81]

Lanterna/2005/[78]

Moussouttas/2012/[88]

Yarlagadda/2006/[84]

Other biomarkers

Study design

Author/year/Ref

Table 3 continued

696

19

72

101

105

108

Spontaneous SAH, >21 years

300

SAH with EVD, HH grade 102 3–5, endovascular aneurysm treatment

Consecutive SAH, with 3-month follow-up data

Spontaneous SAH requiring EVD

Spontaneous SAH

SAH HH grade 1-3

SAH within 48 h of ictus

Aneurysmal SAH

BNP, cTI

Epinephrine

ApoE4 genotype

s100b, ApoE

ApoE4 genotype

Serum

CSF

Blood

CSF

Blood

Blood

Blood

e2, e4–containing genotypes ApoE4 genotype

Blood

Blood

Blood

CSF

CSF, Serum

CSF, Serum

Serum

Sample source

ApoE4

WBC

Fisher grade 3 SAH treated 103 with aneurysm clipping within 24 h of ictus

IL-1Ra, TNFa

IL-1b, IL-6, TNFa

WBC

22

35

pGSN

TNFa, IL-6

52

42

Bio-marker

N

Aneurysmal SAH with vital 173 signs and CBC data (76 % missing data)

SAH patients with EVD

Aneurysmal SAH within 48 h of ictus

Spontaneous SAH, within 96 h of ictus

Spontaneous SAH, within 96 h of ictus

Population

• No standardized time of biosample collection

• cTI >0.3 mg/L (on post-SAH day 9 ± 4) is associated with death (OR = 4.9 [2.1–26.8])

• Initial BNP >600 pg/mL is associated with death (OR = 37.7 [5.0–286.2])

• Elevated CSF epinephrine within 48 h of admission is independently associated with mortality at 15 days (OR = 1.06 [1.01–1.10]) and with death and disability at 30 days (OR = 1.05 [1.02–1.09])

• Apo E4 genotype is associated with negative outcome (OR = 2.558 [1.610–4.065]) and delayed ischemia (OR 2.044 [1.269–3.291])

• Lower ApoE was associated with better clinical outcome

• ApoE is significantly lower in SAH compared to controls.

• s100b is significantly higher in SAH compared to controls

• ApoE4 genotype is associated with poor 6-month outcome (OR = 11.3 [2.2–57.0])

• Apo E4 genotype is associated with development of DIND

• Presence of Apo E4 genotype is associated with negative overall outcome

• Apolipoprotein E e2 or e4–containing genotypes were not associated with outcome or occurrence of cerebral infarction

• Presence of ApoE4 was associated with unfavorable outcome (OR = 2.8 [1.18–6.77])

• WBC counts during days 3–5, 6–8, 9–11, and 12–14 after onset of SAH were significantly higher in patients with than in patients without symptomatic vasospasm

• admission WBC >15 9 109/L shows 55 % mortality vs. 25 % mortality in the lower WBC group

• Elevated IL-1Ra and TNFa on post-SAH days 4–10 were associated with poor outcome

• IL-1Ra was higher in poor grade SAH (HH 3–4; 318 vs. 82 pg/mL)

• CSF TNFa did not show significant association with outcome

• CSF IL-6 on post-SAH day 5 is significantly elevated in poor outcome group

• IL-1b and IL-6 are significantly higher in CSF than in serum in SAH

• Novel pGSN fragments found in SAH CSF but not in controls

• CSF pGSN is decreased in SAH compared to controls.

• Serum pGSN is decreased in SAH compared to controls and decreases over time in SAH

• Neither TNFa nor IL-6 was associated with angiographic vasospasm

• IL-6 is not associated with SAH outcome

• Elevated TNFa over post-SAH days 0–14 is independently associated with poor long-term outcome

Findings

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Pro prospective observational, Retro retrospective, CTRL control subjects, CBC complete blood count, HH grade hunt and hess grade, WFNS World Federation of Neurosurgeons Classification, DIND delayed ischemic neurological deficit, DCI delayed cerebral ischemia, mRS modified Rankins score, OR odds ratio

• Peak cTI and GCS on presentation independently predicted in-hospital mortality

• cTI not independently predictive of 3-month outcome by mRS

Blood Retro Ramappa/2008/[83]

SAH diagnosed by CT scan 83 or CSF, SAH ICD-9 code, with cTI measured

cTI

• Peak cTI was independently predictive of death or severe disability at hospital discharge (OR = 1.4 [1.1–1.9]) Serum cTI Pro Naidech/2005/[82]

Spontaneous non-traumatic 253 SAH

Sample source Study design Author/year/Ref

Table 3 continued

Population

N

Bio-marker

Findings

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outcome (CPC 1–3) [21]. This study raised caution that NSE >33 lg/L does not have 100 % specificity for poor outcome after cardiac arrest in the era of TH. s100b may have better predictive value than NSE for poor outcome in this patient population, but studies reported a wide range of optimal cutoff values for this biomarker [23, 28, 30]. Biomarker combinations such as s100b plus NSE [26] or molecular biomarkers plus physiological markers [28] may improve prediction precision for outcome after cardiac arrest following TH, but all require further validation. Subarachnoid Hemorrhage (Table 3) Molecules of CNS Origin Several prospective studies found that serum s100b is elevated in SAH compared to healthy controls [31] and that elevated blood s100b is associated with initial neurologic severity and long-term outcome [31–33]. However, studies to date are relatively small and have wide standard deviation in s100b levels. Furthermore, external ventricular drain (EVD) insertion in SAH is associated with decreased blood s100b [32], which is an important confounding factor. One study suggested that lower serum s100b is associated with vasospasm while higher serum s100b is associated with mortality [33], which introduces contradicting associations between s100b and SAH. Elevation of CSF CKBB, a marker of astrocytic cell death, has been linked to poor short-term SAH outcome [34]. Biomarkers of Inflammation Inflammation may play a role in secondary brain injury and outcome after SAH [35, 36]. Several prospective cohort studies have found that blood leukocyte elevations are associated with vasospasm [37–39] and poor SAH outcome [37–45], though there are reports to the contrary [46]. Elevation of blood CRP and adhesion molecules, e.g., soluble ICAM-1, are associated with DCI [47] and poor outcome in SAH [48], but other moderately sized studies report the contrary [48]. Elevation of serum von Willebrand factor (vWf), a marker of endothelial cell activation, is associated with DCI [48, 49] and worse outcome after SAH [48], but these results have yet to be validated. Pro-inflammatory cytokines have been implicated in DCI and brain injury after SAH. Human studies found that elevated serum TNFa [50] is associated with poor outcome and elevated blood soluble endoglin (sEng), blood transforming growth factor-b (TGFb), and elevated CSF TNFa, IL-6, and IL-1Ra are associated with vasospasm [51–54]. However, some studies report contrary results with blood TNFa [46, 52] and IL-6 [50]. Studies examining CSF

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cytokine profiles in SAH are all small. While all studies suggest elevated CSF proinflammatory cytokines such as TNFa, IL-1Ra, and IL-6 and soluble TNFa receptor I (sTNFR-1) which are associated with initial SAH clinical severity, there are conflicting reports on the associations between CSF cytokines and SAH outcome [52, 53, 55]. An important consideration is that intracranial hypertension causes CSF IL-6 elevation [56], and this may confound studies of CSF IL-6 levels in SAH and other conditions associated with increased ICP. Metalloproteinases (MMPs) can disrupt neuron-extracellular matrix interaction leading to brain injury [57, 58], and elevated blood and CSF MMP-9 levels have been linked with vasospasm [59] and poor SAH outcome [38]. MMPs can cleave plasma-type gelsolin (pGSN) [60], which is thought to mitigate pro-inflammatory effects of cytokines [61, 62] and may be neuroprotective [63]. SAH is associated with decrease pGSN in blood and CSF; decreased blood pGSN may be associated with poor outcome [64, 65], and novel pGSN breakdown fragments have been identified in SAH CSF [64]. Vasoactive Biomarkers Activity of endopeptidases such as MMPs [66, 67] produce Endothelin-1 (ET-1), the strongest vasoconstrictor in the CNS. ET-1 is implicated in the pathogenesis of vasospasm [68, 69]. Several human studies link elevated CSF ET-1 levels with vasospasm [70–72], though other studies do not [73, 74]. A randomized clinical trial showed that ET-1A antagonist reduced the incidence of angiographic vasospasm but not DCI or poor outcome in SAH [75], raising new questions about the role of ET-1 in SAH. Other Biomarkers ApoE genotype is associated with outcome after brain injury. Several moderately sized studies found conflicting associations between ApoE4 genotype and SAH outcome [76–79]. A meta-analysis of eight studies (n = 696) found ApoE4 is associated with worse SAH outcome [80]. One small study found decreased CSF ApoE protein is associated with higher SAH severity and less favorable outcome [81]. SAH is associated with cardiac dysfunction. Epidemiologic studies describe a positive association between elevated cardiac troponin-I (cTI) and initial SAH clinical severity as well as death or severe disability at discharge [82, 83], though one large study did not support this conclusion [84]. Elevation of another cardiac-derived peptide, BNP, has been linked to hyponatremia [85, 86], DCI [87], and mortality after SAH [84]. It is not known whether the association between cTI and BNP and SAH outcome reflect the effect of cardiac injury on SAH outcome. CSF

123

epinephrine elevation in the first 48 h of SAH has also been independently linked to higher SAH mortality and disability [88]. Acute Ischemic Stroke (Table 4) Advances in AIS therapies have created the need for fast and accurate biomarkers that can reflect extent of real-time brain tissue injury to guide revascularization therapy and to predict the risk of secondary hemorrhagic transformation— a ‘‘brain troponin’’. Molecules of CNS Origin Small (n < 50) prospective studies found that blood s100b, NSE [89], and GFAP [90]—all correlate positively with total infarct volume and outcome after AIS [89, 90], but these biomarkers did not add to the prognostic accuracy of existing clinical predictors. The strongest AIS biomarker studies to date studied patients with middle cerebral artery (MCA) territory infarcts and found that blood s100b at 48–96 h after AIS had the highest predictive value for functional outcome and for total infarct volume [91], and that low serum s100b was associated with early MCA recanalization [92]. Elevated s100b is also associated with the malignant cerebral edema after AIS [93, 94]. Biomarkers of Inflammation and BBB Injury C-reactive protein (CRP) is an acute-phase response protein which may itself have pro-inflammatory effects and increase secondary brain injury [95]. Elevated serum CRP in acute and subacute phases (0–15 days) of AIS is independently associated with mortality or stroke recurrence in large cohort studies [96–98]. One large (n > 100) study found that hyperacute serum CRP elevation was associated with death after IV thrombolysis, regardless of vessel recanalization, and that serum CRP correlated with 3-month modified Rankin scores (mRS) in a dose-dependent fashion [99]. Several other studies [100–102], but not all [103] supported the correlation of hyperacute serum CRP and AIS mortality. The cutoff values for CRP in these studies vary widely. Measurement imprecision and confounding by infection and non-specific inflammation are important limitations in its utility as an AIS biomarker. General leukocyte elevations [104, 105] and elevation of visfatin, a pro-inflammatory factor, [106] also are associated with poor AIS outcome. Leukocytes are a major source of MMP release following ABI [107]. MMPs are implicated in numerous pathogenic mechanisms in AIS including BBB disruption [108, 109], progression of cerebral edema, and worsening of cerebral ischemic injury [110]. In AIS, higher baseline blood MMP-9

Pro

Pro

Pro

Pro

Pro

Foerch/2004/[93]

Missler/1997/[89]

Foerch/2005/[91]

Herrmann/2000/[90]

Foerch/2003/[92]

AIS B5 h of onset with M1 occlusion

Anterior circulation AIS

AIS within 6 h of onset

AIS diagnosed by CT

AIS within 6 h of onset with proximal MCA occlusion

AIS

Population

Pro

Pro

Pro

Pro

Retro

Montaner/2006/[99]

Winbeck/2002/[102]

Topakian/2008/[103]

Shantikumar/2009/[98]

Elkind/2006/[96]

Retro

Nested Pro

Idicula/2009/[101]

Huang/2012/[97]

RCT

Den Hertog/2009/[100]

Age >40, reside in northern Manhattan >3 months

Age >40, reside in northern Manhattan >3 months

AIS surviving >30 days

741

467

394

hs-CRP

hs-CRP

CRP

CRP

AIS in MCA territory treated with IV tPA B6 h of onset, exclude CRP >6 mg/dL

111

CRP

143

CRP

CRP

CRP

s100b

s100b, GFAP

s100b

s100b, NSE

s100b

s100b, OCLN, CLDN5, ZO1

Bio-marker

498

561

23

32

39

44

51

458

N

AIS B12 h onset, NOT treated 127 with IV tPA

AIS in MCA territory treated with IV tPA within 3 h; exclude inflammatory disease or infection

AIS B24 h onset

AIS B12 h onset, no liver disease, prior mRS 3 mg/L was associated with higher mortality at 3 months and all-cause mortality (HR = 6.48 [1.41–29.8])

• Highest quartile of hs-CRP is associated with increased risk of stroke recurrence (HR 2.08 [1.04–4.18]) and with combined outcome of stroke, MI, or vascular death (HR = 1.86 [1.01–3.42])

• CRP is independently predictive of mortality after adjusting for conventional risk factors

• CRP higher in subject who died compared to survivors

• CRP level was not associated with NIHSS within 24 h or outcome at 3 months

• CRP measured before tPA administration

• CRP >0.86 mg/dL 24 h and at 48 h post-stroke are associated with death and lower likelihood of event-free survival at 1 year

• CRP is independently associated with mortality at 3 months (OR = 8.51 [2.16–33.5]).

• CRP was higher in those who died after thrombolysis compared with survivors (0.85 vs. 0.53 mg/dL)

• CRP measured before tPA administration.

• CRP >10 mg/L is independently associated with high NIHSS and high long-term mortality at 2.5 years

• CRP >7 mg/L is associated with poor outcome (OR = 1.6 [1.1–2.4]) and death (OR = 1.7 [1.0–2.9])

• CRP measured within 12 h of stroke onset

• From RCT for paracetamol for ischemic stroke.

• s100b 1.03 lg/L at 24 h post AIS predicted malignant infarction (94 % sensitivity; 83 % specificity)

• Mean s100b were higher in patients with malignant cerebral edema defined.

• Patients with clinical deterioration due to hemorrhagic transformation had higher s100b, OCLN, and CLDN/ZO1 ratio

Findings

Neurocrit Care

123

123

Pro

Pro

Pro

Case control

Pro

Pro

Pro

Pro

Pro

Castellanos/2003/[116]


Moldes/2008/[119]

Serena/2005/[118]

Montaner/2003/[114]

Montaner/2001/[115]


Guo/2011/[57]

Yin/2013/[106]

Case control

Pro

Pro

Haapaniemi/2000/[122]

Lampl/1997/[126]

Chiquete/2013/[124]

Other biomarkers

Study design

Authors/year/Ref

Table 4 continued

AIS

AIS within 18 h from onset

AIS

AIS

First onset AIS

AIS treated with IV tPA by ECASS II criteria

Cardioembolic AIS in MCA territory

AIS in MCA territory treated with IV tPA within 3 h

Malignant MCA infarction, 52 mg/L predicted 1-year mortality (73 % sensitivity; 65.2 % specificity)

• pGSN was independent predictor for 1-year mortality

• pGSN decreased in AIS compared to controls

• Samples from first 24 h of stroke onset obtained

• 71 of the patients were treated within 3 h of AIS onset. Similar results were found in these patients

• c-Fn was independently associated with hemorrhagic transformation in multivariate analysis (OR = 2.1)

• Elevated baseline MMP-9 was associated with late-hemorrhagic transformation in multivariate regression (OR = 9)

• MMP-9 was predictive of hemorrhagic transformation in multivariate model (OR = 9.62)

• Higher baseline (pre-tPA) MMP-9 was associated with hemorrhagic transformation in dose-dependent fashion

• c-Fn >16.6 lg/mL predicted malignant infarction (90 % sensitivity; 100 % specificity; 89 % NPV; 100 % PPV)

• c-Fn and MMP-9 were significantly higher in patients with malignant MCA infarcts

• ET-1 >5.5 fmol/mL before tPA was independently associated with severe brain edema in multivariate analysis

• ET-1 and c-Fn significantly higher in those with severe cerebral edema

• ET-1, MMP-9, and c-Fn measured upon admission before tPA bolus

• c-Fn C3.6 lg/mL predicted hemorrhagic transformation (100 % sensitivity; 60 % specificity; 20 % PPV; 100 % NPV)

• MMP-9 C140 lg/L predicted hemorrhagic transformation (92 % sensitivity; 74 % specificity; 26 % PPV; 99 % NPV)

MMP-9 C140 lg/L predicted hemorrhagic transformation (61 % PPV; 97 % NPV)

Findings

Neurocrit Care

AF atrial fibrillation, NPV negative predictive value, PPV positive predictive value, Pro prospective observational, RCT randomized controlled trial, Retro retrospective, CTRL control subjects, NIHSS NIH stroke scale, OR odds ratio

• Highest d-dimer tertile group had worse outcome compared to middle and lowest tertiles

• d-dimer level at hospital admission is independently associated with infarct volume Plasma Retro Matsumoto/2013/[125]

AIS from non-valvular AF within 48 h of onset

124

d-dimer

Findings Study design Authors/year/Ref

Table 4 continued

Population

N

Bio-marker

Sample source

Neurocrit Care

levels are associated with thrombolysis failure [111] and with increased risk of parenchymal hematoma either with [112–114] or without IV tPA [115, 116]. Higher MMP-9 mRNA level is associated with poor outcome and mortality after AIS [117]. Elevated serum MMP-9, c-fibronectin (cFn), and ET-1 have been associated with malignant cerebral edema after AIS [118, 119], though the data on MMP-9 is inconsistent [119]. The association of blood c-Fn and malignant cerebral edema after AIS is consistent across two moderately sized studies [118, 119]. Plasma c-Fn level also is associated with hemorrhagic transformation in tPA-treated AIS cohort. Pre-tPA blood MMP-9 C140 ng/mL with c-Fn C3.6 lg/mL predicts hemorrhagic transformation with 87 % specificity and PPV of 41 % [94]. Several studies have found contradictory results regarding whether ET-1 levels, in plasma or CSF, are elevated after AIS [120, 121]. The largest study to date found no association between plasma ET-1 levels and AIS or its outcome [122]. Other potential biomarkers of BBB injury include tight junction proteins such as occludin (OCLN), claudin 5 (CLDN5), and zonula occudens 1 (ZO1). Elevated plasma levels of these proteins are associated with hemorrhagic transformation of AIS [123]. Other Biomarkers A large prospective registry found that low serum uric acid level in the first 7 days of AIS is independently associated with good short-term outcome [124]. Admission level of serum d-dimer has also been linked with total infarct volume and outcome at hospital discharge in AIS from atrial fibrillation [125]. Intracerebral Hemorrhage (Table 5) Molecules of CNS Origin Four prospective observational studies (total of 236 subjects) examined s100b in ICH. Three of the four studies found that elevated serum s100b is associated with early deterioration and poor ICH outcome at hospital discharge [126–128]. One found that serum NSE level was associated with poor 3-month ICH outcome while s100b was not [129]. In these studies, serum s100b levels were found to correlate with Glasgow Coma Scale (GCS), ICH volume, and the presence of intraventricular hemorrhage (IVH). Elevated serum myelin basic protein (MBP) has been reported in TBI and ICH [130, 131]. Elevated serum tau protein [132], phosphorylated axonal neurofilament subunit H (pNF-H) [133], and blood glutamate [134] were also found to predict poor outcome in ICH. However, it is unclear whether the addition any of the above biomarkers improved predictive value of known clinical predictors of ICH outcome [126, 128, 133].

123

123

Pro

Pro

Pro

Pro

Case control

Hu/2010/[127]

Delgado/2006/[126]

Brea/2009/[129]

James/2009/[128]

Cai/2013/[133]

Pro

Pro

Retro

Pro

Pro

Pro Posthoc analysis

Pro

Pro

Leira/2004/[137]

Di Napoli/2011/[135]

Agnihotri/2011/[136]

Zhao/2013/[149]

Castillo/2002/[134]

Wang/2011/[139]

Li/2013/[148]

Hernandez-Guillamon/ 2012/[140]

Biomarkers of inflammation

Pro

Study design

Hu/2012/[132]


Authors/year/Ref

ICH within 48 h of onset

66 ICH, 58 CTRL

59

60

ICH within 24 h of onset ICH within 24 h of onset

124

132 ICH, 68 CTRL

423

210

266

112 ICH, 112 CTRL

28

44 ICH, 224 AIS

78

86 ICH, 30 CTRL

176

N


Basal ganglia ICH within 6 h of onset

Spontaneous ICH

ICH


Basal ganglia ICH

ICH

ICH and AIS

ICH

Basal ganglia ICH


Population

Table 5 Biomarkers for intracerebral hemorrhage

Plasma

Blood

Plasma

Blood

Blood

Blood

Plasma

Blood

Blood

Blood

Plasma

Serum

Sample source

VAP-1/SSAO

Plasma

MMP-3, MMP- Plasma 9

sICAM-1, sEselectin

Glutamate, TNFa

pGSN

WBC

WBC, CRP, Glucose

Neutrophils, fibrinogen

pNF-H

s100b, BNP

NSE

s100b

s100b

Tau

Bio-marker

• VAP-1/SSAO activity 12.4 lg/L and MMP-9 >192.4 lg/L were associated with poor outcome in multivariate analysis

• Elevated MMP-3 was independently associated with peri-hematoma edema volume

• Higher levels of sICAM-1 and sE-selectin were found in patients who had a poor outcome at hospital discharge.

• TNFa correlated with volume of peri-hematoma edema

• Glutamate level was an independent predictor of poor outcome

• pGSN improved prognostic value of NIHSS for poor outcome but not for mortality

• pGSN is an independent predictor of 6-month mortality and unfavorable outcome in multivariate analysis

• pGSN was lower in ICH compared to controls

• Change in WBC (difference between max WBC in first 72 h and WBC on admission) correlated with worse discharge disposition and decline in modified Barthel Index at 3 months

• Only CRP remained significantly related to mortality when adjusted for ICH score and the combination of ICH score and CRP had the best predictive ability

• Higher WBC, CRP, and glucose were significantly related to mortality

• Higher neutrophil count (OR = 2.1) and fibrinogen >523 mg/dL (OR = 5.6) on admission were independently associated with early neurological deterioration

• Addition of pNF-H did not improve predictive value of NIHSS

• pNF-H is an independent predictor of 6-month mortality (OR = 1.287), 6-month unfavorable outcome (OR = 1.265) and early neurological deterioration (OR = 1.246)

• pNF-H is higher in ICH compared to controls

• Inclusion of biomarkers added little to the predictive power of ICH score

• s100b and BNP levels correlated with outcome at hospital discharge

• NSE elevation at 24 h post ICH was independently associated with poor outcome (OR = 2.6 [1.9–15.6])

• s100b was higher in patients who deteriorated early and in patients with a poor neurological outcome

• s100b >192.5 pg/mL predicted 1-week mortality (93.8 % sensitivity; 70.4 % specificity)

• s100b is independently associated with mortality at 1 week (OR = 1.046)

• s100b was significantly associated with IVH, GCS scores, and ICH volumes

• Addition of tau improved prognostic value of NIHSS for outcome but not for mortality

• Tau >91.4 pg/mL predicted poor 3-month outcome (83.6 % sensitivity; 75.8 % specificity)

Findings

Neurocrit Care

Pro

Retro

Pro

Case control

Pro

Fang/2005/[141]

Diedler/2009/[138]

Gu/2013/[142]

Huang/2013/[143]

Zhang/2013/[144]

Pro

Pro

Pro

Pro

Retro

Pro

Pro

Pro

Case control

Chiu/2012/[150]

Delgado/2006/[126]

Rodriguez-Luna/2011/ [151]

Ramirez-Moreno/2009/ [152]

Hays/2006/[153]

Chen/2011/[158]

Wang/2012/[155]

Huang/2009/[154]

Zheng/2012/[156]

Other biomarkers

Study design

Authors/year/Ref

Table 5 continued

ICH

Basal ganglia ICH


ICH

ICH


Supratentorial ICH within 6 h of onset

ICH

ICH within 24 h of onset, >16years old

Basal ganglia ICH

Basal ganglia ICH


Supratentorial ICH

ICH

Population

79

36 ICH, 10 CTRL

60 ICH, 60 CTRL

64 ICH, 114 CTRL

235

88

108

98

170

92 ICH, 50 CTRL

128 ICH, 128 CTRL

85 ICH, 85 CTRL

113

43

N

miRNAs

Microparticles

Nuclear DNA

Oxidative markers

cTn1

LDL-C

LDL-C

d-dimer

d-dimer

Leptin

Visfatin

Visfatin

CRP

IL-11

Bio-marker

Blood

Plasma, CSF

Plasma

Blood

Blood

Serum

Serum

Plasma

Serum

Plasma

Plasma

Plasma

Blood

Plasma

Sample source

• Patients with hematoma expansion had different expression pattern of miRNAs (19 with increased expression, 7 with decreased expression)

• Controls have suspected SAH

• Plasma and CSF microparticles levels were associated with GCS score, ICH volume, IVH, and survival

• Nuclear DNA >18.7 lg/L on presentation was associated with poor outcome at discharge (63.6 % sensitivity; 71.4 % specificity)

• Nuclear but not mitochondrial DNA correlated with GCS and ICH volume on presentation

• 8-OHdG elevation was independently associated with 30-day lower Barthel index but not with outcome by mRS

• Measured 8-OHdG, G6PD, GPx, MDA, vitamin E, vitamin A

• Blood collected within 3 days of ICH

• Elevated cTn1 was independent predictor of in-hospital mortality

• LDL-C correlated with NIHSS, GCS, and ICH volume

• Low LDL-C levels were independently associated with death after ICH in multivariate analysis (HR = 3.07)

• Lipid profile measured in first hour after admission

• Lower LDL-C levels were associated with hematoma growth, early neurological deterioration and 3-month mortality but not with NIHSS or ICH volume

• d-dimer >1,900 lg/L is independently associated with early neurological deterioration (OR = 4.5) and with mortality (OR = 8.75)

• d-dimer levels were associated with presence of IVH or SAH extension

• d-dimer is independently associated with 30-day mortality (OR = 2.72)

• Leptin on admission is independent predictor of 6-month mortality and unfavorable outcome

• Leptin higher in ICH compared to controls

• Visfatin correlated with NIHSS and is independent predictor for 6-month mortality and unfavorable outcome

• ICH patients had higher visfatin compared to controls

• Visfatin level was independent predictor of hematoma growth. (OR = 1.154 [1.046–3.018]) and of early neurological deterioration (OR = 1.195 [1.073–3.516])

• Visfatin was higher in ICH compared to controls

• CRP is independent predictor of poor long-term functional outcome

• plasma IL-11 higher in non-survivors compared to survivors

• samples collected in first 4 days of ICH

Findings

Neurocrit Care

123

123

Biomarkers of Inflammation Elevated leukocyte or neutrophil count [135–137], CRP [135, 138], and adhesion molecules such as soluble ICAM1, soluble E-selectin [139], and vascular adhesion protein-1 (VAP-1) [140] have been associated with increased ICH mortality and worse ICH outcome. Elevated cytokines such as TNFa and IL-11 have also been associated with perihematoma edema and ICH mortality [134, 141]. Blood adipokines such as visfatin and leptin are found to be elevated in basal ganglia ICH and are associated with hematoma expansion, early neurological deterioration, and poor long-term outcome [142–144]. Plasma MMP-9 levels have been associated with ICH peri-hematoma edema [145, 146] and ICH enlargement [148], while MMP-3 is associated with poor ICH outcome [146, 148]. Decreased antiinflammatory marker pGSN has also been associated with poor ICH outcome and mortality [149].

• Copeptin did not improve prognostic value of NIHSS

Other Markers

Pro prospective observational, RCT randomized controlled trial, Retro retrospective, CTRL control subjects, OR odds ratio

• Copeptin level is an independent predictor for 1-year mortality, poor outcome, and early neurological deterioration Plasma Copeptin 89 ICH, 50 CTRL Pro Zhang/2012/[157]

Basal ganglia ICH

Sample source Bio-marker N Population Study design Authors/year/Ref

Table 5 continued

Findings

Neurocrit Care

Molecules from the coagulation cascade such as d-dimer [126, 150] and fibrinogen [137] have been associated with increased mortality and early deterioration after ICH. Decreased serum LDL-C levels also correlate with hematoma expansion, ICH volume, and ICH mortality [151, 152]. Elevated cTn-I has been associated with increased in-hospital ICH mortality [153]. Emerging data suggest some novel biomarkers such as blood and CSF microparticles [154], blood nuclear DNA [155], blood microRNA expression patterns [156], plasma copeptin [157], and oxidative marker blood leukocyte 8-hydroxy-20 -deoxyguanosine (8OHdG) [158] may be associated with ICH volume, ICH expansion, mortality, and outcome. Of the above candidate biomarkers of ICH outcome and secondary deterioration, none have been validated or proven to improve the predictive performance of existing clinical predictors of ICH outcome. Traumatic Brain Injury (Table 6) Molecules of CNS Origin Elevated blood and urine levels [159] of s100b and its isoforms s100A1B and s100BB are associated with poor outcome in TBI [160–169], though this may not hold true in the case of mild TBI [170] or severe TBI patients treated with ICP-targeted therapy [171]. In a study of 265 patients, blood s100b levels drawn between 12 and 36 h after injury were associated with neurological outcome. The area under curve (AUC) of s100b levels during the first 48 h after injury had the strongest relationship to neurological outcome [166]. Elevated blood NSE levels have been linked to

Pro

Pro

Pro

Pro

Pro

Pro

Pro

Pro

Pro

Pro

Pro

Retro

Pro

Case control

Case control

Pro

Metting/2012/[170]

Vos/2010/[178]

Vos/2004/[172]

Wiesmann/2009/[167]

Pelinka/2004/[168]

Nylen/2008/[167]

Nylen/2006/[179]

Olivecrona/2009/[171]

Topolovec-Vranic/2011/[175]

Rainey/2009/[165]

Thelin/2013/[166]

Rodriguez-Rodriguez/2012/[159]

Kay/2003/[81]

Mondello/2012/[183]

Brophy/2011/[184]

Study design

Okonkwo/2013/[180]


Authors/year

Table 6 Biomarkers for traumatic brain Injury

94

215

N

141

48

59

59

92

60

85

Severe TBI GCS B8

severe TBI

TBI with GCS < 8

Severe TBI

Severe TBI

86 (blood), 59 (CSF)

95

27 TBI, 28 CTRL

55

265

Severe TBI within 24 h 100

Mild TBI within 4 h

Severe TBI

Severe TBI

Severe TBI

TBI within 12 h

Mild, moderate, & severe TBI

Severe TBI

Moderate & severe TBI 79

Mild TBI

Mild, moderate & severe TBI

Population

UCH-L1

UCH-L1

ApoE, s100b

s100b

s100b

s100b

s100b, NSE

s100b, NSE

GFAP

s100b, s100a1b, s100bb

s100b, GFAP

s100b, GFAP

s100b, NSE, GFAP

s100b, GFAP

s100b. GFAP

GFAP-BDP

Bio-marker

• Levels of s100b between 12 and 36 h of injury were correlated with 6–12 month GOS and remained significantly related to outcome after adjustment for injury severity factors

• s100b >0.53 lg/L predicted poor outcome (>80 % sensitivity; 60 % specificity)

• s100b at 24 h post injury were higher in patients with unfavorable outcome.

• NSE is independently associated with poor cognitive outcome at 6 weeks post injury

• s100b predicted poor cognitive outcome at 1 week

• Levels of NSE and s100b were not significantly related to outcome at 3 or 12 months

• Levels of GFAP were independently associated with 1-year outcome

• Levels of s100b, s100a1b, and s100bb were all related to 1 year GOS

• GFAP and s100b were higher in non-survivors and predicted mortality

• Levels of s100b at 24 h post injury had the highest correlation

• levels of s100b and GFAP were correlated with 6 month GOS

• s100b >1.13 lg/L predicted death with 100 % discrimination.

• s100b, NSE, and GFAP were all higher in non-survivors and in those with poor 6-month outcome.

• Levels of s100b and GFAP on admission were associated with poor outcome at 6 months and with mortality at 6 months even after adjusting for injury severity

• Levels of GFAP but not s100b were related to outcome, but the PPV was not high (5.22 lg/L predicted death with OR = 4.8

Blood, CSF • Blood and CSF levels of UCH-L1 were higher in patients with lower GCS, in patients who died, and in patients with unfavorable outcome. Levels at 6 h had the highest correlation

CSF

• Serum s100b >0.461 lg/L (88.4 % specificity) and urine s100b >0.025 lg/L (62.8 % specificity) predicted mortality

Blood urine • Blood and urine s100b at 24 h postTBI were significantly higher in non-survivors

Blood

Blood

Blood

Blood

Blood

Blood

Blood

Blood

Blood

Blood

Blood

Blood

Sample source

Neurocrit Care

123

123

Pro

Pro

Pro

Pro

Case control

Pro

Papa/2009/[181]

Papa/2012/[185]

Liliang/2010/[177]

Pineda/2007/[186]

Brophy/2009/[187]

Mondello/2010/[188]

Pro

Pro

Pro

Stein/2012/[194]

Tasci/2003/[196]

Antunes/2010/[197]

Pro

Czeiter/2012/[190]

N

severe TBI

mild, moderate, & severe TBI

TBI with hemorrhagic contusions


severe TBI


Severe TBI

Severe TBI

Severe TBI

severe TBI

Mild & moderate TBI GCS 9-15

45

206

30

48

68

127

40 TBI, 24 CTRL

38

41

34

96 TBI, 199 CTRL

TBI GCS B8 with EVD 41 TBI, 25 CTRL

Population

Blood

GFAP, UCH-L1, SBDP145

UCH-L1, GFAP

IL-6

IL-1

IL-8, TNFa

IL-10, TNFa

Serum, CSF

Blood

Blood

Blood

Serum

Blood

SBDP145, SBDP120 CSF



Tau

Blood

CSF

UCH-L1

UCH-L1

Sample source

Bio-marker

• In combination, the IMPACT core model with the first CSF GFAP value, the first serum GFAP value, and the first CSF SBDP145 value performed the best

• When included in a model with IMPACT predictors of outcome, serum GFAP during first 24 h and the first CSF UCH-L1 value obtained were significantly related to mortality and only serum GFAP during first 24 h was significantly related to unfavorable outcome

• GFAP, UCH-L1, and SBDP145 all had at least one measure that was significantly related to unfavorable outcome

• For predicting complete recovery, UCH-L1 in combination with GFAP was not better than GFAP alone. For predicting favorable vs. unfavorable outcome, UCH-L1 is marginally better than GFAP and both together are better than either alone

• UCH-L1 levels were poorly predictive of complete recovery but better at predicting poor outcome

• Levels of UCH-L1 were higher with moderate–severe than with mild TBI

• IL-6 levels at 6 h were higher in patients who would subsequently clinically deteriorate due to evolving contusions

• IL-1 levels within 6 h correlated with the initial injury severity (GCS) and with GOS, but timing of the GOS is not described

• High levels of both IL-8 and TNFa predicted subsequent development of intracranial hypertension (specificity was high but sensitivity was low)

• Levels of IL-10 but not TNFa were related to mortality, even when adjusted for injury severity characteristics

• SBDP145 within 24 h of injury correlated with GCS score

• SBDP145 >6 lg/L (OR = 5.9) and SBDP 120 > 17.55 lg/L (OR = 18.34) predicted death

• SBDP145 and 150 levels were higher in patients with worse GCS and longer ICP elevation

• SBDP145 and 150 levels were significantly related to outcome at 6 months

• Remained significant when adjusted for injury severity factors

• Tau levels were significantly higher in patients with a poor outcome

• UCH-L1 was associated with severity of injury in TBI

• UCH-L1 within 4 h of injury distinguished TBI from uninjured controls (AUC = 0.87 [0.82–0.92])

• Levels of UCH-L1 were higher in patients with a lower GCS at 24 h, post-injury complications, in those died within 6 weeks, and in those with poor outcome at 6 months

• UCH-L1 was higher in TBI compared with controls at all time points up to 168 h

Findings

Pro prospective, PPV positive predictive value, Retro retrospective, CTRL control subjects, GOS Glasgow outcome scale, OR odds ratio, PPV positive predictive value

Pro

Diaz-Arrastia/2013/[189]

Combinations of markers

Pro

Schneider Soares/2012/[195]

Inflammatory markers

Study design

Authors/year

Table 6 continued

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poor outcome in severe [172–174] as well as mild TBI [175], though results have been inconsistent [163, 171, 176]. Elevations in serum and CSF MBP, CKBB [131], and tau protein [177] were also found in TBI. Several studies found elevated blood GFAP levels to predict TBI outcome [167, 168, 172, 178, 179], including mild TBI [170]. GFAP is not elevated in polytrauma without TBI and therefore may have more CNS-specificity compared to s100b or NSE. Limitations in the utility of GFAP as a biomarker include high variability in reported blood GFAP levels after TBI and the rapid decline of blood GFAP levels after TBI requiring measurements within the first hours of TBI [167]. GFAP breakdown products (GFAP-BDP) are emerging as a potential TBI biomarker. In a study of 215 patients with mild to severe TBI, GFAPBDP >0.68 lg/L within 24 h of injury was associated with acute traumatic lesions on the CT and with unfavorable 6-month outcome [180]. Two highly neuron-specific protein biomarkers, ubiquitin c-terminal hydrolase L1 (UCH-L1) and alpha-II spectrin breakdown products (SBDP), are emerging as promising candidate TBI biomarkers. UCH-L1 is involved in the ubiquitination of abnormal proteins for proteasome degradation and is present in almost all neurons. UCH-L1 elevation is detected soon after TBI in both CSF and serum [181], and elevated UCH-L1 levels are associated with lower GCS and poor outcome after TBI [181–185]. AlphaII spectrin is a protein primarily expressed in neurons but not in glia and is most concentrated in axons. It is broken down by the calpain and caspase-3 cysteine proteases, and its breakdown products SBDP120, SBDP145, and SBDP150 in the CSF of TBI patients are associated with worse GCS, longer ICP elevation, and poor outcome following TBI [186–188]. The high neuronal specificity and early detection of these markers make them promising future candidate biomarkers for TBI. Combinations of biomarkers may have better prognostic value than individual biomarkers. In a study of 206 subjects, GFAP and UCH-L1 together had better sensitivity and specificity to discriminate between TBI patients and healthy controls than either biomarker alone. The combination also had better sensitivity and specificity for predicting 3-month outcome [189]. Other combinations of biomarkers found to have prognostic value for TBI outcome include GFAP, UCH-L1, and SBDP145 [190], and NSE and s100b [191].

mortality [195]. Other proinflammatory cytokines such as IL-1 and IL-6 have been linked with initial injury severity and with deterioration following TBI [196, 197], though there are conflicting reports for IL-1 [198]. Decreased levels of pGSN also are linked with mortality and worse outcome in TBI [199, 200]. Though numerous candidate biomarkers have a positive association to TBI outcome, it is not clear that they add significant prognostic value to existing clinical predictors. The heterogeneity of TBI pathophysiology will require large numbers of patients to confirm the clinical usefulness of any of these biomarkers. Combining biomarkers into a panel may provide more information than individual biomarkers.

Limitations Studies to date have identified numerous candidate molecular biomarkers for prognostication and prediction of secondary complications in ABI, but few have been validated in large cohorts and none have translated into routine clinical use in neurocritical care. Major barriers to validate existing biomarkers include high biological and treatment heterogeneity and the lack of standardization in phenotype definition and in methods of sample collection, processing, storage, and biomarker assay. The formation of large collaborative consortiums and multidisciplinary research teams are vital towards the successful identification and validation of high-fidelity biomarkers, particularly in the era of multiplex technology allowing high-throughput and multiplex screening of potential biomarkers [201].

Recommendations (and see Summary Statement) 1.

2.

3.

Biomarkers of Inflammation Leukocyte elevation is associated with poor outcome after TBI [192, 193]. Elevation of blood cytokines TNFa and IL-8 levels are associated with impending intracranial hypertension and cerebral hypoperfusion in TBI [194], while elevation of IL-10 is independently linked to TBI

In comatose post-cardiac hypoxic-ischemic encephalopathy (HIE) patients not treated with TH, we suggest the use of serum NSE in conjunction with clinical data for neurologic prognostication (Weak recommendation, Moderate quality of evidence). We recommend against the use of serum NSE for prognostication in HIE treated with TH (Strong Recommendation, Moderate quality of evidence). We recommend against the routine use of molecular biomarker for outcome prognostication in AIS, SAH, ICH, or TBI (Strong Recommendation, Low quality of evidence).

Additional Conclusions •

Routine use of CSF biomarkers for prognostication in comatose post-cardiac hypoxic-ischemic encephalopathy

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•

•

•

(HIE) patients not treated with TH does not appear to provide valuable information. (Low quality of evidence) There is a limited role for routine use of blood or CSF molecular biomarkers to predict vasospasm and DCI in SAH. (Low quality of evidence) Plasma MMP-9 and c-Fn can be used in conjunction with clinical data to support prediction of hemorrhagic transformation in AIS patients treated with IV tPA within 3 hours of onset. (Low quality of evidence) Routine use of molecular biomarkers does not help predict secondary deterioration after ICH or TBI. (Low quality of evidence)

Acknowledgments Sherry H-Y. Chou is funded by NIH Grant # K23-NS073806 and has received research support from the American Heart Association (Grant # 10CRP2610341). She receives stipend for service as a clinical endpoint committee member for a clinical trial funded by Novartis, as the site principal investigator for ATACH-II study funded by the NIH Grant # U01-NS062091, and as DSMB member for a study funded by NIH Grant # R01-DC12584. She has received speaker honorarium from the American Academy of Neurology and travel scholarship from the Neurocritical Care Society. Conflict of interest conflict of interest.

Claudia S. Robertson declares that she has no

Appendix 1: Participants in the International Multidisciplinary Consensus Conference on Multimodality Monitoring Peter Le Roux, MD, FACS, Brain and Spine Center, Suite 370, Medical Science Building, Lankenau Medical Center, 100 East Lancaster Avenue, Wynnewood, PA 19096, USA. Tel: +1 610 642 3005 Fax: 610 642 3057 [email protected] David K Menon MD PhD FRCP FRCA FFICM FMedSci, Head, Division of Anaesthesia, University of Cambridge Consultant, Neurosciences Critical Care Unit Box 93, Addenbrooke’s Hospital Cambridge CB2 2QQ, UK [email protected] Paul Vespa, MD, FCCM, FAAN, FNCS Professor of Neurology and Neurosurgery Director of Neurocritical Care David Geffen School of Medicine at UCLA Los Angeles, CA 90095 USA [email protected]

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Giuseppe Citerio, MD Director NeuroIntensive Care Unit, Department of Anesthesia and Critical Care Ospedale San Gerardo, Monza. Via Pergolesi 33, Monza 20900, Italy [email protected] Mary Kay Bader RN, MSN, CCNS, FAHA, FNCS Neuro/Critical Care CNS Mission Hospital Mission Viejo CA 92691, USA [email protected] Gretchen M. Brophy, PharmD, BCPS, FCCP, FCCM Professor of Pharmacotherapy & Outcomes Science and Neurosurgery Virginia Commonwealth University Medical College of Virginia Campus 410 N. 12th Street Richmond, Virginia 23298-0533 USA [email protected] Michael N. Diringer, MD Professor of Neurology, Neurosurgery & Anesthesiology Chief, Neurocritical Care Section Washington University Dept. of Neurology, Campus Box 8111 660 S Euclid Ave St Louis, MO 63110 USA [email protected] Nino Stocchetti, MD Professor of Anesthesia and Intensive Care Department of physiopathology and transplant Milan University Director Neuro ICU Fondazione IRCCS Ca` Granda Ospedale Maggiore Policlinico Via F Sforza, 35 20122 Milan Italy e-mail [email protected] Walter Videtta, MD ICU Neurocritical Care Hospital Nacional ‘Prof. a. Posadas’ El Palomar - Pcia. de Buenos Aires Argentina [email protected] Rocco Armonda, MD Department of Neurosurgery MedStar Georgetown University Hospital Medstar Health, 3800 Reservoir Road NW Washington DC 20007

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USA [email protected] Neeraj Badjatia, MD Department of Neurology University of Maryland Medical Center, 22 S Greene St Baltimore, MD, 21201 USA [email protected]

Michael De Georgia, MD Professor of Neurology Director, Neurocritical Care Center Co-Director, Cerebrovascular Center University Hospital Case Medical Center Case Western Reserve University School of Medicine 11100 Euclid Avenue Cleveland, Ohio 44106 [email protected]

Julian Boesel, MD Department of Neurology Ruprect-Karls University Hospital Heidelberg, Im Neuenheimer Feld 400, D-69120 Heidelberg, Germany [email protected]

Anthony Figaji, MD, PhD Head of Pediatric Neurosurgery University of Cape Town 617 Institute for Child Health Red Cross Children’s Hospital Rondebosch, 7700 Cape Town, South Africa [email protected]

Randal Chesnut, MD, FCCM, FACS Harborview Medical Center, University of Washington Mailstop 359766 325 Ninth Ave, Seattle WA 98104-2499 USA [email protected]

Jennifer Fugate, DO Department of Neurology, Mayo Clinic, 200 First Street SW Rochester, MN 55905 [email protected]

Sherry H-Y. Chou, MD, MMSc, FNCS Assistant Professor of Neurology, Harvard Medical School Department of Neurology, Brigham and Women’s Hospital 75 Francis Street Boston MA, 02115 USA [email protected]

Raimund Helbok, MD Department of Neurology, Neurocritical Care Unit Innsbruck Medical University, Anichstr.35, 6020 Innsbruck, Austria [email protected]

Jan Claassen, MD, PhD, FNCS Assistant Professor of Neurology and Neurosurgery Head of Neurocritical Care and Medical Director of the Neurological Intensive Care Unit Columbia University College of Physicians & Surgeons 177 Fort Washington Avenue, Milstein 8 Center room 300, New York, NY 10032 USA [email protected]

David Horowitz, MD Associate Chief Medical Officer University of Pennsylvania Health System, 3701 Market Street Philadelphia, PA, 19104 USA [email protected]

Marek Czosnyka, PhD Department of Neurosurgery University of Cambridge, Addenbrooke’s Hospital, Box 167 Cambridge, CB20QQ United Kingdom [email protected]

Peter Hutchinson, MD Professor of Neurosurgery NIHR Research Professor Department of Clinical Neurosciences University of Cambridge Box 167 Addenbrooke’s Hospital Cambridge CB2 2QQ United Kingdom [email protected]

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Monisha Kumar, MD Department of Neurology Perelman School of Medicine, University of Pennsylvania, 3 West Gates 3400 Spruce Street Philadelphia, PA, 19104 USA [email protected] Molly McNett, RN, PhD Director, Nursing Research The MetroHealth System 2500 MetroHealth Drive, Cleveland, OH 44109 USA [email protected] Chad Miller, MD Division of Cerebrovascular Diseases and Neurocritical Care The Ohio State University 395 W. 12th Ave, 7th Floor Columbus, OH 43210 [email protected] Andrew Naidech, MD, MSPH Department of Neurology Northwestern University Feinberg SOM 710 N Lake Shore Drive, 11th floor Chicago, IL 60611 [email protected] Mauro Oddo, MD Department of Intensive Care Medicine CHUV University Hospital, BH 08-623 Faculty of Biology and Medicine University of Lausanne 1011 Lausanne, Switzerland [email protected] DaiWai Olson, RN, PhD Associate Professor of Neurology, Neurotherapeutics and Neurosurgery University of Texas Southwestern 5323 Harry Hines Blvd Dallas, TX 75390-8897 USA [email protected] Kristine O’Phelan M.D. Director of Neurocritical Care Associate Professor, Department of Neurology University of Miami, Miller School of Medicine JMH, 1611 NW 12th Ave, Suite 405

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Miami, FL, 33136 USA [email protected] Javier Provencio, MD Associate Professor of Medicine Cerebrovascular Center and Neuroinflammation Research Center Lerner College of Medicine Cleveland Clinic, 9500 Euclid Ave, NC30 Cleveland, OH 44195 USA [email protected] Corina Puppo, MD Assistant Professor, Intensive Care Unit, Hospital de Clinicas, Universidad de la Repu´blica, Montevideo Uruguay [email protected] Richard Riker, MD Critical Care Medicine Maine Medical Center, 22 Bramhall Street Portland, Maine 04102-3175 USA [email protected] Claudia Robertson, MD Department of Neurosurgery Medical Director of Center for Neurosurgical Intensive Care, Ben Taub Hospital Baylor College of Medicine, 1504 Taub Loop, Houston, TX 77030 USA [email protected] J. Michael Schmidt, PhD, MSc Director of Neuro-ICU Monitoring and Informatics Columbia University College of Physicians and Surgeons Milstein Hospital 8 Garden South, Suite 331 177 Fort Washington Avenue, New York, NY 10032 USA [email protected] Fabio Taccone, MD Department of Intensive Care, Laboratoire de Recherche Experimentale Erasme Hospital,

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Electrophysiologic monitoring in acute brain injury.

Monitoring nutrition and glucose in acute brain injury.

Targeted Lipid Profiling Discovers Plasma Biomarkers of Acute Brain Injury.

Monitoring inflammation (including fever) in acute brain injury.

Biomarkers of brain injury in cerebral infections.

Monitoring the Neuroinflammatory Response Following Acute Brain Injury.

[Diagnostic biomarkers in traumatic brain injury].

Intracranial pressure monitoring and traumatic brain injury.

Monitoring prognosis in severe traumatic brain injury.

Monitoring brain multiparameters and hypothermia in severe traumatic brain injury.

Cellular basis of anoxic-ischemic brain injury.

Serum biomarkers for traumatic brain injury.

Clinical monitoring scales in acute brain injury: assessment of coma, pain, agitation, and delirium.

Biomarkers of Brain Function and Injury: Biological and Clinical Significance.

Effort test performance in clinical acute brain injury, community brain injury, and epilepsy populations.

Thaliporphine derivative improves acute lung injury after traumatic brain injury.

Current status of fluid biomarkers in mild traumatic brain injury.

Hypotension After Cardiac Operations Based on Autoregulation Monitoring Leads to Brain Cellular Injury.

Continuous monitoring of cerebral oxygenation in acute brain injury: injection of mannitol during hyperventilation.

Renalase and Biomarkers of Contrast-Induced Acute Kidney Injury.

Acute Rehabilitation in Traumatic Brain Injury.

Creatine kinase MB in acute brain injury.

Letter: myocardial injury and death in acute infarction.

Variation in performance of kidney injury biomarkers due to cause of acute kidney injury.