Table 3.

Biomarkers for subarachnoid hemorrhage

Author/year/Ref	Study design	Population	N	Bio-marker	Sample source	Findings
Molecules of CNS origin
Weismann/1997/[31]	Pro	Aneurysmal SAH within 3 days of ictus	70	s100β	Serum	s100β is higher at 24 h, 3 and 7 days post SAH compared to controls Higher s100β levels correlate with worse HH grade. higher s100β in the first week after SAH correlate with worse 6 month outcome
Stranjalis/2007/[32]	Pro	Spontaneous SAH within 48 h of ictus	52	s100β	Serum	Admission s100β >0.3 μg/L predicted unfavorable outcome and is an independent predictor of short-term survival (HR 2.2) (77.8 % sensitivity; 76 % specificity) s100β correlates positively with HH and Fisher scores s100β decreased after EVD insertion
Oertel/2006/[33]	Pro	Aneurysmal SAH	51	s100β, NSE	Serum	s100β during first 3 days of SAH is higher in those who died compared to survivors all patients with s100β >1.0 μg/L had unfavorable outcome NSE had no association with outcome s100β is lower in patients with vasospasm (by transcranial doppler)
Coplin/1999/[34]	Pro	Aneurysmal SAH	27	CKBB	CSF	CKBB >40μ/L is associated with poor outcome at hospital discharge (100 % specificity)
Inflammatory markers
Pan/2013/[65]	Pro	Aneurysmal SAH	262 SAH, 150 CTRL	pGSN	Blood	pGSN were lower in SAH compared with controls pGSN was an independent predictor of poor functional outcome (OR = 0.957) and death (OR = 0.953) at 6 months Adding pGSN improved predictive performance of WFNS and Fisher scores for functional outcome but not for mortality
Frijns/2006/[48]	Pro	SAH within 72 h of ictus, exclude perimesencephalic SAH	106	vWF	Serum	vWf >94.5 nmol/L was independently associated with increased odds for poor outcome at 3 months (OR 1.1–9.8) sICAM-1, sP-selectin, sE-selectin, vWf propeptide and ED 1-fibronectin were not independently associated with outcome
Mack/2002/[47]	Pro	SAH, excluding those with pro-inflammatory disease process	80	sICAM-1	Serum	sICAM-1 was elevated in SAH (293.3 ± 15 μg/L) compared with controls sICAM-1 on post-SAH days 8, 10, and 12 were significantly elevated in those with unfavorable mRS at discharge
Beeftink/2011/[46]	Pro	Aneurysmal SAH	67	TNFα, Leukocytes, CRP	Serum	Neither TNFα nor TNF-α genotype were associated with DCI or with SAH outcome at 3 months High leukocyte count and high CRP are not associated with DCI or SAH outcome
Chou/2011/[38]	Pro	Spontaneous SAH, within 96 h of ictus	55	MMP-9	CSF	Elevation of MMP-9 on post-SAH days 2–3 is associated with poor outcome (mRS 3–6) at 3 months
Chou/2011/[38]	Pro	Spontaneous SAH, within 96 h of ictus	55	Neutrophil, WBC	Blood	Elevated neutrophil count on post-SAH day 3 is associated with poor 3-month outcome Elevated WBC count throughout post-SAH days 0–14 is associated with angiographic vasospasm
Chou/2012/[50]	Pro	Spontaneous SAH, within 96 h of ictus	52	TNFα, IL-6	Serum	Elevated TNFα over post-SAH days 0–14 is independently associated with poor long-term outcome IL-6 is not associated with SAH outcome Neither TNFα nor IL-6 was associated with angiographic vasospasm
Chou/2011/[64]	Pro	Spontaneous SAH, within 96 h of ictus	42	pGSN	CSF, Serum	Serum pGSN is decreased in SAH compared to controls and decreases over time in SAH CSF pGSN is decreased in SAH compared to controls. Novel pGSN fragments found in SAH CSF but not in controls
Fassbender/2001/[52]	Pro	Aneurysmal SAH within 48 h of ictus	35	IL-1β, IL-6, TNFα	CSF, Serum	IL-lβ and IL-6 are significantly higher in CSF than in serum in SAH CSF IL-6 on post-SAH day 5 is significantly elevated in poor outcome group CSF TNFα did not show significant association with outcome
Mathiesen/1997/[53]	Pro	SAH patients with EVD	22	IL-1Rα, TNFα	CSF	IL-IRα was higher in poor grade SAH (HH 3–4; 318 vs. 82 pg/mL) Elevated IL-IRα and TNFα on post-SAH days 4–10 were associated with poor outcome
Weir/1989/[43]	Retro	Aneurysmal SAH with vital signs and CBC data (76 % missing data)	173	WBC	Blood	admission WBC >15 × 109/L shows 55 % mortality vs. 25 % mortality in the lower WBC group
Niikawa/1997/[39]	Retro	Fisher grade 3 SAH treated with aneurysm clipping within 24 h of ictus	103	WBC	Blood	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
Other biomarkers
Niskakangas/2001/[79]	Case control	Aneurysmal SAH	108	ApoE4	Blood	Presence of ApoE4 was associated with unfavorable outcome (OR = 2.8 [1.18–6.77])
Juvela/2009/[76]	Case control	SAH within 48 h of ictus	105	ε2, ε4–containing genotypes	Blood	Apolipoprotein E ε2 or ε4-containing genotypes were not associated with outcome or occurrence of cerebral infarction
Lanterna/2005/[78]	Case control	SAH HH grade 1–3	101	ApoE4 genotype	Blood	Presence of Apo E4 genotype is associated with negative overall outcome Apo E4 genotype is associated with development of DIND
Leung/2002/[77]	Case control	Spontaneous SAH	72	ApoE4 genotype	Blood	ApoE4 genotype is associated with poor 6-month outcome (OR = 11.3 [2.2–57.0])
Kay/2003/[81]	Case Control	Spontaneous SAH requiring EVD	19	s100β, ApoE	CSF	s100β is significantly higher in SAH compared to controls ApoE is significantly lower in SAH compared to controls. Lower ApoE was associated with better clinical outcome
Lanterna/2005/[78]	Meta-analysis	Consecutive SAH, with 3-month follow-up data	696	ApoE4 genotype	Blood	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])
Moussouttas/2012/[88]	Pro	SAH with EVD, HH grade 3–5, endovascular aneurysm treatment	102	Epinephrine	CSF	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])
Yarlagadda/2006/[84]	Pro	Spontaneous SAH, >21 years	300	BNP, cTI	Serum	Initial BNP >600 pg/mL is associated with death (OR = 37.7 [5.0–286.2]) cTI >0.3 mg/L (on post-SAH day 9 ± 4) is associated with death (OR = 4.9 [2.1–26.8]) No standardized time of biosample collection
Naidech/2005/[82]	Pro	Spontaneous non-traumatic SAH	253	cTI	Serum	Peak cTI was independently predictive of death or severe disability at hospital discharge (OR = 1.4 [1.1–1.9]) cTI not independently predictive of 3-month outcome by mRS
Ramappa/2008/[83]	Retro	SAH diagnosed by CT scan or CSF, SAH ICD-9 code, with cTI measured	83	cTI	Blood	Peak cTI and GCS on presentation independently predicted in-hospital mortality

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