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Three Part Question

In [adults with suspected stroke], does [measurement of blood biomarkers] enable [accurate differentiation of hemorrhagic from ischemic stroke]?

Clinical Scenario

A sixty year-old woman presents to the Emergency Department with a three-hour history of right sided hemiparesis. She has a past medical history of hypertension and myocardial infarction. Rapid evaluation and prompt initiation of thrombolytic therapy in acute ischemic stroke is extremely important for prognosis. Diagnosis of acute ischemic stroke usually relies on clinical grounds, after excluding hemorrhagic stroke by computed tomography. The availability of rapid and accurate diagnostic biomarkers to discriminate hemorrhagic from ischemic stroke would be helpful. Ideally, distinction should be made at pre-hospital triage, thereby directing patients to adequate centers for optimal care. We wonder if such biomarkers are present in the evaluation of acute stroke.

Search Strategy

PubMed (MEDLINE) 1966 – 22 june 2011 and Embase 1974 – 22 june 2011 were searched, using the following search string: (biomarker[Title/Abstract] OR marker[Title/Abstract]) AND (cerebrovascular[Title/Abstract] OR stroke[Title/Abstract]) AND (diagnos* OR sensitivity OR specificity OR likelihood ratio). Limits: Humans, English. We selected papers by relevant title and abstract and added useful related articles found in this search.

Search Outcome

981 papers were found using MEDLINE, 1015 papers were found using Embase. Together with useful related articles, 7 papers were relevant to the three part question. Relevant papers were checked for quality by using QUADAS1. A summary of diagnostic test characteristics are presented in the table.

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Undén et al 2009 Sweden	ICH or IS, symptoms <24h Excl: TIA, previous stroke, signs of SAH, other cause than stroke N=97 (of which 14 ICH)	Prospective observational multicenter study (Level: 2b)	GFAP≥40ng/l (t= 1-24h after symptom onset)	Se 79% Sp 64% PPV 27% NPV 95%	-Small sample size. -Not all patients suspected for stroke included (e.g. TIA excluded). -Cut-off levels of tests based upon own data (not validated in a separate cohort). -Indextest not performed in pre-hospital setting.
			APC-PCI <0.35µg/l (t= 1-24h after symptom onset)	Se 86% Sp 42% PPV 20% NPV 95%
			GFAP≥40ng/l and APC-PCI<0.35µg/l and NIHSS≥4	Se 100% Sp 43% PPV 29% NPV 100%
Dvorak et al 2008 Germany	ICH or IS, symptoms<6h Excl: early hemorrhagic transformation of infarction, previous brain injury/stroke, other pre-existing CNS disease N=63 (of which 18 ICH)	Prospective observational single center study (Level: 2b)	GFAP>0.1µg/l (t=1h after symptom onset)	Se 14% Sp 100% PPV 100% NPV 70%	-Small sample size. - Not all patients suspected for stroke included (only ICH or IS) -Cut-off levels of tests based upon own data (not validated in a separate cohort). -Indextest not performed in pre-hospital setting.
			GFAP>0.05µg/l (t=2h after symptom onset)	Se 45% Sp 100% PPV 100% NPV 80%
			GFAP>0.03µg/l (t=3h after symptom onset)	Se 65% Sp 100% PPV 100% NPV 79%
			GFAP>0.04µg/l (t=4h after symptom onset)	Se 70% Sp 100% PPV 100% NPV 84%
			GFAP>0.11µg/l (t=6h after symptom onset)	Se 71% Sp 95% PPV 83% NPV 90%
Kim et al 2010 Korea	Suspected stroke, with symptoms persisting>24h N=139 (of which 11 ICH)	Prospective observational single center study (Level: 2b)	MMP-9, BNP, S100β, D-dimer and composite marker MMX (incorporating4 individual biomarkers) (t=0.2-120h after symptom onset, median 6h, 44% within 3h)	MMX similar in IS vs ICH (p=0.884). BNP higher in IS vs ICH (p=0.008). Discrimination of IS vs ICH by MMP-9, BNP, S100β, D-dimer or MMX value: area under ROC curve 0.293, 0.661, 0.534, 0.168, 0.479 resp.	-Small sample size. -Not all patients suspected for stroke included (e.g. TIA excluded). -Cut-off levels of tests based upon own data (not validated in a separate cohort). -Indextest not performed in pre-hospital setting.
Rainer et al 2007 China	Suspected stroke, with symptoms <24h Excl: a.o. brain trauma, other CNS disease, e.g. meningitis N=197 (of which 35 ICH, 118 IS, 44 other)	Prospective observational single center study (Level: 2b)	β-globin DNA >2500 kgenome equ/l (t= <24h after symptom onset)	Se 40% Sp 86% PPV 39% NPV 87%	-Small sample size. -Cut-off levels of tests based upon own data (not validated in a separate cohort). -Indextest not performed in pre-hospital setting.
			S100 > 0.25µg/l (t= <24h after symptom onset)	Se 66% Sp 36% PPV 18% NPV 83%
			β-globin DNA >2500 kgenome equ/l and S100 > 0.25µg/l	Se 83% Sp 1% PPV 15% NPV 25%
Foerch et al 2006 Germany	ICH or IS, symptoms<6h. Excl: previous ICH/IS/brain injury, pre-existing CNS disease N=135 (of which 42 ICH, 93 IS)	Prospective observational single center study (Level: 2b)	GFAP>2.9ng/l (t= <6h after symptom onset)	Se 79% Sp 98% PPV 94% NPV 91%	-Small sample size. -Only patients included with ICH or IS, not all patients suspected for stroke. -Cut-off levels of tests based upon own data (not validated in a separate cohort). -Indextest not performed in pre-hospital setting.
			GFAP>2.9ng/l and NIHSS≥6 (t= <6h after symptom onset)	Se 82% Sp 97% PPV 94% NPV 92%
			GFAP>2.9ng/l and NIHSS≥6 and <3h after symptom onset	Se 75% Sp 98% PPV 93% NPV 90%
Dambinova et al 2003 Russia	Patients with TIA, ICH or IS, symptoms<3h. Excl: a.o. SAH, death within 1-3days, atrial fibrillation N=49 (of which 18 ICH, 31 IS)	Prospective observational single center study (Level: 2b)	NR2A/2B <2µg/l (t= <3h after symptom onset	Se 100% Sp 97% PPV 95% NPV 100%	-Small sample size. -Only patients included with ICH or IS, not all patients suspected for stroke. -Cut-off levels of tests based upon own data (not validated in a separate cohort). -Indextest not performed in pre-hospital setting.
Allard et al 2004 Switserland	ICH or IS N=31 (of which 15 ICH, 16 IS)	Prospective observational single center study (Level: 2b)	ApoC-I <60 RFU (t= 40min – 3days after symptom onset, median 3h)	Se 73% Sp 94% PPV 92% NPV 79%	-Small sample size. -Only patients included with ICH or IS, not all patients suspected for stroke. -Cut-off levels of tests based upon own data (not validated in a separate cohort). -Indextest not performed in pre-hospital setting.
			ApoC-III <36 RFU (t= 40min – 3days after symptom onset, median 3h)	Se 87% Sp 94% PPV 93% NPV 88%

Comment(s)

In order to direct therapeutic strategy (i.e. to start thrombolytic treatment), the diagnostic test in acute stroke patients must completely rule out ICH (very high NPV). Ideally, the biomarker should be brain specific, plasmatic (not cerebrospinal fluid), early expressed and detected after symptom onset, and the marker should differentiate ICH from IS. So far, no biomarker convincingly showed the required test characteristics to be used as single diagnostic marker. It may well be that the best diagnostic strategy involves a combination of biomarkers rather than a single diagnostic marker. GFAP, probably together with other serum markers, seems promising in discerning ICH from IS, but studies conducted so far are small and do not include all patients with symptoms suspicious of stroke as we see at pre-hospital triage. Moreover, biomarkers tested thus far are not yet validated in an independent cohort and may introduce data dependent thresholds.

Editor Comment

Please see update at http://bestbets.org/bets/bet.php?id=2995

Clinical Bottom Line

Rapid and accurate diagnostic biomarkers to discriminate hemorrhagic from ischemic stroke would be helpful in pre-hospital triage to direct adequate treatment. Large, well-designed prospective studies are needed to further evaluate this diagnostic option.

References

1. Unden et al. Explorative investigation of biomarkers of brain damage and coagulation system activation in clinical stroke differentiation. J Neurol. 2009 Jan;256(1):72-7
2. Dvorak et al. Characterisation of the diagnostic window of serum glial fibrillary acidic protein for the differentiation of intracerebral haemorrhage and ischaemic stroke. Cerebrovasc Dis. 2009;27(1):37-41.
3. Kim et al. Plasma biomarkers in the diagnosis of acute ischemic stroke. Ann Clin Lab Sci. 2010 Fall;40(4):336-41.
4. Rainer et al. Comparison of plasma beta-globin DNA and S-100 protein concentrations in acute stroke. Clin Chim Acta. 2007 Feb;376(1-2):190-6.
5. Foerch et al. Serum glial fibrillary acidic protein as a biomarker for intracerebral haemorrhage in patients with acute stroke. J Neurol Neurosurg Psychiatry. 2006 Feb;77(2):181-4.
6. Dambinova et al. Blood test detecting autoantibodies to N-methyl-D-aspartate neuroreceptors for evaluation of patients with transient ischemic attack and stroke. Clin Chem. 2003 Oct;49(10):1752-62.
7. Allard et al. ApoC-I and ApoC-III as potential plasmatic markers to distinguish between ischemic and hemorrhagic stroke. Proteomics. 2004 Aug;4(8):2242-51.