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A Systematic Review and Meta-Analysis of Molecular Biomarkers Associated with Early Neurological Deterioration Following Acute Stroke

Lookup NU author(s): Dr Alexander MartinORCiD, Professor Christopher PriceORCiD



This is the authors' accepted manuscript of a review published in its final definitive form in 2018. For re-use rights please refer to the publishers terms and conditions.


Background: Early neurological deterioration (END) following acute stroke is associated with poorer long-term outcomes. Identification of patients at risk could assist early monitoring and treatment decisions. This review summarised the evidence describing non-radiological biomarkers for END.Summary: Electronic searches from January 1990-March 2017 identified studies reporting a blood/cerebrospinal fluid (CSF)/urine biomarker measurement within 24 hours of acute stroke and at least two serial assessments of clinical neurological status (<24 hours and <7 days).Out of 12,895 citations, 82 studies were included, mostly focusing on ischaemic stroke. Using higher neurological thresholds, the n-weighted END incidence for ischaemic stroke was 11.9% (95% confidence interval CI 11.4-12.4%) and 18.6% (17.9-19.2%) for lower thresholds. Incidence decreased with advancing study publication year (Pearson r-squared 0.23 and 0.15 for higher and lower threshold studies). After classification into 3 broad categories, meta-analysis showed that biomarkers associated with increased END risk (n; fixed-effects mean difference; 95% CI) were: “metabolic” [glucose (n=9781; 0.90mmol/l; 0.74-1.06), glycosylated haemoglobin (n=3146; 0.33%; 0.19-0.46), low-density lipoprotein (n=5476; 0.13mmol/l; 0.05-0.20), total cholesterol (n=4822; 0.19mmol/l; 0.10-0.29), triglycerides n=4880; 0.10mmol/l; 0.04-0.15), urea (n=1351; 0.55mmol/l; 0.14-0.96), decreasing albumin (n=513; 0.33g/dl; 0.05-0.61)]; “inflammatory & excitotoxic” [plasma glutamate (n=688 60.13umol/l; 50.04-70.22), CSF glutamate (n=369; 7.50umol/l; 6.76-8.23), homocysteine (n=824; 2.15umol/l; 0.68-3.61), interleukin-6 (n=231; 24.80pg/ml; 21.72-27.88), leucocytes (n=3388; 0.41x109/L; 0.21-0.62), high-sensitivity c-reactive protein (n=1707; 3.79mg/l; 1.23-6.35)]; and “coagulation / haematological” [fibrinogen (n=3132; 0.32g/l; 0.25-0.40); decreasing haemoglobin (n=3586; 2.38g/l; 0.15-4.60)].Key messages: Declining incidence of END may represent improving care standards but it remains a frequent occurrence. Although statistical associations exist between biomarkers and an increased risk of END, the most promising still need prospective evaluation to determine their additional value relative to baseline radiological and clinical characteristics.

Publication metadata

Author(s): Martin AJ, Price CI

Publication type: Review

Publication status: Published

Journal: Cerebrovascular Diseases

Year: 2018

Volume: 46

Issue: 5-6

Pages: 230–241

Online publication date: 05/12/2018

Acceptance date: 16/11/2018

ISSN (print): 1015-9770

ISSN (electronic): 1421-9786


DOI: 10.1159/000495572