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Prediction of outcome in Subarachnoid Haemorrhage using biomarkers
Umeå University, Faculty of Medicine, Department of Clinical Sciences, Neurosciences.ORCID iD: 0000-0001-8612-7173
2025 (English)Doctoral thesis, comprehensive summary (Other academic)Alternative title
Att förutspå det kliniska utfallet vid Subarachnoidalblödning med hjälp av biomarkörer (Swedish)
Abstract [en]

Background: Aneurysmal subarachnoid haemorrhage (SAH) is a complex form of stroke affecting approximately 10 per 100,000 individuals in Western populations. In addition to the damage caused by the initial haemorrhage, secondary complications such as rebleeding, hydrocephalus and delayed cerebral ischemia may further contribute to the overall extentof brain injury. Long-term outcomes range widely, from death to full recovery. Predicting functional outcomes during theacute phase of the disease remains challenging, and currently, no blood-based biomarkers are routinely used in clinical practice.

Aim: This thesis investigates whether the biochemical biomarkers myo-inositol (MI), neurofilament light chain (NFL), and S100-beta (S100B) measured in venous blood are associated with secondary complications and long-term functional outcomes. The focus is also on characterizing their trajectories during the acute phase of SAH. The main hypothesis is that levels of the biomarkers are associated with functional outcome 12 months after the haemorrhage.

Method: This work is based on four studies; all derived from a single observational cohort. The cohort included patients aged 18 years or older who were treated for SAH at Umeå University Hospital between 2014 and 2018. Serum samples were collected at multiple time points during hospitalization. Demographic and clinical data were recorded, including neurological status upon admission according to the World Federation of Neurosurgical Societies and Hunt and Hessscores, the amount of subarachnoid blood on the initial CT scan as classified by the Fisher grade, the presence of delayed cerebral ischemia and angiographic vasospasm, as well as the treatment modality used for aneurysm occlusion. Functional status was assessed one year after disease onset using the Glasgow Outcome Scale Extended and the modified Rankin Scale. Outcomes were dichotomized into favourable (Glasgow Outcome Scale 5-8, modified Rankin Scale 0-3) and unfavourable (Glasgow Outcome Scale 1-4, modified Rankin Scale 4-6) groups. In one study, health-related quality of life was also evaluated using the EuroQoL 5-Dimension Index. Biomarker levels were compared between groups, and multivariable logistic regression was applied to assess their predictive value for long-term outcomes.

Results: For MI, levels at admission did not correlate with World Federation of Neurosurgical Societies score, nor did they differ between favourable and unfavourable outcome groups. However, by day seven, significant differences in MI levels emerged between outcome groups, and the change in MI levels over this period also differed significantly. For NFL, levelswere significantly associated with both World Federation of Neurosurgical Societies score at admission and outcome group,with differences observed at admission and throughout follow-up. S100B values obtained during the first days after SAH onset correlated significantly with both modified Rankin Scale and EuroQoL 5-Dimension Index with peak S100B levels showing the strongest association with functional outcome. All three biomarkers were significant predictors of long-termfunctional outcome in univariate analyses. When combined with established predictors, these biomarkers improved the performance of multivariable regression models.

Conclusions: The biomarkers MI, NFL, and S100B are associated with long-term functional outcomes in patients with SAH. Incorporating them into predictive models may provide a valuable tool for outcome prognostication. However, external validation in larger cohorts is required before these biomarkers can be considered for routine clinical implementation. The main hypothesis of this thesis has therefore to be accepted.

Place, publisher, year, edition, pages
Umeå: Umeå University, 2025. , p. 93
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 2383
Keywords [en]
Subarachnoid haemorrhage, Glasgow outcome scale extended, Modified Rankin scale, Myo-Inositol, Neurofilament-Light chain, S100-Beta, Vasospasm, Delayed cerebral ischemia
National Category
Neurology
Research subject
Neurology
Identifiers
URN: urn:nbn:se:umu:diva-246426ISBN: 978-91-8070-805-0 (print)ISBN: 978-91-8070-806-7 (electronic)OAI: oai:DiVA.org:umu-246426DiVA, id: diva2:2013966
Public defence
2025-12-12, ULED.A.310 - Triple Helix, Umeå, 13:00 (Swedish)
Opponent
Supervisors
Available from: 2025-11-21 Created: 2025-11-14 Last updated: 2025-11-17Bibliographically approved
List of papers
1. Serum Levels of Myo-inositol Predicts Clinical Outcome 1 Year After Aneurysmal Subarachnoid Hemorrhage
Open this publication in new window or tab >>Serum Levels of Myo-inositol Predicts Clinical Outcome 1 Year After Aneurysmal Subarachnoid Hemorrhage
2022 (English)In: Neurosurgery, ISSN 0148-396X, E-ISSN 1524-4040, Vol. 91, no 5, p. 790-798Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Early prognostication of long-term outcome in patients suffering from spontaneous subarachnoid hemorrhage (SAH) remains a challenge. No biomarkers are routinely used for prognostication. A previous study has indicated that the metabolite myo-inositol (MI) may be used to predict long-term outcome.

OBJECTIVE: To investigate if MI measured in serum correlates with long-term clinical outcome in patients suffering from SAH.

METHODS: We conducted an observational cohort study including 88 patients treated for SAH at Umeå University Hospital. Serum samples were collected in the hospital, and a gas chromatography/mass spectroscopy method was used to quantitatively measure MI. Patients were assessed after 1 year using the Glasgow Outcome Scale Extended and dichotomized to favorable or unfavorable outcome. Differences in MI levels between the 2 groups were analyzed.

RESULTS: There was no difference in MI levels between the groups upon admission. Myo-inositol levels decreased over time in the entire study population. The decrease was significantly larger in the unfavorable outcome group. A receiver operating characteristics analysis yielded an area under the curve of 0.903 (CI 0.8-1.0, P < .001) for the MI value on day 7 to predict favorable outcome after 1 year.

CONCLUSION: Myo-inositol measured in serum may aid prognostication of outcome in patients with SAH. The mechanism behind this remains unclear, although it can be theorized to reflect processes leading to delayed cerebral ischemia, which affects long-term outcome. This is the first study to quantitively measure MI in serum for prognostication of outcome in patients with SAH.

Place, publisher, year, edition, pages
Lippincott Williams & Wilkins, 2022
Keywords
Cerebral vasospasm, Delayed cerebral ischemia, Glasgow Outcome Scale extended, Inositol, Subarachnoid hemorrhage
National Category
Neurology
Research subject
Neurosurgery
Identifiers
urn:nbn:se:umu:diva-199173 (URN)10.1227/neu.0000000000002112 (DOI)000867871400034 ()35969493 (PubMedID)2-s2.0-85140144606 (Scopus ID)
Available from: 2022-09-07 Created: 2022-09-07 Last updated: 2025-11-14Bibliographically approved
2. Serum neurofilament light as a predictor of outcome in subarachnoid haemorrhage
Open this publication in new window or tab >>Serum neurofilament light as a predictor of outcome in subarachnoid haemorrhage
Show others...
2023 (English)In: Acta Neurochirurgica, ISSN 0001-6268, E-ISSN 0942-0940, Vol. 165, no 10, p. 2793-2800Article in journal (Refereed) Published
Abstract [en]

Background: Prognostication of clinical outcome in patients suffering from aneurysmal subarachnoid haemorrhage (SAH) is a challenge. There are no biochemical markers in routine use that can aid in prognostication. Neurofilament light (NFL) measured in cerebrospinal fluid (CSF) has been associated with clinical outcome in previous studies.

Objective: To investigate if serum levels of NFL correlate with CSF levels and long-term clinical outcome in patients suffering from SAH.

Methods: We conducted an observational cohort study of 88 patients treated for SAH at Umeå University Hospital in 2014–2018. Serum and CSF samples were analysed using an enzyme-linked immunosorbent assay to quantify NFL levels. Outcome was assessed using Glasgow Outcome Scale Extended and dichotomised as favourable or unfavourable. Differences in NFL levels between outcome groups were analysed using repeated measurements ANOVA. Relationship between CSF and serum NFL levels was analysed using Pearson’s correlation. A multivariate binary logistic regression model and a receiver operation characteristic curve were used to assess the predictive value of serum NFL.

Results: A significant correlation between serum and CSF-NFL levels could be seen (Pearson’s correlation coefficient = 0.7, p <.0001). Mean level of serum NFL was higher in the unfavourable outcome group than the favourable outcome group (p <.0001), in all epochs of SAH, and correlated with initial disease severity on the World Federation of Neurosurgical Societies scale. Serum NFL in the late phase displayed the best predictive potential in a receiver operation characteristic curve analysis (AUC=0.845, p <.0001).

Conclusion: Levels of NFL in serum and CSF are correlated. Early serum NFL levels seem to reflect initial tissue damage and serum NFL levels in the late phase may reflect secondary events such as vasospasm or delayed cerebral ischemia. Serum NFL may be used as a prognostic marker of clinical outcome in SAH.

Place, publisher, year, edition, pages
Springer, 2023
Keywords
Cerebral vasospasm, Glasgow Outcome Scale, Neurofilament protein l, Subarachnoid haemorrhage
National Category
Neurology Neurosciences
Identifiers
urn:nbn:se:umu:diva-211994 (URN)10.1007/s00701-023-05673-9 (DOI)001019458300001 ()37351672 (PubMedID)2-s2.0-85163214143 (Scopus ID)
Available from: 2023-07-12 Created: 2023-07-12 Last updated: 2025-11-14Bibliographically approved
3. Serum S100B correlates with health-related quality of life and functional outcome in patients at 1 year after aneurysmal subarachnoid haemorrhage
Open this publication in new window or tab >>Serum S100B correlates with health-related quality of life and functional outcome in patients at 1 year after aneurysmal subarachnoid haemorrhage
Show others...
2022 (English)In: Acta Neurochirurgica, ISSN 0001-6268, E-ISSN 0942-0940, Vol. 164, no 8, p. 2209-2218Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Early, objective prognostication after aneurysmal subarachnoid haemorrhage (aSAH) is difficult. A biochemical marker would be desirable. Correlation has been found between levels of the protein S100 beta (S100B) and outcome after aSAH. Timing and clinical usefulness are under investigation.

METHODS: Eighty-nine patients admitted within 48 h of aSAH were included. Modified ranking scale (mRS), EuroQoL health-related quality of life measure (EQ-5Dindex) and EuroQoL visual analogue scale (EQ-VAS) values were evaluated after 1 year. S100B was measured in blood samples collected at admission and up to day 10.

RESULTS: S100B correlated significantly with EQ-5Dindex and mRS, but not EQ-VAS at 1 year after aSAH. A receiver operating characteristic analysis for peak S100B values (area under the curve 0.898, 95% confidence interval 0.828-0.968, p < 0.0001), with a cutoff of 0.4 μg/l, yielded 95.3% specificity and 68% sensitivity for predicting unfavourable outcome. Dichotomized S100B (> 0.4 μg/l vs ≤ 0.4 μg/l), age and Hunt and Hess grading scale score (HH) were associated with unfavourable mRS outcome in univariate logistic regression analysis. Dichotomized S100B was the only variable independently correlated with unfavourable mRS outcome in a multivariate logistic regression analysis.

CONCLUSIONS: For the first time, S100B was shown to correlate with mRS and health-related quality of life at 1 year after aSAH. Peak S100B can be used as a prognostic factor for unfavourable outcome measured as dichotomized mRS after aSAH. A peak value cutoff of 0.4 μg/l is suggested. Ethical approval no: 2013/366-31, 4th of February 2014.

Place, publisher, year, edition, pages
Springer Nature, 2022
Keywords
EQ-5D-3L: EuroQoL health-related quality of life, Modified ranking scale, S100B, Subarachnoid haemorrhage
National Category
Neurology
Identifiers
urn:nbn:se:umu:diva-203261 (URN)10.1007/s00701-022-05272-0 (DOI)000815436500001 ()35748928 (PubMedID)2-s2.0-85132715929 (Scopus ID)
Available from: 2023-01-17 Created: 2023-01-17 Last updated: 2025-11-14Bibliographically approved
4. Neurofilament-light chain, myo-inositol and S100-beta strengthens a multivariable regression model for predicting long-term clinical outcome in patients suffering from subarachnoid haemorrhage
Open this publication in new window or tab >>Neurofilament-light chain, myo-inositol and S100-beta strengthens a multivariable regression model for predicting long-term clinical outcome in patients suffering from subarachnoid haemorrhage
Show others...
(English)Manuscript (preprint) (Other academic)
Keywords
Subarachnoid haemorrhage, neurofilament protein-l, inositol, Glasgow outcome scale extended, cerebral vasospasm, S100B
National Category
Neurology
Identifiers
urn:nbn:se:umu:diva-246425 (URN)
Available from: 2025-11-14 Created: 2025-11-14 Last updated: 2025-11-17Bibliographically approved

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456789107 of 12
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