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Relationship of White Matter Lesions with Intracerebral Hemorrhage Expansion and Functional Outcome: MISTIE II and CLEAR III

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Abstract

Background/Objective

Intracerebral hemorrhage (ICH) patients commonly have concomitant white matter lesions (WML) which may be associated with poor outcome. We studied if WML affects hematoma expansion (HE) and post-stroke functional outcome in a post hoc analysis of patients from randomized controlled trials.

Methods

In ICH patients from the clinical trials MISTIE II and CLEAR III, WML grade on diagnostic computed tomography (dCT) scan (dCT, < 24 h after ictus) was assessed using the van Swieten scale (vSS, range 0–4). The primary outcome for HE was > 33% or > 6 mL ICH volume increase from dCT to the last pre-randomization CT (< 72 h of dCT). Secondary HE outcomes were: absolute ICH expansion, > 10.4 mL total clot volume increase, and a subgroup analysis including patients with dCT < 6 h after ictus using the primary HE definition of > 33% or > 6 mL ICH volume increase. Poor functional outcome was assessed at 180 days and defined as modified Rankin Scale (mRS) ≥ 4, with ordinal mRS as a secondary endpoint.

Results

Of 635 patients, 55% had WML grade 1–4 at dCT (median 2.2 h from ictus) and 13% had subsequent HE. WML at dCT did not increase the odds for primary or secondary HE endpoints (P ≥ 0.05) after adjustment for ICH volume, intraventricular hemorrhage volume, warfarin/INR > 1.5, ictus to dCT time in hours, age, diabetes mellitus, and thalamic ICH location. WML increased the odds for having poor functional outcome (mRS ≥ 4) in univariate analyses (vSS 4; OR 4.16; 95% CI 2.54–6.83; P < 0.001) which persisted in multivariable analyses after adjustment for HE and other outcome risk factors.

Conclusions

Concomitant WML does not increase the odds for HE in patients with ICH but increases the odds for poor functional outcome.

Clinical Trial Registration

http://www.clinicaltrials.gov trial-identifiers: NCT00224770 and NCT00784134.

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Acknowledgments

We thank participating patients and families and the staff and PIs from contributing centers as mentioned in the original publications [25,26,27]. We also thank Nichol McBee and Karen Lane at the Division of Brain Injury Outcomes at Johns Hopkins University, for administrative support.

Funding

CLEAR III (U01NS062851) and MISTIE II (R01NS046309) were supported by Grants awarded to Dr. Hanley by the National Institutes of Health National Institute of Neurological Disorders and Stroke. Genentech donated alteplase. Dr. Hanley is supported by the National Institutes of Health (U01NS080824 and U24TR001609). Dr. Lindgren is supported by the Swedish Heart and Lung Foundation, Skåne University Hospital; the Freemasons Lodge of Instruction EOS, Lund University; and the Swedish Stroke Association. Dr. Norrving is supported by Stiftelsen Färs and Frosta Sparbank.

Author information

Author notes

  1. Björn M. Hansen, Natalie Ullman, Richard E. Thompson and Arne Lindgren have contributed equally to this work.

Authors and Affiliations

  1. Department of Clinical Sciences Lund, Neurology, Skåne University Hospital, Lund University, Lund, Sweden

    Björn M. Hansen, Bo Norrving & Arne Lindgren

  2. Division of Neurology, The Children’s Hospital of Philadelphia, Philadelphia, PA, USA

    Natalie Ullman

  3. Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA

    John Muschelli & Richard E. Thompson

  4. Division of Brain Injury Outcomes, Johns Hopkins University, Baltimore, MD, USA

    Rachel Dlugash, Radhika Avadhani, Wendy C. Ziai & Daniel F. Hanley

  5. Department of Neurosurgery, University of Chicago, Chicago, IL, USA

    Issam Awad

  6. Department of Neurosurgery, University of Cincinnati, Cincinnati, OH, USA

    Mario Zuccarello

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  1. Björn M. Hansen
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Consortia

for the MISTIE and CLEAR Investigators

Contributions

BMH and NU contributed to study conception and design, acquisition of data, analysis and interpretation of data, and drafting and critical revision of the manuscript. JM, RD, RA, and RET contributed to analysis and interpretation of data, and critical revisions to the manuscript. BN, IA, MZ, WCZ, and AL contributed to study conception and design, interpretation of data, and critical revisions to the manuscript. DFH contributed to study conception and design, acquisition of data, analysis and interpretation of data, and critical revision to the manuscript. All authors approved the final version of the manuscript to be published.

Corresponding author

Correspondence to Natalie Ullman.

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Conflict of interest

Dr. Hanley reports Grants from NIH/NINDS, non-financial support from Genentech, during the conduct of the study and personal fees from BrainScope, Neurotrope, Op2Lysis, Portola Pharmaceuticals, and medicolegal, outside the submitted work. Dr. Lindgren reports personal fees from Bayer, BMS/Pfizer, Astra Zeneca, Portola, outside the submitted work. Dr. Norrving reports personal fees for DMC work in the Navigate-ESUS trial (Bayer) and in the SOCRATES and THALES trials (Astra Zeneca). The other authors report no conflicts.

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Hansen, B.M., Ullman, N., Muschelli, J. et al. Relationship of White Matter Lesions with Intracerebral Hemorrhage Expansion and Functional Outcome: MISTIE II and CLEAR III. Neurocrit Care 33, 516–524 (2020). https://doi.org/10.1007/s12028-020-00916-4

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