WSO - January 2024 - 69

Schleicher et al.
69
reversed by day 90 for both measures. In the first 2 days after stroke, the change in CSF volume was associated with
MLS (ρ = -0.57, p = 0.0001) and HVR (ρ = -0.66, p < 0.0001). In contrast, the change in NWU was not associated with the
other imaging markers (all p ⩾ 0.49). While being directionally consistent, we did not observe a difference in the edema
markers by clinical outcome. In addition, baseline stroke volume was associated with all markers (MLS (p < 0.001), HVR
(p < 0.001), change in CSF volume (p = 0.003)) with the exception of NWU (p = 0.5). Exploratory analysis did not reveal
a difference in cerebral edema markers by treatment arm.
Conclusions: Existing cerebral edema imaging markers potentially describe two distinct processes, including lesional
water concentration (i.e. NWU) and mass effect (MLS, HVR, and CSF volume). These two types of imaging markers may
represent distinct aspects of cerebral edema, which could be useful for future trials targeting this process.
Keywords
Ischemic stroke, edema, imaging markers
Received: 13 January 2023; accepted: 27 May 2023
Introduction
Brain edema is a secondary complication of acute ischemic
stroke that is associated with an increased risk of morbidity
and mortality.1,2 Cerebral edema may worsen outcome by
causing mass effect that impairs microvascular perfusion
through mechanical compression. Mass effect is proportional
to stroke volume and the degree of water accumulation
within the stroke lesion. Consequently, several different
imaging measures have been developed to measure mass
effect more sensitively, or parse the contributing mechanisms
that are independent of initial stroke volume.3-8
These distinctions are particularly relevant to proof-of-concept
phase 2 clinical studies that target hemorrhagic transformation,
brain edema, or both.
The most commonly utilized imaging marker of mass
effect is midline shift (MLS),9 which is easily measured
and is associated with poor neurological recovery10,11 and
early mortality.12 However, MLS may be less sensitive to
edema associated with smaller volume infarction13 and
results from any potential causes of mass effect. Selective
intermediate imaging endpoints could therefore help inform
the interpretation of the mechanism of action of investigational
therapies.5 Three of the more commonly employed
techniques include cerebrospinal fluid (CSF) volumetric
analysis,4 hemisphere volume ratio (HVR)13, and net water
uptake (NWU).6,7 Of these, NWU could provide insight
into the accumulation of water in the stroke lesion, whereas
HVR and CSF volumes reflect contributions to mass effect.
Aims
In this study, we sought to describe edema formation and
resolution over time and test the hypothesis that NWU is
associated with mass effect by utilizing serial neuroimaging
obtained during a phase 2 clinical trial of acute ischemic
stroke, the NeuroNEXT NN104 (RHAPSODY) trial (clinicaltrial.gov
NCT02222714). The acquisition of serial,
protocol-specified imaging facilitated the analysis of serial
measurements of NWU, CSF volume, HVR, and MLS over
time. Using this cohort, we describe the imaging markers
over time, and evaluate the association of NWU with CSF
volume, HVR, and MLS.
Methods
Patient cohort
This was a post hoc analysis of the RHAPSODY trial, a
phase 2 trial investigating the safety and tolerability of four
dose levels of a recombinant variant of human activated
protein C (APC), 3K3A-APC, in moderate-to-severe acute
ischemic stroke patients receiving tissue plasminogen activator
(tPA), mechanical thrombectomy, or both.14 Between
January 2015 and April 2017, patients were enrolled from
22 participating sites. All enrolled patients or their surrogates
provided informed consent following a centralized
institutional review board and met previously published
inclusion and exclusion criteria.15 Randomization was
completed as described in the original trial report.14
Of the 110 participants originally enrolled in RHAPSODY,
patients were excluded from this analysis if the stroke lesion
could not be definitively located on the images (n = 23), the
stroke volume was < 10 mL (n = 12), the stroke lesion was in
the brainstem or was bilateral (n = 6), imaging was distorted
with motion (n = 2), or the image showed evidence of parenchymal
hematoma (PH; n = 2). The final study population
(n = 65) included 37 participants who received study drug at
any dose level and 28 who received placebo. Among the 65
participants, a total of 258 separate imaging studies were
analyzed. During hospitalization, clinical and demographic
data were collected, including admission National Institutes
of Health Stroke Scale (NIHSS), admission modified Rankin
Scale (mRS) score, and recanalization therapy. Information
regarding the type of recanalization therapy received (IV tPA
and/or mechanical thrombectomy) was collected when
International Journal of Stroke, 19(1)
http://www.caltrial.gov
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