Florey Department of Neuroscience and Mental Health - Research Publications

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    Mixed methods evaluation to explore participant experiences of a pilot randomized trial to facilitate self-management of people living with stroke: Inspiring virtual enabled resources following vascular events (iVERVE)
    Purvis, T ; Busingye, D ; Andrew, NE ; Kilkenny, MF ; Thrift, AG ; Li, JC ; Cameron, J ; Thijs, V ; Hackett, ML ; Kneebone, I ; Lannin, NA ; Cadilhac, DA (WILEY, 2022-10)
    INTRODUCTION: Despite digital health tools being popular for supporting self-management of chronic diseases, little research has been undertaken on stroke. We developed and pilot tested, using a randomized controlled design, a multicomponent digital health programme, known as Inspiring Virtual Enabled Resources following Vascular Events (iVERVE), to improve self-management after stroke. The 4-week trial incorporated facilitated person-centred goal setting, with those in the intervention group receiving electronic messages aligned to their goals, versus limited administrative messages for the control group. In this paper, we describe the participant experience of the various components involved with the iVERVE trial. METHODS: Mixed method design: satisfaction surveys (control and intervention) and a focus group interview (purposively selected intervention participants). Experiences relating to goal setting and overall trial satisfaction were obtained from intervention and control participants, with feedback on the electronic message component from intervention participants. Inductive thematic analysis was used for interview data and open-text responses, and closed questions were summarized descriptively. Triangulation of data allowed participants' perceptions to be explored in depth. RESULTS: Overall, 27/54 trial participants completed the survey (13 intervention: 52%; 14 control: 48%); and 5/8 invited participants in the intervention group attended the focus group. Goal setting: The approach was considered comprehensive, with the involvement of health professionals in the process helpful in developing realistic, meaningful and person-centred goals. Electronic messages (intervention): Messages were perceived as easy to understand (92%), and the frequency of receipt was considered appropriate (11/13 survey; 4/5 focus group). The content of messages was considered motivational (62%) and assisted participants to achieve their goals (77%). Some participants described the benefits of receiving messages as a 'reminder' to act. Overall trial satisfaction: Messages were acceptable for educating about stroke (77%). Having options for short message services or email to receive messages was considered important. Feedback on the length of the intervention related to specific goals, and benefits of receiving the programme earlier after stroke was expressed. CONCLUSION: The participant experience has indicated acceptance and utility of iVERVE. Feedback from this evaluation is invaluable to inform refinements to future Phase II and III trials, and wider research in the field. PATIENT OR PUBLIC CONTRIBUTION: Two consumer representatives sourced from the Stroke Foundation (Australia) actively contributed to the design of the iVERVE programme. In this study, participant experiences directly contributed to the further development of the iVERVE intervention and future trial design.
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    A mixed-methods feasibility study of a new digital health support package for people after stroke: the Recovery-focused Community support to Avoid readmissions and improve Participation after Stroke (ReCAPS) intervention
    Cameron, J ; Lannin, NA ; Harris, D ; Andrew, NE ; Kilkenny, MF ; Purvis, T ; Thrift, AG ; Thayabaranathan, T ; Ellery, F ; Sookram, G ; Hackett, M ; Kneebone, I ; Drummond, A ; Cadilhac, DA (BMC, 2022-11-19)
    BACKGROUND: Evidence for digital health programmes to support people living with stroke is growing. We assessed the feasibility of a protocol and procedures for the Recovery-focused Community support to Avoid readmissions and improve Participation after Stroke (ReCAPS) trial. METHODS: We conducted a mixed-method feasibility study. Participants with acute stroke were recruited from three hospitals (Melbourne, Australia). Eligibility: Adults with stroke discharged from hospital to home within 10 days, modified Rankin Score 0-4 and prior use of Short Message System (SMS)/email. While in hospital, recruited participants contributed to structured person-centred goal setting and completed baseline surveys including self-management skills and health-related quality of life. Participants were randomised 7-14 days after discharge via REDCap® (1:1 allocation). Following randomisation, the intervention group received a 12-week programme of personalised electronic support messages (average 66 messages sent by SMS or email) aligned with their goals. The control group received six electronic administrative messages. Feasibility outcomes included the following: number of patients screened and recruited, study retainment, completion of outcome measures and acceptability of the ReCAPS intervention and trial procedures (e.g. participant satisfaction survey, clinician interviews). Protocol fidelity outcomes included number of goals developed (and quality), electronic messages delivered, stop messages received and engagement with messages. We undertook inductive thematic analysis of interview/open-text survey data and descriptive analysis of closed survey questions. RESULTS: Between November 2018 and October 2019, 312 patients were screened; 37/105 (35%) eligible patients provided consent (mean age 61 years; 32% female); 33 were randomised (17 to intervention). Overall, 29 (88%) participants completed the12-week outcome assessments with 12 (41%) completed assessments in the allocated timeframe and 16 also completing the satisfaction survey (intervention=10). Overall, trial participants felt that the study was worthwhile and most would recommend it to others. Six clinicians participated in one of three focus group interviews; while they reported that the trial and the process of goal setting were acceptable, they raised concerns regarding the additional time required to personalise goals. CONCLUSION: The study protocol and procedures were feasible with acceptable retention of participants. Consent and goal personalisation procedures should be centralised for the phase III trial to reduce the burden on hospital clinicians. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry, ACTRN12618001468213 (date 31/08/2018); Universal Trial Number: U1111-1206-7237.
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    Self-evaluation of personal needs by community-living young stroke survivors using an online English language questionnaire
    Sapuppo, D ; Bernhardt, J ; Carvalho, LB ; Churilov, L ; Thijs, V (TAYLOR & FRANCIS LTD, 2023-05-22)
    BACKGROUND: Identifying personal needs of young stroke survivors is crucial for their recovery. PURPOSE: Identify factors, burden, and significance of unmet needs of young community-living stroke survivors. MATERIALS AND METHODS: We used online advertising and word-of-mouth snowballing to recruit participants for an English language online questionnaire constructed for this purpose. Eligible participants aged 18-55 at time of stroke. Needs were classified into seven domains: Healthcare Experience, Impairments from Stroke, Everyday Activities, Work/Study, Finances, Relationships, and Social Participation. Random-effects logistic regression was used to determine the probability of unmet needs and X2 test to determine significance of distribution across domains. RESULTS: Out of 137 responses recorded: 32 did not meet inclusion criteria, 29 duplicates identified were discarded, and 76 eligible participants were analysed. Respondents were median 37 (IQR 32-47) years at time of stroke, and median 3 (1-5) years since stroke. Fifty-eight (76%) females. Modified Rankin Scale median score of 1 (1-3). Of 48 identified potential needs, 25 (IQR 19-30) were rated unmet. Twenty (IQR 15-25) considered of high significance. Unmet needs most frequently occurred in the domains: Impairments from Stroke, Finances, and Social Participation. CONCLUSIONS: There is high burden of unmet needs in community-living young stroke survivors which are spread disproportionately across the identified domains.IMPLICATIONS FOR REHABILITATIONIdentifying personal needs of young stroke survivors is crucial for their recovery.Impairments after Stroke, Finances, and Social Participation were often selected as being high burden unmet needs for community-living young people after stroke.Employing a post-stroke checklist to guide exploration of needs in young stroke may better capture which needs are unmet.
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    Factors associated with paid employment 12 months after stroke in A Very Early Rehabilitation Trial (AVERT)
    Cain, S ; Churilov, L ; Collier, JM ; Carvalho, LB ; Borschmann, K ; Moodie, M ; Thijs, V ; Bernhardt, J (ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER, 2022-05)
    BACKGROUND: Returning to work is an important outcome for stroke survivors. OBJECTIVES: This sub-study of a randomised controlled trial aimed to provide characteristics of working-age stroke participants and identify factors associated with return to work at 12 months. METHODS: We used paid employment data collected as part of A Very Early Rehabilitation Trial (AVERT, n=2104), an international randomised controlled trial studying the effects of very early mobilisation after stroke at 56 acute stroke units across Australia, New Zealand, the United Kingdom, Malaysia and Singapore. For the present analysis, data for trial participants < 65 years old were included if they were working at the time of stroke and had complete 12-month return-to-work data. The primary outcome was 12-month return to paid work. Univariable and multivariable logistic regression analyses were conducted to determine the association of multiple factors with return to work. RESULTS: In total, 376 AVERT participants met the inclusion criteria for this sub-study. By 12 months, 221 (59%) participants had returned to work at a median of 38 hr per week. Similar rates were found across geographic regions. On univariable analysis, the odds of returning to paid employment were increased with younger age (OR per year 0.95, 95%CI 0.92-0.97), no previous diabetes (0.4, 0.24-0.67), lower stroke severity (OR per National Institutes of Health Stroke Scale point 0.82, 0.78-0.86), less 3-month depressive traits (Irritability Depression Anxiety [IDA] scale) (OR per IDA point 0.87, 0.80-0.93), less 3-month disability (modified Rankin Scale), and prior full-time work (2.04, 1.23-3.38). On multivariable analysis, return to work remained associated with younger age (OR 0.94, 95%CI 0.91-0.98), lower stroke severity (0.92, 0.86-0.99), prior full-time work (2.33, 1.24-4.40), and less 3-month disability. CONCLUSIONS: Return to work at 12 months after stroke was associated with young age, acute stroke severity, 3-month disability and full-time employment before stroke. Greater understanding of this topic could help in developing programs to support successful resumption of work post-stroke.
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    Deep profiling of multiple ischemic lesions in a large, multi-center cohort: Frequency, spatial distribution, and associations to clinical characteristics
    Bonkhoff, AK ; Ullberg, T ; Bretzner, M ; Hong, S ; Schirmer, MD ; Regenhardt, RW ; Donahue, KL ; Nardin, MJ ; Dalca, A ; Giese, A-K ; Etherton, MR ; Hancock, BL ; Mocking, SJT ; McIntosh, EC ; Attia, J ; Cole, JW ; Donatti, A ; Griessenauer, CJ ; Heitsch, L ; Holmegaard, L ; Jood, K ; Jimenez-Conde, J ; Kittner, SJ ; Lemmens, R ; Levi, CR ; McDonough, CW ; Meschia, JF ; Phuah, C-L ; Ropele, S ; Rosand, J ; Roquer, J ; Rundek, T ; Sacco, RL ; Schmidt, R ; Sharma, P ; Slowik, A ; Sousa, A ; Stanne, TM ; Strbian, D ; Tatlisumak, T ; Thijs, V ; Vagal, A ; Woo, D ; Zand, R ; McArdle, PF ; Worrall, BB ; Jern, C ; Lindgren, AG ; Maguire, J ; Wu, O ; Frid, P ; Rost, NS ; Wasselius, J (FRONTIERS MEDIA SA, 2022-08-25)
    BACKGROUND PURPOSE: A substantial number of patients with acute ischemic stroke (AIS) experience multiple acute lesions (MAL). We here aimed to scrutinize MAL in a large radiologically deep-phenotyped cohort. MATERIALS AND METHODS: Analyses relied upon imaging and clinical data from the international MRI-GENIE study. Imaging data comprised both Fluid-attenuated inversion recovery (FLAIR) for white matter hyperintensity (WMH) burden estimation and diffusion-weighted imaging (DWI) sequences for the assessment of acute stroke lesions. The initial step featured the systematic evaluation of occurrences of MAL within one and several vascular supply territories. Associations between MAL and important imaging and clinical characteristics were subsequently determined. The interaction effect between single and multiple lesion status and lesion volume was estimated by means of Bayesian hierarchical regression modeling for both stroke severity and functional outcome. RESULTS: We analyzed 2,466 patients (age = 63.4 ± 14.8, 39% women), 49.7% of which presented with a single lesion. Another 37.4% experienced MAL in a single vascular territory, while 12.9% featured lesions in multiple vascular territories. Within most territories, MAL occurred as frequently as single lesions (ratio ∼1:1). Only the brainstem region comprised fewer patients with MAL (ratio 1:4). Patients with MAL presented with a significantly higher lesion volume and acute NIHSS (7.7 vs. 1.7 ml and 4 vs. 3, p FDR < 0.001). In contrast, patients with a single lesion were characterized by a significantly higher WMH burden (6.1 vs. 5.3 ml, p FDR = 0.048). Functional outcome did not differ significantly between patients with single versus multiple lesions. Bayesian analyses suggested that the association between lesion volume and stroke severity between single and multiple lesions was the same in case of anterior circulation stroke. In case of posterior circulation stroke, lesion volume was linked to a higher NIHSS only among those with MAL. CONCLUSION: Multiple lesions, especially those within one vascular territory, occurred more frequently than previously reported. Overall, multiple lesions were distinctly linked to a higher acute stroke severity, a higher total DWI lesion volume and a lower WMH lesion volume. In posterior circulation stroke, lesion volume was linked to a higher stroke severity in multiple lesions only.
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    Association of White Blood Cell Count With Clinical Outcome Independent of Treatment With Alteplase in Acute Ischemic Stroke
    Barow, E ; Quandt, F ; Cheng, B ; Gelderblom, M ; Jensen, M ; Koenigsberg, A ; Boutitie, F ; Nighoghossian, N ; Ebinger, M ; Endres, M ; Fiebach, JB ; Thijs, V ; Lemmens, R ; Muir, KW ; Pedraza, S ; Simonsen, CZ ; Gerloff, C ; Thomalla, G (FRONTIERS MEDIA SA, 2022-06-13)
    INTRODUCTION: Higher white blood cell (WBC) count is associated with poor functional outcome in acute ischemic stroke (AIS). However, little is known about whether the association is modified by treatment with intravenous alteplase. METHODS: WAKE-UP was a randomized controlled trial of the efficacy and safety of magnetic resonance imaging [MRI]-based thrombolysis in unknown onset stroke. WBC count was measured on admission and again at 22-36 h after randomization to treatment (follow-up). Favorable outcome was defined by a score of 0 or 1 on the modified Rankin scale (mRS) 90 days after stroke. Further outcome were stroke volume and any hemorrhagic transformation (HT) that were assessed on follow-up CT or MRI. Multiple logistic regression analysis was used to assess the association between outcome and WBC count and treatment group. RESULTS: Of 503 randomized patients, WBC count and baseline parameters were available in 437 patients (μ = 64.7 years, 35.2% women) on admission and 355 patients (μ = 65.1 years, 34.1% women) on follow-up. Median WBC count on admission was 7.6 × 109/L (interquartile range, IQR, 6.1-9.4 × 109/L) and 8.2 × 109/L (IQR, 6.7-9.7 × 109/L) on follow-up. Higher WBC count both on admission and follow-up was associated with lower odds of favorable outcome, adjusted for age, National Institutes of Health (NIH) Stroke Scale Score, temperature, and treatment (alteplase vs. placebo, adjusted odds ratio, aOR 0.85, 95% confidence interval [CI] 0.78-0.94 and aOR 0.88, 95% CI 0.79-0.97). No interaction between WBC count and treatment group was observed (p = 0.11). Furthermore, WBC count on admission and follow-up was significantly associated with HT (aOR 1.14, 95% CI 1.05-1.24 and aOR 1.13, 95% CI 1.00-1.26). Finally, WBC count on follow-up was associated with larger stroke volume (aOR 2.57, 95% CI 1.08-6.07). CONCLUSION: Higher WBC count is associated with unfavorable outcome, an increased risk of HT, and larger stroke volume, independent of treatment with alteplase. Whether immunomodulatory manipulation of WBC count improves stroke outcome needs to be tested. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01525290.
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    Reversible Relative FLAIR Signal Intensity Changes in the Penumbra Correlate With Severity of Hypoperfusion.
    Scheldeman, L ; Wouters, A ; Dupont, P ; Christensen, S ; Boutitie, F ; Cheng, B ; Ebinger, M ; Endres, M ; Fiebach, JB ; Gerloff, CP ; Muir, KW ; Nighoghossian, N ; Pedraza, S ; Simonsen, C ; Ringelstein, EB ; Chamorro, A ; Grond, M ; Laage, R ; Thomalla, G ; Thijs, V ; Lemmens, R (LIPPINCOTT WILLIAMS & WILKINS, 2021-03)
    In ischemic stroke, the study of edema, measurable as fluid attenuated inversion recovery (FLAIR) signal increase, has mainly focused on the ischemic core and less on the surrounding penumbra. To the naked eye, no FLAIR changes are present in the penumbra. However, changes in perfusion status could induce physiological changes resulting in subtle penumbral FLAIR signal alterations. To investigate penumbral FLAIR changes, we included subjects from the Efficacy and Safety of MRI-Based Thrombolysis in Wake-Up Stroke (WAKE-UP) and Granulocyte Colony-Stimulating Factor in Patients With Acute Ischemic Stroke (AXIS 2) trial with perfusion- and diffusion-weighted imaging (PWI, DWI) and FLAIR at baseline. We used RAPID software to calculate the core and perfusion lesion on DWI and PWI and selected subjects with a minimal mismatch volume (15 ml) and ratio (1.2). We created voxel-based relative FLAIR signal intensity (rFLAIR SI) maps at baseline and follow up (FU) by calculating the ratio of the FLAIR intensity in one voxel and the median FLAIR intensity in a sphere with 15 mm radius around a contralateral homologues voxel. We studied rFLAIR SI in two regions of interest: the baseline penumbra (baseline perfusion lesion - [core lesion + voxels with apparent diffusion coefficient <620 10 -6 mm 2 /s]) and the non-infarcted penumbra (baseline perfusion lesion - FU FLAIR lesion) at 24 hours (WAKE-UP) or 30 days (AXIS 2). Severity of hypoperfusion was defined as the time to maximum of the residue function. In the baseline penumbra, rFLAIR SI was elevated (ratio=1.04, p=1.7*10 -13 , n=126) and correlated with severity of hypoperfusion (Pearson’s r 0.03, p<1.0*10 -4 , n=126). At 24 hours in a subgroup from WAKE-UP, rFLAIR SI in the non-infarcted penumbra further increased (ratio=1.05 at 24h vs 1.03 at baseline, p=7.1*10 -3 , n=43). In a different subgroup from AXIS 2, this increase in rFLAIR SI was reversible (ratio=1.02 at 30d vs 1.04 at baseline, p=1.5*10 -3 n=26) since it was no longer different from 1 at 30 days (ratio=1.01 at 30 days, p=0.099, n=26). Increases in rFLAIR SI, likely representing edema, are not restricted to the ischemic core and correlate with severity of hypoperfusion in the penumbra. They appear early after stroke onset, further increase at 24 hours and are reversible by 30 days.
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    Migraine-Associated Common Genetic Variants Confer Greater Risk of Posterior vs. Anterior Circulation Ischemic Stroke☆.
    Frid, P ; Xu, H ; Mitchell, BD ; Drake, M ; Wasselius, J ; Gaynor, B ; Ryan, K ; Giese, AK ; Schirmer, M ; Donahue, KL ; Irie, R ; Bouts, MJRJ ; McIntosh, EC ; Mocking, SJT ; Dalca, AV ; Giralt-Steinhauer, E ; Holmegaard, L ; Jood, K ; Roquer, J ; Cole, JW ; McArdle, PF ; Broderick, JP ; Jimenez-Conde, J ; Jern, C ; Kissela, BM ; Kleindorfer, DO ; Lemmens, R ; Meschia, JF ; Rosand, J ; Rundek, T ; Sacco, RL ; Schmidt, R ; Sharma, P ; Slowik, A ; Thijs, V ; Woo, D ; Worrall, BB ; Kittner, SJ ; Petersson, J ; Golland, P ; Wu, O ; Rost, NS ; Lindgren, A (Elsevier BV, 2022-08)
    OBJECTIVE: To examine potential genetic relationships between migraine and the two distinct phenotypes posterior circulation ischemic stroke (PCiS) and anterior circulation ischemic stroke (ACiS), we generated migraine polygenic risk scores (PRSs) and compared these between PCiS and ACiS, and separately vs. non-stroke control subjects. METHODS: Acute ischemic stroke cases were classified as PCiS or ACiS based on lesion location on diffusion-weighted MRI. Exclusion criteria were lesions in both vascular territories or uncertain territory; supratentorial PCiS with ipsilateral fetal posterior cerebral artery; and cases with atrial fibrillation. We generated migraine PRS for three migraine phenotypes (any migraine; migraine without aura; migraine with aura) using publicly available GWAS data and compared mean PRSs separately for PCiS and ACiS vs. non-stroke control subjects, and between each stroke phenotype. RESULTS: Our primary analyses included 464 PCiS and 1079 ACiS patients with genetic European ancestry. Compared to non-stroke control subjects (n=15396), PRSs of any migraine were associated with increased risk of PCiS (p=0.01-0.03) and decreased risk of ACiS (p=0.010-0.039). Migraine without aura PRSs were significantly associated with PCiS (p=0.008-0.028), but not with ACiS. When comparing PCiS vs. ACiS directly, migraine PRSs were higher in PCiS vs. ACiS for any migraine (p=0.001-0.010) and migraine without aura (p=0.032-0.048). Migraine with aura PRS did not show a differential association in our analyses. CONCLUSIONS: Our results suggest a stronger genetic overlap between unspecified migraine and migraine without aura with PCiS compared to ACiS. Possible shared mechanisms include dysregulation of cerebral vessel endothelial function.
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    New remote cerebral microbleeds in acute ischemic stroke: an analysis of the randomized, placebo-controlled WAKE-UP trial
    Braemswig, TB ; Vynckier, J ; Jensen, M ; Boutitie, F ; Galinovic, I ; Simonsen, CZ ; Cheng, B ; Cho, T-H ; Scheitz, JF ; Fiehler, J ; Puig, J ; Thijs, V ; Fiebach, JB ; Muir, KW ; Nighoghossian, N ; Ebinger, M ; Pedraza, S ; Thomalla, G ; Gerloff, C ; Endres, M ; Lemmens, R ; Schlemm, L ; Nolte, CH (SPRINGER HEIDELBERG, 2022-10)
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    24-hour blood pressure variability and treatment effect of intravenous alteplase in acute ischaemic stroke
    Barow, E ; Boutitie, F ; Cheng, B ; Cho, T-H ; Ebinger, M ; Endres, M ; Fiebach, JB ; Fiehler, J ; Nickel, A ; Puig, J ; Roy, P ; Lemmens, R ; Thijs, V ; Muir, KW ; Nighoghossian, N ; Pedraza, S ; Simonsen, CZ ; Gerloff, C ; Thomalla, G (SAGE PUBLICATIONS LTD, 2021-06)
    INTRODUCTION: To assess the association between 24 h blood pressure variability (BPV) on functional outcome and treatment effect of intravenous alteplase in acute ischaemic stroke. PATIENTS AND METHODS: In all patients with acute ischaemic stroke of unknown onset randomised in the WAKE-UP (Efficacy and Safety of magnetic resonance imaging [MRI]-based Thrombolysis in Wake-Up Stroke) trial, blood pressure (BP) was measured before randomisation and after initiation of treatment at regular intervals up to 24 hours. Individual BPV was measured by coefficient of variation (CV) of all BP values. Primary outcome measure was favourable outcome defined by a modified Rankin Scale (mRS) score 0 or 1 at 90 days after stroke. RESULTS: BP measurements were available for 498 of 503 patients randomised (177 women [35.5%], mean age [SD] of 65.2 [11.5] years). Systolic BPV was not associated with the treatment effect of thrombolysis (test for interaction, p = 0.46). The adjusted odds ratio (aOR) for favourable outcome with alteplase, adjusted for age, stroke severity and baseline BP on admission, did not show an association across the quintiles of increasing systolic BPV with an aOR 1.89 (95% confidence interval [CI], 0.76-4.70) in the lowest quintile to aOR 1.05 (95% CI, 0.43-2.56) in the highest quintile. Higher mean systolic BP was associated with a smaller treatment effect of thrombolysis with a significant interaction (p = 0.033). The aOR for favourable outcome with alteplase decreased with quintiles of increasing mean systolic BP from aOR 3.16 (95% CI, 1.26-7.93) in the lowest quintile to aOR 0.84 (95% CI, 0.34-2.10) in in the highest quintile. CONCLUSIONS: There was a significant interaction between mean systolic BP and treatment effect of thrombolysis with higher mean systolic BP being associated with poorer outcome. BPV was not associated with outcome after thrombolysis.ClinicalTrials.gov identifier NCT01525290.