International Journal of Stroke

Stroke rehabilitation interventions are routinely personalized to address individuals’ needs, goals, and challenges based on evidence from aggregated randomized controlled trials (RCT) data and meta-syntheses. Individual participant data (IPD) meta-analyses may better inform the development of precision rehabilitation approaches, quantifying treatment responses while adjusting for confounders and reducing ecological bias.

We explored associations between speech and language therapy (SLT) interventions frequency (days/week), intensity (h/week), and dosage (total SLT-hours) and language outcomes for different age, sex, aphasia severity, and chronicity subgroups by undertaking prespecified subgroup network meta-analyses of the RELEASE database.

MEDLINE, EMBASE, and trial registrations were systematically searched (inception-Sept2015) for RCTs, including ⩾ 10 IPD on stroke-related aphasia. We extracted demographic, stroke, aphasia, SLT, and risk of bias data. Overall-language ability, auditory comprehension, and functional communication outcomes were standardized. A one-stage, random effects, network meta-analysis approach filtered IPD into a single optimal model, examining SLT regimen and language recovery from baseline to first post-intervention follow-up, adjusting for covariates identified a-priori. Data were dichotomized by age (⩽/> 65 years), aphasia severity (mild–moderate/ moderate–severe based on language outcomes’ median value), chronicity (⩽/> 3 months), and sex subgroups. We reported estimates of means and 95% confidence intervals. Where relative variance was high (> 50%), results were reported for completeness.

959 IPD (25 RCTs) were analyzed. For working-age participants, greatest language gains from baseline occurred alongside moderate to high-intensity SLT (functional communication 3-to-4 h/week; overall-language and comprehension > 9 h/week); older participants’ greatest gains occurred alongside low-intensity SLT (⩽ 2 h/week) except for auditory comprehension (> 9 h/week). For both age-groups, SLT-frequency and dosage associated with best language gains were similar. Participants ⩽ 3 months post-onset demonstrated greatest overall-language gains for SLT at low intensity/moderate dosage (⩽ 2 SLT-h/week; 20-to-50 h); for those > 3 months, post-stroke greatest gains were associated with moderate-intensity/high-dosage SLT (3–4 SLT-h/week; ⩾ 50 hours). For moderate–severe participants, 4 SLT-days/week conferred the greatest language gains across outcomes, with auditory comprehension gains only observed for ⩾ 4 SLT-days/week; mild–moderate participants’ greatest functional communication gains were associated with similar frequency (⩾ 4 SLT-days/week) and greatest overall-language gains with higher frequency SLT (⩾ 6 days/weekly). Males’ greatest gains were associated with SLT of moderate (functional communication; 3-to-4 h/weekly) or high intensity (overall-language and auditory comprehension; (> 9 h/weekly) compared to females for whom the greatest gains were associated with lower-intensity SLT (< 2 SLT-h/weekly). Consistencies across subgroups were also evident; greatest overall-language gains were associated with 20-to-50 SLT-h in total; auditory comprehension gains were generally observed when SLT > 9 h over ⩾ 4 days/week.

We observed a treatment response in most subgroups’ overall-language, auditory comprehension, and functional communication language gains. For some, the maximum treatment response varied in association with different SLT-frequency, intensity, and dosage. Where differences were observed, working-aged, chronic, mild–moderate, and male subgroups experienced their greatest language gains alongside high-frequency/intensity SLT. In contrast, older, moderate–severely impaired, and female subgroups within 3 months of aphasia onset made their greatest gains for lower-intensity SLT. The acceptability, clinical, and cost effectiveness of precision aphasia rehabilitation approaches based on age, sex, aphasia severity, and chronicity should be evaluated in future clinical RCTs.

In patients with acute ischemic stroke due to large vessel occlusion (AIS–LVO), development of extensive early ischemic brain edema is associated with poor functional outcomes, despite timely treatment. Robust cortical venous outflow (VO) profiles correlate with favorable tissue perfusion. We hypothesized that favorable VO profiles (VO+) correlate with a reduced early edema progression rate (EPR) and good functional outcomes.

Multicenter, retrospective analysis to investigate AIS–LVO patients treated by mechanical thrombectomy between May 2013 and December 2020. Baseline computed tomography angiography (CTA) was used to determine VO using the cortical vein opacification score (COVES); VO+ was defined as COVES ⩾ 3 and unfavorable as COVES ⩽ 2. EPR was determined as the ratio of net water uptake (NWU) on baseline non-contrast CT and time from symptom onset to admission imaging. Multivariable regression analysis was performed to assess primary (EPR) and secondary outcome (good functional outcomes defined as 0–2 points on the modified Rankin scale).

A total of 728 patients were included. Primary outcome analysis showed VO+ (β: –0.03, SE: 0.009, p = 0.002), lower presentation National Institutes of Health Stroke Scale (NIHSS; β: 0.002, SE: 0.001, p = 0.002), and decreased time from onset to admission imaging (β: –0.00002, SE: 0.00004, p < 0.001) were independently associated with reduced EPR. VO+ also predicted good functional outcomes (odds ratio (OR): 5.07, 95% CI: 2.839–9.039, p < 0.001), while controlling for presentation NIHSS, time from onset to imaging, general vessel reperfusion, baseline Alberta Stroke Program Early CT Score, infarct core volume, EPR, and favorable arterial collaterals.

Favorable VO profiles were associated with slower infarct edema progression and good long-term functional outcomes as well as better neurological status and ischemic brain alterations at admission.

Recent studies in the general stroke population treated with endovascular treatment (EVT) reported that higher pre-treatment lesional volumes were independently associated with poor neurological outcome and functional dependence after stroke. However, it has been not evaluated in older patients.

We test the association between the pre-treatment lesional volume on diffusion-weighted magnetic resonance imaging and relevant outcome measures in older adults with stroke treated with EVT.

We included consecutive older adults with stroke (⩾80 years old) treated with EVT in two academic comprehensive stroke centers. The association between pre-treatment lesional volume and relevant outcome measures (poor outcome (modified Rankin scale 4–6), 3-month mortality and symptomatic intracerebral hemorrhage (sICH)) was evaluated using univariate and multivariable models.

Five hundred seventy-nine patients were included (mean age: 85.6 ± 4.1, median lesional volume was 10 ml; interquartile range: 3–30 ml). Pre-treatment lesional volume was associated with poor functional outcome (adjusted odds ratio (aOR): 1.87, 95% confidence interval (CI): 1.60–2.20, for +1 logarithmic increase of lesional volume), 3-month mortality (aOR: 1.50, CI: 1.28–1.76), and sICH (aOR: 1.67, CI: 1.27–2.20). A threshold lesional volume >35 ml predicted 90% of patients with poor functional outcome and a cut-off >51 ml predicted 90% of patients dead at 3 months.

Pre-treatment lesional volume might contribute, in association with other relevant clinical features, to the selection of older stroke patients who will benefit from EVT.

Although anxiety is common in several neurological conditions, it has been poorly investigated after spontaneous intracerebral hemorrhage (ICH).

In consecutive ICH survivors, we assessed the long-term prevalence of anxiety and its clinical and radiological determinants.

Using the Hospital Anxiety and Depression Scale (HADS), we evaluated ICH survivors enrolled in the prospective, single-center Prognosis of Intracerebral Hemorrhage (PITCH) study. The prevalence of anxiety (defined as a HADS-anxiety subscale score >7) was evaluated at three time points (1–2, 3–5, and 6–8 years after ICH), along with neurological symptoms severity, functional disability, and cognitive impairment scores. Clinical and radiological characteristics associated with anxiety were evaluated in univariate and multivariable models.

Of 560 patients with spontaneous ICH, 255 were alive 1 year later, 179 of whom completed the HADS questionnaire and were included in the study. Thirty-one patients (17%; 95% confidence interval (CI) = 12–23) had anxiety 1–2 years, 38 (27%; 95% CI = 19–34) 3–5 years, and 18 (21%; 95% CI = 12–30) 6–8 years after ICH. In patients with anxiety, the prevalence of associated depressive symptoms was 48% 1–2 years, 61% 3–5 years, and 56% 6–8 years after ICH. Among clinical and radiological baseline characteristics, only lobar ICH location was significantly associated with anxiety 1–2 years after ICH (odds ratio = 2.8; 95% CI = 1.2–6.5). Anxiety was not associated with concomitant neurological symptoms severity, functional disability, or cognitive impairment.

Anxiety is frequent in ICH survivors, often in association with depressive symptoms, even many years after the index event.

Preventive screening for intracranial aneurysms is effective in persons with a positive family history of aneurysmal subarachnoid hemorrhage (aSAH), but for many relatives of aSAH patients, it can be difficult to assess whether their relative had an aSAH or another type of stroke.

We aimed to develop a family history questionnaire for people in the population who believe they have a first-degree relative who had a stroke and to assess its accuracy to identify relatives of aSAH patients.

A questionnaire to distinguish between aSAH and other stroke types (ischemic stroke and intracerebral hemorrhage) was developed by a team of clinicians and consumers. The level of agreement between the questionnaire outcome and medical diagnosis was pilot tested in 30 previously admitted aSAH patients. Next, the sensitivity and specificity of the questionnaire were assessed in 91 first-degree relatives (siblings/children) of previously admitted stroke patients.

All 30 aSAH patients were identified by the questionnaire in the pilot study; 29 of 30 first-degree relatives of aSAH patients were correctly identified. The questionnaire had a sensitivity of 97% (95% confidence interval (CI) = 83–100%) and a specificity of 93% (95% CI = 84–98%) when tested in the first-degree relatives of stroke patients.

Our questionnaire can help persons to discriminate an aSAH from other types of stroke in their affected relative. This family history questionnaire is developed in the Netherlands but could also be used in other countries after validation.

Intracranial aneurysm (IA) is a crucial health concern with limited strategies for prevention and treatment.

To identify potentially modifiable risk factors, such as socioeconomic, behaviors, dietary, and cardiometabolic factors, for IA and its subtypes.

Summary statistics for IA were derived from a genome-wide association study with an overall 79,429 participants. Single nucleotide polymorphisms associated with modifiable risk factors at genome-wide significance (P = 5 × 10^–8) were used as instrumental variables. The inverse-variance-weighted method, weighted-median method, Mendelian randomization (MR)-Egger regression, MR-Pleiotropy RESidual Sum and Outlier, and multivariable MR analyses were performed to evaluate the effect estimates.

Genetically predicted educational attainment, insomnia, smoking, and systolic and diastolic blood pressure (SBP and DBP) were significantly associated with the risk of IA. The odds ratios (ORs) were 0.44 (95% confidence interval (CI): 0.37–0.52) for educational attainment, 1.15 (95% CI: 1.08–1.23) for insomnia, 1.56 (95% CI: 1.38–1.75) for smoking initiation, 2.69 (95% CI: 1.77–4.07) for cigarette per day, 2.65 (95% CI: 1.72–4.08) for lifetime smoking, 1.07 (95% CI: 1.06–1.09), and 1.06 (95% CI: 1.04–1.10) for SBP and DBP, respectively. Similar effect estimates were observed for unruptured IAs and aneurysmal subarachnoid hemorrhage.

This study provided genetic evidence that several modifiable risk factors, including blood pressure, smoking, educational attainment, and insomnia were associated with the risk of IA.

Effects of early blood pressure (BP) lowering on cerebral perfusion in patients with moderate/severe occlusive carotid disease after transient ischemic attack (TIA) and non-disabling stroke are uncertain.

We aimed to evaluate the changes in transcranial Doppler (TCD) indices in patients undergoing blood pressure lowering soon after TIA/non-disabling stroke.

Consecutive eligible patients (1 November 2011 to 30 October 2018) attending a rapid-access clinic with TIA/non-disabling stroke underwent telemetric home blood pressure monitoring (HBPM) for 1 month and middle cerebral artery velocities measurements ipsilateral to carotid stenosis on TCD ultrasound in the acute setting and at 1 month. Hypertensive patients (HBPM ⩾ 135/85) underwent intensive BP-lowering guided by HBPM unless they had bilateral severe occlusive disease (⩾ 70%). Changes in BP and TCD parameters were compared in patients with extracranial moderate/severe carotid stenosis (between 50% and occlusion) versus those with no or mild (< 50%) stenosis.

Of 764 patients with repeated TCD measures, 42 had moderate/severe extracranial carotid stenosis without bilateral severe occlusive disease. HBPM was reduced from baseline to 1 month in hypertensive patients both with versus without moderate/severe carotid stenosis (−12.44/15.99 vs −13.2/12.2 mmHg, respectively, p-difference = 0.82), and changes in TCD velocities (4.69/14.94 vs 2.69/13.86 cm/s, respectively, p-difference = 0.52 for peak systolic velocity and 0.33/7.06 vs 1.75/6.84 cm/s, p-difference = 0.34 for end-diastolic velocity) were also similar, with no evidence of greater hemodynamic compromise in patients with stenosis/occlusion.

There was no evidence of worsening of TCD hemodynamic indices in patients with moderate/severe occlusive carotid disease treated with BP-lowering soon after TIA/non-disabling stroke, suggesting that antihypertensive treatment in this group of patients is safe in the acute setting of TIA clinics.

The hyperintense acute reperfusion marker (HARM) describes a phenomenon with a hyperintense signal in the subarachnoid space in Fluid-Attenuated Inversion Recovery (FLAIR) magnetic resonance imaging (MRI) sequences, presumably based on blood–brain barrier breakdown in acute stroke with reperfusion. However, this imaging phenomenon was described in other medical conditions.

Determination of the prevalence and associated clinical findings of this phenomenon in a large sample of patients with different neurological conditions.

This is retrospective, single-center, observational study of 23,948 cerebral MRIs acquired in a Neurological University Clinic over 5 years. The prevalence of HARM, the underlying diagnosis, and damage pattern were examined by chart analysis; MRI was analyzed regarding the type of acute lesions, extent of microangiopathic lesions, and whether gadolinium-based contrast agent (GBCA) was given.

Among the MRI data, 84 images (0.35%) from 61 patients were HARM-positive without a subarachnoid signal abnormality in any other sequence. Etiologies were heterogeneous; 35 patients had a cerebrovascular disease (CVD; 19 patients received recanalization therapy), 12 patients had an inflammatory central nervous system (CNS) disease and 14 patients had epilepsy. GBCA was applied to 64% of the patients.

HARM was a rare radiological finding in a range of different neurological pathologies, not limited to stroke, or to previous reperfusion therapy and was not dependent on previous GBCA administration. Our data suggest that the term is too narrow in terms of the concepts of the underlying pathology. We propose to use the term FLAIR Subarachnoid Hyperintensity (“FLASH”) phenomenon which might better reflect the observation that the radiological sign can be associated with a variety of central neurological conditions without a straightforward association with therapy.

The aim of this study was to better define the shape of association between the degree (“magnitude”) of early (< 1 h) reduction in systolic blood pressure (SBP) and outcomes in patients with acute intracerebral hemorrhage (ICH) through pooled analysis of the second Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage Trial (INTERACT2) and second Antihypertensive Treatment of Acute Cerebral Hemorrhage (ATACH-II) datasets.

Association of the continuous magnitude of SBP reduction described using cubic splines and an ordinal measure of the functional outcome on the modified Rankin scale (mRS) scores at 90 days were analyzed in generalized linear mixed models. Models were adjusted for achieved (mean) and variability (standard deviation, SD) of SBP between 1 and 24 h, various baseline covariates, and trial as a random effect.

Among 3796 patients (mean age 63.1 (SD = 13.0) years; female 37.4%), with a mean magnitude (< 1 h) of SBP reduction of 28.5 (22.8) mmHg, those with larger magnitude were more often non-Asian and female, had higher baseline SBP, received multiple blood pressure (BP) lowering agents, and achieved lower SBP levels in 1–24 h. Compared to those patients with no SBP reduction within 1 h (reference), the adjusted odds of unfavorable functional outcome, according to a shift in mRS scores, were lower for SBP reductions up to 60 mmHg with an inflection point between 32 and 46 mmHg, but significantly higher for SBP reductions > 70 mmHg. Similar J-shape associations were evident across various time epochs across 24 h and consistent according to baseline hematoma volume and SBP and history of hypertension.

A moderate degree of rapid SBP lowering is associated with improved functional outcome after ICH, but large SBP reductions over 1 h (e.g. from > 200 to target < 140 mmHg) were associated with reduction, or reversal, of any such benefit.

To determine if treadmill training embedded in self-management education commencing during stroke inpatient rehabilitation results in more physical activity than usual gait training.

A prospective, parallel-group, randomized trial with concealed allocation, blinded measurement, and intention-to-treat analysis involving 119 stroke survivors undergoing rehabilitation who were able to walk independently was undertaken. The experimental group undertook treadmill training (40–60% heart rate reserve) and self-management education for 30 min, three times a week for 8 weeks, and the control group undertook the same amount of usual gait training. Outcomes were measured at baseline (Week 0), on completion of the intervention (Week 8), and beyond the intervention (Week 26). The primary outcome was physical activity measured as steps/day using an activity monitor. Secondary outcomes were walking ability, cardiorespiratory fitness, cardiovascular risk, depression, self-efficacy, perception of physical activity, participation, and quality of life.

After 8 weeks, the experimental group took 1436 more steps/day (95% confidence interval (CI) = 229 to 2643) than the control group. By 6 months, they took 871 more steps/day (95% CI −385 to 2129) than the control group. There was no difference between groups in any other outcome.

In individuals undergoing rehabilitation after stroke, 8 weeks of treadmill training embedded in self-management resulted in more physical activity than usual gait training and this was largely maintained at 6 months, despite little effect on walking or cardiorespiratory fitness, suggesting the self-management was responsible.

Arterial stiffness index (ASI) is a potential risk factor for cerebrovascular and cardiometabolic diseases, but the causal links between them are inconclusive. The aim is to evaluate the causal effects of ASI on cerebrovascular and cardiometabolic diseases by Mendelian randomization (MR).

Two-sample MR analysis was performed to infer causal links. Genetic variants significantly associated with ASI were extracted. The inverse variance weighted method was used for estimating the effects. Sensitivity analysis was performed to test heterogeneity or pleiotropy.

MR analysis indicated an effect of genetically predicted ASI on the risk of ischemic stroke (IS) of all causes (OR = 1.894, 95% CI 1.210–2.965, p = 0.005). No links were identified between genetically predicted ASI and other cerebrovascular or cardiometabolic diseases (all p > 0.05). Subgroup analysis of IS etiologies found a suggestive association between genetically predicted ASI and large artery atherosclerosis stroke (LAS) (OR = 3.726, 95% CI 1.230–11.286, p = 0.020). There were no effects of ASI on IS due to cardioembolism or small vessel occlusion.

The current MR analysis suggested that genetically predicted ASI was associated with higher risk of IS of all causes. The results and the underlying pathways or mechanisms between ASI and IS needs further investigation.

Tirofiban, a glycoprotein IIb/IIIa receptor inhibitor, has been shown to reduce the risk of thrombotic complications during percutaneous coronary intervention. However, it remains unknown whether tirofiban improves outcomes in large vessel occlusion stroke patients undergoing endovascular treatment.

This trial aims to assess whether additional intravenous tirofiban therapy can improve the clinical outcomes in large vessel occlusion stroke patients who undergo endovascular treatment within 24 h of symptom onset.

The Endovascular Treatment With versus Without Tirofiban for Stroke Patients With Large Vessel Occlusion (RESCUE BT) Trial is an investigator-initiated, randomized, placebo-controlled, double-blind, multicenter trial. Up to 930 eligible patients will be consecutively randomized to intravenous tirofiban or placebo in 1:1 ratio over 3 years across 50 endovascular-capable stroke centers in China.

The primary end point is the disability level as measured by overall distribution of the 90-day modified Rankin Scale scores. Primary safety end points include symptomatic intracerebral hemorrhage at 48 h and mortality at 90 days.

ChiCTR-INR-17014167 (www.chictr.org.cn).

Patients who suffer intracerebral hemorrhage (ICH) are at very high risk of recurrent ICH and other serious cardiovascular events. A single-pill combination (SPC) of blood pressure (BP) lowering drugs offers a potentially powerful but simple strategy to optimize secondary prevention.

The Triple Therapy Prevention of Recurrent Intracerebral Disease Events Trial (TRIDENT) aims to determine the effects of a novel SPC “Triple Pill,” three generic antihypertensive drugs with demonstrated efficacy and complementary mechanisms of action at half standard dose (telmisartan 20 mg, amlodipine 2.5 mg, and indapamide 1.25 mg), with placebo for the prevention of recurrent stroke, cardiovascular events, and cognitive impairment after ICH.

An international, double-blind, placebo-controlled, randomized trial in adults with ICH and mild-moderate hypertension (systolic BP: 130–160 mmHg), who are not taking any Triple Pill component drug at greater than half-dose. A total of 1500 randomized patients provide 90% power to detect a hazard ratio of 0.5, over an average follow-up of 3 years, according to a total primary event rate (any stroke) of 12% in the control arm and other assumptions. Secondary outcomes include recurrent ICH, cardiovascular events, and safety.

Recruitment started 28 September 2017. Up to 31 October 2021, 821 patients were randomized at 54 active sites in 10 countries. Triple Pill adherence after 30 months is 86%. The required sample size should be achieved by 2024.

Low-dose Triple Pill BP lowering could improve long-term outcome from ICH.