'Value-based methodology for person-centred, integrated care supported by Information and Communication Technologies' (ValueCare) for older people in Europe: study protocol for a pre-post controlled trial.

BACKGROUND: Older people receive care from multiple providers which often results in a lack of coordination. The Information and Communication Technology (ICT) enabled value-based methodology for integrated care (ValueCare) project aims to develop and implement efficient outcome-based, integrated health and social care for older people with multimorbidity, and/or frailty, and/or mild to moderate cognitive impairment in seven sites (Athens, Greece; Coimbra, Portugal; Cork/Kerry, Ireland; Rijeka, Croatia; Rotterdam, the Netherlands; Treviso, Italy; and Valencia, Spain). We will evaluate the implementation and the outcomes of the ValueCare approach. This paper presents the study protocol of the ValueCare project; a protocol for a pre-post controlled study in seven large-scale sites in Europe over the period between 2021 and 2023. METHODS: A pre-post controlled study design including three time points (baseline, post-intervention after 12 months, and follow-up after 18 months) and two groups (intervention and control group) will be utilised. In each site, (net) 240 older people (120 in the intervention group and 120 in the control group), 50-70 informal caregivers (e.g. relatives, friends), and 30-40 health and social care practitioners will be invited to participate and provide informed consent. Self-reported outcomes will be measured in multiple domains; for older people: health, wellbeing, quality of life, lifestyle behaviour, and health and social care use; for informal caregivers and health and social care practitioners: wellbeing, perceived burden and (job) satisfaction. In addition, implementation outcomes will be measured in terms of acceptability, appropriateness, feasibility, fidelity, and costs. To evaluate differences in outcomes between the intervention and control group (multilevel) logistic and linear regression analyses will be used. Qualitative analysis will be performed on the focus group data. DISCUSSION: This study will provide new insights into the feasibility and effectiveness of a value-based methodology for integrated care supported by ICT for older people, their informal caregivers, and health and social care practitioners in seven different European settings. TRIAL REGISTRATION: ISRCTN registry number is 25089186 . Date of trial registration is 16/11/2021.

Association of hyperglycemia and computed tomographic perfusion deficits in patients who underwent endovascular treatment for acute ischemic stroke caused by a proximal intracranial occlusion: A subgroup analysis of a randomized phase 3 trial (MR CLEAN).

INTRODUCTION: Hyperglycemia is highly prevalent in patients with acute ischemic stroke and is associated with increased risk of symptomatic intracranial hemorrhage, larger infarct size and unfavorable outcome. Furthermore, glucose may modify the effect of endovascular treatment (EVT) in patients with ischemic stroke. Hyperglycemia might lead to accelerated conversion of penumbra into infarct core. However, it remains uncertain whether hyperglycemia on admission is associated with the size of penumbra or infarct core in acute ischemic stroke. In this study, we aimed to assess the association between hyperglycemia and Computed Tomographic Perfusion (CTP) derived parameters in patients who underwent EVT for acute ischemic stroke. METHODS: We used data from the MR CLEAN study (Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands). Hyperglycemia was defined as admission serum glucose of >7.8 mmol/L. Dichotomized and quantiles of glucose levels were related to size of core, penumbra and core penumbra ratio. Hypoperfused area is mean transient time 45% higher than that of the contralateral hemisphere. Core is the area with cerebral blood volume of <2 mL/100 g and penumbra is the area with cerebral blood volume > 2 mL/100 g. Core-penumbra ratio is the ischemic core divided by the total volume of hypoperfused tissue (core plus penumbra) multiplied by 100. Adjustments were made for age, sex, NIHSS on admission, onset-imaging time and diabetes mellitus. RESULTS: Hundred seventy-three patients were included. Median glucose level on admission was 6.5 mmol/L (IQR 5.8-7.5 mmol/L) and thirty-five patients (20%) were hyperglycemic. Median core volume was 33.3 mL (IQR 13.6-62.4 mL), median penumbra volume was 80.2 mL (IQR 36.3-123.5 mL) and median core-penumbra ratio was 28.5% (IQR 18.6-45.8%). Patients with hyperglycemia on admission had larger core volumes and core penumbra ratio than normoglycemic patients with a regression coefficient of 15.1 (95% confidence interval (CI), 1.8 to 28.3) and 11.5 (95% confidence interval (CI), 3.4 to 19.7) respectively. CONCLUSION: Hyperglycemia on admission was associated with larger ischemic core volume and larger core-penumbra ratio in patients with acute ischemic stroke who underwent endovascular treatment.

Systematic Review - Combining Neuroprotection With Reperfusion in Acute Ischemic Stroke.

Background: Clinical trials of neuroprotection in acute ischemic stroke (AIS) have provided disappointing results. Reperfusion may be a necessary condition for positive effects of neuroprotective treatments. This systematic review provides an overview of efficacy of neuroprotective agents in combination with reperfusion therapy in AIS. Methods: A literature search was performed on the following databases, namely PubMed, Embase, Web of Science, Cochrane Library, Emcare. All databases were searched up to September 23rd 2021. All randomized controlled trials in which patients were treated with neuroprotective strategies within 12 h of stroke onset in combination with intravenous thrombolysis (IVT), endovascular therapy (EVT), or both were included. Results: We screened 1,764 titles/abstracts and included 30 full reports of unique studies with a total of 16,160 patients. In 15 studies neuroprotectants were tested for clinical efficacy, where all patients had to receive reperfusion therapies, either IVT and/or EVT. Heterogeneity in reported outcome measures was observed. Treatment was associated with improved clinical outcome for: 1) uric acid in patients treated with EVT and IVT, 2) nerinetide in patients who underwent EVT without IVT, 3) imatinib in stroke patients treated with IVT with or without EVT, 4) remote ischemic perconditioning and IVT, and 5) high-flow normobaric oxygen treatment after EVT, with or without IVT. Conclusion: Studies specifically testing effects of neuroprotective agents in addition to IVT and/or EVT are scarce. Future neuroprotection studies should report standardized functional outcome measures and combine neuroprotective agents with reperfusion therapies in AIS or aim to include prespecified subgroup analyses for treatment with IVT and/or EVT.

Flow Patterns in Carotid Webs: A Patient-Based Computational Fluid Dynamics Study.

BACKGROUND AND PURPOSE: Carotid webs are increasingly recognized as an important cause of (recurrent) ischemic stroke in patients without other cardiovascular risk factors. Hemodynamic flow patterns induced by these lesions might be associated with thrombus formation. The aim of our study was to evaluate flow patterns of carotid webs using computational fluid dynamics. MATERIALS AND METHODS: Patients with a carotid web in the Multicenter Randomized Clinical Trial of Endovascular Treatment of Acute Ischemic Stroke in the Netherlands (MR CLEAN) were selected for hemodynamic evaluation with computational fluid dynamics models based on lumen segmentations obtained from CT angiography scans. Hemodynamic parameters, including the area of recirculation zone, time-averaged wall shear stress, transverse wall shear stress, and the oscillatory shear index, were assessed and compared with the contralateral carotid bifurcation. RESULTS: In our study, 9 patients were evaluated. Distal to the carotid webs, recirculation zones were significantly larger compared with the contralateral bifurcation (63 versus 43 mm2, P = .02). In the recirculation zones of the carotid webs and the contralateral carotid bifurcation, time-averaged wall shear stress values were comparable (both: median, 0.27 Pa; P = .30), while transverse wall shear stress and oscillatory shear index values were significantly higher in the recirculation zone of carotid webs (median, 0.25 versus 0.21 Pa; P = .02 and 0.39 versus 0.30 Pa; P = .04). At the minimal lumen area, simulations showed a significantly higher time-averaged wall shear stress in the web compared with the contralateral bifurcation (median, 0.58 versus 0.45 Pa; P = .01). CONCLUSIONS: Carotid webs are associated with increased recirculation zones and regional increased wall shear stress metrics that are associated with disturbed flow. These findings suggest that a carotid web might stimulate thrombus formation, which increases the risk of acute ischemic stroke.

Follow-up infarct volume as a mediator of endovascular treatment effect on functional outcome in ischaemic stroke.

OBJECTIVE: The putative mechanism for the favourable effect of endovascular treatment (EVT) on functional outcome after acute ischaemic stroke is preventing follow-up infarct volume (FIV) progression. We aimed to assess to what extent difference in FIV explains the effect of EVT on functional outcome in a randomised trial of EVT versus no EVT (MR CLEAN). METHODS: FIV was assessed on non-contrast CT scan 5-7 days after stroke. Functional outcome was the score on the modified Rankin Scale at 3 months. We tested the causal pathway from intervention, via FIV to functional outcome with a mediation model, using linear and ordinal regression, adjusted for relevant baseline covariates, including stroke severity. Explained effect was assessed by taking the ratio of the log odds ratios of treatment with and without adjustment for FIV. RESULTS: Of the 500 patients included in MR CLEAN, 60 died and four patients underwent hemicraniectomy before FIV was assessed, leaving 436 patients for analysis. Patients in the intervention group had better functional outcomes (adjusted common odds ratio (acOR) 2.30 (95% CI 1.62-3.26) than controls and smaller FIV (median 53 vs. 81 ml) (difference 28 ml; 95% CI 13-41). Smaller FIV was associated with better outcome (acOR per 10 ml 0.60, 95% CI 0.52-0.68). After adjustment for FIV the effect of intervention on functional outcome decreased but remained substantial (acOR 2.05, 95% CI 1.44-2.91). This implies that preventing FIV progression explains 14% (95% CI 0-34) of the beneficial effect of EVT on outcome. CONCLUSION: The effect of EVT on FIV explains only part of the treatment effect on functional outcome. KEY POINTS: • Endovascular treatment in acute ischaemic stroke patients prevents progression of follow-up infarct volume on non-contrast CT at 5-7 days. • Follow-up infarct volume was related to functional outcome, but only explained a modest part of the effect of intervention on functional outcome. • A large proportion of treatment effect on functional outcome remains unexplained, suggesting FIV alone cannot be used as an early surrogate imaging marker of functional outcome.

Impact of Ischemic Lesion Location on the mRS Score in Patients with Ischemic Stroke: A Voxel-Based Approach.

BACKGROUND AND PURPOSE: Previous studies indicated that ischemic lesion volume might be a useful surrogate marker for functional outcome in ischemic stroke but should be considered in the context of lesion location. In contrast to previous studies using the ROI approach, which has several drawbacks, the present study aimed to measure the impact of ischemic lesion location on functional outcome using a more precise voxelwise approach. MATERIALS AND METHODS: Datasets of patients with acute ischemic strokes from the Multicenter Randomized Clinical Trial of Endovascular Therapy for Acute Ischemic Stroke in the Netherlands (MR CLEAN) were used. Primary outcome was functional outcome as assessed by the modified Rankin Scale 3 months after stroke. Ischemic lesion volume was determined on CT scans 3-9 days after stroke. Voxel-based lesion-symptom mapping techniques, including covariates that are known to be associated with functional outcome, were used to determine the impact of ischemic lesion location for outcome. RESULTS: Of the 500 patients in the MR CLEAN trial, 216 were included for analysis. The mean age was 63 years. Lesion-symptom mapping with inclusion of covariates revealed that especially left-hemispheric lesions in the deep periventricular white matter and adjacent internal capsule showed a great influence on functional outcome. CONCLUSIONS: Our study confirms that infarct location has an important impact on functional outcome of patients with stroke and should be considered in prediction models. After we adjusted for covariates, the left-hemispheric corticosubcortical fiber tracts seemed to be of higher functional importance compared with cortical lesions.

Value of Quantitative Collateral Scoring on CT Angiography in Patients with Acute Ischemic Stroke.

BACKGROUND AND PURPOSE: Many studies have emphasized the relevance of collateral flow in patients presenting with acute ischemic stroke. Our aim was to evaluate the relationship of the quantitative collateral score on baseline CTA with the outcome of patients with acute ischemic stroke and test whether the timing of the CTA acquisition influences this relationship. MATERIALS AND METHODS: From the Multicenter Randomized Clinical Trial of Endovascular Treatment of Acute Ischemic Stroke in the Netherlands (MR CLEAN) data base, all baseline thin-slice CTA images of patients with acute ischemic stroke with intracranial large-vessel occlusion were retrospectively collected. The quantitative collateral score was calculated as the ratio of the vascular appearance of both hemispheres and was compared with the visual collateral score. Primary outcomes were 90-day mRS score and follow-up infarct volume. The relation with outcome and the association with treatment effect were estimated. The influence of the CTA acquisition phase on the relation of collateral scores with outcome was determined. RESULTS: A total of 442 patients were included. The quantitative collateral score strongly correlated with the visual collateral score (ρ = 0.75) and was an independent predictor of mRS (adjusted odds ratio = 0.81; 95% CI, .77-.86) and follow-up infarct volume (exponent ß = 0.88; P < .001) per 10% increase. The quantitative collateral score showed areas under the curve of 0.71 and 0.69 for predicting functional independence (mRS 0-2) and follow-up infarct volume of >90 mL, respectively. We found significant interaction of the quantitative collateral score with the endovascular therapy effect in unadjusted analysis on the full ordinal mRS scale (P = .048) and on functional independence (P = .049). Modification of the quantitative collateral score by acquisition phase on outcome was significant (mRS: P = .004; follow-up infarct volume: P < .001) in adjusted analysis. CONCLUSIONS: Automated quantitative collateral scoring in patients with acute ischemic stroke is a reliable and user-independent measure of the collateral capacity on baseline CTA and has the potential to augment the triage of patients with acute stroke for endovascular therapy.

Impaired fasting glucose is associated with unfavorable outcome in ischemic stroke patients treated with intravenous alteplase.

OBJECTIVES: Hyperglycemia on admission and diabetes mellitus type II are associated with unfavorable outcome in stroke patients. We studied whether impaired fasting glucose (IFG) is associated with unfavorable outcome in ischemic stroke patients treated with intravenous alteplase as well and if IFG is a stronger prognostic factor than hyperglycemia on admission. METHODS: We studied 220 consecutive patients with ischemic stroke treated with intravenous alteplase. In all nondiabetic patients, fasting glucose was determined on day 2-5. IFG was defined as fasting glucose level of ≥ 5.6 mmol/L, hyperglycemia on admission as glucose levels ≥ 7.9 mmol/L. The primary effect measure was the adjusted common odds ratio (acOR) for a shift in the direction of worse outcome on the modified Rankin Scale at 3 months, estimated with ordinal logistic regression, and adjusted for common prognostic factors. RESULTS: The fasting glucose levels were available in 194 and admission glucose levels in 215 patients. Sixty-three (32.5%) had IFG, 58 (27%) hyperglycemia on admission and 32 (14.6%) pre-existent diabetes. Patients with IFG showed a shift towards worse functional outcome compared with patients with normal fasting glucose levels (acOR 2.77; 95% CI 1.54-4.97), which was stronger than hyperglycemia on admission (acOR 1.75; 95% CI 0.91-3.4). CONCLUSIONS: IFG is associated with unfavorable outcome after treatment with intravenous alteplase for acute ischemic stroke. IFG predicts unfavorable outcome better than hyperglycemia on admission.

Value of Thrombus CT Characteristics in Patients with Acute Ischemic Stroke.

BACKGROUND AND PURPOSE: Thrombus CT characteristics might be useful for patient selection for intra-arterial treatment. Our objective was to study the association of thrombus CT characteristics with outcome and treatment effect in patients with acute ischemic stroke. MATERIALS AND METHODS: We included 199 patients for whom thin-section NCCT and CTA within 30 minutes from each other were available in the Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute ischemic stroke in the Netherlands (MR CLEAN) study. We assessed the following thrombus characteristics: location, distance from ICA terminus to thrombus, length, volume, absolute and relative density on NCCT, and perviousness. Associations of thrombus characteristics with outcome were estimated with univariable and multivariable ordinal logistic regression as an OR for a shift toward better outcome on the mRS. Interaction terms were used to investigate treatment-effect modification by thrombus characteristics. RESULTS: In univariate analysis, only the distance from the ICA terminus to the thrombus, length of >8 mm, and perviousness were associated with functional outcome. Relative thrombus density on CTA was independently associated with functional outcome with an adjusted common OR of 1.21 per 10% (95% CI, 1.02-1.43; P = .029). There was no treatment-effect modification by any of the thrombus CT characteristics. CONCLUSIONS: In our study on patients with large-vessel occlusion of the anterior circulation, CT thrombus characteristics appear useful for predicting functional outcome. However, in our study cohort, the effect of intra-arterial treatment was independent of the thrombus CT characteristics. Therefore, no arguments were provided to select patients for intra-arterial treatment using thrombus CT characteristics.

Glucose in prediabetic and diabetic range and outcome after stroke.

OBJECTIVES: Newly diagnosed disturbed glucose metabolism is highly prevalent in patients with stroke. Limited data are available on their prognostic value on outcome after stroke. We aimed to assess the association of glucose in the prediabetic and diabetic range with unfavourable short-term outcome after stroke. MATERIALS AND METHODS: We included 839 consecutive patients with ischemic stroke and 168 patients with intracerebral haemorrhage. In all nondiabetic patients, fasting glucose levels were determined on day 2-4. Prediabetic range was defined as fasting glucose of 5.6-6.9 mmol/L, diabetic range as ≥7.0 mmol/L, pre-existent diabetes as the use of anti-diabetic medication prior to admission. Outcome measures were poor functional outcome or death defined as modified Rankin Scale (mRS) score >2 and discharge not to home. The association of prediabetic range, diabetic range and pre-existent diabetes (versus normal glucose) with unfavourable outcome was expressed as odds ratios, estimated with multiple logistic regression, with adjustment for prognostic factors. RESULTS: Compared with normal glucose, prediabetic range (aOR 1.8; 95%CI 1.1-2.8), diabetic range (aOR 2.5; 95%CI 1.3-4.9) and pre-existent diabetes (aOR 2.6; 95%CI 1.6-4.0) were associated with poor functional outcome or death. Patients in the prediabetic range (aOR 0.6; 95%CI 0.4-0.9), diabetic range (aOR 0.4; 95%CI 0.2-0.9) and pre-existent diabetes (aOR 0.6; 95%CI 0.4-0.9) were more likely not to be discharged to home. CONCLUSIONS: Patients with glucose in the prediabetic and diabetic range have an increased risk of unfavourable short-term outcome after stroke. These findings illustrate the potential impact of early detection and treatment of these patients.

Topographic distribution of cerebral infarct probability in patients with acute ischemic stroke: mapping of intra-arterial treatment effect.

BACKGROUND: Since proof emerged that IA treatment (IAT) is beneficial for patients with acute ischemic stroke, it has become the standard method of care. Despite these positive results, recovery to functional independence is established in only about one-third of treated patients. The effect of IAT is commonly assessed by functional outcome, whereas its effect on brain tissue salvage is considered a secondary outcome measure (at most). Because patient and treatment selection needs to be improved, understanding the treatment effect on brain tissue salvage is of utmost importance. OBJECTIVE: To introduce infarct probability maps to estimate the location and extent of tissue damage based on patient baseline characteristics and treatment type. METHODS: Cerebral infarct probability maps were created by combining automatically segmented infarct distributions using follow-up CT images of 281 patients from the MR CLEAN trial. Comparison of infarct probability maps allows visualization and quantification of probable treatment effects. Treatment impact was calculated for 10 Alberta Stroke Program Early CT Score (ASPECTS) and 27 anatomical regions. RESULTS: The insular cortex had the highest infarct probability in both control and IAT populations (47.2% and 42.6%, respectively). Comparison showed significant lower infarct probability in 4 ASPECTS and 17 anatomical regions in favor of IAT. Most salvaged tissue was found within the ASPECTS M2 region, which was 8.5% less likely to infarct. CONCLUSIONS: Probability maps intuitively visualize the topographic distribution of infarct probability due to treatment, which makes it a promising tool for estimating the effect of treatment.

Increased admission and fasting glucose are associated with unfavorable short-term outcome after intra-arterial treatment of ischemic stroke in the MR CLEAN pretrial cohort.

BACKGROUND: Limited data are available on the impact of fasting glucose on outcome after intra-arterial treatment (IAT). We studied whether hyperglycemia on admission and impaired fasting glucose (IFG) are associated with unfavorable outcome after IAT in acute ischemic stroke. METHODS: Patients were derived from the pretrial registry of the MR CLEAN-trial. Hyperglycemia on admission was defined as glucose>7.8mmol/L, IFG as fasting glucose>5.5mmol/L in the first week of admission. Primary effect measure was the adjusted common odds ratio (acOR) for a shift in the direction of worse outcome on the modified Rankin Scale at discharge, estimated with ordinal logistic regression, adjusted for common prognostic factors. RESULTS: Of the 335 patients in which glucose on admission was available, 86 (26%) were hyperglycemic, 148 of the 240 patients with available fasting glucose levels (62%) had IFG. Median admission glucose was 6.8mmol/L (IQR 6-8). Increased admission glucose (acOR 1.2, 95%CI 1.1-1.3), hyperglycemia on admission (acOR 2.6, 95%CI 1.5-4.6) and IFG (acOR 2.8, 95%CI 1.4-5.6) were associated with worse functional outcome at discharge. CONCLUSION: Increased glucose on admission and IFG in the first week after stroke onset are associated with unfavorable short-term outcome after IAT of acute ischemic stroke.

[Serious delayed intracranial complications after mild traumatic brain injury in oral anticoagulant use]. / Ernstige late intracraniële afwijkingen na licht schedel-hersenletsel bij oraal anticoagulantiagebruik.

BACKGROUND: Patients with mild traumatic brain injury (TBI) who use anticoagulants prior to injury have an increased risk of intracranial complications. Sometimes these complications are delayed, even if the initial CT scan of the head is normal. CASE DESCRIPTION: An 84-year-old woman who was using acenocoumarol presented elsewhere with mild TBI. She had no focal neurological deficit. The initial CT scan revealed no abnormalities and the patient was discharged home. That evening she had diffuse headache. The next day she was found with a reduced level of consciousness and was brought to our hospital. Her INR was 9.0 and a new CT scan showed an acute, left-sided subdural haematoma with a large mass effect. CONCLUSION: Serious delayed intracranial complications in patients with mild TBI who use anticoagulants are rare. In these patients INR measurement and a CT scan of the head are always indicated. Admission for observation may be considered. On discharge it is necessary to give clear instructions about warning symptoms.

Assessment of Collateral Status by Dynamic CT Angiography in Acute MCA Stroke: Timing of Acquisition and Relationship with Final Infarct Volume.

BACKGROUND AND PURPOSE: Dynamic CTA is a promising technique for visualization of collateral filling in patients with acute ischemic stroke. Our aim was to describe collateral filling with dynamic CTA and assess the relationship with infarct volume at follow-up. MATERIALS AND METHODS: We selected patients with acute ischemic stroke due to proximal MCA occlusion. Patients underwent NCCT, single-phase CTA, and whole-brain CT perfusion/dynamic CTA within 9 hours after stroke onset. For each patient, a detailed assessment of the extent and velocity of arterial filling was obtained. Poor radiologic outcome was defined as an infarct volume of ≥70 mL. The association between collateral score and follow-up infarct volume was analyzed with Poisson regression. RESULTS: Sixty-one patients with a mean age of 67 years were included. For all patients combined, the interval that contained the peak of arterial filling in both hemispheres was between 11 and 21 seconds after ICA contrast entry. Poor collateral status as assessed with dynamic CTA was more strongly associated with infarct volume of ≥70 mL (risk ratio, 1.9; 95% CI, 1.3-2.9) than with single-phase CTA (risk ratio, 1.4; 95% CI, 0.8-2.5). Four subgroups (good-versus-poor and fast-versus-slow collaterals) were analyzed separately; the results showed that compared with good and fast collaterals, a similar risk ratio was found for patients with good-but-slow collaterals (risk ratio, 1.3; 95% CI, 0.7-2.4). CONCLUSIONS: Dynamic CTA provides a more detailed assessment of collaterals than single-phase CTA and has a stronger relationship with infarct volume at follow-up. The extent of collateral flow is more important in determining tissue fate than the velocity of collateral filling. The timing of dynamic CTA acquisition in relation to intravenous contrast administration is critical for the optimal assessment of the extent of collaterals.

The effect of hypopituitarism on fatigue after subarachnoid hemorrhage.

BACKGROUND AND PURPOSE: Aneurysmal subarachnoid hemorrhage (SAH) survivors often complain of fatigue, which is disabling. Fatigue is also a common symptom of pituitary dysfunction (PD), in particular in patients with growth hormone deficiency (GHD). A possible association between fatigue after SAH and long-term pituitary deficiency in SAH survivors has not yet been established. METHODS: A single center observational study was conducted amongst 84 aneurysmal SAH survivors to study the relationship between PD and fatigue over time after SAH, using mixed model analysis. Fatigue was measured with the Fatigue Severity Scale and its relationships with other clinical variables were studied. RESULTS: Three-quarters of respondents (76%) have pathological fatigue directly after SAH and almost two-thirds (60%) of patients still have pathological levels of fatigue after 14 months. The severity of SAH measured with a World Federation of Neurosurgical Societies (WFNS) score higher than 1 (P = 0.008) was associated with long-term fatigue. There is no statistically significant effect of PD (P = 0.8) or GHD (P = 0.23) on fatigue in SAH survivors over time. CONCLUSIONS: Fatigue is a common symptom amongst SAH survivors. WFNS is a usable clinical determinant of fatigue in SAH survivors. Neither PD nor GHD has a significant effect on long-term fatigue after SAH.

Safety of intra-arterial treatment in acute ischaemic stroke patients on oral anticoagulants. A cohort study and systematic review.

BACKGROUND AND PURPOSE: An elevated international normalized ratio (INR) of >1.7 is a contraindication for the use of intravenous thrombolytics in acute ischaemic stroke. Local intra-arterial therapy (IAT) is considered a safe alternative. The safety and outcome of IAT were investigated in patients with acute ischaemic stroke using oral anticoagulants (OACs). METHODS: Data were obtained from a large national Dutch database on IAT in acute stroke patients. Patients were categorized according to the INR: >1.7 and ≤1.7. Primary outcome was symptomatic intracerebral hemorrhage (sICH), defined as deterioration in the National Institutes of Health Stroke Scale score of ≥4 and ICH on brain imaging. Secondary outcomes were clinical outcome at discharge and 3 months. Occurrence of outcomes was compared with risk ratios and corresponding 95% confidence intervals. Further, a systematic review and meta-analysis on sICH risk in acute stroke patients on OACs treated with IAT was performed. RESULTS: Four hundred and fifty-six patients were included. Eighteen patients had an INR > 1.7 with a median INR of 2.4 (range 1.8-4.1). One patient (6%) in the INR > 1.7 group developed a sICH compared with 53 patients (12%) in the INR ≤ 1.7 group (risk ratio 0.49, 95% confidence interval 0.07-3.13). Clinical outcomes did not differ between the two groups. Our meta-analysis showed a first week sICH risk of 8.1% (95% confidence interval 3.9%-17.1%) in stroke patients with elevated INR treated with IAT. CONCLUSION: The use of OACs, leading to an INR > 1.7, did not seem to increase the risk of an sICH in patients with an acute stroke treated with IAT.

The ThRombolysis in UnconTrolled Hypertension (TRUTH) protocol: an observational study on treatment strategy of elevated blood pressure in stroke patients eligible for IVT.

BACKGROUND: Intravenous thrombolysis (IVT) with (recombinant) tissue plasminogen activator is an effective treatment in acute ischemic stroke. However, IVT is contraindicated when blood pressure is above 185/110 mmHg, because of an increased risk on symptomatic intracranial hemorrhage. In current Dutch clinical practice, two distinct strategies are used in this situation. The active strategy comprises lowering blood pressure with antihypertensive agents below these thresholds to allow start of IVT. In the conservative strategy, IVT is administered only when blood pressure drops spontaneously below protocolled thresholds. A retrospective analysis in two recent stroke trials showed a non-significant signal towards better functional outcome in the active group; robust evidence for either strategy, however, is lacking. We hypothesize that (I) the active strategy leads to a better functional outcome three months after acute ischemic stroke. Secondary hypotheses are that this effect occurs despite (II) increasing the number of symptomatic intracranial hemorrhages, and could be attributable to (III) a higher rate of IVT treatments and (IV) a shorter door-to-needle time. METHODS AND DESIGN: The TRUTH is a prospective, observational, cluster-based, parallel group follow-up study; in which participating centers continue their current local treatment guidelines. Outcomes of patients admitted to centers with an active will be compared to those admitted to centers with a conservative strategy. The primary outcome is functional outcome on the modified Rankin Scale at three months. Secondary outcomes are symptomatic intracranial hemorrhage, IVT treatment and door-to-needle time. We based our sample size estimate on an ordinal analysis of the mRS with the "proportional odds" model. With the aforementioned signal observed in a recent retrospective study in these patients as an estimate of the effect size and with alpha 0 · 05, this analysis would have an 80 % power with a total number of 600 patients. Corrections for expected imbalance in group size and clustering effects resulted in a sample size of 1235 patients. DISCUSSION: The TRUTH is the first large prospective study specifically studying IVT-candidates with elevated blood pressure, and has the potential to change clinical practice and optimize acute stroke care in these patients.

Pituitary dysfunction after aneurysmal subarachnoid haemorrhage: course and clinical predictors­the HIPS study.

OBJECTIVE: We describe the occurrence and course of anterior pituitary dysfunction (PD) after aneurysmal subarachnoid haemorrhage (SAH), and identify clinical determinants for PD in patients with recent SAH. METHODS: We prospectively collected demographic and clinical parameters of consecutive survivors of SAH and measured fasting state endocrine function at baseline, 6 and 14 months. We included dynamic tests for growth-hormone function. We used logistic regression analysis to compare demographic and clinical characteristics of patients with SAH with and without PD. RESULTS: 84 patients with a mean age of 55.8 (±11.9) were included. Thirty-three patients (39%) had PD in one or more axes at baseline, 22 (26%) after 6 months and 6 (7%) after 14 months. Gonadotropin deficiency in 29 (34%) patients and growth hormone deficiency (GHD) in 26 (31%) patients were the most common deficiencies. PD persisted until 14 months in 6 (8%) patients: GHD in 5 (6%) patients and gonadotropin deficiency in 4 (5%). Occurrence of a SAH-related complication was associated with PD at baseline (OR 2.6, CI 2.2 to 3.0). Hydrocephalus was an independent predictor of PD 6 months after SAH (OR 3.3 CI 2.7 to 3.8). PD was associated with a lower score on health-related quality of life at baseline (p=0.06), but not at 6 and 14 months. CONCLUSIONS: Almost 40% of SAH survivors have PD. In a small but substantial proportion of patients GHD or gonadotropin deficiency persists over time. Hydrocephalus is independently associated with PD 6 months after SAH. TRIAL REGISTRATION NUMBER: NTR 2085.

Cost-effectiveness of two endovascular treatment strategies vs intravenous thrombolysis.

OBJECTIVE: To assess the cost-effectiveness of endovascular treatment against intravenous thrombolysis (IVT) when varying assumptions concerning its effectiveness. METHODS: We developed a health economic model including a hypothetical population consisting of patients with ischemic stroke, admitted within 4.5 h from onset, without contraindications for IVT or intra-arterial treatment (IAT). A decision tree and life table were used to assess 6-month and lifetime costs (in Euros) and effects in quality-adjusted life years treatment with IVT alone, IAT alone, and IVT followed by IAT if the patient did not respond to treatment. Several analyses were performed to explore the impact of considerable uncertainty concerning the clinical effectiveness of endovascular treatment. RESULTS: Probabilistic sensitivity analysis demonstrated a 54% probability of positive incremental lifetime effectiveness of IVT-IAT vs IVT alone. Sensitivity analyses showed significant variation in outcomes and cost-effectiveness of the included treatment strategies at different model assumptions. CONCLUSIONS: Acceptable cost-effectiveness of IVT-IAT compared to IVT will only be possible if recanalization rates are sufficiently high (>50%), treatment costs of IVT-IAT do not increase, and complication rates remain similar to those reported in the few randomized studies published to date. Large randomized studies are needed to reduce the uncertainty concerning the effects of endovascular treatment.

Determinants of calcification growth in atherosclerotic carotid arteries; a serial multi-detector CT angiography study.

BACKGROUND: Little is known about the natural course of atherosclerotic plaque in the carotid artery bifurcation. This study investigated the growth pattern of calcifications in atherosclerotic carotid arteries and its determinants using serial multi-detector CT angiography (MDCTA). METHODS: From a cohort of consecutive patients with TIA or ischemic stroke and a baseline MCDTA scan of the carotid arteries, subjects were invited for a follow-up scan after 4-6 years. Calcification volumes were scored semi-automatically on baseline and follow-up scans. Progression of calcification and its determinants were analyzed in two ways: 1. as incidence of newly detectable calcification in patients free of calcification at baseline, using logistic regression analysis; 2. as annual change in calcification volume in all patients, using linear regression analysis. RESULTS: Two-hundred-twenty-two patients (aged 61.0 ± 9.6 years, follow-up time 4.7 ± 0.8 years) were included. Calcification volumes increased significantly (median 2.9 mm³ at baseline versus 9.4 mm³ at follow-up, p < 0.001). Newly detectable calcification during follow-up was found in 27 out of 67 patients without baseline calcification (40.3%) and was independently associated with age (OR 4.6 per 10 years increase in age, p < 0.001) and hypertension (OR 8.2, p = 0.008). Annual calcification growth was independently associated with age, calcification load, glucose, hypertension, and smoking. Baseline calcification load was the most important risk factor for calcification growth in multivariable analysis. CONCLUSION: Several modifiable cardiovascular risk factors are associated with carotid calcification growth, however, time and baseline calcification load remain the most important determinants of calcification development.