Subacute vessel wall imaging at 7-T MRI in post-thrombectomy stroke patients.

PURPOSE: Reports from 3-T vessel wall MRI imaging have shown contrast enhancement following thrombectomy for acute stroke, suggesting potential intimal damage. Comparisons have shown higher SNR and more lesions detected by vessel wall imaging when using 7 T compared with 3 T. The aim of this study was to investigate the vessel walls after stent retriever thrombectomy using high-resolution vessel wall imaging at 7 T. METHODS: Seven patients with acute stroke caused by occlusion of the distal internal carotid artery (T-occlusion), or proximal medial cerebral artery, and treated by stent retriever thrombectomy with complete recanalization were included and examined by 7-T MRI within 2 days. The MRI protocol included a high-resolution black blood sequence with prospective motion correction (iMOCO), acquired before and after contrast injection. Flow measurements were performed in the treated and untreated M1 segments. RESULTS: All subjects completed the MRI examination. Image quality was independently rated as excellent by two neuroradiologists for all cases, and the level of motion artifacts did not impair diagnostic quality, despite severe motion in some cases. Contrast enhancement correlated with the deployment location of the stent retrievers. Flow data showed complete restoration of flow after treatment. CONCLUSION: Vessel wall imaging with prospective motion correction can be performed in patients following thrombectomy with excellent imaging quality at 7 T. We show that vessel wall contrast enhancement is the normal post-operative state and corresponds to the deployment location of the stent retriever.

Pathogenic ischemic stroke phenotypes in the NINDS-stroke genetics network.

BACKGROUND AND PURPOSE: NINDS (National Institute of Neurological Disorders and Stroke)-SiGN (Stroke Genetics Network) is an international consortium of ischemic stroke studies that aims to generate high-quality phenotype data to identify the genetic basis of pathogenic stroke subtypes. This analysis characterizes the etiopathogenetic basis of ischemic stroke and reliability of stroke classification in the consortium. METHODS: Fifty-two trained and certified adjudicators determined both phenotypic (abnormal test findings categorized in major pathogenic groups without weighting toward the most likely cause) and causative ischemic stroke subtypes in 16 954 subjects with imaging-confirmed ischemic stroke from 12 US studies and 11 studies from 8 European countries using the web-based Causative Classification of Stroke System. Classification reliability was assessed with blinded readjudication of 1509 randomly selected cases. RESULTS: The distribution of pathogenic categories varied by study, age, sex, and race (P<0.001 for each). Overall, only 40% to 54% of cases with a given major ischemic stroke pathogenesis (phenotypic subtype) were classified into the same final causative category with high confidence. There was good agreement for both causative (κ 0.72; 95% confidence interval, 0.69-0.75) and phenotypic classifications (κ 0.73; 95% confidence interval, 0.70-0.75). CONCLUSIONS: This study demonstrates that pathogenic subtypes can be determined with good reliability in studies that include investigators with different expertise and background, institutions with different stroke evaluation protocols and geographic location, and patient populations with different epidemiological characteristics. The discordance between phenotypic and causative stroke subtypes highlights the fact that the presence of an abnormality in a patient with stroke does not necessarily mean that it is the cause of stroke.

Multiplicity of risk factors in ischemic stroke patients: relations to age, sex, and subtype--a study of 2,505 patients from the lund stroke register.

BACKGROUND: The prevalence of risk factors for ischemic stroke may vary between different groups of stroke patients. We examined the distribution of individual well-established risk factors as well as the multiplicity of risk factors in different age groups and among subtypes. METHODS: In the Lund Stroke Register, we consecutively enrolled 2,505 patients with first-ever ischemic stroke from 2001 to 2009 and registered hypertension, diabetes mellitus, heart disease, current smoking, hypercholesterolemia as well as stroke subtype. RESULTS: Among young patients (<55 years), at least 50% had ≥2 risk factors and 20-25% had ≥3 risk factors. In patients aged 55 years or older, the proportion with ≥2 risk factors was 70-80% and with ≥3 risk factors 35-45%. Men and women had a similar burden of risk factors. Approximately 50% of the cases classified as cardioembolism (CE) and large artery atherosclerosis (LAA) had ≥3 risk factors, which was significantly more than the other TOAST (Trial of Org 10172 in Acute Stroke Treatment) subtypes (CE p < 0.001, LAA p = 0.001). CONCLUSIONS: The prevalence of well-established risk factors is similar among young and old stroke patients with large proportions (50-80%) having ≥2 risk factors. Even though the prevalence of well-established risk factors differs between pathogenetic subtypes, these risk factors as well as the multiplicity of risk factors seem to be of clinical importance in all major subtypes of ischemic stroke.

Incidence of intracranial hemorrhagic complications after anterior circulation endovascular thrombectomy in relation to occlusion site: a nationwide observational register study.

BACKGROUND: Intracranial hemorrhage (ICH) is a potentially severe complication of endovascular thrombectomy (EVT). However, the relationship between the incidence and severity of ICH and vascular occlusion location is not well described. OBJECTIVE: To present a comprehensive analysis of subtypes of ICHs and their relationship to the occlusion site following EVT in the anterior circulation. METHODS: All patients with anterior circulation vessel occlusion stroke (internal carotid (ICA) and middle cerebral artery's first (M1) and later segments (M2 and beyond)) registered in the two Swedish national quality registers for stroke care and endovascular therapy during 2015-2020 were included. Hemorrhagic complications identified on imaging within 36 hours post-EVT were classified according to Heidelberg Bleeding Classification and further divided into symptomatic (sICH) or non-symptomatic (non-sICH). RESULTS: Of the 3077 patients, ICH frequency was 24.2%, which included 4.5% sICH. Subarachnoid hemorrhage (SAH) was the most frequent subtype of hemorrhage (10.9%). The hemorrhagic subtypes differed significantly by occlusion site, but the frequency of any bleed did not. EVT performed in and beyond the M2 more often resulted in SAH, frequently classified as non-sICH. EVT performed in the ICA was associated with more severe hemorrhages, such as intraventricular and large parenchymal hematomas, that were more often classified as sICH. CONCLUSION: In this nationwide unselected EVT cohort we found that ICH severity significantly differed between different vessel occlusion sites.

Long-term cost-effectiveness of thrombectomy for acute ischaemic stroke in real life: An analysis based on data from the Swedish Stroke Register (Riksstroke).

Background Randomised controlled trials have demonstrated substantial clinical benefit for thrombectomy in patients with acute ischaemic stroke and proximal anterior circulation arterial occlusion. Aim We investigated the long-term cost-effectiveness of thrombectomy after thrombolysis versus thrombolysis alone using real-world outcome data on need for health care, home help and nursing home care. Methods We used real-life resource use and survival data from the Swedish Stroke Register and pooled outcomes from five randomised controlled trials published in 2015 in a newly constructed Markov cost-effectiveness model with a societal perspective. Data were stratified by age (18-64; 65-74; 75-84 years) and modified Rankin scale at three months for patients with an index ischaemic stroke in 2014 fulfilling inclusion criteria NIHSS ≥ 8 before treatment and treated with thrombolysis ( n = 710). Univariate sensitivity analyses explored robustness of results. A life-time perspective and 3% discount rate were applied. Results Thrombectomy increases the health care cost per patient (+GBP 9000) mainly because of intervention costs, but the reduced burden on the social services (home help services -GBP 13,000; nursing home care -GBP 26,000) implies overall cost savings. The average patient gain was 1.0 quality-adjusted life year (QALY) with higher gains for younger age groups. Thrombectomy was a dominant strategy in the base case and all sensitivity analyses where social services were considered. Conclusion Thrombectomy has a small effect on hospital costs except for the direct intervention cost. However, thrombectomy is highly likely to lead to substantial cost savings in the social service sector, up to four times the increase in health-care costs.

PreHospital Ambulance Stroke Test - pilot study of a novel stroke test.

BACKGROUND: There is a need for a prehospital stroke test that in addition to high sensitivity for stroke, also is able to communicate stroke severity similar to the National Institute of Health Stroke Scale (NIHSS). METHODS: The PreHospital Ambulance Stroke Test (PreHAST), an eight item test based on NIHSS, which scores stroke severity from 0-19 points, was designed and adapted for the ambulance services. In the pilot study the ambulance nurses used PreHAST to assess patients with suspected stroke in the prehospital setting. Regardless of the results after PreHAST testing the patients were triaged with a provisional stroke diagnosis. The PreHAST scores were compared with the final diagnosis and the ability to differentiate stroke and transient ischemic attacks (TIA) with ongoing symptoms at evaluation from non-stroke patients was analysed. RESULTS: 69 patients were included in the study, 26 had stroke/TIA and 43 other diagnoses. All stroke/TIA patients were identified by PreHAST (sensitivity 100% (95% CI; 87-100%)). The specificity increased with higher PreHAST scores and the discriminative capacity for PreHAST for different cut off values showed an area under the curve of 0.77 (95%CI; 0.66-0.88) in the receiver operating characteristic (ROC) analysis. DISCUSSION: PreHAST is designed for high sensitivity, screening for a broad range of stroke symptoms including most key components of NIHSS. The promising sensitivity between 87 and 100% in our study has to be confirmed in a larger study also including multiple centres. Higher PreHAST scores implied more typical patterns of stroke and accordingly the proportion of stroke mimics decrease with higher scores. However, also stroke mimics with epilepsy/seizure and patients with deficit after prior stroke could show higher PreHAST scores. Other prehospital stroke tests that evaluate stroke severity have been designed with the main purpose to screen for large vessel occlusion. The advantage of PreHAST is the dual purpose not only to evaluate stroke severity but also to screen for stroke in general. CONCLUSIONS: PreHAST is a new screening test of stroke adapted for ambulance services that in addition to high sensitivity for stroke, provides a grading system with increasing specificity with higher scores.

Agreement between TOAST and CCS ischemic stroke classification: the NINDS SiGN study.

OBJECTIVE: The objective of this study was to assess the level of agreement between stroke subtype classifications made using the Trial of Org 10172 Acute Stroke Treatment (TOAST) and Causative Classification of Stroke (CCS) systems. METHODS: Study subjects included 13,596 adult men and women accrued from 20 US and European genetic research centers participating in the National Institute of Neurological Disorders and Stroke (NINDS) Stroke Genetics Network (SiGN). All cases had independently classified TOAST and CCS stroke subtypes. Kappa statistics were calculated for the 5 major ischemic stroke subtypes common to both systems. RESULTS: The overall agreement between TOAST and CCS was moderate (agreement rate, 70%; κ = 0.59, 95% confidence interval [CI] 0.58-0.60). Agreement varied widely across study sites, ranging from 28% to 90%. Agreement on specific subtypes was highest for large-artery atherosclerosis (κ = 0.71, 95% CI 0.69-0.73) and lowest for small-artery occlusion (κ = 0.56, 95% CI 0.54-0.58). CONCLUSION: Agreement between TOAST and CCS diagnoses was moderate. Caution is warranted when comparing or combining results based on the 2 systems. Replication of study results, for example, genome-wide association studies, should utilize phenotypes determined by the same classification system, ideally applied in the same manner.

A large-sample assessment of possible association between ischaemic stroke and rs12188950 in the PDE4D gene.

Previous reports have shown ambiguous findings regarding the possible associations between ischaemic stroke (IS) and single nucleotide polymorphisms (SNPs) in the phosphodiesterase 4D (PDE4D) gene region. The SNP rs12188950 (or SNP45) has often been studied in this context. We performed a multi-centre study involving a large sample of 2599 IS patients and 2093 control subjects from the south and west regions of Sweden to replicate previous studies regarding IS risk and rs12188950. Subjects from Lund Stroke Register (LSR), Malmö Diet and Cancer Study (MDC) and Sahlgrenska Academy Study on Ischemic Stroke (SAHLSIS) were enroled. Subgroups of participants with hypertension and participants <55 years of age, as well as the TOAST subgroups large vessel disease, small vessel disease and cardioembolism, were also assessed. Univariate odds ratios (ORs) and ORs controlling for hypertension, diabetes and current smoking were calculated. We additionally performed a meta-analysis including 10,500 patients and 10,102 control subjects from 17 publications (including the present study). When assessing pooled data from LSR, MDC and SAHLSIS we obtained no association between IS and rs12188950 for all participants (OR=0.93; 95% confidence interval (CI): 0.83-1.05). Significant associations were not found for hypertensive participants or participants with age <55, or when separately evaluating patients from the three different TOAST subgroups. The meta-analysis showed no significant overall estimate (OR=0.96; 95% CI: 0.89-1.04) with significant heterogeneity for random effect (P=0.042). No effect from rs12188950 on IS was found from either our pooled multi-centre data or the performed meta-analysis. We did not find any association between the examined subgroups and rs12188950 either.

Comprehensive CT Evaluation in Acute Ischemic Stroke: Impact on Diagnosis and Treatment Decisions.

Background. With modern CT imaging a comprehensive overview of cerebral macro- and microcirculation can be obtained within minutes in acute ischemic stroke. This opens for patient stratification and individualized treatment. Methods. Four patients with acute ischemic stroke of different aetiologies and/or treatments were chosen for illustration of the comprehensive CT protocol and its value in subsequent treatment decisions. The patients were clinically evaluated according to the NIHSS-scale, examined with the comprehensive CT protocol including both CT angiography and CT perfusion, and followed up by MRI. Results. The comprehensive CT examination protocol increased the examination time but did not delay treatment initiation. In some cases CT angiography revealed the cause of stroke while CT perfusion located and graded the perfusion defect with reasonable accuracy, confirmed by follow-up MR-diffusion. In the presented cases findings of the comprehensive CT examination influenced the treatment strategy. Conclusions. The comprehensive CT examination is a fast and safe method allowing accurate diagnosis and making way for individualized treatment in acute ischemic stroke.

Explorative investigation of biomarkers of brain damage and coagulation system activation in clinical stroke differentiation.

INTRODUCTION: A simple and accurate method of differentiating ischemic stroke and intracerebral hemorrhage (ICH) is potentially useful to facilitate acute therapeutic management. Blood measurements of biomarkers of brain damage and activation of the coagulation system may potentially serve as novel diagnostic tools for stroke subtypes. METHODS: Ninety-seven stroke patients were prospectively investigated in a multicenter design with blood levels of brain biomarkers S100B, neuron specific enolase (NSE), glial fibrillary acidic protein (GFAP) as well as a coagulation biomarker, activated protein C-protein C inhibitor complex (APC-PCI), within 24 hours of symptom onset. RESULTS: Eighty-three patients (86%) had ischemic stroke and fourteen patients (14%) had ICH. There were no differences in S100B (p=0.13) and NSE (p=0.67) levels between patients with ischemic stroke or ICH. However, GFAP levels were significantly higher in ICH patients (p=0.0057). APC-PCI levels were higher in larger ischemic strokes (p=0.020). The combination of GFAP and APC-PCI levels, in patients with NIHSS score more than 3, had a sensitivity and negative predictive value of 100% for ICH in our material (p=0.0052). CONCLUSION: This exploratory study indicated that blood levels of biomarkers GFAP and APC-PCI, prior to neuroimaging, may rule out ICH in a mixed stroke population.

Clinical significance of serum S100B levels in neurointensive care.

OBJECTIVE: S100B is viewed as the most promising biomarker for brain damage. It has been proposed that this marker is useful in a Neurointensive Care Unit (NICU) as a monitoring parameter. This study aims to examine the clinical usefulness of daily serum S100B measurements in this setting. DESIGN: Prospective consecutive inclusion of patients. PATIENTS: A total of 79 patients with confirmed or suspected head injury or cerebrovascular insults (CVIs) (based upon patient history, computed tomography (CT) and/or magnetic resonance imaging (MRI) and neurological examination including coma scoring) who required neurointensive care were included in the study. INTERVENTIONS: Sampling for S100B was performed at admission and daily until patients were discharged from the NICU. S100B measurements were statistically compared to occurrence of secondary complications and outcome according to Glasgow Outcome Scale (GOS), with focus on clinical prediction. MEASUREMENTS AND MAIN RESULTS: 17 of 79 patients (22%) had secondary neurological complications. Mean S100B levels were found to be an independent parameter associated with these complications (P=0.03). Mean S100B levels were higher in patients with complications compared to those without on both the complication day (P=0.033) and the day after (P=0.015), but not the day prior to the complication (P=0.62). S100B did not predict secondary neurological complication. Neither mean (P=0.182) nor peak (P=0.370) S100B levels were associated with or predicted outcome according to dichotomised GOS. CONCLUSION: Daily S100B measurements are associated with secondary complications but not to outcome. However, daily S100B levels do not predict secondary complications, which limit the usefulness of this brain biomarker in this setting.

Neuropathological and behavioral consequences of adeno-associated viral vector-mediated continuous intrastriatal neurotrophin delivery in a focal ischemia model in rats.

Nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) were continuously delivered to the striatum at biologically active levels via recombinant adeno-associated viral (rAAV) gene transfer 4-5 weeks prior to 30 min of middle cerebral artery occlusion (MCAO). The magnitude of the deficits in a battery of behavioral tests designed to assess striatal function was highly correlated to the extent of ischemic damage determined by unbiased stereological estimations of striatal neuron numbers. The delivery of neurotrophins lead to mild functional improvements in the ischemia-induced motor impairments assessed 3-5 weeks after the insult, in agreement with a small but significant increase of the survival of dorsolateral striatal neurons. Detailed phenotypic analysis demonstrated that the parvalbumin-containing interneurons were spared to a greater extent by the neurotrophin treatment as compared to the projection neurons, which agreed with the specificity for interneuron transduction by the rAAV vector. These data show the advantage of the never previously performed combination of precise quantification of the ischemia-induced neuropathology along with detailed behavioural analysis for assessing neuroprotection after stroke. We observe that intrastriatal delivery of NGF and BDNF using a viral vector system can mitigate, albeit only moderately, neuronal death following stroke, which leads to detectable functional sparing.

Anterograde delivery of brain-derived neurotrophic factor to striatum via nigral transduction of recombinant adeno-associated virus increases neuronal death but promotes neurogenic response following stroke.

To explore the role of brain-derived neurotrophic factor for survival and generation of striatal neurons after stroke, recombinant adeno-associated viral vectors carrying brain-derived neurotrophic factor or green fluorescent protein genes were injected into right rat substantia nigra 4-5 weeks prior to 30 min ipsilateral of middle cerebral artery occlusion. The brain-derived neurotrophic factor-recombinant adeno-associated viral transduction markedly increased the production of brain-derived neurotrophic factor protein by nigral cells. Brain-derived neurotrophic factor was transported anterogradely to the striatum and released in biologically active form, as revealed by the hypertrophic response of striatal neuropeptide Y-positive interneurons. Animals transduced with brain-derived neurotrophic factor-recombinant adeno-associated virus also exhibited abnormalities in body posture and movements, including tilted body to the right, choreiform movements of left forelimb and head, and spontaneous, so-called 'barrel' rotation along their long axis. The continuous delivery of brain-derived neurotrophic factor had no effect on the survival of striatal projection neurons after stroke, but exaggerated the loss of cholinergic, and parvalbumin- and neuropeptide Y-positive, gamma-aminobutyric acid-ergic interneurons. The high brain-derived neurotrophic factor levels in the animals subjected to stroke also gave rise to an increased number of striatal cells expressing doublecortin, a marker for migrating neuroblasts, and cells double-labelled with the mitotic marker, 5-bromo-2'-deoxyuridine-5'monophosphate, and early neuronal (Hu) or striatal neuronal (Meis2) markers. Our findings indicate that long-term anterograde delivery of high levels of brain-derived neurotrophic factor increases the vulnerability of striatal interneurons to stroke-induced damage. Concomitantly, brain-derived neurotrophic factor potentiates the stroke-induced neurogenic response, at least at early stages.

Elevated GDNF levels following viral vector-mediated gene transfer can increase neuronal death after stroke in rats.

Previous studies have indicated that administration of glial cell line-derived neurotrophic factor (GDNF) counteracts neuronal death after stroke. However, in these studies damage was evaluated at most a few days after the insult. Here, we have explored the long-term consequences of two routes of GDNF delivery to the rat striatum prior to stroke induced by 30 min of middle cerebral artery occlusion (MCAO): striatal transduction with a recombinant lentiviral vector or transduction of the substantia nigra with a recombinant adeno-associated viral vector and subsequent anterograde transport of GDNF to striatum. Despite high GDNF levels, stereological quantification of striatal neuron numbers revealed no protection at 5 or 8 weeks after MCAO. In fact, anterograde GDNF delivery exacerbated neuronal loss. Moreover, supply of GDNF did not alleviate the striatum-related behavioral deficits. Thus, we demonstrate that the actions of GDNF after stroke are more complex than previously believed and that high levels of this factor, which are neuroprotective in models of Parkinson's disease, can increase ischemic damage. Our findings also underscore the need for quantitative assessment of long-term neuronal survival and behavioral changes to evaluate the therapeutic potential of factors such as GDNF.