research – European Stroke Organisation

ESSW – Session 7 – Far Horizons

Noémie — Wed, 06 Dec 2023 12:15:02 +0000

06/12/2023/in ESO /by Noémie

By: Anke Wouters, Rustam Al-Shahi Salman

ESO European Stroke Science Workshop 2023

Session 7: Far Horizons

Heavy snow disrupted the exit out of Garmisch, but despite this distraction, a lively debate followed.

Keynote debate: There are no limits to mechanical thrombectomy for acute ischaemic stroke due to medium and large vessel occlusion.

Prof. Mikael Mazighi: PRO

Prof. Mazighi started with a picture of his opponent swimming in the ice-cold Eibsee. Debating against superwoman Else Sandset is not an easy task, but everyone knows the indications for thrombectomy are increasing. Prof. Mazighi started with showing the data about patients with large core ischaemic stroke. In the TENSION trial, using mostly only CT for patient selection, 20% of the patients ended up being functionally independent. Also, the most recent trial, IN EXTREMIS LASTE, showed similar results with a reduction of mortality and an increased functional independence, however at the cost of an increased intracranial hemorrhage risk. The distal medial vessel occlusions (DMVOS) are another important new thrombectomy target with 4 RCTs currently including patients. DMVOS are very common (25-40%), but a higher bleeding risk is associated with a worse outcome. Therefore, we need other strategies to reduce the bleeding risk, with for example new antiplatelet strategies (ACTIMIS trial) or neuroprotective agents (TLR4 antagonists). Prof. Mazighi concluded by stating that there are no limits for mechanical thrombectomy, but that we do need a combined approach: good level of evidence (waiting for results of RCTs), optimisation of reperfusion, prevention of bleeding and adjunctive therapies.

Prof. Else Sandset: CONTRA

EVT is of course a highly effective treatment strategy with a NNT of 2.6 when used within 6 hours of ischaemic stroke onset, but still there are some limitations to this treatment. The most important limitation to EVT might be the fact that the treatment is still not available to many patients. Furthermore, the data for mild ischemic strokes and distal vessel occlusions, are still lacking and we need to wait for the results of the ongoing RCTs before treating those patients outside RCTs. Recent trials demonstrated a benefit of EVT in patients with large ischaemic cores, but the included patients might not be representative of the general population. Those patients were quite young and had a low number of comorbidities. Probably it is still important to consider the ‘frailty’ of a patient when considering EVT. Prof. Sandset ended here arguments with a patient-focussed perspective, by saying that it is important to take your time to talk to family and patients to achieve shared decision making in those situations.

After this intense debate, around 90% of the audience agreed that there are still some limits to mechanical thrombectomy.

Keynote lecture: Better translation for clinical recovery

Prof. Rick Dijkhuizen

Prof. Dijkhuizen spoke about the important translation of basic stroke recovery research to clinical trials. Research about stroke recovery has been limited by a lack of standardisation, variable clinical responses and incomplete recovery. Important initiatives have been initiated which provide recommendations to overcome these limitations: ISRRA, STAIR, Multi-PART. Treatment testing in animals should be standardised, multicentre and use translational outcome measures. Basic science studies remain important for detection of new pathways and targets for treatments. Translational imaging, like diffusion tract MRI or fMRI could potentially bridge the gap to clinical neurorecovery trials.

This was nicely demonstrated by prof. Dijkhuizen In the next part of his talk with the example of repetitive transcranial stimulation (rTMS). rTMS can be used post-stroke to modulate the cortical excitability. To bring rTMS from bench to bedside, a large platform was setup within UMC Utrecht. First, a meta-analysis showed that starting rTMS within 1-month post-stroke, was the most optimal timing. Preclinical research with rat models and skilled research as an outcome measure was started, for which the results are still blinded. In addition, a phase 2 clinical trial (B-stars), investigating the effect of contralateral cTMS (continuous theta burst stimulation) on upper limb recovery, has started. The results of this trial were recently published in Stroke (Vink et al. 2023) and showed a significant effect on upper limb recovery compared to the group with sham stimulation. A large national multicenter phase 3 RCT, called B-STARS² will soon start, and we are all looking forward to the results of a large, definitive trial in the field of neurorehabilitation.

Did GSSW get its priorities right? Evidence from international stroke research priority setting exercises

Prof. Terry Quinn (UK)

In the last talk of the 2023 GSSW edition, prof. Quin summarized ways of getting our research priorities on the right track. To define our priorities, we can use published data, the opinions of different experts or the research goals from guidelines. However, most importantly as academic researchers we need to synergize our research goal with people who suffered from a stroke. It is not always straightforward to get to know the real priorities of patients, because they might be reluctant to discuss certain topics with their physicians. Within the registry of Stroke Care Quality (RES-Q +) project, a chat bot was developed for patients to ask their questions more easily. Following social media is another strategy to get to know patient’s interests. In a more formal prioritisation exercise, all stroke stakeholders are included. The three most used methods are the: `James Lind Alliance`, `Global Health Forum Child Health and Nutrition Research Initiative` and the `Delphi Consensus method`. In stroke rehabilitation and long-term care, a top 10 of research questions included psychological and cognitive problems and fatigue among other things. However, it is important to note that priorities are likely to be contextual, vary with time and by included participants. A study about the effect of priority setting on published articles, didn’t show an impact on the articles that were published. To end this ESSW: Prof Quinn concluded that ESSW could focus on more of the priority areas and the priority for research is to focus on priority setting and implementation!

As ESSW 2023, closed, the snowy weather trapped most of us in Garmisch with no choice but to enjoy an extra snowy day in Garmisch to continue discussions with our colleagues!

The post ESSW – Session 7 – Far Horizons first appeared on European Stroke Organisation.

ESSW – Session 4 – OMICS, OH MY!

Noémie — Wed, 06 Dec 2023 12:10:29 +0000

06/12/2023/in ESO /by Noémie

By: Märit Jensen, Diana Aguiar De Sousa

ESO European Stroke Science Workshop 2023

Session 4: OMICS, OH MY!

The Friday afternoon session with the catchy title “OMICS, OH MY!” presented the first pro and con debate of this year’s ESSW and by this another new feature to the programme of the workshop.

The statement to be debated was: “Genomics will deliver specific stroke treatment in the next 5 years”.

Hugh Markus made the start taking the optimistic view voting for “yes”. He had a difficult task as the pre-debate survey already revealed that the majority of scientists in the audience appeared to be on the sceptic side with regards to the near future promises of genomics for stroke treatment. To support his case, Hugh Markus reminded everybody of the fact that genomics already has led to the identification of new treatment in cardiovascular disease providing the example of PCSK9 inhibitors for treatment of hypercholesterolaemia. In the second part of his talk, he described the prospects of mendelian randomization for the identification of potential therapeutic approaches. Finally, he pointed out that the era of genetic modification to treat stroke has just begun. As an example, he referred to the success in healing sickle cell disease with CRISPR-based gene editing which has been approved in the UK some weeks ago. Other approaches relying on genetic modification are currently being tested for example for cholesterol reduction using base editing of the PCSK9 gene. Against this background, Hugh Markus concluded that the advent of specific novel stroke treatment informed by genomics in the next 5 years is within reach.

Ynte Ruigrok took the role of the opponent. In an enthusiastic talk, she aimed at convincing the audience using five persuasive arguments, ingeniously structured to form the memorable acronym ‘FIASCO’. To start with, given the complexity of the genome and factors involved in stroke, she raised doubts that targeting a single genetic target would work. She also questioned why the next 5 years would bring more progress than the 5 years following the launching of GWAS which also came along with many hopes and promises but failed to deliver. Ynte Ruigrok pointed out that most of the drugs linked to targets identified by genomics had been identified based on other (non-genomic) approaches. Just 1 of 13 identified targets in this milestone analysis had not been known or tested before. This saying she made an excusing remark to the session chairs, Stephanie Debette and Martin Dichgans, who happen to be leading authors of the mentioned paper. Both took it with a smile – no offence taken.

After pros and cons were exchanged the audience was asked again. Obviously Ynte Ruigrok made some good points as the result of the voting was even stronger towards scepticism with 84% voting that genomics will NOT deliver specific stroke treatment in the next 5 years. The talks were followed by a lively discussion acknowledging the huge advances in genomics and also the prospects for future treatments based on genomics while the 5 years perspective might be overoptimistic.

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ESSW – Session 6 – New Horizons

Noémie — Tue, 05 Dec 2023 09:56:15 +0000

05/12/2023/in ESO /by Noémie

By: Corinne Benakis, Arthur Liesz

ESO European Stroke Science Workshop 2023

Session 6: New Horizons

Keynote lecture: Uric acid in stroke: the next frontier

Angel Chamorro (Spain)

Prof. Chamorro started his lecture on uric acid in stroke by first introducing he metabolism of uric acid, which is the end product of purine metabolism in humans. Uric acid is found as an end product in urine, usually known to form crystals and accumulate in joints when in high concentration. In lower concentration, uric acid is an antioxidant, and neutralizes free radicals with potential beneficial effect in ageing and cancer. Prof. Chamorro made the analogy of uric acid as a “vacuum cleaner”. In 2002, he and his team published results that showed that an increase of uric acid in patients with acute ischemic stroke is an independent predictor of good clinical outcome, highlighting the importance of oxidative damage induced early in the ischemic cascade. He re-emphasized the huge disappointment of “neuroprotection failure” in translating positive pre-clinical research to clinical trials. He addressed that perhaps this failure was due to mostly targeting the early excitotoxic events mediated by excessive glutamate toxicity but that might not be relevant since the time course of glutamate peaks very acutely after stroke but quickly recovers thereafter. In contrast, the formation of radical species continues to rise after stroke, especially in the penumbra participating in the no-reflow phenomenon. Hence, he emphasized neuroprotective strategies should be a “redox-centered neuroprotection” strategy, especially targeting the salvageable penumbra tissue in combination with mechanical thrombectomy.

URICO-ICTUS 2b/3 was a randomised, double-blind, placebo-controlled trial, that recruited patients with acute ischaemic stroke (The Lancet Neurology 2014), with a primary outcome of patients with excellent outcome at 90 days. The study showed an absolute treatment effect of 8% but no significance. The speaker mentioned the relatively small number of patients recruited that would make finding any significant results difficult.

He then took the audience on to describe the efforts taken by the Stroke Preclinical Assessment Network (SPAN) to test uric acid in preclinical stroke models. SPAN consisted of six research laboratories that conduced preclinical stroke modelling, with a coordinating center which was solely involved in drug preparation, randomization, collection and management of data, assessing blinded outcomes and performing statistical analysis. Outcome was addressed at 30 days based on behavioural improvement post-stroke as primary end-point. Of all drugs tested, among the four stages (including rodent models with comorbidities: hypertensive, obesity) only uric acid showed efficacy on the primary outcome which was validated iuntil the final stage 4 (validation in a rat model). These very impressive and promising results were published this year in Science Translational Medicine. The next frontier is to perform an interventional clinical trial in patients receiving endovascular thrombectomy (AURORA) in combination with uric acid. The stroke field is following the outcome of such intervention closely, as it could bring important benefits for stroke patients, their relatives and clinical stroke practice.

Prof. Chamorro received a nice round of applause and the first question asked him to explain the rationale behind limiting this kind of clinical trial to patients with thrombectomy. Prof. Chamorro mentioned that ideally uric acid would be administrated to any stroke patients, however it is important now that beneficial effect of uric acid is proven in highly responsive patients. This was followed by a question regarding the best timing of drug administration, and whether blood biomarkers can be used to test efficacy or perhaps to stratify receiver patients. Because previous work showed that the level of uric acid peaks immediately after reperfusion, uric acid will be administered immediately when the thrombectomy is decided. Biomarkers are now not the focus of the study, but rather primary outcome. A participant raised that giving uric acid may be counter intuitive since it can induce gout, however this was a highly epi-phenomenon among the patients enrolled and not specific to the treatment and might underlined pre-existing condition. There was then some debate from participants regarding the interpretation of sub-group analysis, that could be either futile or meaningful. What matters at the end is overall benefit for the patient and perseverance will tell us more.

Stephanie Debette

Multiomics into vascular brain health

Stephanie Debette’s scientific presentation delved into the pressing issue of vascular brain disease, which still lacks adequate treatment. She emphasized that genomics could potentially offer a targeted approach to address this condition, revealing over 150 genetic risk loci associated with vascular brain disease, mostly small vessel disease (SVD) with increased risk of stroke and dementia. However, the mechanisms underlying these genetic risk variants remain poorly understood.

Debette highlighted Montaner et al.’s work in Nat Rev Neurol 2020 (co-authored by Alba Simats, next speaker in this session), showcasing the transition from stroke treatment to multiomics strategies, stressing the importance of circulating biomarkers in understanding the underlying biology and hastening omics-driven discoveries in vascular diseases.

The integration of omics biomarkers such as metabolites, methylation, microRNAs, and proteins, along with genetic information, was emphasized to establish causal relationships, though research in multiomics for stroke has been hindered by limited sample sizes, predominantly focusing on blood-based biomarkers as shown in Chen Nat Comm 2020 and Mishra Nature 2022, utilizing Mendelian Randomization to obtain clues for causality.

Another referenced study by Sliz et al (Circulation 2022) described using mendelian randomization that circulating metabolites are associated with white matter hyperintensities (WMH). Metabolites are either endogenous or from exogenous sources like diet and chemical exposures, associating specific metabolites with risk factors for vascular brain disease, although the precise correlations are not fully investigated.

Debette discussed epigenomics, citing Yang, Brain 2023, and the importance of proteomics due to its proximity to function. Her focus leaned towards plasma proteins, as exemplified in Kuipers JCBFM 2022, which highlighted a cluster of proteins, including coagulation factors, associated with white matter hyperintensities (WMH). Employing a pQTL approach (protein quantitative trait loci), Debette outlined her study associating 21 proteins with a higher risk of SVD, specifically mentioning cathepsin b and immune response enrichment. This research would significantly enhance the prediction of SVD. She posed critical questions in her conclusion, pondering whether the proteins linked to SVD could predict stroke and dementia while exploring the feasibility of developing drugs targeting these proteins. She emphasizes that taking a more global approach towards vascular brain health by integrating multiomics to not only address risk prediction, but also early prevention and to accelerate the development of new drugs. And the development of interdisciplinary experts would significantly accelerate discovery.

Alba Simats

Innate immune memory after stroke drives inflammatory cardiac dysfunction

Alba Simats’ presentation exemplified the profound impact of post-stroke inflammatory responses, and it’s influence on other diseases like atherosclerosis, diabetes, and heart dysfunction. The chronic inflammatory state persisting in stroke patients over time raises questions about its consequences on peripheral organs, such as the heart.

Within a month of stroke, increase of myeloid cells were identified in various peripheral organs, particularly highlighting the dominance of monocytes/macrophages exhibiting a pro-inflammatory signature. Remarkably, the heart emerged as the most affected organ in this cellular population, exhibiting altered left ventricle diastolic dysfunction, a finding mirrored in the SICFAIL previously describing cardiac dysfunction in stroke patients.

Investigations into cardiac fibrosis, collagenase and MMP9 accumulation in the heart showed as association with with an increase in heart and circulating inflammatory CCR2+ monocytes expressing MMP9. A cohort of cardiac autopsy samples from stroke and control patients further substantiated these findings, demonstrating fibrosis, MMP9, CCR2+ expression, and inflammatory genes in the hearts of stroke patients.

Insights into bone marrow as a potential source of these monocytes wasrevealed, showcasing increased monocytes/neutrophils and their precursors after one month post-stroke. Notably, both pluripotent stem cells and monocytes from the bone marrow exhibited distinct gene profiles similar to those in the periphery, speculating that the inflammatory cardiac monocytes originate and are polarized in the bone marrow.

A groundbreaking experiment, showing causality, involved bone marrow transplantation from stroke-affected mice to mice lacking bone marrow, demonstrated that progenitor cells and monocytes carrying the Ly6C high marker exhibited identical signatures, leading to similar cardiac dysfunction characterized by increased fibrosis and MMP9 expression in the heart. The potential therapeutic avenue of inhibiting monocyte infiltration from the bone marrow to the heart using a dual chemokine inhibitor showed promising results. Blocking monocyte access to the heart not only restored left ventricle volume but also decreased cardiac fibrosis, hinting at a potential intervention strategy for post-stroke cardiac complications. These are the first evidence that stroke impacts cardiac function chronically mediated by recruitment of inflammatory monocytes to the heart.

Floris HBM Schreuder

Inflammation after Intracerebral Hemorrhage

Floris HBM Schreuder’s presentation on “Inflammation in Intracerebral Hemorrhage (ICH): The Ugly, The Bad, and The Good” highlighted the nuanced nature of inflammatory responses in this condition. He outlined the phases of inflammation, emphasizing both detrimental and beneficial aspects. Hence, the classical view of good and bad inflammation in ICH is more complicated.

The road map of his talk navigated through three main areas: the role of inflammation in ICH, mechanisms of secondary brain injury, and therapeutic approaches.

In discussing the role of inflammation in ICH, Schreuder focused on the transition to a hemorrhagic phenotype, attributing it to reduced clearance in Amyloid beta deposition, leading to vessel fragmentation (loss of smooth muscle cells) and subsequent perivascular inflammation.

ICH develops into hematoma growth but also to an accumulation of parenchymal blood components inducing secondary brain injury with BBB breakdown, inflammation and perhematomal edema. This was portrayed as a time-dependent process, where the inflammatory response played a complex role.

Preclinical studies faced limitations due to induced ICH via collagenase or blood injection, which do not necessarily recapitulate the complex inflammatory cascade in human ICH. Importantly there is still only limited data derived from investigating human brains and systemic inflammation. He highlighted the recent meta-analysis showing association with circulating inflammatory biomarkers and clinical outcome following ICH (Kirby et al. Wellcome Open Res 2023).

Therapeutic strategies to mitigate post-ICH inflammation include surgical blood removal and reducing perihematomal edema: The Dutch ICH surgery trial, and a new sub-study DIST-INFLAME to investigate immunoprofile between surgically versus conservatively treated patients are investigating these approaches. Schreuder stressed the need for early intervention due to the vulnerability of ICH patients to infections, posing the question of whether modulating inflammation, possibly with steroids like Dexamethasone, could be effective or if this type of intervention is alreafdy a “closed case” considerating previous (futile) studies using this intervention..

Ongoing trials targeting inflammation and potential therapeutic avenues like neutralization of IL-1b as a target were discussed; including potential complications and the their limitations. Schreuder concluded by emphasizing the importance in targeting multiple phases and mechanisms of ICH, such as stopping ICH growth, treat hypertension, reduce secondary brain inflammation (IL1b), promote repair (stem cell strategy?) and rehabilitation, combining experts from different fields from the emergency to the rehab teams. He finished his talk mentioning there is certainly possibility of leveraging inflammation for therapeutic intervention in ICH while acknowledging the complexity and challenges involved.

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ESSW – Session 5 – Too much, too young

Noémie — Mon, 04 Dec 2023 11:24:22 +0000

04/12/2023/in ESO /by Noémie

By: Anke Wouters, Rustam Al-Shahi Salman

ESO European Stroke Science Workshop 2023

Session 5: Too much, too young

Keynote Lecture: Stroke in the young: what are we missing?

Speaker: Frank-Erik De Leeuw, RadboudUMC

Professor De Leeuw, gave an excellent keynote lecture summarizing the missing aspects of stroke in the young. Stroke patients of 18-50y old were considered as young strokes. The increase in the incidence of more than 50% during the last years is very worrisome. In his talk, prof. De Leeuw summarized three key factors about young stroke that we are currently missing: Cryptogenic causes, prognosis and adverse events.

How can we find the unknown causes of these strokes in the young?

Data from the Odyssey study were shown in which 1322 young ischemic stroke patients were included between 2013 and 2017 in 17 centers in the Netherlands. Around 25-30% of these patients had a cryptogenic stroke according to the TOAST-classification. However, risk factors like high temperature, physical exercise, flu-like episodes… all increased the risk of having a cryptogenic stroke in those young patients. Furthermore, according to geographical data, patients living in rural areas were at a greater risk compared to those living in urban areas in the Netherlands. Cancer was another important risk factor that was addressed. In stroke patients, the excess risk of having cancer was higher in young patients compared to older stroke patients. Probably it is not useful to screen all young stroke patients for cancer but only selected patients who are at the highest risk. Known risk factors are anemia, cryptogenic stroke and stroke in three brain regions.

What are we missing about prognosis?

It is important to keep in mind that all individual patients are different, and that the recurrence stroke risk depend on the underlying cause of the stroke. For example, after cervical artery dissection the recurrence risk is very high in the first two weeks, but the risk of recurrence is very low in the long-term, in contrast for patients with underlying atherosclerosis the risk is always high and will increase further over the years. This information can help to inform patients more accurately in clinical practice.

What about the secondary prevention?

Probably the use of antithrombotic therapy should be managed individually depending on both the bleeding and ischemic stroke risk. From the data collected in the Netherlands, the bleeding and ischemic risk are very similar after 5-10 years. Hence, the European guidelines suggest that you can discuss stopping secondary prevention with your patients after 3-5 years if a complete etiological work-up didn’t reveal a cause. Evidence from future clinical trials might be needed to more accurately define if and when we can stop antithrombotic treatment.

This excellent keynote lecture was followed by a lively discussion.

Why is the incidence of stroke in the young rising?

Speaker: Linxin Li (UK)

Dr. Li nicely described the rising incidence of ischemic stroke in the young patients in the last 20 years based on data from the Oxford vascular study. Although the absolute incidence of young stroke showed considerable levels of inconsistencies in other high-income countries, this was consistently less favorable compared to older ages. She nicely demonstrated that the time-trend in the young stroke could not be explained by changes in diagnostic work-up, stroke definition and adjudication, patient behaviour, hospital admission policy or changes in traditional vascular risk factors. Although there is still a high prevalence in modifiable risk factors in young stroke patients which are under-recognized and under-treated. Next, still a lot of research should be done regarding the role of emerging risk factors (migraine, previous auto-immune disease, exercise,…).

Novel types of hereditary small vessel disease: evidence for a unifying mechanism?

Speaker: Elisabeth Tournier-Lasserve

Professor Tournier-Lasserve focused on hereditary causes of small vessel disease. Causative mutations are only identified in 20-25% of the referred patients. Perturbation of the cerebrovascular matrisome is a convergent pathway but through different mechanisms. She nicely demonstrated with the COL4A1 example (HANAC and PADMAL phenotypes), how mutational consequences can be distinct from one class of mutations to another and lead to different small vessel disease (SVD) phenotypes. Many other anomalies can cause an up or down regulation of COL4A1/2 genes and might explain some unresolved SVD cases in the future. Probably a combination of DNA sequencing and functional protein/mRNA fibroblast analysis will be needed to identify them.

Closing comments: PFO as a window on heterogeneity of treatment effect.

Speaker: Guillaume Turc

Professor Turc talked about the selection of people with ischaemic stroke who should undergo PFO closure. The PFO-Associated Stroke Causal Likelihood (PASCAL) classification system is mostly used in clinical practice to select patients for PFO-closure. 15% of young people with ischaemic stroke would be included in the `unlikely` PASCAL category, meaning the stroke was probably not caused by the PFO. Hence these patients are unlikely to derive any benefit from PFO closure (but 95% CI are wide). To determine patients at a high risk for recurrent stroke, a detailed PFO anatomy is important. Data show that patients with both a large shunt and an atrial septal aneurysm are at the highest risk of having a recurrent stroke (SCOPE collaboration) and have the highest treatment effect of PFO closure. Therefore, in the current 2021 AHA/ASA guidelines PFO anatomy has a central role in stratifying patients for PFO closure.

After a lengthy and insightful discussion, the second day of the ESSW was wrapped up.

The post ESSW – Session 5 – Too much, too young first appeared on European Stroke Organisation.

ESSW – Session 3 – Methods Matter

Noémie — Mon, 04 Dec 2023 11:09:05 +0000

04/12/2023/in ESO /by Noémie

By: Thomas Meinel, Diana Aguiar De Sousa

ESO European Stroke Science Workshop 2023

Session 3: Methods Matter

Dr. Sarah McCann

In her excellent keynote lecture on meta-research, Dr. McCann challenged the preclinical stroke research community with an alarming in-depth analysis of published laboratory stroke studies analyzing key quality metrics. A large proportion of preclinical research is not reproducible in humans, mostly due to significant weaknesses of design and reporting.

Weaknesses include selective outcome reporting and publication bias. Frequently, animal models are also not reflective of the human disease population, e.g. an antihypertensive drug tested in young healthy male mice as opposed to an older, more often female human population that this drug would then be used in.

The same tools that we take for granted in clinical research, namely large-sized registries, multicenter studies, randomization and blinding of performing the treatment and outcome assessment are useful tools to overcome those methodological flaws in preclinical studies. Successful examples of such large collaborations are the Stroke Preclinical Assessment Network (SPAN) and INFORM-Stroke.

The recently launched CoReS hub aims to bring together primary researchers and evidence synthesists to provide infrastructure and support systems to empower the community in the performance of systematic reviews on preclinical evidence. Journal policies have also modestly helped to improve design and reporting of animal experiments such as adopted by Nature publishing group and Stroke. Open data policies are another piece of the puzzle to enhance the transparency and external validity. The suggestions have been incorporated into design guidelines (EDA), and publication guidelines (ARRIVE).

The discussion acknowledged the urgent need for improvement and great potential of the proposed improvements.

Overall, the analysis and proposed solutions are a highly relevant contribution to improve validity, transparency, and reproducibility of laboratory stroke research. Following those recommendations ultimately means less waste in preclinical research, less potential harm for patients and more robust and fruitful translational research.

Professor Maren Ranhoff Hov

In her outstanding lecture on innovative trial designs with the example of cluster randomized trials in the prehospital setting, Professor Ranhoff Hov pointed out the particularities and challenges of prehospital research. Learning from the trauma community, that put into place a very standardized approach to ensure fast and high-quality care, she mentioned the potential of such an approach to address the heterogeneity of stroke presentations, especially for those presenting with less severe or less specific symptoms and other hurdles for a rapid activation of the stroke chain of survival. One such approach was the ParaNASPP trial, that used prehospital NIHSS assessment by an app. Since randomization and blinding is not possible on a patient-level, the design was a stepped-wedged cluster randomized trial. This also allowed to provide training of the cluster sequentially. The downside of this approach include a potential secular effect during the trial, especially given the fact that the COVID pandemic happened during recruitment. As an example, the delay of on-scene time of about 5 minutes is not necessarily only due to the use of the prehospital app, but might (partially) be a pandemic effect. She encouraged the stroke research community to engage in prehospital research making use of novel technical solutions such as videocalls and mobile apps with live communication to the stroke center.

Professor Joanna Wardlaw

Professor Joanna Wardlaw presented the tremendous effort to update and expand the STRIVE recommendations for imaging features of small vessel disease in the STRIVE-2 update. This included an analysis of adoption of the recommendations, which was mostly good, but there is ongoing debate mostly about the best term for “recent small subcortical infarcts”. The update includes novel and emerging features such as cortical superficial siderosis as well as small cortical infarcts as well as recommendations on image acquisition and analysis. For sure, those recommendations will continue to influence guidelines and improve research and patient care.

Professor Will Whiteley

How to do research under the time pressure of a pandemic was the topic of the last talk of the session. There was a massive inflation of research, but weaknesses included lack of collaboration with duplicative, small studies instead of larger, well conducted studies. The peer review system failed to filter dogmatic and flawed research. Positive developments to provide timely and truthful information include the use of master protocols, rapid governance, and easy data flow. Since the information should be available freely, researchers should use preprints, as well as open data and open code. In the next pandemic, policy makers should quickly set up few, but well designed and large projects providing sufficient funding combining several perspectives. One such positive example is the RECOVERY trial.

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ESSW – Session 2 – The Heart of Matter

Noémie — Mon, 04 Dec 2023 10:30:49 +0000

04/12/2023/in ESO /by Noémie

By: Thomas Meinel, Rustam Al-Shahi Salman

ESO European Stroke Science Workshop 2023

Session 2: The Heart of Matter

Professor Hooman Kamel

The keynote lecture of the session was given by Professor Hooman Kamel and delved into the intricate relationship between atrial cardiopathy and atrial fibrillation (AF) in the context of stroke patients. Atrial cardiopathy, characterized by structural and functional abnormalities in the atria, has emerged as a significant player, coexisting with or more often preceding AF.

Regarding AF, new data is available from NOAH-AFNET and ARTESIA – two trials that randomised patients with device-detected short episodes of subclinical AF to oral anticoagulation vs placebo or Aspirin. In the meta-analysis of those trials, there was a benefit in the reduction of (disabling) stroke at the cost of a slightly increased risk of major bleeding. The question remains whether those findings can be extrapolated to stroke survivors since only about 10% had prior stroke and most patients in the trial had a previous cardiac condition requiring the implantation of a pacemaker or implantable cardioverter/defibrillator and only a very tiny minority was diagnosed based on implantable cardiac monitors.

With regards to atrial cardiopathy, Professor Kamel explored details of his ARCADIA trial, that overall did not show benefit of oral anticoagulation for patients with atrial cardiopathy. In further analyses, there was also no benefit in patients with a more severe phenotype of atrial cardiopathy based on the biomarkers used (P-terminal force V1, BNP, and left atrial dilatation).

A vivid discussion followed this enlightening lecture. Raised question included whether biomarkers of more severe atriopathy, a combination of atrial myopathy and a thrombogenic condition or older populations might still benefit from oral anticoagulation. Another alternative would be to test the COMPASS regimen (low dose Rivaroxaban + Aspirin) since there is a significant burden of non-stenosing atherosclerosis in people with cryptogenic ischaemic stroke.

Further related trials in the pipeline include the ongoing FIND-AF2 trial, that hopefully clarifies whether prolonged ECG monitoring is able to prevent recurrent events. Another option might include mechanical occlusion of the left atrium as tested in LAAOS-4, CHAMPION-AF or the ELAPSE trial. Additionally, trials testing factor XIa inhibition are ongoing (LIBREXIA-AF, LILAC-TIMI 76), although recently OCEANIC-AF was stopped early for lack of efficacy of the oral factor XIa inhibitor Asundexian.

In conclusion, this keynote session and discussion provided a comprehensive overview of the complex relationship between atrial cardiopathy, AF, and ischaemic stroke. The integration of clinical, imaging, and biomarker insights paved the way for a deeper understanding of these interrelated cardiovascular conditions, offering promising avenues for future research and improved patient care.

Professor Mira Katan

Professor Mira Katan made a strong argument for the potential of biomarkers to find tailored therapeutic management strategies in stroke patients. Biomarkers are available providing etiological clues, but also bearing prognostic significance for recurrence risk stratification. One such option is currently tested in the ongoing MOSES trial, that tests the hypothesis that patients with ischaemic stroke, in sinus rhythm, with an elevated mid-regional pro-atrial natriuretic peptide (MR-proANP) – a biomarker strongly associated with severe atrial cardiopathy at the chosen cut-off – benefit from oral anticoagulation as compared to antiplatelet therapy. Given the complexity and multitude of available biomarkers, artificial intelligence models might be helpful to disentangle.

Dr. Märit Jensen

Dr. Jensen gave a fantastic talk on the concept of early rhythm control for AF. In the EAST-AFNET 4 trial, a strategy of early rhythm control was able to reduce the composite outcome in a cardiology-based AF population. However, a significant proportion of AF is diagnosed after stroke by neurologists. This raises the question, whether those patients should be referred for rhythm control, especially since a subgroup analysis of EAST-AFNET 4 trial led by Dr. Jensen and Professor Götz Thomalla and Professor Paulus Kirchhof showed that the benefit of rhythm control was even more pronounced in the subgroup of patients with prior stroke. The stroke-specific EAST-STROKE trial is in the planning and could provide reliable evidence for this exciting new approach and novel hope for stroke patients with AF.

Associate Professor Signild Åsberg

The last talk of the session looked back at the history of anticoagulation for patients with AF and ischaemic stroke. In recent decades, the transition from Vitamin-K-antagonists to DOACs took place and led to better adherence to anticoagulation given the favorable safety profile. The latest advances include the TIMING trial and ELAN trial that showed that earlier start of DOAC therapy in patients with ischemic stroke and AF is safe and most likely beneficial. The ongoing large OPTIMAS and START trials and a planned individual patient data meta-analysis will hopefully provide definitive evidence of the effectiveness and safety of early initiation of oral anticoagulation for AF after ischaemic stroke both overall and in sub-groups.

A lively discussion started after the talks proving the relevance, timeliness and quality of the topics and speakers. This session was a great start and shed light on exciting developments for the interdisciplinary care of patients with stroke and cardiac disease.

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ESSW – Session 1 – A Delicate Balance

Noémie — Mon, 04 Dec 2023 10:21:37 +0000

04/12/2023/in ESO /by Noémie

By: Märit Jensen, Rustam Al-Shahi Salman

ESO European Stroke Science Workshop 2023

Session 1: A Delicate Balance

The start of this year’s ESSW was hampered by weather conditions in Germany which led to delays and cancellations of trains and flights of many arriving researchers. As a result, the first scientific session got off to a late start, giving those who had already made it to the meeting the opportunity to directly dive into discussion at the bar.

The first session entitled “A delicate balance” then started with the keynote lecture addressing the important topic of sex and gender in stroke care and research. This was followed by 2 prize-winning presentations provided by mid-career researchers selected by the organizing committee which represents one of the new features of this year’s ESSW.

Cheryl Carcel from Australia provided the keynote lecture entitled “Integrating sex and gender to stroke care and research: why and how”. Over the past years, numerous studies have provided evidence that there are important sex- and gender-based differences in stroke treatment as well as stroke research. This comprises differences in risk-factor profiles, pre-hospital assessment, functional outcome, and enrolment in clinical trials, just to name a few. Cheryl highlighted several of these topics in her talk and provided suggestions for overcoming these limitations in future research and stroke care. She presented results from an Australian study, which systematically analysed the results of pre-hospital assessment by paramedics in patients with a later confirmed diagnosis of stroke. In this study the likelihood of having a stroke was similar for women and men but women were more likely to be assessed as having migraine, anxiety and hypertension or other non-stroke diagnosis. She also provided an example underlining the need to be cautious when interpreting sex-specific analysis from smaller trials such as in an analysis of the MR-CLEAN trial suggesting that thrombectomy is not effective in women, a finding which was no longer present in the pooled individual patient-data meta-analysis of 5 thrombectomy trials. In the second part of her talk, she discussed reasons for under representation of women in stroke trials. These include potential trial specific factors that disproportionately exclude women and potential barriers preventing women from participating in trials. Finally, she suggested means for overcoming these limitations in the future including systemic collection of sex and gender data in trials and publication of disaggregated results by sex and gender. Cheryl further pointed to the need for increasing female leadership in stroke clinical research, of which she is a perfect example.

After the keynote lecture, we moved on to the prize-winning mid-career researchers’ presentations that were given by Corinne Benakis and Anke Wouters.

Corinne provided an overview of her research on the gut-brain axis in a talk entitled “Treat outside the box – the gut-brain axis in stroke”. Briefly summarized, current knowledge proposes that stroke causes an intestinal stress response which leads to mucosal barrier dysfunction and alternation of microbiota in the gut. Gut immune cell trafficking then may lead to neuroinflammation. An evolving series of experimental studies supports this understanding. Corinne investigated the gut-brain axis in her working group in a series of impressive studies that build on each other. Based on the findings she presented her research vision of a gut-microbiota “fingerprint” to inform novel therapeutic strategies for stroke treatment.

In the second presentation, Anke Wouters from Belgium gave a talk entitled “Acute stroke imaging: the path forward”. She mainly presented unpublished results of the prospective observational CRISP2 looking at different imaging profiles of lesion growth in acute stroke patients transferred from peripheral hospitals to interventional stroke centers. In this study performed in Leuven and Stanford stroke patients referred to peripheral hospitals underwent a standardized imaging protocol including perfusion imaging and a further imaging study using MRI immediately after admission to the thrombectomy center. Several imaging parameters identified patients with fast progression of the ischaemic lesion, i.e., hypoperfusion intensity ratio (HIR), baseline core volume, a cerebral blood volume (CBV) index, and the baseline collateral status. Patients could also be divided into those with stable imaging patterns, and subgroups who deteriorated or improved. Taken together, these results advocate for the use of perfusion imaging at peripheral stroke centers, as imaging results may not only guide the need for urgent treatment, but also inform enrolment in future trials of neuroprotection.

This first session was a perfect start for this year’s meeting and lively discussions continued over dinner and drinks.

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Should We Be Stenting Symptomatic Atherosclerotic Intracranial Stenoses?

Lara Le Noan — Fri, 09 Dec 2022 07:00:27 +0000

09/12/2022/in ESO, Stroke Research /by Lara Le Noan

Authors: Christine Tunkl, MD

Twitter: @ChrissiTunkl

Neurology Department, University Hospital Heidelberg

Atherosclerotic stenosis accounts for a high proportion of ischemic stroke and can challenge us as treating physicians. Strokes caused by intracranial stenosis have a high risk of recurrence, so we might be tempted to treat those patients with percutaneous transluminal angioplasty and stenting (PTAS). Of course, every patient with intracranial atherosclerotic stenosis receives best medical treatment (BMT) – consisting of (dual) antiplatelet therapy, blood pressure management and lipid-lowering therapy¹. But should patients with symptomatic intracranial stenosis also be treated with stenting or not?

None of the previous trials (VISSIT², SAMMPRIS³) could prove a benefit of additional stenting compared to BMT. SAMMPRIS³ was even terminated earlier because stenting proved harmful in terms of a higher 30-day rate of stroke or death (14.7%) in the intervention group compared to in the medical-management group (5.8%). Still, it seems we were not convinced about the superiority of BMT and it was time for another randomized, controlled trial⁴ to prove what other trials and guidelines had suggested before: that there doesn’t seem to be a benefit in adding percutaneous transluminal angioplasty and stenting to BMT in patients with symptomatic intracranial atherosclerotic stenosis.

The recently published CASSISS Trial⁴ enrolled a total of 380 patients and randomized them 1:1 either into the best medical treatment arm versus best medical treatment combined with stenting. Recruited were patients with TIA or nondisabling ischemic stroke (modified Rankin Scale score, 0-2) and severe stenosis (degree of stenosis: 70%-99%) of a major intracranial artery supplying the territory of the ischemic event. The primary outcome, risk of stroke or death within 30 days or stroke in the respective vascular territory within one year, was not significantly different (stenting 8.0% vs medical 7.2%; HR, 1.10 [95% CI, 0.52-2.35]; P = 0.82). In addition, the investigators did not observe a significant difference in the risk of recurrent stroke or death within three years. Why is that? The authors of the trial discuss that periprocedural complications caused by guidewire perforation of arteries and disturbances of vulnerable, atherosclerotic plaque may lead to the lack of superiority of stenting. It goes without saying that this technically challenging procedure requires a high level of experience.

The CASSISS Trial together with previous trials is highly relevant, as we are faced with symptomatic intracranial atherosclerotic stenosis often in our clinical practice.

The CASSISS trial will now further strengthen the ESO’s recommendation that best medical treatment should be favored over stenting for patients with symptomatic intracranial atherosclerotic stenosis⁴.

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References:

1 – Psychogios M, Brehm A, López-Cancio E, Marco De Marchis G, Meseguer E, Katsanos AH, Kremer C, Sporns P, Zedde M, Kobayashi A, Caroff J, Bos D, Lémeret S, Lal A, Arenillas JF. European Stroke Organisation guidelines on treatment of patients with intracranial atherosclerotic disease. Eur Stroke J. 2022 Sep;7(3):III-IV.

2 – Zaidat OO, Fitzsimmons BF, WoodwardBK, et al; VISSIT Trial Investigators. Effect of a balloon-expandable intracranial stent vs medical therapy on risk of stroke in patients with symptomatic intracranial stenosis. JAMA. 2015;313 (12):1240-1248. doi:10.1001/jama.2015.1693

3 – Chimowitz MI, Lynn MJ, Derdeyn CP, et al; SAMMPRIS Trial Investigators. Stenting versus aggressive medical therapy for intracranial arterial stenosis. N Engl J Med. 2011;365(11):993-1003.

4- Gao P, Wang T, Wang D, Liebeskind DS, Shi H, Li T, Zhao Z, Cai Y, Wu W, He W, Yu J, Zheng B, Wang H, Wu Y, Dmytriw AA, Krings T, Derdeyn CP, Jiao L; CASSISS Trial Investigators. Effect of Stenting Plus Medical Therapy vs Medical Therapy Alone on Risk of Stroke and Death in Patients With Symptomatic Intracranial Stenosis: The CASSISS Randomized Clinical Trial. JAMA. 2022 Aug 9;328(6):534-542.

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Endovascular Thrombectomy in Posterior Circulation Stroke

Lara Le Noan — Fri, 02 Dec 2022 09:02:26 +0000

02/12/2022/in ESO, Stroke Research /by Lara Le Noan

Authors: Silja Räty, MD, PhD

Department of Neurology, Helsinki University Hospital, Finland

Twitter: @HUS_fi

The posterior circulation is affected in the minority of ischaemic strokes, with symptoms ranging from isolated homonymous hemianopia in distal posterior cerebral artery occlusions (PCAo) to coma or locked-in syndrome in the most severe forms of basilar artery occlusion (BAo). Compared to anterior circulation infarcts, posterior circulation strokes are less well recognised in the acute phase, receive less reperfusion therapy, and have longer treatment delays (1,2,3).

Endovascular thrombectomy (EVT) is the standard treatment for anterior circulation large vessel occlusion (4), but similar evidence for posterior circulation stroke has been lacking until recently. Due to its clinical severity, BAo has been a target for reperfusion treatments for decades, but the first large randomised controlled trials on the topic came out only in 2020‒2021, when the BEST and BASICS trials reported neutral results of EVT + best medical treatment (BMT) versus BMT alone (5,6). They were followed by the recently published ATTENTION and BAOCHE trials that were first to demonstrate better functional outcome, as well as lower mortality in the former trial, for patients with BAo receiving EVT + BMT compared to BMT up to 24 hours from symptom onset (7,8). In both trials, 46% of patients in the EVT + BMT group achieved a 3-month modified Rankin Scale score of 0‒3 in comparison to 23 to 24% in the BMT group (adjusted rate ratios 2.06 [95% CI 1.46−2.91] and 1.81 [95% CI 1.26−2.60]). The frequency of symptomatic intracranial haemorrhage did not differ between the treatment arms.

However, the trial results have left some questions unanswered. First, intravenous thrombolysis (IVT) was received by only 14‒34% of the trial populations in ATTENTION and BAOCHE, so it remains uncertain whether EVT is superior to IVT alone. Moreover, the subgroup analysis of patients treated with IVT could not show benefit of additional EVT (7). Second, the positive trials have included mostly patients with moderate to severe symptoms, so the optimal approach to patients with milder clinical presentation is less clear. Finally, intracranial atherosclerosis is remarkably frequent aetiology of BAo in Asia, which hampers applicability of the trial results to European populations.

Lately, EVT has also been explored in isolated PCAo. There are no randomised trials on the topic, so the data are so far solely based on observational findings. The largest study (n=243) compared EVT to BMT for P2 or P3 occlusions and found no difference in early neurological improvement or functional outcome (9). However, it reported that patients with severe symptoms or contraindication to IVT achieved more frequently early neurological improvement after EVT and observed no marked safety concerns related to the procedure. A recent systematic review and meta-analysis of 12 studies and 679 PCAo patients detected no significant difference between EVT + BMT and BMT alone in 3-month good functional outcome, rate of symptomatic intracranial haemorrhage, or mortality (10).

All in all, the current evidence encourages the use of EVT for acute stroke patients with BAo and is likely to shape treatment practices despite remaining uncertainties. When it comes to isolated PCAo, more data on efficacy and safety might be provided in the future by ongoing trials on EVT for medium vessel occlusions (e.g. NCT05029414, NCT05151172 in clinicaltrials.gov).

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References:

Arch AE, Weisman DC, Coca S, Nystrom KV, Wira CR 3rd, Schindler JL. Missed Ischemic Stroke Diagnosis in the Emergency Department by Emergency Medicine and Neurology Services. Stroke. 2016;47(3):668-673.
Sand KM, Naess H, Nilsen RM, Thomassen L, Hoff JM. Less thrombolysis in posterior circulation infarction-a necessary evil? Acta Neurol Scand. 2017;135(5):546-552.
Sommer P, Seyfang L, Posekany A, et al. Prehospital and intra-hospital time delays in posterior circulation stroke: results from the Austrian Stroke Unit Registry. J Neurol. 2017;264(1):131-138.
Turc G, Bhogal P, Fischer U, et al. European Stroke Organisation (ESO) – European Society for Minimally Invasive Neurological Therapy (ESMINT) Guidelines on Mechanical Thrombectomy in Acute Ischaemic StrokeEndorsed by Stroke Alliance for Europe (SAFE). European Stroke Journal. 2019;4(1):6-12.
Liu X, Dai Q, Ye R, et al. Endovascular treatment versus standard medical treatment for vertebrobasilar artery occlusion (BEST): an open-label, randomised controlled trial. Lancet Neurol. 2020;19(2):115-122.
Langezaal LCM, van der Hoeven EJRJ, Mont’Alverne FJA, et al. Endovascular Therapy for Stroke Due to Basilar-Artery Occlusion. N Engl J Med. 2021;384(20):1910-1920.
Tao C, Nogueira RG, Zhu Y, et al. Trial of Endovascular Treatment of Acute Basilar-Artery Occlusion. N Engl J Med. 2022;387(15):1361-1372.
Jovin TG, Li C, Wu L, et al. Trial of Thrombectomy 6 to 24 Hours after Stroke Due to Basilar-Artery Occlusion. N Engl J Med. 2022;387(15):1373-1384.
Meyer L, Stracke CP, Jungi N, et al. Thrombectomy for primary distal posterior cerebral artery occlusion stroke: The TOPMOST Study. JAMA Neurol. 2021;78:434-444.
Berberich A, Finitsis S, Strambo D, et al. Endovascular therapy versus no endovascular therapy in patients receiving best medical management for acute isolated occlusion of the posterior cerebral artery: A systematic review and meta-analysis. Eur J Neurol. 2022;29(9):2664-2673.

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