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Since the time window for acute reperfusion treatments in ischemic strokes has been extended, the number of patients treated by mechanical thrombectomy (MT) increased. Accordingly, we observe more and more frequently cerebral hyperdensities on post-procedural Computed Tomography (CT): however, in routine clinical practice, distinguishing between iodine contrast media extravasation and haemorrhagic transformation may be challenging.

The incidence of post-procedural cerebral hyperdensities (PCH) varies according to delays between revascularization and CT performance, ranging from 60% when brain CT is performed within 4,5 hours after MT ¹, to 30% at 24 hours. When PCH disappear after repeated CT scan, they likely represent contrast extravasation, because contrast is washed out, whereas haemorrhagic transformation persists on follow-up neuroimaging ².

From a physiopathological point of view, either blood or contrast extravasation presuppose blood-brain barrier (BBB) disruption. However, cellular blood elements need a BBB rupture extending to basal lamina to leak into the brain tissue ³ (figure).

Some authors investigated neuroimaging methods that could help distinguishing contrast extravasation from haemorrhagic transformation on CT. Indeed, hounsfield unit (HU) on conventional non enhanced CT can help when PCH attenuation is less than 50 HU on immediate post procedure CT scan, which allows excluding a haemorrhagic transformation, however, the sensitivity is low (56%)². Dual-Energy CT (DECT) image acquisition is acquired by using two different x-ray energy levels, and it is considered the gold standard to distinguish between blood and contrast, with an overall sensitivity of 100% and specificity of 93% ⁴. Gradient Echo (GRE) on Magnetic Resonance Imaging (MRI) allows differential diagnosis: haemorrhagic transformation shows an hypointense signal, while contrast extravasation appears iso- or hyper-intense ⁵.

The clinical impact of PCH is uncertain and whether contrast extravasation itself independently predicts poor outcome after endovascular therapy is unknown ⁶. Indeed, contrast extravasation is also associated with an increased risk of haemorrhagic transformation, suggesting an underlying vessel injury. Consistently, BBB leakage before reperfusion therapy is independently associated with an increased risk of symptomatic haemorrhagic transformation ⁷.

From a therapeutic point of view, the presence of a haemorrhagic transformation often delays the introduction of antithrombotic drugs and an early differentiation between blood and contrast is crucial for a prompt start of the therapy. However, whether contrast extravasation, by means of a damaged BBB, may be a warning sign for future risk of brain haemorrhage needs to be further investigated.

For future research directions, studying contrast extravasation after MT may help quantitively measuring early BBB disruption, with important clinical implications: individual-level prediction of further haemorrhagic transformation after antithrombotic drug introduction, therapeutic effect of drugs targeting BBB and, potentially, candidate selection for neuroprotective agents.

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It is May 22 and, the day is as bright as a Leonardo’s idea and Milan is going to host the 5^th European Stroke Organisation Conference. Indeed, Milan hosted the genius from Vinci too, in late XV Century. As everyone knows, Leonardo was a genius able to put thoughts into action, to imagine divine faces and bodies and to draw them perfectly, to dream of skies and clouds and to project a wooden helicopter. This is why, here at ESOC, the Young Stroke Physician and Researchers Workshop tries to push great scientific ideas towards strong research networks.

We interview Dr. Faddi Saleh Velez, who presents the research entitled “The PASHT trial: randomized crossover sham-controlled trial evaluating safety and feasibility of transcranial direct current stimulation (TDCS) for paroxysmal sympathetic hyperactivity post stroke and TBI” at the YSPR Workshop. Dr. Saleh Velez is a Colombian physician currently training as a neurology resident at the university of Chicago. He previously worked as a Post-doctoral research fellow for 2 years at the Spaulding neuromodulation center in Harvard studying the application of Non-invasive brain stimulation techniques (NIBS) for stroke and neuropathic pain.

How did you get involved in stroke research?

Since the beginning of my career the intricacies and mysteries of the brain led me to focus on neuroscience. My interest in stroke research dates back to medical school in Colombia, South America, where the burden of the disease and the consequences for patients and their families had an extremely high impact. Therefore, I decided to explore several types of possibilities to enhance my training as to improve my abilities to provide better care to my patients. Even thought I had experience in the functional neurosurgery to evaluate novel techniques for the management of neurologic disorders, I wanted to explore less invasive and more accessible therapies, therefore my 2-year post-doctoral fellowship in non-invasive neuromodulation. In Boston, I worked with clinical Translational research therapies for the treatment of stroke, particularly the application of non-invasive brain stimulation techniques such as transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS) as well as pharmacological therapies.

 Why did you choose this topic?

Although in my country the care for patients was of extremely importance, the opportunities to do research and try to find long term solution for stroke complications led me to travel and learn from other countries and several mentors. In Barcelona, I saw first-hand the effect of electrical stimulatory techniques changing people’s life in a second, just with turning on an implanted device. Once completed medical school working as a fellow at a Harvards’ laboratory, I moved to US, where I applied the non-invasive brain stimulatory techniques such as TMS and tDCS at the Spaulding Neuromodulation Center. Together with my research partner, Camila Pinto, we got involved in different research trials on stroke patients. Once I started residency at the University of Chicago Medical center, I was able to experience first-hand clinical challenges with patients with severe strokes and traumatic brain injuries. Here I saw for the first time the extremely negative effects that paroxysmal sympathetic hyperactivity has on patients, which led me to investigate additional therapeutic approaches for this condition. My background skills on NIBS allows us to create this alternative research study that we hope will give us some answers about the safety of these techniques in acute stroke and traumatic brain injury and about the underlying pathophysiologic mechanism of the paroxysmal sympathetic hyperactivity.

What have been the most difficult challenges regarding your research career so far?

I believe that the biggest challenge in my young research career is mostly lack of time. Although I had the amazing opportunity to learn some aspects of research with my dedicated post-doctoral research fellowship, my desire to get close to patient care and to pursue my career as neurologist led me to start my residency at the university of Chicago. Sharing the time required for an adequate clinical training in residency with the required time needed to continue developing my career as a researcher has been challenging. I have been lucky to share this time with amazing colleagues and research mentors that have supported me and helped me to try to find the most time to continue developing my research skills while I keep up with my clinical duties.

How to balance work life and free time/home life?

I believe that the secret to a happy and productive life is a combination of work success, family time and personal care, and I base all my decisions and create all my habits around those 3 areas, making sure that the progress in one positively affects the others. For instance, even though my schedule is tight, I always try to exercise as it helps me be more alert at work, it improves my health to enjoy more time with my family, and it gives me more confidence. Moreover, I have been blessed with a family that supports every decision I make, and that helps me keep grounded to what it is important in life, which has helped me realize my dreams. First of all, my mom has been the key participant of my success. She has not only supported me financially, but also has always reminded me that I could achieve anything I set my mind to. My fiancée, who is a PhD and a researcher, has supported me and helped me developing my projects, providing me with new ideas and a different perspective to analyze things and how to focus and achieve goals. And finally, my sister and brother-in-law, who are entrepreneurs and data scientists, that have helped drive my love for reading and learning from different topics that broaden my knowledge.

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Author: Dr Nicolas Martinez-Majander
Affiliation: Clinical Neurosciences, Department of Neurology, University of Helsinki and Department of Neurology, Helsinki University Hospital, Finland

Medical Management of ESUS

In 2014, a subset of cryptogenic stroke was presented, embolic stroke of undetermined source (ESUS).¹ Exclusion criteria include >50% stenosis in a large proximal artery in the territory of ischemia, major-risk cardioembolism such as atrial fibrillation, lacunar disease, or any other identified uncommon cause. Potential causes of ESUS may include minor-risk cardioembolic sources (e.g. mitral annular calcification, calcific aortic valve, atrial septal aneurysm), cancer-associated strokes, arteriogenic emboli (e.g. aortic arch atherosclerotic paques) and paradoxical embolism involving patent foramen ovale or pulmonary arteriovenous fistula. It was also suggested that ESUS patient might benefit from anticoagulation compared to antiplatelets in secondary prevention.

Now after four years we have received much anticipated results from the two largest international randomized phase III trials comparing novel oral anticoagulants (NOACs) with aspirin in patients with a recent ESUS.

Evidence of medical treatment so far?

Results from NAVIGATE ESUS trial (NCT02313909) were first presented in European Stroke Organisation Conference. Gothenburg and published simultaneously in New England Journal of Medicine.² The trial enrolled 7213 individuals and the baseline characteristics were already presented in March, 2018.³ NAVIGATE ESUS was stopped early, since perhaps quite surprisingly it showed that with a median of 11 months follow-up, rivaroxaban 15 mg was not superior to aspirin 100mg regarding any recurrent stroke or systemic. This was also true for secondary efficacy outcomes, such as any recurrent ischemic stroke alone. In fact, rivaroxaban treatment arm had higher rate of major bleeding and it was discussed that perhaps these patients with ESUS were too heterogeneous after all, harboring several underlying potential embolic sources and having a wide spectrum of risk factor profiles.

In September, the first prespecified subgroup analysis was published in Lancet Neurology, focusing on NAVIGATE ESUS patients with patent foramen ovale.⁴ It also concluded that there was no difference in the risk of recurrent ischemic stroke between treatment arms with PFO patients. Also the risk of major bleeding was similar compared to overall NAVIGATE ESUS population.

However, results from another subgroup analysis were just recently presented in World Stroke Congress in Montreal. It showed that up to 10% of patient in NAVIGATE ESUS had a left atrial enlargement (diameter larger than 4.6 cm) and that rivaroxaban might reduce the risk of recurrent stroke after ESUS in these patients compared to aspirin alone. This supports the hypothesis of atrial myopathy as a significant source of embolism even in the absence of atrial fibrillation, although results have be interpreted with caution and confirmed in future studies.

In the same congress we heard the first results from RE-SPECT ESUS (NCT02239120), comparing dabigatran 110-150 mg twice daily with aspiring 100mg once daily. With 5390 enrolled patients, it also showed that the rate of recurrent stroke was similar in both treatment arms (4.1% with dabigatran vs 4.8%. Median follow-up was slightly longer than in NAVIGATE ESUS (19 months) and Kaplan Meier curves showed a trend of separation between groups in favor of dabigatran with progressing follow-up. In contrast to NAVIGATE ESUS, the rate of major bleedings was actually similar in both arms and all of the fatal bleeds (three of them) occurred in the aspirin arm. These results have not yet been published in any journal.

What’s next?

Finally, a third ESUS trial (multicenter German ATTICUS, NCT02427126) comparing apixaban 5mg twice daily with aspirin 100mg is still enrolling patients and the target of 500 participants should be completed in December 2019. It will be interesting to hear if patients in apixaban have better outcomes, regarding both recurrent stroke and major bleedings.

References:

1. Hart RG, Diener HC, Coutts SB, Easton JD, Granger CB, O’Donnell MJ, et al. Embolic strokes of undetermined source: the case for a new clinical construct. Lancet Neurol 2014;13:429-438.
2. Hart RG, Sharma M, Mundl H, Kasner SE, Bangdiwala SI, Berkowitz SD, et al. Rivaroxaban for Stroke Prevention after Embolic Stroke of Undetermined Source. N Engl J Med 2018;378:2191-2201.
3. Kasner SE, Lavados P, Sharma M, Wang Y, Wang Y, Davalos A, et al. Characterization of Patients with Embolic Strokes of Undetermined Source in the NAVIGATE ESUS Randomized Trial. J Stroke Cerebrovasc Dis 2018;27:1673-1682.
4. Kasner SE, Swaminathan B, Lavados P, Sharma M, Muir K, Veltkamp R, et al. Rivaroxaban or aspirin for patent foramen ovale and embolic stroke of undetermined source: a prespecified subgroup analysis from the NAVIGATE ESUS trial. Lancet Neurol 2018 Sep 28.

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Author: Dr Sarah Moore NIHR/HEE Clinical Lecturer, Newcastle University/Northumbria Healthcare NHS Foundation Trust, UK. Email: s.a.moore@ncl.ac.uk Twitter: Sarah Moore @SarahMoorePhys

Whilst hyper acute stroke care has been revolutionised by the development of blood clot busting medications and clot removal techniques, for those who are unsuitable for these treatments and require rehabilitation (approximately 70% people) the best interventions to promote recovery are yet to be discovered.

Ground-breaking international stroke rehabilitation trials such as AVERT (1), where the impact of early mobility on disability was explored in over 2000 stroke survivors, appear to lead to more questions than answers. Early pilot work indicated that a very early mobility intervention would improve outcome after stroke (measured by the modified Rankin Scale) and was cost effective (2-4).   The AVERT trial demonstrated however that early mobility training could actually interfere with recovery and cause harm compared to usual care.

I am just returning from the World Stroke Congress (2018) in Montreal and more surprising results came from another large recovery trial: VERSE (5). Results in chronic stroke patients demonstrate intensive therapy for aphasia can improve speech and language and pilot work indicated this may also be true for early intensive aphasia interventions (6). But the results of the VERSE study revealed that although feasible and not harmful with the case of this early intervention again ‘more was not better’.

As when the results of the AVERT trial were announced at ESOC (2016) in Glasgow, when the results of VERSE were announced a pin could be heard drop in the auditorium.  Although some would class these results as ‘negative’ one could argue they were anything but for two key reasons. Firstly, these trials answered important clinical questions, albeit not with the answers they expected. Secondly, both trials managed to successfully tackle the ‘beast’ that is rehabilitation research with success and rigour. One of the problems often encountered in rehabilitation research is poor description of what elements go into interventions…what ingredients go into the ‘black box’ that is therapy. Trials such as AVERT and VERSE had clear intervention descriptions with VERSE using the Template for intervention description and replication (TIDieR) (7) to describe content.  VERSE also made efforts to capture whether the intervention was delivered as intended i.e. fidelity. We can only start to determine the efficacy of different rehabilitation interventions if we know they are delivered as intended and start to measure this using frameworks such as the one proposed by Bellg (8).

One of the key messages that abounded at the WSC for recovery research was to move the field forward we need to start unpicking what is ‘just the right amount’ for each stroke survivor. Secondary analysis of AVERT indicated that although the overall outcome for early mobility was negative, individual groups may have different responses to the intervention. For those with a bleed in the brain or severe disability early mobility may have been ‘too much’ whereas for those with mild impairment it may have been ‘too little’. This is what is referred to as the goldilocks principle…..goldilocks tried three different bowls of porridge to find the one that was just right for her.

The clear message from the WSC was that in order to develop recovery research and to discover what is ‘just right’ for stroke survivors we need to develop large trials with rigorous protocols that ask the right questions and measure the right outcomes. The good news is we appear to be moving into a new era for recovery research. Guidelines for stroke recovery and rehabilitation research (SRRR) were developed at the World Stroke Congress 2016 in Hyderabad (9,10). These guidelines will be further be developed following the second roundtable event held straight after the WSC in Montreal. This consensus gathering exercise with experts from around the world is vital for the progression of the rehabilitation and recovery field in stroke.

Using these guidelines international trials would enable the large sample sizes required to answer many recovery questions and bring momentum and advancement to this complex field. Fostering future collaboration in early career researchers is imperative to drive the field forward. I was privileged to be invited to Global Alliance of Independent Networks focused on Stroke trials (GAINS) meeting for early career investigators from around the world held prior to WSC 2018. This meeting provided a chance to gain useful feedback on early project designs and discussion on potential avenues for collaboration and career progression.

So final thoughts from WSC 2018….

..To progress the field of rehabilitation research it appears we may need to pick the right person and right time for each intervention

..Guidelines and international collaboration to develop rigorous protocols appear to be the way forward to start to answer the goldilocks principle for rehabilitation research.

…Defining what goes into the black box of rehabilitation research will help to unpick the most effective interventions

…And if the crowds of people overflowing out of the rehabilitation sessions at WSC 2018 is anything to go by watch this space for the rehabilitation and recovery research revolution…….!!!

1.The AVERT Trial Collaboration Group. Efficacy and safety of very early mobilisation within 24 h of stroke onset (AVERT): a randomised controlled trial. The Lancet. 2015;386(9988):46-55.

2. Bernhardt J, Dewey H, Thrift A, Collier J, Donnan G. A Very Early Rehabilitation Trial for stroke (AVERT): phase II safety and feasibility. Stroke 2008; 39: 390–96.
3. Cumming T, Thrift A, Collier J, et al. Very early mobilisation after stroke fast tracks return to walking: further results from the phase II AVERT randomized controlled trial. Stroke 2011; 42: 153–58.
4. Tay-Teo K, Moodie M, Bernhardt J, et al. Economic evaluation alongside a Phase II, multi-centre, randomised controlled trial of very early rehabilitation after stroke (AVERT). Cerebrovasc Dis 2008; 26: 475–81.
5. E. Godecke, E. Armstrong, T. Rai, S. Middleton, N. Ciccone, M. Rose, A. Holland, A. Whitworth, F. Ellery, G. Hankey, D. Cadilhac, J. Bernhardt^. Very early rehabilitation in speech (VERSE): A prospective, multicentre randmised controlled open-label, blinded-endpoint trail in patients with aphasai following acute stroke. (2018) Presented at world Stroke Congress, Montreal 2018
6. Breitenstein C, Grewe T, Flöel A, Ziegler W, Springer L, Martus P, et al. Intensive speech and language therapy in patients with chronic aphasia after stroke: a randomised, open-label, blinded-endpoint, controlled trial in a health-care setting. The Lancet. 2017;389(10078):1528-38.
7. Glasziou; H, Milne; B, Altman; PM, Macdonald; B, Lamb; J, Dixon-Woods;, et al. Better reporting of interventions: template for intervention description and replication (TIDieR) checklist and guide. BMJ. 2014(348):1687-.
8. Bellg AJ, Borrelli B, Resnick B, Hecht J, Minicucci DS, Ory M, et al. Enhancing treatment fidelity in health behavior change studies: best practices and recommendations from the NIH Behavior Change Consortium. Health Psychology. 2004;23(5):443.
9. Bernhardt J, Borschmann K, Boyd L ea. Moving rehabilitation research forward: developing consensus statements for rehabilitation and recovery research. . Int J Stroke. 2016;11:454-8.
10. Kwakkel G, Lannin NA, Borschmann K, English C, Ali M, Churilov L, et al. Standardized Measurement of Sensorimotor Recovery in Stroke Trials: Consensus-Based Core Recommendations from the Stroke Recovery and Rehabilitation Roundtable. Neurorehabilitation and Neural Repair. 2017;31(9):784-92.

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