Contrast-induced encephalopathy (CIE) is a rare complication of iodinated contrast administration during endovascular treatments, with a described incidence of less than 2% (1,2). CIE most commonly presents as an encephalopathy, ranging from mild confusion to decreased consciousness, with or without focal neurological deficits, including cortical blindness, motor or sensory deficit, aphasia, as well as headache and/or epileptic seizures (3-6). Symptoms may start during neurovascular treatment, immediately after or a few hours afterwards and usually progress over several hours (4, 5). The first case description goes back to 1970, with a report of a woman who experienced transient cortical blindness after a coronary angiogram (7). Over the last few years, CIE is becoming a more and more relevant neurological clinical entity and, with the expanded use of contrast-based diagnostic imaging and endovascular treatments in acute ischaemic stroke, its incidence is expected to increase.

The exact pathophysiology of CIE is not well understood, but temporary disruption of the blood-brain barrier is thought to give way to possible neurotoxic effects of contrast agents. Identified CIE risk factors include patient characteristics, as hypertension, diabetes mellitus, chronic kidney disease and prior stroke (1,3,8), as well as contrast- and treatment-related factors, like higher contrast volume, hyperosmolar-/ionic contrast agents and intra-arterial administration of iodinated contrast (1).

Diagnosis is often challenging because of the heterogeneous symptoms and radiographic features, which are non-specific. Indeed, CIE symptoms closely mimic other causes of neurological deterioration after neurovascular treatment, such as intracerebral haemorrhage (ICH), recurrent ischaemic stroke, posterior reversible encephalopathy syndrome (PRES), post stroke seizures or post-ictal phase, residual sedation, metabolic disturbances such as hypoglycaemia or delirium. Therefore, CIE entity is a diagnosis by exclusion. Neuro-imaging is a pivotal step for helping differential diagnosis, especially for identifying ICH, recurrent ischaemic stroke and PRES. Brain CT features of CIE include parenchymal oedema with loss of grey-white matter differentiation and/or effacement of cortical sulci and contrast enhancement of cortex or subarachnoid space, mostly in the hemisphere of contrast administration, but not limited to a vascular territory. Accordingly, brain MRI may show T2 hyper-intense cortical lesions and new lesions with diffusion restriction not limited to the affected vascular territory (1-4). However, both CT and MRI may also appear normal, especially in the early phase (1,4).

At this moment, there is no standard treatment of CIE. Usually, vigorous hydration is recommended. The efficacy of steroids and mannitol in reducing cerebral oedema remains controversial, and these drugs are not routinely recommended (1,4). When seizures occur, anticonvulsive drugs should be introduced. Importantly, when CIE is a likely diagnosis, the use of additional contrast-based imaging should be very carefully considered. Indeed, CIE has been previously regarded as a transient and benign complication of contrast-administration, characterised by a complete resolution within one to three days, questioning the benefit of specific treatments. However, recent publications on CIE occurrence after neurovascular procedures, reported an association between CIE and poor functional outcome at three months, without impact on mortality-risk (3). In particular, a meta-analysis published in 2021 showed that 15% of patients required mechanical ventilation because of decreased consciousness, and one in ten patients did not completely recover (4).

In conclusion, CIE is a relevant neurological entity that clinicians should not underestimate. Because of the heterogeneous spectrum of clinical signs, it remains a challenging diagnosis. However, when a patient neurologically deteriorates after intravenous or intra-arterial iodinated contrast agents use, we suggest including CIE systematically in the differential diagnosis. Of note, its occurrence might not be as benign as often described and more research is needed to clarify its impact on clinical outcome.

References

1. Meijer FJA, Steens SCA, Tuladhar AM, van Dijk ED, Boogaarts HD. Contrast-induced encephalopathy-neuroimaging findings and clinical relevance. Neuroradiology. Jun 2022;64(6):1265-1268. doi:10.1007/s00234-022-02930-z
2. Zevallos CB, Dandapat S, Ansari S, et al. Clinical and Imaging Features of Contrast-Induced Neurotoxicity After Neurointerventional Surgery. World Neurosurg. Oct 2020;142:e316-e324. doi:10.1016/j.wneu.2020.06.218
3. Chu YT, Lee KP, Chen CH, et al. Contrast-Induced Encephalopathy After Endovascular Thrombectomy for Acute Ischemic Stroke. Stroke. Dec 2020;51(12):3756-3759. doi:10.1161/STROKEAHA.120.031518
4. Quintas-Neves M, Araujo JM, Xavier SA, Amorim JM, Cruz ESV, Pinho J. Contrast-induced neurotoxicity related to neurological endovascular procedures: a systematic review. Acta Neurol Belg. Dec 2020;120(6):1419-1424. doi:10.1007/s13760-020-01508-x
5. Harada Y, Kairamkonda SR, Ilyas U, et al. Pearls & Oy-sters: Contrast-induced encephalopathy following coronary angiography: A rare stroke mimic. Neurology. Jun 9 2020;94(23):e2491-e2494. doi:10.1212/WNL.0000000000009590
6. Spina R, Simon N, Markus R, Muller DW, Kathir K. Contrast-induced encephalopathy following cardiac catheterization. Catheter Cardiovasc Interv. Aug 1 2017;90(2):257-268. doi:10.1002/ccd.26871
7. Fischer-Williams M, Gottschalk PG, Browell JN. Transient cortical blindness. An unusual complication of coronary angiography. Neurology. (1970) 20:353–5. doi: 10.1212/WNL.20.4.353
8. Vigano M, Mantero V, Basilico P, et al. Contrast-induced encephalopathy mimicking total anterior circulation stroke: a case report and review of the literature. Neurol Sci. Mar 2021;42(3):1145-1150. doi:10.1007/s10072-020-04844-1

ESOC is Europe’s leading forum for advances in research and clinical care of patients with cerebrovascular diseases. ESOC 2023 will live up to its expectation, and present to you a packed, high quality scientific programme including major clinical trials, state-of-the-art seminars, educational workshops, scientific communications of the latest research, and debates about current controversies.

Registrations will open in November 2023 for ESOC 2023. Learn more here.

25^th ESO Summer School – a very special week in Birmingham

The 25th ESO Stroke Summer School took place on 5-9 September 2022 in Birmingham, England and was an unforgettable experience – not only because it was a first post-pandemic live (!) Summer School, but also due to very special events taking place in the United Kingdom throughout these five days (announcement of a new Prime Minister, passing of Queen Elisabeth II and appointment of a new King).

In early September, as 50 (aspiring) neurologists from 24 countries gathered in the halls of the University of Birmingham Medical School, the city of Birmingham topped the ranking with a number of stroke enthusiasts per square kilometre. Birmingham, also called “The Heart of England”, temporarily became “The Brain of England” and thanks to fantastic efforts of the organising team – Dr Phil Ferdinand, Professor Christine Roffe, Dr Indira Natarajan, Dr Sissi Ispoglou, Dr Jason Appleton, Dr Don Sims, Dr Girish Muddegowda, all participants of the Summer School enjoyed a delightful mixture of high level stroke education, networking and socialising.

First day was initiated by Professors Gary Ford and Iris Grunwald reminding us about everything we have learned and should know about thrombolysis and mechanical thrombectomy in acute ischaemic stroke. Afterwards, we worked in small groups discussing the importance of venous thromboembolism prevention, oxygen and blood pressure in stroke patients. From Dr Adam Low we learnt about safety considerations of anaesthesia during thrombectomy (always inform the anaesthetist if you expect a complex patient!). Dr Ranjan Sanyal entertained us with an interactive (and very useful!) lecture and provided us with simple algorithm for an often challenging diagnosis in dizzy patients. Dr Sissi Ispoglou triggered a discussion about atypical presentations and underdiagnosis of stroke and Dr Neena Bodasing reminded us of the importance of low-threshold HIV testing and advantages of an opt-out approach. The evening social programme kicked off with a delicious Indian curry dinner (a real Birmingham specialty!).

On a second day, Professors Hanne Christensen and Nikola Sprigg discussed the impact and management of intracerebral haemorrhage. Particularly the difficulty of attaining high quality data and high numbers of patients in intracerebral haemorrhage studies have been highlighted as current problems in the field. An important message was that time is brain – also in intracerebral haemorrhage patients – so do not slow down once you see blood! Consequently, a debate between Dr Adrian Parry-Jones and Dr Jason Appleton on whether elevated blood pressure should be intensively lowered in acute intracerebral haemorrhage patients yielded some unexpected results in voting among the participants – although everyone seemed to agree it should be lowered – the question was – how intensively. Professor David Werring introduced us to cerebral amyloid angiopathy and microbleeds and Mr Edward White took us on a journey from a neurosurgeon’s perspective – arguing that that the guidelines should not be seen as sanctity but that criteria for surgical intervention should be tailored to specific cases. Dr Samer Al-Ali showed us the stroke world from a neuroradiologist’s perspective, and presented a number of interesting cases. Professors Thompson Robinson and Rustam Al-Shahi Salman discussed the role of anti-platelet therapy in both ischemic and haemorrhagic strokes. Professor Joanna Wardlaw introduced us to the small vessel disease – reminding us it is a highly prevalent, important cause of cognitive impairment and very much a dynamic disease. Dr Linxin Li focused on in increased incidence of a young stroke and its possible causes and the scientific part of the day ended with Professor Anita Arsovska giving a comprehensive overview of stroke prevention in women. Evening dinner took place in an Italian restaurant with countless delicious dishes and ended with a luxurious cheese platter.

Third day gave platform to the number of international speakers, also the ESO Executive Committee Members to share their clinical and research interests. Professor Georgios Tsivgoulis gave us an extensive overview of the state of the art of stroke care and frontiers for thrombolysis or thrombectomy (138 slides in 25 minutes challenge?!). Professor Thorsten Steiner gave us perspectives on what future holds for intracerebral haemorrhage. Professor Peter Kelly showed us highly inspiring molecular and imaging approaches to studying inflammation in secondary stroke prevention. Dr Diana Aguiar de Sousa gave us a comprehensive overview of the knowledge about cerebral venous thrombosis (also after COVID-19 vaccination) and future perspectives for this relatively uncommon but highly relevant disease. Professor Martin Dichgans introduced complex but fascinating concepts of genetics in stroke (among others, the use of GWAS) and Dr Else Sandset took us on a personal journey and gave us early career tips (say yes to the opportunities when you are young). Second part of the day was opened by Professors John Camm and Robert Hatala who introduced atrial fibrillation and cardioembolic strokes from a cardiologist’s perspective. Dr Jukka Putaala  discussed the young stroke studies with focus on the cardiac causes of stroke. The day was crowned with a royal steak dinner topped off with an elegant sticky toffee pudding (an absolute highlight according to some).

The focus of the fourth day was life after stroke. Important topics were rehabilitation of the motor function of the limbs – introduced by Professor Nick Ward, management of spasticity – discussed by Dr Sachin Vashistha and balancing the exercise post-stroke to achieve better outcomes (importance of strength and aerobic exercises) – by Dr Ulrike Hammerbeck. After the break, from Dr Joseph Kwan we learned about the holistic approach to stroke care and about how little we know about almost miraculous effects of exercise and diet, we discussed fatigue, depression and anxiety in stroke patients with Professor Gillian Mead, and studied late rehabilitation, reintegration and return to work after stroke (physicians unfortunately rarely encourage patients to return to work…) with Professor Avril Drummond. We also learned from Mr Brin Heliwell about how it is to be a stroke patient – he also gave us recommendation about how we should make our work more meaningful for our patients. After lunch, Professor Silke Walter showed us the progress of work on the Mobile Stroke Unit and the challenges associated with introducing them (price and geographic landscape, just to mention two). Professor Christopher Price explained the pre-hospital stroke assessments, including the newest portable diagnostic technology to help identify large vessel occlusion. Lastly, Dr Deb Lowe, Dr David Hargroves and Dr Ajay Bhalla introduced us to a an integrated approach to Stroke Delivery Networks, Stroke National Audit Program and taught us how to bring change in the stroke field. Last evening was celebrated in the Jewellery Quarter of Birmingham, and dancing to an outstanding live band lasted until late night hours.

Fifth day focused on the challenges ahead in the stroke field. Together with Professor Hugh Markus we studied the vertebral artery disease, with Professor Terry Quinn – the often overlooked topic of cognition in stroke and about the unmet need of post-stroke cognitive screening testing. Professor Serefnur Ozturk took on a highly relevant topic – inequalities in stroke care among migrants and refugees. Professor Craig Smith shared the considerations about stroke and COVID-19 infection. Although the risk of stroke is small, once it occurs, it appears to be more severe, more likely with multiple large vessel occlusions. The summer school was concluded by passionate Professor Christine Roffe with a talk on clinical benefits of the hyper-acute stroke unit.

All in all, we certainly learned a lot about the current stroke practices and newest research directions, interacted with brilliant stroke experts from around the world (also learned that many of them have attended an ESO summer school earlier in their careers) and became even more enthusiastic about the field. We met fellow young stroke physicians and spent fantastic five days in Birmingham (which has more canals than Venice!).

It was a highly successful summer school with a well-rounded programme which surely will remembered for many years to come.

Thank you to everyone who made it possible!

STATEMENT ON THE WHO EUROPEAN FRAMEWORK FOR ACTION TO ACHIEVE THE HIGHEST ATTAINABLE STANDARD OF HEALTH FOR PERSONS WITH DISABILITIES 2022–2030

Stroke is the leading cause of disability and the second highest cause of death [2,3] in the adult population in Europe. It strikes suddenly, often with permanent consequences, in many cases irreversible even when people have access to the best standards of care in the acute phase. Without warning, it causes sudden paralysis, loss of ability to speak, blindness, memory loss, and dementia in people who were living happy and productive lives moments before. It often affects young people, impacting upon their personal, family, work and social life causing a great deal of suffering to them and their families.

Patients benefit from early, systematic and organized rehabilitation services to promote recovery, return to independence, and prevent progressive loss of ability in the years following the stroke event.
While across Europe almost all of those disabled by a stroke confirmed they had improvements from rehabilitation, about one third of the patients consider their rehabilitation experience to be limited and
insufficient. About one fourth of the patients, even after rehabilitation, finds that their overall quality of life remained poor [4].

People with stroke often have sensorimotor disability, and a multitude of cognitive, emotional and relational consequences. For those living after a stroke there are important barriers to well-being. These are visible, like lack of access for people with disability in the built environment and public transport, and invisible, like the stigma around stroke and its effects. The coronavirus pandemic has further penalized stroke patients, making it harder for them to access rehabilitation services.

The European Stroke Organisation (ESO) welcomes the WHO European Framework for action to achieve the highest attainable standard of health for persons with disabilities 2022–2030. This is fully aligned with the ESO Stroke Action Plan for Europe5, to promote the improvement of stroke healthcare and life after stroke across Europe and its neighbor countries.

We join WHO in calling for urgent actions to improve awareness, public health measures, acute health services, post-acute rehabilitation, and multi-sector measures to reduce stroke, improve outcomes, and improve life after stroke for patients with disability. We call on member states to develop coordinated National Stroke Plans, which are funded, implemented, and monitored.

These should include actions to ensure stroke patients’ access to rehabilitation, assistive technology, support services (including peer support), and community-based rehabilitation. We emphasize the importance of developing laws, policies, and plans in health and related sectors, aimed at improving prevention and an environment socially and professionally inclusive for stroke patients and their families after stroke.

References

1. WHO Rehabilitation 2030: a call for action https://www.who.int/initiatives/rehabilitation-2030

2. WHO The top 10 causes of death https://www.who.int/news-room/fact-sheets/detail/the-top-10-causes-ofdeath

3. European Cardiovascular Disease Statistics 2017 European cardiovascular disease statistics 2017.pdf

4. Sanità24, Medicina e ricerca https://www.sanita24.ilsole24ore.com/art/medicina-e-ricerca/2022-04-20/ictus-riabilitazione-insufficiente-un-italiano-tre-e-il-17percento-qualita-vita-scarsa-appello-neurologilinee-guida-121822.php?refresh_ce=1&uuid=AEl1wATB

5. Action Plan for Stroke in Europe 2018-2030
https://journals.sagepub.com/doi/full/10.1177/2396987318808719

Co-signatories:

             

               

The concept of a polypill, i.e. a single pill combining effective single drugs for prevention of cardiovascular events, is as simple as compelling and has been discussed among researchers in cardiovascular medicine for almost two decades^1,2. Usually, the so-called polypill contains aspirin, one or more first line antihypertensive drugs, and a statin, by this combining the effects of lowering of cholesterol, blood-pressure lowering, and of an antiplatelet drug. All these effects are known to reduce adverse cardiovascular events, and the combination of multiple of these drugs in a single pill is proposed to improve patients’ adherence to medication, and to reduce the complexity and costs of prescription. Results of the EU-funded SECURE study³, which was just published and presented at the ESC congress 2022, add novel findings on the effect of a polypill for secondary prevention after myocardial infarction, which also may be of interest for stroke researchers.

In SECURE, patients were randomized within six months of myocardial infarction to secondary prevention using a polypill (including aspirin 100mg, ramipril 2.5, 5, or 10 mg and atorvastatin 20 or 40 mg) or usual care. The primary endpoint was a composite of cardiovascular death, nonfatal myocardial infarction, urgent revascularization, or ischemic stroke. A total of 2499 patients were randomized and followed for a median of 36 months. Assignment to the polypill group was associated with a significant reduction in occurrence of the primary endpoint, with a hazard ratio of 0.76 (95% confidence interval 0.60-0.96, p=0.02). Primary outcome events occurred in 118 of 1237 (9.5%) patients in the polypill group and in 156 of 1229 (12.7%) patients assigned to usual care. The most striking effect was observed for cardiovascular death, which occurred in 48 (3.9%) patients in the polypill group and 71 (5.8%) in the usual care group, representing an absolute reduction of 1.9% over a period of three years. Key secondary endpoints were also observed less frequently in the polypill group, while adverse events and all-cause mortality were comparable between groups. As expected, adherence to medication was higher among patients in the polypill group.

Previous polypill trials have mostly focused on the use of a polypill for primary prevention of cardiovascular events, such as the International Polycap Study 3 (TIPS-3)⁴, or broad inclusion of patients in a pragmatic approach, such as the PolyIran study⁵. In these studies, the use of a polypill was compared to placebo (TIPS-3), or non-pharmacologic interventions (PolyIran study). In contrast, SECURE tested the polypill approach in a setting of secondary prevention after myocardial infarction, and patients in the usual care group also received antiplatelets and medication for lowering of blood pressure and cholesterol, at the discretion of the treating physicians. The additional benefit of the polypill may be explained by the simplified approach resulting in improved adherence to these effective drugs. SECURE also differs to previous polypill studies by offering different polypills containing different doses of the individual drugs, thus allowing for a personalized adaption of the treatment strategy in case of insufficient risk factor control.

To summarize, the findings from SECURE suggest that a polypill adds to the current strategies of secondary prevention after myocardial infarction. Given these results and given the known problems with adherence to intake of drugs for secondary prevention after stroke, a polypill might also be a powerful tool for the prevention of recurrent strokes and other cardiovascular events in secondary prevention after stroke.

References

1. Wang TJ. The Polypill at 20 – What Have We Learned? N Engl J Med 2022.
2. Wald NJ, Law MR. A strategy to reduce cardiovascular disease by more than 80%. BMJ 2003; 326(7404): 1419.
3. Castellano JM, Pocock SJ, Bhatt DL, et al. Polypill Strategy in Secondary Cardiovascular Prevention. N Engl J Med 2022.
4. Yusuf S, Joseph P, Dans A, et al. Polypill with or without Aspirin in Persons without Cardiovascular Disease. N Engl J Med 2021; 384(3): 216-28.
5. Roshandel G, Khoshnia M, Poustchi H, et al. Effectiveness of polypill for primary and secondary prevention of cardiovascular diseases (PolyIran): a pragmatic, cluster-randomised trial. Lancet 2019; 394(10199): 672-83.

ESOC is Europe’s leading forum for advances in research and clinical care of patients with cerebrovascular diseases. ESOC 2023 will live up to its expectation, and present to you a packed, high quality scientific programme including major clinical trials, state-of-the-art seminars, educational workshops, scientific communications of the latest research, and debates about current controversies.

Registrations will open in November 2023 for ESOC 2023. Learn more here.

Anticoagulation with direct oral anticoagulants (DOACs) started early after acute ischemic stroke (IS) or transient ischemic attack (TIA) related to nonvalvular atrial fibrillation (NVAF) is critical to reduce the risk of recurrent stroke and systemic embolism.¹ The optimal timing to start anticoagulation, however, remains elusive.

A 1-3-6-12 rule has been largely adopted in clinical practice, with early DOAC initiation in TIA and later initiation (12 days or more) in severe stroke.¹ Such a timing, proposed on the basis of observational data and consensus/opinions, lacks support from (ongoing) randomized trials. In the meantime, stroke specialists are further shortening the timing for DOAC initiation, with the aim of reducing as much as possible the risk of stroke recurrence and systemic embolism.² This strategy has to take into account the risk of haemorrhagic transformation, which may have several contributors, such as the ischemic volume.²

In a recent paper in Stroke, Kimura and colleagues pooled data from several observational studies to define safety and efficacy of shortening the interval between index stroke and DOAC initiation.³ In a derivation cohort including mainly Japanese patients, they compared an early (n=785) and late (n=1012) DOAC initiation strategy for ischemic and bleeding outcomes across four stroke groups: TIA, mild stroke with, moderate stroke, and severe stroke. The early initiation strategy consisted in a 1-2-3-4 day DOAC initiation rule according to increasing severity of stroke. In the derivation cohort, the rate of recurrent ischemic stroke dropped from 3.9% with late initiation to 1.9% with early initiation (adjusted hazard ratio 0.50 [95% CI, 0.27–0.89]). Major bleeding occurred in six (0.8%) in the early group and 10 (1.0%) in the late group (aHR 0.81 [0.28–2.19]). In the external validation cohort (n=2063), ischemic stroke occurred in 13 patients (2.4%) of the early group and 33 (2.2%) of the late group (aHR 1.07 [95% CI, 0.54–2.00]. ICH occurred in one (0.2%) in the early and nine (0.6%) in the late initiation group (aHR 0.31 [0.02–1.65]).³

Overall, the results of this large collaborative studies suggest that a shorter delay of anticoagulation initiation (1-2-3-4 rule vs 1-3-6-12 rule according to stroke severity) could be feasible and may not carry an increase in risk of bleeding, with a potential higher efficacy among Japanese people.³

At the moment, the timing of anticoagulation resumption is investigated in four ongoing randomized trials (TIMING, OPTIMAS, ELAN, and START, Clinical trials identifier NCT02961348, NCT03759938, NCT03148457, NCT03021928, respectively), which differ in timing of randomization to DOAC initiation. Indeed, in TIMING and OPTIMAS anticoagulation is initiated no earlier than four days, while a severity-based timing is proposed in ELAN and START. Results from these trials are critically needed, as shorter initiation timing might benefit stroke patients.

 

References

1. Kirchhof P, Benussi S, Kotecha D, et al. 2016 ESC Guidelines for the management of atrial fibrillation developed in collaboration with EACTS. Europace 2016; 18: 1609–1678.

2. Paciaroni M, Caso V, Agnelli G, et al. Recurrent Ischemic Stroke and Bleeding in Patients With Atrial Fibrillation Who Suffered an Acute Stroke While on Treatment With Nonvitamin K Antagonist Oral Anticoagulants: The RENO-EXTEND Study. Stroke. Epub ahead of print 11 May 2022. DOI: 10.1161/STROKEAHA.121.038239.

3. Kimura S, Toyoda K, Yoshimura S, et al. Practical ‘1-2-3-4-Day’ Rule for Starting Direct Oral Anticoagulants after Ischemic Stroke with Atrial Fibrillation: Combined Hospital-Based Cohort Study. Stroke 2022; 53: 1540–1549.

A tough clot: platelet-rich thrombi and efficacy of endovascular therapy

In acute ischemic stroke with large vessel occlusion, the efficacy of endovascular treatment (EVT) depends strongly on the ability to obtain successful recanalization. Complete recanalization after a single EVT pass – known as the first pass effect (FPE) – is associated with the best clinical outcome. Using quantitative assays, the study from Delvoye and his colleagues evaluates the potential link between clot cellular composition and outcome after EVT.

This study collected thrombi from stroke patients and had the recanalization status scored by experienced neuro-interventionalists. Thrombi that weight over 10 mg were lysed with a special homogenization method. Then quantification of red blood cells and white blood cells in the thrombus homogenates was performed by measuring the heme concentration, and DNA content respectively. Platelet content was estimated by measuring GPVI levels in the thrombus homogenates.

The study team retrieved a total of 729 thrombi of which 250 were large enough to be homogenized. Of those 250 thrombi, the median number of passes during EVT was 2 (range 1 – 12) and FPE was achieved in 36%.

Thrombus GPVI levels were significantly different between patients with and without FPE; the mean GPVI content being significantly lower in the first pass effect group. After adjusting for potential confounding factors, including use of IV tPA therapy and occlusion site, a lower CPVI concentration remained significantly associated with first pass effect (OR 0.55 (95% CI 0.39 0 0.79; p <0.001). Higher GPVI levels were also associated with an increased number of passes, a longer reperfusion time, and a lower reperfusion rate. No difference was found in heme and DNA content.

Therefore, they authors conclude that platelet concentration seems to be affecting first pass effect occurrence, as opposed to red blood cell content and white blood cell content. This study strengthens the existing evidence of the association between platelet-rich thrombi and a lower recanalization rate. From a pathophysiologic perspective, this might occur because of increased thrombus stiffness and friction caused by platelets colocalizing with fibrin, neutrophils, neutrophil extracellular traps, and von Willebrand factor. In addition, these factors might also form a stronger resistance to cloth lysis with tPA.

Despite having a certain selection of thrombi in this study, e.g., those obtained after successful EVT and selecting thrombi large enough for being homogenized, the study does detect a significant effect.

In conclusion, this study provides additional evidence of a higher platelets content in thrombi being associated with a lower first pass effect rate and a higher number of passes with EVT. These results might also suggest that adjuvant treatments that target platelets could help improve reperfusion therapy in acute ischemic stroke.

Heart and brain: Is there a role for cardiac biomarkers in acute stroke treatment and prognosis?

Heart and brain are strongly connected with each other. Ischemic stroke is a well-known sequelae of cardiac diseases like atrial fibrillation (AF), heart failure, or myocardial infarction. At the same time, diseases of the heart may complicate treatment and outcome of acute stroke. In diagnosis and prognosis of cardiac disease, blood-based biomarkers play a pivotal role, and in the past years, there has been growing evidence indicating the clinical utility of cardiac biomarkers outside cardiac conditions. Increased levels of cardiac biomarkers are frequently observed in stroke patients, but their significance is still less clear.

On the one hand, the predictive value of markers such as N-terminal pro-B-type natriuretic peptide (NT-proBNP), mid-regional pro-atrial natriuretic peptide (MR-proANP) and cardiac toponins for risk of stroke in the general population has been investigated^1-3. On the other hand, by the time a stroke has occurred, cardiac troponins may help in identifying patients at risk for cardiovascular events. Cardiac troponins (troponin I, troponin T) are sensitive markers of acute coronary syndrome (ACS)⁴. Stroke and ACS largely share the same risk factors and thus may occur together. In line with this, current guidelines recommend measurement of troponin in acute stroke⁵. However, there are also other possible explanations for increased troponins in acute stroke, so that they may not exclusively indicate a treatment-relevant emergency calling for acute coronary intervention.

In a small pilot study including 29 patients with acute ischemic stroke (AIS) and increased levels of cardiac troponin who underwent coronary angiography, about 20-25% patients showed culprit lesions, i.e., coronary stenosis or local thrombus representing a target for coronary intervention. In contrast, nearly half of patients did not show any relevant coronary artery diseases⁶. Against this background the PRediction of acute coronary syndrome in acute ischemic StrokE (PRAISE) study has been started in 2018 to develop a diagnostic algorithm to better identify ACS as origin of cardiac troponin elevation in AIS patients. The primary hypothesis will test whether dynamic troponin levels (as compared to stable ones) indicate the presence of ACS. The study has enrolled the planned number of patients last year, and presentation of the results is expected at one of the large stroke meetings in the near future⁷.

Another possible application for cardiac biomarkers in stroke may be the identification of sources of cardiac embolism as cause of stroke, such as AF or severe heart failure. NT-proBNP is an established marker of hemodynamic stress, and increased levels of NT-proBNP are a diagnostic hallmark of heart failure⁸. Recently, MR-proANP has come into focus as a possible indicator of an increased risk of AF in patients with stroke⁹. The ongoing MidregiOnal Proatrial Natriuretic Peptide to Guide SEcondary Stroke Prevention (MOSES) study will address the question, whether stroke patients without AF but with increased levels of MR-proANP indicating atrial pathology may benefit from oral anticoagulation using non-Vitamin K antagonist oral anticoagulants (ClinicalTrials.gov Identifier: NCT03961334).

To summarize, cardiac biomarkers represent a promising diagnostic tool which may help in optimizing acute management and secondary prevention of stroke. Depending on the results of the aforementioned studies in the near future we may get used to measuring and interpreting cardiac biomarkers in the setting of acute stroke in our clinical practice.

References:

1. Di Castelnuovo A, Veronesi G, Costanzo S, Zeller T, Schnabel RB, de Curtis A, et al. Nt-probnp (n-terminal pro-b-type natriuretic peptide) and the risk of stroke. Stroke. 2019;50:610-617
2. Camen S, Palosaari T, Reinikainen J, Sprunker NA, Niiranen T, Gianfagna F, et al. Cardiac troponin i and incident stroke in european cohorts: Insights from the biomarcare project. Stroke. 2020;51:2770-2777
3. Berntsson J, Smith JG, Nilsson PM, Hedblad B, Melander O, Engstrom G. Pro-atrial natriuretic peptide and prediction of atrial fibrillation and stroke: The malmo preventive project. Eur J Prev Cardiol. 2017;24:788-795
4. Lindahl B, Toss H, Siegbahn A, Venge P, Wallentin L. Markers of myocardial damage and inflammation in relation to long-term mortality in unstable coronary artery disease. Frisc study group. Fragmin during instability in coronary artery disease. N Engl J Med. 2000;343:1139-1147
5. Powers WJ, Rabinstein AA, Ackerson T, Adeoye OM, Bambakidis NC, Becker K, et al. 2018 guidelines for the early management of patients with acute ischemic stroke: A guideline for healthcare professionals from the american heart association/american stroke association. Stroke. 2018;49:e46-e110
6. Mochmann HC, Scheitz JF, Petzold GC, Haeusler KG, Audebert HJ, Laufs U, et al. Coronary angiographic findings in acute ischemic stroke patients with elevated cardiac troponin: The troponin elevation in acute ischemic stroke (trelas) study. Circulation. 2016;133:1264-1271
7. Nolte CH, von Rennenberg R, Litmeier S, Scheitz JF, Leistner DM, Blankenberg S, et al. Prediction of acute coronary syndrome in acute ischemic stroke (praise) – protocol of a prospective, multicenter trial with central reading and predefined endpoints. BMC Neurol. 2020;20:318
8. Kragelund C, Gronning B, Kober L, Hildebrandt P, Steffensen R. N-terminal pro-b-type natriuretic peptide and long-term mortality in stable coronary heart disease. N Engl J Med. 2005;352:666-675
9. De Marchis GM, Schneider J, Weck A, Fluri F, Fladt J, Foerch C, et al. Midregional proatrial natriuretic peptide improves risk stratification after ischemic stroke. Neurology. 2018;90:e455-e465