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!

Hyperglycemia after acute stroke is a common phenomenon, reported in up to one third of acute stroke patients, affecting both diabetic and non-diabetic patients.¹ Admission hyperglycemia has been associated with a pathophysiological sequalae that may lead to poor outcomes in stroke patients, including higher mortality and unfavorable functional recovery post-stroke.^1,2 In ischemic stroke patients receiving reperfusion therapies, increased glucose values at admission have also been related with lower recanalization rates^3,4 and higher likelihood of symptomatic intracranial hemorrhage.^3,5 Therefore, appropriate glucose management in the acute setting is expected to lead to better functional results of the stroke patients.

Yet, the results of the largest-to-date study in the field, the SHINE trial, did not demonstrate any significant difference in efficacy outcomes among acute stroke patients administered intensive treatment with continuous intravenous insulin compared to the standard of care.⁶ On the other hand, the patients receiving the intensive treatment showed significantly more hypoglycemic episodes.⁶ Following the somewhat discouraging results of the SHINE trial, testing of other hypoglycemic treatment options that take hypoglycemic risk and glycemic variability into account was thought to be of significant value. Glycemic variability is considered the third component of dysglycemia (along with hyperglycemia and hypoglycemia) and has been also associated with lower likelihood of recovery among acute stroke patients.

Recently, during the ESOC 2022, the result of TEXAIS (Trial of EXenatide in Acute Ischaemic Stroke) trial were presented.^7,8 In this phase II, multi-center, prospective, randomized, open label, blinded endpoint (PROBE) trial, acute ischemic stroke patients were randomized to receive subcutaneous injections of exenatide (n=177) versus standard of care (n=173). Hypoglycemic treatment was initiated within 9 hours of symptom onset and was administered for a total duration of 5 days. The advantage of exenatide, which is a glucagon-like peptide 1 (GLP-1) agonist, is that its action is blood glucose-dependent, meaning that exenatide has no effect when blood glucose values return to normal, thus protecting from downward fluctuations and hypoglycemia.

TEXAIS study showed that, indeed, glucose correction was more stable in the exenatide-treatment group, considering that the daily frequency of hyperglycemic episodes was significantly lower in the active group compared to the usual care. Importantly, no hypoglycemic episodes were recorded in any of the treatment groups. Yet, stroke outcomes were again neutral; no difference was noted regarding the neurological improvement at 7 days or the functional outcomes at 3-months. However, the study was terminated early due to COVID-19-related constraints and was ultimately of limited power to show statistically significant efficacy results.

Professor Christopher Bladin that presented the results on behalf of the TEXAIS investigators, highlighted that the favorable safety profile and the successful glucose management following exenatide treatment are quite promising and should justify a larger phase III trial. Surely, as in the case of blood pressure management, a more individualized approach for glucose management in the acute stroke setting, using agents and algorithms that prevent glucose fluctuations, should be pursued.

Conflict of interest statement

Dr. Palaiodimou reports no conflicts of interest.

References

1. Capes SE, Hunt D, Malmberg K, Pathak P, Gerstein HC. Stress hyperglycemia and prognosis of stroke in nondiabetic and diabetic patients: a systematic overview. Stroke. 2001;32(10):2426-2432.
2. Bruno A, Biller J, Adams HP, Jr., et al. Acute blood glucose level and outcome from ischemic stroke. Trial of ORG 10172 in Acute Stroke Treatment (TOAST) Investigators. Neurology. 1999;52(2):280-284.
3. Poppe AY, Majumdar SR, Jeerakathil T, Ghali W, Buchan AM, Hill MD. Admission hyperglycemia predicts a worse outcome in stroke patients treated with intravenous thrombolysis. Diabetes Care. 2009;32(4):617-622.
4. Ribo M, Molina C, Montaner J, et al. Acute hyperglycemia state is associated with lower tPA-induced recanalization rates in stroke patients. Stroke. 2005;36(8):1705-1709.
5. Goyal N, Tsivgoulis G, Pandhi A, et al. Admission hyperglycemia and outcomes in large vessel occlusion strokes treated with mechanical thrombectomy. J Neurointerv Surg. 2018;10(2):112-117.
6. Johnston KC, Bruno A, Pauls Q, et al. Intensive vs Standard Treatment of Hyperglycemia and Functional Outcome in Patients With Acute Ischemic Stroke: The SHINE Randomized Clinical Trial. Jama. 2019;322(4):326-335.
7. Bladin C, on behalf of the TEXAIS Investigators. Trial of EXenatide in Acute Ischaemic Stroke (TEXAIS). ESOC 2022. May 6, 2022.
8. Muller C, Cheung NW, Dewey H, et al. Treatment with exenatide in acute ischemic stroke trial protocol: A prospective, randomized, open label, blinded end-point study of exenatide vs. standard care in post stroke hyperglycemia. Int J Stroke. 2018;13(8):857-862.

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.

Click here to learn more.

Cancer associated ischemic stroke

In the 19^th century, French internist Armand Trousseau introduced for the first time the theory of hypercoagulable state in patients having malignancy, nowadays known as Trousseau’s syndrome (TS). TS is a systemic complication of malignancy which may manifest itself by thromboembolic events in the central nervous system. Approximately 40% of a general population develop a malignancy during their life span, and cancer as a co-diagnosis develops at certain timepoint in 1-2 of 10 stroke patients.¹ TS is mainly associated with “active cancer” diagnosed within 6-12 months prior or after the stroke event. This group of patients represents up to 5% of a general ischemic stroke population and up to 20% of patients with cryptogenic stroke.^2,3

Cancer associated ischemic stroke (CAIS) represents an increasing burden as the life expectancy lengthens and cancer therapy improves.⁴ Based on the available data, it is clear that CAIS requires a different approach to diagnostics, acute treatment and secondary prevention.⁵

The pathophysiology in CAIS is not completely clear and represents a complex spectrum of mechanisms related to the cancer itself, but also to its treatment with chemotherapeutics and radiotherapy. A hypercoagulable state caused by tumor pro-coagulants or adenocarcinoma released mucins as well as a non-bacterial thrombotic endocarditis may be involved in many of the cases.^6,7 These mechanisms lead to recurrent and usually therapeutically challenging microembolization.

The ischemic stroke may be the first clinical manifestation of occult cancer. Several clinical and diagnostic markers may help to unveil underlying malignancy. History of smoking, recent weight loss, occurrence of venous thromboembolism, upregulated coagulation activity in laboratory tests and multiple territory ischemic lesions on cerebral imaging are specific but lack sensitivity. An important question is when and who to screen for an occult cancer. A probability score consisting of the 3 variables D-Dimer, hemoglobin and history of smoking may guide the clinician in the decision making.⁸

Data on intravenous thrombolysis (IVT) in CAIS are scarce and mostly based on observation studies and sub-analysis of bigger IVT trials. Concerns about bleeding risk are in the front line. Caution and individual approach should be taken in patients with gastrointestinal tumors, CNS metastasis and intra-axial intracranial tumors.^2,9 There are also scarce data on endovascular treatment (EVT) since patients with concomitant cancer diagnosis have been excluded from randomized EVT trials. Similar rates of intracranial hemorrhage and recanalization in CAIS compared to non-cancer associated ischemic stroke have been showed in observational studies. However, platelet rich composition of thrombi and relatively more frequent tandem and multiple large vessel occlusions can make the EVT more challenging.¹⁰ The cancer related life expectancy must be considered in the acute therapeutic decision making and an individualized approach is required.

Patients with CAIS have often worse functional status prior to the stroke event, higher morbidity and higher stroke recurrence rate, all of which has a negative impact on the prognosis and further treatment.^5,11 The approach in secondary prevention is not scientifically established and may be challenging compared to the “traditional” ischemic stroke patients.¹² Injectable heparins are widely used for cancer related venous thromboembolism, mainly in the initial period, however high cost and inconvenience of a long-term administration are main drawbacks. Randomized control trials comparing direct oral anticoagulants (DOAC) and injectable heparins are needed to clarify eventual use of DOAC in this patient group.

CAIS represents an important field of stroke medicine but is quite unexplored. Further research in this field and establishing guidelines is an important task for following years.

1. White MC, Holman DM, Boehm JE, et al. Age and cancer risk: a potentially modifiable relationship. Am J Prev Med 2014; 46(3 Suppl. 1): S7–S15.
2. Selvik HA, Thomassen L, Bjerkreim AT, et al. Cancer-associated stroke: the Bergen NORSTROKE study. Cerebrovasc Dis Extra 2015; 5: 107–113.
3. Kim SJ, Park JH, Lee MJ, et al. Clues to occult cancer in patients with ischemic stroke. PLoS ONE 2012; 7: e44959.
4. Rioux B, Touma L, Nehme A, et al. Frequency and predictors of occult cancer in ischemic stroke: a systematic review and meta-analysis. Int J Stroke 2021; 16: 12–19.
5. Woock, M., Martinez-Majander, N., Seiffge, et al. (2022). Cancer and stroke: commonly encountered by clinicians, but little evidence to guide clinical approach. Therapeutic advances in neurological disorders, 15, 17562864221106362.
6. Dearborn JL, Urrutia VC and Zeiler SR. Stroke and cancer – a complicated relationship. J Neurol Transl Neurosci 2014; 2: 1039.
7. Navi BB, Singer S, Merkler AE, et al. Recurrent thromboembolic events after ischemic stroke in patients with cancer. Neurology 2014; 83: 26–33.
8. Selvik HA, Bjerkreim AT, Thomassen L, et al. When to screen ischaemic stroke patients for cancer. Cerebrovasc Dis 2018; 45: 42–47.
9. Ladak AA, Sandhu S and Itrat A. Use of intravenous thrombolysis in acute ischemic stroke management in patients with active malignancies: a topical review. J Stroke Cerebrovasc Dis 2021; 30: 105728.
10. Jung S, Jung C, Hyoung Kim J, et al. Procedural and clinical outcomes of endovascular recanalization therapy in patients with cancer- related stroke. Interv Neuroradiol 2018; 24: 520–528.
11. Kneihsl M, Enzinger C, Wünsch G, et al. Poor short-term outcome in patients with ischaemic stroke and active cancer. J Neurol 2016; 263: 150–156.
12. Key, N. S., Khorana, A. A., Kuderer, N. M., et al. (2020). Venous thromboembolism prophylaxis and treatment in patients with cancer: ASCO clinical practice guideline update. Journal of Clinical Oncology, 38(5), 496-520.