In HYSR, the most important strength is that it can be considered almost a population-based study with consecutive young patients with first-ever ischemic stroke of any etiology.
Furthermore, data of baseline characteristics and endpoints are nearly complete, with a long follow-up period and endpoints mostly verified from original patient records. However, the long inclusion period of patients from 1994 to 2007 may lead to heterogeneity in the diagnostic work-up, being less complete especially during the early years, further affecting the accuracy of ESUS classification in our study. As in all retrospective studies, also here the later identification of ESUS patients from a pre-existing registry might cause some uncertainty. To take this into consideration, we performed sensitivity analyses comparing definite ESUS and probable ESUS and found only a few differences in baseline characteristics and no essential differences in the adjusted risks for the endpoints of interest. From a broader perspective, it has been suggested that the construct of ESUS itself be rejected due to inaccuracy of the inclusion criteria leading to high heterogeneity of the ESUS population.268
The protocol for SECRETO is robust, the design is prospective, and each patient is included only after an extensive and timely diagnostic work-up. Furthermore, ischemic stroke is verified with MRI in each case, thus minimizing the risk of including patients with stroke mimics. All data are collected with validated questionnaires from both patients and stroke-free controls.
73 Nevertheless, due to practical reasons and limited research funding, none of the controls undergo brain MRI and they are not followed up. Migraine was defined according to the criteria of the International Classification of Headache Disorders, also reducing the risk of misclassification. There were few missing data in the analyses and conditional logistic regression analyses were possible to adjust for a wide range of confounders.
However, in SECRETO, selection bias might still be present to some degree if recruitment of patients with e.g. more severe symptoms is too challenging to execute in a timely manner (within two weeks from stroke onset). Thus, the present analyses included patients with mainly mild to moderate strokes. Regular screening and adherence to study protocol were essential to reduce this bias. Furthermore, primarily recruiting population-based controls was preferred since controls selected from e.g. hospital staff might also cause selection bias. However, sensitivity analyses were performed in addition to the main analyses including only population-based controls. Also interviewing patients relatively soon after the index stroke could cause some inaccuracies due to diverse neurological deficits. In our migraine analyses, the prevalence of migraine in controls was relatively high, perhaps reflecting a potential selection bias of controls. However, rather than overestimating, this should have led to an underestimation of our observed effect size. For detecting PFO, we used TCD-BS, which also detects other right-to-left shunts and is not fully specific for PFO alone. Validation of the migraine screener in our study for MO could be underpowered leading to modest accuracy. In Study IV, endothelial function was assessed with EndoPAT, which is less invasive than FMD. EndoPAT is a validated method to estimate endothelial function. However, it is an indirect measurement, and our results should be confirmed using other methods to measure endothelial dysfunction.
74
7 CONCLUSIONS AND FUTURE DIRECTIONS
In summary, 21% of patients in the HYSR cohort could be retrospectively classified as ESUS, and they were younger and had a lower burden of cardiovascular risk factors than patients with well-established stroke etiology. They also had generally better long-term outcome, except for the risk of recurrent stroke between ESUS and CE. After designing and piloting of the prospective SECRETO study, this study also demonstrated a strong association between any migraine and MA and early-onset cryptogenic ischemic stroke, as well as an association between endothelial dysfunction and cryptogenic stroke in men and slightly older individuals.
Prospective multi-center studies are warranted to determine more accurately the baseline characteristics and long-term outcome of young ESUS patients after comprehensive well-designed diagnostic work-up fulfilling all criteria for ESUS. One such study, an observational Young ESUS Patient Registry (Y-ESUS, NCT03185520), recently completed its enrollment with 535 participants, and its results are expected shortly. Future trials in young adults should focus on optimal primary and secondary prevention, including antithrombotic, lipid-lowering, and antihypertensive medications, but also lifestyle modifications. An interesting aspect is whether PFO closure or treatment with aspirin could also reduce the frequency of migraine attacks in young patients with prior cryptogenic ischemic stroke, and further investigations are justified.
Sufficient diagnostic work-up in early-onset ischemic stroke is also a subject of continuous debate. Whether young stroke patients could benefit from prolonged ECG-monitoring is unclear since the exact prevalence of e.g. AF and the clinical significance of other supraventricular tachycardias in the young remain inconclusive.
The SECRETO study continues to explore comprehensively different aspects of early-onset cryptogenic ischemic stroke, including determining the association between more permanent risk factors and triggers, genetics, optimal secondary prevention, patients’ compliance, and long-term outcome. Several projects have already been planned, including investigating the association of other less well-documented risk factors (such as unhealthy diet, recent infections, and sleep quality) with early-onset ischemic stroke, more detailed imaging findings in MRI and MRA, and extended cardiac investigations.
75
ACKNOWLEDGMENTS
This project was carried out in the Department of Neurology, Helsinki University Hospital and in the Doctoral Programme in Clinical Research, University of Helsinki, Finland.
First of all, my deepest gratitude goes my supervisors, Jukka Putaala and Daniel Gordin, for introducing me to the ever-changing field of stroke, especially early-onset ischemic stroke.
They have given me confidence in both clinical training and research, and this thesis would have not been possible without their support.
I also thank the senior personnel in our department, including Markku Kaste, Turgut Tatlisumak, Daniel Strbian, Sami Curtze, Gerli Sibolt, Marjaana Tiainen, Tiina Sairanen, and Lauri Soinne, for supporting this journey during the past years.
Successful research is never done alone. Thus, I am thankful to co-investigators Karoliina Aarnio, Jani Pirinen, Juha Sinisalo, Mika Lehto, and Ville Artto as well as our experienced research unit personnel Marja Metso, Laura-Leena Kupari, Anu Eräkanto, Saija Eirola, and Terhi Saarikoski. Furthermore, I thank other stroke investigators in our department – Silja, Sini, Hanne, Reetta, and Lauri – thank you also for offering moral support.
I warmly express my gratitude to all SECRETO collaborators in Finland, including Pekka Jäkälä, Heikki Numminen, Juha Huhtakangas, Pauli Ylikotila, and Risto O. Roine, as well as abroad, including Bettina von Sarnowski, Ulrike Waje-Andreassen, Marialuisa Zedde, Ana C Fonseca, Alessandro Pezzini, and Petra Redfors, to name but a few. Your input to SECRETO has been invaluable.
I also wish to thank the reviewers of this thesis, Assistant Professor Aneesh B. Singal and Assistant Professor Jussi Sipilä, as well as my opponent, Professor Heinrich Mattle, and Professor Perttu Lindsberg for all the support.
I am grateful to the Department of Neurology, Helsinki University Hospital and my funders from the Doctoral Programme in Clinical Research, University of Helsinki, the Academy of Finland, the Paavo Nurmi Foundation, the Emil Aaltonen Foundatioin, and the Maire Taponen Foundation.
Finally, I warmly thank my family, Anna-Maija, Karla, Ulla, and Mikko, for supporting me patiently throughout this rewarding project.
76
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