Cryptogenic ischemic stroke in young adults : characteristics and less well-documented risk factors

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1 Department of Neurology

Helsinki University Hospital and University of Helsinki

CRYPTOGENIC ISCHEMIC STROKE IN YOUNG ADULTS

Characteristics and less well-documented risk factors

Nicolas Martinez-Majander

ACADEMIC DISSERTATION To be presented for public discussion, with the permission of the Faculty of Medicine

of the University of Helsinki in the Porthania, PIII (70)

University of Helsinki, Yliopistonkatu 3, Helsinki on the 3^rd of December, 2021 at 13.15 pm.

Doctoral School of Clinical Research Helsinki 2021

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2 SUPERVISORS

Docent Jukka Putaala

Department of Neurology Helsinki University Hospital and University of Helsinki Helsinki, Finland

Docent Daniel Gordin

Abdominal Center Nephrology

Helsinki University Hospital and University of Helsinki Helsinki Finland and Minerva Foundation Institute for Medical Research Helsinki, Finland

and

Joslin Diabetes Center, Harvard Medical School Boston, Massachusetts, USA

REVIEWERS

Associate Professor Aneesh B. Singhal Department of Neurology Massachusetts General Hospital Boston, Massachusetts, USA

Docent Jussi Sipilä Clinical Neurosciences University of Turku Turku, Finland and Siun Sote North Karelia Central Hospital, Department of Neurology

Joensuu, Finland

OPPONENT

Professor Heinrich Mattle

Department of Neurology

Inselspital, University of Bern Bern, Switzerland

The Faculty of Medicine uses the Urkund system (plagiarism recognition) to examine all

doctoral dissertations.

ISBN 978-951-51-7318-8 (Paperback) ISBN 978-951-51-7324-9 (PDF) Unigrafia, Helsinki 2021

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3

ABSTRACT

Despite contemporary studies showing a high prevalence of cardiovascular risk factors in young adults (<50 years) with ischemic stroke, recent large hospital- and population-based studies also show high frequencies (33-50%) for cryptogenic strokes in this patient population.

The proportion of patients without known vascular risk factors was even larger in younger (<30 years) age groups than in patients aged between 30 and 49 years. The risk for recurrence is high even in those with cryptogenic strokes, suggesting a still unknown active underlying pathology. The aim of this study was to explore the characteristics of early-onset cryptogenic ischemic stroke and associated less well-documented risk factors.

In the first study, we explored baseline characteristics and long-term outcome of a carefully phenotyped subgroup of young individuals with early-onset cryptogenic ischemic stroke, embolic stroke of undetermined stroke (ESUS). These patients were identified from the retrospective Helsinki Young Stroke Registry (HYSR), which included all consecutive young patients aged 15-49 years with first-ever ischemic stroke treated at the Helsinki University Hospital between the years 1994 and 2007 and followed up for a median of 10.1 years. Of the 971 eligible patients in HYSR, 203 (20.9%) were classified as ESUS. These patients were more often female (43.3% vs. 35.7%), younger (median age 40 years, interquartile range 32-46 vs.

40 years, 39-47), and had lesser well-established cardiovascular risk factors for ischemic stroke than young patients with other defined stroke etiologies. Within the follow-up, ESUS patients had the lowest cumulative 15-year risk of mortality (9.5%, 95% confidence interval 4.0-15.1%) and the second lowest risk of any recurrent stroke (19.5%, 3.7-35.2%) and composite vascular events (23.9%, 14.1-33.6%) compared with other defined stroke etiologies. Small-vessel disease and large-artery atherosclerosis had a significantly higher risk for recurrent stroke than ESUS, whereas the risk was similar between high-risk cardioembolism and ESUS.

In the second study, we designed and launched a multicenter, prospective case-control SECRETO (Searching for Explanations for Cryptogenic Stroke in the Young: Revealing the Etiology, Triggers, and Outcome; NCT01934725) study. This study includes equally young patients with first-ever cryptogenic ischemic stroke to explore more systematically the risk factors, triggers, and long-term outcome in this stroke subgroup. Patients were age- and sex- matched with stroke-free controls. By using data gathered in the SECRETO, we aimed to assess

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5 the association between migraine and endothelial dysfunction with early-onset cryptogenic ischemic stroke in the third and fourth studies.

In the third study, we included 347 case-control pairs and showed that any migraine and migraine with aura (MA) were associated with early-onset cryptogenic ischemic stroke (odds ratio [OR] 2.48, 1.63-3.76 and OR 3.50, 2.19-5.61, respectively). Migraine without aura (MO) showed no association with stroke. Association for any migraine and MA with early-onset cryptogenic ischemic stroke was significant in both women (OR 2.97, 1.61-5.47 and 4.32, 2.16- 8.65, respectively) and men (OR 2.47, 1.32-4.61 and 3.61, 1.75-7.45, respectively). MA was more frequent in patients with larger right-to-left shunts (29.2% for no shunt, 37.9% for small shunt, 46.7% for moderate shunt, and 49.4% for severe shunt; P=0.042). The association between MA and cryptogenic ischemic stroke remained significant irrespective of the shunt.

In the fourth study, endothelial dysfunction was analyzed with a non-invasive device (EndoPAT 2000 device, Itamar Medical Inc., Caesarea, Israel) by measuring a natural logarithm of Reactive Hyperemia Index (LnRHI), with lower values reflecting dysfunction. An association between endothelial dysfunction and early-onset cryptogenic ischemic stroke was observed in men (OR 3.50, 1.22-10.07 for lowest vs. highest LnRHI tertile) and in patients ≥41 years (5.78, 1.52-21.95). There was no significant association in the entire cohort, in women, or in patients <41 years in 136 case-control pairs included in this sub-analysis. Patients in the lowest tertile of LnRHI were more often men and obese and had more frequently a history of dyslipidemia, lower high-density lipoprotein cholesterol, and lower diet score.

In conclusion, ESUS patients in the retrospective HYSR cohort 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 high-risk cardioembolism. After designing and piloting the SECRETO study, we demonstrated a strong association between any migraine and MA and early-onset cryptogenic ischemic stroke irrespective of sex. We also showed an association between endothelial dysfunction and cryptogenic stroke in men and in slightly older individuals.

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6

TIIVISTELMÄ

Viimeaikaiset tutkimukset ovat osoittaneet, että myös nuorilla (alle 50-vuotiailla) aivoinfarktipotilailla on runsaasti sydän- ja verisuoniperäisiä riskitekijöitä. Siitä huolimatta sairaala- ja väestöpohjaisten tutkimusten perusteella salasyntyisten aivoinfarktien osuus on suuri (33 %-50 %). Myös salasyntyisissä aivoinfarkteissa on havaittu merkittävä uusiutumisriski viitaten piilevään aktiiviseen patofysiologiaan aivoinfarktin taustalla. Tämän tutkimuksen tavoitteena oli tutkia salasyntyisten infarktipotilaiden yleisyyttä, piirteitä ja salasyntyiseen aivoinfarktiin yhdistyviä vähemmän tutkittuja riskitekijöitä.

Ensimmäisessä osatyössä tutkimme potilaita, joilla oli todettu emboliselta vaikuttava salasyntyinen aivoinfarkti (nk. embolic stroke of undetermined source, ESUS). Potilaat identifioitiin takautuvasti Helsinki Young Stroke Registry (HYSR) -aineistosta, joka sisältää Helsingin Yliopistollisessa sairaalassa hoidetut perättäiset nuoret aivoinfarktipotilaat vuosilta 1994-2007. Seuranta-ajan mediaani oli 10,1 vuotta. ESUS-potilaiksi voitiin luokitella 203 potilasta kaikista sopivista 971 potilaasta HYSR-aineistossa. Verrattuna potilaisiin, joilla oli diagnosoitu jokin muu tarkemmin määritelty aivoinfarktin etiologia, ESUS-kriteerit täyttävät potilaat olivat useammin naisia (43,3 % vs. 35,7 %), nuorempia (mediaani-ikä 40 v., kvartiiliväli 32-46 vs. 40 v., kvartiiliväli 39-47) ja heillä oli vähemmän merkittäviä aivoinfarktin riskitekijöitä. ESUS-potilailla oli matalin kumulatiivinen 15 vuoden kuolleisuusriski (19,5 %; 95 %:n luottamusväli 3,7-35,2 %) ja toiseksi matalin kumulatiivinen 15 vuoden riski uusivaan sydän- tai verisuonitapahtumaan (23,9 %; 14,1-33,6 %) verrattuna muihin aivoinfarktin syihin. Pienten suonten taudissa ja suurten suonten valtimokovettumataudissa uusivan aivoinfarktin riski oli merkittävästi korkeampi kuin ESUS- kriteerit täyttävillä potilailla, kun taas riski oli samanveroinen verrattuna korkean riskin sydänperäisiin aivoinfarkteihin.

Toisessa osatyössä suunnittelimme ja käynnistimme etenevän useassa keskuksessa toteutettavan tapaus-verrokki tutkimuksen, Searching for Explanations for Cryptogenic Stroke in the Young: Revealing the Etiology, Triggers, and Outcome (SECRETO; NCT01934725).

Tämä tutkimus sisältää potilaat, jotka ovat sairastaneet ensimmäisen salasyntyisen aivoinfarktin, ja tutkimuksen tarkoituksena on selvittää systemaattisesti nuorten salasyntyisen aivoinfarktin riskitekijöitä, laukaisevia tekijöitä ja pitkäaikaisennustetta. Tutkimukseen rekrytoitiin myös verrokit, jotka ovat kaltaistettu potilaiden kanssa iän ja sukupuolen suhteen.

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7 Osana SECRETO-tutkimusta tutkimme kolmannessa ja neljännessä osatöissä migreenin ja endoteelin toimintahäiriön yhteyttä salasyntyiseen aivoinfarktiin nuorella iällä.

Kolmannessa osatyössä osoitimme 347 potilas-verrokkiparin otoksen käsittävässä analyysissä, että migreeni ja sen alatyyppi, aurallinen migreeni, ovat yhteydessä nuorten salasyntyiseen aivoinfarktiin (vetosuhde 2,48; 95 %:n luottamusväli 1,63-3,76 ja 3,50; 2,19-5,61). Auraton migreeni ei ollut yhteydessä aivoinfarktiin. Migreenin ja aurallisen migreenin yhteys nuorten salasyntyiseen aivoinfarktiin oli merkittävä sekä naisilla (2,97; 1,61-5,47 ja 4,32; 2,16-8,65) että miehillä (2,47; 1,32-4,61 ja 3,61; 1,75-7,45). Aurallinen migreeni oli yleisempi potilailla, joilla oli kookas oikovirtaus oikealta vasemmalle (29,2 % jos ei oikovirtausta, 37,9 % pienissä oikovirtauksissa, 46,7 % kohtalaisissa oikovirtauksissa ja 49,4 % merkittävissä oikovirtauksissa; P-arvo 0,042). Aurallisen migreenin ja salasyntyisen aivoinfarktin yhteys pysyi kuitenkin merkittävänä huolimatta oikovirtauksen olemassaolosta.

Neljännessä osatyössä endoteelin toimintahäiriötä analysoitiin 136 potilaan ja 136 verrokin alatutkimuksessa kajoamattomasti (EndoPAT 2000, Itamar Medical Inc., Caesarea, Israel) mittaamalla reaktiivisen hyperemiaindeksin luonnollista logaritmia (LnRHI), jossa alhaisemmat arvot kuvastavat toimintahäiriötä. Tutkimuksessamme todettiin yhteys endoteelin toimintahäiriön ja nuorten salasyntyisen aivoinfarktin välillä miehillä, kun verrattiin alinta tertiiliä ylimpään tertiiliin (vetosuhde 3,50; 95 %:n luottamusväli 1,22-10,07) ja vähintään 41- vuotiailla henkilöillä (5,78; 1,52-21,95). Tarkastelemalla koko kohorttia, vain naisia tai alle 41- vuotiaita ei todettu vastaavaa yhteyttä. Alimman LnRHI-tertiilin potilaat olivat muita useammin miehiä ja ylipainoisia ja heillä oli useammin dyslipidemiaa, matalampi HDL- kolesterolitaso sekä epäterveellisempi ruokavalio.

Kaiken kaikkiaan ESUS-potilaat takautuvassa HYSR-aineistossa olivat nuorempia ja heillä oli vähemmän kardiovaskulaarisia riskitekijöitä kuin niillä, joiden aivoinfarktin syy oli tiedossa.

Heillä oli myös yleisesti ottaen suotuisampi pitkänajan ennuste lukuun ottamatta uusivan aivoinfarktin riskiä ESUS-ryhmän ja sydänperäisten aivoinfarktien välillä. SECRETO- tutkimuksen suunnittelun ja käynnistämisen myötä osoitimme, että migreenin ja etenkin aurallisen migreenin yhteys nuorten salasyntyisiin aivoinfarkteihin on vahva sukupuolesta riippumatta. Lisäksi tutkimuksemme osoitti yhteyden endoteelin toimintahäiriön ja nuorten salasyntyisen aivoinfarktin välillä miehillä sekä hivenen vanhemmilla potilailla.

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8

LIST OF ORIGINAL PUBLICATIONS

This thesis is based on the following publications, referred to in the text by their Roman numerals:

I. Martinez-Majander N, Aarnio K, Pirinen J, Lumikari T, Nieminen T, Lehto M, Sinisalo J, Kaste M, Tatlisumak T, Putaala J. Embolic strokes of undetermined source in young adults: baseline characteristics and long-term outcome. Eur J Neurol. 2018;25:535-541.

II. Putaala J, Martinez-Majander N, Saeed S, Yesilot N, Jäkälä P, Nerg O, Tsivgoulis G, Numminen H, Gordin D, von Sarnowski B, Waje-Andreassen U, Ylikotila P, Roine RO, Zedde M, Huhtakangas J, Fonseca C, Redfors P, de Leeuw FE, Pezzini A, Kõrv J, Schneider S, Tanislav C, Enzinger C, Jatuzis D, Siegerink B, Martínez-Sánchez P, Grau AJ, Palm F, Groop PH, Lanthier S, Ten Cate H, Pussinen P, Paju S, Sinisalo J, Lehto M, Lindgren A, Ferro J, Kittner S, Fazekas F, Gerdts E, Tatlisumak T. Searching for Explanations for Cryptogenic Stroke in the Young: Revealing the Triggers, Causes, and Outcome (SECRETO): Rationale and design. Eur Stroke J. 2017;2:116-125.

III. Martinez-Majander N, Artto V, Ylikotila P, von Sarnowski B, Waje-Andreassen U, Yesilot N, Zedde M, Huhtakangas J, Numminen H, Jäkälä P, Fonseca AC, Redfors P, Wermer MJH, Pezzini A, Putaala J; SECRETO Study Group. Association between Migraine and Cryptogenic Ischemic Stroke in Young Adults. Ann Neurol. 2021;89:242- 253.

IV. Martinez-Majander N, Gordin D, Joutsi-Korhonen L, Salopuro T, Adeshara K, Sibolt G, Curtze S, Pirinen J, Liebkind R, Soinne L, Sairanen T, Sinisalo J, Lehto M, Groop P-H, Tatlisumak T, Putaala J. Endothelial dysfunction is associated with early-onset cryptogenic ischemic stroke in men and with increasing age. J Am Heart Assoc.

2021;10:e020838.

These articles have been reprinted with permission of their copyright holders. In addition, some unpublished material is presented.

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ABBREVIATIONS

AF atrial fibrillation

APS antiphospholipid syndrome

ASA atrial septal aneurysm

A-S-C-O A, atherosclerosis; S, small-vessel disease; C, cardiac source; O, other cause

ATTICUS Apixaban for Treatment of Embolic Stroke of Undetermined Source

CADASIL cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy

CADISS Cervical Artery Dissection in Stroke Study CCS Causative Classification System

CE cardioembolism from high-risk source

CHA2DS2-VASc

Congestive heart failure, Hypertension, Age >75 years, Diabetes, Stroke or transient ischemic attack, Vascular disease, Age 65-74 years, Sex

CI confidence interval

COC combined oral contraceptive

CRP C-reactive protein

CT computed tomography

CTA computed tomography angiography

DWI diffusion-weighted imaging

ESUS embolic stroke of undetermined source FLAIR fluid-attenuated inversion-recovery

FMD flow-mediated dilatation

HDL high-density lipoprotein

HR hazard ratio

HYSR Helsinki Young Stroke Registry

IQR interquartile range

LAA large-artery atherosclerosis

LDL low-density lipoprotein

MA migraine with aura

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10 MELAS mitochondrial myopathy, encephalopathy, lactic acidosis, and

stroke

MES micro embolic signals

MO migraine without aura

MRA magnetic resonance angiography

MRI magnetic resonance imaging

mRS modified Rankin Scale

NAVIGATE ESUS New Approach Rivaroxaban Inhibition of Factor Xa in a Global Trial versus ASA to Prevent Embolism in Embolic Stroke of Undetermined Source

NIHSS National Institute of Health Stroke Scale

NNT number needed to treat

OR odds ratio

PAT peripheral arterial tonometry

PAI plasminogen activator inhibitor

PFO patent foramen ovale

RCVS reversible cerebral vasoconstriction syndrome

RE-SPECT ESUS Randomized, Double-Blind, Evaluation in Secondary Stroke Prevention Comparing the Efficacy and Safety of the Oral Thrombin Inhibitor Dabigatran Etexilate Versus Acetylsalicylic Acid in Patients With Embolic Stroke of Undetermined Source

RHI reactive hyperemia index

RoPE Risk of Paradoxical Embolism

SPARKLE Subtypes of Ischemic Stroke Classification System

SVD small-vessel disease

TCD-BS transcranial Doppler ultrasound with bubble study

TEE transesophageal echocardiography

TTE transthoracic echocardiography

TOAST Trial of Org 10172 in Acute Stroke Treatment

UE stroke of undetermined etiology

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11

1 INTRODUCTION

Scientific interest in stroke in young adults has been rapidly growing, particularly within the last decade. No uniform criteria exist to define the entity “stroke in young adults”. The upper age cut-offs have varied from 30 to 65 years, most commonly being 50 or 55 years.^1-4 These cut-offs are mainly arbitrary and the differing upper age limits between studies might also explain the varying risk factor prevalence and etiology of stroke. Nevertheless, early-onset ischemic stroke should be considered separately from late-onset stroke for several reasons.

Firstly, young stroke patients have a wider range of potential risk factors and recognized (or established) causes underlying their strokes. These factors are different from those seen in older stroke patients. Young patients also have traditional risk factors, but there are risk factors and phenotype features that are specific to the young or the association appears stronger for young patients. Such risk factors include illicit drug use, combined oral contraceptive (COC) use, pregnancy and postpartum period, and patent foramen ovale (PFO). Furthermore, undetermined causes tend to be more prevalent among the young.^1,2 Secondly, young stroke patients have a social and vocational situation different from that in older stroke patients. They often have an active family life, offspring to nurture, and are at productive age, with their strokes often occurring at a time of decisive career moves—stroke affecting all of these domains. Thirdly, although chances to survive stroke at young age are much better than those at older age, young survivors face increased risk of recurrent strokes and cardiovascular events for a longer time.

The aim of this literature review is to provide an overview on incidence, risk factors, most common causes, specific treatment aspects, and long-term outcome of ischemic stroke in young adults. Focal points are cryptogenic ischemic strokes, embolic strokes of undetermined source, the migraine-stroke relationship, and the role of endothelial dysfunction in stroke mechanisms.

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2 REVIEW OF THE LITERATURE

2.1 Incidence

Incidence of ischemic stroke begins to increase nearly exponentially at early middle age, ranging from 10.8 to 11.4 per 100 000 person-years in individuals aged <50 years in Northern Europe, and is slightly lower in women than men.⁵ There are notable differences in the incidence between geographic areas and ethnic groups. For instance, in the Baltimore-Washington area, the incidence of ischemic stroke for young white people was 10.5 per 100 000, while it was 21.7 per 100 000 for young blacks,⁶ and in sub-Saharan Africa, the incidence is as high as 100 per 100 000 person-years.⁷ Remarkably, the incidence of early-onset ischemic stroke has been increasing worldwide in both high-income and middle-income countries since the 1980s.^8-13 Globally, significant increases were shown to occur between 1990 and 2013 in prevalent cases, total deaths, and disability-adjusted life- years because of both ischemic and hemorrhagic stroke in younger adults (20-64 years).¹⁴ Absolute numbers and prevalence rates of ischemic stroke were significantly increased in younger adults. The exact reasons for the increase remain unknown, but better awareness of the disease, improved diagnostics, increasing prevalence of overweight, tobacco use, unhealthy diet, sedentary lifestyle, excess alcohol use, and adult-onset diabetes may underlie this observation.¹⁵ In Finland, however, the overall stroke hospitalization of working-aged individuals declined between the periods 2004-2005 and 2013-2014, except in men aged 35-44 years for whom hospitalizations due to ischemic stroke increased. Furthermore, in-hospital mortality for ischemic stroke declined as well.¹⁶ A fairly recent study showed that in Finland there was an overall favorable development of population risk factor levels during the past forty years in participants aged 30-59 years.¹⁷ However, after 2007, total serum cholesterol levels had increased again and the decrease in diastolic blood pressure had plateaued.

Smoking prevalence, however, was still markedly decreased. As the authors concluded, this emphasizes the need for continued disease prevention and health promotion.

2.2 Etiologic classification

Here, only an overview of the main subtypes of ischemic stroke in the young will be provided, as rarer etiologies have been covered comprehensively in recent review papers.¹⁸ Stroke subtype distribution can be categorized using the Trial of Org 10172 in Acute Stroke Treatment (TOAST)

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criteria.¹⁹ These criteria were first presented in 1993 by Adams et al. and remain the most commonly applied classification for ischemic stroke in research as well as in clinical practice. Table 1 shows the largest studies on early-onset ischemic stroke published within the last 20 years and subtypes of stroke according to the TOAST criteria.

The most common single established etiology in young adults is cervicocephalic arterial dissection (up to 25% of cases), included in the other determined group of the TOAST. Other common TOAST subgroups comprise stroke of undetermined etiology, i.e. cryptogenic strokes (UE, 19-40%), cardioembolism from high-risk source (CE, 17-34%), and large-artery atherosclerosis (LAA, 7- 26%).^1,2,20-27 The variability of etiologies between studies largely depends on the completeness of the diagnostic work-up and whether e.g. low-risk or uncertain sources of cardioembolism (mainly PFO) are classified as UE or CE. Moreover, the proportion of UE differs significantly between studies since according to the TOAST criteria this subgroup includes all three of the following categories: (1) patients with no evident cause despite extensive evaluation, considered as true cryptogenic strokes, TOAST 5b, (2) patients with incomplete diagnostic evaluation, TOAST 5c, and (3) patients with two or more potential etiologies, TOAST 5a. LAA accounts for approximately 10-25% of early-onset ischemic strokes, but has an even greater proportion in certain ethnic groups such as Asians. In younger stroke patients, the proportion of UE is larger.^1,28 Sporadic small-vessel disease (SVD) accounts for 5-17% of early-onset strokes.

In 2009, Amarenco et al. proposed a new approach to stroke subtyping, the Atherosclerosis-Small- vessel disease-Cardiac pathology-Other causes (A-S-C-O) phenotyping of ischemic stroke,²⁹ which takes multiple simultaneous etiologies better into consideration and grades the level of evidence of diagnostic evaluation.³⁰ Using this classification, however, may leave a larger proportion of definite causes of stroke unidentified.³¹ In 2013, the same authors further highlighted the high frequency of dissection in young stroke patients by adding “D” to the A-S-C-O acronym, producing A-S-C-O-D.³² In the same publication, they also suggested that the cut-off for atherosclerotic stenosis of the significant vessel (either carotid or intracranial) should be as high as 70% instead of the earlier 50%.

Furthermore, in 2005 the Causative Classification System (CCS) was designed to improve the classification of stroke subtypes based on TOAST, with high interrater reliability between multiple investigators.³³ Finally, Subtypes of Ischemic Stroke Classification System (SPARKLE) seems to provide a further advantage in assessing the carotid plaque burden in ischemic stroke etiological classification.³⁴

In summary, several classifications can be used to describe the etiological subgroups, but TOAST remains the most commonly used in both clinical practice and research.

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2.2.1 Cryptogenic stroke

The entity of cryptogenic ischemic stroke was probably first introduced in 1988 as “infarction, unknown cause” within the National Institute of Neurological and Communicative Disorders³⁵ Several criteria have since then been proposed for the minimum diagnostic work-up for cryptogenic ischemic stroke such as the ones from the guidelines of the American Heart Association/American Stroke Association.³⁶ According to these guidelines, the minimum baseline evaluation should consist of non-contrast brain and carotid artery computed tomography (CT) or magnetic resonance imaging (MRI), complete blood count, electrocardiogram (ECG), markers of cardiac ischemia, and serum electrolytes.

However, it is evident that the proportion of cryptogenic stroke diminishes if timely additional examinations are done.¹⁸ These should include e.g. prolonged ECG monitoring, also intracranial artery imaging, both transthoracic echocardiography (TTE) and transesophageal echocardiography (TEE), and extended laboratory measurements to reveal any prothrombotic states. For example, if imaging of carotid vessels is delayed, an etiology such as dissection might be missed and optimal secondary prevention misdirected. This could also lead to other futile etiologic examinations.¹⁸ More extensive diagnostic work-up may also reveal occult atrial fibrillation (AF), valve vegetations, atrial myxomas, and aortic arch atheromas. Also occult cancer and other diseases causing hypercoagulability, heredity prothrombotic disorders, and vasculitis should be sought.^18,37-39 For instance, in approximately one-third of patients with reversible cerebral vasoconstriction syndrome (RCVS), computed tomography angiography (CTA) or MRA may have to be repeated since these might not confirm the diagnosis during the first week. RCVS usually manifests as a bilateral pattern of “string of beads” that should resolve within 12 weeks. Furthermore, in some cases, digital subtraction angiography might be necessary, and it remains the reference imaging for depicting RCVS.^40,41 Cerebrospinal fluid analysis can further help to differentiate RCVS from central nervous system vasculitis. These ancillary diagnostic studies might decrease the proportion of ischemic strokes initially considered as cryptogenic. However, a systematic review by McMahon and colleagues with 16 clinical practice guidelines and 7 consensus statements concluded that there is little agreement on more advanced or specialized investigations for rarer causes of acute ischemic stroke.⁴² This might lead to inappropriate use of costly and specialized resources and skills, as well as a lack or delays in a more specific etiological diagnosis.

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Table 1. Frequencies of the main subtypes of ischemic stroke according to Trial of Org 10172 in Acute Stroke Treatment classification in a large patient series, including young patients, published within the last 20 years.

Paper/year No. of

patients Age range

Inclusion period

Setting LAA (%)

CE (%)

SVD (%)

OTH (%)

UE (%) Rolfs et al. 2013¹ 3291 18-55 2007-

2010

Multicenter 19 17 13 18 33

Yesilot et al. 2013² 3331 15-49 1988- 2010

Jovanovic et al.

2008*²⁰

865 15-45 1989- 2005

Single- center

14 20 14 20 32

Rutten-Jacobs et al.

2013²¹

447 18-50 1980- 2010

Single- center

26 13 12 16 32

Rasura et al. 2006²² 394 14-47 1992- 2001

Single- center

12 34 3 27 24

Cerrato et al. 2004*²³ 273 16-49 1994- 2001

Single- center

16 24 17 19 24

Varona et al. 2007²⁴ 272 15-45 1974- 2002

Single- center

20 17 5 22 36

Ji et al. 2013*²⁵ 215 18-45 2005- 2010

Single- center

2 47 7 34 11

Nedeltchev et al.

2005²⁶

203 16-45 1997- 2002

Kwon et al. 2000²⁷ 149 15-44 1994- 1997

Single- center

21 18 17 27 17

LAA, large-artery atherosclerosis; CE, cardioembolism; SVD, small-vessel disease; OTH, other determined etiology;

UE, undetermined etiology. *Includes patients with transient ischemic attack.

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2.2.2 Embolic stroke of undetermined source

Criteria to define embolic stroke of undetermined source (ESUS) was proposed in 2014 to characterize a subgroup of cryptogenic ischemic strokes.⁴³ Before the publication of ESUS criteria, it was already shown that patients with undetermined strokes with an embolic pattern were younger and had more favorable risk factor profile, but still had a high risk of stroke recurrence.⁴⁴ The diagnostic criteria for ESUS are shown in Table 2.

Table 2. Diagnostic criteria for embolic stroke of undetermined cause.⁴³ Non-lacunar stroke detected by CT or MRI

Absence of extracranial or intracranial atherosclerosis causing ≥50% luminal stenosis in arteries supplying the area of ischemia

No major-risk cardioembolic source of embolism

No other specific cause of stroke identified (e.g. arteritis, dissection, migraine/vasospasm, drug misuse)

CT, computed tomography; MRI, magnetic resonance imaging

Specifically regarding young patients, a preliminary report including just 100 young patients with a mean age of 45 years suggested that up to 4/5 cryptogenic ischemic strokes in the young fulfill the ESUS criteria.⁴⁵ This report also showed that minor embolic sources, including frequent supraventricular extrasystoles, atrial dilatation, or PFO, do not seem to be more prevalent in young ESUS patients than in stroke of determined cause. However, large-scale comparisons between characteristics of ESUS and other defined stroke subtypes in young patients as well as data on their long-term outcome were lacking at that time.

Regarding age-inclusive studies, Ntaios et al. applied ESUS criteria to the Athens Stroke Registry, including more than 2700 stroke patients, and classified approximately 10% of them as ESUS, with a median age of 68 years.⁴⁶ The risk factor profile in ESUS was shown to be similar to the general stroke population, including hypertension (65%) and dyslipidemia (51%). This study also revealed that the most frequently affected arterial territory in ESUS was the entire middle cerebral artery and that the symptoms were maximal at onset. ESUS were of moderate severity (median National Institution of Health Stroke Scale, NIHSS 5) compared with cardioembolic strokes (median NIHSS

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13). Moreover, in the Global ESUS Registry with more than 2100 patients, ESUS patients (16%) were significantly younger than non-ESUS patients and they had a relatively high prevalence of hypertension (64%), diabetes (24%), and prior stroke (17%). The most frequent secondary prevention with ESUS patients was antiplatelet therapy (90% of patients), while only 7% received anticoagulation.⁴⁷

Ntaios et al. showed that the long-term mortality in all-aged ESUS was lower than in cardioembolic strokes, although the frequency of recurrence and composite cardiovascular endpoints were similar.

Moreover, the risk of recurrent strokes in ESUS was higher than in non-cardioembolic strokes.⁴⁸ They also showed that the risk of recurrent ischemic stroke/transient ischemic attack and death in ESUS was reliably stratified by CHA2DS2-VASc score (Congestive heart failure, Hypertension, Age 75 years or older (2 points), Diabetes mellitus, Stroke or transient ischemic attack (2 points), Vascular disease, Age 65 to 74 years, Sex category). The high-risk CHA2DS2-VASc group had approximately a 13-fold risk of ischemic stroke/transient ischemic attack and death relative to the low-risk group.⁴⁹

2.3 Risk factors

2.3.1 Traditional risk factors

Large studies have demonstrated a high prevalence of traditional risk factors in young stroke patients, with risk factor profile to date resembling more that of old stroke patients than in studies published a few decades ago.^50,51 Figure 1 depicts the prevalence of traditional risk factors in the largest current studies, including young patients with ischemic cerebrovascular events. Most of the traditional risk factors are more prevalent among men and accumulate with age.^28,52

The five most prevalent risk factors reported in studies do not differ from those in the general population and include abdominal obesity—defined as a high waist circumference—(56%), current smoking (37-56%), physical inactivity (48%), hypertension (22-47%), and dyslipidemia (24- 46%).^28,52,53 Diabetes mellitus is relatively rare in young patients (4-10%). However, these studies rarely are population-based, and thus, the true prevalence of each risk factor in early-onset ischemic stroke remains unclear. Further, AF being one of the leading risk factors for stroke in the elderly is rarely detected in young patients, although its prevalence might be slightly underestimated since not systematically screened.⁵⁴

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The strength of the association of traditional risk factors specifically in younger individuals has been assessed by relatively few studies. The associations of hypertension^55-61 and smoking55,57-59,61-63 have been consistently demonstrated, with, however, inconsistent results for diabetes.^55-58,64 In younger patients with type 1 diabetes, the duration of diabetes, higher levels of hemoglobin A1c, presence of diabetic nephropathy, severe diabetic retinopathy, higher systolic blood pressure, and history of smoking were shown to be associated with a higher risk of ischemic stroke.^65,66 Interestingly, compared with older adults, young ischemic stroke patients seem to have a stronger dose-response relationship between active cigarette smoking and stroke.^63,67 Only limited studies have investigated the association between cardiac disease and ischemic stroke at younger ages.^57,58,61 Body mass index (>30 kg/m2) was associated with early-onset ischemic stroke only in a recent population-based case- control study when adjusted for demographic factors, but this association diminished after further adjustment for smoking, hypertension, and diabetes mellitus, suggesting that the effect of obesity may be mediated by these risk factors. However, more recent German nationwide case-control study showed that eight modifiable risk factors combined (hypertension, hyperlipidemia, diabetes mellitus, coronary heart disease, smoking, low physical activity, heavy alcohol consumption, and obesity) explain 79% of all early-onset ischemic strokes.⁶⁸ One study with 145 early-onset cryptogenic ischemic stroke patients showed that 52% of them had a risk factor profile similar to small and large vessel disease (e.g. hypertension, diabetes mellitus, and dyslipidemia) and 3% similar to a cardioembolic subgroup (including lower ejection fractions, larger left atrial sizes, and higher levels of B-type natriuretic peptide).⁶⁹

Data on association between dyslipidemia as well as different lipid variables and early-onset ischemic stroke are scarce. In one case-control study, patients with first-ever ischemic stroke had more often low high-density lipoprotein (HDL) cholesterol levels than stroke-free controls (odds ratio [OR] 1.81 for HDL cholesterol <1.0 mmol/L; 95% CI 1.37-2.40). Interestingly, high low-density lipoprotein (LDL) cholesterol was inversely associated with early-onset ischemic stroke.^56,59 An association between low concentrations of HDL cholesterol and its major protein component, apolipoprotein A- I, and early-onset ischemic stroke has been suggested in other studies as well.^56,59,70 This implies that, given the relatively low prevalence of LAA-related strokes, altered functions of lipid particles other than atherogenic lipoproteins may be more relevant contributors to early-onset stroke, including modulation of platelet function, coagulation, and vascular endothelium.⁷¹

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Figure 1. Frequencies of selected vascular risk factors in the three largest multicenter series of young patients with ischemic stroke. All studies did not uniformly report the entire set of risk factors presented and may have applied different criteria. SIFAP1 (Stroke in Young Fabry Patients) applied an age limit of 18-55 years, 15CYSS (15 Cities Young Stroke Study) an age limit of 15-49 years, and IPSYS (Italian Project on Stroke in Young Adults) an age limit of 18-45 years. *High waist circumference (≥94 cm for men and ≥80 cm for women). BMI, body mass index; TIA, transient ischemic attack.

Data adapted from Putaala J and Martinez-Majander N. Chapter 2 Risk Factors; Ischaemic Stroke in the Young, edited by Tatlisumak T and Thomassen L (2018) Fig. 2.1. p.11, Oxford University Press.

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2.3.2 Less well-documented risk factors

With these factors, evidence is considerably weaker since the results may be inconsistent between studies or dose- and time-dependency might be incompletely shown. Less well-documented risk factors are overall fairly frequent in the healthy population as well.

Cardiac interatrial abnormalities

PFO, a slit-like communication in the interatrial septum, is a fetal remnant that remains functional in approximately 25% of adults based on autopsy studies.⁷² With two thin membranes on both sides of the septum, it can open in certain circumstances, such as during an activity inducing the Valsalva maneuver—resulting in a transient right-to-left shunt in systemic circulation. The maneuver causes right atrial pressure to exceed left atrial pressure, opening the slit, while in normal circumstances the positive left-to-right pressure gradient keeps the membranes closed. PFO can occur with or without atrial septal aneurysm (ASA), which is diagnosed when a fixed displacement or mobile excursion of the fossa ovalis bulges to either one of the atriums.⁷³ After increasing evidence of supporting benefits of PFO closure in secondary prevention after cryptogenic ischemic stroke, however, a term “PFO- associated stroke” was proposed, applicable for all etiological classification systems (TOAST, ASCOD, and CCS).⁷⁴

The best-characterized connection to ischemic stroke is paradoxical embolism, where an embolus from the venous circulation passes through the PFO. Although the association between PFO and cryptogenic stroke has been demonstrated also for older patients (age ≥55 years) in case-control studies, it appears stronger for younger individuals. Compared with patients with a known stroke etiology, in an older study, OR for having a PFO was 4.7 (95% CI 1.9-11.7) among younger patients (<55 years) and 2.9 (95% CI 1.7-5.0) among older patients (≥55 years) with unknown stroke etiology.⁷⁵ Later trials exploring the efficacy and safety of percutaneous closure of PFO to prevent recurrent ischemic strokes in younger IS patients have reinforced the causality of PFO and stroke in cryptogenic ischemic stroke.^76-78 However, PFO may remain only an innocent bystander in a large proportion of patients, documented after completed diagnostic work-up; only in a few cases can the actual paradoxical embolism be detected. This uncertainty of PFO’s role has been studied in several systematic meta-analyses. One of them proposed that the overall probability of PFO being incidental in cryptogenic strokes is 33%, being approximately 20% in patients younger than 55 years and 48%

in patients older than 55 years.⁷⁹

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Several PFO characteristics, such as PFO size, tunnel length, magnitude of the shunt, presence of concomitant ASA, and prothrombotic mutations, have been suggested as factors increasing the PFO- related stroke risk.^80,81 In 2013, a 10-point Risk of Paradoxical Embolism (RoPE) score was introduced, including such variables as age, presence of a cortical stroke on imaging, hypertension, smoking, and diabetes. Score higher than six indicates that the PFO might be pathogenic and closure should be considered.⁸²

Migraine

Migraine is characterized by recurrent unilateral pulsatile headaches lasting 4-72 hours and of moderate to severe intensity. These headaches can be associated with sensitivity to light and sound, nausea, and vomiting. Furthermore, migraine attacks may be preceded by visual, somatosensory, motor, vestibular or speech-related aura.⁸³ The population prevalence of migraine is about 12%, approximately 6% in men and 18% in women—with the highest societal burden in the second, third, fourth, and fifth decades of life.⁸⁴ Comorbidities in migraine include stroke, myocardial infarction, epilepsy, sleep disorders, and depression.⁸⁴ Since the first epidemiological study published in 1975 demonstrating that migraine could be an independent risk factor for stroke,⁸⁵ a number of hospital- based or population-based case-control and cohort studies mostly including young patients have addressed this hypothesis.

Potential mechanisms explaining the increased risk of ischemic stroke in individuals with migraine with aura (MA) include vasospasm in the larger intracerebral arteries, cortical spreading depression leading to cerebral microcirculatory vasoconstriction, endothelial dysfunction, increased platelet aggregation, use of non-steroidal anti-inflammatory drugs, immobilization, and paradoxical embolism via PFO.^86-89 Indeed, studies have also suggested that PFO, migraine, and cryptogenic ischemic stroke are intertwined based on findings that MA is approximately 3-fold more common in individuals with PFO than in those without PFO.^90-92 In cryptogenic ischemic stroke specifically, those patients harboring PFO also more frequently had MA or any type of migraine than patients without PFO.^91-94 Other explanations for the increased risk of ischemic stroke in PFO patients with migraine might be serotonin-induced platelet activation and increased expression of plasminogen activator-1 and suppression of fibrinolysis caused by transient hypoxemia.^86,87 Finally, there might be a shared genetic background that links migraine to several cardiovascular diseases, including ischemic stroke.^95-97 However, evidence for all of these associations and mechanisms is controversial and more research is warranted.

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Meta-analyses have produced different results on the association between migraine and ischemic stroke. Etminan et al. showed that the pooled relative risk for all-aged ischemic stroke (of any subtype) in any type of migraine was 2.2 (95% CI 1.9-2.5), for migraine with aura (MA) 2.3 (95%

CI 1.6-3.2), and for migraine without aura (MO) 1.8 (95% CI 1.1-3.2).⁹⁸ By contrast, Schurks et al.

or Spector et al. found no association for MO (relative risk 1.2; 95% CI 0.9-1.7 and 1.2; 95% CI 0.9- 1.8, respectively).^99,100 Spector et al. included 13 case-control studies and 8 cohort studies with more than 620 000 patients and were able to address several confounding factors such as hypertension, smoking, COCs, cholesterol, cardiac disease, and family history of migraine or stroke. In that study, the pooled adjusted OR for ischemic stroke in patients with any type of migraine was 2.0 (95% CI 1.7-2.4) and for MA 2.3 (95% CI 1.5-3.3).¹⁰⁰ A more recent nationwide, population-based cohort study with approximately 51 000 patients with migraine and 510 000 age- and sex-matched controls showed that migraine was positively associated with ischemic stroke with an adjusted hazard ratio (HR) of 2.3 (95% CI 2.1-2.4).¹⁰¹ In general, risk was higher for MA than for MO, but aura status was available only in 59% of patients. Therefore, based on these studies, especially MA can be considered a risk factor for early-onset ischemic stroke, while MO has been recently proven to be more common, especially in older patients with cryptogenic strokes.¹⁰² Thus far, only three studies have explored the strength of the association between migraine and cryptogenic ischemic stroke specifically (Table 3).

However, these comparisons were not examined independently of known vascular comorbidities.

Furthermore, of these studies one compared cryptogenic ischemic stroke patients with stroke patients with determined etiology and two with stroke-free patients.^102-104

These earlier studies exploring the association between migraine and ischemic stroke may have suffered from small sample sizes, inaccuracies in migraine ascertainment (e.g. based on self-reporting or registries), and not assessing the association in defined subtypes of ischemic stroke. It is also important to recognize that most studies have included mainly women because of their higher migraine prevalence, and therefore, the association is more uncertain in men.

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Table 3. Characteristics of studies assessing the strength of the association between migraine and cryptogenic ischemic stroke. Permission to reproduce parts of the table is granted under John Wiley and Sons’ general terms.

First author (year), Study design

Population/no. of

participants Mean age (±SD) of patients

Confounders and method of assessing confounders

Risk estimate for cryptogenic ischemic stroke

Schwaag (2003)¹⁰³ Case- control

Community- convenience sample.

Cases: n=42 with first cryptogenic ischemic stroke or TIA.

Controls: n=160; age- and sex-matched, enrolled from hospital staff, patients with peripheral trauma, and children waiting for a pediatric appointment.

35.1 (7.4) Diabetes, hyperlipidemia, hypertension, smoking, vascular family history, oral contraception.

Logistic regression

Adjusted OR for any migraine 1.1 (0.5-2.4)

MacClellan (2007)¹⁰⁴ Case- control

Population-based sample.

Cases: n=192 with first ischemic stroke due to undetermined cause;

women who were identified through record linkage.

Controls: n=614; 10- year age- and ethnicity-matched from the same region.

39.2 (7.6) First model: Age, race, geographic region.

Second model: Study period, age, race, geographic region, smoking, diabetes, hypertension, myocardial infarction, oral contraceptive use.

Logistic regression

First model: Adjusted OR 1.6 (1.1-2.3)

Second model: Adjusted OR 1.4 (0.9-2.0)

Li (2015)¹⁰² Case- control

Population-based sample.

Cases: n=668 with first cryptogenic ischemic stroke or TIA.

Controls: n=1142 with ischemic stroke or TIA due to known causes.

70.7

(12.7) Age, sex, hypertension, diabetes, angina, myocardial infarction, peripheral vascular disease, history of smoking,

hypercholesterolemia, previous venous thrombosis, cancer, and autoimmune disease.

Logistic regression

Any migraine: Adjusted OR 1.7 (1.3-2.1) Patients aged <55 y (n=89/70): Unadjusted OR 1.1 (0.6-2.2)

Migraine with aura:

Unadjusted OR 1.8 (1.4- 2.3)

Migraine without aura:

Unadjusted OR 2.1 (1.4- 3.0)

CI, confidence interval; IHS, International Headache Society; OR, odds ratio; TIA, transient ischemic attack

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Estrogen-containing contraceptives

COCs are associated with an increased activity of the fibrinolytic inhibitors plasminogen activator inhibitor (PAI) -1 and -2, an increase in many coagulation factors, and a reduced anticoagulant response.¹⁰⁵ A recent systematic Cochrane review with 24 studies showed an overall increased risk for myocardial infarction or ischemic stroke for COCs with increasing doses of estrogen, with the highest for COCs containing ≥50 ug of estrogen (risk ratio 2.14, 95% CI 1.8-3.3). The overall risk ratio for ischemic stroke was 1.7 (95% CI 1.5-1.9) with no dose-response data available. The risk of myocardial infarction or ischemic stroke did not differ significantly according to the generation of progestagen or to progestagen type.¹⁰⁶

Pregnancy and puerperium

Physiological changes as such may increase the risk of ischemic stroke during pregnancy and puerperium, including increasing levels of clotting factors and fibrinogen throughout pregnancy and decreasing levels in natural anticoagulants. Kittner et al. showed in their study including 46 hospitals in the Baltimore-Washington area that the relative risk of ischemic stroke was up to 8.7 (95% CI 4.6- 16.7) in the postpartum period 6 weeks after delivery, but no elevated risk was present during pregnancy.⁶ Another more recent study with over 1 600 000 women with a first recorded delivery showed that the risk of ischemic stroke during the postpartum period of 6 weeks was significantly higher than in the same period one year later (OR 8.5, 95% CI 4.9-14.8).¹⁰⁷

The most important risk factors for ischemic stroke during pregnancy and puerperium include previously diagnosed conditions such as hypertension, diabetes, cardiac diseases, genetic or acquired coagulopathies, sickle-cell disease, and migraine. Other temporal risk factors comprise complications of pregnancy, including preeclampsia, eclampsia, and gestational diabetes, or complications of labor or delivery, including postpartum hemorrhage, fluid, electrolyte or acid-base disorders, anemia, blood transfusion, and thrombocytopenia.^108,109

Other less well-documented risk factors

Excessive alcohol consumption, both recent and long-term as well as binge drinking, can act as a transient trigger⁵⁸ and as a chronic risk factor^61,110 for ischemic stroke at young ages. With long-term heavy drinking, up to 8- to 15-fold increases in the stroke risk in young patients have been shown.

Mechanisms associated with high alcohol consumption and ischemic stroke include adverse effects

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on fibrinolytics, hemostasis, and blood clotting, and cardiac arrhythmias.¹¹¹ One study also showed that mild-to-moderate alcohol intake might be associated with a lower risk of ischemic stroke in young women.¹¹² This finding was supported by a large systematic review and meta-analysis with 27 prospective studies on ischemic stroke, indicating that light-to-moderate alcohol intake might associated with a lower risk of ischemic stroke, whereas heavy drinking was associated with an increased risk.¹¹³ As discussed in this review, further evidence is needed to better understand the genetic variation in alcohol metabolism and its effect on the risk of stroke, especially in the single- nucleotide polymorphism of the alcohol dehydrogenase 1B gene.

Cannabis, opiates, amphetamine and related substances, and cocaine can cause ischemic stroke by several mechanisms, including direct vasoconstriction, platelet activation, septicemia, and endocarditis. Kaku et al. showed that among young drug abusers the stroke risk was 6.5-fold (95%

CI 3.1-13.6).¹¹⁴ Acute cocaine use, especially crack cocaine, within 24 hours had as high as 6-fold risk of ischemic stroke relative to individuals not using cocaine in one study.¹¹⁵

Heikinheimo et al. showed in their study of 681 young stroke patients that 10.7% had preceding infections within four weeks prior to first-ever ischemic stroke, including upper respiratory tract infections, skin or mucous membrane infections, and gastrointestinal infections.¹¹⁶ However, only a few studies have demonstrated the association between microbial pathogens and ischemic stroke in the young. The best-documented chronic and acute infections include dental infections, chronic and active Chlamydia pneumoniae infection, and human immunodeficiency virus.^117-119 In endemic areas, also tuberculosis, syphilis, and neurocysticercosis must be considered.¹²⁰ Infections may predispose to ischemic stroke by e.g. modifying the platelet function, causing endothelial dysfunction or leading to coagulation disorders.

Antiphospholipid syndrome (APS) or antiphospholipid antibodies alone without fulfilling criteria for APS increase the risk for early-onset ischemic stroke. In APS, two blood samples at least 12 weeks apart should demonstrate the presence of antiphospholipid antibodies, most frequently anticardiolipin antibodies, lupus anticoagulant, or anti-β2 glycoprotein I antibodies. The risk for early-onset ischemic stroke is further amplified when a patient is using COCs or smoking (OR 201.0, 95% CI 22.1-1828.0 and OR 87.0, 95% CI 14.5-523.0, respectively).¹²¹ Other inherited hematologic conditions must also be borne in mind, including sickle cell disease and genetic thrombophilias such as V Leiden G1691A and prothrombin G20210A mutations.¹²² Rare monogenic causes of early-onset ischemic stroke include e.g. MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke), CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and

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leukoencephalopathy), and Fabry disease. However, these or other rare genetic disorders will not be presented in this review in detail.

Furthermore, such risk factors as air pollution, carotid artery webs, and intrinsic coagulation factors combined with COCs warrant more attention in future studies.^123-126 Also preterm birth might be associated with early-onset stroke.^127,128 One longitudinal study including individuals with obstructive sleep apnea suggested a higher stroke risk for women aged ≤35 years than for older age groups and a relatively higher risk for women overall.¹²⁹ There are also incidental reports of the associations of psychosocial distress,¹³⁰ both unipolar and bipolar depression, and anxiety disorders with ischemic stroke at young age.^131,132 Finally, especially in cryptogenic stroke, cancer must be kept in mind. A Finnish study with 1002 young patients showed that 3.9% had cancer-diagnosed prestroke.³⁸ A population-based study from the United Kingdom with 180 000 young cancer patients reported a 50% higher than expected incidence of ischemic stroke.¹³³

Several less well-documented risk factors are listed in Table 4.

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Table 4. Examples of risk factors for ischemic stroke that may be considered specific to young adults.

Table adapted from Putaala, Eur Stroke J (2016)⁵ and updated.

Risk factor Estimated prevalence in patients†

Strength of association‡

Comment

Pregnancy/puerperium⁶ 7.5% in women RR 8.7 during puerperium No significant association shown for pregnancy

Combined oral contraceptives¹⁰⁶

10-40% in women OR 2.4 for pills with ≥50 µg of estrogen vs. non- use

Stronger association with increasing estrogen dose, yet dose- response effect shown only for combined endpoint of myocardial infarction or stroke

Migraine^98-100 20-27% OR 2.3 for migraine with

aura

More consistent association for migraine with aura; Stronger association found for women, smokers, oral contraceptive users, active migraine, and cryptogenic stroke Patent foramen

ovale^134,135

24-50% OR 5.1 for age <55 years No association found in population-based studies

Antiphospholipid antibodies*121,136-141

17-46% Lupus anticoagulant: OR

2.2-43.1 (women);

Anticardiolipin antibodies:

non-significant to OR of 1.8, depending on isotype;

Anti-β2-glycoprotein-I antibodies (cut-off 90^th percentile of control subjects): OR 2.3 (women)

Mixed results; Studied mostly in women;

Stronger association for smokers and oral contraceptive users

Genetic

thrombophilia^142-146

Prothrombin G20210A mutation: 2-6%

Factor V Leiden Arg506Gln mutation:

3-8%

Protein C deficiency:

4-21%

Protein S deficiency: 6- 23%

Antithrombin III deficiency: 0.3-8%

OR 1.5 for prothrombin G20210A mutation for those aged ≤55 years with stronger association for cases ≤42 years (2.5);

Factor V Leiden G1691A mutation: OR 1.4-2.7 depending on patient selection;

Methylenetetrahydrofolate reductase C677T: OR 1.2;

OR not reported for protein C, protein S, and antithrombin III deficiency

Often studied in selected populations;

Heterogeneous and conflicting results between individual studies

Activated intrinsic coagulation proteins¹²⁵

≈50% in women OR for all studied coagulation proteins ≈2.5

Studied in young women (mean age 39

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years); Increasing risk with oral contraceptive use

Periodontitis¹¹⁹ Unknown OR 6.1 for >6 mm attachment loss

Significant association only for patients <60 years; Stronger association for cryptogenic stroke

Long work hours¹⁴⁷ ≈9% RR 1.3 for working ≥55

hours/week

RR is for all stroke;

Dose-response association found

Shift work¹⁴⁸ Unknown RR 1.1

Air pollution¹²⁶ NA OR 1.1 for particulate

matter <10 μm

Case-crossover analysis; Significant association found for individuals aged <55 years but not for those

≥55 years Heavy drinking58,61,149,150 12-59% OR 15.3 for long-term

alcohol consumption of

≥60 g/d

Association might be stronger for younger adults

Illicit drug use115,151-154 9-20% OR 1.2 for cannabis OR 2.6 for cocaine OR 2.2 for amphetamine

Inconclusive results for cannabis and amphetamine; Only frequent use of cocaine significant

*In absence of antiphospholipid antibody syndrome or systemic lupus erythematosus.

OR, odds ratio; RR, relative risk.

†Variability in prevalence is primarily due to selection of cohorts and usually higher for cryptogenic cases.

‡Pooled estimate of the risk if meta-analysis level of data available.

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2.4 Diagnostic work-up

An accurate and timely minimum diagnostic work-up in early-onset ischemic stroke is necessary to target treatment properly, prevent recurrent stroke, and facilitate recovery.¹⁸

Imaging of brain parenchyma and vasculature supplying the brain

The first step in etiological diagnosis of ischemic stroke is imaging of the brain and intra- and extra-cranial arteries, including the aortic arch. In clinical practice and especially in a hyperacute setting, the first imaging is most often performed with CT and, if needed, with a CTA. The radiation dose of a head CT is comparable to approximately 3 months of background radiation.¹⁵⁵ However, with its best sensitivity and spatial resolution, MRI offers improved differential diagnosis,¹⁵⁶ and it should include at least diffusion-weighted imaging (DWI), fluid-attenuated inversion-recovery (FLAIR), and susceptibility-weighted imaging (SWI). It was also shown in systematic reviews that contrast-enhanced magnetic resonance angiography (MRA) is the most specific and sensitive non-invasive modality to exclude intracranial or extracranial arterial abnormalities, such as intramural hematoma, in dissection with axial T1 fat- saturated sequences of the neck.^157,158 As described above, in some cases, e.g. with strong suspicion of RCVS, arterial imaging should be repeated after the first week of symptom onset and also DSA might be necessary if the diagnosis remains unclear. Furthermore, in brain vasculitis, especially in primary angiitis of the central nervous system, biopsy of the leptomeninges and the cortex is still considered the gold standard since with suspected vasculitis high-resolution contrast-enhanced vessel wall imaging is recommended.¹⁵⁹ However, MRI findings might not be specific, and angiography has a low sensitivity and specificity.¹⁶⁰

Clinical examination and laboratory testing

In addition to imaging, patients should be interviewed for full clinical and family history and examined for cardiovascular status, inspecting the skin, extremities, nails, eyes, mouth, and mucous membranes. Stature and deformities should be registered.¹¹¹ Diagnostic work-up in early-onset stroke should include routine blood samples and hypercoagulability testing to exclude disorders such as prothrombin gene mutation and the presence of antiphospholipid antibodies.¹⁶¹ When rarer etiologies as suspected, such as vasculitis, a wider spectrum of blood

Cryptogenic ischemic stroke in young adults : characteristics and less well-documented risk factors