The syndrome of hidden impairments and return to work after mild cerebral stroke

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The syndrome of hidden impairments and return to work after mild cerebral stroke

Georgios Vlachos

Faculty of Medicine University of Oslo

Oslo University Hospital

2023

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© Georgios Vlachos, 2023

Series of dissertations submitted to the Faculty of Medicine, University of Oslo

ISBN 978-82-348-0147-1

reproduced or transmitted, in any form or by any means, without permission.

Print production: Graphics Center, University of Oslo.

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Acknowledgements

I would like to thank all patients and their relatives for their time and great contribution to complete this piece of work. What I have learned from them is priceless. Our conversations and collaboration have helped to become both a better doctor and a better person.

I would like to thank the Department of Geriatric Medicine for giving me the opportunity to enter the researchers’ world and for funding my Ph.D. study. I am also grateful to the former and the current leader of the stroke unit at Ullevål hospital Sigurd Vatn and Hege Ihle-Hansen, the head of the Department of Geriatric Medicine Nina Bjørgill Tallaksen, and the former head of the Department of Neurology Hanne Flinstad Harbo for offering me the flexibility to conduct my research in combination to clinical work.

I am grateful to my main supervisor, Brynjar Fure, for giving me the opportunity to initiate this project, and supporting me all through these 8 years. His availability to answer all my questions even though he has been living and working in Sweden during the last years is highly appreciated. Even covid pandemic has not hindered us from having effective physical and digital meetings.

I wish to thank all my co-supervisors for their support and valuable inputs: Hege Ihle-Hansen, my latest leader at the stroke unit at Ullevål Hospital, for including patients at Bærum Hospital and sharing with me her experience in data collection and paper writing; Torgeir Bruun Wyller for helping me to understand data analysis, and for his valuable comments on my work; Anne Brækhus, for helping me to understand, and get trained in assessment of cognitive tests used in this study; Margrete Mangset, for teaching me how to understand better patients’ world through the eyes of their relatives.

Many thanks to my co-author and my collaborator Charlotta Hamre, for patient inclusion, data collection, and her encouragement and great cooperation during all these years.

I thank physicians, nurses, physiotherapists, and occupational therapists at the stroke units and the stroke outpatient clinics at Oslo University Hospital, Ullevål and Bærum Hospital for their contribution in selecting, examining, and following up the included patients.

Thanks to occupational therapists Elisabeth Kjelgaard, Sonja Aune, and Karla Ascencio at Oslo University Hospital for collecting data and encouraging me all through the study period.

I thank nurse Anne-Mette Brenden contributed by performing cognitive and emotional assessments and following up the patients included at Bærum Hospital.

Many thanks to my colleagues at the Memory Clinic at Ullevål hospital, especially Peter Bekkhus-Wetterberg, for teaching me how to understand and perform cognitive tests, and to colleagues and co-students at Loftet for their valuable inputs.

I am also grateful to Else Charlotte Sandset for all discussions, support, and flexibility that facilitated this work.

Special thanks and respect to Vasilis and Astrid for their love, care, and for being like second parents to me in Norway. I would like to thank Marc and Vibecke, Nikos and Elisa, Antonis and Steinunn for supporting me, and for being valuable friends.

Finally, I cannot be grateful enough to my own family. My lovely wife, Georgia, for supporting me in both bad and good times, encouraging me, and showing patience and understanding.

My beloved daughter Eva, and son Kostas, for making my world brighter, and for giving a real

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meaning to my life. Finally, my sister, my parents, and my parents-, sister- and brothers-in-law for all the support and encouragement.

This long journey has been from time to time tough and frustrating, but mostly exciting, inspirational, and full of learnings. Hopefully, it came to a nice end!

Thank you all!

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Summary

Background: Due to better prevention and acute treatment, the prognosis after stroke has improved during the last years. Most strokes today can be defined as mild, as two out of three patients experience only mild visible impairments. One incentive to initiate this study was our experience from the stroke outpatient clinic, where we observed that several young patients in working age with minimal or no neurological sequelae, reported difficulties involving cognitive functions, such as memory, concentration, attention, planning, and execution of certain actions. Other patients struggled with fatigue, apathy, anxiety, depression, or mood swings. Such impairments, although frequently hidden, can affect both daily activities and family and work life.

Aims: The overall aim of this thesis is to explore and define the syndrome of hidden impairments 12 months after a first-ever mild stroke in persons 70 years of age or younger. It also aims to investigate whether a mild stroke can affect returning to full-time work one year post-stroke, and which factors are associated with staying out of full-time work.

Methods: The study included patients with first-ever ischemic or haemorrhagic stroke admitted to the acute stroke units of Oslo University Hospital, Norway, and Bærum Hospital, Vestre Viken, Norway from December 2014 until December 2016. The patients were aged 18- 70 years, previously cognitively healthy and had suffered mild strokes defined as having a National Institutes of Health Stroke Scale (NIHSS) score ≤ 3 points at discharge.

The diagnosis of stroke was based on the history of symptoms, the findings on the neurological examination, and the findings of an acute infarction or intracerebral haemorrhage on CT or MRI scans.

All participants were invited to a 12-month follow-up at the stroke outpatient clinic, where cognitive and emotional assessments were performed. Patients who suffered a recurrent stroke during the first year after discharge from the stroke unit were not invited to follow-up.

Statistical analyses: In all three papers, table analyses and descriptive statistics were performed. Multiple logistic regression analyses were performed to identify possible predictors for hidden cognitive and emotional impairments 12 months after stroke, and to examine possible factors associated with not returning to full-time work at 12-month follow- up.

Results: In total, 127 patients were included. The mean age was 55.7 years (± 11.3; range 30- 70), and 98 (77%) were male. The mean education length was 15.3 years (± 3.6). Of the included patients, 119 (94%) suffered an ischemic and eight patients (6%) a haemorrhagic stroke. At discharge, the mean NIHSS was 0 (range 0-3), and 77% of the included patients had a modified Rankin Scale (mRS) score ≤ 1. At the 12-month follow-up, 117 patients (92%) attended.

18% of the total sample had neither cognitive nor emotional deficits detectable with our instruments one year after stroke. 39% of the sample had only cognitive, 15% had only emotional, while 28% had both cognitive and emotional deficits after one year. 67% had difficulties with one or a combination of cognitive domains and might have a cognitive impairment 12 months after first-ever mild stroke. 43% of the patients had a score outside the reference range on at least one instrument evaluating anxiety and depression symptoms, fatigue, apathy, and emotional lability.

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Younger age, not working prior to stroke, and having multiple stroke lesions on CT or MRI were significantly related to cognitive impairments after 12 months. Having diabetes mellitus was a borderline significant predictive factor for such impairments. Female sex and a higher NIHSS score at discharge were significantly associated with emotional impairments including anxiety, depressive symptoms, fatigue, apathy, emotional lability after one year, but these associations were only seen in the unadjusted models.

In total, 89 participants were in full-time work at stroke onset, out of those 19% were females, and the mean age was 52.5 (± 10.7) years. At 12-month follow-up, 82 patients (92%) attended.

81% had returned to work, 74% of them to full-time work. Low educational level in years, female sex, and diabetes mellitus were baseline risk factors for not returning to full-time work after 12 months. Moreover, a low functional level (mRS > 1) at follow-up was significantly associated, while a high score on the fatigue scale was borderline significantly associated with not returning to full-time work. Those who did not return to full-time work had also a higher score on the anxiety and depression scale, than those who did, but this relationship was deflated by adjustment for relevant covariates.

Conclusion: Patients in working age with stroke but without obvious neurological symptoms frequently have hidden impairments such as subtle cognitive decline, fatigue, and emotional symptoms one year after first-ever stroke. In addition, younger patients can experience difficulties with returning to paid work one year after suffering a mild stroke. Focus on patients with mild impairments need to be strengthened in stroke units and stroke outpatient clinics.

It is important to offer an evaluation of their cognitive and emotional status by using a wide screening battery during a following period of up to 12 months after stroke. Finally, there is need to evaluate how such identified impairments may affect patients’ social and family life.

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Sammendrag

Bakgrunn: Grunnet bedre forebygging, og bedre og mer avansert akuttbehandling, har prognosen etter hjerneslag blitt bedre de siste årene. De fleste hjerneslag kan i dag defineres som milde, da to av tre pasienter kun opplever milde synlige nevrologiske utfall. Inspirasjon for å sette i gang denne studien fikk vi fra Slagpoliklinikken, hvor vi observerte at flere unge pasienter i yrkesaktiv alder med minimale eller ingen nevrologiske utfall etter et mildt hjerneslag, rapporterte vansker med kognitive funksjoner, som feks. hukommelse, konsentrasjon, oppmerksomhet, og eksekutiv funksjon. Andre pasienter klaget over tretthet, apati, angst, depresjon eller humørsvingninger. Slike utfall er ofte skjult for omgivelser og kan påvirke både pasientenes daglige aktiviteter og familie- og arbeidsliv.

Mål: Det overordnede målet til denne avhandlingen er å utforske og definere syndromet med skjulte utfall 12 måneder etter et førstegangs mildt hjerneslag hos pasienter 70 år eller yngre.

I tillegg undersøker vi om et mildt hjerneslag kan påvirke tilbakevending til fulltidsjobb ett år etter hjerneslag, og evt. hvilke faktorer som påvirker dette.

Metoder: Vi inkluderte pasienter med iskemisk eller hemorragisk førstegangs hjerneslag, innlagt ved slagenheten ved Oslo universitetssykehus og Bærum sykehus, Vestre Viken i perioden fra desember 2014 til desember 2016. Pasientene var i aldersgruppen 18-70 år, kognitivt friske fra før, og var rammet av mildt hjerneslag definert som en score på National Institutes of Health Stroke Scale (NIHSS) på ≤ 3 poeng ved utskrivning fra sykehus.

Diagnosen hjerneslag var basert på symptomene, funn ved nevrologisk undersøkelse og CT- eller MR-funn forenlig med akutt infarkt eller intracerebral blødning. Alle studiens deltakere ble invitert til 12 måneders kontroll ved slagpoliklinikken, hvor det ble utført kognitive og emosjonelle tester. Pasienter som fikk et nytt hjerneslag innen ett år etter utskrivelse fra slagenheten, ble ikke invitert til kontroll.

Statistiske analyser: I alle tre artiklene ble det utført tabellanalyser og deskriptiv statistikk.

Logistiske regresjonsanalyser ble utført for å identifisere mulige prediktorer for skjulte kognitive og emosjonelle utfall 12 måneder etter hjerneslag, og for å undersøke faktorer assosiert med å ikke komme tilbake til fulltids arbeid ved 12 måneders kontroll.

Resultater: Totalt ble 127 pasienter inkludert. Gjennomsnittlig alder var 55,7 år (± 11,3;

rekkevidde 30-70), og 98 (77%) var menn. Gjennomsnittlig utdanningslengde var 15,3 år (±

3,6). Av de inkluderte pasientene hadde 119 (94%) hjerneinfarkt og åtte pasienter (6%) hjerneblødning. Ved utskrivning var gjennomsnittlig NIHSS 0 (0-3), og 77% av de inkluderte pasientene hadde en score på modified Rankin Scale (mRS) ≤ 1. Ved 12 måneders kontroll deltok 117 pasienter (92%).

Ett år etter hjerneslaget påviste vi ingen kognitive eller emosjonelle utfall hos 18% av pasientene. 39% hadde kun kognitive, 15% hadde kun emosjonelle, mens 28% hadde både kognitive og emosjonelle utfall etter ett år. 67% hadde vansker med ett eller en kombinasjon av flere kognitive domener, og kan ha hatt kognitiv svikt 12 måneder etter førstegangs mildt hjerneslag. 43% av pasientene hadde en score utenfor referanseområdet på minst en test som evaluerte angst- og depresjonssymptomer, fatigue, apati og emosjonell labilitet.

Ung alder, å ikke være i arbeid før hjerneslaget og funn av flere slaglesjoner på CT eller MR var signifikant relatert til kognitive utfall etter 12 måneder. Å ha diabetes mellitus var en

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grensesignifikant prediktiv faktor for slike utfall. Kvinnelig kjønn, og en høyere NIHSS-score ved utskrivning var signifikant assosiert med emosjonelle utfall som angst, depressive symptomer, fatigue, apati, emosjonell labilitet etter ett år, men disse assosiasjonene ble bare sett i de ujusterte modellene.

Totalt 89 deltakere var i fulltidsarbeid ved debut av hjerneslag. 19% var kvinner, og gjennomsnittsalderen var 52,5 (± 10,7). Ved 12 måneders oppfølging deltok 82 pasienter (92%). 81% hadde vendt tilbake til arbeid, 74 % av dem til fulltidsarbeid. Lavt utdanningsnivå, kvinnelig kjønn og diabetes mellitus var risikofaktorer for ikke å vende tilbake til fulltidsarbeid etter 12 måneder. Dessuten var lavt funksjonsnivå (mRS > 1) ved oppfølging signifikant assosiert, og høy skår på fatigue skala ved oppfølging grensesignifikant assosiert med ikke å komme tilbake til fulltidsarbeid. De som ikke kom tilbake til fulltidsarbeid hadde også en høyere score på angst- og depresjonsskalaen, men denne assosiasjonen forsvant ved justering for relevante kovariabler.

Konklusjon: Pasienter i yrkesaktiv alder, men uten synlige nevrologiske symptomer etter hjerneslag, har ofte skjulte utfall, som kognitiv svikt, fatigue og emosjonelle symptomer etter ett år. I tillegg kan yngre pasienter oppleve vanskeligheter med å komme tilbake til lønnet arbeid ett år etter et mildt hjerneslag. I slagenheter og slagpoliklinikker bør vi ha mer fokus på pasienter med lettere funksjonsnedsettelse. Det er viktig å tilby en evaluering av slag- rammedes kognitive og emosjonelle funksjoner ved å bruke et bredt testbatteri under en oppfølging som bør strekke seg opp til 12 måneder etter hjerneslag. Vi må også evaluere hvordan slike utfall kan påvirke pasientenes familieliv og sosiale liv.

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List of papers

Paper I

Vlachos G, Ihle-Hansen H, Wyller TB, Brækhus A, Mangset M, Hamre C, Fure B.

Cognitive and emotional symptoms in patients with first-ever mild stroke: The syndrome of hidden impairments.

J Rehabil Med. 2020 Nov 4.

Paper II

Predictors of cognitive and emotional symptoms 12 months after first-ever mild stroke.

Neuropsychol Rehabil. 2022 Feb 24:1-18.

Paper III

Staying out of full-time work 12 months after a mild stroke.

Submitted

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Abbreviations

ADL – Activities of Daily Living

AES-S - Apathy Evaluation Scale-Self report APOE-ε4 - apolipoprotein E-epsilon 4 BMI - body mass index

COWA – Controlled Oral World Association CT - computed tomography

CVLT II – California Verbal Fluency Test

DSM-5 - Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition FSS - Fatigue Severity Scale

GP – General Practitioner

HADS - Hospital Anxiety and Depression Scale

IQCODE - Informant Questionnaire on Cognitive Decline in the Elderly MMSE NR2 – Mini Mental Status Examination Norwegian Revision 2 MRI - magnetic resonance imaging

mRS - modified Rankin Scale score

NIHSS - National Institutes of Health Stroke Scale

OCSP - Oxfordshire Community Stroke Project Classification ROCF – Rey-Osterrieth Complex Figure

TMT – Trail Making Test

TOAST - Trial of ORG 10172 in Acute Stroke Treatment

VASCOG – International Society for Vascular Behavioral and Cognitive Disorders VCI – Vascular Cognitive Impairment

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1 Background

Although stroke can lead to serious functional impairments, the prognosis of stroke has improved during the last years due to better prevention, and acute treatment in stroke units (1) including reperfusion therapy (2) as thrombolysis (3), and mechanical thrombectomy (4).

However, independently of patient’s age and the size of the stroke lesion, cognitive and emotional impairments may occur, with a prevalence of mild cognitive impairment (MCI) of 38% and of dementia up to 20% in a general stroke sample one year after onset (5).

It has been shown that even a mild first-ever stroke may lead to cognitive deficits in patients who are previously cognitively intact (6). It is also shown (7) that dementia can occur in 8.2%

of patients who suffered a minor stroke one year earlier.

These patients may also face emotional impairments, such as anxiety, depression, and apathy (8, 9). Fatigue seems to be common after stroke, with a prevalence of up to 60% (10).

In patients < 65 years of age and patients in working age, female sex, stroke severity, smoking, pre-stroke depression and unemployment at stroke onset can be associated with both anxiety, depression and reduced cognitive function post-stroke (11-13). A cortical stroke localisation can be related to the development of both executive dysfunction, reduced memory, and processing speed (14) by disrupting cortical networks and white matter fibre tract integrity (14), while infarctions in the central brain structures, such as the basal ganglia and the thalami, and in the brain stem can be associated with both fatigue, anxiety, depression, and apathy (15-21). Other studies have shown no relationship between stroke localisation or the type of stroke (ischemic or haemorrhagic) and fatigue (22), depression (23) or apathy (24).

It has also been found that stroke can hinder up to 53% of patients from returning to work one year post-stroke (25). Less neurological deficits, better cognitive ability, greater independence in daily life activities and male sex were predictors of returning to work (25, 26).

One incentive to initiate this study was our own experience from the stroke outpatient clinic, where we observed that several young working patients with minimal or no neurological sequelae after a mild stroke, reported difficulties involving cognitive functions, such as memory, concentration, attention, planning, and execution of certain actions. In addition, some of them struggled with fatigue, indifference or apathy, anxiety, depression, or mood swings. Such hidden outcomes can hinder the patients from returning to normal daily activities and affect both family and work life (27). Due to the lack of visible neurological symptoms and the false impression of total recovery, both patients themselves and people around them have high expectations of returning to their normal daily life (28). Often, they experience lack of understanding of stroke by employers (29) even though 49% of young patients with stroke report fatigue as the only remaining symptom after stroke (28).

Intellectual fulfilment, assistance with finances, non-care activities and social contacts and personalized information about stroke, possible invisible symptoms, and age-adapted rehabilitation interventions are reported as unmet needs for patients (29). Emotional and cognitive symptoms can lead to frustration since the rehabilitation setting does not necessarily acknowledge the different needs of young working patients compared with older (27). Especially, the rehabilitation process can be insufficient in preparing patients for returning to work (30). Generally, younger patients experience a lack of balance between their needs and the health services` philosophy, methods and aims (29). Today, very few stroke

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units and outpatient clinics utilize diagnostic, therapeutic or rehabilitation options for patients with mild or no visible impairments after stroke (31, 32).

1.1 Definition, incidence, classification, treatment, and prognosis of stroke

Stroke has been described since ancient times. The term "apoplexy" (Greek: αποπληξία) was introduced by Hippocrates (ca 460-377 BC) and it meant the "stagnation or blockage of the blood's circulation, whereby all motion and action of the spirit were (suddenly) taken away"

(33). It described several diseases such as stroke, craniocerebral lesions, tumours, and degenerative brain diseases, not always limited to the central nervous system.

According to World Health Organisation (WHO) stroke is defined as “rapidly developed clinical signs of focal (or global) disturbance of cerebral function, lasting more than 24 hours or leading to death, with no apparent cause other than of vascular origin” (34). Stroke has been classified in three main groups: ischemic which is the most frequent accounting for 80-85%, intracerebral haemorrhage accounting for 10-15%, and subarachnoid haemorrhage with <5%.

In 2013, the American Heart Association/American Stroke Association moved towards a tissue-based definition and the stroke concept now includes silent cerebral, spinal, and retinal infarctions, and silent haemorrhages (35, 36). A definition of central nervous system infarction must allow for clinical criteria when neuropathological or neuroimaging data such as computed tomography (CT) or magnetic resonance imaging (MRI) scans either do not provide evidence of infarction or such data are inadequate.

A transient ischaemic attack (TIA) was previously defined as “a sudden, focal neurologic deficit that lasts for less than 24 hours, is presumed to be of vascular origin, and is confined to an area of the brain or eye perfused by a specific artery” (37). The American Heart Association/American Stroke Association has removed the time aspect from the definition, and now a TIA represents “a transient episode of neurological dysfunction caused by focal brain, spinal cord or retinal ischaemia, without acute infarction” (35, 38).

Cerebrovascular disease remains the leading cause of disease burden, the second leading cause of death, and the third leading cause of death and disability combined, in the world (39).

During the last 30 years (1990-2019), we have seen lower stroke incidence rates due to better control of risk factors, especially hypertension and tobacco use, but the absolute number of incident strokes has increased by 70%, the absolute number of prevalent strokes by 85%, and the deaths from stroke by 43% (40, 41). It is also remarkable that both the prevalence and the incidence of stroke in the age group < 70 years have risen by 22% and 15% (41). 61 % of all people who are living with the effects of ischemic stroke are <70 years, while 10% are <44 years of age (40). The rates for haemorrhagic stroke are 67% and 15% in these two age groups, respectively. 5.5 million people die from stroke per year; 39% of them are younger than 70 years, and 4% are under 44 years (40).

On the other hand, age-standardized stroke burden has an increasing tendency in low-income countries, caused by poorer acute stroke health care, poorer stroke awareness, and a high prevalence of vascular risk factors. Generally, the incidence of ischemic strokes is two times higher than the incidence of haemorrhagic strokes (62.4 vs 27.9%), but we can see an increasing incidence of haemorrhagic strokes in low-income countries due to higher hypertension rates (41).

In Norway (42), the most frequent stroke risk factors are hypertension (57%), hyperlipidaemia (38%), atrial fibrillation (25%), smoking 18%), diabetes mellitus (19%), previous TIA (9%), and previous myocardial infarction (13%).

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In Norwegian hospitals (42), the median age of patients admitted to stroke units was 75 years.

46.7% of all stroke patients were ≤74 years and 8.7% ≤55 years. The majority of strokes can be defined as mild, since two out of three patients scored 0-5 points, and 44.5 % scored 0-2 points on the National Institutes of Health Stroke Scale (NIHSS) (43).

In Norway, 21% of all ischemic strokes in 2020 have been treated with thrombolysis, while 5.3% by mechanical thrombectomy. In addition, 95% of patients suffering from stroke have been treated in an interdisciplinary stroke unit.

All this can contribute to the fact that 73% of patients report that they are self-reliant in activities of daily living three months after stroke. Even though 81% of patients report that their need for assistance has been met three months after stroke, only 56% are still at work, and 50% are satisfied with how they are three months after stroke.

1.2 Follow-up after stroke

The 2020 data from the Norwegian Stroke Registry (42) showed that 35% of the patients with stroke were discharged to their own homes without the need for assistance.

Three months after discharge, this percentage increased to 67%, but it was still lower than the proportion of patients (87%) who lived at home without help pre-stroke.

According to the National Norwegian guidelines for cerebral stroke treatment and rehabilitation (44), a follow-up at the outpatient clinic one to three months after stroke onset is recommended. An interdisciplinary approach is preferable, and both stroke nurses, stroke physicians, physiotherapists, and occupational therapists should be involved. The tasks that should be followed up are reviewing secondary prevention, such as the treatment with antihypertensives, statins, and antithrombotic drugs, and the need for further rehabilitation.

If specialised health services are not available for the patients, e.g. due to geography, the general practitioners should take over the follow-up in cooperation with a specialised stroke team.

When extended and more continuous rehabilitation is indicated, patients should be referred to specialist or communal rehabilitation centres, either directly from an acute stroke unit or after a follow-up at an outpatient clinic or general practitioner (GP).

Internationally (45), there are no clear recommendations regarding the duration of the follow-up period, the type of professionals involved in the post-stroke care, and which tasks other than secondary prevention should be followed up.

It is recommended that patients with stroke (32) are examined concerning cognitive impairment, and mood disorders including fatigue and depression during the initial stay in the acute stroke unit, before and after rehabilitation, during follow-up appointments with consulting stroke physicians, and during periodic assessments with GPs. Studies have not concluded on therapeutic options for post-stroke depression, but common antidepressants, especially selective serotonin reuptake inhibitors (SSRIs), are proven to have some positive effects on post-stroke depression (46).

1.3 Cognitive impairment after stroke including definition of cognitive domains, prevalence, diagnostic criteria, and risk factors

The term “Cognition” is defined as the states and processes involved in knowing, which in their completeness include perception and judgment. Cognition includes all conscious and

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unconscious processes by which knowledge is accumulated, such as perceiving, recognizing, conceiving, and reasoning. Put differently, cognition is a state or experience of knowing that can be distinguished from an experience of feeling or willing (Encyclopedia Britannica) (47).

The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) (48) defines key domains of cognitive function: language, learning and memory, complex attention, perceptual motor function, and social cognition, and each of these has subdomains (49) (See Table 1).

Table 1 : Key domains and subdomains of cognitive function

1. Attention and processing speed : sustained attention, divided attention, selective attention, information processing speed 2. Frontal-executive function : planning, decision-making, working memory, responding to feedback/error correction, novel situations, over-riding habits, mental flexibility, judgment

3. Learning and memory : immediate memory, recent memory [including free recall, cued recall], and recognition memory 4. Language : naming, expressive, grammar and syntax, receptive

5. Visuoconstructional-perceptual ability : construction, visual perception, and reasoning

6. Praxis-gnosis-body schema : praxis, gnosis, right/left orientation, calculation ability, body schema, facial recognition 7. Social cognition : recognition of emotions and social cues, appropriate social inhibitions, theory of mind, empathy (Sachdev 2014)

Cognitive impairment that is associated with or caused by vascular factors has been referred to as vascular cognitive impairment (VCI) (50). The concept includes not only multiple cortical and/or subcortical infarcts, but also strategic single infarcts, non-infarction white matter lesions, hemorrhages, and hypoperfusion as possible causes of vascular dementia (51). The temporal relationship between the cognitive decline and the stroke (within the last six months) differentiates post-stroke dementia from other forms of major VCI also referred as vascular dementia (VaD) (51, 52).

The Vascular Impairment of Cognition Classification Consensus Study (VICCCS) guidelines (52) define major VCI (VaD) as clinically significant impairment in at least one cognitive domain that is of sufficient severity to affect instrumental or personal activities of daily living (IADL or PADL) whereas mild VCI is defined as impairment in at least one cognitive domain and mild to no impairment in IADL or PADL (52). The second requirement for mild or major VCI is imaging evidence for cerebrovascular disease. This new definition evolved from the American Heart Association/ American Stroke Association (53) and National Institute of Neurological Disorders and Stroke-Canadian Stroke Network (50) consensus statements, and is in line with DSM-5, which distinguishes between major and minor neurocognitive disorders.

According to current criteria from both the International Society for Vascular Behavioral and Cognitive Disorders (VASCOG) (51), DSM-5 (48), and the International Classification of Disease 11^th (ICD-11) (54), mild neurocognitive disorder is characterised by the subjective experience of a decline from a previous level of cognitive functioning, accompanied by objective impairment in one or more cognitive domains evaluated by validated neuropsychological tests. The presence of memory deficit, which is more typical for Alzheimer`s disease (50, 52), is not required. In patients with vascular cerebral lesions (55), the impairments of executive function and processing speed are more common.

The above-mentioned definitions and criteria of vascular cognitive impairment are attached as Supplementary material.

MCI may be more prevalent than previously shown (5) even among patients with minor stroke (56). It has also been found (57) that the prevalence of mild cognitive impairment but

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no dementia after stroke varies due to heterogeneity in cognitive instruments, used diagnostic criteria, and demographic factors such as educational level, vascular risk factors, and comorbidity. Predictive factors for the development of dementia after stroke have been reported to be older age, low educational level, diabetes mellitus, atrial fibrillation, stroke severity, and stroke in the left hemisphere (58). The presence of any apolipoprotein E-epsilon 4 (APOE-ε4) allele (59, 60) is also found to be associated with cognitive impairment post- stroke. Concerning stroke localisation, it has been reported that cortical infarcts and stroke severity are predictors of cognitive impairments such as executive dysfunction, reduced memory, and processing speed (14). Multiple infarctions and bilateral infarctions in hippocampi and thalami can be associated with both post-stroke cognitive impairment and dementia (61).

1.4 Fatigue and emotional impairments after stroke including definition of domains, prevalence, diagnostic criteria, and risk factors

Fatigue is described as a reversible decrease or loss of abilities associated with a heightened sensation of physical or mental strain, an overwhelming feeling of exhaustion, which leads to inability or difficulty to sustain even routine activities, and which is commonly expressed verbally as a loss of drive (21). Fatigue can be classified as physical, emotional, or cognitive (62). Fatigue can be the only sequela after stroke (21) and is probably the most common hidden impairment after stroke and the one-year prevalence in previous studies has been reported to be up to 60 % (10, 63). Fatigue is not only related to stress due to a recent stroke, comorbidity, or medication (19), but it is related to younger age, unemployment before stroke onset, and executive impairment, depression, anxiety, and stroke severity (10, 19, 21, 22, 28, 64, 65). Studies have shown that stroke localisation in the brain stem, the thalami or the basal ganglia can be associated with post-stroke fatigue(21, 66), while other authors (22) have not found any relation between stroke localisation and fatigue.

Anxiety is taken to mean something that feels uncomfortable, with feelings such as frustration, boredom, worry, despair, and guilt all fitting within this concept. The physical aspect of anxiety is stress, a restlessness, a discomfort. A low level of anxiety is often described as worry or trouble, while a higher level often seems like fear or panic (67).

According to DSM-5, post-stroke depression is a mood disorder superimposed from another medical condition, i.e., stroke with features of depression, mania, or mixed symptoms (48). The diagnosis of post-stroke depression requires having either depressed mood or loss of interest in previously pleasurable activities, along with two to four other symptoms of depression occurring for at least two weeks (46, 48). During the last years the term vascular depression has been used more often. It is regarded to be a subtype of late-life depression due to cerebrovascular damage affecting frontal-subcortical-limbic circuits that regulate emotions in humans (68). The diagnosis may be made based on the presence of subcortical pathology, such as small-vessel ischemia and white matter hyperintensities on MRI scans (32, 69). Patients with vascular depression have higher age at onset, greater cognitive impairment, less family and personal history of depression, and greater physical impairment than geriatric patients with non-vascular depression (70, 71). Previous studies have shown a prevalence of anxiety and depression symptoms 12 months after stroke of up to 30-35 % (67, 69, 72). Age

<65 years, female sex, stroke severity, low functional level, smoking, and pre-stroke

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depression, inability to work and unemployment at stroke onset seem to be associated with anxiety and depression up to three years after stroke (11-13).

Apathy is a syndrome of diminished goal-directed behaviour, emotion, and cognition (73). People present with loss of motivation, concern, interest, and emotional response, resulting in a loss of initiative, decreased interaction with their environment, and a reduced interest in social life (74). The prevalence of apathy post-stroke can be up to 29-40% (24, 74).

Apathy can be present as a distinct entity and concomitant depression can be present in only 40% of patients (74). Some studies have found a relation between subcortical infarctions and apathy (15, 17, 18, 20), while other authors (24) have not shown any relationship between stroke type, i.e. ischemic vs hemorrhagic or affected cerebral hemisphere, and apathy.

Emotional lability, sometimes referred as emotionalism, pathological laughter and crying or emotional incontinence, is characterised by frequent episodes of crying and laughing without feelings of sadness or happiness (75). The persons have difficulty controlling their emotional behaviour. Patients with stroke may suddenly start crying or laughing for no apparent reason (76). The prevalence of emotionalism is 10-15% at one year post-stroke (77, 78). Emotional lability can be associated with stroke localisation (subcortical structures, cerebellum, pons, medulla oblongata), low functional level, and depression after stroke (77, 79).

1.5 Return to work after stroke including definition, prevalence, and risk factors We defined unemployment as not working due to retirement, unemployment, or sick leave. Unemployed persons can have an increased risk of developing poor physical health (80), cardiovascular disease (81), and can develop both depression (82), anxiety (83), and reduced quality of life (84), and therefore returning to work seems to be very important for patients with stroke (29).

Work can for some patients with stroke be a cause of stress and therefore potentially a risk, whereas for others it is a way of demonstrating recovery (85). Psychiatric morbidity and post- stroke fatigue might hinder younger patients from returning to professional activity for as long as two years after first-ever mild stroke (22, 65, 86). It has previously been found that 60 % of patients returned to work two years after stroke (29, 30), the proportion being lower in women than in men (26).

It is also indicated (87) that one out of two patients working full-time pre-stroke were still working full-time one year later, while 27% were no longer in work, and 24% were working fewer hours a week. Predictors of returning to work after stroke were less neurological deficits, better cognitive ability, greater independency in daily life activities, male sex, and high socioeconomic status (25, 88-90). Finally, functional level post-stroke, psychiatric morbidity, fatigue, and depressive and other emotional symptoms can affect returning to work and social participation for as long as two years after first-ever mild stroke (22, 30, 65, 86, 90-92).

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19 1.6 The syndrome of hidden impairments

It is previously shown that even a mild stroke can affect patients’ quality of life and participation in the community due to difficulties in cognitive and executive function (93).

These deficits may be invisible and are therefore frequently overlooked by health workers.

In order to emphasize the importance of recognizing such difficulties, patients with stroke, stroke patients’ organizations and health professionals have introduced the concept of hidden impairments (94) sometimes referred to as the astheno-emotional syndrome (95), which was introduced in 1993 as a disorder within “organic psychiatry” (96). Hidden impairments are proposed to include cognitive and emotional impairments that are not revealed through routine neurological examination or commonly used cognitive and emotional screening instruments (94, 97).

During the last years, stroke physicians all over the world have been more conscious about the importance of identifying and following up patients with such hidden impairments after mild strokes, by interviewing and using well known and established screening tools (32, 45, 62).

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2 Aims of the thesis

- The overall aim of this thesis is to explore and define the syndrome of hidden impairments 12 months after a first-ever mild stroke in persons 70 years of age or younger. It also aims to investigate factors associated with returning to full-time work one year post-stroke.

- More specifically, the aims of each paper are:

1. To study the prevalence of cognitive decline, fatigue, depression, anxiety, apathy, and pathological laughter and crying 12 months after discharge (Paper I)

2. To identify which baseline and stroke characteristics in the acute phase are associated with cognitive and emotional impairments 12 months post-stroke (Paper II) 3. To study whether a mild stroke can affect returning to full-time work 12 months later (Paper III)

4. To explore which factors and variables in the acute phase and at 12-month follow- up are associated with staying out of full-time work 12 months post-stroke

(Paper III)

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3 Materials and methods

3.1 Design

This thesis describes the results from the study “Hidden impairments after cerebral stroke” at Oslo University Hospital, Norway and Bærum Hospital, Vestre Viken, Norway. The study was a prospective, observational, cohort study which followed patients from the acute phase and up to 12 months after inclusion.

3.2 Participants

From December 2014 until December 2016, patients with first-ever ischemic or haemorrhagic stroke admitted to the acute stroke units of Oslo University Hospital and Bærum Hospital, Vestre Viken were included. The patients were aged 18-70 years and had suffered mild strokes defined as having a National Institutes of Health Stroke Scale (NIHSS) (43) score ≤ 3 points at discharge (98).

Patients with pre-stroke cognitive decline as indicated by a score > 3.2 on the short form of the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE) (99), patients who did not speak Norwegian, and patients with known psychiatric disease were not eligible for inclusion. Patients who had previously been diagnosed with dementia or mild cognitive impairment were not included. Patients who suffered a recurrent stroke during the first year after discharge from the stroke unit were not invited to follow-up.

All participants were invited to a 12-month follow-up at the stroke outpatient clinic.

The duration of the sessions was at most two hours. Pauses during the tests were allowed if needed. The cognitive and emotional assessments (see Table 2) were performed by either stroke physicians, occupational therapists, or by a nurse in the stroke units and the stroke outpatient clinics. The professionals carrying out the tests had been trained by physicians with wide experience in that field.

Table 2. Cognitive domains, emotional symptoms and used tests

Cognitive domains, emotional symptoms Used tests

Global cognitive functioning MMSE NR2

Visuoconstructional-perceptual ability

(construction, visual perception, and reasoning) Clock Drawing test ROCF, copy Psychomotor speed

(information processing speed) TMT A

TMT B

COWA Verbal Fluency Test Attention

(sustained attention, divided attention, selective attention) TMT A TMT B

COWA Verbal Fluency Test Executive functioning

(planning, decision-making, working memory, responding to

feedback/error correction, novel situations, over-riding habits, mental flexibility, judgment)

Clock Drawing Test TMT B

COWA Verbal Fluency test ROCF, copy and delayed recall Language ability

(naming, expressive, grammar and syntax, receptive) COWA Verbal Fluency Test Visual memory, verbal memory and learning ability

(immediate memory, recent memory [including free recall, cued recall], and recognition memory)

ROCF, delayed recall CVLT II, total learning CVLT II, short delay, free recall CVLT II, long delay, free recall

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Praxis-gnosis-body schema

(praxis, gnosis, right/left orientation, calculation ability, body schema, facial recognition)

ROCF

Anxiety and depression HADS

Fatigue FSS

Apathy AES-S

Emotional Instability PLACS

MMSE-NR2, Norwegian Revised version 2 of the Mini-Mental State Examination; ROCF, Rey-Osterrieth Complex Figure; TMT, Trail Making Test; COWA, Controlled Oral Word Association; CVLT II, California Verbal Learning Test- II; HADS, Hospital Anxiety and Depression Scale; FSS, Fatigue Severity Scale; AES-S, Apathy Evaluation Scale-Self Report; PLACS, Pathological Laughter And Crying Scale

The forms of ROCF, HADS, FSS, AES-S, and PLACS are attached as Supplementary material.

3.3 Measurements

3.3.1 Baseline characteristics

At admission we recorded patients’ sex, age, educational level as years, employment status (employed or not employed), and marital status (living or not living alone).

Vascular risk factors including hypertension, hyperlipidaemia (cholesterol >5 mmol/I or LDL (low-density lipoprotein)-cholesterol >3 mmol/l), coronary heart disease (myocardial infarction, angina pectoris), atrial fibrillation, cigarette smoking (≥1 cigarette/day), diabetes mellitus (type 1 and 2) and the presence of any APOE-ε4 allele were recorded, and body mass index (BMI) calculated. A diagnosis of atrial fibrillation required electrocardiogram (ECG) confirmation pre-stroke or during the acute hospital stay.

The diagnosis of stroke was based on the history of symptoms, the findings on the neurological examination, and the findings of an acute infarction or intracerebral haemorrhage on CT or MRI scans. Patients with no acute haemorrhagic or ischemic lesions on CT or MRI (eight patients), but with neurological deficits compatible with cerebrovascular disease lasting more than 24 hours, were considered to have an ischemic stroke (34).

Ischemic strokes can be caused by either cardioembolic disease, large vessel disease, small vessel disease, other determined or undetermined etiology (100).

Ischemic strokes can also be classified based on the lesion topography and the clinical symptoms, and the strokes can be defined as either total anterior circulation infarcts (TACI), partial anterior circulation infarcts (PACI), lacunar infarcts (LACI) or posterior circulation infarcts (POCI) (101).

Intracerebral haemorrhagic strokes can be caused by either hypertension, cerebral amyloid angiopathy or secondary to structural lesions such as central venous thrombosis, vessel aneurysms or tumours, and haemorrhagic transformation of ischemic strokes (102).

Finally, strokes can be classified as mild, moderate, or severe according to the severity of symptoms. A mild stroke can be defined as a score of either ≤ 3 or ≤ 5 points (103, 104) in the NIHSS (43). In our study we defined a mild stroke as a NIHSS score of ≤ 3 points (98).

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23 3.3.2 Functional and neurological assessments

Neurological impairments and their severity were assessed by NIHSS (43) at admission, at discharge and at the 12-month follow-up, performed by a stroke physician or a stroke nurse. The NIHSS contains 11 items, each of which scores a specific ability, i.e.

consciousness, eye movement, visual field, facial palsy, limb motor and ataxia, sensory, language and speech and inattention, between zero and four. A higher score is indicative of some level of impairment in that specific ability. Thereby, the total score can be between zero and 42 (43).

General functional level and ADL at discharge and at 12-month follow-up were assessed by the Barthel ADL index (BI) (105, 106) and the modified Rankin Scale (mRS) (106). BI describes ADL-abilities, i.e. eating, toilet use, dressing, bathing, and mobility, i.e. walking and stairs climbing. Each item is rated with zero to one or two, where a higher score is associated with a greater degree of independency and ability to live at home. The total score can vary from zero to 20.

The mRS is a six-level scale ranging from zero indicating no symptoms to six indicating death.

A score between zero and one indicates no significant disability despite some symptoms, and thereby a favourable outcome after stroke.

3.3.3 Cognitive assessment and tools

The information about the pre-stroke cognitive functioning, psychiatric diseases, fatigue due to comorbidities or used drugs, was obtained through asking patients, their dependents, and their family doctors, or by reviewing patients’ hospital medical records. All the patients eligible for inclusion had been asked if they had any objections to us receiving information from their next of kin. We then screened cognitive function in all the stroke patients 70 years or younger admitted to our two stroke units by asking their dependents to fill in the 16-item IQCODE (55, 99), and so we got a clearer impression whether the patient in question was cognitively impaired or not.

The IQCODE lists 16 everyday situations where a person uses hers or his memory and several other cognitive functions, such as executive function and attention. Examples of items are “remembering things about family and friends”, “learning new things in general”, and

“following a story in a book or on TV”. The aim of this questionnaire is to describe any change in each situation for the last ten years. The score range for each item can vary from one point, indicating much improved function, to five, indicating much worse function. The total score is an average of the ratings across all the 16 situations. A person who has no cognitive decline will have an average score of three, while scores of greater than three indicate that some decline has occurred. Various cut-off scores have been used to distinguish dementia from normal functioning. In community samples, cut-off scores for possible dementia have ranged from 3.3 and above to 3.6 and above, while in patient samples the cut-off scores have ranged from 3.4 and above to 4.0 and above (99). A limitation is that this questionnaire is validated for an elderly population (99). Due to the younger age and high educational level of included patients, we used a cut-off of 3.2 (107) to minimize the probability of including patients with a pre-stroke cognitive impairment. Patients who had previously been diagnosed with mild cognitive impairment or dementia were not included.

Patients who met the inclusion criteria were then asked if they would participate in the study. Information about the study itself was provided both orally and in writing via the consent form.

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At the 12-month follow-up, we used an extended test protocol (see Table 2) :

The Mini Mental State Examination Norwegian Revision 2 (MMSE NR2) (108) is a global screening test of cognitive functions, such as orientation, attention and calculation, memory, and complex demands. A total score of 24 out of 30 points indicates a normal cognitive function, but the optimal cut-off values vary with age and educational level. We chose a relatively high score (<27 points) as a cut-off, since most patients were younger than 70 years and well educated (109).

The Clock Drawing test (110) is sensitive for visuospatial and executive functions. The participants are asked to draw a clock reading a specific time (10 minutes past 11). The score can be between five and zero and depends on the ability to put the numbers and the hour and minute hands on the right places. Patients who scored <4/5 points on the Clock Drawing test were considered to be cognitively impaired.

The Trail Making Tests (TMT) A and B (111) were used to assess psychomotor speed and focused or divided attention. In addition, TMT B is sensitive for executive functioning. The patients are asked to draw a line as fast as they can connecting circles containing numbers from one up to 25 for the TMT A, and a line between circles alternating between numbers and letter (1-A-2-B-3-C etc) for TMT-B. Time needed to do so is registered as seconds. We choose a cut-off between normal and pathologic functioning to be correct administration of the TMT A within 60 sec, and the TMT B within 120 seconds. TMT B was interrupted after five minutes (300 seconds) when the participant was not able to complete it during that time.

The Controlled Oral Word Association (COWA) Verbal Fluency test (112) evaluates language ability, psychomotor speed, attention, and executive functioning. The patients should name as many words beginning with letters F, A, S as possible within one minute for each letter.

Performing of the Rey-Osterrieth Complex Figure Test (ROCF) (113) tests memory as well as visuospatial and executive functions, and consists of copying a complex figure, and after a short delay reproduce it from memory. After a longer delay of about 20 minutes, the persons are asked to redraw the figure from memory. The copy and the second drawing are scored for the reproduction and placement of 18 design elements.

For the assessment of learning ability and memory, we used the California Verbal Learning Test II (CVLT II) (114) where patients try to learn a 16-words list from four unrelated semantic categories, and to recall it after 20 minutes.

According to the International Society for Vascular Behavioural and Cognitive Disorders (VASCOG) criteria (51) for the diagnosis of cognitive impairment, mild cognitive disorder can be present when the performance on objective validated cognitive tools in one or more cognitive domains (attention, processing speed, executive function, learning and memory, language, visuocontructional-perceptual ability, praxis-gnosis-body schema, social cognition) is in the range between 1 and 2 standard deviations (SD) below appropriate norms.

Due to the evidence for age-related and, in some tests, gender-related differences on cognitive test scores, we chose to convert raw scores into standardized scores [mean 50;

standard deviation (SD) 10] separately for each gender and age category for CVLT II, for age for ROCF, and for age and education level for COWA and the Trail Making tests. Impairment of each cognitive domain was defined as a score of at least one standard deviation (SD) below appropriate normative sample according to the test manuals used by the Norwegian Registry of Persons Assessed for Cognitive Symptoms in Specialist Health Care services (NorCog).

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25 3.3.4 Emotional assessment and tools

The presence of anxiety and depression symptoms was evaluated by using the 14-item Hospital Anxiety and Depression Scale (HADS) (115). Each anxiety and depression subscale contains seven items. Each item is scored from zero to three points, and the total score for each subscale can vary from 0 to 21. The cut off was >7 points for each of the two domains depression and anxiety.

Fatigue is evaluated by the 9-item Fatigue Severity Scale (FSS) (10, 116) which is a widely used instrument in stroke studies. It contains nine items where the subjects state to which extent fatigue has affected their physical, social, and cognitive functioning in the last seven days. Each item is scored from one (strongly disagree) to seven points (strongly agree).

The average score is calculated, and the presence of post-stroke fatigue was defined as the well-established cut-off of ≥ 4 points.

The Apathy Evaluation Scale-Self report (AES-S) (117) was used to assess the presence and severity of post-stroke apathy. It consists of in total 18 behavioural, cognitive, and emotional items, where the score for each of them can vary from one to four points, giving a total score between 18 and 72 points. Patients with a score ≥ 34 points were classified as having clinically relevant apathy.

The Pathological Laughter and Crying Scale (PLACS) (75) was used to assess the presence of emotional lability characterized as uncontrolled laughter or crying in appropriate situations. In total it contains ten laughter-related items, and eight crying-related items. The score for each item could be from 0 (rarely or not at all or very brief) to three (frequently or prolonged). The total score can vary from zero to 54, and the cut-off is set to ≥13 points.

3.4 Statistical analyses

The Statistical Package for Social Sciences (SPSS), versions 25.0 (paper I), 26.0 (paper II), 27.0 (paper III), and 28.0 (paper II and III), was used for all statistical analyses. In all three papers, table analyses and descriptive statistics were performed and descriptive data are presented with means and standard deviations (SD) for continuous variables, and with proportions and percentages for categorical variables. The rating scale scores with highly skewed data distributions are represented with median and range.

In paper II, to identify possible predictors for hidden impairments, we performed logistic regression analyses separately for cognitive and emotional impairments as dependent variables. Regression analyses were not performed for the combined outcome “cognitive and emotional impairments”, because this occurred too rarely (32 cases) to perform a robust multivariate analysis. First, an unadjusted regression analysis was performed for each variable.

The explanatory variables included baseline characteristics (age, sex, marital state, employment status, educational level, hyperlipidaemia, cardiovascular disease, smoking, diabetes mellitus, hypertension, atrial fibrillation, BMI, APOE-ε4 allele), stroke characteristics, i.e. reperfusion therapy, infarction or bleeding, localisation (right hemisphere, left hemisphere, cerebellum/brainstem, multiple brain regions, no acute lesions), TOAST and OCSP classifications, and functional level at discharge from hospital (NIHSS, mRS, Barthel score).

Age, sex, and variables associated with the outcome with a p-value <0.2 were then entered into multivariable logistic regression models (one for each of the two outcomes).

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Potential explanatory variables for the cognitive impairment outcome were not working at admission, BMI, diabetes mellitus, stroke location in the left hemisphere, multiple infarctions and mRS>1 at discharge, whereas for the emotional impairment outcome, potential explanatory variables were OCSP subtype LACI, NIHSS at discharge, BI at discharge and mRS>1 at discharge.

Paper III: Logistic regression analyses were performed separately in order to identify possible risk factors (“risk factors model”) and associated factors (“associations model”) for the dependent variable of not returning to full-time work 12 months after a mild stroke. First, unadjusted regression analyses were performed using baseline characteristics, stroke characteristics such as subtype, i.e. infarction or bleeding, location, TOAST classification, and functional level expressed as NIHSS, mRS, BI at discharge from hospital, treatment with intravenous thrombolysis and thrombectomy, as independent variables for the “risk factors model”. The functional level, presence of cognitive impairment, and the scores on the anxiety, depression, fatigue, and apathy scales at 12-month follow-up were used as independent variables in unadjusted regression analyses for the “associations model”.

Age, sex, and variables associated with the outcome with a p-value <0.2 in unadjusted analyses were then entered into multivariate logistic regression models (one for each of the two models). Potential explanatory variables for the “risk factors model” were age, sex, educational level in years, diabetes mellitus, treatment with thrombectomy, NIHSS at discharge and mRS>1 at discharge. For the “associations model”, potential explanatory variables were mRS>1 and the scores on the anxiety, depression, and fatigue scales at 12- month follow-up.

Regarding the use of the anxiety, depression, fatigue, and apathy scales, we decided not to dichotomize these variables, but to use the raw scores in order not to lose information and statistical power (118).

In paper II and III, both unadjusted and adjusted logistic regression analyses were carried out.

In multivariate regression analyses, it is recommended to use one independent variable per five to ten events (118), and we chose to limit the number of explanatory variables in each regression model to six and eight in paper II and to seven and four in paper III. Results are presented as odds ratio (OR) with 95% confidence interval (CI). p<0.05 was considered as statistically significant.

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4 Results

The flowchart (Figure 1) and Table 3 describe the inclusion process and baseline characteristics of the participants.

In paper III, the extra inclusion criterion was being in full-time work at stroke onset, which was met by 89 participants (see Table 4).

In total, 127 patients with first-ever ischemic or haemorrhagic stroke admitted to the acute stroke units of Oslo University Hospital (99 patients) or Bærum Hospital (28 patients), were included. We aimed for an inclusion period of two years due to the financial situation of the project. Mean age was 55.7 years (SD 11.3; range 30-70), and 98 (77%) were male. The mean education length was 15.3 years (SD 3.6). 71% of the patients had hyperlipidaemia, 47% had hypertension, and 26% were smokers. Of the included patients, 119 (94%) suffered an ischemic and eight patients (6%) a haemorrhagic stroke. At discharge, the mean NIHSS was 0 (range 0-3), and 77% of the included patients had mRS ≤ 1. One included patient had expressive aphasia at discharge diagnosed by a speech therapist.

At the 12-month follow-up, 117 patients (92%) attended, and they were evaluated in Paper I and II. During the first post-stroke year, four patients suffered a recurrent stroke and were not invited to the follow-up, one patient died from cardiac disease and five patients did not wish to complete the follow-up period.

Figure 1. Flowchart showing the inclusion of patients

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Table 3. Baseline characteristics of all patients (paper I-II). Mean ± standard deviation (SD) for continuous data, n (%) for categorical data, unless otherwise specified.

Baseline characteristics Total sample

N=127 Male

n=98 Female

n=29

Variables

Demographics

Age (range) 55.7 ± 11.3 (30-70) 56.5 ± 10.7 (31-70) 53.4 ± 12.9 (30-69)

Age group 18-39 years 13 (10) 10 (10) 3 (10)

Age group 40-59 years 55 (43) 42 (43) 13 (45)

Age group 60-70 years 59 (47) 46 (47) 13 (45)

Education in years 15.3 ± 3.6 15.5 ± 3.5 14.5 ± 3.9

Risk factors

Hypertension 59 (47) 50 (51) 9 (31)

Hyperlipidaemia (total cholesterol>5 or LDL> 3mmol/l) 90 (71) 76 (78) 14 (48)

Coronary disease (myocardial infarction, angina pectoris) 14 (11) 14 (14) 0 (0)

Atrial fibrillation 11 (9) 10 (10) 1 (3)

Cigarette smoking (≥ 1 cigarette/day) 33 (26) 27 (27) 6 (20)

Diabetes mellitus 15 (12) 14 (14) 1 (3)

BMI 26.9 ± 4.4 27.4 ± 4.4 25.4 ± 4.1

Stroke subtype

Ischemic 119 (94) 92 (94) 27 (93)

Hemorrhagic 8 (6) 6 (6) 2 (7)

TOAST classification (ischemic strokes)

Large vessel disease 20 (17) 16 (18) 4 (15)

Cardio embolic disease 32 (27) 26 (28) 6 (22)

Small vessel disease 33 (28) 28 (30) 5 (19)

Stroke of other determined etiology 3 (2) 1 (1) 2 (7)

Stroke of undetermined etiology 31 (26) 21 (23) 10 (34)

OCSP classification at admission (ischemic strokes)

Total anterior circulation infarct (TACI) 4 (3) 3 (3) 1 (4)

Partial anterior circulation infarct (PACI) 53 (45) 39 (42) 14 (52)

Lacunar infarct (LACI) 27 (23) 21 (23) 6 (22)

Posterior circulation infarct (POCI) 35 (29) 29 (32) 6 (22)

Topography, MR/CT-findings

Right hemisphere 46 (36) 38 (39) 8 (28)

Left hemisphere 36 (28) 24 (25) 12 (41)

Cerebellum/brainstem 20 (16) 14 (14) 6 (21)

Multiple brain regions 17 (13) 15 (15) 2 (7)

No acute lesions on CT or MRI 8 (6) 7 (7) 1 (3)

Assessments

NIHSS day 1, median (range) 1 (0-22) 1 (0-22) 1 (0-8)

NIHSS at discharge, median (range) 0 (0-3) 0 (0-3) 0 (0-3)

mRS at discharge, median (range) 1 (0-4) 1 (0-4) 1 (0-4)

mRS 0-1 at discharge 98 (77) 76 (78) 22 (76)

Barthel Index at discharge (range) 19.7 ± 1.1 (11-20) 19.7 ± 1.1 (11-20) 19.7 ± 1.3 (13-20)

Cognitive assessments

IQCODE 3.02 ± 0.07 3.03 ± 0.08 3.01 ± 0.03

LDL, low-density lipoprotein; BMI, body mass index; TOAST, Trial of Org 10172 in Acute Stroke Treatment; OCSP, Oxfordshire Community Stroke Project Classification; NIHSS, National Institutes of Health Stroke Scale; mRS, modified Rankin Scale; IQCODE, Informant Questionnaire on Cognitive Decline in the Elderly

The syndrome of hidden impairments and return to work after mild cerebral stroke