University of Groningen The impact of the invisible Buunk, Anne Marie

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The impact of the invisible

Buunk, Anne Marie

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Buunk, A. M. (2019). The impact of the invisible: Cognitive deficits, behavioral changes, and fatigue after

subarachnoid hemorrhage. Rijksuniversiteit Groningen.

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Cognitive deficits, behavioral changes,

and fatigue after subarachnoid hemorrhage

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The impact of the invisible

Cognitive deficits, behavioral changes, and fatigue

after subarachnoid hemorrhage

Proefschrift

ter verkrijging van de graad van doctor aan de Rijksuniversiteit Groningen

op gezag van de

rector magnificus prof. dr. E. Sterken en volgens besluit van het College voor Promoties.

De openbare verdediging zal plaatsvinden op woensdag 23 januari 2019 om 16.15 uur

door

Anne Marie Buunk

geboren op 11 juni 1988

te Groningen

This research was financially supported by Stichting Catharina Heerdt.

ISBN digital version

978-94-034-1311-2

ISBN printed version

978-94-034-1312-9

Design cover illustration

Emma Leever

Design/lay-out

Wendy Bour-van Telgen, Ipskamp Printing, Enschede

Print

Ipskamp Printing, Enschede © Anne Marie Buunk, 2018

All rights are reserved. No part of this book may be reproduced, distributed, stored in a retrieval system,or transmitted in any form or by any means, without prior written permission of the author.

The impact of the invisible:

Cognitive deficits, behavioral changes,

and fatigue after subarachnoid hemorrhage

Proefschrift

op gezag van de

door

Anne Marie Buunk

geboren op 11 juni 1988 te Groningen

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The impact of the invisible

Cognitive deficits, behavioral changes, and fatigue

after subarachnoid hemorrhage

Proefschrift

op gezag van de

door

Anne Marie Buunk

geboren op 11 juni 1988

te Groningen

The impact of the invisible:

Cognitive deficits, behavioral changes,

and fatigue after subarachnoid hemorrhage

Proefschrift

op gezag van de

door

Anne Marie Buunk

geboren op 11 juni 1988 te Groningen

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Paranimfen

M.E. Buunk M.A. Coenen

Beoordelingscommissie

Prof. dr. G.H.M. Pijnenborg Prof. dr. G.J.E. Rinkel Prof. dr. J.M.A. Visser-Meily

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Chapter 2 Leisure and social participation in patients 4–10 19 years after aneurysmal subarachnoid hemorrhage

Chapter 3 Mental versus physical fatigue after subarachnoid 43 hemorrhage: differential associations with outcome

Chapter 4 Cognitive deficits after aneurysmal and angiographically 63 negative subarachnoid hemorrhage: memory, attention, executive functioning, and emotion recognition

Chapter 5 Social cognition impairments after aneurysmal 89 subarachnoid hemorrhage: associations with

deficits in interpersonal behavior, apathy, and impaired self-awareness

Chapter 6 Return to work after subarachnoid hemorrhage: 121 the influence of cognitive impairments

Chapter 7 General discussion 143

Nederlandse samenvatting (Summary in Dutch) 163

Dankwoord 169

List of Publications 178

Curriculum Vitae 179

Beoordelingscommissie

Prof. dr. G.H.M. Pijnenborg Prof. dr. G.J.E. Rinkel Prof. dr. J.M.A. Visser-Meily

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Introducing subarachnoid hemorrhage

A subarachnoid hemorrhage (SAH) is a severe bleeding in the subarachnoid space, between the pia mater and the arachnoid membrane. In the majority of cases, SAH is characterized by the rupture of an intracranial aneurysm, defined as aneurysmal SAH (aSAH). In 15% of the cases of SAH, no structural cause for the hemorrhage can be detected, typed as angiographically negative SAH (anSAH). SAH accounts for only 3-5% of all strokes, but is the type of stroke with the highest morbidity and mortality rates (Feigin, Lawes, Bennett, Barker-Collo, & Parag, 2009). The incidence of SAH in the Netherlands is between 5 and 7 cases per 100,000 per year (Risselada et al., 2011). A SAH still carries a case fatality of approximately 35%, despite the fact that this is reduced during the past thirty years, mostly because new diagnostic techniques and therapeutic interventions have emerged (Rinkel & Algra, 2011). Generally, aSAH is treated by either endovascular treatment (coiling and/or stenting) or microsurgical occlusion (clipping or wrapping) of the aneurysm.

A sudden severe headache is the most distinctive symptom of SAH. Other symptoms are neck stiffness, nausea, photophobia, focal neurological deficits or unconsciousness. Main complications are acute hydrocephalus, rebleeding, and vasospasm, with possible delayed cerebral ischemia (van Gijn, Kerr, & Rinkel, 2007). Acute hydrocephalus is generally treated with an external ventricular drain or external lumbar drain. Hydrocephalus that persists beyond the acute stage, i.e. chronic hydrocephalus, requires cerebrospinal fluid (CSF) shunting.

Emotional, cognitive, and behavioral consequences

SAH has a great impact both on the patient and relatives. Cognitive impairment may occur in up to 83% of cases, with main cognitive domains being affected: memory, attention, and language (Al-Khindi, Macdonald, & Schweizer, 2010; Kapadia, Schweizer, Spears, Cusimano, & Macdonald, 2014). However, most of the studies on post-SAH cognitive functioning have focused on patients after aneurysmal SAH, not after angiographically negative SAH. In general, it is suggested that cognitive deficits can remain over years. Cognitive impairment has been associated with clinical features such as hydrocephalus and delayed cerebral ischemia (Ogden, Mee, & Henning, 1993) and demographic variables

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such as high age and low education (Kreiter et al., 2002).

Next to objective cognitive deficits as assessed with neuropsychological tests, SAH patients report a wide range of cognitive complaints, such as forgetfulness or planning problems. Furthermore, behavioral problems are often mentioned after SAH, for example apathy (Marin, Biedrzycki, & Firinciogullari, 1991) and inadequate social behavior (Ogden, Utley, & Mee, 1997; Storey, 1970). These behavioral problems are usually measured with self-report questionnaires, but could possibly also be examined using neuropsychological assessment.

Lastly, mood disorders, sleep disturbances and fatigue are major post-SAH consequences (Kutlubaev, Barugh, & Mead, 2012; Rinkel & Algra, 2011; Schuiling, Rinkel, Walchenbach, & de Weerd, 2005). Reported frequencies of fatigue are high (up to 90%) and the numbers vary depending on the instrument used and timing of testing. Depression and anxiety are common after SAH, with prevalence rates up to 54% (Al-Khindi, Macdonald, & Schweizer, 2010; Boerboom, Heijenbrok-Kal, Khajeh, van Kooten, & Ribbers, 2016; Caeiro, Santos, Ferro, & Figueira, 2011; Hedlund, Zetterling, Ronne-Engstrom, Carlsson, & Ekselius, 2011), and presence of symptoms even in the chronic stage post-SAH (Ackermark et al., 2017; von Vogelsang, Forsberg, Svensson, & Wengstrom, 2015). Additionally, post-traumatic stress disorder (PTSD) has been described in SAH patients, with rates varying between 18% and 34% (Huenges Wajer et al., 2018; Hutter & Andermahr, 2014; Hutter, Kreitschmann-Andermahr, & Gilsbach, 2001; Noble et al., 2011; Visser-Meily et al., 2013).

Functional outcome

As SAH usually occurs at a relatively young age (mean age of 55 years), post-SAH consequences may influence daily functioning for many years (de Rooij, Linn, van der Plas, Algra, & Rinkel, 2007). Although recovery to functional independence is common, many patients still experience a reduced Quality of Life (QoL) (Hackett & Anderson, 2000; Hop, Rinkel, Algra, & van Gijn, 2001). Furthermore, return to work is seriously affected after SAH; up to two-thirds of all patients are unable to return to their pre-SAH employment (Passier, Visser-Meily, Rinkel, Lindeman, & Post, 2011; Powell, Kitchen, Heslin, & Greenwood, 2004). Also, changes in social participation and leisure activities have been reported (Carter, Buckley, Ferraro, Rordorf, & Ogilvy, 2000; Johansson, Hogberg, &

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Bernspang, 2007). Different factors have been related to problems in everyday life functioning, such as cognitive complaints, mood disorders, and behavioral disturbances (Carter et al., 2000; Morris, Wilson, & Dunn, 2004; Ogden et al., 1997; Vilkki, Juvela, Malmivaara, Siironen, & Hernesniemi, 2012).

Aneurysmal SAH versus angiographically negative

SAH

Traditionally, anSAH has been regarded as a benign entity, considering the good overall neurological outcomes and low risk of rebleeding (Rinkel et al., 1991; Ruelle, Lasio, Boccardo, Gottlieb, & Severi, 1985). More recently, persistent complaints of fatigue, mood disorders, and behavioral problems have been found after anSAH (Alfieri et al., 2008; Canhao, Ferro, Pinto, Melo, & Campos, 1995; Marquardt, Niebauer, Schick, & Lorenz, 2000). Studies on the cognitive consequences of anSAH show conflicting results; some authors reported cognitive functions in the normal range (Germano et al., 1998; Krajewski et al., 2014), others found evidence for cognitive impairment post-anSAH (Boerboom, Heijenbrok-Kal, Khajeh, van Kooten, & Ribbers, 2014; Hutter, Gilsbach, & Kreitschmann, 1994; Sonesson, Saveland, Ljunggren, & Brandt, 1989). Also, two studies revealed problems in the resumption of daily activities after anSAH, comparable to those after aSAH (Alfieri, Gazzeri, Pircher, Unterhuber, & Schwarz, 2011; Canhao et al., 1995).

Higher-order prefrontal cognitive functions

Although behavioral disturbances, such as apathy and inadequate social behavior, are frequently reported after SAH, the underlying mechanism is unclear. Over thirty years ago, Brooks (1984) already recognized the need to investigate behavioral consequences of brain injury. He argued that especially behavioral problems negatively affect everyday life functioning and cause stress for families and caregivers. Over the course of years, researchers have shown an increased interest in the assessment and treatment of these behavioral disturbances. Specifically, recent studies have focused on the underlying neuropsychological mechanisms of these problems and concentrated on the objective neuropsychological assessment of social behavioral changes. This

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has led to the hypothesis that impairments in so called higher-order prefrontal cognitive functions, executive functions and social cognition, may underlie changes in behavior and social competence.

Executive functions comprise those mental capacities needed to initiate, monitor, and regulate complex, goal-directed behavior (Lezak, 1995). These capacities allow us to adapt to new, unstructured situations. Symptoms of executive dysfunction are for instance impulsivity, impaired abstract thinking, poor decision making, and perseveration (Burgess & Simons, 2005). Social cognition is defined as the ability to understand others’ behavior and react adequately in social situations (Adolphs, 2001; Lieberman, 2007). Different aspects can be distinguished, such as the recognition of facial emotional expressions and understanding someone else’s behavior and intentions. A distinction is often drawn between ‘hot’ social cognition, that is the ability to understand others’ emotional states and to show empathy, and ‘cold’ social cognition, that is thinking about something from another person’s point of view (Blair, 2003). An important aspect of cold social cognition is Theory of Mind (ToM): the ability to understand behavior of others, based on their feelings, beliefs, intentions, and experiences. Deficits in social cognition can manifest themselves in several ways; symptoms are for example inappropriate behavior, an inability to show empathy or diminished interest in others.

The prefrontal cortex, as a part of cortical-subcortical circuits, plays a key role in both executive functions and social cognition, hence the name ‘higher-order prefrontal cognitive functions’. More specifically, the dorsolateral prefrontal cortex is important for executive functions and the orbitofrontal and ventromedial prefrontal cortices are mainly involved in social cognition (Lichter & Cummings, 2001). However, these prefrontal areas are largely overlapping regions, and executive functions and social cognition are not solely located in the frontal areas of the brain (Tekin & Cummings, 2002). Therefore, it is interesting to investigate the relationship between higher-order cognitive functions and focal (frontal) as well as diffuse brain damage.

General aim and outline of this dissertation

The main objective of this thesis is to investigate several neuropsychological consequences of subarachnoid hemorrhage, namely cognitive impairments, behavioral problems, and fatigue, and to define their mutual relationship with

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long-term outcome. Specifically, this project set out to examine impairments in higher-order prefrontal cognitive functions, social cognition and executive functions, after SAH. A better characterization of post-SAH consequences and their predictive value leads to a better understanding of the nature of disturbances and consequently, can lead to better treatment methods.

First, a general introduction to the subject is given (Chapter 1). In

chapter 2, a study on long-term resumption of leisure and social activities is presented, focusing on the influence of executive complaints and lesion location.

Chapter 3 presents a study on two major characteristics of fatigue (mental and physical fatigue) and their relationship with long-term functional outcome after SAH. Chapter 4 comprises a description of the cognitive consequences of SAH and comparisons between aSAH and anSAH, focusing on higher-order prefrontal functions. Subsequently, we present a study on a broad range of aspects of social cognition after aSAH in chapter 5. In this chapter, relationships between behavioral disturbances and focal as well as diffuse brain damage will also be described. The predictive value of cognitive functions for return to work is studied in chapter 6. Chapter 7 is a general discussion of the preceding articles, with final conclusions and implications of our findings.

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W. (2013). Post-traumatic stress disorder in patients 3 years after aneurysmal subarachnoid haemorrhage. Cerebrovascular Diseases (Basel, Switzerland), 36(2), 126–130. https://doi. org/10.1159/000353642 [doi]

von Vogelsang, A.-C., Forsberg, C., Svensson, M., & Wengstrom, Y. (2015). Patients Experience High Levels of Anxiety 2 Years Following Aneurysmal Subarachnoid Hemorrhage. World Neurosurgery, 83(6), 1090–1097. https://doi.org/10.1016/j.wneu.2014.12.027

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Leisure and social participation in

patients 4–10 years after aneurysmal

subarachnoid hemorrhage

Anne M. Buunk1 Rob J. M. Groen2 Wencke S. Veenstra2 Jacoba M. Spikman1

1_{Department of Neuropsychology and}2_{Department of Neurosurgery,} University of Groningen, University Medical Center Groningen, The Netherlands

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Abstract

Objective. To investigate the long-term resumption of leisure and social activities in patients with aneurysmal subarachnoid hemorrhage (aSAH) and to determine the role of executive dysfunction and aneurysms in anterior brain regions in particular.

Methods. Leisure and social functioning of 200 patients with aSAH having anterior or posterior aneurysms was determined using the Role Resumption List (RRL). Executive functioning was investigated using the Dysexecutive Questionnaire (DEX) and sub-scales Social Convention (SC) and Executive Cognition (EC). Mood, fatigue and cognitive problems were investigated with the Hospital Anxiety and Depression Scale (HADS) and Brain Injury Symptom Checklist (BISC).

Results. Of all patients, 46.5% reported complete return to previous leisure activities and 61.5% reported no changes in social interactions. HADS depression score, fatigue, DEX-EC sub-scale score and work status post-aSAH were predictors of leisure resumption. For social reintegration, HADS depression score, cognitive problems and fatigue were predictors. Aneurysm location did not influence leisure and social re-integration.

Conclusions. A substantial number of the patients still experience problems in resuming previous activities in the chronic phase post-aSAH, influenced by cognitive, executive and depressive problems, as well as current work status and fatigue. Aneurysm location does not seem to influence this resumption.

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Introduction

Aneurysmal subarachnoid hemorrhage (aSAH) accounts for only 3–5% of all strokes, but is associated with the highest mortality and morbidity (Rinkel & Algra, 2011). Occurring at a relatively young age with a peak incidence between 40–60 years, aSAH has a major, long-lasting influence on patients’ daily functioning (de Rooij, Linn, van der Plas, Algra, & Rinkel, 2007). Many survivors experience physical, cognitive, emotional, social and vocational problems, even with relatively good neurological outcome (Al-Khindi, Macdonald, & Schweizer, 2010; Dombovy, Drew-Cates, & Serdans, 1998; Fertl et al., 1999; Passier et al., 2012; Visser-Meily et al., 2013). The influence of bleeding location on these problems is not clear (Carter, Buckley, Ferraro, Rordorf, & Ogilvy, 2000; Hutter, Kreitschmann-Andermahr, & Gilsbach, 2001; Kreiter et al., 2002; Manning, Pierot, & Dufour, 2005; Passier et al., 2010).

In the assessment of functional outcome after brain injury, work resumption is an important component in the definition of ‘good recovery’. However, leisure participation and social activities may also provide substantial contributions to this definition. In patients with stroke, restricted social-recreational activity was found to have several negative effects, such as reduced Quality-of-Life (QoL) and social isolation (Mayo, Wood-Dauphinee, Cote, Durcan, & Carlton, 2002). Bhogal et al. (Bhogal, Teasell, Foley, & Speechley, 2003) even found that failure to resume leisure activities was a major determinant of worse post-stroke functioning. Also, diminished social and leisure participation is related to lower life satisfaction in patients with traumatic brain injury (TBI) (Eriksson, Kottorp, Borg, & Tham, 2009).

Until now, changes in leisure and social participation were predominantly investigated and found in patients with stroke and TBI (Engberg & Teasdale, 2004; Hartman-Maeir, Soroker, Ring, Avni, & Katz, 2007; Johansson, Hogberg, & Bernspang, 2007; T. W. Teasdale & Engberg, 2005). Similar changes were found in patients with aSAH, but only sub-groups were studied; patients under 60 years at the time of SAH (Hutter et al., 2001), a relatively small sub-set of patients with aSAH from a mixed brain injury group (Johansson et al., 2007) or patients with aSAH with relatively good neurological outcome (Carter et al., 2000).

To date, there are no studies in which the extent and predictors of resumption of leisure activities and social relationships are explored in a consecutive group of patients with aSAH. Cognitive changes are relatively well

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documented after aSAH, including executive dysfunction. Executive dysfunction might be a determining factor for reduced leisure and social activities. Executive functions are higher order capacities regarding planning, organizing, initiation and regulation of complex, goal-directed behavior, underpinned by prefrontal brain areas (Burgess et al., 2006; Lezak, 1982; Shallice, 1982). These capacities are important for controlling behavior and adapting to and coping with environmental requests (Burgess & Simons, 2005) and essential for functional independence and community integration (McDonald, Flashman, & Saykin, 2002; Ponsford, Draper, & Schonberger, 2008; Shallice, 1982).

Executive problems are common after aSAH (Ogden, Mee, & Henning, 1993; Uchikawa et al., 2014) and negatively associated with long-term employment (Vilkki, Juvela, Malmivaara, Siironen, & Hernesniemi, 2012). Hence, it is likely that executive problems will impede resumption of social and leisure activities in patients with aSAH. Since integrity of prefrontal brain areas is crucial for intact executive functioning, executive deficits and impaired daily life functioning might be related to damage to anterior cerebral regions (Benedictus, Spikman, & van der Naalt, 2010; Hanks, Rapport, Millis, & Deshpande, 1999; Spikman et al., 2013). Indeed, Kreiter et al. (2002) found more executive deficits in patients with aSAH with aneurysms in anterior compared to posterior regions. Other studies failed to find such a relationship (Hutter et al., 2001; Manning et al., 2005).

This study aimed to investigate leisure and social participation up to 10 years after aSAH and to determine the role of executive dysfunction and anterior aneurysms in particular. In addition, it aimed to identify the role of other factors known to influence daily life functioning, for instance mood (Carter et al., 2000; Passier et al., 2010), fatigue (Al-Khindi et al., 2010; Passier, Post, et al., 2011; Powell, Kitchen, Heslin, & Greenwood, 2004) and cognitive complaints (Fertl et al., 1999; Passier, Visser-Meily, Rinkel, Lindeman, & Post, 2013), as well as demographic factors, initial clinical characteristics and work status, to gain insight in long-term functioning of patients after aSAH.

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Methods

Participants

All patients who had been treated by either coiling or clipping after aSAH between August 2002 and November 2009 at the University Medical Center Groningen (UMCG) were eligible for inclusion in this study, which took place in 2012 and 2013. This group of patients received a written invitation. After giving consent, questionnaires were sent, which will be described below. Patients who completed and returned these questionnaires were asked about changes in vocational functioning, social interaction, leisure activities and mobility during a structured telephonic outcome interview. For this study, only changes in social interaction and leisure activities were analyzed. Excluded were individuals lacking command of Dutch or with severe comorbidity, other neurological diseases, psychiatric disorders or substance abuse.

Questionnaires

Executive functioning

Executive dysfunction in daily life was investigated by the Dysexecutive Questionnaire (DEX and DEX-proxy) (Wilson, Alderman, Burgess, Emslie, & Evans, 1996), a 20-item questionnaire measuring behavioral problems that are part of the dysexecutive syndrome. Higher total scores indicate more severe problems (range = 0–80). Scores were dichotomized (Spikman et al., 2013): ‘no dysexecutive syndrome’ (total score ≤ 27) and ‘dysexecutive syndrome’ (total score > 27) Proxy versions about the patient were to be completed by a relative or close friend. Recent re-analyses of the DEX found evidence for different sub-scales (Bodenburg & Dopslaff, 2008; Simblett & Bateman, 2011). Simblett and Bateman (2011) defined an Executive Cognition (EC) scale (range = 0–16), based on a Rasch analysis. Bodenburg and Dopslaff (2008) defined a scale measuring awareness of social conventions and the ability to incorporate social interaction in one’s own behavior, the Social Convention (SC) scale (range = 0–16). These two sub-scales were created for both the DEX and DEX-Proxy ratings.

Cognitive, physical and emotional complaints

Cognitive, physical and emotional complaints were investigated by a 19-item brain injury checklist (Brain Injury Symptom Checklist; BISC), comparable to

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the Head Injury Symptom Checklist (van der Horn, Spikman, Jacobs, & van der Naalt, 2013). Based on strong (> 0.60) correlations, four domains were selected which were considered relevant for this study, measuring cognitive complaints (BISC-Cog), emotional lability (BISC-EL), fatigue (BISC-Fat) and headache (BISC-HA). BISC-Cog consists of the items ‘memory’, ‘concentration’ and ‘mental slowness’. BISC-EL includes the items ‘having anxious dreams’ and ‘irritability’. Lastly, BISC-Fat consists of the items ‘more often tired’ and ‘need for more sleep’ and BISC-HA of ‘headache’ and ‘dizziness’. Complaints before and after aSAH were scored as follows: never (0), sometimes (1) and often (2). Total scores were dichotomized into ‘no complaints’ (0) and ‘complaints’ (1–2). The severity of complaints was defined as the sum of the separate difference scores (total score after minus total score before), controlling for pre-aSAH concurrence.

Mood

Higher scores on the Hospital Anxiety and Depression Scale (HADS) (Zigmond & Snaith, 1983) indicated lower mood or higher anxiety (range = 0–21). Total scores were dichotomized using standard cut-off scores on the sub-scales anxiety (A): ‘anxiety’ (> 7) and ‘no anxiety’ (≤ 7) and HADS-depression (HADS-D): ‘HADS-depression’ (> 7) and ‘no HADS-depression’ (≤ 7).

Structured outcome interview

Resumption of leisure activities and changes in social interaction were measured using the Role Resumption List (RRL) (Spikman, Boelen, Lamberts, Brouwer, & Fasotti, 2010), a structured telephonic interview in which participants are asked about changes in amount and quality of activities compared with pre-morbid levels in four daily life domains (vocational functioning, social interaction, leisure activities and mobility). Changes in leisure activities and social interaction were both scored on a 5-point scale (0 = no change, 4 = no leisure activities/inability fulfilling previous social role). Since this scale measures data at an ordinal level, it was adjusted to perform a logistic regression analysis. To analyze the influence of possible predictors on changes in leisure or social activities, the scales were dichotomized into: ‘complete resumption of activities’ (0) and ‘incomplete resumption of activities’ (1–4).

Demographic and SAH data

Demographic data (age at the time of the interview, sex, relationship status), date of the aSAH, clinical condition on admission (WFNS; World Federation of

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Neurological Surgeons; Teasdale et al., 1988), location of the ruptured aneurysm on the computed tomographic (CT) scan, treatment, diagnosed hydrocephalus and presence of motor impairments were obtained from the patient’s medical reports of the UMCG. WFNS grade and aneurysm location were dichotomized; respectively ‘WFNS low’ (grades 1–3) and ‘WFNS high’ (grades 4–5) and ‘anterior circulation’ (aneurysms of the anterior cerebral or communicating artery, middle cerebral artery or internal carotid artery) and ‘posterior circulation’ (aneurysms of the posterior communicating artery or vertebrobasilar artery). Motor impairment was defined as the partial or total loss of a body function, such as paralysis. Educational level (Verhage, 1964) ranged from 1 (no primary school) to 7 (university), which was dichotomized as low (1–4) and high (5–7). Work status (a part of the RRL) was dichotomized as ‘no paid job’ and ‘paid job’.

Data analysis

All analyses were performed using the Statistical Package for the Social Sciences (SPSS) version 20.0. Descriptive statistics were used to describe the aSAH population, cognitive, emotional and behavioral complaints. Spearman correlations were calculated to determine the relationships between variables. Differences between groups were calculated using t-tests and Mann-Whitney U-tests (in case of not normally distributed or categorical data). Independent relationships between leisure and social re-integration and possible predictors were tested using the backward method for binary logistic regression. For all statistical tests, the overall alpha level was set at 0.05. In case of multiple comparisons, Bonferroni Holm corrections were used (Holm, 1979).

Results

Four hundred and twenty-eight patients with an aSAH were admitted between 2002–2009 to the UMCG; 130 patients died, 32 survivors were excluded because of severe comorbidity, inability to speak Dutch or living at an unknown address. Two hundred and sixty-six patients were eligible for the present study; 206 patients agreed to participate, received and returned the questionnaires and were afterwards approached for the structured interview. Five could not be reached by telephone and one had died in the meantime. Consequently, 200 patients were analyzed (73 males, 127 females) with a mean age of 58.7 years (SD= 12.2 years, range= 17–90). Mean time since aSAH was 4.6 years

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(SD = 1.6 years, range = 2–10). Proxies were partners or family members of the patients (n = 188).

The 200 participants did not differ significantly from the 60 non-participants regarding age (Mparticipate = 58.68, SDparticipate = 12.27, Mnon-participate = 56.96, SDnon-participate = 13.03, t(263) = -0.95, p > 0.05), time since aSAH (Mparticipate = 4.60, SDparticipate = 1.59, Mnon-participate = 4.30, SDnon-participate = 1.49, t(263) = -1.26,

p > 0.05) and neurological condition on admission (WFNS) (Mdnparticipate = 2.00, Mdnnon-participate = 1.00, z = -0.37, p > 0.05). Between-group comparisons (Mann-Whitney U-test) revealed that the participant group contained relatively more women (z = -2.90, p < 0.05). Demographic and disease characteristics of the participants are listed in Table 1.

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27 Table 1. Characteristics of aSAH patients

n = 200 Demographic characteristics

Sex, number of women 127 (63.5%)

Mean age, years 58.7

Relationship status pre-SAH

In a relationship 162 (81%) Not in a relationship 38 (19%) Educational level Low (1-4) 99 (49.5%) High (5-7) 101 (50.5%) SAH characteristics WFNS Low (1-3) 158 (79.0%) High (4-5) 41 (20.5%) Missing 1 (0.5%) Aneurysm circulation Posterior 33 (16.5%) Anterior 167 (83.5%) Treatment Clipping 73 (36.5%) Coiling 124 (62.0%) None 3 (1.5%) Hydrocephalus Yes 91 (45.5%) No 106 (53.0%) Missing 3 (1.5%) Motor impairment Yes 11 (5.5%) No 189 (94.5%)

Educational level, recorded using the Dutch classification system ranging from 1 (no primary school) to 7 (university); WFNS, neurological condition on admission; aneurysm circulation, divided in anterior (aneurysms of the anterior cerebral or communicating artery, middle cerebral artery or internal carotid artery) and posterior (aneurysms of the posterior communicating artery or vertebrobasilar artery); hydrocephalus, presence of a treated hydrocephalus according to CT scan and/or clinical picture. aSAH, aneurysmal subarachnoid hemorrhage; WFNS, World Federation of Neurological Surgeons.

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Leisure activities and social interactions after aSAH

Table 2 shows that about half of the patients with SAH reported complete return to previous leisure activities and no changes in social interactions. Only a small proportion of patients did not participate in any leisure activities or could not fulfil their previous social role post-aSAH; 5.6% of all patients who were in a relationship before the aSAH ended this relationship after.

Table 2. Changes in leisure activities and social roles after aSAH as assessed by the RRL Total No Work Work Low WFNS High WFNS n = 200 n = 120 n = 80 n = 158 n = 41 Changes in leisure activities after aSAH

No change 93 (46.5%) 42 (35%) 51 (63.7%) 80 (50.6%) 13 (31.7%) Less intensity, fewer

hours 31 (15.5%) 21 (17.5%) 10 (12.5%) 25 (15.8%) 6 (14.6%) Other activities, at a lower level or more passive 54 (27.0%) 37 (30.8%) 17 (21.3%) 39 (24.7%) 14 (34.1%) More accompanied leisure time 14 (7%) 13 (10.8%) 1 (1.3%) 9 (5.7%) 5 (12.2%) No activities 8 (4%) 7 (5.8%) 1 (1.3%) 5 (3.2%) 3 (7.3%) Changes in social interaction after aSAH

No change 123 (61.5%) 66 (55%) 57 (71.3%) 101 (63.9%) 22 (53.7%) Less intensity, fewer hours 34 (17%) 20 (16.7%) 14 (17.5%) 23 (14.6%) 11 (26.8%) Some changes in social relationships 27 (13.5%) 20 (16.7%) 7 (8.8%) 23 (14.6%) 4 (9.8%) Clear loss of relationships 11 (5.5%) 9 (7.5%) 2 (2.5%) 7 (4.4%) 3 (7.3%) Cannot fulfill social

role 5 (2.5%) 5 (4.2%) 0 (0%) 4 (2.5%) 1 (2.4%)

aSAH, aneurysmal subarachnoid hemorrhage; RRL, Role Resumption List; WFNS, World Federation of Neurological Surgeons.

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Change in leisure activities correlated significantly but moderately with change in social interactions (r = 0.45, p < 0.01). Patients who were employed post-aSAH had significantly better resumption of leisure activities and social activities (M = 0.64 and M = 0.43, respectively) than those who were unemployed (M = 1.35, M = 0.89, z = - 4.25, z = -2.75, respectively, all ps < 0.05). Time since aSAH did not correlate significantly with changes in leisure activities or social interactions (r = -0.05 and r = 0.12, respectively, all ps > 0.05). Employed patients had significantly lower WFNS scores (M = 1.66, SD = 0.98) than unemployed patients (M = 2.25, SD = 1.42, t(197) = 3.24, p < 0.05). However, low WFNS grades were over-represented in both groups; 90% of employed patients and 71% of unemployed patients had a low WFNS grade.

Factors influencing resumption of leisure activities and social

activities

Table 3 shows demographic characteristics, SAH characteristics and questionnaire scores of patients who did and did not report a change in leisure and/or social activities. There was no significant association between aneurysm location (anterior or posterior) and resumption of social activities (χ2_{(1) = 0.45,}

p > 0.05) or leisure activities (χ2_{(1) = 0.80, p > 0.05). Patients who reported} changes had significantly higher scores on all questionnaires except on BISC-HA.

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Table 3. Patient characteristics and questionnaire scores No change in leisure activities n = 93 Change in leisure activities n = 107 No change in social interaction n = 123 Change in social interaction n = 77 Demographic characteristics Age 57.6 (11.3) 59.7 (12.9) 58.9 (12.0) 58.6 (12.5) Sex, number of women (%) 56 (60) 71 (66) 74 (60) 53 (68.8) SAH characteristics

WFNS, high (%) 13 (14)* 28 (26.2)* 22 (17.9) 19 (24.7) Aneurysm circulation, anterior

(%) 80 (86.0) 87 (81.3) 101 (82.1) 66 (85.7) Questionnaire scores HADS-D 2.4 (3.2)* 5.8 (4.4)* 2.5 (2.9)* 7.0 (4.7)* HADS-A 3.4 (3.6)* 5.5 (4.2)* 3.3 (3.6)* 6.5 (4.1)* DEX Total 11.6 (11.5)* 22.1 (14.3)* 11.6 (10.6)* 26.1 (14.4)* DEX-EC 2.3 (2.8)* 5.6 (3.8)* 2.6 (2.9)* 6.4 (3.9)* DEX-SC 2.4 (3.0)* 3.6 (3.1)* 2.2 (2.6)* 4.3 (3.5)* DEX-Proxy Total 12.6 (12.5)* 21.4 (15.9)* 12.1 (11.1)* 25.7 (16.7)* DEX-EC-Proxy 2.3 (2.8)* 5.2 (4.1)* 2.5 (2.8)* 6.0 (4.2)* DEX-SC-Proxy 2.7 (3.2)* 3.9 (3.7)* 2.5 (2.9)* 4.7 (4.1)* BISC Total 5.0 (5.3)* 10.2 (6.4)* 5.4 (5.5)* 11.6 (6.1)* BISC-Cog 1.3 (1.7)* 3.0 (1.9)* 1.4 (1.6)* 3.5 (1.8)* BISC-EL 0.4 (0.9)* 0.9 (1.2)* 0.5 (0.9)* 0.9 (1.3)* BISC-Fat 1.0 (1.2)* 2.0 (1.5)* 1.1 (1.3)* 2.3 (1.4)* BISC-HA 0.2 (1.2) 0.5 (1.3) 0.3 (1.1) 0.5 (1.5)

Aneurysm circulation, divided in anterior (aneurysms of the anterior cerebral or communicating artery, middle cerebral artery or internal carotid artery) and posterior (aneurysms of the posterior communicating artery or vertebrobasilar artery).

SAH, subarachnoid hemorrhage; WFNS, World Federation of Neurological Surgeons; HADS, Hospital Anxiety and Depression Scale; HADS-D, HADS Depression; HADS-A, HADS Anxiety; DEX, Dysexecutive Questionnaire; DEX-EC, DEX Executive Cognition; DEX-SC, DEX Social Convention; DEX-EC-Proxy, DEX Executive Cognition Proxy; DEX-SC-Proxy, DEX Social Convention Proxy; BISC, Brain Injury Symptom Checklist; BISC-Cog, BISC Cognition; BISC-EL, BISC Emotional Lability; BISC-Fat, BISC Fatigue; BISC-HA, BISC Headache Values given as mean (SD) unless otherwise noted.

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Considering resumption of leisure activities, moderate positive correlations (> 0.40) were found with HADS-D (r = 0.45, p < 0.01), DEX total (r = 0.41, p < 0.01), DEX-EC (r = 0.46, p < 0.01) and BISC-Cog (r = 0.44, p <0.01); the higher the scores the more problems with leisure resumption.

As for resumption of social activities, moderate positive correlations were found with HADS-D (r = 0.51, p < 0.01), DEX total (r = 0.52, p < 0.01), DEX-EC (r = 0.49, p < 0.01), DEX-Proxy total (r = 0.44, p < 0.01), DEX-EC-Proxy (r = 0.44, p < 0.01) and BISC-Cog (r = 0.51, p < 0.01); higher scores indicate more problems with resumption of social activities.

Executive functioning

Dysexecutive problems (DEX score > 27) were reported by 21.7% of the patients and by 20% of their proxies. Table 4 shows mean scores on the DEX, DEX-proxy and the subscales EC and SC. No significant differences were found between patients with anterior and posterior aneurysms (all ps > 0.05). Unemployed patients post-aSAH had significantly higher DEX total, DEX-EC, DEX-Proxy total and DEX-EC-proxy scores than patients who had a job (t(196) = 2.17; t(196) = 3.17, t(186) = 2.38; t(186) = 3.05, respectively, all ps < 0.05).

Cognitive, emotional and physical complaints

In total, 70.4% of the patients reported cognitive complaints after aSAH, 66% reported fatigue, 43.9% reported emotional lability and 37.2% reported headache and/or dizziness. Table 4 shows means of the different variables. Non-employed patients reported significantly more cognitive complaints than employed patients (t(194) = 4.15, p < 0.05); no differences were found for the other BISC scales (all ps > 0.05).

Mood

In total, 23.5% and 25% of all patients had HADS scores indicating depression or anxiety, respectively. Non-employed patients were more depressed than employed patients (t(198) = 3.29, p < 0.05); no significant differences were found for anxiety (t(198) = 0.89, p > 0.05). Significant correlations are found between all questionnaires, except between BISC-HA, DEX-SC and DEX-Proxy scores.

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Table 4. Questionnaire scores divided by work status, WFNS grade, and aneurysm location

Total No Work Work _WFNSLow _WFNSHigh _circulationAnterior _circulationPosterior N = 200 N = 120 N = 80 N = 158 N = 41 N = 167 N = 33 Scores (range) DEX Total (0-75) _(14.06)17.34 _(14.62)*18.95 _(12.82)*14.57 _(14.35)17.19 _(12.92)16.82 _(14.02)17.04 _(14.48)18.00 DEX-EC (0-16) _(3.77)4.10 _(3.89)*4.77 _(3.36)*3.08 _(3.72)3.93 _(3.81)4.56 _(3.83)4.02 _(3.47)4.45 DEX-SC (0-16) _(3.13)3.00 _(3.23)3.16 _(2.99)2.76 _(3.23)3.08 _(2.76)2.62 _(3.16)3.04 _(3.05)2.82 DEX-Proxy Total (0-76) 17.21 ₍₁₅₎ _(15.68)*19.38 _(13.51)*14.15 _(15.42)17.75 _(13.37)15.08 _(15.03)17.18 _(15.14)17.38 DEX-EC-Proxy (0-16) _(3.80)3.83 _(4.03)*4.53 _(3.24)*2.85 _(3.79)3.78 _(3.96)4.03 _(3.84)3.77 _(3.63)4.14 DEX-SC-Proxy (0-16) _(3.52)3.33 _(3.66)3.58 _(3.30)2.97 _(3.64)3.58 _(2.91)2.35 _(3.58)3.37 _(3.26)3.10 BISC-Cog (-1-6) _(1.96)2.22 _(1.99)*2.68 _(1.70)*1.54 _(1.93)2.15 _(2.06)2.45 _(1.97)2.19 _(1.93)2.41 BISC-EL (-2-4) _(1.10)0.66 _(1.14)0.67 _(1.04)0.64 _(.09)*0.74 _(0.94)*0.34 _(1.14)0.63 _(0.89)0.79 BISC-Fat (-1-4) _(1.43)1.54 _(1.45)1.70 _(1.37)1.30 _(1.38)1.45 _(1.56)1.85 _(1.44)1.54 _(1.37)1.53 BISC-HA (-3-4) _(1.26)0.34 _(1.29)0.28 _(1.23)0.28 _(1.22)0.38 _(1.40)0.13 _(1.24)0.32 _(1.37)0.41 HADS-D (0-18) _(4.25)4.20 _(4.57)*4.98 _(3.41)*3.01 _(4.30)4.33 _(3.85)3.46 _(4.29)4.01 _(3.98)5.15 HADS-A (0-17) _(4.07)4.50 _(4.19)4.71 _(3.88)4.19 _(4.18)4.68 _(3.50)3.68 _(3.95)4.26 _(4.47)5.70

Values given as mean (SD) Aneurysm circulation, divided in anterior (aneurysms of the anterior cerebral or communicating artery, middle cerebral artery or internal carotid artery) and posterior (aneurysms of the posterior communicating artery or vertebrobasilar artery). WFNS, World Federation of Neurological Surgeons; HADS, Hospital Anxiety and Depression Scale; HADS-D, HADS Depression; HADS-A, HADS Anxiety; DEX, Dysexecutive Questionnaire; DEX-EC, DEX Executive Cognition; DEX-SC, DEX Social Convention; DEX-EC-Proxy, DEX Executive Cognition Proxy; DEX-SC-Proxy, DEX Social Convention Proxy; BISC, Brain Injury Symptom Checklist; BISC-Cog, BISC Cognition; BISC-EL, BISC Emotional Lability; BISC-Fat, BISC Fatigue; BISC-HA, BISC Headache

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Variables predicting resumption of leisure activities and social

activities

Variables that correlated significantly with leisure resumption were included in the logistic regression analysis predicting resumption of leisure activities: work status post-aSAH, WFNS, DEX-SC, DEX-EC, HADS-D and HADS-A, BISCCog, BISC-EL and BISC-Fatigue. A test of the full model against a constant only model was statistically significant, indicating that the predictors as a set reliably distinguished between patients who did and did not resume their leisure activities. Table 5 shows the variables that explained a significant part of the variance in leisure; patients with higher depression scores, who experienced more fatigue, reported more complaints on the DEX-EC and were not

employed after aSAH were more likely to have problems in leisure activities. Variables that correlated significantly with social re-integration were included in the logistic regression analysis predicting social re-integration: work status post-aSAH, DEX-SC, DEX-EC, HADS-D and HADS-A, BISC-Cog, BISC-EL and BISC-Fat. A test of the full model against a constant only model was statistically significant, indicating that the predictors as a set reliably distinguished between patients who resumed social activities and who did not. Table 5 shows the variables that explained a significant part of the variance in social re-integration; patients with higher depression scores, who experienced more fatigue and had cognitive problems were more likely to have problems with resumption of social activities.

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Table 5. Results of binary logistic regression on leisure activities and social interaction 95% CI for Odds Ratio B (SE) Lower Odds Ratio Upper Leisure

Constant -2.08 (0.38)

HADS-D 0.13* (0.06) 1.01 1.14 1.27

DEX-EC 0.16* (0.07) 1.03 1.18 1.35

BISC-Fat 0.35* (0.14) 1.08 1.42 1.86

Work status post-aSAH 0.99* (0.36) 1.33 2.67 5.43 Social

Constant -2.92 (0.42)

HADS-D 0.26* (0.06) 1.16 1.29 1.45

BISC-Cog 0.25* (0.13) 1.01 1.29 1.65

BISC-Fat 0.43* (0.16) 1.14 1.54 2.09

CI, confidence interval; HADS-D, Hospital Anxiety and Depression Scale Depression; DEX, Dysexecutive Questionnaire; DEX-EC, DEX Executive Cognition; BISC-Fat, Brain Injury Severity Checklist Fatigue; BISC-Cog, BISC Cognition.

Leisure R² = 0.39 (Nagelkerke). Model χ²(65.70), p < 0.01; Social R² = 0.49 (Nagelkerke). Model χ²(84.29), p < 0.01 * = p < 0.05

Discussion

To date, this is the first study investigating predictors of social interaction and leisure activities in a consecutive cohort of patients with aSAH. The results show that resumption of previous leisure and social activities is seriously affected up to 10 years after aSAH. Furthermore, this resumption is associated with the presence of executive, cognitive and emotional problems. Moreover, patients who are employed after aSAH have less problems in the resumption of their leisure activities and social relationships. Aneurysm location did not influence leisure and social re-integration.

More than half of the patients in the cohort were not able to return to previous leisure activities and more than one-third experienced impairment in social re-integration. These results are in line with previous studies in which an impaired reintegration in previous lifestyle after SAH was found (Al-Khindi et al., 2010; Carter et al., 2000; Fertl et al., 1999). Negative changes in leisure

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activities and social interactions were found to be associated with each other, which suggests that these domains are related. In this group, the majority of the patients who have not fully resumed activities are participating at lower levels or intensities. This finding is comparable to the proportions found in a study by Passier et al. (2011) on work resumption; almost two-thirds of their aSAH patient group returned to work, but only one-third reported complete work resumption. Furthermore, an influence was found of work status; patients who were employed post-aSAH had significantly better resumption of leisure and social activities. Ergo, patients who resume work apparently do not compensate this by decreasing leisure or social activities. Moreover; work resumers had significantly less executive, cognitive and emotional problems. On average, this sub-group of working participants had a better clinical condition on admission than non-employed patients, although patients with a low WFNS grade were over-represented in both groups. However, WFNS grade was not a significant predictor of return to leisure activities, whereas work status post-aSAH was. Consequently, a milder initial clinical condition does not fully explain the better outcome of working patients.

More than one fifth of all patients and proxies in this study reported behavioral changes indicative of a dysexecutive syndrome. This study found not only more problems in daily life executive functioning, but also more problems in keeping to social conventions and showing appropriate social behavior. Since prefrontal brain areas are important for executive functioning and social cognition, an association was expected between anterior circulation aneurysms and these problems, but this was not found. Passier et al. (2010) found no differences in cognitive complaints between patients with an anterior versus posterior aSAH. However, other studies did find executive deficits in patients with aneurysms in the anterior region of the brain (Escartin et al., 2012; Kreiter et al., 2002). The DEX sub-scales applied measure self-reported deficits in psychosocial behavior and executive functioning. Perhaps using neuropsychological tests for social cognition or executive functions might provide objective information regarding the relationship between these functions and aneurysm localization in patients with aSAH.

In line with previous studies (Passier et al., 2010; Toomela et al., 2004), it was found that the majority of the patients reported cognitive complaints and fatigue and that feelings of anxiety or depression were present in around a quarter of all patients (Morris, Wilson, & Dunn, 2004; Vetkas, Lepik, Eilat, Ratsep, & Asser, 2013; Wermer, Kool, Albrecht, Rinkel, & Group, 2007). It was found