A subarachnoid hemorrhage (SAH) is a hemorrhage in the subarachnoid space, which is located between the pia mater and the arachnoid mater. In 75% to 80% of cases, a SAH is caused by a ruptured intracranial aneurysm; this is termed an aneurysmal SAH (aSAH). In approximately 15% of cases, no structural cause for the hemorrhage can be detected; this is defined as an angiographically negative SAH (anSAH). Despite the fact that SAH only accounts for 3% to 5% of all strokes, it has the highest morbidity and mortality rates of all stroke types [1]. One of the main clinical characteristics of SAH is an extremely severe headache with an acute onset. Half of all patients experience a loss of consciousness at onset [2]. Other symptoms include nausea, vomiting, neck stiffness, and focal neurological deficits. The main complications that may occur are acute hydrocephalus, recurrent hemorrhage, and cerebral vasospasm [3].

A distinctive feature of SAH is the relatively young age at which it occurs, with a peak incidence between 40 and 60 years [4]. Although recovery of functional independence is common, many SAH patients still experience negative long-term effects in everyday life functioning, which has a large impact on both patients and relatives. For example, previous studies have shown that more than 50% of all SAH patients are unable to resume their previous work, even in the absence of physical limitations [5,6]. In addition, many patients experience problems in leisure activities and social contacts after SAH [7,8]. Factors such as cognitive complaints, mood disorders, and behavioral deficits are related to these problems.

After aSAH, disorders arise in both basic cognitive functions (such as memory, attention, and language) and higher-order functions (such as executive functions and social cognition) [5,9]. Even patients who are functionally independent (ie, able to perform activities of daily living without help) can experience cognitive impairment, causing disability in patients for months or even years after aSAH [7,10]. In addition, high rates of residual symptoms have been reported after aSAH, predominantly including fatigue, anxiety, and mood disturbances. These persistent cognitive and emotional sequelae may have a significant impact on the social and work life of patients. Previous studies have found that approximately 40% of aSAH patients are not able to return to their previous work between 1 to 4 years after ictus [6,11-13]. This can lead to reduced quality of life (QoL) in this patient group [14,15].

Cognitive outcomes following anSAH have been less well studied, and the existing literature shows contradictory results. While some studies have not found evidence of cognitive deficits in this patient group, others have found lower scores for divided attention, information processing speed, and memory [16-18]. A recent systematic review by Burke and colleagues [19] implied that a diffuse pattern of cognitive impairments can be seen in anSAH patients, with primarily attention and executive functioning being affected. Moreover, subjective complaints related to cognitive functioning, fatigue, and mood have been steadily reported after anSAH and seem to significantly influence QoL [16,20-22].

Furthermore, both aSAH and anSAH patients show changes in behavior and personality, such as apathy [23] and inadequate social behavior [24-26]. Changes in behavior are often accompanied by impaired self-awareness [27]. This casts doubt on whether self-reported measures alone can be used to assess the presence and frequency of long-term consequences of SAH and emphasizes the importance of obtaining measures from informants. Although cognitive, emotional, and behavioral deficits after SAH have been frequently explored, the explanatory value of these domains for long-term recovery in the subacute stage after SAH has not yet been investigated.

SAH may result in diffuse injury caused by the initial hemorrhage, complications (eg, vasospasms, hydrocephalus, and recurrent hemorrhage), or secondary damage due to delayed cerebral ischemia. Treatment of the aneurysm in the case of aSAH generally involves either microsurgical occlusion (clipping) or endovascular obliteration (coiling, stenting, or both). Previous studies have investigated the effects of clinical parameters (eg, the characteristics of the aneurysm, the treatment modality, vasospasm, and cerebrospinal fluid drainage) on outcomes after SAH. However, no clear evidence for the effects of these parameters has been found. For example, in a study of 32 aSAH patients, no association was found between the site of the aneurysm or the mode of treatment with neuropsychological outcomes [28]. The authors did find that the severity of the hemorrhage was significantly linked with intelligence and memory. Another study, which included 23 aSAH patients who underwent coiling or clipping, found no differences in cognitive outcomes with different treatment modalities [29]. The aneurysm location also did not seem to be related to the resumption of social activities in a group of 200 aSAH patients [7]. It is therefore of great importance to take a more in-depth look into the diffuse brain damage that may occur after SAH.

Brain imaging techniques, such as magnetic resonance imaging (MRI), can identify structural changes after SAH. For example, T2-weighted, fluid-attenuated inversion recovery and 3D T1-weighted images can depict a variety of etiologies, such as ischemic lesions and brain abnormalities that can be the result of aneurysm treatment (either microsurgical or endovascular), lesions associated with external ventricular drains or permanent shunt placement, and previous infarctions [30]. A recent study obtained complete T1-weighted data 3 months post-aSAH and found no difference in total gray-matter or white-matter volume between patients and controls [31]. However, that study did find a significantly higher gray-matter volume in the cerebellum of aSAH patients than controls, and the study also found an association with neurocognitive impairment.

There are some promising imaging techniques that have not been used, or have barely been used, in the SAH patient population; these techniques have the potential to contribute to knowledge about the long-term cognitive consequences of SAH. First, diffusion tensor imaging (DTI) can identify microstructural white matter lesions that are not visible with standard brain MRI [32]. The most-examined parameters in DTI studies are fractional anisotropy (FA), mean diffusivity (MD), and apparent diffusion coefficient (ADC). Previous research has shown that 2 weeks after ictus, aSAH patients have higher MD values than patients with an unruptured intracranial aneurysm [33]. Higher MD values were associated with cognitive impairment 3 months after ictus in these patients. Another study found decreased FA in the corpus callosum and increased ADC values in the frontal centrum semiovale in aSAH patients 8 to 10 days after ictus [34]. To date, DTI has not been used in anSAH patients, and it is therefore unknown to what extent damage in the white-matter microstructure relates to less favorable cognitive outcomes in this patient group and whether this differs between aSAH and anSAH patients. A more advanced and promising technique is diffusion kurtosis imaging (DKI). DKI has the potential to further delineate microstructural aspects of the white matter [35] and has been used in the assessment and differentiation of stroke, brain tumor, and neurodegenerative diseases [36,37]. To our knowledge, DKI has not yet been used in SAH patients. Second, arterial spin labeling data can be used to measure blood flow in brain tissue (ie, perfusion) and has demonstrated clinical usefulness in various diseases, including vascular spasm, brain tumors, and Alzheimer disease [38-40]. Third, susceptibility weighted imaging (SWI), a relatively new tool for imaging blood vessels, hemorrhage, iron and blood products, and calcifications [41,42], has been used to detect parenchymal hemorrhage and can detect small amounts of SAH more sensitively than conventional gradient-echo sequences [43]. SWI data can be used as input for quantitative susceptibility mapping (QSM.) QSM is a novel MRI technique that has been used to study brain iron and blood degeneration products in various patient populations, such as those with traumatic brain injury, brain tumors, or neurodegenerative diseases [44]. QSM has the potential to indicate hemorrhages and microhemorrhages in a more accurate and qualitative way than SWI in a variety of neuropathologies [45]. Fourth, vessel architectural imaging (VAI) is a new dual-echo dynamic susceptibility contrast (DSC) perfusion sequence technique that can reveal the microvascular architecture and oxygen saturation status. To date, VAI has only been used in tumor patients and has been shown to provide better insights than other noninvasive imaging techniques into the complex nature and heterogeneity of vascular changes [46,47]. In addition, single-echo DSC can be used to gain a better understanding of heterogeneity in microvascular and capillary transit time and the oxygen extraction fraction [48]. Finally, synthetic MRI is a technique whereby a single scan can be used to create multiple different contrast-weighted snapshots, allowing automatic brain segmentation and myelin volumetric measurements [49]. In short, the above MRI methods may allow the evaluation of brain damage after SAH, particularly vascular damage, in a more comprehensive and sensitive way. Moreover, the application of these techniques may offer important new insights into the brain damage that underlies cognitive impairment and difficulties in daily functioning after SAH.

The overall aims of the Imaging, Cognition and Outcome of Neuropsychological functioning after Subarachnoid hemorrhage (ICONS) study are to determine whether and to what extent there are deficits in multiple domains after SAH (including cognition, emotion, and behavior) and to investigate whether brain damage can be detected in this patient group. If this is the case, we aim to determine which early measures (including measures of cognition, emotion and behavior, and brain damage) in the subacute stage play a role in long-term recovery after SAH. Recovery is defined as societal participation, focusing on resuming and maintaining work, leisure activities, and social relationships over the long term. Furthermore, the study has 12 specific objectives that focus on the domains of cognition, emotion and behavior, and brain damage, which will be targeted in multiple future papers. These objectives are described in Textbox 1. We expect that all studied measures will have an effect on recovery individually, but that in an overall explanatory model the neuropsychological factors will play a more decisive role than the initial brain damage. Early identification of decisive factors may provide target points for rehabilitation in this patient group.

The ICONS study is a longitudinal, prospective, single-center cohort study that aims to include 150 patients with SAH who will be followed up at 6 months, 1 year, and 2 years after ictus.

Patients are being recruited from the Neurosurgery Unit of the University Medical Centre Groningen (UMCG), the Netherlands. Based on the admission rate of approximately 120 patients with SAH per year at the UMCG, and accounting for unwillingness to participate and loss to follow-up, we aim to recruit 150 patients with SAH. In addition, 100 matched healthy controls will be recruited through convenience sampling. Inclusion criteria are an aSAH or anSAH diagnosis established by means of a computed tomography (CT) scan. The presence or absence of an intracranial aneurysm (ie, aSAH or anSAH, respectively) is evaluated using CT angiography, digital subtraction angiography, or both. Other inclusion criteria include sufficient knowledge of the Dutch language and age older than 18 years. Exclusion criteria for both patients and healthy controls are a poor physical condition that makes it impossible for participants to undergo the neuropsychological assessment or MRI scan and a history of severe neurological disorders.

The data are stored in an electronic case report form (eCRF) using REDCap. Imaging data are stored on a local secured server at the UMCG. Metadata are stored in the eCRF. Study monitoring is performed by in-house study monitors from the UMCG. Since our data contain potentially sensitive information and therefore pose privacy concerns (even when anonymized), there will be ethical restrictions on sharing our data set. Restrictions will be imposed by the Medical Ethical Committee of the UMCG.

Descriptive statistics (including frequencies, means, and 95% CIs) will be used to describe the samples, and data from each variable will be summarized separately for patients and healthy controls. Deficits in multiple domains will be determined by comparing patients with healthy controls (at the group level) and by comparing patients’ scores with normative data (at the individual level). Test performance below the 10th percentile will be considered impaired. Statistical analyses will be performed according to the applicable objectives shown in Textbox 1. Furthermore, we will develop three explanatory models: (1) cognition, (2) emotion and behavior, and (3) brain damage; this will use binary logistic regression analyses with recovery (ie, IPA ≤20 or IPA ≥21) as the dependent variable. A significance of α=.05 will be used as the cut-off for each variable. Only variables that are expected to have a strong relationship with the dependent variable will be included, based on a priori expectations from the literature and clinical experience. Measures for the same cognitive domains (Table 1) will be taken together as a composite score. The composite score will be generated by converting raw test scores from individual measures to z scores and averaging them. Lastly, we will create an overall comprehensive explanatory model that takes into account the most sensitive measures from each domain (ie, cognition, emotion and behavior, and brain damage) to see how these measures relate to each other in explaining recovery 1 year after SAH.

In multivariable logistic regression models, a sample size of 10 events per variable (EPVs) is desirable to preserve the validity of the model [53]. This rule indicates that 1 independent variable can be studied for every 10 events. For logistic regression, the number of events is given by the smallest number of events within the 2 outcome categories. Based on previous literature, we expect that around half the patients (n=75) will have a complete recovery 1 year after SAH, while the other half (n=75) will have an incomplete recovery 1 year after SAH [7]. This implies that 7 (ie, 75 / 10 = 7.5) variables will be able to be reliably fitted to the model. However, in analyses of causal influences in observational data, control for confounding variables may require adjustment for more covariates than the rule of 10 EPVs allows. Vittinghof and McCullough [54] demonstrated that problems are fairly frequent with 2 to 4 EPVs, uncommon with 5 to 9 EPVs, and still observed with 10 to 16 EPVs when regarding CI coverage less than 93 percent, type 1 error larger than 7 percent, or relative bias larger than 15 percent as problematic. Following these findings, using 5 EPVs will allow for 15 (ie, 75 / 5 = 15) independent variables in each model.

Additionally, 100 healthy controls will be included in order to perform comparisons with the patient group and determine reference values. Since the ICONS study will use new neuroimaging methods, reference values will be needed to compare and interpret the MRI data. Healthy subjects show less variability in results than patients, which means that a smaller number of healthy subjects will be required. Previous MRI studies with SAH patients have shown that the number of healthy controls targeted in the ICONS study will be sufficient [55,56].

The ICONS study will be conducted according to the principles of the Declaration of Helsinki (World Medical Association Declaration of Helsinki, 64th World Medical Association General Assembly, Fortaleza, Brazil, October 2013) and the national and international standards of Good Clinical Practice. Potential participants receive detailed written and oral information on the study procedures and all participants will provide written informed consent. Ethical approval of the study protocol was obtained from the Medical Ethical Committee of the UMCG (2019/346). The ICONS study protocol is registered at the Dutch Central Committee of Research Involving Human Subjects, with trial registration number NL69873.042.19. In addition, the study was registered on June 19th, 2019, at the Netherlands Trial Register with identifier NL7803.