Cognitive Impairments and Associated Factors After Ruptured Anterior Communicating Artery Aneurysm Treatment in Low-Grade Patients <60 Years: A Multicenter Retrospective Study

Background Aneurysmal subarachnoid hemorrhage (SAH) is a kind of destructive cerebrovascular disease which could affect people's cognition, even the life expectancy. People with SAH are considered in a fatal situation, especially in the young population. This study aimed to investigate cognitive impairment and related factors in young patients with ruptured anterior communicating artery (ACoA) aneurysms. Methods We conducted a multicentre retrospective follow-up study at three hospitals in China. The young patients (18-50 years) who underwent ruptured ACoA aneurysm treatment by microsurgical clipping or endovascular coiling at three academic institutions in China from January 2015 to November 2017 were recruited. Patient cognition and life quality were assessed by using modied Telephone Interview for Cognitive Status (TICS-m), the modied Rankin Scale (mRS), and the instrumental activities of daily living (IADL) scale 2. Multiple cox-regression analysis was used to identify variables independently associated with cognitive impairment. Results Of the total of 59 patients, 54 (91.5%) achieved good clinical outcomes (mRS score 0-2) and 51 (86.4%) had excellent quality of life (IADL score 8). Ten (16.9%) patients showed cognitive impairments (TICS-m<27). The multivariate COX regression analysis showed that mRS scores of 3-5 at discharge, female sex, and aneurysm size <5 mm was independently associated with cognitive impairment. TICS-m scores at the latest follow-up were similar after open surgery and coiling. Conclusion In this relatively young sample that excluded patients with very poor-grade SAH or serious complications, microsurgical clipping led to better clinical outcomes than endovascular coiling, while cognitive outcomes were similar across treatment modalities. These results are not completely consistent with previous studies, and should therefore be considered in the clinical practice as well as further investigated in larger patient samples.


Background
Anterior communicating artery (ACoA) aneurysms are the most common intracranial aneurysms and are the most likely to cause aneurysmal subarachnoid hemorrhage (aSAH) [1,2]. The survival rate for ruptured aneurysms has increased to 65% because of improved medical care and based on the Glasgow Outcome Scale beyond 80% of the survivors have recovered well [3]. However, 46% of survivors after SAH may develop cognitive dissonance, and 62% had cognitive impairment with a Glasgow score of 1 [4].
Unlike other types of stroke, aSAH tends to affect young, productive people. The combination of young age and high incidence places a heavy nancial burden on individuals and societies, with some studies showing that < 50% of survivors struggle to recover to the same level of work [8,9]. Studies focusing on the long-term functional outcomes and quality of life after microsurgical clipping or endovascular embolization of ruptured ACoA aneurysms in this young and productive population are rare.
The aim of our multicenter retrospective study was thus to evaluate the long-term cognitive outcomes of young patients (< 50 years) with good clinical grade SAH after treatment for ruptured ACoA aneurysms, and analyze various associated factors using the modi ed Telephone Interview of Cognitive Status (TICSm), the modi ed Rankin Scale (mRS), and the instrumental activities of daily living (IADL) scale. We also compared cognitive outcomes in two groups of patients who underwent either microsurgical clipping or endovascular coiling.

Methods
This multicenter retrospective follow-up study was conducted at three institutes in China. Patients with ruptured ACoA aneurysms admitted to these three institutions between January 2015 and December 2017 were reviewed. The inclusion criteria include following: 1) SAH caused by rupture of ACoA aneurysm, con rmed by CT scanning and then by CT angiography or digital subtraction angiography; 2) early treatment of ruptured ACoA aneurysm by clipping or coiling; 3) no severe postprocedural complications, and functional recovery allowing the patient to participate in the comprehensive neuropsychological battery of tests; 4) Hunt and Hess grade of 0 ~ III at admission; 5) aneurysm diameter ≤ 25 mm; 6) at least primary school education level, and 7) postoperative follow-up for more than two years. The exclusion criteria were as follows: 1) Hunt and Hess grade of IV ~ V; 2) history of neurosis and psychosis; 3) addiction behaviour (alcoholism in particular); 4) below primary school education level or illiterate; and 5) severe complications after the procedure and inability to cooperate in cognitive assessments. All patients gave their consent to be included in the evaluations and analyses after having been informed about the purpose of the study. Demographic data included sex, age, smoking behaviour, and level of education. The initial neurological status and severity of SAH were assessed using the Hunt and Hess scale. Vascular risk factors such as hypertension, diabetes, and hypercholesterolemia were de ned based on the patient's history and use of appropriate medication, and smoking was de ned as the patient currently smoking at the time of study entry.

Management of SAH and Aneurysm Exclusion
The routine medical treatment was given for SAH, which included calcium antagonists and monitoring by daily transcranial Doppler, uid and blood pressure management, pain therapy, anticonvulsants, deep venous thrombosis prophylaxis, and postoperative hypervolemia [10].
The neurovascular team comprised of interventional radiologists and neurosurgeons discussed the choice of the treatment which between microsurgical clipping and endovascular coiling. Meanwhile, within 72 hours of the aneurysm rupturing, the surgical or neuroradiologic treatment for aneurysms was performed as soon as possible. The optimal method of aneurysm treatment, decided on a patient to -patient basis, was then proposed to the patient and relatives after discussion. Generally, right-sided approaches were used when feasible. A left-sided method was used when the aneurysmal neck and the feeding arteries were more easily accessible from the left. Partial resection of the gyrus rectus (GR) was performed in patients with high-positioned aneurysms or in patients with the limited surgical view and visible brain swelling.

Long-term Follow-up
The follow-up was performed via telephone interviews with patients and their family members. Cognitive function was assessed with the TICS-m-a 12-item questionnaire that provides an assessment of global cognitive function based on verbal communication via telephone; scores range from 0 to 50, with higher scores indicating better function [11,12]. Ratings equal to or below 27 indicate impaired cognitive function (TICS-m < 27). Quality of life was assessed by using the IADL questionnaire which includes eight domains of daily life: using the telephone, using transportation means, shopping, handling medications, coping with a nancial issue, doing the laundry, preparing meals, and tidying the house. Every item is scored 0 or 1 according to the patient's inability or ability to perform the corresponding activity. The nal score is the sum of the eight items and ranges from 0 to 8, with 0 representing the lowest degree of autonomy and eight the highest one.

Statistical Analysis
Independent-samples t-tests or Mann-Whitney U test was used to analyze the numeric variables. The difference between the two means was calculated using the least-squares method. Categorical variables were analyzed with chi-square tests or Fisher's exact test. All variables were included in the multiple Cox regression with a backward variable selection algorithm to identify the independent predictors of cognitive impairment at long-term follow-up. We determined the level of association between the predictive variables and cognitive impairment by the hazard ratio and the respective 95% con dence interval (HR, CI 95%). All statistical tests were 2-tailed. A P value of less than 0.05 was considered to be of statistical signi cance (unless otherwise indicated). Statistical analyses were performed with the SPSS 25.0 software package (SPSS Inc, Chicago, IL).

Population
Between January 2014 and January 2017, 209 patients with ruptured ACoA aneurysms of Hunt and Hess grade 1-3 were treated at the three included institutes. Of these, a total of 96 patients were < 50 years, and 59 met the inclusion criteria and completed more than two years of postprocedural follow-up. The mean age was 41.3 ± 7.5 years (ranging from 22 to 49 years), and 35.6% of the patients were female.
Seventeen patients (28.8%) underwent endovascular treatment and 42 patients (71.2%) underwent microsurgical treatment. All enrolled patients underwent cognitive assessment. The mean duration between procedure and assessment was 40.3 ± 9.2 months (ranging from 23 to 58 months).

Functional Outcome and IADL
A total of 54 (91.5%) patients achieved excellent clinical outcomes (mRS scores 0-2). The distribution of patients into the distinct categories of the mRS was signi cantly different between the clipping and coiling groups (P < 0.001). As detailed in Table 2, 92.9% of patients in the microsurgical clipping group and 70.6% in the endovascular coiling group had mRS scores of 0-2.  According to the multivariate COX regression analysis, an mRS score of 3-5 at discharge (HR: 12.4; 95% CI: 1.2-23.3; P = 0.035), female sex (HR: 9.5; 95% CI: 1.1-80.3; P = 0.037), and aneurysm size < 5 mm (OR: 17.0; 95% CI: 1.8-67.5; P = 0.004) were independently associated with cognitive impairment. Age < 40 years and higher Hunt and Hess grades showed a tendency to be associated with a higher risk of cognitive impairment; however, this result was not statistically signi cant (Table 3). Based on the treatment method, the baseline clinical characteristics, clinical outcomes, and questionnaire outcomes of patients who completed the questionnaires were divided into the different group (Table 4). There was no statistical difference between patients treated with microsurgical clipping and endovascular coiling in demographics and baseline clinical characteristics (Table 4). Additionally, patients treated with microsurgical clipping had higher mRS scores (0-2) than patients treated with endovascular coiling (56% vs 97.6% and 76.5%, respectively, P < 0.001). However, those treated with microsurgical clipping had similar rates of TICS-m scores at the latest follow-up than patients treated with endovascular coiling (mean TICS-m score: 33.0 ± 5.8 vs 33.9 ± 7.3, P = 0.030; TICS-m < 27: 16.7% vs 17.6%, P = 0.929). Moreover, the mean IADL score of the microsurgical group was higher than that of the endovascular group, but the difference was not statistically signi cant (7.8 ± 0.7 vs 7.3 ± 1.5, respectively, P = 0.057).

Discussion
Aneurysmal SAH is a devastating subtype of stroke affecting relatively young people who have a mean premorbid life expectancy of 30 years. Case fatality can reach 35%, and many survivors experience longterm disability and cognitive impairments across multiple cognitive domains [13]. These cognitive impairments reduce a patient's quality of life, participation in work, and social activities. However, few studies have directly explored the functional outcomes of young patients with good-grade SAH. Moreover, although many studies have compared cognitive outcomes in microsurgical procedures and endovascular coiling, none of these studies excluded patients with very poor-grade SAH or with serious complications such as hydrocephalus, delayed cerebral ischemia, and intracranial rebleeding [14][15][16][17][18].
Poor-grade SAH and serious complications have, however, been found to signi cantly affect the cognitive outcome of patients with SAH [19][20][21]. In addition, elderly patients included in these previous studies may have had other age-related cognitive dysfunctions, which may have led to a variety of biases. In many studies, cognitive impairments were nevertheless attributed to SAH itself, and not assigned to the complications of SAH or the treatment. In this cohort of young patients with ruptured ACoA aneurysms, we therefore excluded patients with poor-grade SAH (Hunt and Hess grade 4-5), postoperative hydrocephalus, or intracranial rebleeding, to control for the possible confounding effects of these factors.
On the one hand, cognitive impairment may be caused by the transient cessation of circulation and the blood entering the brain at the time of the aneurysm rupture [7,14]. On the other hand, these factors reduce perfusion in some regions of the brain and decrease metabolism; therefore, the subsequent cognitive impairments could be related to the location of the aneurysm [22]. ACoA aneurysms are among the most commonly identi ed ruptured aneurysms [23,24], and ACoA aneurysm rupture and treatment are more strongly associated with cognitive and behavioural de cits than aneurysms at other locations [25]. In earlier studies, impairments in both short-term and long-term memory, amnesia, confabulation, and personality changes were described as the main symptoms that in uenced by the rupture of ACoA aneurysms [22,25]. These symptoms can be attributed to the intraoperative challenges unique to ACoArelated aneurysms and to damage to anterior cerebral structures such as the frontal cortex, the ventromedial prefrontal (orbitofrontal) cortex, or the striatum [26].

Factors Associated with Quality of Life and Cognitive Outcome Between Microsurgical Clipping and Endovascular Coiling
Shen et al. investigated 152 patients with aneurysmal SAH treated with endovascular coiling, and found that 59 patients (39%) developed cognitive impairment six months later. The authors also reported that ACoA aneurysms, delayed cerebral ischemia, and hydrocephalus was independently associated with a higher risk of mild cognitive impairment after aneurysmal SAH [27]. After adjustments for age, Wong et al. found that admission World Federation of Neurosurgical Societies (WFNS) grade, mode of aneurysm treatment, and delayed cerebral infarction were independently associated with reduced cognitive outcomes [28].After excluding patients with poor Hunt and Hess grades (4)(5), postoperative hydrocephalus, intracranial rebleeding, and symptomatic delayed cerebral ischemia, the multivariate COX regression analysis showed that higher mRS scores at discharge, female sex, and aneurysm size < 5 mm were independent risk factors associated with cognitive impairment after treatment for ruptured ACoA aneurysms. One of the more novel ndings of our study is that small ACoA aneurysms in young patients were more prone to cognitive impairment. A possible reason for this observation is that small-sized aneurysms are di cult to clamp or embolize, and it is therefore easy to cause potential brain function damage during the operation. This nding needs to be veri ed by further prospective large data research.

Comparison of Quality of Life and Cognitive Outcome Between Microsurgical Clipping and Endovascular Coiling
Endovascular coiling could be the primary choice in patients with ruptured ACoA aneurysms when the con guration is appropriate. Still, microsurgical clipping also supplies an option that allows the patient to attain the same quality of life, functional outcome, and executive function [29]. Many studies suggest that microsurgical clipping may lead to more severe cognitive impairment and higher rates of patient dependency compared with endovascular coil embolization, possibly caused by retraction injury to the frontal lobe or other causes of cerebral infarction [30][31][32]. Frontal lobe infarction and RAH infarction are more common after surgical clipping of ruptured ACoA aneurysms, and coiled patients have better outcomes at discharge and are more likely to be functionally independent than clipped patients [33]. However, results regarding cognitive functions of young and low-grade patients remain limited, and studies analyzing cognition outcomes in terms of treatment procedure are rare. Thus, our analyses provide a unique opportunity to compare the cognitive consequences of coiling and clipping treatment for the ACoA location. In this study with a long-term follow-up of more than two years, patients treated with microsurgical clipping had higher rates of good clinical outcomes (mRS scores 0-2) than patients treated with endovascular coiling. Otherwise, the mean IADL score was higher in the microsurgical group than in the endovascular group, but this difference was not statistically signi cant. As for cognitive outcomes, those treated with microsurgical clipping had similar TICS-m scores at the latest follow-up than patients treated with endovascular coiling. These results are not entirely consistent with previous studies, suggesting that clinical outcomes (measured with the mRS and the IADL) and cognitive function outcomes for microsurgical clipping and endovascular treatment are similar in younger patients (< 50 years) with low-grade SAH.

Limitations
There are several limitations to our study. Firstly, although we excluded patients with symptomatic delayed cerebral ischemia, this study did not consider brain damage on postoperative MR imaging (because only a subset of patients had undergone MRI scanning). Thus, we were unable to assess whether patients had cerebral infarctions after treatment, which might affect cognitive outcomes.
Secondly, the size of the patient group did not allow for subgroup analyses regarding age and aneurysms size. Thirdly, our study did not use other reported cognitive screening tests such as the Montreal Cognitive Assessment [34] or the Mini-Mental State Examination [35]. This is because these screening tests require face-to-face interviews, which are challenging to conduct in a group of patients from all over the country.
Fourthly, our study could not assess the relative impact of mild cognitive impairment on the total degree of cognitive impairment (de ned by two or more cognitive domain de cits) for the small number of patients. Finally, as patients did not complete cognitive evaluations of TICS-m when they were admitted to the hospital, we were unable to retrospectively determine whether they had cognitive impairments before onset or surgery.

Conclusions
Our results indicate that in a sample of relatively young patients, and when excluding patients with very poor-grade SAH or serious complications, microsurgical clipping leads to higher rates of good clinical outcomes than endovascular coiling. Our results are somewhat inconsistent with previous studies that suggested similar clinical outcomes in younger patients with low-grade SAH, and should therefore be considered in the clinical practice as well as further investigated in larger patient samples. All participants gave their written informed consent prior to their inclusion in the study. Details that might disclose the identity of the subjects under study have been omitted from the data analysis and this publication.

Consent for publication
Not applicable.

Availability of data and materials
The datasets in this study are available from the corresponding author on reasonable request.