Age‐specific clinical characteristics and outcome in patients over 60 years old with large hemispheric infarction

Abstract Objective We aimed to investigate age‐specific clinical characteristics in patients aged >60 years with large hemispheric infarction (LHI). Methods We prospectively enrolled consecutive patients with LHI. Patients were divided into two groups: ≤60 vs. >60 years, and demographics, vascular risk factors, clinical feature, in‐hospital treatment, 3‐month mortality, and unfavorable outcome (defined as a mRS score of 4–6) rate were compared. Results Of the 256 cases included, 140 (54.7%) were older than 60 years. Compared with the younger, the older patients had higher rates of hypertension (66.4% vs. 31.0%), coronary heart disease (19.3% vs. 2.6%), atrial fibrillation (53.6% vs. 31.0%; all p < 0.001), more history of stroke (21.4% vs. 5.2%, p < 0.001), less history of rheumatic heart disease (16.4% vs. 30.1%, p = 0.009), and alcohol consumption (12.1% vs. 21.6%, p = 0.043). Cardio‐embolism is the most common stroke etiology regardless of age (55.7% and 38.8%, respectively). Furthermore, the elderly less frequently received decompressive hemicraniectomy (4.3% vs. 15.5%, p = 0.005) and mechanical ventilation (7.9% vs. 16.4%, p = 0.035) and had a higher frequency of stroke‐related complication (83.6% vs. 66.4%, p = 0.001). A total of 26 (18.6%) older patients and 15 (12.9%) younger patients died during hospitalization (p = 0.221), and 59 (42.1%) older patients and 35 (30.2%) younger patients died at 3 months (p = 0.061). Patient aged >60 years had significantly higher unfavorable outcome rate at 3 months (adjusted odds ratio, OR 4.30, 95% confidence interval [CI] 2.08–8.88; p < 0.05]. However, older age is not independently associated with 3‐month mortality (42.1% vs. 30.2%, p = 0.095 [log‐rank test]). Conclusions Large hemispheric infarction patients over 60 years old were a little more than those aged ≤60 years and constitute more than half of those suffered from malignant brain edema and two thirds of in‐hospital death and 3‐month mortality. The elderly had more cardio‐origin risk factors, received less aggressive hospital treatment, and showed higher risk of unfavorable outcome than the younger.


| INTRODUC TI ON
As we know, aging is the most important independent risk factor for stroke and the incidence of stroke increases significantly with age (Rothwell et al., 2005). It is estimated that the incidence of stroke doubles with each decade of life after the age of 55 years (Sacco et al., 2006). With increasing life expectancy, the world is facing a rapid expansion in its elderly population, especially in developed countries (Wang et al., 2011). Meanwhile, the burden of stroke-related death and disability is expected to increase together with life expectancy .
Large hemispheric infarction (LHI), which usually refers to total or partial anterior circulation infarct caused by occlusion of internal carotid artery or the proximal middle cerebral artery (MCA), constitutes up to 10% of all supratentorial ischemic strokes (Huttner & Schwab, 2009). LHI is a devastating condition with a high mortality rate of approximately 80% in two intensive care-based series (Berrouschot, Sterker, Bettin, Köster, & Schneider, 1998;Hacke et al., 1996). Meanwhile, almost no medical treatment has been proven effective (Heiss, 2016). Because of the limitations of medical therapies, decompressive hemicraniectomy (DHC) has been proposed as a therapeutic option for malignant MCA infarction (mMCAi) that is characterized by severe edema and mass effect. Data from pooled analysis of three European randomized trials had demonstrated that early DHC reduced mortality without increasing the risk of severe disability among patients 60 years of age or younger with complete or subtotal space-occupying MCA infarction (Vahedi et al., 2007). As about 40% of patients with mMCAI are older than 60 years, whether these patients might also benefit from surgery remains unclear (Huttner & Schwab, 2009).
The impact of age on outcome has not yet been well studied in LHI. There are reports of reduced mortality but with poor functional outcome in older patients who undergo DHC in a previous pooled analysis of observational studies and two randomized clinical trials (Gupta, Connolly, Mayer, & Elkind, 2004;Jüttler et al., 2014;Zhao et al., 2012). Older patients have more compensation capacity for space-occupying stroke; however, those patients tend to have comorbid conditions that are likely to increase the risk of mortality and poor functional outcome. In contrast, younger patients would expect to have better outcome, but a lack of cerebral atrophy may not allow them to tolerate severe edema compared with older patients (Gupta et al., 2004). As risk factors, stroke features were different between younger and older patients (Pohjasvaara, Erkinjuntti, & Vataja, 1997), knowledge of age-specific characteristics of LHI is essential to establish diagnostic and therapeutic pathways and to set up prevention programs. However, no study is yet available focusing on age-specific characteristics of patients with LHI over 60 years old.
The objective of the present study is to explore differences in demographics, vascular risk factors, clinical presentation, inhospital treatment, and 3-month outcome in patients with LHI aged >60 years compared with the younger age group in Chinese population.

| Study design and subjects
Between 1 October 2011 and 30 September 2014, patients with either a first-ever stroke or recurrent stroke were registered consecutively after they were admitted to Department of Neurology, People's Hospital of Deyang City. Data were recorded at the time of assessment using a standardized structured form. Detailed methods for data collection have been previously described (Yi, Lin, & Wang, 2014). In present study, we enrolled patients who were admitted within 30 days from symptoms onset and diagnosed with LHI, which was defined as an ischemic stroke involving more than 50% of the territory of the MCA in computed tomography (CT) scan and/or standard magnetic resonance imaging (MRI), with or without involvement of the adjacent territories (Uhl et al., 2004). All patients had a brain CT scan before initial treatment. A second CT scan or MRI was performed within first 7 days of hospitalization. Other CT scans were performed if patients were suffered neurological deterioration, to identify brain edema or hemorrhagic transformation.
We excluded cases with incomplete hospital records or missing imaging that would prevent complete data collection. We also excluded cases with preexisting score of more than 2 on the modified Rankin scale (mRS, a scale of 0-6, with 0 indicating no symptoms and 6 indicating death) and lived dependently (Haan, Limburg, Bossuyt, Meulen, & Aaronson, 1995).
The study protocol was submitted to and approved by the Ethics Committee of People's Hospital of Deyang City. Written informed consent was obtained from all patients before they were enrolled, or from their legal proxies if the patient lost capacity to give the consent.

| Data collection and outcome
Baseline data on age, sex, living environment (rural or urban), admission delay, initial stroke severity assessed by the National Institutes of Health Stroke Scale (NIHSS), baseline systolic and diastolic blood pressure, serum glucose on admission, and vascular risk factors were collected. Vascular risk factors investigated in this study included hypertension, diabetes mellitus, dyslipidemia, coronary heart disease, atrial fibrillation, rheumatic heart disease, previous stroke/transient ischemic attack (TIA), current smoking, and alcohol consumption, which have been described in a previous study (Yi et al., 2014). The potential etiology of LHI was classified as large-artery atherosclerosis, cardio-embolism, stroke of other determined etiology, and stroke of undetermined etiology according to the Trial of Org 10172 in Acute Stroke Treatment (TOAST) criteria (Adams et al., 1993). In-hospital treatment analyzed in our study included thrombolysis, DHC, mechanical ventilation, osmotic agents (such as mannitol), antiplatelet agents, anticoagulants, antihypertensives, statins, and antidiabetics. DHC was conducted according to the eligibility and exclusion criteria from the pooled analysis of three European randomized trials (Vahedi et al., 2007), without consideration of the age group, when written informed consent was obtained from the patient or a legal representative. Stroke-related complications, including both neurological and medical complications during hospitalization, were reviewed by our staff members from hospital records after patient discharge. Neurological complications included brain edema, hemorrhagic transformation, seizures/epilepsy, central hyperthermia, and recurrent stroke, while medical complications during hospitalization included pneumonia, urinary tract infection, gastrointestinal bleeding, electrolyte disturbance, urinary incontinence, acute renal failure, deep venous thrombosis, bedsore, and falls (Johnston et al., 1998).
Patients were followed up at 3-month after stroke onset by using questionnaires via telephone interview or letter inquiries. The primary outcomes measures in our study were 3-month mortality and unfavorable outcome (defined as a mRS score of 4-6; Haan et al., 1995).

| Statistical analyses
Baseline characteristics were compared between two age groups using student's t tests, Mann-Whitney U tests, chi-square or Fisher exact tests, as appropriate. Univariate analysis was performed to test variables which may affect outcome. The included variables were as follows: (a) age group, (b) NIHSS score on admission, (c) all the risk factors surveyed in our study, (d) in-hospital treatments, and (e) stroke-related complication. The odds ratios (ORs) for variables associated with unfavorable outcomes were determined using multivariable logistic regression analyses by the backward stepwise procedure adjusted for variables with p < 0.05 on univariate analyses. Cox proportional hazards model was performed to calculate adjusted hazard ratios (HR) of possible influencing factors on 3-month mortality. Three-month survival was estimated by Kaplan-Meier method and a log-rank test was used for survival comparisons between patient groups. All statistical levels quoted are 2-tailed and a value of p < 0.05 was considered significant for all results. The 95% confidence intervals (CIs) were calculated to describe the precision of the estimates. All statistical analysis was performed with SPSS for Windows, version 16.0 (SPSS Inc).

| RE SULTS
During the 3-year study period, 1,542 patients with acute ischemic stroke were consecutively and prospectively registered. Of those,  Table 2).
The median length of stay in hospital (LOS) was 9 days in the younger age group and 10 days in the older age group. Meanwhile, the mean LOS was 11.3 ± 9.3 and 12.8 ± 11.8 days in the two age groups, respectively.  (Table 4). The most common cause of 3-month mortality was also brain herniation in both age groups (25 patients in the older age group and 20 patients in the younger age group, p = 0.166), and there were more patients over 60 years old died of pulmonary infection at 3 months (18 patients in the older age group and four patients in the younger age group, p = 0.035). The 3-month survival rates of the older patients were not significantly lower than the younger age (p = 0.095, log-rank test; Figure 1). Cox proportional hazards model was employed to determine the independent factors associated with of 3-month mortality with HR and 95% CI (

| D ISCUSS I ON
Up to date, little information is yet available focusing on age-specific characteristics of LHI patients aged >60 years compared with the younger. In the present study, we found that LHI patients over 60 years old were a little more than those aged ≤60 years (54.7% and 45.3%, respectively), which is a little higher than that reported in previous studies (about 40%-50%; Huttner & Schwab, 2009;Jüttler et al., 2011). It is similar to the data from a randomized trail conducted in Chinese population that included 49 mMCAI patients for DHC and 29 of which (61.7%) were older than 60 years (Zhao et al., 2012). Differences in the proportion of the older between our study and others might be explained by that the elderly were more likely to have cardio-embolism and total anterior circulation infarct in Asian hospital-based stroke patients (Chen, Lin, & Po, 2013 in the older age group, for most of cases of rheumatic heart disease occur in younger populations living in poverty (White et al., 2010). In our study, the older patients had higher rates of hypertension, coronary heart disease, atrial fibrillation, and more history of stroke. These results fall in line with results of previous study conducted in very old Asians (Chen et al., 2013;Lee, Huang, & Weng, 2007;Wang et al., 2011). Cardio-embolism is the most common stroke etiology in LHI patients regardless of age, followed with large-artery atherosclerosis in the older age group.
This could be explained by the pathogenesis of occlusion of internal carotid artery or proximal MCA is almost always embolic, either from a proximal cardiac source or atherosclerotic carotid disease (Subramaniam & Hill, 2005). In our study, hypertension and atrial fibrillation were the top two common risk factors of LHI patients especially in the older age group that highlighted the importance of antihypertensive and anticoagulant therapy for the elderly, when regarding the prevention of LHI (Meschia et al., 2014).
In the present study, we found that patients of older age less frequently received DHC and mechanical ventilation (4.3%, 7.9% vs. 15.5%, 16.4%, respectively). This may be due to less active management in older patients Olindo et al., 2003) and insufficient evidence of DHC in mMCAI patients over 60 years old (Gupta et al., 2004;Jüttler et al., 2014;Zhao et al., 2012). DHC is now recommended for the management of mMCAI patients younger than 60 years of age, but its benefit in older patients is still controversial (Arac, Blanchard, & Lee, 2009;Huttner & Schwab, 2009;Uhl et al., 2004). Meta-analysis of observational studies indicated that DHC reduced mortality with increasing the risk of poor functional outcome among patients older than 60 years and age may be a crucial factor in predicting functional outcome after DHC in patients with mMCAi (Gupta et al., 2004). DESTINY II trial indicated that DHC increased survival among patients older than 60 years of age with mMCAi, but most survivors were left with disabilities and needed assistance for daily living (Jüttler et al., 2014), which was also confirmed in a small sample randomized trial with Chinese patients (Zhao et al., 2012). Results from the multivariable model of our cohort showed that DHC was a protective factor for 3-month mortality of LHI patients (HR 0.41; 95% CI, 0.20-0.87).
However, the risk of unfavorable outcome was 9-fold higher than that without receiving DHC after adjusting for potential confounding factors. Nevertheless, a systematic review concluded that despite high rates of physical disability and depression, the majority of patients and/or caregivers are satisfied with life and do not regret having undergone DHC (Rahme, Zuccarello, & Kleindorfer, 2012). As we know, survival with substantial disability instead of death is an outcome that may be acceptable to some patients and caregivers but may not be acceptable to others, especially in older patients. Since 50% of patients died at 90 days were aged 60-80, the decision to perform DHC should be made on an individual basis in every patient older than 60 years of age, especially for patient aged 60-80.
Of note, in our study, mechanical ventilation is not an effective management for reducing 3-month mortality or unfavorable outcome. More than half of LHI patients receiving mechanical ventilation over 60 years old (6/11) died in hospital, three of the survivors died at 3-month, and the rest two patients were severely disabled (both mRS score 5). Our finding is consistent with the result of a community-based study conducted by Mayer et al. (2000), which found TA B L E 5 Predictors of 3-month mortality and poor outcome in LHI patients that two thirds of stroke patients treated with mechanical ventilation died during hospitalization, and most survivors were profoundly disabled. Meanwhile, there is already some evidence that older age is a considerable predictor of increased mortality in mechanically ventilated stroke patients (Bushnell et al., 1999;Gujjar, Deibert, & Manno, 1998;Steiner et al., 1997). When clinical decision is made for patients with life-threatening stroke, patients and surrogates should be informed that approximately more than one half of those who are intubated die in hospital and that most of the survivors may remain severely disabled, especially for the elderly.
In the present study, we ascertained cases of older age had a higher frequency of stroke-related complications and pulmonary infection was the most common complication regardless of age, which resembled the results of previous study in Chinese hospitalized stroke population (Wang et al., 2011 In our study, the most common neurological complication in LHI patients was malignant brain edema, followed with hemorrhagic transformation and seizures/epilepsy. Unexpectedly, there was no significant difference in the events rate of brain edema, hemorrhagic transformation, and seizures/epilepsy between the two age groups, which could partially explain why older age was not associated with in-hospital death and 3-month mortality in our cohort. Although previous systematic review about predictors of brain edema in LHI indicated that the mean age of patients with life-threatening edema was 3.2 years lower than those patients without (Hofmeijer, Algra, & Kappelle, 2008), more than half of patients suffered from brain edema were over 60 years of age in our cohort. This might be partly explained by the higher rate of atrial fibrillation (53.57% vs. 31.03%) and higher proportion of cardioembolism (55.71% vs.38.79%) in the older age group, and those patients are more likely to exhibit internal carotid artery or the proximal MCA occlusion which was associated with early recanalization failure, developing severe ischemic stroke and brain edema (Koga et al., 2013;Sakamoto et al., 2014). Although DHC within 48 hr after symptom onset has been proven to benefit highly selected patients with LHI (Huttner & Schwab, 2009), only 0.3% of all ischemic stroke patients would be eligible for DHC on the basis of the strict eligibility criteria in the European hemicraniectomy trials and age >60 years was the most common reason for ineligibility of hemicraniectomy (Rahme, Curry, et al., 2012). Since more than half of patients with mMCAi are older than 60 years, clinical characteristics of those elderly associated with a greater or lesser benefit from DHC require further research.
The results of the present study should be interpreted with caution given its limitations. First, it was a single-hospital-based study, with limited generalizability. Some patients with LHI might not be hospitalized, especially those who died before admitted to hospital, so we could not exclude inclusion bias in this study.
Second, we only conduct a 3-month follow-up so that the longterm effect of chronic disability remains unclear. Third, since our hospital is one of national comprehensive stroke centers in China, many LHI patients were coming to our hospital by referral from township hospitals and primary stroke centers, and were admitted beyond 48 hr time window, we did not specifically report patients whose LHI was detected within 48 hr after symptom onset. Finally, follow-up in our study was performed by telephone interview or postal questionnaire instead of a clinic visit which may result in a reporting bias.

| CON CLUS IONS
We identified that LHI patients over 60 years old were a little more than those aged ≤60 years and constitute more than half of those suffered from malignant brain edema and two thirds of inhospital death and 3-month mortality. The elderly had more cardio-origin risk factors, received less aggressive hospital treatment, and showed higher risk of unfavorable outcome than the younger.
Early management of cardiovascular risk should be strengthened in the elderly for prevention of LHI. Meanwhile, since there is significant difference in clinical characteristics, stroke-related complications, hospital management and outcome between LHI patients over 60 years and the younger, well-designed randomized trials enrolling the elderly on hospital management, especially on the prevention and treatment of stroke-related complications, are urgently needed. Furthermore, aggressive hospital treatment such as DHC and mechanical ventilation in the elderly needs more evidence.

CO N FLI C T O F I NTE R E S T S
All authors declare that they have no conflict of interests.