Large hemispheric infarction (LHI), which usually results from occlusion of the internal carotid artery or proximal middle cerebral artery (MCA), is a devastating condition with a high mortality rate (1, 2). LHI is commonly associated with varying degrees of brain swelling, with subsequently raised intracranial pressure, midline shift, and brain herniation, giving rise to the term malignant brain edema (MBE) (3). Until recently, no pharmacological strategies have been proven effective by clinical trials (4). Decompressive hemicraniectomy (DHC) conducted within 48 h after symptom onset has been proven effective for patients with LHI with MBE (5). However, only 0.3% of highly selected ischemic stroke patients would be eligible for DHC based on the strict eligibility criteria in the DHC trials (6).

It has also been reported that that poststroke complications are the leading cause of death and unfavorable outcomes in ischemic stroke patients (7, 8). Roth et al. have indicated that neurological impairment level is the most substantial factor predicting the rate of complications (9). Our previous work has demonstrated that stroke-related complication occurred in more than three fourths of the patients with LHI and was related to unfavorable outcome, whereas only MBE and pneumonia are independent predictors of a 3-month unfavorable outcome (10). As we know, the NIHSS score are weighted toward left hemisphere lesions (11). It is reasonable to suspect that stroke-related complications might frequently occur in left hemisphere stroke and result in poor outcomes. However, previous works have found that MBE seemed to be more common in the right hemisphere (12). Meanwhile, there is no consensus on the impact of the stroke hemisphere on outcomes of AIS (12–15).

Nowadays, limited data exist regarding the hemispheric differences in the incidence of stroke-related complications and outcomes of patients with imaging-diagnosed LHI. Therefore, we conducted a retrospective cohort study using the prospective data of Deyang stroke registry to assess the hemispheric differences in characteristics, stroke-related complications, and outcomes of patients with LHI.

During the study period, 3,551 patients with AIS were registered. Of those patients, 314 (8.8%) unilateral patients with LHI admitted with 24 h were enrolled in the present study [mean age: 68.1 ± 14.8 years; 181 (57.6%) men; median NIHSS score on admission: 20]. A flow diagram of included and excluded patients is provided in Figure 1. All patients with LHI received CT scan at least one time and 156 (49.7%) patients received MRI. Among the enrolled patients, 171 (54.5%) were right hemisphere stroke and 143 (45.5%) were left hemisphere stroke. Sixty-one (19.4%) cases were treated with IVT and 46 (14.6%) were treated with EVT at the hyperacute stage. Thirty (9.6%) cases received DHC and 99 (31.5%) received mechanical ventilation during hospitalization. Five (1.6%) cases were lost to follow-up and 93 (29.6%) patients died at 30 days. Seven (2.2%) patients were lost to follow-up at 90 days (three in right-sided group and four in left-sided group). Among the entire cohort, 104 (33.1%) patients died and 221 (70.4%) patients had unfavorable outcome at 3 months.

Several studies have reported the left-right propensity of cardioembolic infarcts, but no consensus has been reached so far (29–34). Although the left hemisphere propensity of cardiogenic emboli has been reported (29, 30), some researches supported the right-sided propensity of cardio-embolism, especially those associated with atrial fibrillation (31, 32). A recently published work indicated that bovine aortic arch was associated with left hemisphere laterality of cardioembolic stroke compared with standard arches (33). Another work suggested that there was a trend toward right-sided lesions in patients with standard arches, but no significant difference in cardio-embolic stroke laterality of patients with bovine arches was demonstrated (34). In this work, we found that LHI patients with right hemisphere involvement had higher frequency of atrial fibrillation and cardio-embolism, supporting the right-sided propensity of cardio-embolism in LHI patients. It is worth noting that although there were 1.6% (5/314) left-handed patients (all with right hemisphere infarction) in the present cohort, there was no significant difference in the presence of left-handedness among LHI patients with a stroke etiology of cardiogenic embolism or not, supporting that the right-sided propensity of cardio-embolism in LHI patients was independent of whether it was a non-dominant hemisphere or not. Our results could be explained by the fact that the brachiocephalic artery is the first branch off the aortic arch, has the largest ostium, and heads upward and parallel to the direction of the ascending aorta. So large-sized cardiogenic emboli would therefore have a higher propensity to enter the brachiocephalic artery (which supplies the right common carotid and right subclavian) rather than the left common carotid artery, which arises second from the aortic arch and has an orientation perpendicular to it (33–35). Further study is warranted to determine whether there is a difference in the laterality of cardiogenic infarct depending on the size of embolic particles besides the aortic arch branching pattern.

Previous works have suggested that higher baseline NIHSS score was one of the early predictors for MBE after ischemic stroke (36). Meanwhile, the NIHSS score are also weighted toward left hemisphere lesions (11). As a result, right hemisphere infarctions can be deemed to be less severe than left-sided, such that physicians and surgeons might be less aggressive in treatment. However, our study found that patients with LHI with right hemisphere involvement had higher incidence rate of MBE (48.5 vs. 30.8%) than those with the left. Multivariate analysis suggested that right hemisphere stroke (OR 2.37, 95 % CI 1.26-4.43) was an independent risk factor of MBE in patients with LHI. Although there was a lower successful recanalization rate of right-sided stroke patients following EVT in our cohort (57.1 vs. 80.0%), multivariate analysis including EVT, successful recanalization, and hemorrhagic transformation also identified right hemisphere involvement as an independent risk factor of MBE in LHI patients. These results are consistent with the result of a systematic review, which included a total of 73 relevant studies and concluded that “malignant” MCA infarction appears to be more common in the right hemisphere (12). These results can be explained because the right hemisphere plays a crucial role in cardiovascular regulation due to autonomic nervous system lateralization, leading to greater alterations of norepinephrine levels and sympathetic activation after right hemispheric insular infarction than the left (37). Increased levels of norepinephrine can result in vasoconstriction, increasing the permeability of blood–brain barrier and the levels of extracellular glutamate by stimulation of β-adrenoreceptor, creating an intracellular Ca²⁺ and Na⁺ osmotic gradient and thus attracting extracellular fluid into the cell resulting in the development of cytotoxic edema (12, 37, 38). Moreover, increased levels of norepinephrine can stimulate the α-1 adrenergic receptors in the supraoptic nucleus of the hypothalamus and thereby enhance the release of vasopressin, leading to the downregulation of aquaporin-4 and increasing the plasma membrane permeability (12, 39). Vasopressin can also participate in the ischemic cascade, leading to neuroinflammation, necrosis, and apoptosis that might be another factor in the asymmetrical development of MBE (12, 39).

Several clinical works indicate that the effect on the cardiovascular system depends on the stroke lateralization (40–43). It has been reported that when brain damage affects the right insular cortex, the consequences on cardiac function are more deleterious and more frequent (40–42). Conversely, another work indicates that left insular stroke appears to be an independent predictor of severe cardiovascular consequences such as cardiac death, acute myocardial infarction, angina, or heart failure (41). The phenomenon of stroke lateralization has also been observed in experimental models (44, 45). It has been demonstrated that right MCA occlusion (MCAO) in rats had more cardiovascular consequences than the left MCAO (44, 45). In our work, we found that right-sided LHI patients had higher rate of composite of cardiovascular events (29.8 vs. 17.5%) during hospitalization than the left-sided. After adjusting for age, sex, baseline NIHSS score, predisposing vascular risk factors (hypertension, diabetes mellitus, dyslipidemia, previous ischemic stroke/TIA, current smoking, and alcohol consumption), prior-to-stroke heart diseases (coronary heart disease, atrial fibrillation, rheumatic heart disease), and acute reperfusion therapies (IVT and EVT), which had a potential association with composite of cardiovascular events, right hemisphere involvement was still an independent risk factor of composite of cardiovascular events in patients with LHI (OR 2.04, 95% CI 1.12–3.72). This result could be explained by the fact that right hemisphere stroke, especially those with insular cortex involvement, is responsible for autonomic disturbances and triggers inflammatory processes including the release of cytokines such as monocyte chemoattractant protein-1, C-reactive protein, growth differentiation factor, leading to an increased risk of cardiac death, acute myocardial infarction, and heart failure (46).

Our work found that although the right-sided LHI had higher incidence rate of 1-month mortality (34.5 vs. 23.8%) in univariate analysis, multivariate analysis suggested that stroke lateralization was not an independent predictor of mortality and unfavorable outcome in LHI patients. Previous studies have not reached a consensus on the impact of the stroke hemisphere on outcomes of AIS (12–15). A cohort study indicated that left-hemispheric AIS were often associated with a worse outcome than their right-hemispheric counterparts (14). However, several studies suggested an association between right hemisphere involvement and higher risk of death and unfavorable functional outcome in AIS patients, especially for those with mild/moderate strokes (13, 47). The results of our work are in line with previous published systematic review and metaanalysis, which indicated that stroke lateralization was not an independent predictor of mortality and unfavorable outcome and did not modify the treatment effect of MCA territorial infarction (12, 15).

We identified that patients with LHI with right hemisphere involvement had higher frequency of atrial fibrillation and cardio-embolism. Right hemisphere involvement was independently associated with increased risk of MBE and composite of cardiovascular events during hospitalization, whereas hemispheric difference was not an independent predictor of mortality and unfavorable outcome in LHI patients. Implement of early pharmacological or non-pharmacological intervention for autonomic restoration might improve the outcome of right-sided LHI patients, especially those with insular cortex involvement.

The raw data supporting the conclusions of this article will be made available by the corresponding author on reasonable request.

The studies involving human participants were reviewed and approved by the Ethics Committee of People's Hospital of Deyang City. The patients/participants provided their written informed consent to participate in this study.

JL and PZ collected, analyzed, and interpreted the data, as well as drafted the manuscript. YL and WC participated in data interpretation and revised the manuscript. XY participated in study conception and design. CW contributed substantially to study design and supervision, data interpretation and manuscript writing. All authors critically revised the manuscript for important intellectual content and approved the final manuscript.

This research was funded by Universal Application Program, Health and Family Planning Commission of Sichuan Province (17PJ084), the Science and Technology Research Foundation of Deyang City (2020SZZ069), and Applied Basic Research Program, Science and Technology Department of Sichuan Province (No. 2018JY0389) in China.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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