Right insular cortex involvement is consistently associated with death after ischaemic stroke

Involvement of the insular cortex in patients with ischaemic stroke is frequent and has been associated with increased risk of death after stroke [1], albeit with some controversy [2]. The main source of dispute is that insular strokes are usually more severe [2,3] and associated with larger brain infarcts [2], meaning that stroke severity or infarct size should be considered as potential confounders to be included in regression models for death. Notably, outcomes of left and right insular cortex strokes may differ due to the laterality of autonomic representation in the brain [4]. Indeed, there is dispute regarding whether left, right or both insular strokes are associated with higher mortality [1,2]. In this issue of European Journal of Neurology, in an initiative based on the cohort of the 1000 Plus study conducted by researchers from the University of Berlin and Helmholtz Association of German Research Centres, Hanne et al. [5] report an association between right insular cortex involvement and increased risk of death at 90 days. The 1000 Plus is a magnetic resonance imaging (MRI) study enrolling consecutive patients with stroke or transient ischaemic attack seen in the emergency department at Charit e Campus Benjamin Franklin (Berlin, Germany) within 24 h of symptoms onset, between 1 September 2008 and 11 November 2012. The main outcome was death, ascertained at 90 days by telephone interviews. 3 T diffusion-weighted imaging (DWI) MRI comprising 50 axial slices with a thickness of 2.5 mm without gaps allowed for a highly accurate identification of ischaemic strokes involving the insular cortex. Although the baseline 1000 Plus cohort included patients presenting clinically with transient symptoms, this study is solely based on 736 patients with identifiable ischaemic stroke in DWI MRI with complete follow-up data. In Cox regression analyses adjusted for lesion volume and stroke severity, right insular cortex involvement but not infarct volume or left insular involvement was associated with death (hazard ratio 2.60). Stroke severity and age were also associated with increased case fatality. A secondary analysis using the Stroke Lesion Atlas, an in-house software that creates overlap images of lesion topographies of patients sharing specific outcomes (e.g. death), showed that the maximum lesion overlap was registered in the insula both for patients alive and for dead patients at 90 days. However, maximum overlap was greater amongst those who were dead at the end of the follow-up period, further supporting that right insular involvement is related to death. Similarly to this study, we recently found that right insular involvement was independently associated with increased death 6 months after ischaemic stroke in the cohort of the Third International Stroke Trial (IST-3) after adjusting for lesion size and stroke severity amongst other variables [6]. Furthermore, right insular infarcts were also independently associated with disability and combined death or dependence. Together, the study by Hanne et al. [5] and ours [6] contribute to highlight that ischaemic damage to the right insula is independently related to increased risk of death after stroke, ensuring the need to elucidate the underlying pathophysiology. Unfortunately, in neither study was the cause of death ascertained. Regardless, and as hypothesized by the authors, a handful of mechanisms comprising cardiac arrhythmias, pneumonia and hyperglycaemia could be regarded as potential causes of more death after right insular infarction. Amongst them, neurogenically mediated cardiac arrhythmias and/or sudden death emerge as the most likely mechanisms. Accordingly, cardiac arrhythmias are triggered by autonomic imbalances [7] and lesions to the right insula can result in increased sympathetic tone, cardiac arrhythmias and sudden death [1,8]. Handedness may reflect different brain organizations for autonomic control. Right-handers are five times as likely to die from sudden death after a transient ischaemic attack or minor stroke as left-handers or ambidextrous patients [9]. Future research should assess whether death after right insular ischaemic stroke is truly caused by fatal cardiac arrhythmias and sudden death and how cardiac arrhythmias are initiated by brain lesions. It will be important to determine the type of arrhythmias. If a lesion causes parasympathetic predominance, one would expect death resulting from bradycardia and eventual asystole. If sympathetic tone prevails, death