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Lateralization of Insular Ischemic Stroke is Not Associated With Any Stroke Clinical Outcomes: The Athens Stroke Registry
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Lateralization of Insular Ischemic Stroke is Not Associated With Any Stroke Clinical Outcomes: The Athens Stroke Registry Sophia Vassilopoulou, MD,* Eleni Korompoki, MD, PhD,*,† Argyro Tountopoulou, MD, PhD,* Dimos D. Mitsikostas, MD, PhD,* Efstathios Manios, MD, PhD,† Georgios Georgiopoulos, MD, PhD,† George Ntaios, MD, PhD,‡ Haralampos Milionis, MD, PhD,§ Sophia Fontara, MD,{ and Konstantinos Vemmos, MD, PhD†,jj
Background: Controversial evidence suggests that right insular stroke may be associated with worse outcomes compared to the left insular ischemic lesion. Objectives: We investigated whether lateralization of insular stroke is associated with early and late outcome in terms of in-hospital complications, stroke recurrence, cardiovascular events, and death. Methods: Data were prospectively collected from the Athens Stroke Registry. Insular cortex involvement was identified based on brain CT scans or MRI images. Patients were followed up prospectively at 1, 3, 6 months after hospital discharge and yearly thereafter up to 5-years or until death. The assessed outcomes were in-hospital complications, functional outcome assessed by the modified Rankin Scale, stroke recurrence, cardiovascular events, and death. Cox-regression analysis was performed to estimate the cumulative probability of each outcome according to the lateralization of insular strokes. Results: Among the 1212 patients, 650 had left insular stroke involvement and 562 had right. New onset of in-hospital atrial fibrillation was similar between right and left insular strokes (11.6% versus 12.9%, P = .484). During the 5-year follow-up sudden death occurred in 21 (3.7%) patients with right insular compared to 30 (4.6%) with left insular stroke (P = .476). There was no difference between left and right insular strokes regarding mortality (adjusted odds ratio [OR]: .92, 95% confidence interval [CI]: .80-1.06), stroke recurrence (4.3% versus 4.9%; adjusted OR: .81 95% CI: .58-1.13), cardiovascular events, and sudden death (adjusted OR: .99, 95% CI: .76-1.29) and on death and dependency (adjusted OR: .88, 95% CI: .75-1.02) during a 5-year follow up. Conclusions: Lateralization of insular ischemic stroke involvement is not associated with stroke outcomes. Key Words: Insular stroke—lateralization—stroke recurrence—mortality— cardiovascular events © 2019 Elsevier Inc. All rights reserved.
From the *Department of Neurology, National and Kapodistrian University of Athens, Greece; †Department of Clinical Therapeutics, National and Kapodistrian University of Athens, Greece; ‡Department of Medicine, University of Thessaly, Larissa, Greece; §Department of Internal Medicine, University of Ioannina, Greece; {Department of Radiology, National and Kapodistrian University of Athens, Greece; and jjHellenic Cardiovascular Research Society, Athens, Greece. Received September 17, 2019; accepted November 7, 2019. Sources of funding: None. Address correspondence to Sophia Vassilopoulou, MD, PhD, 1st Department of Neurology Eginition Hospital, National and Kapodistrian University of Athens, 72-74 Vas. Sofias, 11528 Athens, Greece. E-mail: [email protected]. 1052-3057/$ - see front matter © 2019 Elsevier Inc. All rights reserved. https://doi.org/10.1016/j.jstrokecerebrovasdis.2019.104529
Journal of Stroke and Cerebrovascular Diseases, Vol. &&, No. && (&&), 2019: 104529
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Introduction Insula, the island of the brain cortex, seems to play a crucial role in the regulation of central autonomic nervous system.1 Experimental data support insula’s role in cerebrogenic arrhythmias and sudden cardiac death, in patients with acute ischemic stroke (IS) with insular involvement although this assumption is not well established.2-5 Insular damage has been associated with outcomes of IS at the acute phase as well as with long-term prognosis.4,6-8 Cerebral infarcts involving the insula region tend to be more severe and have been associated with poorer prognosis compared to noninsular IS.4,8-10 Nevertheless the exact pathophysiological mechanisms underlying this association are not well understood. There is some evidence supporting that laterality of insular lesions may play a role in short-term and longterm prognosis after stroke mainly based on the concept of laterality of autonomic representation in the brain.10,11 Nevertheless, there is still a controversy whether right or left insular involvement is mainly associated with unfavorable outcome. The prognostic value of insular lesion laterality in terms of long term outcomes after IS has been not evaluated so far. The present study sought to examine the association between the lateralization of insular ischemic lesions with long-term hard outcomes in a large population of prospectively collected consecutive acute stroke patients.
Subjects and Methods Study Population The study population was derived from the Athens Stroke Registry, a prospective registry of consecutive patients presented with an acute first-ever stroke between June 1992 and August 2012. The methodology followed to register data in the Athens Stroke Registry has been described in detail elsewhere.12 Patients with lacunar strokes, infratentorial infarcts, noninsular and multiple territory infracts and patients presented more than 48 hours after symptom onset were excluded from the present study (Fig 1). The local Ethics Committee approved the scientific use of the data collected in the Athens Stroke Registry. Data including baseline characteristics, medical history, traditional cardiovascular risk factors, stroke pathophysiological mechanism according to TOAST classification,13 vital signs, and findings from physical examination, laboratory investigations, cardiac work up, in-hospital treatment as well as a detailed description of brain imaging were prospectively collected. Stroke severity was assessed using the National Institute of Health Stroke Scale (NIHSS) score on admission.14 Functional outcome was assessed using the modified Rankin scale at regular follow-up visits.
Brain Imaging According to the imaging protocol, all patients had a computed tomography (CT) at admission and a repeat CT or magnetic resonance imaging (MRI) within the first week after symptom onset. The choice of CT or MRI as the second imaging modality depended on the available resources and on clinical presentation (eg, for patients with symptoms suggesting a posterior circulation infarct, MRI was preferred). Only the patients who underwent the first brain scan within 48 hours from symptom onset have been included in the present study. All scans were assessed retrospectively, by a board certified radiologist (S.F.) who was blinded to the study hypothesis. The presence and side of insular involvement was assessed on baseline and follow-up scans. Insular lesions were defined as indistinct gray matter outline or as hypodense attenuation of the insula.15 Location and lateralization of brain infarcts were recorded. All cerebral infarctions in the insular cortex or at least in a portion of the insula, regardless if they affected other brain regions too, were classified as insular strokes. Cerebral edema was defined as the presence of midline shift, sulcal effacement, or ventricular compression in patients with acute IS and cerebral damage as the irreversible brain herniation.
Stroke Complications A routine 12-lead electrocardiogram (ECG) upon admission was recorded in all patients. Cardiac arrhythmias were documented by means of: (a) repeated ECGs during hospital stay, (b) continuous ECG monitoring for 1 week or until discharge for patients treated in the acute stroke unit, and (c) 24-hour Holter ambulatory ECG monitoring in cases that AF or other arrhythmias were strongly suspected from the clinical presentation, cardiac echocardiogram and brain imaging findings. Diagnosis of AF required an episode of AF lasting at least 30 seconds documented at least by one modality. Other cardiovascular events, such as acute heart failure, sudden death, severe arrhythmias (supraventricular or ventricular tachycardias and atrio-ventricular blocks), were also recorded. Pulmonary and urinary infections, deep venous thrombosis, and pulmonary embolism were evaluated and registered by the stroke physicians.
Follow-up and Stroke Outcomes Patients were followed up prospectively at the outpatient clinic at 1, 3, and 6 months after hospital discharge and yearly thereafter or until death. For patients not able to attend the outpatient clinic, follow-up was assessed by telephone interview with the patient or patient’s next of kin, or at the patient's residence by medical personnel. Lost-to-follow-up was defined as inability to reach the patient or the patient’s proxies at a scheduled point in time. The assessed outcomes were 5-year all-cause mortality, stroke recurrence, functional outcome, and major cardiovascular event (comprising of recurrent stroke,
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3315paents in the Athens Stroke Data Bank
483 excluded because of Intracerebral hemorrhage 2832 paents with ischemic stroke
1620 paents excluded aer applying inclusion/exclusion criteria: 660: lacunar infarcs 540: non insular infarcts 302: infratentorial infarcts 51: mulple territory infarcts 45: presented >48 hours aer onset 22: missing data
1212 paents included in the analysis
650 paents with le insular infarcts
562 paents with right insular infarcts
Figure 1. Study flow chart.
myocardial infarction, systemic embolism, aortic aneurysm rupture, or sudden cardiac death). Recurrent stroke was defined as a cerebrovascular event of sudden onset, lasting more than 24 hours, subsequent to the initial stroke, resulted in a new neurological deficit or in deterioration of the previous neurological deficit, demonstrated on brain imaging. Dependency was defined as modified Rankin Scale Score greater than or equal to 3. Death and causes of death were assessed from death certificates, patients' hospital records, and information from general practitioners or family physicians.
Statistical Analysis Continuous variables are presented as mean value § standard deviation and categorical covariates as absolute
numbers and proportion (%). For patients lost during follow-up, survival data were censored at the last time known to be alive. Patients who experienced more than one composite vascular event during the follow-up were censored at the time of the first event. Student’s t-test was applied to compare continuous variables; chi-square or Fisher’s exact test was applied for categorical variables. The Kaplan-Meier product limit method was used to estimate the cumulative probability of each outcome according to insular infarct lateralization. Differences in Kaplan-Meier curves were evaluated with the log-rank test. Cox-regression analyses were performed to assess whether lateralization was an independent predictor of outcomes in patients with insular infarcts. The covariates entered in the analyses included age, sex, stroke severity (evaluated by NIHSS score), stroke etiology, cardiovascular
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Table 1. Basic characteristics of the study population according to lateralization of insular infarct
Sex (men) Age (mean) Delay admission (mean, h) Days of hospital stay (mean, days) History of Hypertension Diabetes Dyslipidemia Smoking Transient ischemic Attacks Coronary artery diseases Atrial Fibrillation Admission values NIHSS1 Systolic BP (mmHg) Diastolic BP (mmHg) Glucose (mg/dl) Stroke classification* Atherosclerosis Cardioembolism Undetermined Other etiology Inhospital treatment Thrombolysis Aspirin Hepariny
Right insula n = 562
Left insula n = 650
P value
302 (53.7) 71.5 (12.3) 5.6 (10.7) 12.5 (7.6)
351 (54.0) 71.3 (12.7) 5.2 (9.2) 13.1 (7.9)
.954 .832 .481 .180
363 (64.6) 129 (23.0) 173 (30.8) 165 (29.4) 56 (10.1) 120 (21.4)
433 (66.6) 158 (24.3) 194 (29.8) 185 (28.5) 54 (8.3) 148 (22.8)
.467 .589 .754 .751 .318 .579
11.7 (8.2) 153.4 (26.5) 86.6 (12.8) 134.5 (56.9)
13.6 (8.5) 151.7 (25.7) 85.4 (11.7) 132.4 (57.0)
.001 .255 .081 .528 .637
84 (14.9) 272 (48.4) 191 (34.0) 15 (2.7)
113 (17.4) 298 (45.8) 224 (34.5) 15 (2.3)
16 (2.8) 437 (77.8) 341 (60.7)
17 (2.6) 493 (75.8) 408 (62.8)
.860 .454 .477
Abbreviations: NIHSS, National Institute Stroke Scale. Numbers in parentheses for nominal data indicate percentages and for continuous SD. *Stroke classification based on TOAST criteria. † Heparin: Low dose for prophylaxis of venous thromboembolism.
risk factors, and comorbidities (history of hypertension, diabetes mellitus, smoking, dyslipidemia, coronary artery disease, atrial fibrillation, admission blood pressure, and glucose), and in-hospital treatment (thrombolysis, antithrombotics). Significant factors in the univariate analyses were included in the multivariate Cox model. For the univariate analysis, the level of significance was set at .1 to reduce the risk of a type II error. In the final multivariate analyses, the level of significance was set at .05. Associations are presented as hazard ratios with their corresponding 95% confidence intervals (95% CI) using the right location as the comparator in insular. Statistical analyses were performed with the Statistical Package for Social Science (SPSS Inc, version 17.0 for Windows; Chicago, IL).
Results From the original study cohort of 3315 acute stroke patients, the analysis included 1212 patients with insular involement: left insula was impaired in 650 patients (45.8% with partial involvement) and right insula in 562 patients (43.6% with partial involvement; Fig 1). The study population was divided in two groups in terms of
insular infarct laterality. Patients’ baseline characteristics are summarized in Table 1. Patients’ age was the same between the two groups. Arterial hypertension was the most frequent risk factor in both groups. Stroke severity was higher in patients with left insular infarcts (median NIHSS score on admission: 13.6 versus 11.7, P< .001). The most common stroke subtype according to TOAST classification in both groups was cardioembolic, 48.4% in right insular lesions and 45.8% in left insular strokes. Patients’ treatment during hospitalization was completely comparable between left or right insular stroke. In-hospital stroke complications and the causes of death according to the lesion topography are presented in the Table 2. No differences were observed between right and left insular infarcts. The most frequent complications and in-hospital causes of death in both groups were infections and brain edema. In-hospital new-onset AF was comparable between right and left insular strokes (11.6% versus 12.9%, P = .484). The occurrence of other severe arrhythmias did not differ significantly between the two groups (3.0% among patients with right insular infarcts and 2.2% among the left ones, P = .366; Tables 1 and 3).
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Table 2. Inhospital stroke complications and causes of death according to the lateralization of insular infarct
Inhospital complications Brain edema with mass effect Infections Cardiovascular New atrial fibrillation Other severe arrhythmias Stroke recurrence Venous thromboembolism Seizures Other Inhospital causes of death Brain damage Infections Cardiovascular Sudden death Stroke recurrence Other causes Unknown cause 5 years causes of death Brain damage at the acute phase Infections Cardiovascular Sudden death Stroke recurrence Other causes Unknown cause
Right n = 562
Left n = 650
P value
85 (15.1) 153 (27.2) 10 (1.8) 65 (11.6) 17 (3.0) 11 (2.0) 4 (0.7) 10 (1.8) 12 (2.1)
85 (13.1) 194 (29.8) 11 (1.7) 84 (12.9) 14 (2.2) 14 (2.2) 11 (1.7) 20 (3.1) 6 (0.9)
.320 .339 1.000 .484 .366 .842 .191 .194 .097
32 (5.7) 32 (5.7) 3 (0.5) 4 (0.7) 1 (0.2) 2 (0.4) 1 (0.2)
34 (5.2) 29 (4.5) 5 (0.8) 5 (0.8) 4 (0.6) 1 (0.2) 2 (0.3)
.800 .358 .731 1.000 .381 .600 1.000
34 (6.0) 70 (12.5) 24 (4.3) 21 (3.7) 24 (4.3) 25 (4.4) 35 (6.2)
35 (5.4) 69 (10.6) 40 (6.2) 30 (4.6) 32 (4.9) 24 (3.7) 35 (5.4)
.622 .322 .158 .476 .681 .560 .540
Numbers in parentheses indicate percentages.
During the 5-year- follow up (mean 30.1 § 24.1 months), the main causes of death were initial brain damage, infections, cardiovascular events, and sudden death without any significant difference between patients with left insular involvement and right insular lesion (P = .622, P = .322, P = .158, and P = .476, respectively; Table 2). Overall, 24 patients (4.3%) with right insular lesions experienced a new cardiovascular event as compared to 40 (6.2%) with the left insular lesions (P = .158). A recurrent stroke occurred in 4.9% of patients with left insular lesions and in 4.3% of patients with right insular involvement (Odds Ratio (OR): .81, 95% CI: .58-1.13, P = .681). The association between lateralized insular involvement and stroke outcome is presented in Table 3 and Figure 2. In Cox regression analysis, after adjustment for age, sex, stroke severity (NIHSS score), stroke risk factors, etiology, and treatment, no differences were identified on mortality, death or dependence, stroke recurrence, cardiovascular events, and sudden death between right and left insular infarcts. Moreover, the cumulative risk for all outcomes was similar between right and left insular ischemic lesions; (adjusted OR (aOR) for mortality .92, 95% CI .80-1.06; aOR for death or dependency .99, 95% CI .76-1.29; aOR for stroke recurrence 0.81, 95% CI .58-1.13; aOR for cardiovascular events and sudden death .99, 95% CI .76-1.29).
Table 3. Univariate and multivariate cox regression analysis for the 5-year outcomes according to the lateralization of insular infarcts Right insular versus left insular
Mortality Death or dependencey Stroke Recurrence Cardiovascular events and sudden death
Unadjusted OR (95% CI)
Adjusted* OR (95% CI)
.95 (.83-1.08) .98 (.86-1.15) .79 (.57-1.10) .98 (.76-1.27)
.92 (.80-1.06) .88 (.75-1.02) .81 (.58-1.13) .99 (.76-1.29)
*Adjusted: by age, sex, NIHSS score, stroke risk factors, stroke etiology by TOAST criteria, stroke inhospital treatment, admission BP and glucose. † Modified Rankin Score 3.
Discussion This cohort study evaluated 1212 consecutive prospectively collected patients with acute IS involving the right or left insula. The most significant finding was that no difference emerged in in-hospital and long-term outcomes between right and left insular strokes during an extended follow-up period of 5 years. The present study offers important insights into the long-standing debate whether
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Figure 2. Cumulative risk for stroke mortality (A), stroke recurrence (B) and cardiovascular events/sudden death (C) according to the lateralization of insular stroke.
the right or left insula is the one most associated with unfavorable outcomes and poorer prognosis after acute IS. Our findings seem to be contradictory with previous research supporting the hypothesis that only right and not left insular ischemia is associated with poor outcomes.7,10,15,16 An analysis from the IST-3 Trial reported higher odds of death and worse functional outcomes in IS patients with right insular lesions compared to noninsular strokes in the left side within 6 months after the index event.10 Adjusted mortality was not different between insular and noninsular strokes on the left side. Nevertheless, although not directly compared, causes of death were similar between left-insular and right insular strokes at 6 months: cerebrovascular death 63.6% versus 64.2%, cardiovascular death 8.4% versus 7.4%, infections 17.8% versus 16.6%, respectively.10 This is in accordance with our findings. Additionally, the worse functional outcome and the higher number of deaths and dependency, observed in right insular strokes compared to any other strokes, was more prominent in mild to moderate strokes.10 However, among more severe strokes outcomes did not differ significantly. Another study showed that right insular infarctions were independently associated with mortality after adjusting for various confounders including left insular involvement nevertheless the follow up was restricted to 90 days after the index event.9 Nevertheless authors acknowledged that reported higher mortality after right insular infarcts could be partially attributed to exclusion of aphasic patients with left insular involvement because of their inability to provide informed consent.9 Previous research has shown abnormal ECG findings, arrhythmias, and increased risk of sudden death in patients with acute stroke with insular involvement.2,17 In addition, there is some evidence supporting the laterality of autonomic representation in the brain10,11 between right and left insular cortex, and particularly the reduction in cardiac parasympathetic innervation18 and the concomitant unbalanced sympathetic activation and arrhythmiogenesis in
right lesions.19 It has been postulated that right insular infarcts are associated with autonomic system dysfunction leading to arrhythmias,15,18 blood pressure elevation and sudden death.10 In our study, no difference has emerged in newly diagnosis of AF or other serious arrhythmias between lateralized insula's ischemic insult,20 challenging the neurogenic hypothesis of arrhythmiogenesis and the concept that arrhythmias and AF are the cardiac consequence rather than the cause of cerebral ischemia.21 In addition, in our study sudden death occurred equally in both groups. Similarly, blood pressure and glucose levels on admission, that may reflect impaired autonomic activity, did not differ in patients with insular involvement either left or right. These observations do not support the hypothesis that the lateralized autonomic control from the right insula is the underlying pathophysiology of these complications.22,23 This is in accordance with previous research showing that insular infarctions are not predictors of significant cardiovascular events at the acute phase of stroke.4 In our study, a significant difference was observed in patients’ NIHSS on admission, since patients with ischemic left insular involvement have scored higher (13.6 versus 11.7, P = .001). One could speculate that except for the motor disability, which has been assumed to be comparable between equal sized ischemic lesions, aphasia contributed to the higher NIHSS score of left hemisphere. On the other hand in right hemispheric lesions we recognize serious cognitive impairment such as neglect, spatial or visual, and nosoagnosia24 which affect the stroke severity and contribute to an unfavorable functional outcome,10 however severe aphasia scores higher than extinction/inattention at NIHSS. Our findings have to be considered in the light of certain strengths and limitations. This analysis has been based on a large cohort of prospectively collected patients, evaluating hard outcomes like mortality, stroke recurrence, and major cardiovascular events during an extended follow up of 5 years, although it was a single center study. A limitation of our study is that we were not able to adjust for the ischemic lesion volume since the stroke imaging modality
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varied among patients.1 According to a study by Rizos et al, it seems that the infarct size is the most significant predictor of stroke outcome and, in particular, of cardiovascular complications and not the lesion per se in specific cerebral structures.25 Another drawback of the study is that abnormalities on QTc interval, PR interval as well as premature atrial complexes and short runs of AF (<30 s) have not been systematically recorded. In conclusion, the present analysis of a large registry of prospectively collected patients with acute IS, revealed no differences in early and late outcomes between right and left insular lesions during a follow-up up to 5 years.
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Conflict of Interest SV: none; EK: no COI related to manuscript. Unrelated potential COI: Speaker honoraria from Amgen and BMS/ Pfizer; honoraria for participation to advisory board from BMS/Pfizer; AT: no COI related to manuscript. Unrelated potential COI: received fees for consultancy from GSK; DDM: received honoraria, research and travel grants and consultation fees from Allergan, Amgen, Brain Research, Genesis Pharma, Eli Lily, Merck-Serono, Novartis, Roche, Specifar and Teva; EM: none; GG: none; GN: received through his institution honoraria for participation in clinical trials, contribution to advisory boards or oral presentations from Sanofi, Boehringer-Ingelheim, Galenica, Elpen, BMS/ Pfizer, Amgen, and Bayer; research support from BMS/ Pfizer; has no ownership interest and does not own stocks of any pharmaceutical company; HM: none; SF: none; KV: received honoraria, travel grants and oral presentations fees from Amgen, Sanofi, Boehringer-Ingelheim, Elpen, Pfizer and Bayer. Has no ownership interest and does not own stocks of any pharmaceutical company.
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Author Contributions SV, EK: study concept, drafting, critical revision of manuscript. KV: study concept, data collection, critical revision of the manuscript. GG: statistical analysis, critical revision of the manuscript. EM, SF: data collection, critical revision of the manuscript. AT, DDM, GN, HM: critical revision of the manuscript.
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Lateralization of Insular Ischemic Stroke is Not Associated With Any Stroke Clinical Outcomes: The Athens Stroke Registry Sophia Vassilopoulou, MD,* Eleni Korompoki, MD, PhD,*,† Argyro Tountopoulou, MD, PhD,* Dimos D. Mitsikostas, MD, PhD,* Efstathios Manios, MD, PhD,† Georgios Georgiopoulos, MD, PhD,† George Ntaios, MD, PhD,‡ Haralampos Milionis, MD, PhD,§ Sophia Fontara, MD,{ and Konstantinos Vemmos, MD, PhD†,jj
Background: Controversial evidence suggests that right insular stroke may be associated with worse outcomes compared to the left insular ischemic lesion. Objectives: We investigated whether lateralization of insular stroke is associated with early and late outcome in terms of in-hospital complications, stroke recurrence, cardiovascular events, and death. Methods: Data were prospectively collected from the Athens Stroke Registry. Insular cortex involvement was identified based on brain CT scans or MRI images. Patients were followed up prospectively at 1, 3, 6 months after hospital discharge and yearly thereafter up to 5-years or until death. The assessed outcomes were in-hospital complications, functional outcome assessed by the modified Rankin Scale, stroke recurrence, cardiovascular events, and death. Cox-regression analysis was performed to estimate the cumulative probability of each outcome according to the lateralization of insular strokes. Results: Among the 1212 patients, 650 had left insular stroke involvement and 562 had right. New onset of in-hospital atrial fibrillation was similar between right and left insular strokes (11.6% versus 12.9%, P = .484). During the 5-year follow-up sudden death occurred in 21 (3.7%) patients with right insular compared to 30 (4.6%) with left insular stroke (P = .476). There was no difference between left and right insular strokes regarding mortality (adjusted odds ratio [OR]: .92, 95% confidence interval [CI]: .80-1.06), stroke recurrence (4.3% versus 4.9%; adjusted OR: .81 95% CI: .58-1.13), cardiovascular events, and sudden death (adjusted OR: .99, 95% CI: .76-1.29) and on death and dependency (adjusted OR: .88, 95% CI: .75-1.02) during a 5-year follow up. Conclusions: Lateralization of insular ischemic stroke involvement is not associated with stroke outcomes. Key Words: Insular stroke—lateralization—stroke recurrence—mortality— cardiovascular events © 2019 Elsevier Inc. All rights reserved.
From the *Department of Neurology, National and Kapodistrian University of Athens, Greece; †Department of Clinical Therapeutics, National and Kapodistrian University of Athens, Greece; ‡Department of Medicine, University of Thessaly, Larissa, Greece; §Department of Internal Medicine, University of Ioannina, Greece; {Department of Radiology, National and Kapodistrian University of Athens, Greece; and jjHellenic Cardiovascular Research Society, Athens, Greece. Received September 17, 2019; accepted November 7, 2019. Sources of funding: None. Address correspondence to Sophia Vassilopoulou, MD, PhD, 1st Department of Neurology Eginition Hospital, National and Kapodistrian University of Athens, 72-74 Vas. Sofias, 11528 Athens, Greece. E-mail: [email protected]. 1052-3057/$ - see front matter © 2019 Elsevier Inc. All rights reserved. https://doi.org/10.1016/j.jstrokecerebrovasdis.2019.104529
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Introduction Insula, the island of the brain cortex, seems to play a crucial role in the regulation of central autonomic nervous system.1 Experimental data support insula’s role in cerebrogenic arrhythmias and sudden cardiac death, in patients with acute ischemic stroke (IS) with insular involvement although this assumption is not well established.2-5 Insular damage has been associated with outcomes of IS at the acute phase as well as with long-term prognosis.4,6-8 Cerebral infarcts involving the insula region tend to be more severe and have been associated with poorer prognosis compared to noninsular IS.4,8-10 Nevertheless the exact pathophysiological mechanisms underlying this association are not well understood. There is some evidence supporting that laterality of insular lesions may play a role in short-term and longterm prognosis after stroke mainly based on the concept of laterality of autonomic representation in the brain.10,11 Nevertheless, there is still a controversy whether right or left insular involvement is mainly associated with unfavorable outcome. The prognostic value of insular lesion laterality in terms of long term outcomes after IS has been not evaluated so far. The present study sought to examine the association between the lateralization of insular ischemic lesions with long-term hard outcomes in a large population of prospectively collected consecutive acute stroke patients.
Subjects and Methods Study Population The study population was derived from the Athens Stroke Registry, a prospective registry of consecutive patients presented with an acute first-ever stroke between June 1992 and August 2012. The methodology followed to register data in the Athens Stroke Registry has been described in detail elsewhere.12 Patients with lacunar strokes, infratentorial infarcts, noninsular and multiple territory infracts and patients presented more than 48 hours after symptom onset were excluded from the present study (Fig 1). The local Ethics Committee approved the scientific use of the data collected in the Athens Stroke Registry. Data including baseline characteristics, medical history, traditional cardiovascular risk factors, stroke pathophysiological mechanism according to TOAST classification,13 vital signs, and findings from physical examination, laboratory investigations, cardiac work up, in-hospital treatment as well as a detailed description of brain imaging were prospectively collected. Stroke severity was assessed using the National Institute of Health Stroke Scale (NIHSS) score on admission.14 Functional outcome was assessed using the modified Rankin scale at regular follow-up visits.
Brain Imaging According to the imaging protocol, all patients had a computed tomography (CT) at admission and a repeat CT or magnetic resonance imaging (MRI) within the first week after symptom onset. The choice of CT or MRI as the second imaging modality depended on the available resources and on clinical presentation (eg, for patients with symptoms suggesting a posterior circulation infarct, MRI was preferred). Only the patients who underwent the first brain scan within 48 hours from symptom onset have been included in the present study. All scans were assessed retrospectively, by a board certified radiologist (S.F.) who was blinded to the study hypothesis. The presence and side of insular involvement was assessed on baseline and follow-up scans. Insular lesions were defined as indistinct gray matter outline or as hypodense attenuation of the insula.15 Location and lateralization of brain infarcts were recorded. All cerebral infarctions in the insular cortex or at least in a portion of the insula, regardless if they affected other brain regions too, were classified as insular strokes. Cerebral edema was defined as the presence of midline shift, sulcal effacement, or ventricular compression in patients with acute IS and cerebral damage as the irreversible brain herniation.
Stroke Complications A routine 12-lead electrocardiogram (ECG) upon admission was recorded in all patients. Cardiac arrhythmias were documented by means of: (a) repeated ECGs during hospital stay, (b) continuous ECG monitoring for 1 week or until discharge for patients treated in the acute stroke unit, and (c) 24-hour Holter ambulatory ECG monitoring in cases that AF or other arrhythmias were strongly suspected from the clinical presentation, cardiac echocardiogram and brain imaging findings. Diagnosis of AF required an episode of AF lasting at least 30 seconds documented at least by one modality. Other cardiovascular events, such as acute heart failure, sudden death, severe arrhythmias (supraventricular or ventricular tachycardias and atrio-ventricular blocks), were also recorded. Pulmonary and urinary infections, deep venous thrombosis, and pulmonary embolism were evaluated and registered by the stroke physicians.
Follow-up and Stroke Outcomes Patients were followed up prospectively at the outpatient clinic at 1, 3, and 6 months after hospital discharge and yearly thereafter or until death. For patients not able to attend the outpatient clinic, follow-up was assessed by telephone interview with the patient or patient’s next of kin, or at the patient's residence by medical personnel. Lost-to-follow-up was defined as inability to reach the patient or the patient’s proxies at a scheduled point in time. The assessed outcomes were 5-year all-cause mortality, stroke recurrence, functional outcome, and major cardiovascular event (comprising of recurrent stroke,
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3315paents in the Athens Stroke Data Bank
483 excluded because of Intracerebral hemorrhage 2832 paents with ischemic stroke
1620 paents excluded aer applying inclusion/exclusion criteria: 660: lacunar infarcs 540: non insular infarcts 302: infratentorial infarcts 51: mulple territory infarcts 45: presented >48 hours aer onset 22: missing data
1212 paents included in the analysis
650 paents with le insular infarcts
562 paents with right insular infarcts
Figure 1. Study flow chart.
myocardial infarction, systemic embolism, aortic aneurysm rupture, or sudden cardiac death). Recurrent stroke was defined as a cerebrovascular event of sudden onset, lasting more than 24 hours, subsequent to the initial stroke, resulted in a new neurological deficit or in deterioration of the previous neurological deficit, demonstrated on brain imaging. Dependency was defined as modified Rankin Scale Score greater than or equal to 3. Death and causes of death were assessed from death certificates, patients' hospital records, and information from general practitioners or family physicians.
Statistical Analysis Continuous variables are presented as mean value § standard deviation and categorical covariates as absolute
numbers and proportion (%). For patients lost during follow-up, survival data were censored at the last time known to be alive. Patients who experienced more than one composite vascular event during the follow-up were censored at the time of the first event. Student’s t-test was applied to compare continuous variables; chi-square or Fisher’s exact test was applied for categorical variables. The Kaplan-Meier product limit method was used to estimate the cumulative probability of each outcome according to insular infarct lateralization. Differences in Kaplan-Meier curves were evaluated with the log-rank test. Cox-regression analyses were performed to assess whether lateralization was an independent predictor of outcomes in patients with insular infarcts. The covariates entered in the analyses included age, sex, stroke severity (evaluated by NIHSS score), stroke etiology, cardiovascular
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Table 1. Basic characteristics of the study population according to lateralization of insular infarct
Sex (men) Age (mean) Delay admission (mean, h) Days of hospital stay (mean, days) History of Hypertension Diabetes Dyslipidemia Smoking Transient ischemic Attacks Coronary artery diseases Atrial Fibrillation Admission values NIHSS1 Systolic BP (mmHg) Diastolic BP (mmHg) Glucose (mg/dl) Stroke classification* Atherosclerosis Cardioembolism Undetermined Other etiology Inhospital treatment Thrombolysis Aspirin Hepariny
Right insula n = 562
Left insula n = 650
P value
302 (53.7) 71.5 (12.3) 5.6 (10.7) 12.5 (7.6)
351 (54.0) 71.3 (12.7) 5.2 (9.2) 13.1 (7.9)
.954 .832 .481 .180
363 (64.6) 129 (23.0) 173 (30.8) 165 (29.4) 56 (10.1) 120 (21.4)
433 (66.6) 158 (24.3) 194 (29.8) 185 (28.5) 54 (8.3) 148 (22.8)
.467 .589 .754 .751 .318 .579
11.7 (8.2) 153.4 (26.5) 86.6 (12.8) 134.5 (56.9)
13.6 (8.5) 151.7 (25.7) 85.4 (11.7) 132.4 (57.0)
.001 .255 .081 .528 .637
84 (14.9) 272 (48.4) 191 (34.0) 15 (2.7)
113 (17.4) 298 (45.8) 224 (34.5) 15 (2.3)
16 (2.8) 437 (77.8) 341 (60.7)
17 (2.6) 493 (75.8) 408 (62.8)
.860 .454 .477
Abbreviations: NIHSS, National Institute Stroke Scale. Numbers in parentheses for nominal data indicate percentages and for continuous SD. *Stroke classification based on TOAST criteria. † Heparin: Low dose for prophylaxis of venous thromboembolism.
risk factors, and comorbidities (history of hypertension, diabetes mellitus, smoking, dyslipidemia, coronary artery disease, atrial fibrillation, admission blood pressure, and glucose), and in-hospital treatment (thrombolysis, antithrombotics). Significant factors in the univariate analyses were included in the multivariate Cox model. For the univariate analysis, the level of significance was set at .1 to reduce the risk of a type II error. In the final multivariate analyses, the level of significance was set at .05. Associations are presented as hazard ratios with their corresponding 95% confidence intervals (95% CI) using the right location as the comparator in insular. Statistical analyses were performed with the Statistical Package for Social Science (SPSS Inc, version 17.0 for Windows; Chicago, IL).
Results From the original study cohort of 3315 acute stroke patients, the analysis included 1212 patients with insular involement: left insula was impaired in 650 patients (45.8% with partial involvement) and right insula in 562 patients (43.6% with partial involvement; Fig 1). The study population was divided in two groups in terms of
insular infarct laterality. Patients’ baseline characteristics are summarized in Table 1. Patients’ age was the same between the two groups. Arterial hypertension was the most frequent risk factor in both groups. Stroke severity was higher in patients with left insular infarcts (median NIHSS score on admission: 13.6 versus 11.7, P< .001). The most common stroke subtype according to TOAST classification in both groups was cardioembolic, 48.4% in right insular lesions and 45.8% in left insular strokes. Patients’ treatment during hospitalization was completely comparable between left or right insular stroke. In-hospital stroke complications and the causes of death according to the lesion topography are presented in the Table 2. No differences were observed between right and left insular infarcts. The most frequent complications and in-hospital causes of death in both groups were infections and brain edema. In-hospital new-onset AF was comparable between right and left insular strokes (11.6% versus 12.9%, P = .484). The occurrence of other severe arrhythmias did not differ significantly between the two groups (3.0% among patients with right insular infarcts and 2.2% among the left ones, P = .366; Tables 1 and 3).
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Table 2. Inhospital stroke complications and causes of death according to the lateralization of insular infarct
Inhospital complications Brain edema with mass effect Infections Cardiovascular New atrial fibrillation Other severe arrhythmias Stroke recurrence Venous thromboembolism Seizures Other Inhospital causes of death Brain damage Infections Cardiovascular Sudden death Stroke recurrence Other causes Unknown cause 5 years causes of death Brain damage at the acute phase Infections Cardiovascular Sudden death Stroke recurrence Other causes Unknown cause
Right n = 562
Left n = 650
P value
85 (15.1) 153 (27.2) 10 (1.8) 65 (11.6) 17 (3.0) 11 (2.0) 4 (0.7) 10 (1.8) 12 (2.1)
85 (13.1) 194 (29.8) 11 (1.7) 84 (12.9) 14 (2.2) 14 (2.2) 11 (1.7) 20 (3.1) 6 (0.9)
.320 .339 1.000 .484 .366 .842 .191 .194 .097
32 (5.7) 32 (5.7) 3 (0.5) 4 (0.7) 1 (0.2) 2 (0.4) 1 (0.2)
34 (5.2) 29 (4.5) 5 (0.8) 5 (0.8) 4 (0.6) 1 (0.2) 2 (0.3)
.800 .358 .731 1.000 .381 .600 1.000
34 (6.0) 70 (12.5) 24 (4.3) 21 (3.7) 24 (4.3) 25 (4.4) 35 (6.2)
35 (5.4) 69 (10.6) 40 (6.2) 30 (4.6) 32 (4.9) 24 (3.7) 35 (5.4)
.622 .322 .158 .476 .681 .560 .540
Numbers in parentheses indicate percentages.
During the 5-year- follow up (mean 30.1 § 24.1 months), the main causes of death were initial brain damage, infections, cardiovascular events, and sudden death without any significant difference between patients with left insular involvement and right insular lesion (P = .622, P = .322, P = .158, and P = .476, respectively; Table 2). Overall, 24 patients (4.3%) with right insular lesions experienced a new cardiovascular event as compared to 40 (6.2%) with the left insular lesions (P = .158). A recurrent stroke occurred in 4.9% of patients with left insular lesions and in 4.3% of patients with right insular involvement (Odds Ratio (OR): .81, 95% CI: .58-1.13, P = .681). The association between lateralized insular involvement and stroke outcome is presented in Table 3 and Figure 2. In Cox regression analysis, after adjustment for age, sex, stroke severity (NIHSS score), stroke risk factors, etiology, and treatment, no differences were identified on mortality, death or dependence, stroke recurrence, cardiovascular events, and sudden death between right and left insular infarcts. Moreover, the cumulative risk for all outcomes was similar between right and left insular ischemic lesions; (adjusted OR (aOR) for mortality .92, 95% CI .80-1.06; aOR for death or dependency .99, 95% CI .76-1.29; aOR for stroke recurrence 0.81, 95% CI .58-1.13; aOR for cardiovascular events and sudden death .99, 95% CI .76-1.29).
Table 3. Univariate and multivariate cox regression analysis for the 5-year outcomes according to the lateralization of insular infarcts Right insular versus left insular
Mortality Death or dependencey Stroke Recurrence Cardiovascular events and sudden death
Unadjusted OR (95% CI)
Adjusted* OR (95% CI)
.95 (.83-1.08) .98 (.86-1.15) .79 (.57-1.10) .98 (.76-1.27)
.92 (.80-1.06) .88 (.75-1.02) .81 (.58-1.13) .99 (.76-1.29)
*Adjusted: by age, sex, NIHSS score, stroke risk factors, stroke etiology by TOAST criteria, stroke inhospital treatment, admission BP and glucose. † Modified Rankin Score 3.
Discussion This cohort study evaluated 1212 consecutive prospectively collected patients with acute IS involving the right or left insula. The most significant finding was that no difference emerged in in-hospital and long-term outcomes between right and left insular strokes during an extended follow-up period of 5 years. The present study offers important insights into the long-standing debate whether
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Figure 2. Cumulative risk for stroke mortality (A), stroke recurrence (B) and cardiovascular events/sudden death (C) according to the lateralization of insular stroke.
the right or left insula is the one most associated with unfavorable outcomes and poorer prognosis after acute IS. Our findings seem to be contradictory with previous research supporting the hypothesis that only right and not left insular ischemia is associated with poor outcomes.7,10,15,16 An analysis from the IST-3 Trial reported higher odds of death and worse functional outcomes in IS patients with right insular lesions compared to noninsular strokes in the left side within 6 months after the index event.10 Adjusted mortality was not different between insular and noninsular strokes on the left side. Nevertheless, although not directly compared, causes of death were similar between left-insular and right insular strokes at 6 months: cerebrovascular death 63.6% versus 64.2%, cardiovascular death 8.4% versus 7.4%, infections 17.8% versus 16.6%, respectively.10 This is in accordance with our findings. Additionally, the worse functional outcome and the higher number of deaths and dependency, observed in right insular strokes compared to any other strokes, was more prominent in mild to moderate strokes.10 However, among more severe strokes outcomes did not differ significantly. Another study showed that right insular infarctions were independently associated with mortality after adjusting for various confounders including left insular involvement nevertheless the follow up was restricted to 90 days after the index event.9 Nevertheless authors acknowledged that reported higher mortality after right insular infarcts could be partially attributed to exclusion of aphasic patients with left insular involvement because of their inability to provide informed consent.9 Previous research has shown abnormal ECG findings, arrhythmias, and increased risk of sudden death in patients with acute stroke with insular involvement.2,17 In addition, there is some evidence supporting the laterality of autonomic representation in the brain10,11 between right and left insular cortex, and particularly the reduction in cardiac parasympathetic innervation18 and the concomitant unbalanced sympathetic activation and arrhythmiogenesis in
right lesions.19 It has been postulated that right insular infarcts are associated with autonomic system dysfunction leading to arrhythmias,15,18 blood pressure elevation and sudden death.10 In our study, no difference has emerged in newly diagnosis of AF or other serious arrhythmias between lateralized insula's ischemic insult,20 challenging the neurogenic hypothesis of arrhythmiogenesis and the concept that arrhythmias and AF are the cardiac consequence rather than the cause of cerebral ischemia.21 In addition, in our study sudden death occurred equally in both groups. Similarly, blood pressure and glucose levels on admission, that may reflect impaired autonomic activity, did not differ in patients with insular involvement either left or right. These observations do not support the hypothesis that the lateralized autonomic control from the right insula is the underlying pathophysiology of these complications.22,23 This is in accordance with previous research showing that insular infarctions are not predictors of significant cardiovascular events at the acute phase of stroke.4 In our study, a significant difference was observed in patients’ NIHSS on admission, since patients with ischemic left insular involvement have scored higher (13.6 versus 11.7, P = .001). One could speculate that except for the motor disability, which has been assumed to be comparable between equal sized ischemic lesions, aphasia contributed to the higher NIHSS score of left hemisphere. On the other hand in right hemispheric lesions we recognize serious cognitive impairment such as neglect, spatial or visual, and nosoagnosia24 which affect the stroke severity and contribute to an unfavorable functional outcome,10 however severe aphasia scores higher than extinction/inattention at NIHSS. Our findings have to be considered in the light of certain strengths and limitations. This analysis has been based on a large cohort of prospectively collected patients, evaluating hard outcomes like mortality, stroke recurrence, and major cardiovascular events during an extended follow up of 5 years, although it was a single center study. A limitation of our study is that we were not able to adjust for the ischemic lesion volume since the stroke imaging modality
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varied among patients.1 According to a study by Rizos et al, it seems that the infarct size is the most significant predictor of stroke outcome and, in particular, of cardiovascular complications and not the lesion per se in specific cerebral structures.25 Another drawback of the study is that abnormalities on QTc interval, PR interval as well as premature atrial complexes and short runs of AF (<30 s) have not been systematically recorded. In conclusion, the present analysis of a large registry of prospectively collected patients with acute IS, revealed no differences in early and late outcomes between right and left insular lesions during a follow-up up to 5 years.
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Conflict of Interest SV: none; EK: no COI related to manuscript. Unrelated potential COI: Speaker honoraria from Amgen and BMS/ Pfizer; honoraria for participation to advisory board from BMS/Pfizer; AT: no COI related to manuscript. Unrelated potential COI: received fees for consultancy from GSK; DDM: received honoraria, research and travel grants and consultation fees from Allergan, Amgen, Brain Research, Genesis Pharma, Eli Lily, Merck-Serono, Novartis, Roche, Specifar and Teva; EM: none; GG: none; GN: received through his institution honoraria for participation in clinical trials, contribution to advisory boards or oral presentations from Sanofi, Boehringer-Ingelheim, Galenica, Elpen, BMS/ Pfizer, Amgen, and Bayer; research support from BMS/ Pfizer; has no ownership interest and does not own stocks of any pharmaceutical company; HM: none; SF: none; KV: received honoraria, travel grants and oral presentations fees from Amgen, Sanofi, Boehringer-Ingelheim, Elpen, Pfizer and Bayer. Has no ownership interest and does not own stocks of any pharmaceutical company.
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Author Contributions SV, EK: study concept, drafting, critical revision of manuscript. KV: study concept, data collection, critical revision of the manuscript. GG: statistical analysis, critical revision of the manuscript. EM, SF: data collection, critical revision of the manuscript. AT, DDM, GN, HM: critical revision of the manuscript.
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