Clinical course, prognostic factors, and long-term outcomes of malignant middle cerebral artery infarction patients in the modern era
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0028-3886.181567
Source of Support: None, Conflict of Interest: None
Background: Recanalization therapies have been increasingly applied in clinical practice, which might change the outcomes of patients with large middle cerebral artery (MCA) infarction. The purpose of this study was to study the clinical course, prognostic factors, and long-term outcomes of patients with an acute large MCA infarction.
Keywords: Asia; decompressive surgery; malignant infarct; middle cerebral artery
The prognosis of patients with a malignant middle cerebral artery (MCA) infarction is poor, with the case fatality rates in previous intensive care-based series of nearly 80%., Life-threatening brain edema causing transtentorial herniation is the common cause of early death in these patients. Complications occurring during the hospital stay are also common, which cause a longer length of stay and result in higher costs as compared to those with less severe stroke. Patients who survive usually have a residual disability. No medical treatment has been proven to be effective. Early decompressive surgery has shown to decrease the mortality and also morbidity in a couple of studies.,
In the modern era, the intravenous thrombolytic treatment and an early endovascular treatment are increasingly used in clinical practice. Stroke units with experienced multidisciplinary care teams are widely accepted as the standard of care for patients with an acute ischemic stroke. Furthermore, with increasing rates of early decompressive surgery, the outcomes of patients with an acute malignant cerebral artery infarction are expected to be better than in previous studies. The purpose of this study was to study the clinical course, prognostic factors, and long-term outcomes of patients with an acute large MCA infarction.
Patients with an acute large MCA infarction who were treated at Thammasat University Hospital during January, 2011 – March, 2014 were studied. The inclusion criteria were severe stroke; National Institute of Health Stroke Scale [NIHSS] value of at least 15; clinical deficits suggestive of a large infarction in the territory of the MCA (such as gaze preference, aphasia and neglect); and, patients who presented within 24 h after the onset of stroke. All patients were treated according to the standard care protocol. Thrombolysis was administered in some eligible patients who presented within 4.5 h and had no exclusion criteria for intravenous recombinant-tissue-plasminogen activator (rtPA) treatment. All patients were admitted and treated at the stroke unit with an experienced multidisciplinary stroke care team taking care of the stroke patients. Computed tomography was performed at baseline, when the patients deteriorated, and before starting anticoagulants. Uncal herniation was defined by clinical deterioration and radiographic findings; and, the presence of large hypodensity lesions in the cerebral hemisphere causing a midline shift and obliterating the ipsilateral perimesencephalic spaces. A carotid duplex scan, transcranial Doppler imaging, magnetic resonance imaging/angiography, chest X-ray, at least 24 h continuous electrocardiography monitoring, and blood chemistry were done in patients to find out the causes of stroke.
Data regarding the baseline characteristics of the patients, course of the disease, stroke subtypes, neuroimaging, treatment, complications, and outcomes were collected. The stroke subtypes were classified by the TOAST (Trial of ORG 10172 in Acute Stroke Treatment) criteria as: Large-artery atherosclerosis (LAA), cardioembolic (CE) stroke, stroke of another determined cause, and stroke of an undetermined cause. Clinical outcomes were evaluated using modified Rankin Scale (mRS). A favorable outcome was considered when the mRS score remained between 0–2. All patients were followed up at 3, 6, 9, and 12 months. If the patients were unable to come for follow-up at an outpatient clinic, they were contacted by a well-trained research assistant to assess their clinical outcomes (mRS) and complications.
The data were presented as a mean or a median for continuous variables and percentage (number) for dichotomous variables. The demographics and vascular risk factors were compared between patients with and without clinical outcomes of interest; a favorable outcome and death using Student's t-test (for the continuous variables) and the chi-square test (for the proportions). Stepwise multivariate analyses were performed by including the pre-specified factors that were associated with the measured outcome variables in the univariate analysis. The research protocol was approved by the Human Ethic Committee of Thammasat University no. 1, Faculty of Medicine.
Two hundred patients were included during the study period. Large MCA infarct accounted for 13% (200 out of 1538 cases) of all acute ischemic stroke cases in our cohort study. The mean age was 67 years. Baseline characteristics of the patients are presented in [Table 1]. The mean time from the onset to stroke to admission to a hospital was 289 min (range from 15 to 1391 min). Intravenous rtPA was given in 50 patients (25%). The mean follow-up time was 13 months (range from 3 to 36 months). 9 patients were lost to follow-up. 51 patients (51/191, 27%) had a favorable outcome (mRS 0–2) at the final follow-up. 81 patients (81/191, 42%) died during the follow-up period [Table 2].
Clinical and radiographic-confirmed uncal herniation was found in 42 (21%) patients. The mean time required for the deterioration of patients was 2.5 days from the onset of stroke (range from the first day of stroke to day 6 after stroke).
Complications during hospital admission
One hundred and thirty-two patients (66%) had at least one complication during admission. Infection was the most common complication; respiratory tract infection in 29% of cases and urinary tract infection in 11%. Gastrointestinal bleeding was found in 4 patients and intracerebral hemorrhage in 3 patients. Cardiac complications were found in 8 patients. The mean length of stay was 11 days (range from 1 to 65 days), and the cost during admission was 2490 US dollars (82,177 bahts) [range from 162 to 15,372 US dollars].
At discharge, only 30 patients (15%) had a favorable outcome (mRS 0–2) and 31 patients (15.5%) died. The causes of death during the hospital admission were brain herniation (13 patients), cardiac conditions (acute coronary syndrome, congestive heart failure, arrhythmia; 7 patients), sepsis (5 patients), other stroke-related conditions (1 patient), other causes (2 patients), and unknown causes (3 patients). At final follow-up (average 13 months), 9 patients missed the follow-up and were unable to be contacted in any way. 51 patients (27%) had a favorable outcome [Figure 1]. Clinical outcomes at final follow-up categorized by the age group are presented in [Figure 1].
The baseline characteristics of patients who had outcomes of interest are presented in [Table 2]. Multivariate analysis showed that younger age, less severe stroke, large artery atherosclerosis (LAA) stroke subtype (odds ratio [OR]: 6.16; 95% confidence interval [CI]: 1.8–21.05, P = 0.004) and rtPA treatment (OR: 12.94, 95% CI: 4.21–39.7) were associated with a favorable outcome. With each 10 year increase in age of the patient, there was a less chance of having a favorable outcome; OR = (Exp. B)year = (0.911)10 = 0.393, P < 0.001. In addition, with more severe stroke, that is, an increase of 5 points on the NIHSS, a less favorable outcome was found; OR = (Exp. B)point = (0.798)5 = 0.32, P = 0.009.
Eighty-one patients (42%) died during the course of the study. The causes of death after discharge were sepsis (18 patients), stroke-related death (4 patients), major bleeding (1 patient), a cardiac cause (2 patients), and unknown causes (25 patients). A multivariate analysis showed that an older age and the presence of coronary artery disease (OR: 3.34, 95% CI: 1.28–8.72, P = 0.014) were associated with death, while rtPA treatment was inversely related to death (OR: 0.13, 95% CI: 0.048–0.341, P < 0.001). As the mean age of the groups of patients included in the study increased by 10 years, a higher chance of death was observed; OR = (Exp. B)year = (1.036)10 = 1.842, P < 0.001.
Fourteen patients did not undergo surgery. This decision was based on the will that they had made prior to the development of stroke. 36 patients underwent decompressive surgery. Presurgical uncal herniation occurred in 29 patients (29/36; 81%). At discharge, of the patients aged ≤60 years, 3 patients (3/14, 21%) had a favorable outcome (mRS 0–2), and 1 patient died. For older patients (>60 years old) who underwent the decompressive surgery, no patient had a favorable outcome at discharge, and 8 patients (8/22, 36%) died. At the final assessment, 3 patients (3/29, 10%, all aged ≤60 years) had a favorable outcome, and 17 patients died (17/29, 59%; 14 patients aged >60 years).
Previous studies had shown that malignant MCA infarction was associated with 70–80% mortality.,,, However, some of these studies were published between 1996–1998, and although others were more recently reported, they did not include all of the patients with a large MCA infarct immediately after the onset of stroke (and who might benefit from recanalization therapy). A recently published study showed a lower rate of in-hospital deaths (25%) in 32 patients with malignant MCA infarction. Intravenous thrombolysis is approved as the standard treatment in eligible patients, when administered within 4.5 h after the onset of stroke which increases the odds of a favorable outcome (OR: 1.9, 95% CI: 1.2–2.9). Our study included all patients with an acute large MCA infarction irrespective of any treatments that they had received. Thammasat University Hospital serves as a “hub” with 25 “spoke” hospitals in the Thammasat Stroke Network; therefore, most of the patients with a large MCA infarct were included and an early intravenous rtPA was prescribed in 25% of the patients.
With the mean follow-up time of 13 months, 51 patients (51/191, 27%) had a favorable outcome (mRS 0–2). The rate was rather high as compared to the results from previous studies., This might be explained by the improvement due to the early administration of thrombolytic treatment since almost half of the patients with a favorable outcome in our cohort received intravenous rtPA. The multivariate analysis showed that rtPA treatment was associated with a favorable outcome (OR: 12.94, 95% CI: 4.21–39.7) and inversely correlated with death (OR: 0.13, 95% CI: 0.048–0.341, P < 0.001). Most of the rtPA studies showed that severe stroke was associated with a poor outcome or death; severe stroke was also often associated with an increased incidence of symptomatic intracerebral hemorrhage in patients receiving intravenous rtPA.,, Thus, the question regarding whether or not the benefit of the rtPA treatment outweighs the risks in those with severe stroke as compared to those who did not undergo thrombolytic treatment still remains unanswered. A subgroup analysis from the third international stroke trial-3 revealed that patients with more severe stroke tended to have favorable outcomes after rtPA treatment as compared to the control group. Patients with an NIHSS score of 10 or more have a greater than 80% likelihood of a major arterial occlusion., Intravenous thrombolysis achieves partial or complete recanalization in 30–50% of patients, but lower recanalization rates in proximal, large vessel occlusions. This probably explained the limited efficacy of the intravenous rtPA treatment. The combination of a rapid endovascular treatment and intravenous thrombolysis has recently shown to be having a higher rate of recanalization and clinical benefit as compared to the standard treatment or intravenous thrombolysis alone.,, However, most of the positive trials include selected patients with a small infarct core and a rather good collateral circulation; and, the endovascular treatment needs to be carried out rapidly (the median time from stroke onset to groin puncture ranges from 185 to 260 min).,, The endovascular treatment also requires an organized system of stroke care, health care personnel with special expertise, interventionists available 24 hours a day on all days of a week, and advanced neuroimaging capabilities. These are facilities which are available in only comprehensive stroke centers.
Atrial fibrillation and the cardioembolic (CE) stroke subtypes were related to an unfavorable outcome and higher death rate in our study. Arboix et al., also showed that in-hospital mortality in patients with atrial fibrillation was significant higher than those with nonatrial fibrillation both in patients in the CE and atherothrombotic stroke subgroups.
Patients with a large MCA infarct usually have a longer length of hospital stay, and this is partly due to the higher complication rates as compared to patients with less severe stroke. In this study, the mean length of stay was 11 days, and two-third of the patients had at least 1 complication, which was higher than those reported in a previous multicenter countrywide prospective study. Nilanont et al., showed that in Thai patients with acute, nonselected, ischemic stroke (1222 patients, mean NIHSS of 6.5), the median length of stay was 4 days, and the complication rate was 14%. A good recovery at discharge (mRS 0–1) was found in 26%, and 3% of patients died during hospitalization.
Eighty-one patients (41%) died in this study. In nearly half of the patients (13/31, 42%) who died early (during admission), death was caused by brain herniation. 50 patients died after discharge, and the major cause of death was infection. In Thailand, at present, there are few nursing facilities and the costs are high. Most disabled patients who survived in this study returned home and were taken care of by their relatives, who usually had to work for a living, and most of them did not have enough knowledge, time, and skill to care for the patients. This might explain the high mortality rate in the study after the patients had been discharged.
Thirty-six patients (18%) had decompressive surgery. Due to the limited numbers of neurosurgeons, the main reason for performing the decompressive surgery was to save life, and not with the aim of avoiding the disability or to prevent the disability from progressing. Presurgical uncal herniation was found in 29 patients (29/36; 81%). The outcomes of those patients with an age ≤60 years were comparable with those in a pooled study. However, considering the outcomes in older patients (>60 years old), it was found that there were no patients with a favorable outcome, and a higher death rate (64%) was seen as compared to a previous study. Decompressive hemicraniectomy in younger patients (≤60 years old) was found to save life. However, the outcomes of hemicraniectomy in those in the older age group (>60 years old) were poor. Thus, in the latter age group, the procedure may not be routinely recommended.
This is a large cohort study of patients with an acute large MCA infarct, which includes patients from the very acute phase. The study also has a long-term follow-up. Our study showed that favorable outcomes were found in a fourth of the patients with a large MCA infarct. A younger age, less severe stroke, rtPA treatment, and LAA stroke subtype were related to a favorable outcome. In eligible patients with MCA infarction, the intravenous rtPA treatment should be recommended. A high mortality rate in patients with a large MCA infarct was still found. The main cause of the early death was brain herniation, while infection was a major cause of death after the patient had been discharged. Intravenous rtPA treatment seemed to be related to a favorable outcome.
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Faculty of Medicine, Thammasat University.
Conflicts of interest
There are no conflicts of interest.
[Table 1], [Table 2]