Clinical Investigative Study Natural History of Acute Stroke due to Occlusion of the Middle Cerebral Artery and Intracranial Internal Carotid Artery ´ ´ ´ ` ´ MD, PhD, Mar´ıa Hernandez-P erez, MD, Natalia Perez de la Ossa, MD, PhD, Aitziber Aleu, MD, Monica Millan, ´ ´ Meritxell Gomis, MD, PhD, Laura Dorado, MD, PhD, Elena Lopez-Cancio, MD, PhD, Tudor Jovin, MD, Antoni Davalos, MD, PhD From the Stroke Unit, Department of Neurosciences, Hospital Universitari Germans Trias i Pujol, Badalona, Spain (MH-P, NPO, AA, MM, MG, LD, EL-C, AD); UPMC Stroke Institute, Pittsburgh, Pennsylvania (TJ).
ABSTRACT BACKGROUND AND PURPOSE
The natural history of acute ischemic stroke (AIS) due to anterior circulation large artery occlusion is not well established. This information is essential for assessment of clinical benefit derived from recanalization therapies. METHODS
Patients with AIS due to anterior circulation large artery occlusion not treated with reperfusion therapies admitted from January 2005 to September 2010 were consecutively selected. Site of occlusion was assessed with transcranial duplex according to Thrombolysis in Brain Infarction (TIBI) grades. Poor outcome was considered as a modified Rankin Scale>2 at 90 days. RESULTS
A total of 120 patients were studied. Site of occlusion was terminal internal carotid artery (TICA) in 13 (10.8%), proximal middle cerebral artery (MCA) in 69 (57.5%), and distal MCA in 38 (31.7%) patients. Overall, 74.2% of patients had poor outcome. There were significant differences in poor outcome between patients with TICA, proximal MCA, and distal MCA occlusion (92%, 87%, 47%, P < .001) and mortality at 90 days (23%, 12%, 3%, P = .001).
Keywords: Acute stroke, prognosis, natural history, large artery occlusion. Acceptance: Received November 7, 2012, and in revised form January 22, 2013. Accepted for publication July 5, 2013. Correspondence: Address correspondence to Dr. Natalia Perez de la ´ Ossa, Stroke Unit. Department of Neurosciences. Hospital Universitari Germans Trias i Pujol. Carretera del Canyet s/n. 08916 Badalona (Barcelona), Spain. Email: [email protected]. Disclosures: None. J Neuroimaging 2014;24:354-358. DOI: 10.1111/jon.12062
CONCLUSIONS
Outcome of AIS patients with anterior circulation large artery occlusion not treated with reperfusion therapies is extremely poor in TICA and proximal MCA occlusions with better outcomes noted in distal MCA occlusions. These findings are relevant for estimation of treatment effect of reperfusion therapies according to occlusion location.
Background Intravenous thrombolytic therapy with recombinant tissue plasminogen activator (tPA) has demonstrated efficacy and safety in the acute ischemic stroke (AIS) treatment within 4.5 hours from symptoms onset.1 Intra-arterial therapies (IAT) such as mechanical thrombectomy, offer a therapeutic alternative for patients with persistent large artery occlusion after intravenous tPA and for patients with contraindications to systemic thrombolysis. Moreover, the longer therapeutic window for IAT allows treatment in selected cases, including wake up stroke.2, 3 Although IAT are rapidly evolving in the past few years, the efficacy of endovascular approach remains to be proven by randomized controlled studies. Despite the growing knowledge on stroke pathophysiology, prevention and treatment, the natural history of AIS due to anterior circulation large artery occlusion (ACLAO) is not well established. Available studies date back to the 1980s.4, 5 How-
354
Copyright
ever, these studies do not apply nowadays when acute stroke units and intravenous thrombolysis are standards of care. Intraarterial thrombolysis randomized trials as PROACT and MELT used angiography to select patients with M1 and M2 MCA occlusions and provide a small control group.6 Overall, favorable outcome was found in 40% and 49% of the active group and in 25% and 38% of the control group in each study, but the good outcome rate by site of the occlusion was not reported in either of these two studies. Other thrombolysis randomized clinical trials as ATLANTIS, ECASS, DIAS, and NINDS7, 8 provided a large placebo group, however, the presence and location of the occlusion is not specified. Only post hoc analyses of the randomized EPITHET study provide functional outcome data according to the site of occlusion (ICA and MCA without distinguishing between M1 and M2 occlusions). However results must be considered carefully because of the small sample size.9 Noncontrolled studies using endovascular procedures have
◦ 2013 by the American Society of Neuroimaging C
reported rates of successful recanalization range between 46% and 90% and good outcome at 3 months achieved in 25%-55% of patients, depending on the treatment modality.10–16 However, comparison of these results with the outcome of patients not treated with reperfusion therapies is not possible as no control group is available. Our aim was to describe the natural history of stroke due ACLAO in a large series of patients not treated with reperfusion therapies. This data may be useful as a control group for existing and future noncontrolled studies of endovascular treatment in acute stroke.
Methods Patients From a prospective database of AIS (BADISEN; www. renisen.org) admitted at the Stroke Unit of our Comprehensive Stroke Center between January 2005 and September 2010, patients with a ACLAO who were admitted within the first 24 hours from symptom onset were selected. ACLAO was diagnosed using transcranial duplex (TCDx) (Ecograph General Electric Vivid/Pro). According to previously reported findings, proximal occlusion (M1 occlusion) was defined as Thrombolysis in Brain Infarction (TIBI) 0-1 and distal occlusion (M2 or more distal occlusion) as TIBI 2-3 at ≤54 mm depth without carotid disease. Terminal internal carotid artery (TICA) occlusion was diagnosed according to the following criteria; (1) absent flow signal of MCA, anterior cerebral artery and distal ICA; (2) high resistance profile in the extracranial ipsilateral ICA and common carotid artery.17, 18 Out of 394 patients with ACLAO, those treated with reperfusion therapies (n = 217, 54%) were excluded from the analysis. Other exclusion criteria were previous disability defined as modified Rankin Scale (mRS) score ≥ 2 (n = 23), occlusion of extracranial carotid artery with (n = 4) or without intracranial occlusion (n = 30) and time from onset longer than 24 hours (n = 5). Finally 120 patients with ACLAO not treated with reperfusion therapies were eligible for this study. The main reasons for exclusion from treatment were signs of early ischemic changes on neuroimaging (n = 64), presentation beyond accepted time windows – 3 hours prior to ECASS III publication and 4.5 hours thereafter (n = 30), anticoagulation (n = 15), minor stroke (n = 4) and other causes as high blood pressure or recent surgical interventions (n = 7). Since some of these conditions may confer a worse prognosis that could influence our results, we performed a separate analysis in a subgroup of patients in whom the only reason for exclusion from endovascular therapy was that it was not available at the time patients were admitted. For this analysis, patients not considered candidates for endovascular treatment due to early signs of ischemia on baseline neuroimaging studies were excluded.
Clinical variables Demographic data, risk factors, vital signs at admission and stroke etiology accordingly with TOAST classification were recorded. All studied patients were admitted to our stroke unit and managed following EUSI (European Stroke Initiative) guidelines and our institutional protocol. Stroke severity was
assessed using the National Institutes of Health Stroke Scale (NIHSS) on admission, and daily thereafter until seventh admission day or discharge. A noncontrast cranial CT scan or MRI was performed on admission and repeated during hospitalization. Infarct volume was measured on the follow-up neuroimaging (a × b × c/2).19 Medical complications, including cardiac (coronary acute syndrome, cardiac insufficiency), infectious (pneumonia, urinary infections or fever > 37.5 ◦ C) and neurological complications (brain edema with mass effect, hemorrhagic transformation or stroke recurrence) were prospectively recorded. Poor outcome was defined as mRS > 2 at 3 months. A total of 15 patients (12.5%) were lost during followup; in these cases, the discharge mRS was considered as the functional outcome at 3 months.
Statistical analysis Statistical analysis was performed using SPSS 12.0 software. Continuous variables were expressed as mean and standard deviation or median and quartiles, and compared by the Student t-test, Mann-Whitney test or the Kruskal-Wallis test as appropriate. Proportions between the three groups were compared with the χ 2 test. Influence of clinical variables on clinical outcome was assessed by a logistic regression analysis adjusting for those baseline variables showing a P value < 0.1 on univariate analysis and age. Results of logistic regression are shown as odds ratio (OR) and 95% confidence intervals (CI). A P value of < .05 was considered significant.
Results Baseline Characteristics A total of 120 patients (45% female, mean age 68 ± 12 years) were included in our study. Site of occlusion was TICA in 13 patients (10.8%), proximal MCA in 69 patients (57.5%) and distal MCA in 38 patients (31.7%). Table 1 shows the baseline characteristics according to the site of occlusion. NIHSS score at admission was significantly higher in TICA and proximal MCA occlusions than in distal occlusions. No other differences were found between groups. Time from symptoms onset to hospital admission was less than 3 hours in 27% and less than 6 hours in 54% of patients.
Clinical Outcome Poor outcome at 3 months was present in 75% of the patients. Rate of poor outcome was significantly higher in patients with TICA and proximal MCA occlusion compared with distal MCA occlusion (92.3% of TICA, 87.0% of proximal MCA, and 47.4% of distal MCA; P < .001). Patients with TICA and proximal MCA occlusion had also higher rates of mortality at 3 months (23.1%, 11.6%, and 2.6%), higher frequency of infectious complications during hospital admission (38.5%, 36.2%, and 10.5%; P = .01) and of neurological complications, especially brain edema with mass effect (23.0%, 30.4%, and 5.2%; P = 0.01) (Table 2). There were no significant differences on clinical outcome between left and right proximal MCA occlusions (proximal right MCA 89.3%, proximal left MCA 84.2%), but in distal
´ ´ Hernandez-P erez et al: Natural History of Large Cerebral Artery Occlusion
355
Table 1. Baseline Characteristics of Patients Accordingly to Site of Arterial Occlusion Total (n = 120)
TICA (n = 13)
Proximal (n = 69)
Distal (n = 38)
P Value
Age (years) Gender (female) Hypertension Diabetes Dyslipidemia Ischemic heart disease Atrial Fibrillation Smoking habit Stroke severity (NIHSS)
68.2 ± 12 54 (45.0%) 71 (59.%) 34 (28.3%) 55 (45.8%) 20 (16.7%) 38 (31.7%) 33 (27.5%) 17 [9-21]
70.5 ± 12 8 (61.5%) 10 (76.9%) 5 (38.5%) 5 (38.5%) 2 (15.4%) 7 (53.8%) 2 (15.4%) 20 [11-24]
68.9 ± 12 29 (42.0%) 43 (62.3%) 19 (27.5%) 29 (42.0%) 15 (21.7%) 22 (31.9%) 21 (30.4%) 18 [15-21]
66.2 ± 13 17 (44.7%) 18 (47.4%) 10 (26.3%) 21 (55.3%) 3 (7.9%) 9 (23.7%) 10 (26.3%) 10 [4-17]
.48 .43 .12 .69 .36 .18 .13 .53
ABSTRACT BACKGROUND AND PURPOSE
The natural history of acute ischemic stroke (AIS) due to anterior circulation large artery occlusion is not well established. This information is essential for assessment of clinical benefit derived from recanalization therapies. METHODS
Patients with AIS due to anterior circulation large artery occlusion not treated with reperfusion therapies admitted from January 2005 to September 2010 were consecutively selected. Site of occlusion was assessed with transcranial duplex according to Thrombolysis in Brain Infarction (TIBI) grades. Poor outcome was considered as a modified Rankin Scale>2 at 90 days. RESULTS
A total of 120 patients were studied. Site of occlusion was terminal internal carotid artery (TICA) in 13 (10.8%), proximal middle cerebral artery (MCA) in 69 (57.5%), and distal MCA in 38 (31.7%) patients. Overall, 74.2% of patients had poor outcome. There were significant differences in poor outcome between patients with TICA, proximal MCA, and distal MCA occlusion (92%, 87%, 47%, P < .001) and mortality at 90 days (23%, 12%, 3%, P = .001).
Keywords: Acute stroke, prognosis, natural history, large artery occlusion. Acceptance: Received November 7, 2012, and in revised form January 22, 2013. Accepted for publication July 5, 2013. Correspondence: Address correspondence to Dr. Natalia Perez de la ´ Ossa, Stroke Unit. Department of Neurosciences. Hospital Universitari Germans Trias i Pujol. Carretera del Canyet s/n. 08916 Badalona (Barcelona), Spain. Email: [email protected]. Disclosures: None. J Neuroimaging 2014;24:354-358. DOI: 10.1111/jon.12062
CONCLUSIONS
Outcome of AIS patients with anterior circulation large artery occlusion not treated with reperfusion therapies is extremely poor in TICA and proximal MCA occlusions with better outcomes noted in distal MCA occlusions. These findings are relevant for estimation of treatment effect of reperfusion therapies according to occlusion location.
Background Intravenous thrombolytic therapy with recombinant tissue plasminogen activator (tPA) has demonstrated efficacy and safety in the acute ischemic stroke (AIS) treatment within 4.5 hours from symptoms onset.1 Intra-arterial therapies (IAT) such as mechanical thrombectomy, offer a therapeutic alternative for patients with persistent large artery occlusion after intravenous tPA and for patients with contraindications to systemic thrombolysis. Moreover, the longer therapeutic window for IAT allows treatment in selected cases, including wake up stroke.2, 3 Although IAT are rapidly evolving in the past few years, the efficacy of endovascular approach remains to be proven by randomized controlled studies. Despite the growing knowledge on stroke pathophysiology, prevention and treatment, the natural history of AIS due to anterior circulation large artery occlusion (ACLAO) is not well established. Available studies date back to the 1980s.4, 5 How-
354
Copyright
ever, these studies do not apply nowadays when acute stroke units and intravenous thrombolysis are standards of care. Intraarterial thrombolysis randomized trials as PROACT and MELT used angiography to select patients with M1 and M2 MCA occlusions and provide a small control group.6 Overall, favorable outcome was found in 40% and 49% of the active group and in 25% and 38% of the control group in each study, but the good outcome rate by site of the occlusion was not reported in either of these two studies. Other thrombolysis randomized clinical trials as ATLANTIS, ECASS, DIAS, and NINDS7, 8 provided a large placebo group, however, the presence and location of the occlusion is not specified. Only post hoc analyses of the randomized EPITHET study provide functional outcome data according to the site of occlusion (ICA and MCA without distinguishing between M1 and M2 occlusions). However results must be considered carefully because of the small sample size.9 Noncontrolled studies using endovascular procedures have
◦ 2013 by the American Society of Neuroimaging C
reported rates of successful recanalization range between 46% and 90% and good outcome at 3 months achieved in 25%-55% of patients, depending on the treatment modality.10–16 However, comparison of these results with the outcome of patients not treated with reperfusion therapies is not possible as no control group is available. Our aim was to describe the natural history of stroke due ACLAO in a large series of patients not treated with reperfusion therapies. This data may be useful as a control group for existing and future noncontrolled studies of endovascular treatment in acute stroke.
Methods Patients From a prospective database of AIS (BADISEN; www. renisen.org) admitted at the Stroke Unit of our Comprehensive Stroke Center between January 2005 and September 2010, patients with a ACLAO who were admitted within the first 24 hours from symptom onset were selected. ACLAO was diagnosed using transcranial duplex (TCDx) (Ecograph General Electric Vivid/Pro). According to previously reported findings, proximal occlusion (M1 occlusion) was defined as Thrombolysis in Brain Infarction (TIBI) 0-1 and distal occlusion (M2 or more distal occlusion) as TIBI 2-3 at ≤54 mm depth without carotid disease. Terminal internal carotid artery (TICA) occlusion was diagnosed according to the following criteria; (1) absent flow signal of MCA, anterior cerebral artery and distal ICA; (2) high resistance profile in the extracranial ipsilateral ICA and common carotid artery.17, 18 Out of 394 patients with ACLAO, those treated with reperfusion therapies (n = 217, 54%) were excluded from the analysis. Other exclusion criteria were previous disability defined as modified Rankin Scale (mRS) score ≥ 2 (n = 23), occlusion of extracranial carotid artery with (n = 4) or without intracranial occlusion (n = 30) and time from onset longer than 24 hours (n = 5). Finally 120 patients with ACLAO not treated with reperfusion therapies were eligible for this study. The main reasons for exclusion from treatment were signs of early ischemic changes on neuroimaging (n = 64), presentation beyond accepted time windows – 3 hours prior to ECASS III publication and 4.5 hours thereafter (n = 30), anticoagulation (n = 15), minor stroke (n = 4) and other causes as high blood pressure or recent surgical interventions (n = 7). Since some of these conditions may confer a worse prognosis that could influence our results, we performed a separate analysis in a subgroup of patients in whom the only reason for exclusion from endovascular therapy was that it was not available at the time patients were admitted. For this analysis, patients not considered candidates for endovascular treatment due to early signs of ischemia on baseline neuroimaging studies were excluded.
Clinical variables Demographic data, risk factors, vital signs at admission and stroke etiology accordingly with TOAST classification were recorded. All studied patients were admitted to our stroke unit and managed following EUSI (European Stroke Initiative) guidelines and our institutional protocol. Stroke severity was
assessed using the National Institutes of Health Stroke Scale (NIHSS) on admission, and daily thereafter until seventh admission day or discharge. A noncontrast cranial CT scan or MRI was performed on admission and repeated during hospitalization. Infarct volume was measured on the follow-up neuroimaging (a × b × c/2).19 Medical complications, including cardiac (coronary acute syndrome, cardiac insufficiency), infectious (pneumonia, urinary infections or fever > 37.5 ◦ C) and neurological complications (brain edema with mass effect, hemorrhagic transformation or stroke recurrence) were prospectively recorded. Poor outcome was defined as mRS > 2 at 3 months. A total of 15 patients (12.5%) were lost during followup; in these cases, the discharge mRS was considered as the functional outcome at 3 months.
Statistical analysis Statistical analysis was performed using SPSS 12.0 software. Continuous variables were expressed as mean and standard deviation or median and quartiles, and compared by the Student t-test, Mann-Whitney test or the Kruskal-Wallis test as appropriate. Proportions between the three groups were compared with the χ 2 test. Influence of clinical variables on clinical outcome was assessed by a logistic regression analysis adjusting for those baseline variables showing a P value < 0.1 on univariate analysis and age. Results of logistic regression are shown as odds ratio (OR) and 95% confidence intervals (CI). A P value of < .05 was considered significant.
Results Baseline Characteristics A total of 120 patients (45% female, mean age 68 ± 12 years) were included in our study. Site of occlusion was TICA in 13 patients (10.8%), proximal MCA in 69 patients (57.5%) and distal MCA in 38 patients (31.7%). Table 1 shows the baseline characteristics according to the site of occlusion. NIHSS score at admission was significantly higher in TICA and proximal MCA occlusions than in distal occlusions. No other differences were found between groups. Time from symptoms onset to hospital admission was less than 3 hours in 27% and less than 6 hours in 54% of patients.
Clinical Outcome Poor outcome at 3 months was present in 75% of the patients. Rate of poor outcome was significantly higher in patients with TICA and proximal MCA occlusion compared with distal MCA occlusion (92.3% of TICA, 87.0% of proximal MCA, and 47.4% of distal MCA; P < .001). Patients with TICA and proximal MCA occlusion had also higher rates of mortality at 3 months (23.1%, 11.6%, and 2.6%), higher frequency of infectious complications during hospital admission (38.5%, 36.2%, and 10.5%; P = .01) and of neurological complications, especially brain edema with mass effect (23.0%, 30.4%, and 5.2%; P = 0.01) (Table 2). There were no significant differences on clinical outcome between left and right proximal MCA occlusions (proximal right MCA 89.3%, proximal left MCA 84.2%), but in distal
´ ´ Hernandez-P erez et al: Natural History of Large Cerebral Artery Occlusion
355
Table 1. Baseline Characteristics of Patients Accordingly to Site of Arterial Occlusion Total (n = 120)
TICA (n = 13)
Proximal (n = 69)
Distal (n = 38)
P Value
Age (years) Gender (female) Hypertension Diabetes Dyslipidemia Ischemic heart disease Atrial Fibrillation Smoking habit Stroke severity (NIHSS)
68.2 ± 12 54 (45.0%) 71 (59.%) 34 (28.3%) 55 (45.8%) 20 (16.7%) 38 (31.7%) 33 (27.5%) 17 [9-21]
70.5 ± 12 8 (61.5%) 10 (76.9%) 5 (38.5%) 5 (38.5%) 2 (15.4%) 7 (53.8%) 2 (15.4%) 20 [11-24]
68.9 ± 12 29 (42.0%) 43 (62.3%) 19 (27.5%) 29 (42.0%) 15 (21.7%) 22 (31.9%) 21 (30.4%) 18 [15-21]
66.2 ± 13 17 (44.7%) 18 (47.4%) 10 (26.3%) 21 (55.3%) 3 (7.9%) 9 (23.7%) 10 (26.3%) 10 [4-17]
.48 .43 .12 .69 .36 .18 .13 .53
