|Year : 2020 | Volume
| Issue : 2 | Page : 70-74
The role of leukoaraiosis on outcomes and recombinant tissue-plasminogen activator-related symptomatic intracerebral hemorrhages in acute stroke
Ezgi Sezer Eryildiz1, Atilla Özcan Özdemir1, Dilek Yılmaz1, Demet Funda Baş2
1 Department of Neurology, Eskişehir Osmangazi University, Eskişehir, Turkey
2 Department of Neurology, University of Health Sciences, İzmir Tepecik Education and Research Hospital, İzmir, Turkey
|Date of Submission||29-Jan-2020|
|Date of Decision||23-Mar-2020|
|Date of Acceptance||29-Mar-2020|
|Date of Web Publication||29-Jun-2020|
Ezgi Sezer Eryildiz
Department of Neurology, Medical Faculty, Eskisehir Osmangazi University, 26040, Odunpazarı, Eskişehir
Source of Support: None, Conflict of Interest: None
Background and Purpose: We aimed to assess whether severe leukoaraiosis (LA) is associated with outcomes and symptomatic intracerebral hemorrhages (sICH) in patients who were treated with recombinant tissue-plasminogen activator (rt-PA) for acute stroke. Methods: We analyzed the data of anterior circulation stroke patients who were treated with rt-PA at our stroke center during 2009–2016. LA was scored according to the van Swieten scale (VSS) on computed tomography (CT) and dichotomized into groups as absent or moderate versus severe LA. We used the safe implementation of thrombolysis in stroke definition for sICH and the modified Rankin Scale (mRS) scores at 3 months after rt-PA were recorded. Results: Of 302 patients, 47 (15.6%) showed severe LA (VSS >4) on CT. The overall sICH rate was 3.6%. Moreover, sICH was significantly more frequent in patients with severe LA (n = 5 of 47; 10.6%) than in patients with absent/moderate LA (n = 6 of 255; 2.4%; P = 0.017). In addition, patients with severe LA had higher baseline glucose level (P = 0.006) and systolic blood pressure (P = 0.005) compared to patients with absent/moderate LA. Patients with severe LA were more likely to have a poor outcome (mRS: 3–6) compared to those without severe LA (P = 0.009). Conclusion: The presence of severe LA on CT increases the risk of sICH and poor outcome in patients treated with rt-PA for acute stroke.
Keywords: Acute stroke, intracerebral hemorrhage, leukoaraiosis, outcome, thrombolysis
|How to cite this article:|
Eryildiz ES, Özdemir A&, Yılmaz D, Baş DF. The role of leukoaraiosis on outcomes and recombinant tissue-plasminogen activator-related symptomatic intracerebral hemorrhages in acute stroke. Neurol Sci Neurophysiol 2020;37:70-4
|How to cite this URL:|
Eryildiz ES, Özdemir A&, Yılmaz D, Baş DF. The role of leukoaraiosis on outcomes and recombinant tissue-plasminogen activator-related symptomatic intracerebral hemorrhages in acute stroke. Neurol Sci Neurophysiol [serial online] 2020 [cited 2021 Apr 13];37:70-4. Available from: http://www.nsnjournal.org/text.asp?2020/37/2/70/288414
| Introduction|| |
The major complication of thrombolysis with recombinant tissue-plasminogen activator (rt-PA) in acute ischemic stroke is symptomatic intracerebral hemorrhage (sICH). Previous studies have determined some clinical markers that indicate an increased risk of sICH, such as advanced age, early ischemic changes, an elevated mean arterial blood pressure before treatment, a history of diabetes mellitus (DM), and cardiac disease.,
Leukoaraiosis (LA) is a radiologic finding to describe the areas of hypoattenuation of the subcortical brain white matter on computed tomography (CT), which is usually seen bilaterally. This finding is a characteristic of cerebral small vascular diseases such as amyloid angiopathy, hypertensive arteriopathy, and cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. The clinical importance of LA is not certain.
Several reports have demonstrated the relationship between LA and intracerebral hemorrhage., According to these studies, hypertension (HT), and thereby, hypertensive changes in small penetrating vessels were the causes of that relationship. In addition, the pathological changes in spontaneous intracerebral hemorrhage have also been shown in patients with chronic HT, lacunes, and LA. In later years, using gradient-echo T2-weighted magnetic resonance imaging (MRI) sequences, deep microbleeds have been associated with the severity of periventricular hyperintensities. Furthermore, a strong connection has been determined between clinically silent microbleeds and hemorrhages in the same areas.
In accordance with this information in the literature, it is suggested that there is a potential relationship between LA and sICH in patients who were treated with rt-PA. In the current study, we aimed to investigate whether severe LA confirmed on CT may be a risk factor for sICH and poor clinical outcome after intravenous (IV) thrombolysis.
| Methods|| |
We retrospectively analyzed the data of consecutive patients who were treated with IV rt-PA within the 4–5 h of symptom onset for acute anterior circulation stroke from January 2009 to January 2016 in our stroke center. The patients who undergone mechanical thrombectomy with or without intra-arterial rt-PA were excluded from the analyses. IV rt-PA was given according to the European Stroke Organization guidelines. Patient data including demographic features, the time between symptom onset and treatment, National Institutes of Health Stroke Scale (NIHSS) and Alberta Stroke Program Early CT (ASPECT) scores, serum glucose and arterial blood pressure levels, and platelet count on admission were assessed.
CT was performed before treatment and within the 24 h of treatment or immediately in case of clinical deterioration. According to the European Cooperative Acute Stroke Study Classification, intracerebral hemorrhages were radiologically graded as hemorrhagic infarct Type 1, hemorrhagic infarct Type 2, parenchymal hemorrhage Type 1, and parenchymal hemorrhage Type 2. We used the safe implementation of thrombolysis in stroke definition for sICH; type 2 parenchymal hemorrhage on CT performed within the 22–36 h of treatment accompanied by a neurological deterioration of ≥4 NIHSS points from the baseline or leading to death.
Two blinded reviewers have rated the severity of LA on CT using the scale suggested by van Swieten et al. According to this scale, the anterior and posterior regions of each hemisphere on axial brain CT scan were separately rated from 0 to 2: 0 – no LA; 1 – involving white matter partially; and 2 – extending up to the cortex. The total score was varied from 0 to 4 for each hemisphere. We defined severe LA as a total score over 4 for the whole brain.
To assess the outcomes of patients, the modified Rankin Scale (mRS) scores at 3 months after rt-PA were recorded. mRS scores of 0–2 were defined as “favorable” outcome, whereas mRS scores of 3–6 were defined as “poor” outcome.
The study was approved by the local institutional ethics committee (Decision number: 2018/137).
Patients were dichotomized into two groups: those with severe LA versus those without. The data of these groups were compared with demographic, clinical, and radiological variables. Continuous variables were determined as median and categorical variables as a percentage. The Shapiro–Wilk W-test was used for normality. Unevenly distributed continuous variables were analyzed by the Mann–Whitney U-test. In addition, the relationship between these variables was analyzed by the Spearman correlation. Two-proportion test was used to determine the difference between the groups. Categorical variables were compared using the Chi-square test or Fisher's exact test. For the statistical analysis, IBM SPSS Statistics 21.0 (IBM Corp. Released 2012. IBM SPSS Statistics for Windows, Version 21.0. Armonk, NY: IBM Corp.) was used. A two-sided P < 0.05 was considered statistically significant.
| Results|| |
Three hundred and two patients who fulfilled the inclusion criteria were enrolled in the study. Forty-seven of 302 patients (15.6%) showed severe LA of deep white matter (van Swieten scale >4) on CT. These patients were significantly older than those with absent/moderate LA and were more likely to have a history of DM and HT. Furthermore, patients with severe LA had higher NIHSS scores and serum glucose and systolic blood pressure (SBP) levels compared to those without. No significant difference was found between the other baseline demographic and clinical variables. [Table 1] summarizes the differences in demographic and clinical variables between the two groups.
|Table 1: Comparisons of demographic and clinical variables in patients with and without severe leukoaraiosis before thrombolysis|
Click here to view
The sICH rate was higher in patients with severe LA compared to the patients without severe LA (P = 0.017). At 3 months of thrombolysis, patients with severe LA were more likely to have a poor functional outcome estimated by the mRS (mRS: 3–6) and these patients had higher mRS scores at 3 months compared to those without (66% vs. 44%; P = 0.009). Death at 3 months was not associated with severe LA. [Table 2] summarizes the differences in clinical variables between the two groups after thrombolysis.
|Table 2: Comparisons of clinical variables in patients with and without severe leukoaraiosis after thrombolysis|
Click here to view
The overall sICH rate was 3.6%. Patients were dichotomized into two groups: those with or without sICH. Patients with sICH had higher serum glucose levels and lower ASPECT scores than patients without sICH and they were more likely to have a history of DM (P = 0.045). There was no significant difference between the other demographic and clinical variables. [Table 3] summarizes the differences in demographic and clinical variables between patients with and without sICH.
|Table 3: Comparisons of demographic, clinical, and radiological variables in patients with and without symptomatic intracerebral hemorrhages|
Click here to view
| Discussion|| |
According to the current study, severe LA significantly increases the risk of sICH in patients treated with rt-PA for acute stroke. The rate of sICH was 10.6% in patients with severe LA and 2.4% in patients with absent/moderate LA. Patients with severe LA were significantly older and more likely to have a history of DM and HT. Furthermore, they had higher baseline NIHSS scores and SBP and serum glucose levels than the patients without severe LA. The association between LA and intracerebral hemorrhage has been determined and primarily related to HT. It has been shown that hypertensive changes in small penetrating vessels are correlated with the size of LA. In addition, the patients with chronic HT, lacunes, and LA have pathological changes such as microaneurysm, fibrinoid degeneration, and lipohyalinosis, similarly to the patients with spontaneous intracerebral hemorrhage., Depending on the underlying pathology, hemorrhages seen in patients with LA were more often located in the deep basal ganglia. More recently, Kato et al. demonstrated that the number of silent microbleeds is correlated with the severity of periventricular hyperintensities on MRI.
According to the results of the Stroke Prevention in Reversible Ischemia Trial assessing anticoagulation as a seconder prophylaxis after cerebral ischemia, LA was an independent risk factor for major hemorrhage. Thereafter, the patients with LA have been excluded from the European/Australasian Stroke Prevention in Reversible Ischaemia Trial. Another study exploring the association between vascular risk factors and intracerebral hemorrhages in patients with acute ischemic stroke found that microbleeds in cortical–subcortical areas and deep gray matter are associated with hemorrhages in the same areas. Furthermore, the rate of sICH was 10.5% in a study involving patients with moderate and severe LA, while in another study, the rate of sICH was found to be 8.4% in patients only with severe LA., The current study that found a 10.6% risk of sICH in patients with severe LA is consistent with the previous studies.
The association of microbleeds with DM, chronic HT, and severe white matter disease supports the underlying small vascular disease mechanism., In accordance with that, we found the patients with severe LA have higher serum glucose and SBP levels at the time of admission than those without. The history of DM and HT was more common in the patients with severe LA.
Local blood–brain barrier damage and increased permeability in white matter predispose to endothelial dysfunction and LA.,, Moreover, in patients with acute ischemic lesions and severe white matter lesions, ischemic damage may further increase the endothelial dysfunction and blood–brain barrier damage, leading to blood extravasation and parenchymal damage. Apart from this, both rt-PA itself and its degradation products may contribute to the blood–brain barrier damage and hemorrhages after thrombolysis. In the current study, higher serum glucose level in the severe LA group may contribute the increased rate of sICH. There is experimental evidence regarding the effects of hyperglycemia on ischemic brain damage; in animal models, hyperglycemia has been shown to cause hemorrhagic transformation of cerebral infarction by enlarging blood–brain barrier damage. In addition, hyperglycemia may increase the blood–brain barrier deterioration by increasing the matrix metalloproteinase (MMP)-9 expression. rt-PA is an MMP that may aggravate ischemic involvement and cause hemorrhage by basal lamina damage and loss of vascular wall integrity. The presence of hyperglycemia may potentiate this harmful effect. According to our results, serum glucose level at the time of admission and the history of DM were found to be significantly higher in patients with both severe LA and sICH. Given our results, the presence of severe LA in acute stroke patients may be a marker of preexisting systemic disease including uncontrolled DM and HT, and hence, these patients may be more vulnerable to sICH after the administration of r-tPA.
The outcomes of the patients at 3 months were evaluated and we found that the rate of poor outcome (mRS 3–6) in patients with severe LA was significantly higher than those without, but mortality was not found to be statistically different between the two groups. Previous studies have shown that LA worsens the outcome in ischemic stroke patients, regardless of the treatment.,,, However, it would be appropriate to evaluate the outcome with multivariate analysis, as the factors such as increased age and stroke severity may have contributed a poor outcome in our study.
The main limitation of our study was that the cohort size of patients with sICH was small and did not allow for multivariate analysis. Thus, the effects of variables such as DM, serum glucose level, and severe LA on sICH were not evaluated together. Another limitation was that a CT-based scale was used to assess the LA, the reason of that was both easy application of CT and difficulty in reaching MRI before the treatment. The use of MRI can provide more detailed information. Finally, evaluating LA, we did not define its location as the anterior or posterior side of the hemisphere, so we could not get any information about the relationship of sICH with the location of LA. Nevertheless, the sICH rate in our analysis is similar to results of the previous studies performed in large stroke centers, and our patient population reflects the population treated in those stroke centers. We think that this study can shed light on the decision and management of IV thrombolytic therapy for clinicians.
| Conclusion|| |
Although the patients with severe LA were found to have a higher rate of sICH than those without, severe LA is not a contraindication for thrombolytic therapy. However, considering the increased risk of sICH in these patients, the clinician should be aggressive in the management of the factors that may cause an additional risk for hemorrhage such as elevation of arterial blood pressure and serum glucose level.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Tanne D, Kasner SE, Demchuk AM, Koren-Morag N, Hanson S, Grond M, et al
. Markers of increased risk of intracerebral hemorrhage after intravenous recombinant tissue plasminogen activator therapy for acute ischemic stroke in clinical practice: The multicenter rt-PA stroke survey. Circulation 2002;105:1679-85.
von Kummer R, Allen KL, Holle R, Bozzao L, Bastianello S, Manelfe C, et al
. Acute stroke: Usefulness of early CT findings before thrombolytic therapy. Radiology 1997;205:327-33.
Hachinski VC, Potter P, Merskey H. Leuko-araiosis. Arch Neurol 1987;44:21-3.
Tveiten A, Ljøstad U, Mygland A, Naess H. Leukoaraiosis is associated with short- and long-term mortality in patients with ıntracerebral hemorrhage. J Stroke Cerebrovasc Dis 2013;22:919-25.
Selekler K, Erzen C. Leukoaraiosis and intracerebral hematoma. Stroke 1989;20:1016-20.
Inzitari D, Giordano GP, Ancona AL, Pracucci G, Mascalchi M, Amaducci L. Leukoaraiosis, intracerebral hemorrhage, and arterial hypertension. Stroke 1990;21:1419-23.
Kato H, Izumiyama M, Izumiyama K, Takahashi A, Itoyama Y. Silent cerebral microbleeds on T2-weighted MRI: Correlation with stroke subtype, stroke recurrence, and leukoaraiosis. Stroke 2002;33:1536-40.
Lee SH, Bae HJ, Kwon SJ, Kim H, Kim YH, Yoon BW, et al
. Cerebral microbleeds are regionally associated with intracerebral hemorrhage. Neurology 2004;62:72-6.
European Stroke Organisation (ESO) Executive Committee, ESO Writing Committee. Guidelines for management of ischaemic stroke and transient ischaemic attack 2008. Cerebrovasc Dis 2008;25:457-507.
Larrue V, von Kummer R R, Müller A, Bluhmki E. Risk factors for severe hemorrhagic transformation in ischemic stroke patients treated with recombinant tissue plasminogen activator: A secondary analysis of the European-Australasian Acute Stroke Study (ECASS II). Stroke 2001;32:438-41.
Mazya M, Egido JA, Ford GA, Lees KR, Mikulik R, Toni D, et al
. Predicting the risk of symptomatic intracerebral hemorrhage in ischemic stroke treated with intravenous alteplase: Safe Implementation of treatments in stroke (SITS) symptomatic intracerebral hemorrhage risk score. Stroke 2012;43:1524-31.
van Swieten JC, Hijdra A, Koudstaal PJ, van Gijn J. Grading white matter lesions on CT and MRI: A simple scale. J Neurol Neurosurg Psychiatry 1990;53:1080-3.
Gorter JW. Major bleeding during anticoagulation after cerebral ischemia: Patterns and risk factors. Stroke prevention ın reversible ıschemia trial (SPIRIT). European atrial fibrillation trial (EAFT) study groups. Neurology 1999;53:1319-27.
The European/Australasian Stroke Prevention in Reversible Ischaemia Trial (ESPRIT) Study Group. Oral anticoagulation in patients after cerebral ıschemia of arterial origin and risk of ıntracranial hemorrhage. Stroke 2003;34:e45-47.
Neumann-Haefelin T, Hoelig S, Berkefeld J, Fiehler J, Gass A, Humpich M, et al
. Leukoaraiosis is a risk factor for symptomatic intracerebral hemorrhage after thrombolysis for acute stroke. Stroke 2006;37:2463-6.
Palumbo V, Boulanger JM, Hill MD, Inzitari D, Buchan AM, CASES Investigators. Leukoaraiosis and intracerebral hemorrhage after thrombolysis in acute stroke. Neurology 2007;68:1020-4.
Hanyu H, Tanaka Y, Shimizu S, Takasaki M, Fujita H, Kaneko N, et al
. Cerebral microbleeds in Binswanger's disease: A gradient-echo T 2*-weighted magnetic resonance imaging study. Neurosci Lett 2003;3:213-6.
Nighoghossian N, Hermier M, Adeleine P, Blanc-Lasserre K, Derex L, Honnorat J, et al
. Old microbleeds are a potential risk factor for cerebral bleeding after ischemic stroke: A gradient-echo T 2*-weighted brain MRI study. Stroke 2002;3:735-42.
Smith EE. Leukoaraiosis and stroke. Stroke 2010;41:S139-43.
Hassan A, Hunt BJ, O'Sullivan M, Parmar K, Bamford JM, Briley D, et al
. Markers of endothelial dysfunction in lacunar infarction and ischaemic leukoaraiosis. Brain 2003;126:424-32.
Fernando MS, Simpson JE, Matthews F, Brayne C, Lewis CE, Barber R, et al
. White matter lesions in an unselected cohort of the elderly: Molecular pathology suggests origin from chronic hypoperfusion injury. Stroke 2006;37:1391-8.
Shi ZS, Loh Y, Liebeskind DS, Saver JL, Gonzalez NR, Tateshima S, et al
. Leukoaraiosis predicts parenchymal hematoma after mechanical thrombectomy in acute ischemic stroke. Stroke 2012;43:1806-11.
Kahles T, Foerch C, Sitzer M, Schroeter M, Steinmetz H, Rami A, et al
. Tissue plasminogen activator mediated blood-brain barrier damage in transient focal cerebral ischemia in rats: Relevance of interactions between thrombotic material and thrombolytic agent. Vascul Pharmacol 2005;43:254-9.
Gisselsson L, Smith ML, Siesjö BK. Hyperglycemia and focal brain ischemia. J Cereb Blood Flow Metab 1999;19:288-97.
Khatri P, Wechsler LR, Broderick JP. Intracranial hemorrhage associated with revascularization therapies. Stroke 2007;38:431-40.
Hamann GF, del Zoppo GJ, von Kummer R. Hemorrhagic transformation of cerebral infarction – Possible mechanisms. Thromb Haemost 1999;82 Suppl 1:92-4.
Leys D, Englund E, Del Ser T, Inzitari D, Fazekas F, Bornstein N, et al
. White matter changes in stroke patients. Relationship with stroke subtype and outcome. Eur Neurol 1999;42:67-75.
Choi JH, Bae HJ, Cha JK. Leukoaraiosis on magnetic resonance ımaging ıs related to long-term poor functional outcome after thrombolysis in acute ıschemic stroke. J Korean Neurosurg Soc 2011;50:75-80.
Curtze S, Melkas S, Sibolt G, Haapaniemi E, Mustanoja S, Putaala J, et al
. Cerebral computed tomography-graded white matter lesions are associated with worse outcome after thrombolysis in patients with stroke. Stroke 2015;46:1554-60.
Arsava EM, Rahman R, Rosand J, Lu J, Smith EE, Rost NS, et al
. Severity of leukoaraiosis correlates with clinical outcome after ischemic stroke. Neurology 2009;72:1403-10.
[Table 1], [Table 2], [Table 3]