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Year : 2020  |  Volume : 37  |  Issue : 2  |  Page : 70-74

The role of leukoaraiosis on outcomes and recombinant tissue-plasminogen activator-related symptomatic intracerebral hemorrhages in acute stroke

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 Submission29-Jan-2020
Date of Decision23-Mar-2020
Date of Acceptance29-Mar-2020
Date of Web Publication29-Jun-2020

Correspondence Address:
Ezgi Sezer Eryildiz
Department of Neurology, Medical Faculty, Eskisehir Osmangazi University, 26040, Odunpazarı, Eskişehir
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/NSN.NSN_11_20

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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 2023 Jun 10];37:70-4. Available from: http://www.nsnjournal.org/text.asp?2020/37/2/70/288414

  Introduction Top

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.[1],[2]

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.[3] 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.[4] The clinical importance of LA is not certain.

Several reports have demonstrated the relationship between LA and intracerebral hemorrhage.[5],[6] 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.[7] Furthermore, a strong connection has been determined between clinically silent microbleeds and hemorrhages in the same areas.[8]

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 Top

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.[9] 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.[10] 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.[11]

Two blinded reviewers have rated the severity of LA on CT using the scale suggested by van Swieten et al.[12] 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).

Statistical analyses

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 Top

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

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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

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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

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  Discussion Top

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.[5] 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.[5],[6] 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.[13]

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.[13] Thereafter, the patients with LA have been excluded from the European/Australasian Stroke Prevention in Reversible Ischaemia Trial.[14] 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.[8] 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.[15],[16] 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.[17],[18] 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.[19],[20],[21] 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.[22] Apart from this, both rt-PA itself and its degradation products may contribute to the blood–brain barrier damage and hemorrhages after thrombolysis.[23] 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.[24] In addition, hyperglycemia may increase the blood–brain barrier deterioration by increasing the matrix metalloproteinase (MMP)-9 expression.[25] rt-PA is an MMP that may aggravate ischemic involvement and cause hemorrhage by basal lamina damage and loss of vascular wall integrity.[26] 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.[27],[28],[29],[30] 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 Top

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.

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  [Table 1], [Table 2], [Table 3]

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