MRI-guided Thrombolysis for Lenticulostriate Artery Stroke within 12 Hours after the Onset of Symptoms


 Background and purpose: We sought to analyze the efficacy of magnetic resonance imaging (MRI)-guided thrombolysis in patients with lenticulostriate artery stroke (LSAS) within 12 hours after onset of symptoms. Methods: LSAS patients identified on diffusion-weighted imaging (DWI) within 12h after onset of symptoms were assigned to receive intravenous alteplase (iv-tPA). DWI/ T2-weighte imaging (T2WI) mismatch -/+ was defined as an acute ischemic lesion on DWI with/without a corresponding lesion on T2WI in the territory of lenticulostriate artery. Favorable clinical outcome was defined as modified Rankin Scale (mRS) score <2 at 90 days. Baseline demographic data and medical history were compared between outcomes. Results: There were 160 LSAS patients received iv-tPA (104 within 4.5h) in 2008-2018 who had MRI data before treatment. DWI/T2WI-mismatch was detected in 73.1% (117/160) of patients. Lower admission systolic blood pressure (SBP) was significantly associated with 90d mRS<2 [adjusted odds ratio (OR) 0.93, 95%CI 0.88-0.99, p=0.026]. In overall patients, whether they received iv-tPA within 4.5h or not and whether they had DWI/T2WI-mismatch or not did not significantly impact the outcome. In DWI/T2WI-mismatch (+) group, hypertension negatively associated with favorable outcome (adjusted OR 0.15, 95% CI 0.04-0.59, p=0.007). In DWI/T2WI-mismatch (-) group, iv-tPA within 4.5h was an independent predictor of 90d mRS<2 (adjusted OR 7.38, 95% CI 1.25-43.48, p=0.027).Conclusion: MRI-guided iv-tPA within 12h is safe and effective for LSAS patients. Hypertension and higher admission SBP are associated with poor outcome. In patients who have no DWI/T2WI-mismatch, iv-tPA within 4.5h independently predicts favorable outcome.


Introduction
Lenticulostriate arteries (LSA) infarctions are defined as cerebral ischemia involving the territory supplied by the deep perforating branches of the middle cerebral artery (MCA), including the regions of basal ganglia and periventricular. They represent approximately 11-13% of cerebral infarctions related to anterior circulation. [1][2][3] For patients with acute ischemic stroke (AIS), intravenous tissue-3 type plasminogen activator (iv-tPA) remains the only effective medical treatment shown to improve outcomes. [4][5][6] However, the efficacy of iv-tPA and the predictive factors associated with the clinical outcome in patients with lenticulostriate arteries stroke (LSAS) have not been well addressed.
Magnetic resonance imaging (MRI) based selection trials showed AIS patients who had diffusionweighted imaging (DWI)/ fluid-attenuated inversion recovery (FLAIR) mismatch with unknown onset time were benefited from iv-tPA, most of whom were with large vessel occlusion. 7,8 It is unclear whether DWI/ T2-weighte imaging (T2WI) mismatch, represent a salvageable tissue window, is also useful for the selection of LSAS patients for iv-tPA beyond 4.5h time window.
The aim of this study was to analyze the efficacy of MRI-guided thrombolysis in patients with LSAS within 12 hours after onset of symptoms and to analyze the predictive factors associated with the clinical outcome of iv-tPA in acute LSAS patients who were with or without DWI/T2WI mismatch in 12h after onset of symptom.

Methods
We performed a retrospective observational cohort study in patients with LSAS based on a single stroke center hospital database, analyzing data from July 2008 to April 2018. This study was approved by the hospital ethical committee. Written informed consent was obtained from all patients or their legal representatives.
Detection of neuroimaging evidence of LSA infarction within 12h of acute stroke symptom onset was mandatory for inclusion in this study. This evidence comprised a hyperintensity on diffusion-weighted sequences on MRI, with LSA region of basal ganglia, paraventricular and corresponding with the clinical deficit ( Figure 1). We excluded patients with imaging evidence of extracranial or intracranial carotid stenosis, proximal vessel occlusion, clot retrieval, or with contraindications to iv-tPA.
Noncontrast CT and MRI, including DWI, T2WI and MRA, were performed before thrombolysis. The fast MRI scan required 5-10 minutes to complete, and an additional 10 minutes were used to transfer/position the patient and to process the MRI. Necessary lab tests, informed consent, and drug preparation for thrombolytic therapy were completed in conjunction with the fast MRI examination to shorten the time duration before administration of thrombolytic therapy. 4 MRI were retrospectively reviewed by using standard PACS software, allowing reviewers to freely window and view the images. DWI/T2WI-mismatch -/+ was defined as an acute ischemic lesion on DWI with/without a corresponding acute ischemic lesion on T2WI in the territory of LSA. DWI/T2WI mismatch was first independently assessed by a consultant neurologist and a senior stroke neurologist, blinded to clinical outcomes, and then reached consensus. As shown in Figure 1, MR images of LSAS patients with mismatch or no mismatch of DWI-T2WI within 12h after onset of symptom are provided.
Patients' characteristics, baseline National Institutes of Health Stroke Scale (NIHSS) score and clinical outcomes were obtained from data base. Favorable clinical outcome was defined as modified Rankin Scale (mRS) score <2 at 90 days.
Statistical analyses were performed by using the Statistical Package for the Social Sciences, Version 24 (IBM, Armonk, New York). P value<0.05 was considered statistically significant. Patients were dichotomized by using the 90-day mRS score into favorable (mRS score, <2) versus poor (mRS score, 2-6) outcome, in total and then in each DWI/T2WI mismatch subgroup. Differences in patient characteristics between outcomes were tested by the Chi-square test for categoric and the Mann-Whitney U test for continuous values. Multivariate binary logistic regression (including variables with P values<0.1) was used to assess the independent association of significances with 90-day outcome.

Data Availability Statement
Anonymized data will be shared by request from any quailified investigator.
No significant difference was seen in percent of DWI/T2WI mismatch (p=0.823), percent of treatment within 4.5h (p=0.722) and onset to treatment time (OTT) (p=0.463).

Discussion
Our study suggests that fast MRI-guided intravenous thrombolysis is safe and effective in LSAS patients within 12 hours of symptom onset. No history of hypertension and lower admission SBP are two protective factors for patients to reach the good functional outcome. There was no significant difference in the outcome between treatment within 4.5h and 4.5h-12h, or DWI/T2WI mismatch and no DWI/T2WI mismatch patients. However, in patients who had no DWI/T2WI mismatch, iv-tPA within 4.5h time window was an important factor which brings more benefits.
LSAS, which occurs in a phylogenetically ancient part of the brain, the "vascular centrencephalon", 6 where short straight arteries with few branches transmit high blood pressure straight through to endarterioles. Hypertension can accelerate neurological deficits in LSAS for the impaired auto-regulation of cerebral blood flow (CBF) and blood pressure (BP) gradients in lenticulostriate arteries. During acute ischemia, early activation of sympathetic adrenomedullary pathway and altered cerebral autoregulation within ischemic penumbra, 9 systemically elevated BP levels and increased BP variability (BPV are associated with compromised cerebral perfusion, 10,11 increased baseline thrombus burden and impaired endogenous capacity for fibrinolysis, 12 that likely predispose to poor functional outcomes in acute ischemic stroke (AIS) patients treated with IVT.
Our findings are in line with European Cooperative Acute Stroke Study (ECASS)and 13 ECASSII 14 documenting poor outcomes in AIS patients with elevated baseline SBP levels. No history of hypertension and lower SBP on admission may protect against brain ischemia through increased arterial compliance, normalization of cerebrovascular auto-regulation, reduced CBF decrease during ischemia at the periphery of the lesion, and enhancement of collateral circulation during hypoperfusion.
Previous studies rarely focused on the validity of iv-tPA in LSAS because of the unpopular usage of MR in emergency, which make it difficult to detect the acute LSAS at admission. WAKE-UP trial provide evidence of benefit from iv-tPA among patients with acute stroke and an unknown time of symptom onset who had mismatch between MRI findings on DWI and FLAIR. 8 The results of secondary post hoc analysis suggest iv-tPA is safe and improves functional outcome in patients with lacunar infarct with a similar outcome as in patients with other stroke subtypes. 15 In the present study, we also identified LSAS patients by using emergency MR and found those within 4.5h-12h after onset of symptoms who have DWI/T2WI-mismatch may equally benefit from iv-tPA, compared with those within 4.5h.In patients with no DWI/T2WI-mismatch, iv-tPA within 4.5h was an independent predict factor associated with favorable outcome. That phenomenon suggests "DWI/T2WI-mismatch positive" is a radiological mark of LSAS patients who are appropriate for iv-tPA within 12h time window, however, patients with no DWI/T2WI-mismatch should not be excluded for iv-tPA within 4.5h time window.

7
In this study, we used T2WI instead of FLAIR because performing T2W images (50s) were about 100s faster than performing FLAIR. 16 Although cytotoxic edema on T2WI is less clearly indicated due to the increasing artefact and partial volume effect from cerebral spinal fluid (CSF) than FLAIR, 17 LSA infarctions are away from CSF and could be weakly influenced by those limitations. Meanwhile, the faster image formation of T2WI can save the time of OTT and reduce the impact of motion in less cooperative patients during the process of MR examination.
Results of this study are limited by the retrospective nature of analysis and small number of patients from a single center. Whether iv-tPA between 4.5-12h is superior than other therapy was not analyzed in our study due to the absence of randomization for different treatments.

Conclusions
MRI-guided iv-tPA within 12h is safe and effective for LSAS patients. Hypertension and higher admission SBP are associated with poor outcome. In patients who have no DWI/T2WI-mismatch, iv-tPA within 4.5h independently predicts favorable outcome.