Stroke Aetiology and Collateral Status in Acute Ischemic Stroke Patients Receiving Reperfusion Therapy—A Meta-Analysis

Round 1

Reviewer 1 Report

This article found patients with LAA were associated significantly with an increased rate of good collaterals (RR 1.24; 95% CI 1.04-1.50; p=0.020). Contrarily, CE aetiology was associated significantly with a decreased rate of good collaterals (RR 0.83; 95% CI 0.71-0.98; p=0.027).

The recent study showed atrial fibrillation increased symptomatic ICH. (DOI https://doi.org/10.2147/NDT.S320574). The symptomatic ICH increased mortality and disabilities. That can support the poor outcome. It needs more descriptions  about outcomes about CE patients.

In line 267, A higher neutrophil count one day after hospital admission was associated with symptomatic intracranial haemorrhage (sICH) while a higher neutrophil-lymphocyte-ratio was associated with parenchymal haemorrhage and sICH. How are the differences between LAA and CE?

Author Response

Authors' Responses to Reviewers

 We would like to thank you, and all the reviewers for the valuable feedback. The comments and feedback we received have helped us to significantly improve our manuscript. We have made the best of our efforts to incorporate changes as suggested. The revised manuscript with changes (underlined) is attached.

Our point-by-point rebuttal to the comments are presented below;

C#2.1: This article found patients with LAA were associated significantly with an increased rate of good collaterals (RR 1.24; 95% CI 1.04-1.50; p=0.020). Contrarily, CE aetiology was associated significantly with a decreased rate of good collaterals (RR 0.83; 95% CI 0.71-0.98; p=0.027).

Reply# We thank the reviewer for the review of our work and for the suggestions.

C#2.2: The recent study showed atrial fibrillation increased symptomatic ICH. (DOI https://doi.org/10.2147/NDT.S320574). The symptomatic ICH increased mortality and disabilities. That can support the poor outcome. It needs more descriptions about outcomes about CE patients.

Reply# We thank the reviewer for the valuable suggestions. We have included the reference as indicated and clarified this in detail. The following paragraph has been added.

 With regards to outcomes in AIS patients with CE aetiology, a recent study showed atrial fibrillation was associated with symptomatic intracerebral haemorrhage (sICH) in AIS patients treated with IVT¹. This could be explained by the presence of poor collaterals in AF patients, or with CE aetiology, leading to an increased risk of sICH after reperfusion. A meta-analysis by Lu et al about the safety and efficacy of IVT for AIS patients with AF and found worse outcomes in AIS patients with AF than those without AF. Authors also reported a higher incidence of sICH in AF patients than that in non-AF patients (6.4% vs 4.1%; P < 0.001) as well as in AF patients receiving IVT compared to AF patients not receiving IVT (5.7% vs. 1.6%; P < 0.001)².

C#2.3: In line 267, A higher neutrophil count one day after hospital admission was associated with symptomatic intracranial haemorrhage (sICH) while a higher neutrophil-lymphocyte-ratio was associated with parenchymal haemorrhage and sICH. How are the differences between LAA and CE?

Reply# We thank the reviewer for the comment. We have added the following sentence to clarify this.

 

“We postulate that the progression to poor outcomes despite good collateral status and successful reperfusion, e.g., in AIS patients with LAA, may be explained by other factors such as NLR ³ and severity of leukoaraiosis ^4,5.”

 

We hope all the changes incorporated and additional information provided has adequately addressed the concerns and comments of the reviewers and the editorial team.

 

Sincerely yours,

Dr Sonu M. M. Bhaskar, MD PhD

References

1. Guo H, Xu W, Zhang X, et al. A Nomogram to Predict Symptomatic Intracranial Hemorrhage After Intravenous Thrombolysis in Chinese Patients. Neuropsychiatr Dis Treat. 2021;17:2183-2190.
2. Hu Y, Ji C. Efficacy and safety of thrombolysis for acute ischemic stroke with atrial fibrillation: a meta-analysis. BMC Neurology. 2021;21(1):66.
3. Sharma D, Spring KJ, Bhaskar SMM. Neutrophil-lymphocyte ratio in acute ischemic stroke: Immunopathology, management, and prognosis. Acta Neurol Scand. 2021;144(5):486-499.
4. Rastogi A, Weissert R, Bhaskar SMM. Leukoaraiosis severity and post-reperfusion outcomes in acute ischaemic stroke: A meta-analysis. Acta Neurologica Scandinavica.n/a(n/a).
5. Rastogi A, Weissert R, Bhaskar SMM. Emerging role of white matter lesions in cerebrovascular disease. European Journal of Neuroscience. 2021;54(4):5531-5559.

Author Response File: Author Response.pdf

Reviewer 2 Report

Interesting and well written meta-analysis regarding how Stroke aetiology can influence the collateral status in acute ischemic stroke patients receiving reperfusion therapy. 

Scientific quality of the study is good, as well English grammar. The interest for the reader is high. Furthermore a meta-analysis represents the highest level of evidence in medicine.

I think this study deserves publication since it regards a crucial point in treatment timing; indeed the collateral leptomeningeal circulation is the main reservoir for the ischemic tissue, and large collateral circulation permits delayed treatment (the so called slow-progressor patients - by Nogueira). 

 

It's interesting the correlation found in this meta-analysis between collateral circulation and stroke aetiology, even if in some cases this does not correspond to common clinical practice. It's not infrequent an embolic aetiology with a large collateral circulation, probably in patients with a coexisting large artery atherosclerosis ? This aspect should be better clarified in the discussion. 

I would add some lines in discussion regarding the assessment of collateral circulation status with non invasive imaging: for example the study by Verdolotti et al. Colorviz, a new and rapid tool for assessing collateral circulation during stroke. Brain Sciences, 2020, 10(11), pp. 1–8, 882. Which discuss an algorithm of reconstruction on CTA to assess collateral circulation in acute phases. In this context multiphase CTA plays an important role in predicting collateral circulation and potential salvable brain tissue. This aspects are discussed by several authors (e.g.: Alexandre AM et al. May endovascular thrombectomy without CT perfusion improve clinical outcome? Clinical Neurology and Neurosurgery, 2020, 198, 106207), as you also wrote in the text.

Conclusion are well exposed.

Author Response

Please see the attachment.

Author Response File: Author Response.docx

Round 2

Reviewer 1 Report

Abstract

conclusion: Why did LAA with good response and CE with poor outcome received reperfusion treatment? Please discuss the potential reasons.

Author Response

We thank the reviewer for the suggestion. We have revised the manuscript and the updated Abstract/Conclusions reads, "Conclusion: This study demonstrates that, in AIS patients receiving reperfusion therapy, LAA and CE aetiologies are associated significantly with collateral status."

Moreover, the following explanation has been added to the Discussion to elaborate on the influence of aetiology on clinical outcomes?

Page 5 (Discussion)

"Stroke aetiology may mediate collateral recruitment – potentially influencing response to time-critical reperfusion therapies in AIS [1]. This meta-analysis didn’t investigate this aspect. We postulate that in LAA patients, better collaterals develop over time in a proportion of patients resulting in high-grade stenosis [1]. Currently, data on whether stroke aetiology impacts reperfusion and outcome after reperfusion therapy in AIS patients with large vessel occlusion in the anterior circulation, especially those treated with EVT or combined therapies (EVT±IVT), are limited [2,3]. However, previous studies have shown that CE patients have worse outcomes than LAA [1,4,5], presumably due to greater successful reperfusion rates [4,5]. However, other studies found no statistically significant difference in successful reperfusion rates between LAA and CE, despite higher rates of better 90 days functional outcomes for LAA [1-3]. Notably, in other studies, successful reperfusion is potentially more important for better outcomes, particularly in CE strokes than the LAA [6]. It is worth noting that heart failure is more prevalent in stroke with CE than LAA, which may also contribute to poorer outcomes in the CE subgroup [7]."

References

1. Zotter, M.; Piechowiak, E.I.; Balasubramaniam, R.; Von Martial, R.; Genceviciute, K.; Blanquet, M.; Slavova, N.; Sarikaya, H.; Arnold, M.; Gralla, J.; et al. Endovascular therapy in patients with large vessel occlusion due to cardioembolism versus large-artery atherosclerosis. Ther Adv Neurol Disord 2021, 14, 1756286421999017-1756286421999017, doi:10.1177/1756286421999017.
2. Sun, B.; Shi, Z.; Pu, J.; Yang, S.; Wang, H.; Yang, D.; Hao, Y.; Lin, M.; Ke, W.; Liu, W.; et al. Effects of mechanical thrombectomy for acute stroke patients with etiology of large artery atherosclerosis. J Neurol Sci 2019, 396, 178-183, doi:10.1016/j.jns.2018.10.017.
3. Giray, S.; Ozdemir, O.; Baş, D.F.; İnanç, Y.; Arlıer, Z.; Kocaturk, O. Does stroke etiology play a role in predicting outcome of acute stroke patients who underwent endovascular treatment with stent retrievers? J Neurol Sci 2017, 372, 104-109, doi:10.1016/j.jns.2016.11.006.
4. Guglielmi, V.; LeCouffe, N.E.; Zinkstok, S.M.; Compagne, K.C.J.; Eker, R.; Treurniet, K.M.; Tolhuisen, M.L.; van der Worp, H.B.; Jansen, I.G.H.; van Oostenbrugge, R.J.; et al. Collateral Circulation and Outcome in Atherosclerotic Versus Cardioembolic Cerebral Large Vessel Occlusion. Stroke 2019, 50, 3360-3368, doi:10.1161/strokeaha.119.026299.
5. Schulz, U.G.; Rothwell, P.M. Differences in vascular risk factors between etiological subtypes of ischemic stroke: importance of population-based studies. Stroke 2003, 34, 2050-2059, doi:10.1161/01.Str.0000079818.08343.8c.
6. Rha, J.H.; Saver, J.L. The impact of recanalization on ischemic stroke outcome: a meta-analysis. Stroke 2007, 38, 967-973, doi:10.1161/01.Str.0000258112.14918.24.
7. Savarese, G.; Lund, L.H. Global Public Health Burden of Heart Failure. Card Fail Rev 2017, 3, 7-11, doi:10.15420/cfr.2016:25:2.