Acute Ischaemic Stroke in Infective Endocarditis: Pathophysiology and Clinical Outcomes in Patients Treated with Reperfusion Therapy

Round 1

Reviewer 1 Report

In the manuscript “Acute ischaemic stroke in infective endocarditis: pathophysiology and clinical outcomes in patients treated with reperfusion therapy”, authors have written abstract in well convincing manner. A good attempt is made by writing introduction and discussion with relevant background.  However following points need to be addressed.

1. More details of antimicrobial therapy need to be discussed. In line of this more details of reperfusion/thrombolytic therapy need to be discussed although authors have discussed some part.
2. Schematic diagram for treatment of Acute ischaemic stroke in infective endocarditis enhanced reader interest.
3. Pathophysiology of AIS with respect to infective endocarditis is not properly discussed.

Author Response

REVIEWER 1

C#1: In the manuscript “Acute ischaemic stroke in infective endocarditis: pathophysiology and clinical outcomes in patients treated with reperfusion therapy”, authors have written abstract in well convincing manner. A good attempt is made by writing introduction and discussion with relevant background. 

Reply# We thank the reviewer for the time and review of our manuscript.

C#2: More details of antimicrobial therapy need to be discussed. In line of this more details of reperfusion/thrombolytic therapy need to be discussed although authors have discussed some part.

Reply# We thank the reviewer for the suggestion. We have added the following to the Discussion.

“Whilst promptly initiating empirical antibiotic treatment on high suspicion of IE, the antimicrobial selection approach based on the sensitivity of the antibiotic to the specific microbial, once confirmed, is recommended¹. Moreover, an interprofessional team approach in selecting optimal antibiotic regimens involving treating physicians/neurologists, nurses, primary care physicians and pharmacists is recommended¹.

C#3: Schematic diagram for treatment of Acute ischaemic stroke in infective endocarditis enhanced reader interest.

Reply# The schematic diagram 2 illustrates the various treatment options available to acute ischemic stroke patients with a history of infective endocarditis.

C#4: Pathophysiology of AIS with respect to infective endocarditis is not properly discussed.

Reply# Thank you for the suggestion. We have added following to the section on “Acute Ischaemic Stroke in the setting of Infective Endocarditis”

         “Stroke in the setting of IE may be caused by embolization of endocardial vegetations followed by blockage of an intracerebral artery^{2, 3}. Besides, embolisation to cerebral or meningeal arteries can also cause meningitis or intracerebral abscess.”

References:

1. Tackling G, Lala V. Endocarditis Antibiotic Regimens. [Updated 2021 Apr 21]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2021 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK542162/.
2. Heiro M, Nikoskelainen J, Engblom E, Kotilainen E, Marttila R, Kotilainen P. Neurologic manifestations of infective endocarditis: a 17-year experience in a teaching hospital in Finland. Archives of internal medicine. 2000;160(18):2781-7.
3. Ruttmann E, Willeit J, Ulmer H, Chevtchik O, Höfer D, Poewe W, et al. Neurological Outcome of Septic Cardioembolic Stroke After Infective Endocarditis. Stroke. 2006;37(8):2094-9.

Reviewer 2 Report

This is a very well written comprehensive review.

Minor comments:

1) Line 34: 1.Introduction and line 294: 13. Association with Adverse Events, please remove the numbers 1 and 13.

2) The first 3 paragraphs of the Discussion and Conclusion describe stroke prevention in patients with IE. In my opinion, it will be more appropriate if the authors split this section in two: Stroke prevention in IE and Conclusions.

Author Response

REVIEWER 2

C#1: This is a very well written comprehensive review.

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

Minor comments:

C#2: 1) Line 34: 1. Introduction and line 294: 13. Association with Adverse Events, please remove the numbers 1 and 13.

Reply# We have removed the numbers.

C#3: 2) The first 3 paragraphs of the Discussion and Conclusion describe stroke prevention in patients with IE. In my opinion, it will be more appropriate if the authors split this section in two: Stroke prevention in IE and Conclusions.

Reply# Thank you for the suggestion. We have split this section as suggested.

Round 2

Reviewer 1 Report

Authors have addressed  all comments satisfactory.

Still following comments need to be addressed.

1. Schematic diagram for treatment of Acute ischaemic stroke in infective endocarditis enhanced reader interest. In manuscript it is just overview. 
2. Pathophysiology of AIS with respect to infective endocarditis is not properly discussed.

Author Response

Thank you for your comment.

We have now created two separate sections: "Pathophysiology of Acute Ischaemic Stroke in the setting of Infective Endocarditis" and "Aetiology of Acute Ischaemic Stroke in the setting of Infective Endocarditis". 

Pathophysiology of Acute Ischaemic Stroke in the setting of Infective Endocarditis

         Stroke in the setting of IE may be caused by embolization of endocardial vegetations followed by blockage of an intracerebral artery (Figures 1 & 2) [25,26]. The thrombus in acute IE can be caused by the invading organism (e.g., S aureus) (spontaneous bacteraemia) or by valvular damage resulting from invasive procedures such as intravenous catheters or pacing wires[27-29]. Staphylococcus aureus can infiltrate endothelial cells, also called endotheliosis, and amplify the expression of adhesion molecules and procoagulant function on the cellular surface[29]. When bacteria colonise the surface of the vegetation, the process of platelet aggregation and fibrin buildup accelerates. As the bacteria proliferate, they are shielded from neutrophils as well as other host immunity by expanding layers of platelets and thrombin. Because of the nutrient scarcity, organisms at the deeper levels of vegetation hibernate, making them less vulnerable to bactericidal antimicrobials that infringe the bacterial cell membrane production. Besides, embolisation to cerebral or meningeal arteries can also cause meningitis or intracerebral abscess.