Time to Refocus the Target in Stroke Therapy Again?
===================================================

* K.-O. Lövblad

Stroke treatment has made enormous advances during the past decades. While initial research was focused on the brain parenchyma and its eventual demise, it was actually the arrival of treatments of clot that completely changed the game. Indeed, while from a basic point of view, the pathophysiology of stroke is well-investigated and partly understood enough to develop a pharmaceutical agent,1,2 these approaches have, until now, failed. Indeed, while the animal models were very often able to create an ideal model of stroke, the translation into the clinical setting has not met with great success for neuroprotection. However, now that imaging and revascularization have made great progress, it may be time to reassess if neuropotection could be possible. Indeed, whether by using CT3 or MR imaging4 or even DSA-based techniques5 or even bypassing these and going directly into the catheter lab, it is possible to obtain imaging of the brain that will diagnose an ischemic event with high certitude and a short time interval. This fast and improved global brain imaging approach, together with the recent successes of interventional revascularization, shows increased rates of recovery6⇓⇓-9 within a longer therapeutic window than previously achievable.10

The combination of improved diagnostics and interventional measures could make us reassess whether the era of neuroprotective agents may come again. Indeed, while revascularization itself by interventional techniques is now the standard, the results, on the one hand, may be improved if the drugs can now be given directly into the target zone,11 which could lead to new therapeutic drug trials. This means that we also have to reassess the way we conceive the penumbra or the tissue at risk.12,13 Indeed, from being at the beginning a metabolic event that was supposed to become the therapeutic target, the penumbral model evolved into a hemodynamically based one with new imaging technologies. This evolution coincided with the initial thrombolysis trials and led to the initial successes against the disease. However, now that we see that not just collaterals play a role in maintaining tissue vitality, we may need to additionally assess the topics of tissular fragility more with advanced imaging techniques and possibly artificial intelligence algorithms to demonstrate the potential activity of pharmaceutical treatment. This assessment could, in the end, also facilitate treatment by offering additional therapies with wider access than is currently available to patients who have an ischemic event and do not live close to an integrated stroke center.

## Footnotes

*   The article was funded by a grant from the Swiss National Science Foundation, grant No. 32003B_182382/1.

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## References

1.  1.Siesjö BK. Pathophysiology and treatment of focal cerebral ischemia, Part II: mechanisms of damage and treatment. J Neurosurg 1992;77:337–54 doi:10.3171/jns.1992.77.3.0337 pmid:1506880
    
    [CrossRef](http://www.ajnr.org/lookup/external-ref?access_num=10.3171/jns.1992.77.3.0337&link_type=DOI) 
    
    [PubMed](http://www.ajnr.org/lookup/external-ref?access_num=1506880&link_type=MED&atom=%2Fajnr%2F41%2F3%2FE13.atom) 
    
    [Web of Science](http://www.ajnr.org/lookup/external-ref?access_num=A1992JK67600001&link_type=ISI) 

2.  2.Siesjö BK. Pathophysiology and treatment of focal cerebral ischemia, Part I: pathophysiology. J Neurosurg 1992;77:169–84 doi:10.3171/jns.1992.77.2.0169 pmid:1625004
    
    [CrossRef](http://www.ajnr.org/lookup/external-ref?access_num=10.3171/jns.1992.77.2.0169&link_type=DOI) 
    
    [PubMed](http://www.ajnr.org/lookup/external-ref?access_num=1625004&link_type=MED&atom=%2Fajnr%2F41%2F3%2FE13.atom) 
    
    [Web of Science](http://www.ajnr.org/lookup/external-ref?access_num=A1992JE70500001&link_type=ISI) 

3.  3.Lövblad KO, Baird AE. Computed tomography in acute ischemic stroke. Neuroradiology 2010;52:175–87 doi:10.1007/s00234-009-0633-5 pmid:19953234
    
    [CrossRef](http://www.ajnr.org/lookup/external-ref?access_num=10.1007/s00234-009-0633-5&link_type=DOI) 
    
    [PubMed](http://www.ajnr.org/lookup/external-ref?access_num=19953234&link_type=MED&atom=%2Fajnr%2F41%2F3%2FE13.atom) 

4.  4.Lövblad KO, Laubach HJ, Baird AE, et al. Clinical experience with diffusion-weighted MR in patients with acute stroke. AJNR Am J Neuroradiol 1998;19:1061–66 pmid:9672012
    
    [Abstract](http://www.ajnr.org/lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6NDoiYWpuciI7czo1OiJyZXNpZCI7czo5OiIxOS82LzEwNjEiO3M6NDoiYXRvbSI7czoxOToiL2FqbnIvNDEvMy9FMTMuYXRvbSI7fXM6ODoiZnJhZ21lbnQiO3M6MDoiIjt9) 

5.  5.Mueller A, Wagner M, Hattingen E, et al. Flat panel computed tomography pooled blood volume and infarct prediction in endovascular strok**e** treatment. Stroke 2019;50:3274–76 doi:10.1161/STROKEAHA.119.025973 pmid:31495326
    
    [CrossRef](http://www.ajnr.org/lookup/external-ref?access_num=10.1161/STROKEAHA.119.025973&link_type=DOI) 
    
    [PubMed](http://www.ajnr.org/lookup/external-ref?access_num=31495326&link_type=MED&atom=%2Fajnr%2F41%2F3%2FE13.atom) 

6.  6.Jovin TG, Chamorro A, Cobo E, et al; REVASCAT Trial Investigators. Thrombectomy within 8 hours after symptom onset in ischemic stroke. N Engl J Med 2015;372:2296–306 doi:10.1056/NEJMoa1503780 pmid:25882510
    
    [CrossRef](http://www.ajnr.org/lookup/external-ref?access_num=10.1056/NEJMoa1503780&link_type=DOI) 
    
    [PubMed](http://www.ajnr.org/lookup/external-ref?access_num=25882510&link_type=MED&atom=%2Fajnr%2F41%2F3%2FE13.atom) 

7.  7.Saver JL, Goyal M, Bonafe A, et al; SWIFT PRIME Investigators. Stent-retriever thrombectomy after intravenous t-PA vs. t-PA alone in stroke. N Engl J Med 2015;372:2285–95 doi:10.1056/NEJMoa1415061 pmid:25882376
    
    [CrossRef](http://www.ajnr.org/lookup/external-ref?access_num=10.1056/NEJMoa1415061&link_type=DOI) 
    
    [PubMed](http://www.ajnr.org/lookup/external-ref?access_num=25882376&link_type=MED&atom=%2Fajnr%2F41%2F3%2FE13.atom) 

8.  8.Goyal M, Demchuk AM, Menon BK, et al; ESCAPE Trial Investigators. Randomized assessment of rapid endovascular treatment of ischemic stroke. N Engl J Med 2015;372:1019–30 doi:10.1056/NEJMoa1414905 pmid:25671798
    
    [CrossRef](http://www.ajnr.org/lookup/external-ref?access_num=10.1056/NEJMoa1414905&link_type=DOI) 
    
    [PubMed](http://www.ajnr.org/lookup/external-ref?access_num=25671798&link_type=MED&atom=%2Fajnr%2F41%2F3%2FE13.atom) 

9.  9.Campbell BC, Mitchell PJ, Kleinig TJ, et al; EXTEND-IA Investigators. Endovascular therapy for ischemic stroke with perfusion-imaging selection. N Engl J Med 2015;372:1009–18 doi:10.1056/NEJMoa1414792 pmid:25671797
    
    [CrossRef](http://www.ajnr.org/lookup/external-ref?access_num=10.1056/NEJMoa1414792&link_type=DOI) 
    
    [PubMed](http://www.ajnr.org/lookup/external-ref?access_num=25671797&link_type=MED&atom=%2Fajnr%2F41%2F3%2FE13.atom) 

10. 10.Nogueira RG, Jadhav AP, Haussen DC, et al; DAWN Trial Investigators. Thrombectomy 6 to 24 hours after stroke with a mismatch between deficit and infarct. N Engl J Med 2018;378:11–21 doi:10.1056/NEJMoa1706442 pmid:29129157
    
    [CrossRef](http://www.ajnr.org/lookup/external-ref?access_num=10.1056/NEJMoa1706442&link_type=DOI) 
    
    [PubMed](http://www.ajnr.org/lookup/external-ref?access_num=29129157&link_type=MED&atom=%2Fajnr%2F41%2F3%2FE13.atom) 

11. 11.Shi L, Rocha M, Leak RK, et al. A new era for stroke therapy: integrating neurovascular **protection** with optimal reperfusion. J Cereb Blood Flow Metab 2018;38:2073–91 doi:10.1177/0271678X18798162 pmid:30191760
    
    [CrossRef](http://www.ajnr.org/lookup/external-ref?access_num=10.1177/0271678X18798162&link_type=DOI) 
    
    [PubMed](http://www.ajnr.org/lookup/external-ref?access_num=30191760&link_type=MED&atom=%2Fajnr%2F41%2F3%2FE13.atom) 

12. 12.Astrup J, Siesjö BK, Symon L. Thresholds in cerebral ischemia: the ischemic penumbra. Stroke 1981;12:723–25 doi:10.1161/01.str.12.6.723 pmid:6272455
    
    [FREE Full Text](http://www.ajnr.org/lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6MzoiUERGIjtzOjExOiJqb3VybmFsQ29kZSI7czo5OiJzdHJva2VhaGEiO3M6NToicmVzaWQiO3M6ODoiMTIvNi83MjMiO3M6NDoiYXRvbSI7czoxOToiL2FqbnIvNDEvMy9FMTMuYXRvbSI7fXM6ODoiZnJhZ21lbnQiO3M6MDoiIjt9) 

13. 13.Schlaug G, Benfield A, Baird AE, et al. The ischemic penumbra: operationally defined by diffusion and perfusion MRI. Neurology 1999;53:1528–37 doi:10.1212/wnl.53.7.1528 pmid:10534263
    
    [Abstract/FREE Full Text](http://www.ajnr.org/lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6OToibmV1cm9sb2d5IjtzOjU6InJlc2lkIjtzOjk6IjUzLzcvMTUyOCI7czo0OiJhdG9tIjtzOjE5OiIvYWpuci80MS8zL0UxMy5hdG9tIjt9czo4OiJmcmFnbWVudCI7czowOiIiO30=) 

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