The Forest and the Trees

T.M. Leslie-Mazwi; J.A. Hirsch

doi:10.3174/ajnr.A6864

Coronavirus disease 2019 (COVID-19) is a multisystem disease;¹ the brain is not spared, and neurologic presentations are increasingly reported. Neurologic symptoms, including headache, altered mental status, and anosmia, occur in many infected patients.² Pathologic findings range from white matter disease³ to encephalitis,⁴ with only small samples of pathologic specimens published to date.⁵ Thrombosis is common in critically ill patients with COVID-19,⁶ and vasculopathy has been described, clinically and pathologically.⁷ Given this widespread vascular involvement, the impact of the pandemic on stroke has been a prominent concern.⁸ Reports to date suggest large-vessel occlusion (LVO) stroke in unusual populations⁹ and friable clot with an increased propensity for clot fragmentation during thrombectomy.¹⁰

In this issue of the American Journal of Neuroradiology, these considerations are further informed by an article by John et al,¹¹ from a large private medical center in the United Arab Emirates. The authors reviewed the experience of LVO care in patients positive for COVID-19 with stroke from March to May 2020, and compared this with a similar period in 2019. They found, in 2020, an increase in total stroke presentations and in LVOs (20 versus 44 patients, P = .008), attributed to changes in referral pathways during the pandemic in the region. Despite increasing case frequency, longer door-to-groin puncture times were seen in 2020 (68 versus 104 minutes, P = .001), caused by delays incurred by new safety protocols. A remarkably high rate of LVO in patients positive for COVID-19 with stroke was identified, 75% of COVID-19-associated stroke presentations in this series. Reperfusion was achieved in 67% of patients positive for COVID-19 with LVO undergoing thrombectomy, with excellent groin-to-reperfusion times. Who were these patients? Typically, younger (mean age of 46 years) with a preponderance of men (93%) who lacked traditional vascular risk factors (absent in 60% of the patients). Consistent with prior observations about prothrombotic tendencies, in this sample, a quarter of patients positive for COVID-19 with stroke had additional systemic thrombotic disease, and the burden of LVO clot and the multiplicity of vessels affected were notable. Forty percent of patients had more than a single intracranial arterial vessel affected by thrombosis or occlusion.

These results provide a snapshot of the potential impact of COVID-19 on stroke. The observational literature is growing. The study findings and similar reports⁹ have strong pathophysiologic plausibility. However, we must maintain appropriate caution. Beyond small sample sizes, there is the distinct risk of reporting bias in the literature available on COVID-19 and stroke. Reports of similar findings are lacking for other epicenters in China, Europe, and much of the most affected regions in the United States. This finding is surprising given the incidence reported in this and other positive samples. The additional variable of stroke geographies and stroke systems of care is also relevant. These results from Abu Dhabi compare technically very favorably with US or European centers, but stroke populations and systems of care are different, as the authors carefully highlight.

Despite these cautions, it seems likely that stroke presentations are affected directly by the virus. Perhaps this impact is as described in the available literature for particular subpopulations. What should we make of these and similar small series? These findings may have implications for prophylactic measures in patients severely affected by the virus, in whom coagulation abnormalities are widespread.¹² The role of therapeutic dosing of anticoagulation or antiplatelet therapy in patients with COVID-19 prophylactically remains controversial (though clearly deep venous thrombosis prophylaxis is widely indicated).¹³ Venous cerebrovascular disease has also been reported,¹⁴ for which anticoagulation clearly has a role, but whether addressing thrombotic risk in patients with COVID-19 impacts arterial stroke rates is unknown. It also seems likely that in patients who are positive for COVID-19 and have an LVO, our thrombectomy expectations must evolve. These patients pose a technical challenge with possibly reduced likelihood of recanalization and the need to treat potentially more than a single circulation. These are points of conjecture currently. Are findings specific to Severe Acute Respiratory Syndrome COVID-19 or should they be expected in any systemic viral illness of this severity, and are they only prominent because of the pandemic nature of this one? This, too, is uncertain.

To understand these questions better, we need large-dataset analysis, looking at incidence rates, therapies, and outcomes. For instance, the American Heart Association/America Stroke Association Get With The Guidelines stroke campaign (https://www.heart.org/en/professional/quality-improvement/get-with-the-guidelines/get-with-the-guidelines-stroke) collects data for hospitals treating stroke and will offer a window into this issue as data are progressively collated. This effort will be central to our understanding of the broader impact of COVID-19 on stroke pathophysiology, as distinct from its effect in currently reported pockets of patients.

While we may rightly debate the pathophysiology of COVID-19 and stroke, there should be less debate about the impact of COVID-19 on stroke systems of care.^15⇓-17 The identified decreases in overall stroke presentations are driven largely by a decrease in presentation of patients with milder strokes.¹⁸ Severely affected patients with stroke still present for care, consistent with the findings of John, et al;¹¹ 75% of acute stroke presentations in their patients with COVID-19 had LVOs. John et al further reported systems approaches in the centralization of care that led to their increased stroke and LVO numbers. Localization of expertise has already been pursued in disease epicenters¹⁹ and is acknowledged as effective in improving outcomes and using resources.²⁰ Although not the focus of the article by John et al, the response at a systems level bears special emphasis. We may experience limitations in our ability to impact stroke in the individual patient with COVID-19. Much remains unknown and may remain unknown. It is well within our power, however, to positively influence the impact of this disease on stroke systems of care.²¹ This is the forest, not just the trees. Such system adaptations, when pursued thoughtfully and collaboratively, build a resilient stroke-care system to handle this pandemic, as well as other challenges in the future, despite the numerous uncertainties about stroke mechanisms.

Indicates open access to non-subscribers at www.ajnr.org

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1. Spence JD,
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1. Oxley TJ,
2. Mocco J,
3. Majidi S, et al
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CrossRef PubMed
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1. Wang A,
2. Mandigo GK,
3. Yim PD, et al
. Stroke and mechanical thrombectomy in patients with COVID-19: technical observations and patient characteristics. J Neurointerv Surg 2020;12:648–53 doi:10.1136/neurintsurg-2020-016220 pmid:32451359
Abstract/FREE Full Text
11.↵
1. John S,
2. Kesav P,
3. Mifsud VA, et al
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Abstract/FREE Full Text
12.↵
1. Bowles L,
2. Platton S,
3. Yartey N, et al
. Lupus anticoagulant and abnormal coagulation tests in patients with Covid-19. N Engl J Med 2020;383:288–90 doi:10.1056/NEJMc2013656 pmid:32369280
CrossRef PubMed
13.↵
1. Thachil J,
2. Tang N,
3. Gando S, et al
. ISTH interim guidance on recognition and management of coagulopathy in COVID-19. J Thromb Haemost 2020;18:1023–26 doi:10.1111/jth.14810 pmid:32338827
CrossRef PubMed
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1. Cavalcanti DD,
2. Raz E,
3. Shapiro M, et al
. Cerebral venous thrombosis associated with COVID-19. AJNR Am J Neuroradiol 2020;41:1370–76 doi:10.3174/ajnr.A6644 pmid:32554424
Abstract/FREE Full Text
15.↵
1. Rudilosso S,
2. Laredo C,
3. Vera V, et al
. Acute stroke care is at risk in the era of COVID-19: experience at a comprehensive stroke center in Barcelona. Stroke 2020;51:1991–95 doi:10.1161/STROKEAHA.120.030329 pmid:32438895
CrossRef PubMed
16.↵
1. Kansagra AP,
2. Goyal MS,
3. Hamilton S, et al
. Collateral effect of Covid-19 on stroke evaluation in the United States. N Engl J Med 2020;383:400–01 doi:10.1056/NEJMc2014816 pmid:32383831
CrossRef PubMed
17.↵
1. Montaner J,
2. Barragan-Prieto A,
3. Perez-Sanchez S, et al
. Break in the stroke chain of survival due to COVID-19. Stroke 2020;51:2307–14 doi:10.1161/STROKEAHA.120.030106 pmid:32466738
CrossRef PubMed
18.↵
1. Siegler JE,
2. Heslin ME,
3. Thau L, et al
. Falling stroke rates during COVID-19 pandemic at a comprehensive stroke center. J Stroke Cerebrovasc Dis 2020;29:104953 doi:10.1016/j.jstrokecerebrovasdis.2020.104953 pmid:32689621
CrossRef PubMed
19.↵
1. Stefanini GG,
2. Azzolini E,
3. Condorelli G
. Critical organizational issues for cardiologists in the COVID-19 outbreak: a frontline experience from Milan, Italy. Circulation 2020;141:1597–99 doi:10.1161/CIRCULATIONAHA.120.047070 pmid:32207994
CrossRef PubMed
20.↵
1. Vonlanthen R,
2. Lodge P,
3. Barkun JS, et al
. Toward a consensus on centralization in surgery. Ann Surg 2018;268:712–24 doi:10.1097/SLA.0000000000002965 pmid:30169394
CrossRef PubMed
21.↵
1. Leslie-Mazwi TM,
2. Fargen KM,
3. Levitt M, et al
. Preserving access: a review of stroke thrombectomy during the COVID-19 pandemic. AJNR Am J Neuroradiol 2020;41:1136–41 doi:10.3174/ajnr.A6606 pmid:32439650
Abstract/FREE Full Text

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[1] 1.↵
Mahajan A,
Hirsch JA
. Novel coronavirus: what neuroradiologists as citizens of the world need to know. AJNR Am J Neuroradiol 2020;41:552–54 doi:10.3174/ajnr.A6526 pmid:32198164
FREE Full Text

[2] Mahajan A,

[3] Hirsch JA

[4] 2.↵
Mao L,
Jin,
H,
Wang,
M, et al
. Neurological manifestations of hospitalized patients with COVID-19 in Wuhan, China: a retrospective case series study. JAMA Neurol 2020 Apr 10. [Epub ahead of print] doi:10.1001/jamaneurol.2020.1127 pmid:32275288
CrossRef PubMed

[5] Mao L,

[6] Jin,

[7] H,

[8] Wang,

[9] M, et al

[10] 3.↵
Lang M,
Buch K,
Li MD, et al
. Leukoencephalopathy associated with severe COVID-19 infection: sequela of hypoxemia? AJNR Am J Neuroradiol 2020 Jun 20. [Epub ahead of print] doi:10.3174/ajnr.A6671 pmid:32586959
Abstract/FREE Full Text

[11] Lang M,

[12] Buch K,

[13] Li MD, et al

[14] 4.↵
Bernard-Valnet R,
Pizzarotti B,
Anichini A, et al
. Two patients with acute meningoencephalitis concomitant with SARS-CoV-2 infection. Eur J Neurol 2020 Jun 20. [Epub ahead of print] doi:10.1111/ene.14298 pmid:32586959
CrossRef PubMed

[15] Bernard-Valnet R,

[16] Pizzarotti B,

[17] Anichini A, et al

[18] 5.↵
Solomon IH,
Normandin E,
Bhattacharyya S, et al
. Neuropathological features of Covid-19. N Engl J Med 2020;383:989–92 doi:10.1056/NEJMc2019373 pmid:32530583
CrossRef PubMed

[19] Solomon IH,

[20] Normandin E,

[21] Bhattacharyya S, et al

[22] 6.↵
Klok FA,
Kruip M,
van der Meer NJ, et al
. Confirmation of the high cumulative incidence of thrombotic complications in critically ill ICU patients with COVID-19: an updated analysis. Thromb Res 2020;191:148–50 doi:10.1016/j.thromres.2020.04.041 pmid:32381264
CrossRef PubMed

[23] Klok FA,

[24] Kruip M,

[25] van der Meer NJ, et al

[26] 7.↵
Varga Z,
Flammer AJ,
Steiger P, et al
. Endothelial cell infection and endotheliitis in COVID-19. Lancet 2020;395:1417–18 doi:10.1016/S0140-6736(20)30937-5 pmid:32325026
CrossRef PubMed

[27] Varga Z,

[28] Flammer AJ,

[29] Steiger P, et al

[30] 8.↵
Spence JD,
de Freitas GR,
Pettigrew LC, et al
. Mechanisms of stroke in COVID-19. Cerebrovasc Dis 2020 Jul 20. [Epub ahead of print] doi:10.1159/000509581 pmid:32690850
CrossRef PubMed

[31] Spence JD,

[32] de Freitas GR,

[33] Pettigrew LC, et al

[34] 9.↵
Oxley TJ,
Mocco J,
Majidi S, et al
. Large-vessel stroke as a presenting feature of Covid-19 in the young. N Engl J Med 2020;382:e60 doi:10.1056/NEJMc2009787 pmid:32343504
CrossRef PubMed

[35] Oxley TJ,

[36] Mocco J,

[37] Majidi S, et al

[38] 10.↵
Wang A,
Mandigo GK,
Yim PD, et al
. Stroke and mechanical thrombectomy in patients with COVID-19: technical observations and patient characteristics. J Neurointerv Surg 2020;12:648–53 doi:10.1136/neurintsurg-2020-016220 pmid:32451359
Abstract/FREE Full Text

[39] Wang A,

[40] Mandigo GK,

[41] Yim PD, et al

[42] 11.↵
John S,
Kesav P,
Mifsud VA, et al
. Characteristics of large-vessel occlusion associated with COVID-19 and ischemic stroke. AJNR Am J Neuroradiol 2020 Aug 27. [Epub ahead of print] doi:10.3174/ajnr.A6799pmid:32855182
Abstract/FREE Full Text

[43] John S,

[44] Kesav P,

[45] Mifsud VA, et al

[46] 12.↵
Bowles L,
Platton S,
Yartey N, et al
. Lupus anticoagulant and abnormal coagulation tests in patients with Covid-19. N Engl J Med 2020;383:288–90 doi:10.1056/NEJMc2013656 pmid:32369280
CrossRef PubMed

[47] Bowles L,

[48] Platton S,

[49] Yartey N, et al

[50] 13.↵
Thachil J,
Tang N,
Gando S, et al
. ISTH interim guidance on recognition and management of coagulopathy in COVID-19. J Thromb Haemost 2020;18:1023–26 doi:10.1111/jth.14810 pmid:32338827
CrossRef PubMed

[51] Thachil J,

[52] Tang N,

[53] Gando S, et al

[54] 14.↵
Cavalcanti DD,
Raz E,
Shapiro M, et al
. Cerebral venous thrombosis associated with COVID-19. AJNR Am J Neuroradiol 2020;41:1370–76 doi:10.3174/ajnr.A6644 pmid:32554424
Abstract/FREE Full Text

[55] Cavalcanti DD,

[56] Raz E,

[57] Shapiro M, et al

[58] 15.↵
Rudilosso S,
Laredo C,
Vera V, et al
. Acute stroke care is at risk in the era of COVID-19: experience at a comprehensive stroke center in Barcelona. Stroke 2020;51:1991–95 doi:10.1161/STROKEAHA.120.030329 pmid:32438895
CrossRef PubMed

[59] Rudilosso S,

[60] Laredo C,

[61] Vera V, et al

[62] 16.↵
Kansagra AP,
Goyal MS,
Hamilton S, et al
. Collateral effect of Covid-19 on stroke evaluation in the United States. N Engl J Med 2020;383:400–01 doi:10.1056/NEJMc2014816 pmid:32383831
CrossRef PubMed

[63] Kansagra AP,

[64] Goyal MS,

[65] Hamilton S, et al

[66] 17.↵
Montaner J,
Barragan-Prieto A,
Perez-Sanchez S, et al
. Break in the stroke chain of survival due to COVID-19. Stroke 2020;51:2307–14 doi:10.1161/STROKEAHA.120.030106 pmid:32466738
CrossRef PubMed

[67] Montaner J,

[68] Barragan-Prieto A,

[69] Perez-Sanchez S, et al

[70] 18.↵
Siegler JE,
Heslin ME,
Thau L, et al
. Falling stroke rates during COVID-19 pandemic at a comprehensive stroke center. J Stroke Cerebrovasc Dis 2020;29:104953 doi:10.1016/j.jstrokecerebrovasdis.2020.104953 pmid:32689621
CrossRef PubMed

[71] Siegler JE,

[72] Heslin ME,

[73] Thau L, et al

[74] 19.↵
Stefanini GG,
Azzolini E,
Condorelli G
. Critical organizational issues for cardiologists in the COVID-19 outbreak: a frontline experience from Milan, Italy. Circulation 2020;141:1597–99 doi:10.1161/CIRCULATIONAHA.120.047070 pmid:32207994
CrossRef PubMed

[75] Stefanini GG,

[76] Azzolini E,

[77] Condorelli G

[78] 20.↵
Vonlanthen R,
Lodge P,
Barkun JS, et al
. Toward a consensus on centralization in surgery. Ann Surg 2018;268:712–24 doi:10.1097/SLA.0000000000002965 pmid:30169394
CrossRef PubMed

[79] Vonlanthen R,

[80] Lodge P,

[81] Barkun JS, et al

[82] 21.↵
Leslie-Mazwi TM,
Fargen KM,
Levitt M, et al
. Preserving access: a review of stroke thrombectomy during the COVID-19 pandemic. AJNR Am J Neuroradiol 2020;41:1136–41 doi:10.3174/ajnr.A6606 pmid:32439650
Abstract/FREE Full Text

[83] Leslie-Mazwi TM,

[84] Fargen KM,

[85] Levitt M, et al

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