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      COVID-19-Related Stroke: Barking up the Wrong Tree?


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          Dear Editor, We are grateful to Hooshmandi et al. [1] (ENE-2020-4-59) for the interest shown in our article and for their comments. At the time of writing, Piacenza was the second most heavily hit Italian city by COVID-19 pandemic (1.415%) [2], providing an exceptional perspective of the current situation in the neurological field. We previously emphasized how the main limit of our comments was the brief observation period, that is, 1 month, that is when the outbreak of SARS-CoV-2 peaked. In the following period, only few small case series of COVID-19 stroke patients have been reported [3, 4, 5, 6, 7, 8]. Therefore, little information is available on stroke in this unknown pathological scenario. Despite the lack of current scientific literature on the topic, which is limited to anecdotal reports, numerous hypotheses have been put forward as to the role of the thrombophilic state induced by 2019-nCoV and the likely increased risk of stroke in infected patients [9, 10, 11]. From February 21 to April 28, 2020, 854 COVID-19 patients were admitted to our facility, 17 of whom with concomitant ischemic stroke symptoms (mean age 76.1 ± 8.8). No young adult stroke patient was observed. There was no rare stroke etiology or unforeseen high incidence in stroke subtypes. Severity of stroke evaluated by the NIHSS seems to correlate with extension of interstitial pneumonia documented with chest CT scan (personal data, in press). However, anecdotal evidence is collected in a casual or informal manner and relies entirely on personal testimony. Therefore, it is generally considered to have a limited value, due to a number of potential weaknesses. For this reason, we agree with Hooshmandi et al. that it is too early to consider a direct “cause-effect” relationship between 2019-nCoV infection and stroke occurrence so that further prospective and large-volume studies are warranted. The occurrence of different types of cerebrovascular diseases during the 2019-nCoV pandemic can be documented only by international multicenter studies. Indeed, the prevalence of COVID-19 is so high in pandemic hotspots that an incidental association between infection and neurological manifestations cannot be excluded. During a pandemic, when science and medicine are asked to provide answers, neurologists should strive to keep high scientific research standards and place trust in their clinical methods, starting with an accurate patient interview and then moving through standard neurological examination. The clinical path is then completed by the diagnostic confirmation through imaging, laboratory, electrophysiological, and pathological techniques. All of which leads to the question as to whether relating stroke to COVID-19 may be tantamount to barking up the wrong tree. Hopefully, time and research will be our mentors, as has often been the case. Disclosure Statement The authors have no conflicts of interest to declare. Funding Sources This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. No financial support was provided for the research, authorship and/or publication of this article. Author Contributions Study concepts: N. Morelli, E. Rota, and C. Terracciano. Study design: N. Morelli, E. Rota, and M. Spallazzi, Data analysis/interpretation: N. Morelli, D. Zaino, P. Immovilli, and D. Colombi. Manuscript preparation and definition of intellectual content: N. Morelli, E. Rota, and C. Terracciano. Manuscript editing: N. Morelli, E. Rota, and Arens Taga. Manuscript revision/review: D. Guidetti and E. Michieletti.

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          Neurologic Manifestations of Hospitalized Patients With Coronavirus Disease 2019 in Wuhan, China

          The outbreak of coronavirus disease 2019 (COVID-19) in Wuhan, China, is serious and has the potential to become an epidemic worldwide. Several studies have described typical clinical manifestations including fever, cough, diarrhea, and fatigue. However, to our knowledge, it has not been reported that patients with COVID-19 had any neurologic manifestations.
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            Neurologic Features in Severe SARS-CoV-2 Infection

            To the Editor: We report the neurologic features in an observational series of 58 of 64 consecutive patients admitted to the hospital because of acute respiratory distress syndrome (ARDS) due to Covid-19. The patients received similar evaluations by intensivists in two intensive care units (ICUs) in Strasbourg, France, between March 3 and April 3, 2020. Six patients were excluded because of paralytic neuromuscular blockade when neurologic data were collected or because they had died without a neurologic examination having been performed. In all 58 patients, reverse-transcriptase–polymerase-chain-reaction (RT-PCR) assays of nasopharyngeal samples were positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The median age of the patients was 63 years, and the median Simplified Acute Physiology Score II at the time of neurologic examination was 52 (interquartile range, 37 to 65, on a scale ranging from 0 to 163, with higher scores indicating greater severity of illness). Seven patients had had previous neurologic disorders, including transient ischemic attack, partial epilepsy, and mild cognitive impairment. The neurologic findings were recorded in 8 of the 58 patients (14%) on admission to the ICU (before treatment) and in 39 patients (67%) when sedation and a neuromuscular blocker were withheld. Agitation was present in 40 patients (69%) when neuromuscular blockade was discontinued (Table 1). A total of 26 of 40 patients were noted to have confusion according to the Confusion Assessment Method for the ICU; those patients could be evaluated when they were responsive (i.e., they had a score of −1 to 1 on the Richmond Agitation and Sedation Scale, on a scale of −5 [unresponsive] to +4 [combative]). Diffuse corticospinal tract signs with enhanced tendon reflexes, ankle clonus, and bilateral extensor plantar reflexes were present in 39 patients (67%). Of the patients who had been discharged at the time of this writing, 15 of 45 (33%) had had a dysexecutive syndrome consisting of inattention, disorientation, or poorly organized movements in response to command. Magnetic resonance imaging (MRI) of the brain was performed in 13 patients (Figs. S1 through S3 in the Supplementary Appendix, available with the full text of this letter at NEJM.org). Although these patients did not have focal signs that suggested stroke, they underwent MRI because of unexplained encephalopathic features. Enhancement in leptomeningeal spaces was noted in 8 patients, and bilateral frontotemporal hypoperfusion was noted in all 11 patients who underwent perfusion imaging. Two asymptomatic patients each had a small acute ischemic stroke with focal hyperintensity on diffusion-weighted imaging and an overlapping decreased apparent diffusion coefficient, and 1 patient had a subacute ischemic stroke with superimposed increased diffusion-weighted imaging and apparent diffusion coefficient signals. In the 8 patients who underwent electroencephalography, only nonspecific changes were detected; 1 of the 8 patients had diffuse bifrontal slowing consistent with encephalopathy. Examination of cerebrospinal fluid (CSF) samples obtained from 7 patients showed no cells; in 2 patients, oligoclonal bands were present with an identical electrophoretic pattern in serum, and protein and IgG levels were elevated in 1 patient. RT-PCR assays of the CSF samples were negative for SARS-CoV-2 in all 7 patients. In this consecutive series of patients, ARDS due to SARS-CoV-2 infection was associated with encephalopathy, prominent agitation and confusion, and corticospinal tract signs. Two of 13 patients who underwent brain MRI had single acute ischemic strokes. Data are lacking to determine which of these features were due to critical illness–related encephalopathy, cytokines, or the effect or withdrawal of medication, and which features were specific to SARS-CoV-2 infection.
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              Venous and arterial thromboembolic complications in COVID-19 patients admitted to an academic hospital in Milan, Italy

              Background Few data are available on the rate and characteristics of thromboembolic complications in hospitalized patients with COVID-19. Methods We studied consecutive symptomatic patients with laboratory-proven COVID-19 admitted to a university hospital in Milan, Italy (13.02.2020–10.04.2020). The primary outcome was any thromboembolic complication, including venous thromboembolism (VTE), ischemic stroke, and acute coronary syndrome (ACS)/myocardial infarction (MI). Secondary outcome was overt disseminated intravascular coagulation (DIC). Results We included 388 patients (median age 66 years, 68% men, 16% requiring intensive care [ICU]). Thromboprophylaxis was used in 100% of ICU patients and 75% of those on the general ward. Thromboembolic events occurred in 28 (7.7% of closed cases; 95%CI 5.4%–11.0%), corresponding to a cumulative rate of 21% (27.6% ICU, 6.6% general ward). Half of the thromboembolic events were diagnosed within 24 h of hospital admission. Forty-four patients underwent VTE imaging tests and VTE was confirmed in 16 (36%). Computed tomography pulmonary angiography (CTPA) was performed in 30 patients, corresponding to 7.7% of total, and pulmonary embolism was confirmed in 10 (33% of CTPA). The rate of ischemic stroke and ACS/MI was 2.5% and 1.1%, respectively. Overt DIC was present in 8 (2.2%) patients. Conclusions The high number of arterial and, in particular, venous thromboembolic events diagnosed within 24 h of admission and the high rate of positive VTE imaging tests among the few COVID-19 patients tested suggest that there is an urgent need to improve specific VTE diagnostic strategies and investigate the efficacy and safety of thromboprophylaxis in ambulatory COVID-19 patients.

                Author and article information

                Eur Neurol
                Eur. Neurol
                European Neurology
                S. Karger AG (Allschwilerstrasse 10, P.O. Box · Postfach · Case postale, CH–4009, Basel, Switzerland · Schweiz · Suisse, Phone: +41 61 306 11 11, Fax: +41 61 306 12 34, karger@karger.com )
                11 June 2020
                : 83
                : 2
                : 218-219
                [1] aNeurology Unit, Guglielmo da Saliceto Hospital, Piacenza, Italy
                [2] bNeurology Unit, San Giacomo Hospital, Alessandria, Italy
                [3] cRadiology Unit, Guglielmo da Saliceto Hospital, Piacenza, Italy
                [4] dDepartment of Neurology, Johns Hopkins University, Baltimore, Maryland, USA
                Author notes
                *Nicola Morelli, Neurology and Radiology Unit, Guglielmo da Saliceto Hospital, Via Taverna 49, IT–29121 Piacenza (Italy), nicola.morelli.md@ 123456gmail.com

                All authors contributed equally to the manuscript.

                Copyright © 2020 by S. Karger AG, Basel

                This article is made available via the PMC Open Access Subset for unrestricted re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the COVID-19 pandemic or until permissions are revoked in writing. Upon expiration of these permissions, PMC is granted a perpetual license to make this article available via PMC and Europe PMC, consistent with existing copyright protections.

                : 15 May 2020
                : 22 May 2020
                : 2020
                Page count
                References: 11, Pages: 2
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