Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2021 Feb 26:14:1756286421993701.
doi: 10.1177/1756286421993701. eCollection 2021.

Observational cohort study of neurological involvement among patients with SARS-CoV-2 infection

Michael Fleischer  1 , Martin Köhrmann  1 , Sebastian Dolff  2 , Fabian Szepanowski  1 , Karsten Schmidt  3 , Frank Herbstreit  3 , Cansu Güngör  1 , Benjamin Stolte  1 , Katharina Marie Steiner  1 , Christine Stadtler  1 , Joachim Riße  4 , Melanie Fiedler  5 , Gerd Meyer Zu Hörste  6 , Anne-K Mausberg  1 , Clemens Kill  4 , Michael Forsting  7 , Ulrich Sure  8 , Ulf Dittmer  5 , Oliver Witzke  2 , Thorsten Brenner  3 , Christoph Kleinschnitz  1 , Mark Stettner  9
Affiliations

Observational cohort study of neurological involvement among patients with SARS-CoV-2 infection

Michael Fleischer et al. Ther Adv Neurol Disord. .

Abstract

Background: A growing number of reports suggest that infection with SARS-CoV-2 often leads to neurological involvement; however, data on the incidence and severity are limited to mainly case reports and retrospective studies.

Methods: This prospective, cross-sectional study of 102 SARS-CoV-2 PCR positive patients investigated the frequency, type, severity and risk factors as well as underlying pathophysiological mechanisms of neurological involvement (NIV) in COVID-19 patients.

Results: Across the cohort, 59.8% of patients had NIV. Unspecific NIV was suffered by 24.5%, mainly general weakness and cognitive decline or delirium. Mild NIV was found in 9.8%; most commonly, impaired taste or smell. Severe NIV was present in 23.5%; half of these suffered cerebral ischaemia. Incidence of NIV increased with respiratory symptoms of COVID-19. Mortality was higher with increasing NIV severity. Notably, 83.3% with severe NIV had a pre-existing neurological co-morbidity. All cerebrospinal fluid (CSF) samples were negative for SARS-CoV-2 RNA, and SARS-CoV-2 antibody quotient did not suggest intrathecal antibody synthesis. Of the patients with severe NIV, 50% had blood-brain barrier (BBB) disruption and showed a trend of elevated interleukin levels in CSF. Antibodies against neuronal and glial epitopes were detected in 35% of the patients tested.

Conclusion: Cerebrovascular events were the most frequent severe NIV and severe NIV was associated with high mortality. Incidence of NIV increased with respiratory symptoms and NIV and pre-existing neurological morbidities were independent risk factors for fatality. Inflammatory involvement due to BBB disruption and cytokine release drives NIV, rather than direct viral invasion. These findings might help physicians define a further patient group requiring particular attention during the pandemic.

Keywords: COVID-19; Cerebrovascular events; Neuro-COVID.

PubMed Disclaimer

Conflict of interest statement

Conflict of interest: M. Fleischer reports no disclosures relevant to the manuscript. M. Köhrmann reports no disclosures relevant to the manuscript. S. Dolff reports no disclosures relevant to the manuscript. F. Szepanowski reports no disclosures relevant to the manuscript. K. Schmidt reports no disclosures relevant to the manuscript. F. Herbstreit has received speaker honoraria from Biotest and Maquet Getinge. C. Güngör reports no disclosures relevant to the manuscript. B. Stolte reports no disclosures relevant to the manuscript. Ch. Stadtler reports no disclosures relevant to the manuscript. J. Riße reports no disclosures relevant to the manuscript. O. Witzke has received research grants for clinical studies, speaker’s fees, honoraria and travel expenses from Amgen, Alexion, Astellas, Basilea, Biotest, Bristol-Myers Squibb, Correvio, Chiesi, Gilead, Hexal, Janssen, Dr. F. Köhler Chemie, MSD, Novartis, Roche, Pfizer, Sanofi, TEVA and UCB. M. Fiedler reports no disclosures relevant to the manuscript. A. Mausberg reports no disclosures relevant to the manuscript. C. Kill reports no disclosures relevant to the manuscript. G. Meyer zu Horste has received speaker honoraria and served in advisory boards for LFB Pharma. K. Steiner reports no disclosures relevant to the manuscript. M. Forsting reports no disclosures relevant to the manuscript. U. Sure reports no disclosures relevant to the manuscript. U. Dittmer reports no disclosures relevant to the manuscript. T. Brenner reports no disclosures relevant to the manuscript. C. Kleinschnitz reports no disclosures relevant to the manuscript. M. Stettner served on the scientific advisory and/or received speaker honoraria or travel funding from UCB, Biogen Idec; Grifols, Genzyme, Roche, Merck, Novartis, Octapharma, Sanofi-Aventis, TEVA, and Bayer Healthcare. All authors declare approval of the version that is to be published.

Figures

Figure 1.
Figure 1.
Clinical characteristics of the COVID-19 cohort. (A) Proportion of patients showing unspecific, mild focal and severe focal neurological symptoms according to severity of COVID-19 classified as mild, moderate or severe. Proportion of patients (%) showing each type of neurological symptom grouped within the categories of unspecific, mild focal and severe focal neurological symptoms. (B) Mortality (% of patients) in relation to severity of COVID-19 and neurological involvement (none, unspecific, mild focal or severe focal). Inlays show all deaths, and proportion of NIV classification and COVID-19 severity. (C) Distribution of age in relation to neurological involvement categories (none, unspecific, mild focal or severe focal). (D) Proportion of patients (%) who had pre-existing neurological morbidity within each of the neurological involvement categories (none, unspecific, mild focal or severe focal). (E) Number of comorbidities in relation to neurological involvement categories. Classification *p < 0.05, **p < 0.01. (none, unspecific, mild focal or severe focal). NIV, neurological involvement; Unsp., unspecific.
Figure 2.
Figure 2.
Cerebrospinal fluid (CSF) analysis of COVID-19 patients. (A) and (B) CSF cell counts (n/µl) and level of CSF protein (mg/dl) according to neurological involvement categories (none, unspecific, mild focal or severe focal). (C) Extinction of IgG antibody against SARS-CoV-2 against albumin ratio. The colour-coding shows each of the neurological symptom categories: none (green), mild focal (orange) or severe focal (red). (D) Integrity of the blood–brain barrier (BBB), graphed by number of patients who showed a disruption or an intact BBB within each of the neurological involvement categories (none, unspecific, mild focal or severe focal). AB, antibody; NIV, neurological involvement; Unsp., unspecific.
Figure 3.
Figure 3.
Cerebrospinal fluid (CSF) and blood analysis of COVID-19 patients. (A)–(C). Concentration of IL-6, IL-8, TNF-alpha (pg/ml) in the CSF by neurological symptom involvement (none, unspecific, mild focal or severe focal classification *p < 0.05). Inlays: respective status of blood–brain barrier (BBB) in relation to interleukin level. (D) Antibodies against neuronal or glial epitopes in serum in relation to neurological involvement categories (none, unspecific, mild focal or severe focal). (E) Measurement of neurofilament in CSF grouped according to each of the neurological involvement categories (none, unspecific, mild focal or severe focal). (F) Measurement of neurofilament in serum grouped according to each of the neurological involvement categories (none, unspecific, mild focal or severe focal). AB, antibody; NIV, neurological involvement; Unsp., unspecific; IL, interleukin.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Mao L, Jin H, Wang M, et al. Neurologic manifestations of hospitalized patients with coronavirus disease 2019 in Wuhan, China. JAMA Neurol 2020; 77: 683–690. - PMC - PubMed
    1. Werner C, Scullen T, Mathkour M, et al. Neurological impact of coronavirus disease of 2019: practical considerations for the neuroscience community. World Neurosurg 2020; 139: 344–354. - PMC - PubMed
    1. Poyiadji N, Shahin G, Noujaim D, et al. COVID-19-associated acute hemorrhagic necrotizing encephalopathy: CT and MRI features. Radiology 2020; 296: E119–E120. - PMC - PubMed
    1. Wong PF, Craik S, Newman P, et al. Lessons of the month 1: a case of rhombencephalitis as a rare complication of acute COVID-19 infection. Clin Med (Lond) 2020; 20: 293–294. - PMC - PubMed
    1. Li YC, Bai WZ, Hashikawa T. The neuroinvasive potential of SARS-CoV2 may play a role in the respiratory failure of COVID-19 patients. J Med Virol 2020; 92: 552–555. - PMC - PubMed

LinkOut - more resources