Increased CSF levels of IL-1β, IL-6, and ACE in SARS-CoV-2–associated encephalitis
Citation Manager Formats
Make Comment
See Comments

A national outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in December 2019 in Wuhan, China, rapidly evolving to the coronavirus disease 2019 (COVID-19) pandemic. Neurologic complications of COVID-19 include headache, confusion, hyposmia, and dysgeusia,1 with encephalitis being rarely reported. Coronaviruses can potentially invade the CNS through trans-synaptic propagation via nasal entry, likely causing hyposmia. Alternatively, CNS dysfunction may result from the systemic hyperinflammatory response to the virus. We report 2 patients supporting this hypothesis.
Patient 1
A 25-year-old healthy man presented with 1-day history of headache, left-sided paresthesias, and ipsilateral paresis progressing within 12 hours to confusion and agitation. His axillary temperature was 38.2°C. Brain CT and MRI scans were normal. CSF showed lymphocytic pleocytosis and increased proteins. He was started on IV acyclovir, ampicillin, and ceftriaxone, which were discontinued when CSF cultures and PCR ruled bacterial or viral etiologies. PCR of SARS-CoV-2 was negative in CSF but positive in the nasopharyngeal swab. On day 2, he fully recovered except for amnesia of the previous 2 days.
Patient 2
A healthy 49-year-old man presented with fever, myalgias, and dry cough lasting 1 week. A few hours after admission, he developed difficulty naming objects, temporospatial disorientation, confusion, and agitation. A thoracic CT scan showed bilateral peripheral opacities suggestive of COVID-19 pneumonia. Brain CT and MRI scans obtained 2 days later were unremarkable. CSF showed lymphocytic pleocytosis and increased proteins. The patient was empirically started on acyclovir, ampicillin, and ceftriaxone, which were discontinued once CSF cultures and PCR returned negative. PCR for SARS-CoV-2 was positive in the nasopharyngeal swab, but negative in CSF. Three days later, he was back to normal except for amnesia of the previous days.
None of the patients developed severe respiratory problems or required intensive care support.
Clinical features, serum, and CSF characteristics including cytokines and angiotensin-converting enzyme (ACE) profile from both cases are shown in the table.
Basic demographic and clinical data of both cases
Discussion
These patients suggest that encephalitis may be the first or dominant manifestation of COVID-19. For patient 1, the focal neurologic deficits were the first symptom manifestation; his young age, absence of risk factors, and comprehensive studies ruling out other etiologies suggest a link between the neurologic symptoms and systemic SARS-CoV-2 infection. By contrast, patient 2 presented with typical COVID-19 symptoms, but confusion, disorientation, and aphasia rapidly dominated the clinical picture.
Three previous case reports of CNS involvement in COVID-19 suggest different pathogenic mechanisms: direct CNS infection demonstrated by detection of SARS-CoV-2 RNA in CSF,2 recrudescence of symptoms related to previous lesions (e.g., brain infarction) in the context of systemic infection,3 and inflammatory-mediated mechanisms resulting in acute hemorrhagic necrotizing encephalopathy. This is a rare complication of viral infections, usually influenza, considered to result from severe systemic inflammation associated with elevated cytokine levels, such as interleukin (IL)-6 and tumor necrosis factor-α.4 No information on serum or CSF cytokine levels was provided for any of these 3 patients.
In our 2 patients, we cannot completely rule out a direct infectious mechanism, despite the negative CSF testing of SARS-CoV-2, but the rapid recovery in less than 3 days makes it unlikely. Alternatively, and in keeping with the abovementioned cytokine-mediated systemic inflammation, there is evidence that patients with coronaviruses can develop a cytokine storm syndrome with increased IL-1 and IL-6 among other inflammatory mediators. Hence, in a study of children with acute encephalitis–like syndrome, serum anti–human coronavirus-OC43 immunoglobulin M antibodies were present in 12% of patients and levels of IL-6, IL-8, monocyte chemotactic protein-1, and Granulocyte Macrophage Colony-Stimulating Factor were increased in their CSF.5 The elevated CSF levels of IL-6 in our 2 patients, and IL-1β in 1 of them, are in line with those studies. Biological anti-IL treatments targeting IL-1 (anakinra) or IL-6 (tocilizumab and siltuximab) are useful to treat symptoms of CNS involvement related to the cytokine storm triggered by chimeric antigen receptor T-cell therapy.6 Our patients improved spontaneously, but these treatments could be considered in more severe cases of COVID-19–associated encephalitis with increased CSF levels of ILs. Finally, our 2 patients also had increased CSF levels of ACE. It has been postulated that SARS-CoV-2 enters the cell using the ACE2 receptor.7 Although it is difficult to interpret the meaning of increased CSF levels of ACE in these 2 patients, they could be linked to the postulated alteration in the ACE pathway in COVID-19.
The main implication of these 2 patients is that physicians should be aware of COVID-19 infections presenting or predominantly manifesting as encephalitis, likely resulting from activation of inflammatory pathways with increased ILs and ACE in CSF.
Study funding
No targeted funding reported.
Disclosure
The authors report no disclosures relevant to the manuscript. Go to Neurology.org/NN for full disclosures.
Acknowledgment
The authors acknowledge the patients for their generosity and to all other people suffering the COVID-19 pandemics, as well as to all the health professionals and other staff crucially involved in their care and the handling of this unprecedented global crisis.
Appendix 1 Authors

Appendix 2 Coinvestigators




Footnotes
Go to Neurology.org/NN for full disclosures. Funding information is provided at the end of the article.
↵* Both these authors contributed equally to this work.
The Article Processing Charge was funded by the authors.
“Hospital Clínic Infecto-COVID-19” group and “Hospital Clínic Neuro-COVID-19” group coinvestigators are listed in appendix 2 at the end of the article.
- Received May 1, 2020.
- Accepted in final form May 19, 2020.
- Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.
This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.
References
- 1.↵
- 2.↵
- 3.↵
- Poyiadji N,
- shahin G,
- Noujaim D,
- Stone M,
- Patel S,
- Griffith B
- 4.↵
- Filatov A,
- Sharma P,
- Hindi Fawzi,
- Espinosa PS
- 5.↵
- Li Y,
- Li H,
- Fan R, et al
- 6.↵
- Hays P,
- Costello C,
- Asudani D
- 7.↵
- Patel AB,
- Verma A
Letters: Rapid online correspondence
REQUIREMENTS
You must ensure that your Disclosures have been updated within the previous six months. Please go to our Submission Site to add or update your Disclosure information.
Your co-authors must send a completed Publishing Agreement Form to Neurology Staff (not necessary for the lead/corresponding author as the form below will suffice) before you upload your comment.
If you are responding to a comment that was written about an article you originally authored:
You (and co-authors) do not need to fill out forms or check disclosures as author forms are still valid
and apply to letter.
Submission specifications:
- Submissions must be < 200 words with < 5 references. Reference 1 must be the article on which you are commenting.
- Submissions should not have more than 5 authors. (Exception: original author replies can include all original authors of the article)
- Submit only on articles published within 6 months of issue date.
- Do not be redundant. Read any comments already posted on the article prior to submission.
- Submitted comments are subject to editing and editor review prior to posting.
You May Also be Interested in
Hastening the Diagnosis of Amyotrophic Lateral Sclerosis
Dr. Brian Callaghan and Dr. Kellen Quigg
► Watch
Related Articles
- No related articles found.
Topics Discussed
Alert Me
Recommended articles
-
Views & Reviews
Presentations and mechanisms of CNS disorders related to COVID-19Marta Bodro, Yaroslau Compta, Raquel Sánchez-Valle et al.Neurology: Neuroimmunology & Neuroinflammation, December 11, 2020 -
Article
Encephalopathies Associated With Severe COVID-19 Present Neurovascular Unit Alterations Without Evidence for Strong NeuroinflammationRaphael Bernard-Valnet, Sylvain Perriot, Mathieu Canales et al.Neurology: Neuroimmunology & Neuroinflammation, June 16, 2021 -
Review
Potential Neurologic Manifestations of COVID-19Anna S. Nordvig, Kathryn T. Fong, Joshua Z. Willey et al.Neurology: Clinical Practice, June 30, 2020 -
Commentary
Looking aheadThe risk of neurologic complications due to COVID-19Carlos A. Pérez et al.Neurology: Clinical Practice, April 09, 2020