Neurologic Complications in Adult and Pediatric Patients with SARS-CoV-2 Infection

Round 1

Reviewer 1 Report

most of the issues I believe that are now settled in this brief review. I would only suggest to be added a final conclusion paragraph, because as it is now, ends somehow abruptly.

Author Response

We thank the reviewers for providing comments to improve the quality of this manuscript! They have been addressed and changes have been made in the manuscript where needed.

1. most of the issues I believe that are now settled in this brief review. I would only suggest to be added a final conclusion paragraph, because as it is now, ends somehow abruptly.

We agree. A final conclusion has been added to the manuscript.

Reviewer 2 Report

My comments have been addressed appropriately by the authors.

Author Response

We thank the reviewers for providing comments to improve the quality of this manuscript!

Reviewer 3 Report

1. The title implies a review on clinical spectrum, but the manuscriopt focuses on pathophysiology; this has to be changed
2. "In particular, focal encephalitis can progress to acute disseminated encephalomyelitis through inflammation and degen-eration of myelin within the CNS": encephalitis is misleading; the liquor does not show elevated white cells in most of the patients
3. "Currently, the proportion of patients who experience neurologic complications is unknown, as is whether any longstanding effects exist among those who experience complications." this is not true. There are very good publications from large studies, like NY cohort or EAN cohort. 

Author Response

We thank the reviewers for providing comments to improve the quality of this manuscript! They have been addressed and changes have been made in the manuscript where needed.

1. The title implies a review on clinical spectrum, but the manuscriopt focuses on pathophysiology; this has to be changed
2. "In particular, focal encephalitis can progress to acute disseminated encephalomyelitis through inflammation and degen-eration of myelin within the CNS": encephalitis is misleading; the liquor does not show elevated white cells in most of the patients
3. "Currently, the proportion of patients who experience neurologic complications is unknown, as is whether any longstanding effects exist among those who experience complications." this is not true. There are very good publications from large studies, like NY cohort or EAN cohort.

Thank you for those comments. We addressed those points, changed the title, and modified the manuscript accordingly. 

Round 2

Reviewer 3 Report

None

This manuscript is a resubmission of an earlier submission. The following is a list of the peer review reports and author responses from that submission.

Round 1

Reviewer 1 Report

This is a well written, concise, review of the mechanisms that may govern neurological manifestations of COVID-19.

The only observation is that the comment “… has the potential to abolish the gag reflex leading to fatal respiratory arrest [36] ”  is not mentioned in the cited reference; furthermore, abolished gag reflex does not lead to respiratory arrest. Please, rephrase.

Reviewer 2 Report

In this critical review, Howard and co-authors summarize recent evidence on neurological complications in patients diagnosed with COVID19, focusing on proposed mechanisms leading to neurologic complications (especially stroke and encephalopathy). They also address COVID19-related complications in the pediatric population and report incidences of specific disorders identified during or in the months after a COVID19 infection.

To improve this manuscript, I suggest adding a brief statement at the end of the introduction about the aim and purpose of this review. Also it should be clarified what type of review this is, namely a critical (and not systematic) review. Thus, it bears the risk of a selection bias, which is one of the limitations of this manuscript. Also, I strongly suggest to more precisely report / summarize findings from cited studies (see further below for specific studies I identified inconsistencies).

Specific comments

Title:

neuroprotection is actually not discussed, but rather mechanisms that lead to neuronal damage. thus I suggest rephrasing the title.

Abstract:

please re-check selected keywords. I am missing references to stroke and would also add cytokine storm and pediatric complications

Introduction:

Here I am missing a brief statement about the purpose and type of this review.

Vessel:

None

Neural tissue:

“Case reports from the United Kingdom analyzed 143 patients with neurological symptoms, revealing 32% developed altered mental status and almost 50% required intensive level care [27].“

This is a highly selected subpopulation of COVID19 patients (physicians were asked to report patients with neurologic complications). Findings reported in this subset of patients should be put into relation with all COVID19 cases reported in this population during the study period.

“Additionally, the 48.7% overall incidence of epileptiform abnormalities has been associated with high mortality and increased severity of those abnormalities in patients who had a delayed positive COVID-19 test [28].“

This statement needs to be rephrased, as in the study cited there was a selection bias (they reported on a subset of COVID19 patients that were referred for EEG due to suspicion of seizures).

“A recent multicenter case study documented 22% of pediatric cases with neurological involvement including 12% who developed life threatening neurologic complications [29]“

Again, the findings from this study should be summarized more precisely. This was a study on children hospitalized due to COVID 19 (selection bias!) and those 12% with life threatening complications are in relation to all children with neurologic complications (i.e., 43/365).

“This includes the possibility of strokes, parkinsonism, dementia, and anxiety disorder, which have had a 33% incidence in patients following 6 months after COVID-19 diagnosis [35].“

Note that amongst these diagnoses anxiety disorders were by far the most frequent (approx. 17%), while all others mentioned here (stroke, PD, dementia) were much less frequent. This should be stated more clearly.

Reviewer 3 Report

The structure of the manuscript is a bit confusing, jumping from vessel to neuroinvasion. Especially the overview on data on neurological complication is listed under 3) instead at the beginning of the manuscript.

The cited literature regarding the knowledge on neurological complications is not up to date and the results of smaller case series should be replaced by the available data of large series (for example from the prospective registry of EAN).

Available data speaks against a frequent direct virus invasion (fist hypothesis described), this should be highlighted.

Finally, the title implies a focus on neuroprotection, which cannot be found within the manuscript.