PONE-D-21-14243

De-novo nonconvulsive status epilepticus in adult medical inpatients without known epilepsy: analysis of mortality related factors and literature review.

PLOS ONE

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PLOS ONE

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Reviewers' comments:

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Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #2: No

Reviewer #3: Yes

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2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #2: No

Reviewer #3: Yes

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3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #2: No

Reviewer #3: Yes

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4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #2: Yes

Reviewer #3: Yes

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5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #2: In this study, Garcia-villafranca et al., reviewed 54 general medical patients over a three year period with a diagnosis of NCSE, and examined important factors that determined their outcome, finding that hyponatraemia and atrial fibrillation were significantly associated with mortality secondary to NCSE.

The study highlights a condition that should be considered promptly when diagnosing fluctuant conscious state, particularly in older patients. In addition, the literature review of over 600 papers initially is commendable. However there are some major flaws with the study that inevitably minimise the findings described, that I will discuss in turn.

Major points

1. It appears the initial analysis, the main factor associated with NCSE was antibiotic use (96%), so a crucial question is the indication, e.g. systemic infection such as UTI versus brain specific e.g. encephalitis. Other factors that were associated with NCSE were statistically addressed individually. However a number of the factors would seem related e.g. atrial fibrillation and presence of stroke, neuroleptic use and chronic psychiatric disturbance, etc. and should not be analysed separately. In addition other important factors such as glucose level, functional status (MRS), are not presented. It appears more patients had hyponatraemia compared with hypernatraemia, despite the subsequent mortality analysis. Indeed comparing just 3 patients (deceased) to 1 (survived) is quite underpowered. Other factors such as potassium, hypertension or hepatic levels were not subsequently included in the multivariate analysis for mortality, is there any reason for this? Finally no actual values for biochemistry across the group are given, just the threshold values chosen for definition; this is very important when relating factors such as hypernatraemia to NCSE and its mortality.

2. A significant number of patients with NCSE were on benzodiazepine therapy (57%) prior to diagnosis (page 16) – why was this?

Minor points

1. In addition (page 15) 10 patients (1/5 of total number) had previous seizures although the authors state that patients with previous epilepsy were not included.

2. In the methods (page 13) what ‘characteristic’ EEG findings were observed to diagnose NSCE. Were all the of the Salzburg criteria satisfied for all patients?

Reviewer #3: This paper is a manuscript which can be a good contribution to the literature for nonconvulsive status epilepticus (NCSE). Here are my suggestions:

1) How was seizure response characterized? Were the authors able to collect standardized data on EEG response? If not, please discuss and add as limitation.

2) The Discussion needs a greater depth to compare your data to the literature.

3) We await the development of your treatment guidelines.

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Reviewer #2: No

Reviewer #3: No

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De-novo nonconvulsive status epilepticus in adult medical inpatients without known epilepsy: analysis of mortality related factors and literature review.

PONE-D-21-14243R1

Dear Dr. Novo-Veleiro,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

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Kind regards,

Emilio Russo

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #2: All comments have been addressed

Reviewer #3: All comments have been addressed

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2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #2: Yes

Reviewer #3: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #2: Yes

Reviewer #3: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #2: Yes

Reviewer #3: Yes

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5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #2: Yes

Reviewer #3: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #2: The authors have adequately addressed my previous comments, in particular inclusion criteria for the study and associated limitation of the relatively small cohort being analysed.

Reviewer #3: (No Response)

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7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #2: No

Reviewer #3: No