Timing Mechanisms for Circadian Seizures

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

Review of Manuscript “Timing mechanisms for circadian seizures” submitted by Kristina Slabeva and Maxime O. Baud.

In this review, the authors comprehensively summarize literature data on the circadian timing of seizures. The review provides detailed information on seizure timing in patients with epilepsy and different experimental models. Moreover, the authors outlined the existing theoretical and experimental chronobiology paradigm revealing the complicated intertwined circadian and sleep-wake timing mechanisms. Additionally, they described in detail the connection of both circadian and sleep-wake cycles in specific seizure chronotypes, both in clinical epileptology and epilepsy research. So, they conclude that individual seizure chronotypes may result from an interplay between the existing timing mechanisms.

Overall, the review is very well organized and written in very good English. All data is well summarized and presented competently. The manuscript is effortless to read and all included complicated information is easily understandable.

 

I do not have any recommendations, except one technical mistake. All mentioned authors in numbers in the text must be superscripted.

Author Response

We thank the Reviewer for their praising of our review. We did not understand the technical issue, and will most likely be able to any formatting issue at the production stage. 

Reviewer 2 Report

Comments and Suggestions for Authors

This is a comprehensive review of the influence of circadian factors on seizure occurrence. The only omission that is significant is in the section of 4.4.1 Forced desynchrony. Pavlova et al 2009, to my knowledge, is the only study that used forced desychrony in a cohort of patients with epilepsy; the authors should cite the findings; basically, the spike-wave discharges follow both a sleep- and a circadian rhythm. 

Author Response

The only omission that is significant is in the section of 4.4.1 Forced desynchrony. Pavlova et al 2009, to my knowledge, is the only study that used forced desychrony in a cohort of patients with epilepsy; the authors should cite the findings; basically, the spike-wave discharges follow both a sleep- and a circadian rhythm. 

Reply: We thank the Reviewer for their appreciation of the review. We had included Pavlova et al 2009 as a reference in other section of the Review. We nevertheless fully agree that it had to be discussed in more detail in paragraph 4.4. We added the following sentence: " On the experimental side, one study forcing desynchrony in human patients with genetic generalized epilepsy showed the importance of sleep stages on the expression of interictal epileptiform discharges (a permissive effect), with hints of an added circadian modulation (a cyclical effect)⁴⁹.   "

Reviewer 3 Report

Comments and Suggestions for Authors

This manuscript discusses the role of biological rhythms in the timing of epileptic seizures and also introduces a framework for future related studies. Authors demonstrates the timing mechanisms into environmental cycles, circadian cycles, sleep homeostasis, switches in vigilance states. Authors also include several experimental paradigms to study the mechanism of seizure timing. The manuscript is well-written and multiple directions for future investigation. Here are my comments:

1.     Please ensure a thorough and careful review of the manuscript to verify that all citations are correct. There is a citation style change on page 2, 2^nd paragraph of the "Seizure Chronotypes" section. Additionally, some sentences are missing citations.

2.     3. Timing Mechanisms for Seizures is somewhat general. Authors may consider combine this section with 5. Current Evidence to discuss the timing mechanisms.

Comments on the Quality of English Language

The Language is fine.

Author Response

We thank the Reviewer for their appreciation of the manuscript. 

Please ensure a thorough and careful review of the manuscript to verify that all citations are correct. There is a citation style change on page 2, 2^nd paragraph of the "Seizure Chronotypes" section. Additionally, some sentences are missing citations.

Reply: we did not find a citation style change on page 2, 2^nd paragraph of the "Seizure Chronotypes" section. All citations appear as superscript numbers. We highlighted the name of Franz Halberg, and wish to maintain that. 

 

2. 3. Timing Mechanisms for Seizures is somewhat general. Authors may consider combine this section with 5. Current Evidence to discuss the timing mechanisms.

Reply: we thank the Reviewer for this suggestion. It is true that our discussion of the timing mechanisms is well-known to a sleep research audience. But not to an epilepsy-research readership. Therefore, we would like to maintain the structure of the chapters as is for clarity. 

Reviewer 4 Report

Comments and Suggestions for Authors

This is an interesting review on the circadian nature of seizures. The authors discus seizure chromotypes, timing mechanisms for seizures, environmental cycles, the circadian cycle, the sleep-wake cycle, switches in vigilance stages, sleep homeostasis, experimental paradigms, current evidence for timing mechanisms for seizures, temporal ictal-interictal relationship, and next steps.

The paper is clearly written and comprehensive. I think the discussion of future steps would benefit by expanding upon this section.

Author Response

I think the discussion of future steps would benefit by expanding upon this section.

Reply: We agree with the Reviewer that this discussion benefits from a few more points. We have added the following sentences: "A holistic approach must make use of experimental paradigms and concepts from both fundamental chronobiology and sleep research. This research agenda will span at least a decade, as each animal model of epilepsy may have their own seizure chronotype based on different contributions of the timing mechanisms exposed here. Thus, comparison across models will be important to fully understand the relative contributions of the circadian and sleep-wake cycles in specific epileptic networks. "