A Gluten Free Diet in the Management of Epilepsy in People with Coeliac Disease or Gluten Sensitivity

Round 1

Reviewer 1 Report

The research theme is not well known and this review brings contribution to the filed.

For the general article idea: if the CD diagnosis is clear, the GFD is the treatment to choose, it is a must. So, the GFD might be useful for a part of epileptic crises arising in CD patients, in which the etiology is probably directly linked to CD itself. So maybe the idea might be nuanced, the GFD cannot be a direct treatment/ recommendation for epilepsy.

The introduction of the manuscript is too long, especially for a review, it looks to have more than 1/3 of the all manuscript and it is also mucg larger than the results section, which is unusual.

I think that the method used for the systemic review is good and it was well presented. I have only one comment for the inclusion criteria, how was the CD diagnosis sustained in the studies included in the analysis? The diagnosis was based on biopsy (gold standard) or only serology (and what serology? EMA or only tTG).

I think that the following phrase is not a conclusion of the current research " Exploring GS with antigliadin antibody threshold and further
20 investigation of the relationship between tTG levels and epilepsy are also recommended.".

Author Response

Response to Peer Review 24^th August 2020

Thank you for reviewing our paper and the constructive comments which we have found most helpful. Responses to points are below:-

Reviewer 1

The research theme is not well known and this review brings contribution to the filed. Thank you.

For the general article idea: if the CD diagnosis is clear, the GFD is the treatment to choose, it is a must. So, the GFD might be useful for a part of epileptic crises arising in CD patients, in which the etiology is probably directly linked to CD itself. So maybe the idea might be nuanced, the GFD cannot be a direct treatment/ recommendation for epilepsy.   We have added in to conclusion  ‘when comorbid with CD’. All studies were on participants with CD, and we have specified this as well –conclusion is about GFD in epilepsy where there is also a CD diagnosis.

The introduction of the manuscript is too long, especially for a review, it looks to have more than 1/3 of the all manuscript and it is also mucg larger than the results section, which is unusual. We have edited out some of the background information about epilepsy and CD, we have also structured the introduction – but we need to cover epilepsy, CD and NCGS and dietary approaches such as ketogenic diet and have had to add in a section on microbiome in response to reviewer 2 comments.

I think that the method used for the systemic review is good and it was well presented. I have only one comment for the inclusion criteria, how was the CD diagnosis sustained in the studies included in the analysis? The diagnosis was based on biopsy (gold standard) or only serology (and what serology? EMA or only tTG). Details used for diagnosis of CD was detailed in Supplementary Information table 3 (last column coeliac disease)  – we have expanded the details on serology to specify which antibodies were used. We also suggest table 3 from supplementary information is added to the main manuscript in response to the these comments.

I think that the following phrase is not a conclusion of the current research " Exploring GS with antigliadin antibody threshold and further
20 investigation of the relationship between tTG levels and epilepsy are also recommended.". we have reworded this and hope it is now clearer.

A marked up manuscript showing corrections in response to all comments is attached 

Author Response File: Author Response.pdf

Reviewer 2 Report

I have carefully read the manuscript entitled “A gluten free diet in the management of epilepsy in people with coeliac disease or gluten sensitivity”. The topic is of great interest for the readers and warrants further attention from the academic community.  

There are some issues which need to be addressed:

• There is some inconsistency in results – Abstract, page 1, “GFD was effective in 45 out of 70 participants across the studies in terms of a reduction of seizures” and then “A total of 44 participants showed a reduction in seizures (across 8 studies) and complete cessation of seizures was reported in 22 participants”
• The title discusses GFD in the management of epilepsy in both CD and GS, but from the results one cannot discriminate how many studies were on CD patients and how many on non-celiac gluten sensitivity patients
• Results should also include criteria used for CD/GS diagnosis in selected studies and how follow-up was done after starting the GFD
• Also, if considering malabsorption as potential mechanism for seizures in CD patients, nutritional status of CD patients in selected studies should be detailed (if this information is available)
• When proposing GFD as an alternative to AED and surgery, with “low likelihood of harm”, its drawbacks should be discussed.
• Considering recent research on the link between gut microbiome and epilepsy, the authors could discuss the changes in microbiome in GFD patients and its role in seizure outcomes
• Discussion needs structuring
• Limitations of available studies should be better highlighted – lack of controls, heterogeneity (or lack of data) with regard to diagnostic criteria, lack of imaging

Author Response

Response to Peer Review 24^th August 2020

Thank you for reviewing our paper and the constructive comments which we have found most helpful. Responses to points are below:-

Reviewer 2

I have carefully read the manuscript entitled “A gluten free diet in the management of epilepsy in people with coeliac disease or gluten sensitivity”. The topic is of great interest for the readers and warrants further attention from the academic community.   Thank you

There are some issues which need to be addressed:

There is some inconsistency in results – Abstract, page 1, “GFD was effective in 45 out of 70 participants across the studies in terms of a reduction of seizures” and then “A total of 44 participants showed a reduction in seizures (across 8 studies) and complete cessation of seizures was reported in 22 participants” Thank you for spotting this, we have double checked the studies and it was a typographical error and is 44. This has been amended.

The title discusses GFD in the management of epilepsy in both CD and GS, but from the results one cannot discriminate how many studies were on CD patients and how many on non-celiac gluten sensitivity patients – we have  made reference to the fact that no studies met inclusion criteria about GS and epilepsy and this is now reflected in abstract, results and conclusion.

Results should also include criteria used for CD/GS diagnosis in selected studies and how follow-up was done after starting the GFD  - This was in supplementary information  table 3 - which  detailed whether diagnosis is biopsy proven and if serological testing was undertaken – we suggest this is moved from supplementary information and included in main manuscript.   We also now refer to this in the results.

Also, if considering malabsorption as potential mechanism for seizures in CD patients, nutritional status of CD patients in selected studies should be detailed (if this information is available) can you check to see if available – perhaps bring into limitations in discussion if not available? None of the studies consider nutritional status of participants so we have detailed this in the discussion. 

When proposing GFD as an alternative to AED and surgery, with “low likelihood of harm”, its drawbacks should be discussed. We have added information on this (nutritional imbalances, high lipids, sugar, low calcium iron and associations with metabolic syndrome).  

Considering recent research on the link between gut microbiome and epilepsy, the authors could discuss the changes in microbiome in GFD patients and its role in seizure outcomes – We have added a small section on the microbiome to the introduction – and also bought this into discussion re. immune mechanisms.

Discussion needs structuring – we have added subheads

Limitations of available studies should be better highlighted – lack of controls, heterogeneity (or lack of data) with regard to diagnostic criteria, lack of imaging in discussion limitations   We have amended section 5.8 Limitations to cover these points

A marked up manuscript is attached. 

Author Response File: Author Response.pdf

Round 2

Reviewer 2 Report

Suggestions from my review report have been appropriately addressed in the revised version of the manuscript. The only remaining comment is about the introduction, which is quite long, some of the paragraphs could be integrated into discussion. 

Author Response

Thank you for reviewing the manuscript again.

Some edits were suggested by us previously to the section on epilepsy in the introduction, but they were not made for some reason, but they are now shown (with strike through Lines 39-48) to reduce the length of that section in the introduction.

We have also moved a paragraph on extra intestinal manifestations of non coeliac gluten sensitivity to the discussion and moved the section on the microbiome, from the introduction to the discussion as well

So overall the introduction is now shorter.