Multimodal FDG-PET and EEG assessment improves diagnosis and prognostication of disorders of consciousness

  1. Bertrand Hermann
  2. Johan Stender
  3. Marie-Odile Habert
  4. Aurélie Kas
  5. Mélanie Denis-Valente
  6. Federico Raimondo
  7. Pauline Pérez
  8. Benjamin Rohaut
  9. Jacobo Diego Sitt
  10. Lionel Naccache

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Abstract

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  1. Version published to 10.1016/j.nicl.2021.102601
  2. eLife

    ###Reviewer #3:

    The manuscript consists of a nice confirmation study and further validate the PET-index (Stender et al., 2016) as well as the EEG classification (Sitt et al., 2014; Engemann et al., 2018). The introduction is clear, the method is clear as well, results are well described and the discussion is concise and precise. The clinical impact of the study would greatly benefit from the availability of the PET index code on a platform such as GiHub to allow all centers with a PET scanner to use this index and provide a better diagnosis for DoC patients.

    Major comments:

    1. Regarding the behavioural assessment (i.e., number of CRS-r), is there a minimum of CRS-R performed? This should be stated in the method. Based on the table, some patients received only 2 CRS-R, while the rate of misdiagnosis with 2 CRS-R is as high as 26% for UWS patients (Wannez et al 2017). This is an important limitation. The number of CRS-R should be included in supplementary material, in a table providing all individual data (see next comment). Some UWS patients with a high index (>3.07) may have received only 2 CRS-R, which would have an important impact on the validity of the results.

    2. Were the EEG and PET acquisitions done on the same day? Which CRS-R was taken? The best or the one done on the day of the PET-scan? As the study compared the validity of the PET index and EEG classification, the fact that the two exams may not have been performed on the same day, and knowing that DoC patients fluctuate a lot, is a clear limitation and should be clearly acknowledged and discussed in the limitation section.

    3. For the PET voxel-based analysis, the significance threshold was set at p<0.005 uncorrected. Why did the authors use this threshold? It seems a bit arbitrary or convenient for the authors. It would be interesting and more transparent to present the corrected results too (e.g. in Supplementary Material).

    4. It is crucial to add a limitation section. The study has many limitations (not 5 CRS-R, heterogeneity of the population, PET-EEG and behavioural assessments not done on the same day, while comparing their respective accuracy, PET isn't easily available which limits the clinical impact of the present study, etc.).

    5. Individual data should be added (initial diagnostic, gender, age, etiology, best crsr, number of crs-r, index, eeg classification, outcome etc.) in supplementary material. The excel file provided is terrible to read. Could the authors at least tabulate the columns and provide a legend? In any case, I strongly suggest adding a table in supplementary material with the individual data.

    6. The references should be carefully checked. Some of them are in the text but not in the list, and some of them are in the list but not referenced in the text. The reference "Wannez et al 2018" does not seem to be the appropriate one.

  3. eLife

    ###Reviewer #2:

    The study is a prospective cohort study evaluating both PET and EEG regarding the diagnosis and prognosis in VS/MCS patients. Thus, it represents a logical advancement from Stender et al 2016 and Bekinschtein et al 2009 towards clinical evaluation of the retrospectively established methods. To my knowledge there is no other prospective data set examining these methods. The authors plausibly show that the methods are capable of improving the diagnosis. The included number of subjects of 57 sufficient given the high effort necessary for this multimodal assessment. The results regarding the prognosis using the combined methods though significant certainly needs a targeted study with a fixed design before use in clinical practice.

    In the following I would propose some minor improvements:

    1. I would move the first two sentences of paragraph 2 (31 ff) to the discussion. They introduce a new concept that is not necessary to understand your major points in the introduction. I would stick to your story a) DoCs are important clinically because we don't know who is aware of what (a potential nightmare for the patient) b) PET seems to be really robust at telling but is actually not evaluated prospectively c) EEG might also help but in the past was not very robust in prospective studies d) Maybe a combination of both helps too. Second problem is what to tell relatives how the prognosis is. Actually, we know only little mainly as a side finding of Stender 2014 and 2016. In my opinion the latter points are told nicely.

    2. I would remove the regional differences as a discriminator. I have two concerns about them. The first is technical in nature: you applied an anatomical atlas to potentially deformed brains after injury. The paper does not convince me that this worked sufficiently because it is not described in detail and from my experience it is very difficult to segment this type of brains. The second concern is that the result does not really support your main findings and is thus dispensable. I would recommend to focus on the main points: PET is really robust in your sample (even the cut-off from Stender et al 2016 is pretty much reproducible) and EEG is also pretty robust (although sensitivity drops from 94% in-sample to 58% out-of-sample). Also, the combination works well. I think these are the main findings that have potential to make it into clinical routine.

    3. I would also focus the discussion on two points. First, the clinical impact of your findings. I think if you would deliver a fully automatized tool to reproduce your data pipeline people world-wide would be willing to use PET for their VS patients. As a second point you should also discuss the concept of the cortically mediated state and how your work is related to that.

    In conclusion, I think the study presented is technically and conceptually strong and provides a valuable step towards clinical routine application of the demonstrated methods. The language is also enjoyable to read.

  4. eLife

    ###Reviewer #1:

    The authors intended to test whether FDG-PET pseudo-quantitative metabolic index of the best preserved hemisphere (MIBH), as well as EEG-based classification (the auditory local-global paradigm) , and combination of the two methods, were accurate complementary markers to discriminate VS from MCS. Their results showed that an MIBH was accurate and robust procedure across sites to diagnose MCS, which can even be improved in combination with EEG-based classification allowing the detection of covert cognition and 6- month responsiveness recovery in unresponsive patients. Additionally, their results indicated that the behavioral diagnosis of MCS does not correspond to an elusive and generic conscious state, but rather to a CMS that reveals the preservation of metabolic activity in specialized cortical networks. These results provide valuable information for the clinic use of MIBH and local-global paradigm in the future. There are several issues which should be mentioned:

    1. As the authors put the "methods and materials" before the results, they should describe the patients’ information in a clear way in the "methods and materials", not in the results.

    2. The authors may need to provide more information about the EEG design. For example, what is the exact experiment design, ITI, stimulus number, and so on. More importantly, the authors need to provide the exact number of the left epochs after the rejection of the bad epochs for each patient.

    3. The authors indicated that the auditory local-global paradigm could be used to detect the consciousness. Furthermore, they also mentioned the cognitive-motor dissociation patients (CMD). If they can discuss the distinction of local-global paradigm and motor imagery tasks (or other tasks) which were used to detect the CMD, this will be very helpful.

    4. The results about accuracy of MIBH to discriminate between MCS and VS are not strongly related to results about how MCS did not correspond to an elusive and generic conscious state. The latter is more interesting. I would suggest the authors put them into two independent papers.

    5. Please provide more information about the "MCS items are associated with metabolic specific of subscales", such as how many patients in the analysis for each subscale?

    6. Please clarify why there are results about Motor CRS-R subscale: one in Fig.5 and the other one in supplementary Figure e-1.

  5. eLife

    ##Preprint Review

    This preprint was reviewed using eLife’s Preprint Review service, which provides public peer reviews of manuscripts posted on bioRxiv for the benefit of the authors, readers, potential readers, and others interested in our assessment of the work. This review applies only to version 1 of the manuscript.

    ###Summary:

    All reviewers in general agree that your study is solid with clear-cut results. In particular, the multimodal assessments of both PET and EEG, regarding the diagnosis and prognosis in VS/MCS patients, were carefully executed. As such, the results provide valuable information for future prognosis research guiding clinic use, e.g., a targeted study with a fixed design.

  6. Version published to 10.1101/2020.06.16.20132514v1 on medRxiv