Rhombencephalitis in Pregnancy—A Challenging Case of Probable Listeria Infection

Round 1

Reviewer 1 Report

Thank you very much for giving me the possibility of reviewing this paper.

This is a well-written case report and a review of the literature on a challenging case of a 31-y old female diagnosed with rhomboencephalitis in pregnancy. The authors describe the complex and long clinical path to achieve the final diagnosis, which is still not confirmed even if realistically related to an infection of Listeria monocytogenes. The Authors discussed the lack of confirmation by lab tests and describe in the title the diagnosis as "probable".

Moreover, the Authors reported the therapeutic strategies and a little section dedicated to neonatal infection and some proper experiments showing in vitro pro-inflammatory effects of L. monocitogenes.

The figures and tables are very informative.

This paper may be useful for scholars and physicians coping with similar challenges. 

Minor remarks:

In figure 2, what "ITU" stands for? Do you mean ICU?

A list of abbreviations should be reported in all the captions.

Author Response

Dear Reviewer, thank you for taking the time to review this manuscript. Below are our responses. Thank you. 

 

Thank you very much for giving me the possibility of reviewing this paper.

This is a well-written case report and a review of the literature on a challenging case of a 31-y old female diagnosed with rhomboencephalitis in pregnancy. The authors describe the complex and long clinical path to achieve the final diagnosis, which is still not confirmed even if realistically related to an infection of Listeria monocytogenes. The Authors discussed the lack of confirmation by lab tests and describe in the title the diagnosis as "probable".

Moreover, the Authors reported the therapeutic strategies and a little section dedicated to neonatal infection and some proper experiments showing in vitro pro-inflammatory effects of L. monocitogenes.

The figures and tables are very informative.

This paper may be useful for scholars and physicians coping with similar challenges. 

Minor remarks:

In figure 2, what "ITU" stands for? Do you mean ICU?

Thank you for these comments. We have changed to ICU and have defined this as Intensive Care Unit in the figure legend.

A list of abbreviations should be reported in all the captions.

We have added the following:

Caption for figure 2: ICU (intensive care unit), CN (cranial nerve), WCC (white cell count), CRP (C-reactive protein), MRI (magnetic resonance imaging), MRV (magnetic resonance venography) CT (computerised tomography), OD BD TDS (Latin abbreviations referring to once, twice and three times a day respectively).

Caption for Figure 3: Non- stim (non-stimulated), HKLM (Heat-killed Listeria Monocytogenes), Peripheral blood mononuclear cells (PBMCs), PGE2 (prostaglandin E2).

Caption for Figure 4: TLRs (Toll like receptors).

Reviewer 2 Report

Dear Editor and author,

 

I’m pleased to review this article to report a pregnant woman with suspected neurolisteriosis. The review is comprehensive. I have some comments.

 

1.      The most important debate is the diagnosis. The diagnosis of listeriosis is not convincing. Although extensive survey had been performed, direct evidence of listeriosis is lacking. The PCR for L. moncytogenes is negative.

2.      How about the history of raw meat, cheese, or potentially contaminated food?

3.      The lumbar puncture was performed on day 13. Do you think an earlier lumbar puncture is suggested?

4.      This patient received six times of CT/MRI. Do you think they are necessary?

5.      The review is good.

 

Thank you.

 

Author Response

Dear Reviewer, thank you for taking the time to review this manuscript. Below are our responses. Thank you. 

 

I’m pleased to review this article to report a pregnant woman with suspected neurolisteriosis. The review is comprehensive. I have some comments.

1. The most important debate is the diagnosis. The diagnosis of listeriosis is not convincing. Although extensive survey had been performed, direct evidence of listeriosis is lacking. The PCR for moncytogenesis negative.

 

Whilst we acknowledge that the PCR for was negative, it is often negative. It is not a sensitive test, the pathogen is intracellular and therefore hard to detect in CST/ blood, often the CSF volume is insufficient to provide a positive result, and often the CSF is collected too long after symptoms and/or after treatment. We have made these points in the discussion, and we have been transparent in using the word ‘“probable” Listeria infection’ in the title. However, we feel that there is ample evidence for the symptoms being attributed to Listeria for three reasons: 1) from the clinical picture, 2) the exclusion of other diagnoses with a wide range of other investigations that have higher sensitivities, and 3) that she responded to the correct antibiotics used in the treatment of neurolisteriosis.

2. How about the history of raw meat, cheese, or potentially contaminated food?

Thank you for this, we have added the following sentence in the first paragraph of section 2 (case presentation) in the resubmitted version.

“There was no history of recent foreign travel, or of eating raw meat or unpasteurised food.”

3. The lumbar puncture was performed on day 13. Do you think an earlier lumbar puncture is suggested?

Thank you for this comment. She originally presented on day 5 of her symptoms but was discharged as she was generally well in herself. She re presented on day 8, but it was not until day 12 and 13 that she developed neurological symptoms of confusion. Whilst in retrospect, an earlier lumbar puncture may well have helped with detection of listeria, there had been not enough clinical signs to warrant an earlier lumbar puncture. We have included this in the conclusion for clarity. “In particular, our case had a long period of time whereby symptomatology was non-specific, which led to a delay in testing for Listeria monocytogenes. “

 

4. This patient received six times of CT/MRI. Do you think they are necessary?

We believe that all of the images were necessary for the following reasons and we have included these reasons in the timeline figure legend (figure 2).

1. Day 12 MRI to determine a cause of her persistent frontal headache and confusion
2. Day 14 MRV to determine if there was a venous thrombosis causing her headache, although acknowledgement this was of low suspicion.
3. Day 15 CT was performed due to her fluctuating glasgow coma scale
4. Day 17 MRI head/ thoracic/ abdomen/ pelvis was performed to rule out the possibility of a paraneoplastic syndrome and to see if there were any changes in the MRI head, given ongoing neurological symptoms
5. Day 33 MRI head to determine response to treatment
6. 6- month MRI head to confirm improvement
7. The review is good.

Thank you.

Reviewer 3 Report

Comments for author File: Comments.docx

Author Response

Dear Reviewer, thank you for taking the time to review this manuscript. Below are our responses. Thank you. 

This is a very well written case reports.

The case presentation is very detailed.  The figure showing the timeline of presentation helps understand the clinical course clearly.  Images are of good quality and marked appropriately for readers.  Diagrammatical representations are clear and appropriate.

Few questions/suggestions that arise on review of case are as follows:

1. Line 114-- I would suggest changing the sentence to “no focal neurological deficits noted on examination”.

 

Thank you, we have altered this comment.

 

2. Line 180—expand abbreviations.

Thank you we have altered the sentence to read

“Investigation for auto-immune encephalitis was negative for anti-N-methyl D-aspartate (NMDA) receptor, anti–leucine-rich glioma-inactivated 1 (Lgl1), anti-contactin-associated protein-like 2 (CASPR2), and anti-neuronal antibodies.”

3. Line 231 -- the authors mention in line 293 about cross reactivity and low sensitivity of serological testing for listeria infection which is appropriate. There were other PCR testings such as Borrelia, TB and Viral testing sent on the CSF sample. Did the authors request a Listeria monocytogenes PCR testing on CSF. Is this not a part of the concise meningitis/encephalitis PCR testing at your institution?. In retrospect, addition of Listeria PCR to the sample, would have helped make a more clear diagnosis. Listeria meningitis/encephalitis can continue to progress despite of appropriate antibiotic, as written by the authors.  This possibly explains worsening of clinical status initially in the course of disease when patient was on ampicillin.

We tested the CSF taken on day 12 for Listeria DNA and the result came back negative. However, the report stated that low volume CSF samples can lead to a false negative result. We have now included this in the discussion in the section on “clinical features and diagnosis”. Listeria testing is not a routine test for meningitis/encephalitis screen in our hospital trust.

“ In our case, despite a negative PCR, it was acknowledged and reported by the laboratory team that low volume CSF can lead to a false negative result, and that PCR is insensitive for Listeria.”

 

4. Line 261-- can authors provide appropriate citation. “Confusion is pre dominantly seen in those with infectious etiology”

 

We have altered the sentence and added the reference.

“Altered consciousness is seen predominantly seen in those with infectious aetiology.”

Relevent reference: Jubelt B, Mihai C, Li TM, Veerapaneni P. Rhombencephalitis / brainstem encephalitis. Curr Neurol Neurosci Rep. 2011;11(6):543-52.