Exploring CNS Involvement in Pain Insensitivity in Hereditary Sensory and Autonomic Neuropathy Type 4: Insights from Tc−99m ECD SPECT Imaging

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

The Authors present a case report of a girl with a clinical diagnosis of HSAN4, a disease primary affecting PNS, that showed spasticity signs, thus a SPECT was performed to assess CNS involvement. According to the Authors, SPECT results could improve our understanding of this disease.

There are serious flaws in this case report:

1) The report is lacking basic standard of care information (Complete neurological exam, brain and spine MRI, Nerve conduction study)

2) Since the diagnosis is solely clinical, the lack of sweating and pain perception should have been investigated and quantified and should not rely only on physicians' bedside assessment. Quantitative Sensory Testing, Laser Evoked Potentials, skin biopsy with quantification of intraepidermal nerve fibre density are widely agreed tools to study pain pathways, while sudoscan, Dynamic Sweating Test and skin biopsy with quantification of sweat glands innervation are methods used to investigate sweating function. None of the numerous techniques available has been performed.

3) In this patient the causative mutation has not been found, so the Authors’ findings may not be applicable to the general HSAN4 population, markedly dampening their significance.

4) The clinical signs of possible UMN involvement detected by the Authors (bilateral extension plantar response and a spasticity-like alteration in the feet posture) are of low specificity and should be evaluated in the broader patient's clinical picture. I agree with the Authors that these findings encourage further investigations at the CNS level, which was the original aim of SPECT. However, it seems that SPECT did not show any UMN involvement, so the pathophysiological framework of these signs is not of clear-cut interpretation.

5) Since MRI has not been reported, it is not clear if using SPECT in HSAN4 patients could add something to standard of care.

6)The authors focalize their discussion on the pathophysiological significance that the finding of a reduced brain perfusion may have on our understating of pain insensitivity. However, the patient showed also intellectual disability, and the finding of reduced brain perfusion in this kind of patients is more than expected.  

 

 

 

 

Comments on the Quality of English Language

Quality of english is not the problem of this manuscript

Author Response

Please see the attachment.

Author Response File: Author Response.pdf

Reviewer 2 Report

Comments and Suggestions for Authors

The manuscript approach a new imaging methodology based on a classical nuclear medicine technique that utilizing a Tc-99m ECD SPECT protocol provides advance diagnostic precision in HSAN4 cases. Regarding its scope, the authors should improve the significance of their study by:

Quantitative evaluation. All the imaging findings have been evaluated by a qualitative process. However, the SPECT study has to be validated utilizing numerical measures. The increase of the uptake of the specific anatomical area / organ that appeared as intensity enhancement should be measured utilizing radios and absolute values. Such an approach would provide significant numerical data for the comparison of pathological vs healthy tissues.  

 

Increasing patient’s number.  

Since the present study is a case report it is based on a single patient suffering from HSAN4. It is clear that the generalization and the importance of the outcome and it clinical significance should be increased only through the involvement of additional patient’s.   

 

Author Response

Please see the attachment.

Author Response File: Author Response.pdf

Reviewer 3 Report

Comments and Suggestions for Authors

Dear authors,

Congratulations for the great case report on brain SPECT abnormalities in a Pain Insensitivity in Hereditary Sensory and Autonomic Neuropathy Type 4, with a excellent description and discussion.

There is a previously publish paper from Sarasola et al.(BMC Medical Genetics 2011, 12:86 http://www.biomedcentral.com/1471-2350/12/86) describes a normal brain SPECT in 6 yo HSAN4 patient, so it is advisable to make adjustments in the following allegations:

• Page 1 line 26-27: "This study represents the first visualization of CNS perfusion in an HSAN4 patient". You can change into: This study represents the first visualization of CNS perfusion abnormality in an HSAN4 patient"
•  
• Page 4  line 145-146: "This study represents the pioneering effort to visualize brain perfusion in an HSAN4 patient, and the findings are nothing short of groundbreaking". 
•  
• Page 7 lines 229-232: "As the first study to visualize CNS perfusion in HSAN4, it propels us toward more targeted treatment strategies and enhanced patient care, underlining the value of bridging the peripheral and central nervous systems in managing this complex disorder". You can change into: As the first study to visualize CNS perfusion abnormality in HSAN4, it propels us toward more targeted treatment strategies and enhanced patient care, underlining the value of bridging the peripheral and central nervous systems in managing this complex disorder”.

 

Regarding the perfusion brain scan, it is not usually employed to image hemorrhagic strokes (Page 2 line 73-74). It would be better to substitute: "In stroke assessment, for instance, it plays a vital role in distinguishing between ischemic and hemorrhagic strokes [18], guiding critical treatment decisions.” to "In stroke assessment, the localization and extent of lesions as a result of defects in blood supply can be assessed by perfusion SPECT studies [18], guiding critical treatment decisions”. The reference can be maintained.

 

It will be desirable to provide reference for the following allegations: 

 

• “Page 2 line 52-54:  "While several features and pathological aspects of HSAN4 have been partially elucidated, limited research has explored the condition of the central nervous system (CNS) in HSAN4 patients.
•  
• Page 7 line 180-181: "In essence, our findings suggest that pain signals are not exclusively processed at the peripheral level but involve intricate CNS mechanisms.
•  
• Page 7 line 180-181: "Another intriguing aspect of our Tc-99m ECD SPECT imaging results was the presence of a perfusion deficit in the right cerebellum, a region not commonly associated with pain processing but known for its diverse functions”.

 

Figure A3 page 5 has a wrong labeling and Figure A2 (page 5): "Axial view of the Tc-99m ECD brain perfusion SPECT study. A decreased uptake of the tracer(Tc-ECD) can be observed in the cerebellum area (arrow)". It should be better described as in the right cerebellar hemisphere.

Author Response

Please see the attachment.

Author Response File: Author Response.pdf

Round 2

Reviewer 3 Report

Comments and Suggestions for Authors

Dear Authors,

Thanks for accepting the suggestions. I have done  a great work.

Author Response

Dear Reviewer,

Thank you for your kind words. We're pleased that the suggested revisions meet your expectations.

Best regards,

Authors