Hyperostosis Cranii Ex Vacuo in Shunted Children: A Proposed Fifth Subtype of CSF Overdrainage Syndrome
Round 1
Reviewer 1 Report
Comments and Suggestions for AuthorsThis study emphasizes the pathophysiological mechanisms of cranial hyperostosis in long-term shunt-dependent pediatric patients and its potential impact on neurodevelopment. It proposes "hyperostosis cranii ex vacuo" as a fifth subtype of CSF overdrainage syndrome, filling a gap in current classification systems and demonstrating significant clinical relevance. Below are suggestions to improve the manuscript:
1. The reliability of the study results is relatively low. Factors including retrospective study bias, small sample size (only 9 patients), lack of control groups, absence of statistical analysis, and undefined diagnostic criteria (no direct intracranial pressure measurement) raise concerns about the reliability of the findings. Although these limitations are acknowledged in the "Limitations" section of the original text, their combined impact is substantial. We recommend conducting multicenter studies to increase sample size.
2. The Methods section mentions MRI/CT examinations but does not specify slice thickness, contrast agent dosage, or acquisition sequences. We recommend including these details (which are important for result reproducibility).
3. Some of the references are relatively outdated; additional discussion of recent literature and research perspectives is recommended.
Author Response
Comments 1:The reliability of the study results is relatively low. Factors including retrospective study bias, small sample size (only 9 patients), lack of control groups, absence of statistical analysis, and undefined diagnostic criteria (no direct intracranial pressure measurement) raise concerns about the reliability of the findings. Although these limitations are acknowledged in the "Limitations" section of the original text, their combined impact is substantial. We recommend conducting multicenter studies to increase sample size.
Response 1: We fully agree that the reliability of the results is limited due to the retrospective design, small sample size (9 patients), lack of a control group, absence of statistical analysis, and undefined diagnostic criteria (including no direct intracranial pressure measurement). The primary aim of our study, however, was to highlight the phenomenon of hyperostosis cranii ex vacuo and to provide an initial framework for further investigations. At present, establishing a suitable control group is challenging, as potential risk factors remain undefined, which could introduce further bias. In future stages, we plan to expand the project through multicentre collaboration, enabling both the recruitment of a larger patient cohort and the addition of a proper comparative group. This will also allow for more robust statistical evaluation. Diagnostic inclusion criteria were defined based on a review of available literature, focusing on the most frequently reported calvarial changes. We acknowledge the limitations of this approach and emphasise that our present study represents the first step towards more comprehensive investigations.
Comments 2: The Methods section mentions MRI/CT examinations but does not specify slice thickness, contrast agent dosage, or acquisition sequences. We recommend including these details (which are important for result reproducibility).
Response 2: We thank the reviewer for this valuable suggestion. The Methods – Data Collection section has been revised and supplemented with detailed information regarding slice thickness, contrast agent dosage, and acquisition protocols, thereby improving reproducibility and transparency of our results (lines 160-172).
Comments 3: . Some of the references are relatively outdated; additional discussion of recent literature and research perspectives is recommended.
Response 3: We appreciate this comment. The phenomenon of hyperostosis cranii ex vacuo was first described by Moseley et al. in 1966. Since then, only a handful of publications have been dedicated to this entity, the most recent being a case report in shaken baby syndrome from 2003 (PMID: 12521376). Both PubMed and Embase contain only a very limited number of references directly addressing this condition. Due to the scarcity of dedicated studies, it was not feasible to perform a systematic analysis of the available literature. The existing reports mainly comprise incidental mentions of calvarial thickening in the broader context of cerebrospinal fluid overdrainage syndrome. The absence of contemporary research underlines both the originality and the importance of our observations, and highlights the need for further systematic studies. We consider our work to be a preliminary step towards filling this significant gap in knowledge. We included the most recent studies available regarding management of hyperostosis in overdrainage syndrome in section "Clinical Implications of Hyperostosis Cranii ex Vacuo"
Reviewer 2 Report
Comments and Suggestions for AuthorsThe authors present a case series on calvarial thickening in children after ventriculoperitoneal shunt surgery and shunt dysfunction with overdrainage.
While the idea is compelling, all patients naturally presented with increased intracranial pressure followed by a period of overdrainage. The causal interference is not straightforward.
The authors could strengthen their case by adding total number of shunt placements in their department during the study period and how many developed overdrainage? Where the any children fulfilling the inclusion criteria with calvarial thickening without shunt placement?
The five syndromes if intracranial overdrainage are unknown to me as a term. Is there literature describing these five syndromes? There is at least one more feature of intracranial hypotension/overdrainage: reduced/empty optic nerve sheath (doi: 10.3174/ajnr.A2120).
A case series might be a more appropriate format.
The quality of the CT/MRI images could be improved by cropping and magnification of the measurements. The convention for the sagittal images is for the patient to look left.
The meaning of the yellow markers are unclear.
Author Response
Comments 1: While the idea is compelling, all patients naturally presented with increased intracranial pressure followed by a period of overdrainage. The causal interference is not straightforward.
Response 1: We thank the reviewer for this valuable observation. The indication for shunt implantation in all cases was elevated intracranial pressure. In our cohort, 7 out of 9 patients initially received fixed-pressure valves. In these patients, episodes of overdrainage were likely recurrent or chronic, given the inability to regulate the opening pressure and to control the total CSF outflow in such systems. Due to the retrospective design of our study, we were unable to precisely determine the total duration of the overdrainage periods. We plan to conduct prospective studies to better define the temporal and causal relationship between overdrainage and the development of hyperostosis cranii ex vacuo. An additional argument supporting our hypothesis is the chronological sequence of events: overdrainage preceded the development of hyperostosis, with a mean interval of 66 months, which represents a sufficient timeframe for progressive bone remodeling and inner-table thickening. The exclusion criteria were designed to minimize confounding factors, eliminating conditions that could independently cause calvarial thickening (such as metabolic, hematologic, or endocrine disorders). Finally, our radiological observations, including signs of overdrainage, dural enhancement, reduction of the sella turcica dimensions, and premature cranial suture closure support the interpretation that overdrainage was not a single transient episode, but rather a repetitive or chronically progressive process.
Comment 2: The authors could strengthen their case by adding total number of shunt placements in their department during the study period and how many developed overdrainage? Where the any children fulfilling the inclusion criteria with calvarial thickening without shunt placement?
Response 2: During the study period (2016–2025), approximately 200 ventriculoperitoneal shunt procedures were performed in our department, including both primary implantations and revisions. The exact number of patients who developed clinically significant overdrainage is difficult to determine retrospectively, since intracranial pressure measurements were rarely performed and most children currently receive programmable valves, where adjustments of opening pressure are made based on clinical symptoms rather than documented ICP values. As a result, not every episode of overdrainage is consistently recorded in medical charts. One of the inclusion criteria for our retrospective analysis was “radiologically confirmed calvarial hyperostosis following shunt implantation” (Section 2: Materials and Methods > Population). We did not identify any children fulfilling these imaging criteria without a history of shunt placement. Although the literature describes several conditions that may result in diffuse calvarial thickening (e.g., hematologic, metabolic, or genetic bone disorders), our study specifically focused on the association between chronic CSF overdrainage and secondary hyperostosis after shunt implantation.
Comment 3: The five syndromes if intracranial overdrainage are unknown to me as a term. Is there literature describing these five syndromes? There is at least one more feature of intracranial hypotension/overdrainage: reduced/empty optic nerve sheath (doi: 10.3174/ajnr.A2120).
Response 3: We thank the reviewer for this insightful comment. The term “five syndromes of intracranial overdrainage” is not standardized in the literature. Current reviews describe four major clinical and radiological manifestations of CSF overdrainage: (1) slit ventricle syndrome, (2) subdural collections (hematoma or hygroma), (3) premature cranial suture closure (secondary craniosynostosis), and (4) low intracranial pressure syndrome. Our study aims to propose hyperostosis cranii ex vacuo as an additional - fifth, structural manifestation within this spectrum. We have included an updated citation to recent reviews describing these forms (Ros et al., J Clin Med, 2021; Pedersen et al., Acta Neurochir, 2023).
Pedersen SH, Prein TH, Ammar A, Grotenhuis A, Hamilton MG, Hansen TS, Kehler U, Rekate H, Thomale UW, Juhler M. How to define CSF overdrainage: a systematic literature review. Acta Neurochir (Wien). 2023 Feb;165(2):429-441. doi: 10.1007/s00701-022-05469-3. Epub 2023 Jan 14. PMID: 36639536.
Comment 4: A case series might be a more appropriate format.
Response 4: We agree that our study can be presented as a case series. However, we would like to emphasize that, to the best of our knowledge, this is first study to perform morphometric measurements of the sella turcica and bone densitometry analyses in patients with hyperostosis cranii ex vacuo. These findings support the concept of a physiological bone remodeling process secondary to chronic CSF overdrainage. Although our work is based on a retrospective cohort, we believe it provides valuable insights for future studies exploring the pathophysiological role of CSF overdrainage in calvarial remodeling. The translational aspect of our study may also assist clinicians in better understanding and managing this rare complication of long-term shunting.
Comments 5: The quality of the CT/MRI images could be improved by cropping and magnification of the measurements. The convention for the sagittal images is for the patient to look left.
Response 5: We thank the reviewer for this important comment. In the revised version, all CT and MRI figures have been improved according to the reviewer’s suggestions. We add additional summary of the measurments in the description below figures.
Comments 6: The meaning of the yellow markers are unclear.
Response 6: We thank the reviewer for pointing out this issue regarding the imaging figures.
The yellow lines visible at the image margins are auxiliary measurement guides automatically generated by the radiological analysis software. They were used only to facilitate size comparison between structures and do not carry any diagnostic or interpretative meaning.
Round 2
Reviewer 1 Report
Comments and Suggestions for AuthorsThe authors have provided a serious and meticulous response to the review comments, addressing each previously raised issue with corresponding revisions and improvements.
I have thoroughly reviewed the authors' response letter and the revised manuscript, and have conducted a comprehensive evaluation of the modifications. The scientific rigor and logical coherence of the revised manuscript have been significantly enhanced. I recommend acceptance for publication.
Author Response
Comment 1: The authors have provided a serious and meticulous response to the review comments, addressing each previously raised issue with corresponding revisions and improvements.
I have thoroughly reviewed the authors' response letter and the revised manuscript, and have conducted a comprehensive evaluation of the modifications. The scientific rigor and logical coherence of the revised manuscript have been significantly enhanced. I recommend acceptance for publication.
Response 1: We would like to express our sincere gratitude for the positive opinion regarding the possibility of publishing our manuscript in the journal. The comments we received were highly insightful and helped us to enrich the paper with additional clinical aspects, as well as to view the issue of hyperostosis from a different and very valuable perspective.
Reviewer 2 Report
Comments and Suggestions for AuthorsThe figures, especially the measurements are not discernible. Sagittal images per convention are pointed left. This should be improved.
Author Response
Comments 1: The figures, especially the measurements are not discernible. Sagittal images per convention are pointed left. This should be improved.
Response 1: We thank the Editor for this valuable advice. The sagittal image orientation has been verified in accordance with radiologic convention. To improve figure clarity, we have enhanced image resolution, and increased the font size and contrast of measurement labels to ensure all morphometric details are clearly visible in the revised version.
