Risk factors for hydrocephalus following fourth ventricle tumor surgery: A retrospective analysis of 121 patients.

BACKGROUND AND AIM: Most patients who present with a fourth ventricle tumor have concurrent hydrocephalus, and some demonstrate persistent hydrocephalus after tumor resection. There is still no consensus on the management of hydrocephalus in patients with fourth ventricle tumor after surgery. The purpose of this study was to identify the factors that predispose to postoperative hydrocephalus and the need for a postoperative cerebrospinal fluid (CSF) diversion procedure.
MATERIALS AND METHODS: We performed a retrospective analysis of patients who underwent surgery of the fourth ventricle tumor between January 2013 and December 2018 at the Department of Neurosurgery in West China Hospital of Sichuan University. The characteristics of patients and the tumor location, tumor size, tumor histology, and preventive external ventricular drainage (EVD) that were potentially correlated with CSF circulation were evaluated in univariate and multivariate analysis.
RESULTS: A total of 121 patients were enrolled in our study; 16 (12.9%) patients underwent postoperative CSF drainage. Univariate analysis revealed that superior extension (p = 0.004), preoperative hydrocephalus (p<0.001), and subtotal resection (p<0.001) were significantly associated with postoperative hydrocephalus. Multivariate analysis revealed that superior extension (p = 0.013; OR = 44.761; 95% CI 2.235-896.310) and subtotal resection (p = 0.005; OR = 0.087; 95% CI 0.016-0.473) were independent risk factors for postoperative hydrocephalus after resection of fourth ventricle tumor.
CONCLUSION: Superior tumor extension (into the aqueduct) and failed total resection of tumor were identified as independent risk factors for postoperative hydrocephalus in patients with fourth ventricle tumor.

Introduction

Posterior fossa tumors represent 7.9% of intracranial lesions and approximately 20–90% of patients with posterior fossa tumors present with hydrocephalus before tumor surgery.[1-6] Although in posterior fossa tumor, tumor removal can restore CSF circulation, 10–30% of patients tend to experience persistent hydrocephalus following posterior fossa resection.[4, 5, 7–9] The patients may present with signs and symptoms of increased intracranial pressure from hydrocephalus (headache, nausea/vomiting, vertigo, unsteady gait, diplopia, papilledema, etc.), which affect the patient's life quality and may result in a prolonged hospital stay.[2, 10] Fourth ventricle tumors, in particular, present a high rate of postoperative hydrocephalus because of the compression of tumor to the cerebrospinal fluid (CSF) pathways.[11, 12]

Surgery for fourth ventricular tumors is plagued by potential pitfalls caused by proximity to deep eloquent structures and the risk of injury to perforating arteries supplying subcortical regions and lesions of the fourth ventricle, which make up only a fraction of this subset.[13, 14] The lack of cases limits clinical experience data on the spectrum of pathologies in this region.[2–9, 15–18] We aimed to sought factors, which might be correlated with the development of persistent hydrocephalus following resection of fourth ventricle tumors to evaluate the indication for postoperative CSF drainage.

Materials and methods

Study population and data collection

This retrospective descriptive cohort study investigated the incidence of postoperative hydrocephalus and its causative factors in a consecutive group of patients who underwent surgery of fourth ventricle tumors between January 2013 and December 2018 at the Department of Neurosurgery in West China Hospital of Sichuan University.

The inclusion criteria were: 1) single intracranial neoplasm detected by preoperative magnetic resonance imaging; 2) surgical resection of the lesion; 3) a tumor confirmed by pathologic diagnosis. Patients were excluded if 1) there was evidence of multiple tumors or repeated surgery for tumor; 2) the patients underwent biopsy rather than resection.

The West China Hospital Ethics Committee approved this study. Individual patient identification data were not collected when the database was developed, and this is the reason why patient consent was not required for this study.

After selecting the patient population, the data recorded during the course of routine clinical practice (statistical data, case histories, surgery, and procedure reports) were taken from the electronic health record of the hospital by the first author. The following clinical and statistical data were included in the analysis: basic patient characteristics, tumor histology, EVD placement, surgical treatment, and shunt placement. An independent neuroradiologist reviewed preoperative MRI scans for the location of the tumor, tumor size, and preoperative hydrocephalus. Assessment of hydrocephalus was made by an Evans index (the maximum width between the frontal horns divided by the maximal width of the inner table) larger than 0.3 with or without clinical symptoms and signs (headache, nausea, vomiting, lethargy, papilledema, etc.) [16, 19]. Location of the tumor was classified as follows: superiorly (into the aqueduct of Sylvius), caudally (into the foramen magnum), laterally (into the foramen of Luschka or cerebellopontine angle), or anteriorly (invading or distorting the brainstem) (Fig 1). The extent of resection was evaluated by reviewing the postoperative MRI images obtained within 72 hours after surgical treatment, and the gross-total resection was defined as complete tumor resection with no evidence of residual tumor on postoperative MRI [20]. The number and duration of the external ventricular drain (EVD) and ventriculoperitoneal (VP) shunts were noted after surgery. The follow-up was done on postoperative days 30 and 90 and at 6 months after surgery.

Fig 1

Cases of extension of fourth ventricle tumor.

(A and B) The axial and sagittal contrast-enhanced T1-weighted image shows the lesion invading into the brainstem. (C and D) The axial and sagittal contrast-enhanced T1-weighted image shows the lesion invading into the foramen magnum. (E and F) The axial and sagittal contrast-enhanced T1-weighted image shows the lesion invading into the left foramen of Luschka. (G and H) The axial and sagittal contrast-enhanced T1-weighted image shows the lesion invading into the aqueduct of Sylvius.

Clinical management and surgical procedures

The surgical procedures were all performed by three senior neurosurgeons (Yuekang Z, Xuhui H, and Yan J). Resection of the tumor was performed with the patient in a prone or a park bench/side position. The lesions were approached through a standard midline suboccipital approach. The indication of prophylactic EVD placement included one of the following two types: 1) symptomatic hydrocephalus and 2) asymptomatic ventriculomegaly. Prophylactic EVD placement was performed immediately after preoperative hydrocephalus had been confirmed by imaging radiological examination. Gross-total removal or subtotal resection was achieved in all patients. During the operation, electrophysiological monitoring was performed. Postoperatively, all patients were monitored in the ICU for at least 1 day. In patients with EVD, CSF was drained via the EVD for 3–5 days. The EVD was removed when no further symptomatic elevated ICP appeared over a period of turning off EVD for 24 hours. In patients without EVD placement, an EVD was rapidly placed if symptomatic high ICP was observed.

Outcomes

The indication for VP shunt placement was a failed reduction of CSF drainage due to constantly elevated ICP with clinical symptoms (headache, vomiting, lethargy, papilledema, and upward gaze paresis) lasting for more than 1–2 weeks. The postoperative hydrocephalus was defined as symptomatic hydrocephalus requiring CSF drainage following tumor removal.

Statistical analysis

Data analysis was performed using the SPSS software version 23.0 (IBM Corp., Armonk, New York, USA). Categorical variables were reported as counts (%) and continuous variables were described by median (interquartile range [IQR]). The chi-square test and Fisher exact test were employed to complete the univariate analysis of patients with and without postoperative hydrocephalus. Differences in continuous variables between patients with and without postoperative hydrocephalus were compared by the Wilcoxon-Mann-Whitney test. The significant factors in the univariate analysis were used as covariates in the multivariate analysis, which was performed using logistic regression. All statistical tests were 2-sided; if P <0.05, the data were considered statistically significant.

Results

Patient characteristic

In total, 121 patients (60 males and 61 females) were included in our study. The median patient age was 24 years (IQR, 9–41 years). Histologically, the most common tumor was ependymoma (30.6%), followed by medulloblastoma (24.2%) and pilocytic astrocytoma (16.5%). Rare lesions included cholesteatoma, hemangioblastoma, vascular malformation, choroid plexus papilloma, and metastatic lesions. Most tumors extended beyond the boundaries of the fourth ventricle. The anterior extension was the most frequent and was observed in 81.0% of cases, while the caudal extension (57.0%) was the least frequent. The lateral extension was apparent in 28.1% of cases. The superior extension was found in 11.6% of cases. In terms of surgery, gross-total resection was achieved in 91 patients (73.4%), and there was no perioperative mortality. Details are shown in .

Predictors for postoperative hydrocephalus which need CSF diversion

Overall, there were 56 patients with prophylactic EVD placement and 65 patients without EVD insert before tumor resection. Fifteen patients underwent postoperative CSF diversion, which included 10 VP shunts and 5 EVDs. Of the 10 VP shunts, 9 cases had a prophylactic EVD placement, and only one underwent postoperative EVD before VP shunt placement. This accounted for 17.9% (10/56) of the patients with prophylactic inserted EVDs. In the univariate analysis, the need for postoperative CSF drainage in patients was significantly correlated with sex (p = 0.012), superior extension (p = 0.015), preoperative hydrocephalus (p<0.001), and subtotal resection (p<0.001) (). Meanwhile, the need for postoperative VP in patients was significantly correlated with superior extension (p = 0.016), preoperative hydrocephalus (p<0.005), prophylactic EVD (0.006), and subtotal resection (p<0.001) (). In the multivariate analysis, superior extension (p = 0.013; OR = 44.761; 95% CI 2.235–896.310) and subtotal resection (p = 0.005; OR = 0.087; 95% CI 0.016–0.473) were confirmed as independent influencing factors for CSF drainage requirement (). However, only prophylactic EVD (p = 0.042; OR = 10.431; 95% CI 1.093–99.514) were confirmed as independent influence factors for postoperative VP. When considering the subgroup of patients who had prophylactic EVD placement prior to surgery, superior extension (p = 0.003), and subtotal resection (p<0.001) were significantly correlated with the need for postoperative CSF drainage (). Multivariate analysis identified superior extension (p = 0.012; OR = 23.400; 95% CI 1.982–276.230) and subtotal resection (p = 0.004; OR = 0.036; 95% CI 0.004–0.344) as the independent influencing factors ().

Discussion

There is still no consensus for management of hydrocephalus before and after fourth ventricle lesions surgery. In the present study, we retrospectively analyzed clinical parameters, including sex, age, preoperative hydrocephalus, tumor type, size and location, the extent of resection, and prophylactic EVD to identify whether these factors were correlated with persistent postoperative hydrocephalus. Superior tumor extension and failed total resection of tumors were identified as significant risk factors for the development of postoperative hydrocephalus. To the best of our knowledge, this is the first study confirming that superior tumor extension (into the aqueduct) increases the incidence of postoperative hydrocephalus. Our findings may be used to preoperatively identify patients at high risk of postoperative hydrocephalus after resection of the fourth ventricle tumor.

Previous studies have shown that younger patients with posterior fossa are at higher risk for the development of persistent hydrocephalus.[3, 4, 15, 21, 22] Bognar et al.[3] and Kumar et al. [21] have demonstrated that age< 3 years at tumor surgery is a significant predictor of postoperative CSF diversion. This might be explained by the finding that the younger patient with fourth ventricle tumor related to the higher incidence of congenital and malignant tumors, like medulloblastoma, frequently accompanied by leptomeningeal metastases which may develop impaired CSF absorption at the subarachnoid level because of the more aggressive nature of tumors [22-24]. However, we did not find age to be significantly associated with postoperative CSF drainage, which might be explained by a larger number of enrolled adults in the current compared to previous studies and a small group of medulloblastoma. The relationship between age and postoperative hydrocephalus in patients with fourth ventricle tumor needs to be further explored.

There are conflicting findings on the association between preoperative hydrocephalus and postresection hydrocephalus. Our results did not confirm preoperative hydrocephalus to be correlated with the need for a postoperative CSF drainage. However, Gopalakrishnan et al. [7] and Morelli et al. [18] found that patients with severe hydrocephalus on preoperative MRI were at a higher rate of postoperative CSF division procedure, which might be because severe hydrocephalus leads to higher venous and CSF pressures and possibly a longer time to resolution of the pressure. This inconsistency with previous reports may be due to evaluating preoperative hydrocephalus by a dichotomized variable rather than calculating the extent of hydrocephalus into 3 groups (mild, moderate, and marked).

In previous studies, tumors in posterior fossa predominantly located in the midline were associated with a higher incidence of postoperative CSF diversion procedure compared with those tumors situated in the cerebellar hemispheres [12, 15, 25]. In our study, we classified the location of tumors by displayed extension: superior extension (into the aqueduct), caudal extension (into the foramen magnum), lateral extension (into the foramen of Luschka or cerebellopontine angle), and anterior extension (invading or distorting the brainstem). Notably, we find superior extension was a significant predictor for needing the postoperative CSF division, while other extensions were not associated with a postoperative shunt. The inflation after resection of tumor could result in stenosis of the CSF pathway in patients with tumor extension (aqueduct, foramina of Luschka, and foramen of Magendie). For the management of hydrocephalus in patients with fourth ventricle tumor, endoscopic third ventriculostomy (ETV) is a safe and durable means of controlling obstruction hydrocephalus and the risk of ETV failure may be lower than the risk of shunt failure surgery when ETV Success Score (ETVSS) ≥ 80 [26-30]. However, fourth ventricle tumor resection frequently developed adhesive arachnoiditis and secondary hydrocephalus when some cases with communication hydrocephalus after tumor resection could benefit from shunt rather than ETV in the study. In cases where the CSF flow from the aqueduct was well seen, there was a trend for shunt insertion based on the assumption that there was impaired CSF absorption at the subarachnoid level. Factors like the presence of postoperative cerebellar edema, especially in cases with triventricular hydrocephalus appeared on imaging, favored ETV rather than shunt insertion.

In the present study, the size of the tumor was not correlated with the need for a postoperative CSF drainage. Similarly, in their study, Sherise et al. [16] found no association between the size of the tumor and persistent postoperative hydrocephalus. The study by Kumar et al. [21] demonstrated that incidence of a CSF diversion procedure was highest after the surgical removal of medulloblastoma and ependymoma, and lowest among patients with astrocytoma, which may be explained by the observed higher incidence of astrocytoma in a lateral rather than a midline location and the higher number of such patients in the series. Meanwhile, Won et al. [23] found medulloblastoma was a predictor for the development of hydrocephalus, including noncommunicating hydrocephalus due to occlusion of the fourth ventricle or its outlets and communicating hydrocephalus secondary to leptomeningeal metastases due to the more aggressive nature of medulloblastoma. Yet, no significant correlation was found in this study. Inconsistency between our results and those reported by previous studies may be explained by the small group of medulloblastoma. The small group of each kind of tumor in this study might make us fail to find the association between pathology and the incidence of postoperative hydrocephalus.

In the present series, gross total resection of the tumor was statistically associated with a lower incidence of the need for postoperative CSF diversion procedure, by the way, there is no residual tumor near the aqueduct and the residual tumors are located in the brain stem and the bottom of the fourth ventricle in failed-total resection cases on postoperative MRI. This association was also confirmed by Culley et al. [15], Kumar et al. [21], and Gnanalingham et al. [31], which may be due to residual tumor obstructing CSF flow. Conversely, more recent studies did not find a relationship between the extent of tumor resection and postoperative hydrocephalus [2, 5, 7, 32], which could be due to the less volume of the residual tumor with sophisticated surgical techniques and the continuous development of neurosurgical instruments. However, compared with GTR, whether near-total resection (< 1.5 cm3 residual) could lead to a higher incidence of postoperative hydrocephalus remained unknown because the volume of residual tumor was not accurately measured in these studies. Therefore, further studies are necessary to determine the association between the volume of residual tumor and postoperative hydrocephalus.

Our results showed no statistically significant association between the prophylactic EVD placement and postoperative CSF drainage. In contrast to our study, Culley et al. [15] demonstrated that a more extended EVD placement might be significantly correlated with persistent hydrocephalus. A possible explanation for this may be a different indication of prophylactic EVD placement in our study. Nevertheless, it is important to note that prolonged placement of an EVD might be a sign of difficult weaning instead of a physiological predictor of persistent hydrocephalus.

The present study has some limitations. First, as a single-center retrospective study, admission bias may be present in our sample. Second, details of the treatment of posterior fossa tumor, including surgical techniques and perioperative management, may vary among hospitals. Thus, our findings should be confirmed by other multi-center prospective studies with a larger sample.

Conclusion

Superior tumor extension (into the aqueduct) and failed total resection of tumor resulted as significant risk factors for postoperative hydrocephalus in patients with fourth ventricle tumor. These findings may help to identify the patients who are at high risk of postoperative hydrocephalus and require medical interventions.

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7 Sep 2020

PONE-D-20-23644

Risk factors for hydrocephalus following fourth ventricle tumor surgery: A retrospective analysis of 121 patients

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Reviewer #1: This study is a retrospective chart review that addresses the incidence of persistent postoperative hydrocephalus requiring surgery, in patients undergoing surgery for resection of fourth ventricular tumors. The study adds significantly to existing knowledge about this issue. The study includes a large number of patients, who were treated using a relatively standardized protocol. The analysis was thoughtfully designed and uses statistics appropriately. I believe that this study will be useful for practicing neurosurgeons, in order tocounsel patients and their families appropriately about the likelihood of needing additional surgeries (ETV or shunt) to treat hydrocephalus, after resection of 4th ventricular tumors, and in order to assess the likelihood of EVD weaning after these surgeries.

Reviewer #2: PONE-D-20-23644

Title: Risk factors for hydrocephalus following fourth ventricle tumor surgery: A retrospective analysis of 121 patients

Aim: Identify risk factors for postoperative hydrocephalus and the need for a postoperative CSF diversion.

Retrospective study of 121 patients with fourth ventricle tumor treated with tumor resection (histologically verified single intracranial lesion). Main outcome variable – post resection CSF diversion (EVD or VP-shunt)

Main results: 121 patients. Median age was 24 years (IQR, 9-41 years). The most common tumors were ependymoma (30.6%), followed by medulloblastoma (24.2%) and pilocytic astrocytoma (16.5%). 56/121 patients had prophylactic EVD placement. Fifteen patients underwent postoperative CSF diversion, which included 10 VP shunts and 5 EVDs. Of the 10 VP shunts, 9 cases had a prophylactic EVD placement, and only one underwent postoperative EVD before VP shunt placement. Multivariate analysis identified superior extension and subtotal resection as independent risk factors for post resection CSF drainage (EVD or VP-shunt).

Comments:

1. The manuscript is well written and easy to read.

2. The topic is relevant and of general interest.

3. My main objection to this manuscript is the choice of main outcome variable. In my opinion, the combination of post-resection EVD and permanent VP is confusing, all the time 56/121 had placement of EVD before resection. I would have preferred to use permanent VP alone as main outcome variable. Doing this, pre-operative HC will most likely remain significantly associated with post-resection VP placement. I encourage the authors to at least include such an analysis. It is of course interesting to note that 5/65 patients without pre-resection placement of EVD needed EVD in the early postoperative period, but only on of these five ended up with VP.

4. Identifying superior extension and subtotal resection as independent risk factors for post resection CSF drainage (EVD or VP-shunt) is absolutely of clinical interest, but will be even more interesting if analyzed according to the comment above.

5. Pre-resection endoscopic third ventriculostomy (ETV) is an alternative to EVD, and may reduce the need for permanent VP. The mention of ETV in the discussion is somewhat brief.

Reviewer #3: The authors have sufficiently addressed my concerns and feel that with the changes the article is not suitable for publication.

The authors have significantly enhanced the discussion section that was previously lacking.

Reviewer #4: This is a nice series which outlines the 4th ventricular tumor situations which are more likely to lead to persistent hydrocephalus requiring shunting. The authors are to be congratulated on this analysis.

Reviewer #5: This is a large series but the results are not surprising. The conclusions are simple yet well known to the reader. Several comments that deserve further discussion are

1. what were indications for preoperative EVD placement and timing for such procedure in relation to tumor surgery.

2. What was the timing for definitive CSF diversion surgery in relation to the index tumor operation

3. What was incidence of complications with the shunt procedure

4. What was the shunt infection rate?

5. Did the authors consider an ETV rather than VP shunt

Reviewer #6: Manuscript review: Risk factors for hydrocephalus following fourth metrical tumor surgery: a retrospective analysis of 121 patients. (PONE-D-20-23644)

The authors of this retrospective review describe their experience from 2013-2018 with 121 patients who presented with fourth ventricular tumors and had a first time resection surgery for the lesion. Patients had a median age of 24 years and all had six months follow up after initial surgery.

The objective of the study was to identify factors that predispose such patients to develop hydrocephalus and needing (ventriculo-peritoneal shunt) VPS for CSF diversion. Of the total 121 patients enrolled 16 patients eventually underwent permanent VPS placement. The univariate analysis demonstrated that superior extension into the aqueduct, preoperative hydrocephalus, and subtotal resection of the mass were significantly associated with postoperative hydrocephalus. This retrospective analysis is well written and a significant univariate and multivariate statistical analysis was completed in an attempt to identify specific factors associated with this patient population but a few questions arise.

The median age of the patient population is 24 years of age and this should be more explicitly mentioned, perhaps even in the title of the manuscript, as typically fourth ventricular tumors tend to be more highly concentrated in a pediatric population.

The conclusions from the paper state that superior tumor extension and failed gross total resection were independent risk factors for VPS placement. However this makes one wonder whether a subtotal resection within the aqueduct led to hydrocephalus. If this is the case then this is an obvious conclusion in that the obstruction through the ventricular system was not alleviated. However, if indeed, superior extension and failed total resection were not factors related to the same patients then this needs to be further explained in the manuscript and the manuscript would benefit from the authors’ hypotheses on how this would then lead to hydrocephalus. In addition to having a data analysis on initial extension of the tumor on patient presentation, a further explanation of which areas of tumor were left behind when a gross total resection was not possible would also assist in explaining the results.

Further, the authors mentioned that endoscopic third ventriculostomy (ETV) was a consideration for patients with fourth ventricular obstruction. The paper does not address why none of the patients who eventually underwent VPS placement were or were not considered for ETV as this may have been able to avoid permanent CSF diversion through a shunt.

In conclusion the manuscript nicely evaluates many different factors associated with this patient population however the manuscript in its current state seems to address the conclusions in a rather simplistic fashion and as such the conclusions do not seem to add much new knowledge in the field.

Reviewer #7: The authors present a series of 121 patient's with posterior fossa tumors to try to determine prognostic indicators for the development of postoperative hydrocephalus that requires CSF diversion. There is a basic assumption in this manuscript which may be falacious: Regardless of pathology it is the anatomic extent of the tumor that determines hydrocephalus. Although using appropriate statistical analysis the office did not demonstrate significance of pathology, the subgroup's may be too small to provide a true "real world answer".

My 2nd concern is that this is predominantly an article of teenagers and young adults. In the discussion the role of age and its implication for development of hydrocephalus is briefly reviewed but I believe this needs to be further expanded. It is not just age but the more aggressive nature of the tumors that we see in children under 5 years of age and particularly under 3 years of age with leptomeningeal dissemination that may increase the risk of hydrocephalus. The older patients in this study and the relatively small number of those with medulloblastoma may give a false impression of watch factors truly influence the development of hydrocephalus.

The statistically significant finding of superior extent of the tumor increasing the risk for postoperative hydrocephalus is novel and of interest. I would be curious if this finding would hold up if the authors limited the population studied 2 patients over 16 years of age, that is those that are anatomically adult. I am not certain that this finding would be seen in younger children, particular with medulloblastoma where the mean age is below that of the study population in this manuscript.

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Reviewer #1: Yes: Ronald Benveniste

Reviewer #2: Yes: Eirik Helseth

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Reviewer #4: Yes: Lawrence M Shuer

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24 Sep 2020

Dear Editors:

Thank you for your letter and comments concerning our manuscript entitled "Risk factors for hydrocephalus following fourth ventricle tumor surgery: A retrospective analysis of 121 patients" (PONE-D-20-23644). We have studied the comments carefully and made corresponding modifications. All modifications in the manuscript were highlighted in red. The main corrections in the paper and the responses to the reviewers’ and editor’s comments are as follows:________________________________________

Reviewers’ comments:

Reviewer #1

1. This study is a retrospective chart review that addresses the incidence of persistent postoperative hydrocephalus requiring surgery, in patients undergoing surgery for resection of fourth ventricular tumors. The study adds significantly to existing knowledge about this issue. The study includes a large number of patients, who were treated using a relatively standardized protocol. The analysis was thoughtfully designed and uses statistics appropriately. I believe that this study will be useful for practicing neurosurgeons, in order to counsel patients and their families appropriately about the likelihood of needing additional surgeries (ETV or shunt) to treat hydrocephalus, after resection of 4th ventricular tumors, and in order to assess the likelihood of EVD weaning after these surgeries.

Authors’ response: Thank you for the comments.

Reviewer #2

1. The manuscript is well written and easy to read.

Authors’ response: Thank you for the comment.

2. The topic is relevant and of general interest.

Authors’ response: Thank you for the comment.

3. My main objection to this manuscript is the choice of main outcome variable. In my opinion, the combination of post-resection EVD and permanent VP is confusing, all the time 56/121 had placement of EVD before resection. I would have preferred to use permanent VP alone as main outcome variable. Doing this, pre-operative HC will most likely remain significantly associated with post-resection VP placement. I encourage the authors to at least include such an analysis. It is of course interesting to note that 5/65 patients without pre-resection placement of EVD needed EVD in the early postoperative period, but only one of these five ended up with VP.

Authors’ response: We have added this analysis. (Page8, line172-179)

4. Identifying superior extension and subtotal resection as independent risk factors for post resection CSF drainage (EVD or VP-shunt) is absolutely of clinical interest, but will be even more interesting if analyzed according to the comment above.

Authors’ response: It has been analyzed according to the comment above.

5. Pre-resection endoscopic third ventriculostomy (ETV) is an alternative to EVD, and may reduce the need for permanent VP. The mention of ETV in the discussion is somewhat brief.

Authors’ response: We have added some details about EVT in the discussion. (Page13, line 264-274)

Reviewer #3

1. The authors have sufficiently addressed my concerns and feel that with the changes the article is not suitable for publication. The authors have significantly enhanced the discussion section that was previously lacking.

Authors’ response: Thank you for your comment. But we did not make a revision before.

Reviewer #4

1. This is a nice series which outlines the 4th ventricular tumor situations which are more likely to lead to persistent hydrocephalus requiring shunting. The authors are to be congratulated on this analysis.

Authors’ response: Thank you for the comment.

Reviewer #5

1. what were indications for preoperative EVD placement and timing for such procedure in relation to tumor surgery

Authors’ response: We have described the indications in the sentence (Page5, line 114-116). And we have added details about the timing for preoperative EVD placement (Page5, line 116-118).

2. What was the timing for definitive CSF diversion surgery in relation to the index tumor operation

Authors’ response: We have described them in the sentence (Page 5, line 126-128).

3. What was incidence of complications with the shunt procedure

Authors’ response: No serious complications occurred in any of the cases of VP shunting during the follow-up period.

4. What was the shunt infection rate?

Authors’ response: No patient with shunt infection was found during the follow-up period.

5. Did the authors consider an ETV rather than VP shunt

Authors’ response: Thank you for your valuable comment. We did not routinely perform ETV when the patients in this study were treated for hydrocephalus. But now, ETV was performed more than VP in our hospital. Moreover, the type of surgery for postoperative hydrocephalus do not affect the occurrence of postoperative hydrocephalus as well as the risk factors.

Reviewer #6

1. The median age of the patient population is 24 years of age and this should be more explicitly mentioned, perhaps even in the title of the manuscript, as typically fourth ventricular tumors tend to be more highly concentrated in a pediatric population.

Authors’ response: We have explicitly mentioned and added details about age in the outcome. (Table 1)

2. The conclusions from the paper state that superior tumor extension and failed gross total resection were independent risk factors for VPS placement. However, this makes one wonder whether a subtotal resection within the aqueduct led to hydrocephalus. If this is the case then this is an obvious conclusion in that the obstruction through the ventricular system was not alleviated. However, if indeed, superior extension and failed total resection were not factors related to the same patients then this needs to be further explained in the manuscript and the manuscript would benefit from the authors’ hypotheses on how this would then lead to hydrocephalus. In addition to having a data analysis on initial extension of the tumor on patient presentation, a further explanation of which areas of tumor were left behind when a gross total resection was not possible would also assist in explaining the results.

Authors’ response: I am sorry we did not mention this information. There were no cases with the residual tumor in the aqueduct. During the operation, the surgeons ensured regarding the adequacy of visualization of the aqueduct and CSF flow after tumor removal. Meanwhile, there is no residual tumor near the aqueduct and the residual tumors are located in the brain stem and the bottom of the fourth ventricle in failed-total resection cases on postoperative MRI. We have added this sentence (Page 14, line 296-299).

3. Further, the authors mentioned that endoscopic third ventriculostomy (ETV) was a consideration for patients with fourth ventricular obstruction. The paper does not address why none of the patients who eventually underwent VPS placement were or were not considered for ETV as this may have been able to avoid permanent CSF diversion through a shunt.

Authors’ response: We do not routinely use ETV for hydrocephalus with fourth ventricle tumor, and this will be improved in the future. Thank you for this valuable comment.

Reviewer #7

1. There is a basic assumption in this manuscript which may be fallacious: Regardless of pathology it is the anatomic extent of the tumor that determines hydrocephalus. Although using appropriate statistical analysis the office did not demonstrate significance of pathology, the subgroup's may be too small to provide a true "real world answer".

Authors’ response: Thank you for this valuable comment. We have mentioned this in the limitations. (Page, line 282-294)

2. In the discussion the role of age and its implication for development of hydrocephalus is briefly reviewed but I believe this needs to be further expanded. It is not just age but the more aggressive nature of the tumors that we see in children under 5 years of age and particularly under 3 years of age with leptomeningeal dissemination that may increase the risk of hydrocephalus. The older patients in this study and the relatively small number of those with medulloblastoma may give a false impression of watch factors truly influence the development of hydrocephalus.

Authors’ response: We have further expanded the part in the discussion (Page 13, line 230-240). Thank you for this valuable comment.

3. I would be curious if this finding would hold up if the authors limited the population studied 2 patients over 16 years of age, that is those that are anatomically adult. I am not certain that this finding would be seen in younger children, particular with medulloblastoma where the mean age is below that of the study population in this manuscript.

Authors response: Superior tumor extension and subtotal resection were identified as independent risk factors for hydrocephalus after resection of tumor in the fourth ventricle in this study. But only subtotal resection was significantly associated with hydrocephalus when only patients older than 16 years were enrolled. This seems to be a type II error, which might be attributed to a smaller sample size when pediatric patients were excluded.

Finally, we earnestly appreciate the Editor’s helpful work and hope that these answers and corrections will meet with approval. Once again, thank you very much for your comments and suggestions.

Best regards.

Yuekang Zhang

Department of Neurosurgery, West China Hospital, Sichuan University, China

E-mail: 2012zykyx@sina.cn

Submitted filename: Response to Reviewers.docx

Click here for additional data file.

12 Oct 2020

PONE-D-20-23644R1

Risk factors for hydrocephalus following fourth ventricle tumor surgery: A retrospective analysis of 121 patients

PLOS ONE

Dear Dr. Zhang,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

Please add a paragraph into the discussion part of the manuscript where you explain whether or not less than 1.5 cc of residual tumor coating the floor of the fourth ventricle will necessitate ultimate CSF diversion.

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Reviewer #2: Yes

Reviewer #4: Yes

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Reviewer #7: Yes

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I recommend publication in its current form

I recommend publication in its current form

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I believe the authors have answered the reviewers concerns to my satisfaction.

Reviewer #5: (No Response)

Reviewer #7: I still take issue with the comment that a gross total resection versus a near total resection is a significant indicator for the need of a shunt procedure particularly in younger children. I would urge the authors to further expand the discussion, particularly questioning whether less than 1.5 cc of residual tumor coating the floor of the fourth ventricle will necessitate ultimate CSF diversion. This is particularly pertinent since it has been well-established in the pediatric neuro-oncology literature that there is no survival advantage for gross total resection versus minimal residual disease

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Reviewer #1: Yes: Ronald Benveniste

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20 Oct 2020

Editor’s comments：

1. Please add a paragraph into the discussion part of the manuscript where you explain whether or not less than 1.5 cc of residual tumor coating the floor of the fourth ventricle will necessitate ultimate CSF diversion.

Authors’ response: We have further expanded the part in the discussion (Page 14, line 288-298). Thank you for this valuable comment.

Reviewers’ comments:

Reviewer #1

1. I recommend publication in its current form

Authors’ response: Thank you for the comments.

Reviewer #2

1. In my opinion, the authors have responded well to the reviewers comments, and the revised manuscript is improved compared to the original manuscript.

Authors’ response: Thank you for the comment.

Reviewer #4

1. I believe the revisions improve the quality of the article. I believe the authors have answered the reviewers concerns to my satisfaction.

Authors’ response: Thank you for the comment.

Reviewer #5

(No Response)

Reviewer #7

1. I still take issue with the comment that a gross total resection versus a near total resection is a significant indicator for the need of a shunt procedure particularly in younger children. I would urge the authors to further expand the discussion, particularly questioning whether less than 1.5 cc of residual tumor coating the floor of the fourth ventricle will necessitate ultimate CSF diversion. This is particularly pertinent since it has been well-established in the pediatric neuro-oncology literature that there is no survival advantage for gross total resection versus minimal residual disease.

Authors’ response: We have further expanded the part in the discussion (Page 14, line 288-298). Thank you for this valuable comment.

Submitted filename: Response to Reviewers.docx

Click here for additional data file.

22 Oct 2020

Risk factors for hydrocephalus following fourth ventricle tumor surgery: A retrospective analysis of 121 patients

PONE-D-20-23644R2

Dear Dr. Zhang,

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Reviewers' comments:

9 Nov 2020

PONE-D-20-23644R2

Risk factors for hydrocephalus following fourth ventricle tumor surgery: A retrospective analysis of 121 patients

Dear Dr. Zhang:

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Academic Editor

PLOS ONE

Table 1

Patients’ characteristics and details of tumor.

Variables	Value
Sex
Female	61 (50.4%)
Male	60 (49.6%)
Tumor size (mm)	37 (30–44)
Age (years)	24 (9–41)
<3	11 (9.1%)
3–5	10 (8.3%)
5–18	35 (28.9%)
>18	65 (53.7%)
Tumor pathology
Ependymoma	37 (30.6%)
Medulloblastoma	29 (24.0%)
Astrocytoma	20 (16.5%)
Hemangioblastoma	7 (5.8%)
Cholesteatoma	7 (5.8%)
Choroid plexus papilloma	7 (5.8%)
Metastatic	4 (3.3%)
Non-Hodgkin lymphoma	1 (0.8%)
Other	9 (7.5%)
Tumor growth characteristics a
Lateral extension	34 (28.1%)
Anterior extension	98 (81.0%)
Caudal extension	69 (57.0%)
Superior extension	14 (11.6%)
No extension beyond the fourth ventricle	8 (6.6%)

Values are number of patients (%) or median (interquartile range).

a Percentages do not add up to 100 because some patients had more than 1 growth characteristic.

Table 2

Univariate analysis of the association between each factor and postoperative hydrocephalus.

Variables	Postoperative CSF diversion		P-value
	Yes (15)	No (106)
Sex			0.012a
Female	3 (4.9%)	51 (95.1%)
Male	12 (20%)	48 (80%)
Tumor size (mm)	40 (34–49)	36 (30–43)	0.100
Age (years)	18 (3–38)	24 (9–41)	0.301
Tumor pathology
Ependymoma	3 (8.1%)	34 (91.9%)	0.226b c
Medulloblastoma	5 (17.2%)	24 (82.8%)	1.0b c
Astrocytoma	4 (20.0%)	16 (80.0%)
Lateral extension			0.553b
Yes	3 (8.8%)	31 (91.2%)
No	12 (13.8%)	75 (86.2%)
Anterior extension			0.159b
Yes	88 (89.8%)	10 (10.2%)
No	5 (21.7%)	18 (78.3%)
Caudal extension			0.420a
Yes	10 (14.5%)	59 (85.5%)
No	5 (9.6%)	47 (90.4%)
Superior extension			0.015b
Yes	5 (35.7%)	9 (64.3%)
No	10 (9.3%)	97 (90.7%)
Extent of resection			<0.001b
GTR	3 (3.3%)	87(96.7%)
STR	12 (38.7%)	19(61.3%)
Preoperative hydrocephalus			<0.001a
Yes	15 (21.4%)	55 (78.6%)
No	0 (0%)	51 (100%)
Prophylactic EVD			0.091a
Yes	10 (17.9%)	46 (82.1%)
No	5 (7.7%)	60 (92.3%)

CSF, cerebrospinal fluid; GTR, gross total resection; STR, subtotal resection; EVD, external ventricular drainage.

a Chi-square test.

b Fisher exact test.

c p value compared with astrocytoma.

Table 3

Univariate analysis of the association between each factor and postoperative VP.

Variables	Postoperative VP		P-value
	Yes (10)	No (110)
Sex			0.054b
Female	2 (3.3%)	59 (96.7%)
Male	8 (13.3%)	52 (86.7%)
Tumor size (mm)	44 (33–53)	36 (30–43)	0.032
Age (years)	16 (1–45)	24 (9–41)	0.533
Tumor pathology
Ependymoma	2 (5.4%)	35 (94.6%)	0.170b c
Medulloblastoma	3 (10.3%)	26 (89.7%)	0.422b c
Astrocytoma	4 (20.0%)	16 (80.0%)
Lateral extension			0.724b
Yes	2 (5.9%)	32 (94.1%)
No	8 (9.2%)	79 (90.8%)
Anterior extension			0.339b
Yes	7 (7.1%)	91 (92.9%)
No	3 (13%)	20 (87%)
Caudal extension			1.000b
Yes	6 (8.7%)	63 (91.3%)
No	4 (7.7%)	48 (92.3%)
Superior extension			0.016b
Yes	4 (28.6%)	10 (71.4%)
No	6 (5.6%)	101 (94.4%)
Extent of resection			<0.001b
GTR	1 (1.1%)	89(98.9%)
STR	9 (29%)	22(71%)
Preoperative hydrocephalus			<0.005b
Yes	10 (14.3%)	60 (85.7%)
No	0 (0%)	51 (100%)
Prophylactic EVD			0.006b
Yes	9 (16.1%)	47 (83.9%)
No	1 (1.5%)	64 (98.5%)

a Chi-square test.

b Fisher exact test.

c p value compared with astrocytoma.

Table 4

Multivariate analysis of factors associated with postoperative hydrocephalus.

Variables	Odds ratio (95% CI)	p-value
Superior extension	44.761(2.235–896.310)	0.013
Gross total resection	0.087(0.016–0.473)	0.005

Table 5

Univariate analysis of the association between each factor and postoperative hydrocephalus in a subgroup of perioperative EVD placement.

Variables	Postoperative CSF diversion		p-value
	Yes (10)	No (46)
Sex			0.162b
Female	2(8.3%)	22(91.7%)
Male	8(25.0%)	24(75.0%)
Tumor size (mm)	41(33–50)	36(31–41)	0.174
Age (years)	22.5(1–45)	25.5(11–41)	0.528
Tumor pathology
Ependymoma	3(20.0%)	12(80.0%)	0.239b c
Medulloblastoma	2(15.4%)	11(84.6%)	0.357b c
Astrocytoma	4(36.4%)	7(63.6%)
Lateral extension			0.713b
Yes	2(13.3%)	13(86.7%)
No	8(19.5%)	33(80.5%)
Anterior extension			0.361b
Yes	7(15.2%)	39(84.8%)
No	3(30.0%)	7(70.0%)
Caudal extension			0.727b
Yes	7(20.0%)	28(80.0%)
No	3(14.3%)	18(85.7%)
Superior extension			0.003b
Yes	5(62.5%)	3(37.5%)
No	5(10.4%)	43(89.6%)
Extent of resection			<0.001b
GTR	2(5.0%)	38(95.0%)
STR	8(50.0%)	8(50.0%)

a Chi-square test.

b Fisher exact test.

c p value compared with astrocytoma.

Table 6

Multivariate analysis of factors associated with postoperative hydrocephalus in a subgroup of perioperative EVD placement.

Variables	Odds ratio (95% CI)	p-value
Superior extension	23.400(1.982–276.230)	0.012
Gross total resection	0.036(0.004–0.344)	0.004