Comparison of endoscopic third ventriculostomy with or without choroid plexus cauterization in pediatric hydrocephalus: a systematic review and meta-analysis

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  • 1 Michael G. DeGroote School of Medicine, McMaster University, Hamilton;
  • | 2 Faculty of Medicine, University of Toronto; and
  • | 3 Division of Neurosurgery, Department of Surgery, McMaster University, Hamilton, Ontario, Canada
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OBJECTIVE

Pediatric hydrocephalus is a significant contributor to infant morbidity and mortality, particularly in developing countries. The mainstay of treatment has long been shunt placement for CSF diversion, but recent years have seen the rise of alternative procedures such as endoscopic third ventriculostomy (ETV), which provides similar efficacy in selected patients. The addition of choroid plexus cauterization (CPC) to ETV has been proposed to increase efficacy, but the evidence of its utility is limited. This systematic review and meta-analysis aimed to determine the efficacy and safety of ETV+CPC in comparison to ETV alone for the treatment of pediatric all-cause hydrocephalus.

METHODS

MEDLINE, Embase, Cochrane CENTRAL, ClinicalTrials.gov, and ICRCTN databases were searched from conception through to October 2018 for comparative studies including both ETV+CPC and ETV in a pediatric population. The primary outcome was success rate, defined as no secondary procedure required for CSF diversion; secondary outcomes included time to failure, mortality, and complications. Data were pooled using random-effects models of meta-analysis, and relative risk (RR) was calculated.

RESULTS

Five studies were included for final qualitative and quantitative analysis, including 2 prospective and 3 retrospective studies representing a total of 963 patients. Overall, there was no significant difference in success rates between ETV and ETV+CPC (RR 1.24, 95% CI 0.88–1.75, p = 0.21). However, a subgroup analysis including the 4 studies focusing on African cohorts demonstrated a significant benefit of ETV+CPC (RR 1.38, 95% CI 1.08–1.78, p = 0.01). There were no notable differences in complication rates among studies.

CONCLUSIONS

This systematic review and meta-analysis failed to find an overall benefit to the addition of CPC to ETV; however, a subgroup analysis showed efficacy in sub-Saharan African populations. This points to the need for future randomized clinical trials investigating the efficacy of ETV+CPC versus ETV in varied patient populations and geographic locales.

ABBREVIATIONS

CENTRAL = Central Register of Controlled Trials; CI = confidence interval; CPC = choroid plexus cauterization; ETV = endoscopic third ventriculostomy; ETVSS = ETV Success Score; IVH = intraventricular hemorrhage; M-H = Mantel-Haenszel; MINORS = Methodological Index for Non-Randomized Studies; MM = myelomeningocele; NPIH = non-PIH; PIH = postinfectious hydrocephalus; PRISMA = Preferred Reporting Items for Systematic Reviews and Meta-Analyses; RR = relative risk; TTF = time to failure.

OBJECTIVE

Pediatric hydrocephalus is a significant contributor to infant morbidity and mortality, particularly in developing countries. The mainstay of treatment has long been shunt placement for CSF diversion, but recent years have seen the rise of alternative procedures such as endoscopic third ventriculostomy (ETV), which provides similar efficacy in selected patients. The addition of choroid plexus cauterization (CPC) to ETV has been proposed to increase efficacy, but the evidence of its utility is limited. This systematic review and meta-analysis aimed to determine the efficacy and safety of ETV+CPC in comparison to ETV alone for the treatment of pediatric all-cause hydrocephalus.

METHODS

MEDLINE, Embase, Cochrane CENTRAL, ClinicalTrials.gov, and ICRCTN databases were searched from conception through to October 2018 for comparative studies including both ETV+CPC and ETV in a pediatric population. The primary outcome was success rate, defined as no secondary procedure required for CSF diversion; secondary outcomes included time to failure, mortality, and complications. Data were pooled using random-effects models of meta-analysis, and relative risk (RR) was calculated.

RESULTS

Five studies were included for final qualitative and quantitative analysis, including 2 prospective and 3 retrospective studies representing a total of 963 patients. Overall, there was no significant difference in success rates between ETV and ETV+CPC (RR 1.24, 95% CI 0.88–1.75, p = 0.21). However, a subgroup analysis including the 4 studies focusing on African cohorts demonstrated a significant benefit of ETV+CPC (RR 1.38, 95% CI 1.08–1.78, p = 0.01). There were no notable differences in complication rates among studies.

CONCLUSIONS

This systematic review and meta-analysis failed to find an overall benefit to the addition of CPC to ETV; however, a subgroup analysis showed efficacy in sub-Saharan African populations. This points to the need for future randomized clinical trials investigating the efficacy of ETV+CPC versus ETV in varied patient populations and geographic locales.

ABBREVIATIONS

CENTRAL = Central Register of Controlled Trials; CI = confidence interval; CPC = choroid plexus cauterization; ETV = endoscopic third ventriculostomy; ETVSS = ETV Success Score; IVH = intraventricular hemorrhage; M-H = Mantel-Haenszel; MINORS = Methodological Index for Non-Randomized Studies; MM = myelomeningocele; NPIH = non-PIH; PIH = postinfectious hydrocephalus; PRISMA = Preferred Reporting Items for Systematic Reviews and Meta-Analyses; RR = relative risk; TTF = time to failure.

In Brief

Pediatric hydrocephalus is routinely managed with endoscopic third ventriculostomy (ETV). Choroid plexus cauterization (CPC) has been introduced as an adjunct treatment to ETV that helps prevent the requirement of a CSF diversion procedure. This systematic review and meta-analysis found no statistically significant difference between patients managed with ETV alone and in combination with CPC. A subgroup analysis in African cohorts found a significant increase in success rate with ETV combined with CPC.

In North America and Europe, pediatric hydrocephalus affects approximately 0.5–0.8 per 1000 births, most commonly caused by intraventricular hemorrhage (IVH) of prematurity, Chiari type II malformation, tumors, and infection.1–6 The mainstay of care has long been CSF shunt placement, but recently, endoscopic third ventriculostomy (ETV) has become a popular alternative procedure in many patients, avoiding the significant complications with shunts (e.g., infection or malfunction) with comparable outcomes.7 However, ETV is not efficacious for certain patient populations and success can depend on patient age and hydrocephalus etiology, among other factors. The ETV Success Score (ETVSS) was developed to try to predict the likelihood of success; older age, noninfectious etiology (in particular aqueductal stenosis and tectal tumor), and no past shunt placement were important factors associated with success.8 In the original study, patients with moderate to low ETVSSs had significantly lower success rates at 36 months; this finding was corroborated by a 2016 multicenter study that reported a failure rate of 42% at 18 months’ follow-up.9,10

As a result of the relatively high failure rate of ETV, the addition of choroid plexus cauterization (CPC) has been proposed to improve success rates. The rationale behind this approach has traditionally been based on the belief that the choroid plexus produces a large amount of CSF; therefore, by eliminating this source of CSF, the surgeon is likely reducing the amount of CSF required to be reabsorbed by the arachnoid villi, as well as the force applied to the ventricles.11,12 Both of these processes should therefore ideally help to restore CSF balance and theoretically alleviate hydrocephalus, but initial studies of CPC alone failed to show efficacy in treating hydrocephalus, and recent work has indicated several flaws in the bulk-flow model of CSF on which the proposed mechanism of CPC is based.11,12 Despite this, several studies have demonstrated efficacy of the combined ETV+CPC procedure, many of which focused on specific patient populations in sub-Saharan Africa.13,14 Furthermore, a 2014 prospective series including 91 patients in a single North American center who underwent ETV+CPC demonstrated success rates comparable to those of primary shunt placement.15 A 2016 systematic review including 11 retrospective studies of ETV+CPC found that success was greater in patient cohorts from sub-Saharan Africa than those in North America, with an overall success rate of 63% at follow-up periods ranging from 6 months to 8 years.16 Despite the initial promising results from ETV+CPC treatment, there is no current consensus on the utility of the procedure in regular practice, and whether it should be preferred to ETV alone as a first-line treatment option. Furthermore, the long-term impacts of CPC are unclear, complicating the decision to include this procedure in treatment. The data on this topic have been somewhat conflicting; certain groups reporting on African patient cohorts have shown an increase in success with the addition of CPC to ETV as compared to ETV alone, whereas other studies in North American cohorts have failed to find a benefit.14,17,18

Currently, there is no contemporary comprehensive comparative review of success rates and outcomes for pediatric all-cause hydrocephalus treated by ETV+CPC versus ETV alone. The aim of this systematic review and meta-analysis was to synthesize the current evidence comparing ETV versus ETV+CPC for pediatric hydrocephalus and identify particular patient cohorts in which differences in success rates might occur.

Methods

Search Strategy

We conducted a systematic search of the following databases covering the period from database inception through October 2018: MEDLINE, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), and the major clinical trial registries (ClinicalTrials.gov and ICRCTN) for ongoing studies. The search was conducted without any language restrictions. The search terms and strategy were designed with the help of an expert medical librarian with input from study investigators. The search strategy included keywords such as “hydrocephalus,” “endoscopic third ventriculostomy,” “choroid plexus cauterization,” and more. A sample search strategy is provided in the Appendix. We also manually searched the references of published studies and searched “gray” literature to ensure that relevant articles were not missed. For conference abstracts, we searched for the associated published study and excluded the abstract if no published paper was found. This systematic review and meta-analysis is reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA).19

Eligibility Criteria

Articles were eligible for inclusion if the study investigators performed ETV with or without CPC in children presenting with hydrocephalus of any etiology. Exclusion criteria were as follows: 1) noncomparative, single-arm study, 2) nonhuman studies, or 3) adult population (≥ 18 years old).

Primary and Secondary Outcomes

The primary outcome was success rate of the index procedure, defined as not requiring further intervention for hydrocephalus during the study period. Secondary outcomes included 1) time to failure (TTF), 2) mortality, and 3) adverse events associated with the surgery (e.g., readmission, reoperation, or complications).

Data Abstraction

Screening of searched titles, abstracts, and full texts was conducted independently by two reviewers (Y.E., K.B.). Reviewers were not blinded to author name, institution, or where the paper was published. Any discrepancies that occurred during the title and abstract screening stages were resolved by automatic inclusion to ensure that all relevant publications were not missed. Two reviewers independently conducted data abstraction onto a standardized spreadsheet designed a priori. The following data were abstracted from included studies: study characteristics (author, country, year of publication, study design [i.e., prospective vs retrospective, randomized controlled trial, etc.]), patient demographics (age at time of surgery, etiology of hydrocephalus [i.e., infectious, congenital aqueductal stenosis, etc.], number of patients included, percentage female, prior treatments, ETVSS), and outcomes. Discrepancies at the full-text and data-abstraction stages were resolved by consensus between two reviewers, and if disagreement persisted, a third reviewer was consulted. The Methodological Index for Non-Randomized Studies (MINORS) tool was used to assess the risk of bias for individual studies.20

Statistical Analysis

All statistical analyses and meta-analyses were performed on Cochrane Review Manager (version 5.3). The threshold for statistical significance was set a priori at α = 0.05. We performed pairwise meta-analyses using a Mantel-Haenszel (M-H) random-effects model for dichotomous outcomes. Pooled effect estimates were obtained by calculating the relative risk (RR) for each dichotomous outcome, along with the respective 95% confidence interval (CI). Attempts were made to contact authors for any missing data. Assessment of heterogeneity was completed using the inconsistency (I2) statistic. We considered I2 > 50% to represent considerable heterogeneity.21 Heterogeneity was not assessed via funnel plot as the meta-analysis consisted of fewer than 10 studies.22,23

Results

Study Characteristics

One hundred seventy-three studies were captured from the initial database search. Of these, 7 studies met the inclusion criteria. However, 2 of these studies24,25 consisted of completely overlapping cohorts and were excluded, leaving 5 unique studies included in qualitative and quantitative analysis.14,17,18,26,27 Of these 5 studies, 3 included patients with partially overlapping cohorts, but due to an unknown amount of overlap, these studies were included in the analysis.14,26,27 However, a sensitivity analysis was conducted without including the 2 additional studies (Warf et al. [2012],14 Warf [2013]27), and it did not alter the results of the meta-analysis. The included studies consisted of 2 prospective and 3 retrospective studies, comprising a total of 963 patients. A PRISMA flow diagram detailing the study selection process can be found in Fig. 1. Four studies were from African countries, and 1 study was from North America. The publication date of the included studies ranged from 2005 to 2018. The duration of follow-up ranged from 6 to 51.6 months. The weighted mean age at index surgery was 11.29 months. The indications for ETV included postinfectious hydrocephalus (PIH), non-postinfectious hydrocephalus (NPIH), myelomeningocele (MM), posthemorrhagic hydrocephalus, congenital idiopathic hydrocephalus, and congenital aqueductal stenosis. Notably, in 1 study, all patients who underwent ETV+CPC had failed a prior trial of ETV.14 Detailed study characteristics of the included studies are reported in Table 1.

FIG. 1.
FIG. 1.

PRISMA diagram outlining the search strategy results from initial search to included studies.

TABLE 1.

Study characteristics

Authors & YearStudy DesignGroupLocationNo. Treated% FemaleMean Age ± SD (yrs)Prior ProceduresIndication/EtiologyOperative Technique
Warf, 200526PETV/CPCUganda, Kenya, Tanzania, Malawi, Somalia, Rwanda, Congo, & Mauritius266NR14 ± NRNRPIH (n = 320), NPIH (n = 152), MM (n = 73), PHH (n = 5)*Fenestration of floor of 3rd ventricle; unilateral or bilateral CPC, flexible endoscope used
ETV284NRNR
Warf et al., 201214PETV/CPCUganda23573.5 ± NRNRCongenital aqueductal stenosis who failed a trial of ETVFenestration of floor of 3rd ventricle; unilateral or bilateral CPC, flexible endoscope used
ETV12254.7 ± NRNRCongenital aqueductal stenosis
Warf, 201327PETV/CPCUganda48476.1 ± NRNRCongenital idiopathic hydrocephalusFenestration of floor of 3rd ventricle; unilateral or bilateral CPC, flexible endoscope used
ETV16NR
Biluts & Admasu, 201617RETV/CPCEthiopia, Somalia, & South Sudan215511.22 ± 15.02NRNo systematic inclusion criteria, surgeon preference; MM (n = 42), aqueductal stenosis (n = 41), PIH (n = 15), Dandy-Walker (n = 10), tumors (n = 8), IVH (n = 1), no clear cause (n = 4)Fenestration of floor of 3rd ventricle, bilateral complete CPC of both ventricles; flexible endoscope used
ETV101NR
Kulkarni et al., 201818PETV/CPCCanada, US11842.44.8 ± 4.8NRNew-onset hydrocephalus, or failure of a previous CSF shunt, w/ anatomy suitable for ETV+CPC on preop MRI; IVH of prematurity (n = 3), aqueductal stenosis (n = 10), other etiology (n = 21)Unilateral coronal entry site, fenestration of floor of 3rd ventricle, w/ complete CPC of both lateral ventricles; both flexible & rigid endoscope used
ETV7448.69.6 ± 6.7NR

NR = not reported; P = prospective cohort; PHH = posthemorrhagic hydrocephalus; R = retrospective cohort.

Study protocol was refined throughout study due to preliminary analysis to provide ETV/CPC only in patients < 1 year of age with NPIH, MM, or PIH type A; PIH type B was randomized.

Outcomes

From the 5 studies included, all reported success rates after ETV or ETV+CPC, defined as survival without the need for a subsequent operation (shunt or repeat ETV ± CPC). Four hundred eighty-seven patients were enrolled in the ETV group and 476 in the ETV+CPC group. Of these, 445 patients in the ETV group and 465 patients in the ETV+CPC group were included in the final analysis. Compared to the ETV group, the ETV+CPC group achieved comparable rates of success (RR 1.24, 95% CI 0.88–1.75, p = 0.21) with a heterogeneity measure of I2 = 72% (Fig. 2). Subgroup analysis for studies from African countries that compared ETV to ETV+CPC demonstrated a significant benefit of ETV+CPC (RR 1.38, 95% CI 1.08–1.78, p = 0.01) with a heterogeneity measure of I2 = 32% (Fig. 3). A detailed list of the available study outcomes is summarized in Table 2.

FIG. 2.
FIG. 2.

Random-effects meta-analysis of all included studies comparing success after ETV+CPC versus ETV alone. Figure is available in color online only.

FIG. 3.
FIG. 3.

Random-effects meta-analysis of African cohort studies comparing success after ETV+CPC versus ETV alone. Figure is available in color online only.

TABLE 2.

Study outcomes

StudyGroupNo. Included in Final AnalysisMean FU (mos)No. Lost to FU (%)No. w/Success (%)Mean TTF ± SD (days)Salvage Procedures
Warf, 200526ETV/CPC2559.2 ± NR21/550 (3.8)174 (68.2)54 ± NRRepeat ETV-CPC (n = 61)
ETV26819 ± NR145 (54.1)
Warf et al., 201214ETV/CPC2331.2 ± NRNR19 (82.6)120 ± NRNR
ETV1251.6 ± NRNR6 (50.0)51.6 ± NR
Warf, 201327ETV/CPC4834.4 ± NR4 (6.25)35 (72.9)NRNR
ETV1634.4 ± NR3 (18.8)NR
Biluts & Admasu, 201617ETV/CPC217.2 ± 11.2839*/122 (32.0)12 (57.1)60.0 ± 80.7NR
ETV7532 (42.7)
Kulkarni et al., 201818ETV/CPC118At least 6None prior to 6 mos43 (36.4)63.6 ± 64.42NR
ETV7436 (48.6)155.9 ± 305.76

30 days postoperatively.

TTF of the primary treatment was reported by 4 of 5 studies, although 2 of these studies did not report standard deviations. Warf (2005)26 reported an overall TTF of 54 days (SD not reported) for both treatment groups. Similarly, Biluts and Admasu (2016)17 reported an overall TTF of 60 ± 80.7 days for both treatment groups. Warf et al. (2012)14 included a breakdown of ETV+CPC versus ETV and found a longer TTF of 120 days in the ETV+CPC group compared with 51.6 days in the ETV-alone group. Conversely, Kulkarni et al. (2018),18 the only study with a North American cohort, showed a longer TTF of 155.9 ± 305.76 days in the ETV-alone group as compared to 63.6 ± 64.42 days for ETV+CPC. Warf (2005)26 performed salvage surgery in 61 patients who failed the initial procedure; this included reopening of an occluded ETV or dissection of membranes below the floor of the third ventricle. No other studies reported specific repeat procedures performed for those who failed ETV or ETV+CPC treatment.

In terms of complications, 4 of the 5 studies reported mortality within their designated follow-up period. In total, 20 deaths (2.6%) were reported; however, most studies did not stratify by treatment. The causes of mortality either in-hospital or in follow-up related to the procedure included ventriculitis, cardiac arrest, pneumonia, and other unknown illnesses. Other nonfatal complications were reported in 3 of the 5 studies. One case of postoperative mild ptosis that self-resolved was reported in 1 study (ETV+CPC group),26 and another study reported 1 case of nonfatal ventriculitis (ETV group).27 Intraoperative complications were noted in 1 study, which reported a composite of ipsilateral forniceal injury, major arterial injury, venous injury, and thalamic contusion in 9 patients (7.6%) in the ETV+CPC group and in 20 patients (27%) in the ETV group.18 A comprehensive list of causes of mortality and reported complications is provided in Table 3.

TABLE 3.

Adverse events related to ETV and ETV+CPC

StudyGroupNo. of Deaths (%)Time Point (mos)Cause of MortalityComplications
Warf, 200526ETV/CPC2 (0.75)1Ventriculitis (n = 1), cardiac arrest (n = 2), aspiration (n = 1), pneumonia (n = 1), undocumented illness (n = 2)Mild ptosis (n = 1)
ETV5 (1.8)1None
Warf et al., 201214ETV/CPC7 (20)NRNRNR
ETVNRNRNR
Warf, 201327ETV/CPC01NANone
ETV01NAVentriculitis (n = 1)
Biluts & Admasu, 201617ETV/CPC6 (4.9)1Cardiac arrest (n = 2), intracranial bleeding (n = 1), unknown causes (n = 3)Infection (n = 7), postop bleeding (n = 6), fever (n = 1), gaze palsy (n = 1), seizure (n = 1)
ETV1
Kulkarni et al., 201818ETV/CPCNR>6Seizure (n = 6), bleeding during procedure (n = 48), other intraop complication* (n = 9), other postop complication (n = 11)
ETVSeizure (n = 1), bleeding during procedure (n = 26), other intraop complication* (n = 20), other postop complication (n = 3)

Other intraoperative complications included ipsilateral forniceal injury, major arterial injury, venous injury, and thalamic contusion.

Other postoperative complications included hyponatremia, CSF leak, hemorrhage, pseudomeningocele, new neurological deficits, and documented bacterial meningitis.

Quality Assessment

The mean MINORS score of included studies was 18.4 ± 1.52 out of a maximum of 24 for comparative cohort studies, thus indicating a fair quality of evidence for nonrandomized comparative studies. A comprehensive list of MINORS scores for included studies is outlined in Table 4. In summary, all studies had adequate control/contemporary groups, adequate statistical analysis, and greater than 6 months of follow-up. Four of 5 studies collected data prospectively and had a clearly stated aim. Two studies reported a loss to follow-up of less than 5%. Finally, none of the studies had employed an unbiased assessment of the study endpoint such as blind evaluation of outcomes, nor had a prospective calculation of study size.

TABLE 4.

MINORS criteria assessment of included comparative studies

Authors & Year
MINORS CriteriaWarf, 200526Warf et al., 201214Warf, 201327Biluts & Admasu, 201617Kulkarni et al., 201818
A clearly stated aim22212
Inclusion of consecutive patients22022
Prospective collection of data22212
Endpoints appropriate to the aims of the study22222
Unbiased assessment of the study endpoint11111
Follow-up period appropriate to the aim of the study22222
Loss to follow-up <5%20112
Prospective calculation of the study size00000
Adequate control group22222
Contemporary group22222
Baseline equivalence12200
Adequate statistical analysis22222
Total2019181619

0 = not reported, 1 = reported but inadequate, 2 = reported and adequate.

Discussion

Summary of Main Findings

To the best of our knowledge, this is the most comprehensive and up-to-date comparative systematic review and meta-analysis of ETV versus ETV+CPC in the treatment of pediatric hydrocephalus. In our analysis, we failed to find a significant increase in the overall success rate of ETV+CPC versus ETV alone when all studies and patient cohorts were included. However, in a subgroup analysis of just the 4 studies of African cohorts, which had a dual function as a sensitivity analysis, there was a significant increase in percentage success in patients who underwent ETV+CPC compared to ETV alone (RR 1.38, 95% CI 1.08–1.78, p = 0.01). The 4 cohorts included in this subgroup analysis were all from patient populations in sub-Saharan Africa, and the relatively high efficacy of the combined ETV+CPC procedure in these populations has been well researched and reported previously in the literature.14,15,17 Indeed, various past noncomparative systematic reviews and retrospective studies have found increased success of the combined ETV+CPC procedure in African cohorts as compared to North American cohorts.1,2,17

The difference in efficacy between these populations may be due to various factors, including nuances in the surgical techniques, preexisting comorbidities in the patient populations, differences in patient selection criteria between studies, and the threshold for defining “success” and repeat CSF diversion procedure between varying surgical centers and surgeons. In particular, Warf (2005) randomized infants with PIH or NPIH type C to ETV or ETV+CPC, but all patients with MM and NPIH or PIH type A received ETV+CPC, while patients at least 1 year of age received ETV alone.26 This is in contrast to other included studies such as that of Kulkarni et al., which did not separate patients into different treatment groups based on etiology.18 In addition, in 1 of the included studies, all patients who underwent ETV+CPC had previously failed treatment with ETV alone.14 These and other differences in baseline equivalence between eligible patient populations might have had an important impact on outcomes, and therefore robust and standardized randomized prospective trials are critical to determining whether there is a true benefit to the addition of CPC to ETV and whether this benefit is seen only in specific patient populations. Past systematic reviews and meta-analyses on ETV+ CPC and ETV in the pediatric population that have included single-arm studies have found a benefit of CPC addition primarily in African populations as well, consistent with our findings in this study.16,28 However, the limited available data have precluded the generation of evidence-based guidelines about the utility of CPC.

Safety and Quality of Data

All but 1 of the studies did not report complications stratified by treatment group. Additionally, there were no notable differences in the reported complications between studies. The overall quality of the studies as assessed by MINORS was determined to be fair, as all of the studies had a reasonable comparison group, sufficient statistical analysis, and adequate follow-up (at least 6 months). Importantly, however, no studies blinded outcome assessment, which is a significant factor that may have contributed to bias in the results, particularly as there was no clear and consistent definition of “success” of ETV reliably used between studies.

Strengths and Limitations

One of the principal strengths of our study is the sole inclusion of studies that directly compared ETV with ETV+CPC, providing greater insight into the utility of the addition of CPC to the traditional ETV procedure. However, in doing so, the exclusion of single-arm studies greatly reduced the number of included studies in this analysis. Another notable limitation of the meta-analysis is that 3 of the included studies were conducted by the same principal investigator, which might impart biases specific to surgical techniques and patient selection protocols utilized in these centers. Differences in surgical technique might prevent replicability of results in any one particular study and might contribute to heterogeneity in results. Specifically, the degree of CPC may differ between surgeons and surgical centers, and this lack of standardization might be an important factor in determining whether the procedure is efficacious; to this end, Kulkarni et al. found that an increased amount of CPC was correlated with a higher rate of success of the ETV+CPC procedure.18 Furthermore, some of the patients included in these studies were overlapping (i.e., long-term follow-ups) with those included in the original study, but the exact number of repeated patients was unclear.14,26,27 With regard to generalizability, there was only 1 non-African cohort included, which did not find significant benefit from the addition of CPC. The issue of patient population, therefore, represents an important factor that is not sufficiently explored by the literature today, and future prospective trials must be conducted, particularly in non-African settings, to evaluate the generalizability of the superiority of ETV+CPC that has been repeatedly demonstrated in African patient cohorts. In addition, the choice of treatment success as our endpoint of interest was defined as not requiring further treatment. As discussed, this definition of success is subjective as there may be varying definitions of treatment failure across surgical centers and individual surgeons. As this study included all-cause hydrocephalus, it cannot address whether certain etiologies of hydrocephalus might benefit from ETV+CPC. This is a particularly notable limitation as it has been posited that the CPC would be of benefit specifically in infants with MM and IVH of prematurity, as demonstrated in several prospective and retrospective studies in sub-Saharan African patient cohorts.26,29 Furthermore, the patients lost to follow-up in each of the studies may have had specific characteristics that could have differed across locales, which might have impacted the final analysis of each study.

Future Directions

Based on our findings, the greatest amount of benefit from the addition of CPC to ETV was found in studies reported by a single surgical group (Warf and colleagues). This is an important factor to consider in the design and development of new prospective studies to evaluate this procedure further. As the uptake of ETV+CPC increases across more surgical centers, it will be important to assess the external validity by seeing whether the benefit can be replicated in other centers, or if it is significantly dependent on surgical expertise and specific experience. We believe future studies should focus on a prospective multicenter randomized controlled trial design, include multiple countries to account for geographic variability, and balance demographic factors such as patient age that may bias the results. The inclusion of multiple surgical teams across geographic locales will allow for comparison of technique and patient population.

Conclusions

This systematic review and meta-analysis failed to find a significant increase in shunt-free survival in patients who underwent ETV+CPC compared to ETV alone in a pooled analysis. The available literature on this topic is limited, and specifically, studies assessing this procedure in developed nations are lacking. Future multicenter randomized clinical trials are warranted to delineate which patient populations may benefit from CPC in addition to ETV and, in particular, whether geographic differences might be an important factor in predicting greater success with ETV+CPC.

Acknowledgments

We would like to thank Dr. Abhaya Kulkarni, Dr. John Kestle, and the Hydrocephalus Clinical Research Network (HCRN) for providing additional data of their included study.

Appendix

Embase Search Strategy (1947–2018)

  1. 1. exp third ventriculostomy/ (379)
  2. 2. (endoscopic third ventriculostomy or ventriculostomy or third ventriculostomy).mp. [mp = title, abstract, heading word, drug trade name, original title, device manufacturer, drug manufacturer, device trade name, keyword, floating subheading word, candidate term word] (5016)
  3. 3. 1 or 2 (5016)
  4. 4. exp hydrocephalus/ (50741)
  5. 5. hydrocephalus.mp. (50745)
  6. 6. 4 or 5 (56296)
  7. 7. (child* or infant* or neonate* or newborn* or toddler* or pediatric* or pediatric*).mp. [mp=title, abstract, heading word, drug trade name, original title, device manufacturer, drug manufacturer, device trade name, keyword, floating subheading word, candidate term word] (3554203)
  8. 8. exp cauterization/ and exp choroid plexus/ (99)
  9. 9. choroid plexus cauter*.mp. (108)
  10. 10. 8 or 9 (138)
  11. 11. 3 and 6 and 10 (105)
  12. 12.11 and 7 (95)
  13. 13. limit 11 to (infant < to one year > or child < unspecified age >; or preschool child < 1 to 6 years > or school child <7 to 12 years> or adolescent <13 to 17 years>) (45)
  14. 14. 12 or 13 (95)

Disclosures

The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper.

Author Contributions

Conception and design: Ajani, Ellenbogen. Acquisition of data: Ellenbogen, Brar. Analysis and interpretation of data: Ellenbogen, Brar, Yang. Drafting the article: Ellenbogen, Brar. Critically revising the article: all authors. Reviewed submitted version of manuscript: all authors. Approved the final version of the manuscript on behalf of all authors: Ajani. Statistical analysis: Ellenbogen, Lee. Administrative/technical/material support: Ajani. Study supervision: Ajani.

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    • Export Citation
  • 5

    Tully HM, Capote RT, Saltzman BS. Maternal and infant factors associated with infancy-onset hydrocephalus in Washington State. Pediatr Neurol. 2015;52(3):320325.

    • Search Google Scholar
    • Export Citation
  • 6

    Tully HM, Dobyns WB. Infantile hydrocephalus: a review of epidemiology, classification and causes. Eur J Med Genet. 2014;57(8):359368.

    • Search Google Scholar
    • Export Citation
  • 7

    Limbrick DD Jr, Baird LC, Klimo P Jr, et al. Pediatric hydrocephalus: systematic literature review and evidence-based guidelines. Part 4: Cerebrospinal fluid shunt or endoscopic third ventriculostomy for the treatment of hydrocephalus in children. J Neurosurg Pediatr. 2014;14(suppl 1):3034.

    • Search Google Scholar
    • Export Citation
  • 8

    Kulkarni AV, Drake JM, Mallucci CL, et al. Endoscopic third ventriculostomy in the treatment of childhood hydrocephalus. J Pediatr. 2009;155(2):254259.e1.

    • Search Google Scholar
    • Export Citation
  • 9

    Kulkarni AV, Drake JM, Kestle JR, et al. Predicting who will benefit from endoscopic third ventriculostomy compared with shunt insertion in childhood hydrocephalus using the ETV Success Score. J Neurosurg Pediatr. 2010;6(4):310315.

    • Search Google Scholar
    • Export Citation
  • 10

    Kulkarni AV, Riva-Cambrin J, Holubkov R, et al. Endoscopic third ventriculostomy in children: prospective, multicenter results from the Hydrocephalus Clinical Research Network. J Neurosurg Pediatr. 2016;18(4):423429.

    • Search Google Scholar
    • Export Citation
  • 11

    Brinker T, Stopa E, Morrison J, Klinge P. A new look at cerebrospinal fluid circulation. Fluids Barriers CNS. 2014;11:10.

  • 12

    Dewan MC, Naftel RP. The global rise of endoscopic third ventriculostomy with choroid plexus cauterization in pediatric hydrocephalus. Pediatr Neurosurg. 2017;52(6):401408.

    • Search Google Scholar
    • Export Citation
  • 13

    Kulkarni AV, Schiff SJ, Mbabazi-Kabachelor E, et al. Endoscopic treatment versus shunting for infant hydrocephalus in Uganda. N Engl J Med. 2017;377(25):24562464.

    • Search Google Scholar
    • Export Citation
  • 14

    Warf BC, Tracy S, Mugamba J. Long-term outcome for endoscopic third ventriculostomy alone or in combination with choroid plexus cauterization for congenital aqueductal stenosis in African infants. J Neurosurg Pediatr. 2012;10(2):108111.

    • Search Google Scholar
    • Export Citation
  • 15

    Stone SS, Warf BC. Combined endoscopic third ventriculostomy and choroid plexus cauterization as primary treatment for infant hydrocephalus: a prospective North American series. J Neurosurg Pediatr. 2014;14(5):439446.

    • Search Google Scholar
    • Export Citation
  • 16

    Weil AG, Westwick H, Wang S, et al. Efficacy and safety of endoscopic third ventriculostomy and choroid plexus cauterization for infantile hydrocephalus: a systematic review and meta-analysis. Childs Nerv Syst. 2016;32(11):21192131.

    • Search Google Scholar
    • Export Citation
  • 17

    Biluts H, Admasu AK. Outcome of endoscopic third ventriculostomy in pediatric patients at Zewditu Memorial Hospital, Ethiopia. World Neurosurg. 2016;92:360365.

    • Search Google Scholar
    • Export Citation
  • 18

    Kulkarni AV, Riva-Cambrin J, Rozzelle CJ, et al. Endoscopic third ventriculostomy and choroid plexus cauterization in infant hydrocephalus: a prospective study by the Hydrocephalus Clinical Research Network. J Neurosurg Pediatr. 2018;21(3):214223.

    • Search Google Scholar
    • Export Citation
  • 19

    Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Ann Intern Med. 2009;151(4):264269, W64.

    • Search Google Scholar
    • Export Citation
  • 20

    Slim K, Nini E, Forestier D, et al. Methodological index for non-randomized studies (MINORS): development and validation of a new instrument. ANZ J Surg. 2003;73(9):712716.

    • Search Google Scholar
    • Export Citation
  • 21

    Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ. 2003;327(7414):557560.

  • 22

    Lau J, Ioannidis JP, Terrin N, et al. The case of the misleading funnel plot. BMJ. 2006;333(7568):597600.

  • 23

    Sterne JA, Sutton AJ, Ioannidis JP, et al. Recommendations for examining and interpreting funnel plot asymmetry in meta-analyses of randomised controlled trials. BMJ. 2011;343:d4002.

    • Search Google Scholar
    • Export Citation
  • 24

    Warf BC, Kulkarni AV. Intraoperative assessment of cerebral aqueduct patency and cisternal scarring: impact on success of endoscopic third ventriculostomy in 403 African children. J Neurosurg Pediatr. 2010;5(2):204209.

    • Search Google Scholar
    • Export Citation
  • 25

    Warf BC, Mugamba J, Kulkarni AV. Endoscopic third ventriculostomy in the treatment of childhood hydrocephalus in Uganda: report of a scoring system that predicts success. J Neurosurg Pediatr. 2010;5(2):143148.

    • Search Google Scholar
    • Export Citation
  • 26

    Warf BC. Comparison of endoscopic third ventriculostomy alone and combined with choroid plexus cauterization in infants younger than 1 year of age: a prospective study in 550 African children. J Neurosurg. 2005;103(6)(suppl):475481.

    • Search Google Scholar
    • Export Citation
  • 27

    Warf BC. Congenital idiopathic hydrocephalus of infancy: the results of treatment by endoscopic third ventriculostomy with or without choroid plexus cauterization and suggestions for how it works. Childs Nerv Syst. 2013;29(6):935940.

    • Search Google Scholar
    • Export Citation
  • 28

    Zandian A, Haffner M, Johnson J, et al. Endoscopic third ventriculostomy with/without choroid plexus cauterization for hydrocephalus due to hemorrhage, infection, Dandy-Walker malformation, and neural tube defect: a meta-analysis. Childs Nerv Syst. 2014;30(4):571578.

    • Search Google Scholar
    • Export Citation
  • 29

    Warf BC, Campbell JW. Combined endoscopic third ventriculostomy and choroid plexus cauterization as primary treatment of hydrocephalus for infants with myelomeningocele: long-term results of a prospective intent-to-treat study in 115 East African infants. J Neurosurg Pediatr. 2008;2(5):310316.

    • Search Google Scholar
    • Export Citation

Illustration from Guida et al. (pp 346–352). Copyright Lelio Guida. Published with permission.

Contributor Notes

Correspondence Olufemi Ajani: McMaster University, McMaster Children’s Hospital, Hamilton, Ontario, Canada. ajanio@mcmaster.ca.

INCLUDE WHEN CITING Published online July 3, 2020; DOI: 10.3171/2020.4.PEDS19720.

Y.E. and K.B. contributed equally to this work.

Disclosures The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper.

  • View in gallery

    PRISMA diagram outlining the search strategy results from initial search to included studies.

  • View in gallery

    Random-effects meta-analysis of all included studies comparing success after ETV+CPC versus ETV alone. Figure is available in color online only.

  • View in gallery

    Random-effects meta-analysis of African cohort studies comparing success after ETV+CPC versus ETV alone. Figure is available in color online only.

  • 1

    Fernell E, Hagberg G, Hagberg B. Infantile hydrocephalus epidemiology: an indicator of enhanced survival. Arch Dis Child Fetal Neonatal Ed. 1994;70(2):F123F128.

    • Search Google Scholar
    • Export Citation
  • 2

    Garne E, Loane M, Addor M-C, et al. Congenital hydrocephalus—prevalence, prenatal diagnosis and outcome of pregnancy in four European regions. Eur J Paediatr Neurol. 2010;14(2):150155.

    • Search Google Scholar
    • Export Citation
  • 3

    Jeng S, Gupta N, Wrensch M, et al. Prevalence of congenital hydrocephalus in California, 1991–2000. Pediatr Neurol. 2011;45(2):6771.

  • 4

    Persson E-K, Anderson S, Wiklund L-M, Uvebrant P. Hydrocephalus in children born in 1999–2002: epidemiology, outcome and ophthalmological findings. Childs Nerv Syst. 2007;23(10):11111118.

    • Search Google Scholar
    • Export Citation
  • 5

    Tully HM, Capote RT, Saltzman BS. Maternal and infant factors associated with infancy-onset hydrocephalus in Washington State. Pediatr Neurol. 2015;52(3):320325.

    • Search Google Scholar
    • Export Citation
  • 6

    Tully HM, Dobyns WB. Infantile hydrocephalus: a review of epidemiology, classification and causes. Eur J Med Genet. 2014;57(8):359368.

    • Search Google Scholar
    • Export Citation
  • 7

    Limbrick DD Jr, Baird LC, Klimo P Jr, et al. Pediatric hydrocephalus: systematic literature review and evidence-based guidelines. Part 4: Cerebrospinal fluid shunt or endoscopic third ventriculostomy for the treatment of hydrocephalus in children. J Neurosurg Pediatr. 2014;14(suppl 1):3034.

    • Search Google Scholar
    • Export Citation
  • 8

    Kulkarni AV, Drake JM, Mallucci CL, et al. Endoscopic third ventriculostomy in the treatment of childhood hydrocephalus. J Pediatr. 2009;155(2):254259.e1.

    • Search Google Scholar
    • Export Citation
  • 9

    Kulkarni AV, Drake JM, Kestle JR, et al. Predicting who will benefit from endoscopic third ventriculostomy compared with shunt insertion in childhood hydrocephalus using the ETV Success Score. J Neurosurg Pediatr. 2010;6(4):310315.

    • Search Google Scholar
    • Export Citation
  • 10

    Kulkarni AV, Riva-Cambrin J, Holubkov R, et al. Endoscopic third ventriculostomy in children: prospective, multicenter results from the Hydrocephalus Clinical Research Network. J Neurosurg Pediatr. 2016;18(4):423429.

    • Search Google Scholar
    • Export Citation
  • 11

    Brinker T, Stopa E, Morrison J, Klinge P. A new look at cerebrospinal fluid circulation. Fluids Barriers CNS. 2014;11:10.

  • 12

    Dewan MC, Naftel RP. The global rise of endoscopic third ventriculostomy with choroid plexus cauterization in pediatric hydrocephalus. Pediatr Neurosurg. 2017;52(6):401408.

    • Search Google Scholar
    • Export Citation
  • 13

    Kulkarni AV, Schiff SJ, Mbabazi-Kabachelor E, et al. Endoscopic treatment versus shunting for infant hydrocephalus in Uganda. N Engl J Med. 2017;377(25):24562464.

    • Search Google Scholar
    • Export Citation
  • 14

    Warf BC, Tracy S, Mugamba J. Long-term outcome for endoscopic third ventriculostomy alone or in combination with choroid plexus cauterization for congenital aqueductal stenosis in African infants. J Neurosurg Pediatr. 2012;10(2):108111.

    • Search Google Scholar
    • Export Citation
  • 15

    Stone SS, Warf BC. Combined endoscopic third ventriculostomy and choroid plexus cauterization as primary treatment for infant hydrocephalus: a prospective North American series. J Neurosurg Pediatr. 2014;14(5):439446.

    • Search Google Scholar
    • Export Citation
  • 16

    Weil AG, Westwick H, Wang S, et al. Efficacy and safety of endoscopic third ventriculostomy and choroid plexus cauterization for infantile hydrocephalus: a systematic review and meta-analysis. Childs Nerv Syst. 2016;32(11):21192131.

    • Search Google Scholar
    • Export Citation
  • 17

    Biluts H, Admasu AK. Outcome of endoscopic third ventriculostomy in pediatric patients at Zewditu Memorial Hospital, Ethiopia. World Neurosurg. 2016;92:360365.

    • Search Google Scholar
    • Export Citation
  • 18

    Kulkarni AV, Riva-Cambrin J, Rozzelle CJ, et al. Endoscopic third ventriculostomy and choroid plexus cauterization in infant hydrocephalus: a prospective study by the Hydrocephalus Clinical Research Network. J Neurosurg Pediatr. 2018;21(3):214223.

    • Search Google Scholar
    • Export Citation
  • 19

    Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Ann Intern Med. 2009;151(4):264269, W64.

    • Search Google Scholar
    • Export Citation
  • 20

    Slim K, Nini E, Forestier D, et al. Methodological index for non-randomized studies (MINORS): development and validation of a new instrument. ANZ J Surg. 2003;73(9):712716.

    • Search Google Scholar
    • Export Citation
  • 21

    Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ. 2003;327(7414):557560.

  • 22

    Lau J, Ioannidis JP, Terrin N, et al. The case of the misleading funnel plot. BMJ. 2006;333(7568):597600.

  • 23

    Sterne JA, Sutton AJ, Ioannidis JP, et al. Recommendations for examining and interpreting funnel plot asymmetry in meta-analyses of randomised controlled trials. BMJ. 2011;343:d4002.

    • Search Google Scholar
    • Export Citation
  • 24

    Warf BC, Kulkarni AV. Intraoperative assessment of cerebral aqueduct patency and cisternal scarring: impact on success of endoscopic third ventriculostomy in 403 African children. J Neurosurg Pediatr. 2010;5(2):204209.

    • Search Google Scholar
    • Export Citation
  • 25

    Warf BC, Mugamba J, Kulkarni AV. Endoscopic third ventriculostomy in the treatment of childhood hydrocephalus in Uganda: report of a scoring system that predicts success. J Neurosurg Pediatr. 2010;5(2):143148.

    • Search Google Scholar
    • Export Citation
  • 26

    Warf BC. Comparison of endoscopic third ventriculostomy alone and combined with choroid plexus cauterization in infants younger than 1 year of age: a prospective study in 550 African children. J Neurosurg. 2005;103(6)(suppl):475481.

    • Search Google Scholar
    • Export Citation
  • 27

    Warf BC. Congenital idiopathic hydrocephalus of infancy: the results of treatment by endoscopic third ventriculostomy with or without choroid plexus cauterization and suggestions for how it works. Childs Nerv Syst. 2013;29(6):935940.

    • Search Google Scholar
    • Export Citation
  • 28

    Zandian A, Haffner M, Johnson J, et al. Endoscopic third ventriculostomy with/without choroid plexus cauterization for hydrocephalus due to hemorrhage, infection, Dandy-Walker malformation, and neural tube defect: a meta-analysis. Childs Nerv Syst. 2014;30(4):571578.

    • Search Google Scholar
    • Export Citation
  • 29

    Warf BC, Campbell JW. Combined endoscopic third ventriculostomy and choroid plexus cauterization as primary treatment of hydrocephalus for infants with myelomeningocele: long-term results of a prospective intent-to-treat study in 115 East African infants. J Neurosurg Pediatr. 2008;2(5):310316.

    • Search Google Scholar
    • Export Citation

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