Endoscopic third ventriculostomy (ETV) with the added use of choroid plexus cauterization (CPC) has been shown to have promising results in the treatment of hydrocephalus in Africa.^10,13,14 Based on retrospective work conducted by our group and others in North America, ETV+CPC appears to be a safe procedure but with varying degrees of treatment success.^1,7,12 It is still not firmly established which infants will benefit most from ETV+CPC and in whom it represents a reasonable alternative to the traditional CSF shunt. Here, we present the results of a prospective study within the Hydrocephalus Clinical Research Network (HCRN; Appendix 1) to describe the success and complications of ETV+CPC in infants and to compare results to a historical cohort of infants treated with either shunt placement or ETV alone. Uniquely, in the current multicenter prospective study, we applied a predefined consensus definition for infants with hydrocephalus who were eligible for ETV+CPC, as well as a strict definition for treatment failure.

Methods

The study population consisted of infants (corrected age ≤ 24 months) receiving treatment at 1 of 9 HCRN centers who required treatment for new-onset hydrocephalus, or failure of a previous CSF shunt, with anatomy suitable for ETV+CPC on preoperative MRI and life expectancy greater than 12 months. Suitable anatomy was defined as < 3-mm-thick third ventricle floor, ventriculomegaly sufficient to allow safe passage of an endoscope, and the absence of marked prepontine subarachnoid adhesions on constructive interference in steady state (CISS)/fast imaging employing state-steady acquisition (FIESTA) MRI. We developed the following consensus clinical eligibility criteria for treatment: 1) presence of clear ventriculomegaly with a frontal and occipital horn ratio (FOHR)^4,11 > 0.45 and 2) at least one of the following: head circumference > 98th percentile for the patient’s corrected age, bulging fontanelle, splayed sutures, upgaze paresis or palsy (i.e., sundowning), CSF leak, papilledema, tense pseudomeningocele or tense fluid tracking along a shunt, vomiting or irritability with no other attributable cause, bradycardias or apneas with no other attributable cause, or intracranial pressure monitoring showing persistent elevation of pressure with or without plateau waves. While surgeons followed these criteria to determine patient eligibility, exceptions could be made to include other patients at the surgeon’s discretion, and this was monitored. Study consent for data collection was obtained from parents when required by the local institutional review board or research ethics board. Patient recruitment began in some centers as early as June 2014, with staggered entry of all 9 centers by October 2014.

The historical cohort consisted of similar patients (corrected age < 24 months) who were treated at the same 9 participating HCRN centers with either a shunt or ETV alone. All patients in the historical cohort had been treated before January 1, 2013. This was before ETV+CPC became popular within the HCRN, thus allowing us to identify a patient group with characteristics as similar as possible to those who would later undergo ETV+CPC. These data were obtained from the existing HCRN Core Data Project, in which data are collected prospectively, and, for this analysis, analyzed retrospectively. For these analyses, only patients who were undergoing the first permanent treatment of hydrocephalus were included.

Intervention

The details of the ETV+CPC procedure are now widely known, practiced within the HCRN, and include the following steps: unilateral coronal entry site, fenestration of the floor of third ventricle, and attempting complete CPC of both lateral ventricles with septum pellucidotomy when needed. Although most surgeons used the flexible endoscope exclusively, a few surgeons used a rigid endoscope but almost always in combination with the flexible endoscope. Insertion of a reservoir or external ventricular drain and the use of postoperative CSF drainage (e.g., external ventricular drain, lumbar puncture) was performed at the surgeon’s discretion. Detailed intraoperative data were collected at the time of surgery from the operating surgeon, including 3 different means of estimating the degree of CPC: the surgeon’s estimate of CPC percentage, category of CPC percentage (0%, < 40%, 40%–60%, 60%–90%, and ≥ 90%), and a diagrammatic representation of the amount of CPC (surgeons completed a diagram to indicate how many of the 14 sectors of the choroid plexus they successfully cauterized; the number of sectors cauterized was divided by the number of sectors in which choroid plexus was present to obtain a percentage estimate of CPC) (Fig. 1).

Diagrammatic representation of the amount of CPC performed. Each of the 7 areas is meant to represent a different sector of the choroid plexus in each lateral ventricle. For each sector, the surgeon indicates if the choroid plexus in that sector was cauterized (Ct), not cauterized (NotCt), or absent (Abs). The percentage of CPC is calculated as the percentage of sectors marked Ct divided by the total number of sectors with choroid plexus.

Results

A total of 118 infants were enrolled at the 9 HCRN centers between June 2014 and September 2015. Their baseline characteristics are shown in Table 1. Of these 118 infants, 113 (96.0%) met the consensus clinical eligibility criteria for treatment. The details of the ETV+CPC procedure are shown in Table 2, and postoperative complications are shown in Table 3. The median duration of surgery was 105 minutes. The most common postoperative complication was seizure in 6 patients (5.1%). Of these 6 infants, 5 had a corrected age of less than 1 month, 5 had bleeding during surgery (4 mild and 1 severe), and the duration of surgery ranged from 61 to 141 minutes (median 99.5 minutes). Their etiologies were myelomeningocele in 3 infants and IVH of prematurity, aqueductal stenosis, and another complication in 1 infant each.

A total of 76 patients (64.4%) met the primary outcome of treatment failure. The median survival after ETV+CPC was 90 days. Among those patients with failed treatment, the median time to failure was 48 days. The modes of failure are listed in Table 4. The Kaplan-Meier survival curve for time to treatment failure is shown in Fig. 2. Overall, the 6-month success rate was 36%.

Kaplan-Meier survival curve for the time to treatment failure for the prospective ETV+CPC cohort (n = 118), with time since surgery on the horizontal axis and survival probability on the vertical axis.

Comparison with the Historical HCRN Cohort

The historical cohort consisted of 969 infants with shunts and 74 infants with ETV alone. Using the matching algorithm, 112 ETV+CPC and shunt-matched pairs and 34 ETV+CPC and ETV alone–matched pairs were identified. The characteristics of these matched pairs are shown in Table 6. Kaplan-Meier survival curves comparing the matched cohorts are shown in Fig. 3. ETV+CPC had a shorter time to failure compared with shunts (p < 0.001) but not when compared with ETV alone (p = 0.73) using the log-rank test. The robustness of these findings was confirmed using the log-rank test and stratified by age and etiology for the entire cohort rather than restricted to the matched pairs. Both approaches produced similar results.

TABLE 6.

Distribution of matched pairs for ETV+CPC with shunt or ETV alone

Etiology & Corrected Age Group	No. of Patients (%)
	ETV+CPC & Shunt	ETV+CPC & ETV Alone
No. of pairs	112	34
IVH of prematurity	25 (22.3)	3 (8.8)
<1 mo	16 (14.3)	1 (2.9)
1–6 mos	7 (6.3)	1 (2.9)
6–12 mos	1 (0.9)	0 (0)
12–24 mos	1 (0.9)	1 (2.9)
Myelomeningocele	36 (32.1)	0 (0)
<1 mo	21 (18.8)	0 (0)
1–6 mos	12 (10.7)	0 (0)
6–12 mos	3 (2.7)	0 (0)
12–24 mos	0 (0)	0 (0)
Aqueductal stenosis	25 (22.3)	10 (29.4)
<1 mo	11 (9.8)	1 (2.9)
1–6 mos	10 (8.9)	5 (14.7)
6–12 mos	2 (1.8)	2 (5.9)
12–24 mos	2 (1.8)	2 (5.9)
Other etiology	26 (23.2)	21 (61.8)
<1 mo	9 (8.0)	4 (11.8)
1–6 mos	7 (6.3)	7 (20.6)
6–12 mos	5 (4.5)	5 (14.7)
12–24 mos	5 (4.5)	5 (14.7)

Kaplan-Meier survival curves comparing matched cohorts, with time since surgery on the horizontal axis and survival probability on the vertical axis. Upper: ETV+CPC and shunting (n = 112 pairs). Lower: ETV+CPC and ETV alone (n = 34 pairs).

Discussion

Our multicenter prospective study of ETV+CPC has shown that this procedure can be carried out quite safely, with low rates of intraoperative complications and with a high degree of success in obtaining a substantial amount of CPC. We also confirmed that established predictors of ETV+CPC success include older age, greater degree of CPC,^7,14 and smaller ventricle size, which has not been consistently reported before. We also found the diagrammatic method of estimating the amount of CPC performed was valuable and could provide a standardized measuring tool in future studies.

Although our overall complication rates were low and would generally be considered acceptable, the rate of postoperative seizures was rather high (5.1%). In long-term studies of mostly shunt-treated children with hydrocephalus, the prevalence of seizures (at least 1 per year) is nearly 15%.^3,9 Regardless, the 5.1% incidence of early postoperative seizures is worrisome and could be related to the overall extent of surgical manipulation required by the CPC component of the surgery or perhaps to the amount of irrigation required during a prolonged operation, thereby making the infant brain more susceptible to seizures. It is perhaps notable that most of the 6 children who had postoperative seizures were very young (corrected age less than 1 month) and had some evidence of bleeding during the procedure. Long-term follow-up will be necessary to see the extent to which seizures persist in these children. This is a particularly concerning complication because previous work on hydrocephalus has shown that one of the most consistent predictors of poor quality of life is the presence of epilepsy.^3,9

Larger preoperative ventricle size as a predictor of ETV+CPC failure has not been widely reported before. Although this finding will need corroboration in future studies, it can be interpreted in at least one of 2 ways. On one hand, it might suggest that we are treating some patients too late to truly achieve the maximum benefit of ETV+CPC. Alternatively, it could be interpreted that some patients with smaller ventricles are being overtreated and might not have needed the procedure at all. This is a particular concern with endoscopic procedures for which there can be an insidious lowering of the threshold for treatment compared with shunt placement, i.e., surgeons and families might be more willing to consider treatment with ETV+CPC in a questionably symptomatic child, whereas they would not agree to place a shunt in the same situation. We tried to mitigate this latter point by having standardized consensus clinical eligibility criteria that included a minimum degree of symptomatology and signs and at least moderate ventriculomegaly (FOHR > 0.45) to convince us that these patients were truly in need of CSF diversion. These criteria were met by 96% of our cohort.

Direct comparisons between ETV+CPC, shunting, and ETV alone in North American settings are greatly lacking. We used a matched historical control group to provide some estimate of the relative success rates of these procedures. Our matched comparison with shunting, which included 112 matched pairs, reconfirms that on average the failure rate of ETV+CPC is higher than shunting in the early postoperative phase (< 6 months). We would expect, however, that the failure curve for ETV+CPC will level off (if it is analogous to what we know about ETV),⁵ while the curve for shunting will continue to deteriorate; this will need a longer follow-up period to confirm. Despite the emerging evidence of the superiority of shunting in achieving, at least, short-term treatment success, it is our anecdotal experience that some families still prefer to attempt ETV+CPC over shunting as the initial surgical treatment for their child. This suggests that some families see inherent benefit in being shunt free and are willing to undergo a riskier surgery with a lower chance of success for the possibility of achieving this shunt freedom. This has implications about how we, as surgeons, present the treatment options to families.

Our matched comparison with ETV alone is very limited, however, because the number of patients is very small and the matched cohort consisted mostly of patients with aqueductal stenosis and other etiologies. We could only match ETV+CPC patients to those infants whom surgeons had previously and specifically selected for ETV alone. The latter is, presumably, a highly select group. As such, the matched cohort is not at all representative of a typical population of infants with hydrocephalus and, in particular, grossly underrepresents the patients most likely to benefit from CPC: infants with myelomeningocele and IVH of prematurity. These infants were virtually never offered ETV alone (e.g., there were only 3 such patients in the matched cohort). As well, given the fact that the greater extent of CPC was a predictor of ETV+CPC success, at least some infants do seem to benefit from the addition of CPC. Regardless, it does beg the question of whether there are subsets of infants who might, in fact, have little to gain from the addition of CPC to ETV. As an example, the recent prospective International Infant Hydrocephalus Study reported a very high success rate for ETV alone in infants with pure aqueductal stenosis (66% success rate at 1 year), especially in those older than 6 months (80% success rate at 1 year).⁸ ETV alone might be sufficient for such a subgroup.

Conclusions

In a large, broad cohort of North American infants, our data show that overall ETV+CPC appears to have a higher failure rate than shunting. Although the ETV+CPC results were similar to ETV alone, this comparison was limited by the small sample size and skewed etiological distribution. Within the ETV+CPC group, a greater extent of CPC was associated with treatment success, thereby suggesting that there are subgroups who benefit from the addition of CPC. Further work will focus on identifying these subgroups.

Appendix 1

Appendix 2

Acknowledgments

The Hydrocephalus Clinical Research Network has been funded by the National Institute of Neurological Disorders and Stroke (grant no. 1RC1NS068943-01), the Patient Centered Outcome Research Institute (grant no. CER-1403-13857), The Gerber Foundation (reference no. 1692-3638), private philanthropy, and the Hydrocephalus Association. None of the sponsors participated in the design and conduct of this study; collection, management, analysis, and interpretation of the data; or preparation, review, or approval of this manuscript. Its contents are solely the responsibility of the authors and do not necessarily represent the official view of the sponsors.

We thank our colleagues who kindly agreed to participate in this HCRN project and allowed the collection of patient data for the purposes of this publication: D. Brockmeyer, M. Walker, R. Bollo, J. Blount, J. Johnston, B. Rocque, L. Ackacpo-Satchivi, P. Dirks, J. Rutka, M. Taylor, D. Curry, R. Dauser, A. Jea, S. Lam, R. Ellenbogen, J. Ojemann, A. Lee, A. Avellino, I. Pollack, S. Greene, E. Tyler-Kabara, T. S. Park, J. Leonard, M. Smyth, N. Tulipan, A. Singhal, P. Steinbok, W. Hader, C. Gallagher, M. Benour, E. Kiehna, J. G. McComb, A. Robson, M. Handler, B. O’Neill, C. Wilkinson, L. Governale, J. Leonard, and E. Sribnick. In addition, this work would not have been possible without the outstanding support of the dedicated personnel at each clinical site and the data coordinating center. Special thanks go to J. Clawson, N. Tattersall, T. Bach (Salt Lake City); A. Arynchyna, A. Bey (Birmingham); H. Ashrafpour, L. O’Connor, (Toronto); S. Martinez, S. Ryan (Houston); A. Anderson, G. Bowen (Seattle); K. Diamond, A. Luther (Pittsburgh), D. Morales, D. Berger, D. Mercer (St. Louis); S. Gannon (Nashville); A. Cheong, R. Hengel (British Columbia); and M. Langley, V. Wall, N. Nunn, V. Freimann, and B. Miller (Utah Data Coordinating Center).

Disclosures

Dr. Limbrick: receives non–study-related clinical or research support from Medtronic, Inc., Karl Stortz, Inc., and Microbot Medical, Inc.

Author Contributions

Conception and design: Kulkarni, Riva-Cambrin, Holubkov, Whitehead, Kestle. Acquisition of data: Kulkarni, Riva-Cambrin, Rozzelle, Naftel, Browd, Limbrick, Tamber, Wellons, Kestle. Analysis and interpretation of data: Kulkarni, Riva-Cambrin, Rozzelle, Naftel, Kestle. Drafting the article: Kulkarni, Riva-Cambrin, Kestle. Critically revising the article: Kulkarni, Riva-Cambrin, Naftel, Alvey, Reeder, Holubkov, Cochrane, Limbrick, Simon, Tamber, Wellons, Whitehead, Kestle. Reviewed submitted version of manuscript: all authors. Approved the final version of the manuscript on behalf of all authors: Kulkarni. Statistical analysis: Kulkarni, Alvey, Reeder, Holubkov. Study supervision: Kulkarni.