Characterization of a multicenter pediatric-hydrocephalus shunt biobank

Pediatric hydrocephalus, a condition caused by altered cerebrospinal fluid (CSF dynamics), affects approximately 1 in 1100 people in the USA [1]. The perturbation of CSF homeostasis can lead to increased ventricular size and compression of vital brain structures [2]. There are a variety of hydrocephalus etiologies. Those most common in pediatrics include congenital central nervous system (CNS) malformations, infection, intraventricular hemorrhage (IVH), genetic defects, trauma, and teratogens [3]. Risk factors associated with pediatric hydrocephalus include birth weight less than 1500 grams, prematurity (gestational age less than or equal to 30 weeks), maternal diabetes, low socioeconomic status, and male sex. Incidence is lower in Asians than other races [4, 5].

Shunting of CSF from the ventricles became the mainstay of treatment for pediatric hydrocephalus in the 1950s, with ventriculoatrial shunts (VAS) being the preferred configuration. Shunts utilizing valves for CSF pressure or flow control soon became the norm. In the 1980s the VAS was superseded by the ventriculoperitoneal shunt (VPS) for hydrocephalus management. In the 1990s endoscopic third ventriculostomy (ETV) became an option to manage some types of obstructive hydrocephalus, obviating the need for fallible shunt hardware [6]. In 2005 and again in 2012, the National Institutes of Health sponsored an expert panel to discuss priorities for hydrocephalus research, this panel concluded both times that current methods of diagnosis, treatment and outcome monitoring need improvement [7, 8]. More recently, the Hydrocephalus Clinical Research Network (HCRN), a consortium of 14 North American Pediatric Hospitals, developed a standardized operating protocol that was shown to reduce rates of post-operative infection associated with shunt procedures [9].

Pediatric CSF shunt systems have a failure rate of up to 85% within 10 years from initial insertion [10, 11]. Annual hospitalizations for hydrocephalus have reached 70,000 per year in the USA. Nearly all patients with hydrocephalus (98%) will experience shunt failure in their lifetime [12]. Pediatric patients experience higher rates of failure, with 40% of shunts failing within 2 years of implantation [13]. The annual cost of pediatric hydrocephalus intervention is approximately $195.5–204.5 million [14] and the overall burden to the healthcare system is between $1.4 and 2.0 billion; over half of these expenses are due to shunt revisions [15].

Tissue obstruction of the proximal (i.e. ventricular) catheter is the main source of failure in VPS systems, accounting for approximately 50% of failures within the pediatric population [16]. The mechanisms underlying this failure are still poorly understood. Sekhar et al. [17] provided the earliest description of the cell types involved in shunt catheter occlusion, and more recent efforts have shown that astrocytes and microglia likely play a central role in this tissue obstruction [18]. The molecular pathways underpinning this phenomenon, which could serve as targets for pharmacologic intervention, are not yet known. Likewise, there is a lack of understanding as to how clinical decision-making influences shunt failure rates. With the new opportunities offered by cheaper sequencing and tissue-clarification, the field stands poised to gain a deeper understanding of the biological processes underlying shunt failure due to obstruction. To facilitate investigation of this question, we created a national biorepository of all failed shunt hardware, following other institutions that have created biobanks for different medical conditions [19, 20]. Centered at Wayne State University (WSU), this shunt biobank and corresponding clinical database has the potential to be a global cohort of explanted central nervous system hardware.

In this paper, the authors set out to detail the biobank and demonstrate how participating centers can benchmark their performance against others. Moreover, by modeling the effects of collected variables on the number of revisions, this paper attempts to build the foundation for prognostic algorithms—something which has been lacking for pediatric hydrocephalus.

This biobank has a broad range of sample types from pediatric hydrocephalus patients with various etiologies; as such, it allows for easy investigation into the prevalence of different etiologies and reasons for failure. As it stands, our bank shows a lower prevalence of hydrocephalus due to brain tumors than previously reported [18]. The prevalence across the various causes of failure was similar to previously reported values [18]. The rate of failure due to suspected infection was similar to historic rates, but not as low as during the HCRN study (5.7%) [9]. This is understandable as sample collection for this study was already underway when that protocol was published, and its implementation would take some time for centers to adopt. Additionally, our study shows a persistence of intraventricular hemorrhage of prematurity as the leading cause of hydrocephalus, despite recent reductions in the rates of IVH [23, 24]. The most common etiology at all centers was post-hemorrhagic hydrocephalus. A final advantage over previous collections is the multicenter design, which will increase the generalizability of future studies and allow for comparisons between centers. The diversity and generalizability of this biobank are unique features that increase its utility to fellow researchers.

Significant differences existed between centers for the primary outcomes of number of revisions and proximal catheter obstructions. Regression showed non-modifiable demographic factors and clinical site to predict revision number. Additionally, hydrocephalus etiology, physician performing the surgery, weight, and age predicted variance in the number of ventricular obstructions. While this is not immediately actionable in a clinical setting, it does provide prognostic information.

The historic measurements of performance, i.e. prior revisions and ventricular obstructions, showed a difference between sites; however, duration of implantation for ventricular catheters did not. Since the latter reflects the most recent surgeries, this implies that the clinical sites are currently performing more similarly than in the past.

No other study has attempted to build a prognostic algorithm for all etiologies of pediatric hydrocephalus. The lack of prior work in this area is likely due to the heterogeneity between patients. The number of samples currently in the bank is not yet sufficient to deal with this heterogeneity, as shown by the R² = 0.319. Since we only modeled the effect of the most commonly studied variables, this insufficiency is evidence that a broad approach will be required to understand these complex relationships. The initial reason why we elected for a broad approach was recent studies showing microglia and astrocytes to compose most of the tissue obstructing proximal catheters and previous collections of failed shunts did not have variables relating to inflammation [18, 25]. By casting a wide net during the retrospective review, this biobank can better serve future studies.

The extensive characterization of revision history is a component of this broad focus, it is our hope that this will allow future studies to characterize the biologic impact of long-term clinical decision making. Moreover, by collecting failed shunt samples longitudinally, we have several patients for whom multiple samples are banked. This will allow for intra-patient comparisons during translational studies. For example, studying how immune responses adapt to repeated introduction of foreign material in the CNS.

We invite readers at other hospitals to join as one of our centers and contribute samples to the biobank. Additionally, we welcome new collaborators to make use of the current biobank.

We have begun our own ex vivo studies using some samples from the biobank to better understand proximal obstruction. As a part of our analysis, we are recording the degree of flow volume transport with a buffered solution column. This, along with cellular imaging, provides a detailed and objective assessment of ventricular obstruction. We have found that physical obstruction is not always present when an operative report lists ventricular obstruction as the suspected cause for removal. This disparity could explain why physician performing the operation was predictive of the number ventricular obstructions. By better understanding the adherent cells, new materials and coatings can be trialed to better repel them.

The major limitation to our current study was our collection rate. The low collection rate leaves room for sampling bias which could have affected the outcomes reported in this study. Specific information such as hydrocephalus etiology or revision history could not be obtained for samples not collected since those patients had not enrolled in the study. Qualitatively, we observed that a high percentage of samples not collected were distal catheters which had fractured and valves which were obstructed. Therefore, Table 4 likely underestimates the true prevalence for these causes. This bias could be explained by the prominence of proximal obstruction in current literature, lending surgeons to more often remember to save proximal catheters. In general, there are two major hurdles for a center in obtaining a high collection rate. The first is working with surgeons to adopt a new research protocol and collect failed shunts. The other issue is timely communication to the research team so that consent can be obtained before the family leaves. This second issue can be a major hurdle due to emergent nature of shunt failure.

There is another factor which could affect collection rates and contribute to unintentional selection bias: shunts that are clinically found to be obstructed, or otherwise have failed, but are adherent to underlying tissue and are abandoned in the patient. In our experience, this represents a very small number of proximal catheters. Ultimately, we defer to clinical judgement and see this as a non-modifiable factor until further advances in catheter material decrease rates of tissue adherence.

In the future, there are two changes which we would like to institute. The first is to use pre-operative imaging to determine when a proximal catheter is in contact with choroid plexus vs a ventricular wall, instead of relying on the operative report. Understanding this correlation may lead to new investigative strategies to mechanisms of shunt obstruction. The second change is to include additional variables related to long-term medications and comorbid conditions. Future uses of the clinical data will take into consideration the finding from this study that clinical site should be controlled for during regression analyses until the underlying cause and effect relationships are better understood; additionally, further work is needed to elucidate why revisions differed between sites.

We have created a biobank for samples from failed shunt systems in pediatric patients with hydrocephalus for which there is a corresponding database with clinical variables. Currently 6 centers are participating; however, only 4 were presented in this paper due to the limited number of samples from 2 newer centers. Among the 4 centers, there were significant differences in patient age and the number of revisions prior to enrollment in our study; however, the mean interval between replacement of ventricular catheters did not vary significantly. Our current model accounted for 31.9% of the variability in the total number of revisions. As our N increases, we will be able to add more variables to our model and hopefully account for a larger amount of variance. The ultimate goal is a prognostic algorithm.