Background: Choroid plexectomy was first performed around 1910. Later, the technique evolved into subtotal choroid plexus cauterization (CPC) but was largely abandoned following the invention of the ventriculoperitoneal shunt. Over time, with improved understanding of the pathophysiology of hydrocephalus and improvement in endoscopic techniques and equipment, the procedure of CPC was reintroduced. However, little is known about the biomolecular consequences of ablation of a significant portion of the choroid plexus on metabolic brain homeostasis, neurogenesis, and neuroimmunology. Summary: The physiological functions of choroid plexus in neurogenesis and neuroimmunology and its role in diseases, such as AD and MS, should alert to possible as yet to be determined consequences. Studies, both in children and in adults, are needed not only on the success in hydrodynamic stabilization of hydrocephalus but also on the long-term outcome, especially premature neurodegeneration and inflammatory changes and on compensatory metabolic mechanisms. Key Messages: The value of CPC for treatment of hydrocephalus in medically underserved areas should be remembered, yet when alternative treatment options are available, we cannot responsibly advocate against or for the use of CPC. Therefore, perhaps a more detailed discussion of risks and benefits of a CPC with parents would be best to include the possible implications in brain development and function.

Choroid plexectomy was first performed around 1910 [1]. Initially the choroid plexus (CP) of one lateral ventricle was removed through open surgery, and then, the technique evolved into endoscopic cauterization [2]. It was largely abandoned following the invention of the ventriculoperitoneal (VP) shunt in the 1950’s, which at that time was associated with less morbidity and mortality [3]. Over time, with improved understanding of the pathophysiology of hydrocephalus and improvement in endoscopic techniques and equipment, the procedure of CP cauterization (CPC) was reintroduced [4-6]. It became an important tool for care of older children and adults with communicating hydrocephalus in order to avoid the effects of chronic shunt dependence including shunt revisions and life-threatening risk of shunt malfunction.

In 2005, Warf [7] published his seminal study on the use of endoscopic third ventriculostomy combined with CPC (ETV-CPC) for treatment of hydrocephalus in infants in African children, leading to a resurgence in the use of this technique. Following the publication of the original manuscript, there was expansion in the criteria for patients selected for this procedure to include intraventricular hemorrhage of prematurity [8, 9], Dandy-Walker syndrome, congenital communicating hydrocephalus [7], and encephaloceles [10]. These initial studies ultimately led to a prospective cohort study by the Hydrocephalus Clinical Research Network to independently identify patient selection, operative technique, and surgical training predictors of ETV-CPC success in infants with hydrocephalus [11]. Currently, the Hydrocephalus Clinical Research Network is conducting a multicenter randomized controlled trial in North America comparing ETV-CPC with VP shunt for infantile hydrocephalus (ClinicalTrials.gov Identifier NCT04177914). It replicates the randomized trial performed in Uganda, which evaluated ETV-CPC compared to VP shunting in infants with postinfectious hydrocephalus, published in 2017 [12].

Notwithstanding advances in surgical technology and treatment of hydrocephalus, little is known about the biomolecular consequences of ablation of a significant portion of the CP on metabolic brain homeostasis, neurogenesis, and immunology. We would thus like to reflect upon the role of CP in normal physiology and in disease. While the intent of this brief report is not an encyclopedic review of the blossoming interest and new information on the role of the CP in processes other than secretion of cerebrospinal fluid (CSF), it is important to mention but a few of the important roles as they are known at this time.

The CP is embedded in the metabolic circuit being regulated by nervous and endocrine mechanisms and serving as a source of outgoing signals to the brain. These processes are of importance during embryogenesis during which the CP is involved in a molecular cascade including IGF-2, prolactin, and transthyretin [13]. Other CP secreted molecules include growth factors and axonal guidance molecules such as IGF-2, which was shown to contribute to the development the cortex in murine models [14]. Moreover, a study in chicken embryos showed that there are neural progenitor cells within the CP [15].

However, the role of the CP does not end early in brain development. Recent studies have looked into the complexity of the regulation of neuronal stem cells in brain development and adult neurogenesis in which regulation by molecules secreted by the CP plays a critical role [16, 17]. In particular, the cell population in the subventricular zone (SVZ) is subject to modulation by CP born molecules [18]. Neuronal stem cells in the adult SVZ give rise to progenitor cells that migrate through the rostral migratory stream to reach the olfactory bulb where they differentiate into neurons. This process is partially regulated by factors secreted by the vasculature, neurons and by the CP into the spinal fluid [19, 20]. Recently, OTX2 homeoprotein transcription factor secreted by CP into the CSF was found to be one of the factors that influence neurogenesis in adult mice by impacting migratory neuroblast streams in the SVZ [21].

The CP also has neuroimmonological functions. It represents the entrance site of lymphocytes to the CSF and is also embedded in the glial-lymphatic pathway, in which CSF clears solutes from the brain along the arteriovenous gradient utilizing aquaporin 4 water channels [22].

It is estimated that 70–80% of the CSF is produced by the CP [23, 24]. However the hydrodynamics of CSF has recently been reevaluated, demonstrating that the distribution and production of CSF are mainly regulated by the osmotic pressure changes in the central nervous system microvessels [25]. The epithelial cells of the microvasculature of the CP, similar to the endothelial cells of the blood-brain barrier, transport inflammatory cells, electrolytes (especially sodium), and important nutrients for supporting brain function, including glucose, amino acids, folate, and ascorbate [16, 26, 27]. CP is also involved in the homeostasis of metals such as iron, copper, and magnesium. This is possible due to the presence of transporters, channels, and receptors [16].

Specific features of CP functions have been studied in selected pathology, most of all in Alzheimer’s disease (AD). During aging, the CP changes with decreased CSF production as well as structural degeneration. There is significant atrophy and thickening of the basement membrane and decreased metabolism, namely, synthetic capacity and regulation of receptors and transporters [16, 28]. That CP may play a role in the pathophysiology of AD is evidenced by the increased accumulation of amyloid-β peptide (ABP) in its stroma, as found in postmortem examinations [28]. While this finding is not direct evidence of a causal relationship, CP is crucial for ABP clearance involving ABP transporters, transthyretin, clusterin, and IGF-1 [28]. ABP accumulation in turn is thought to compromise the blood CSF barrier integrity, impairing the CP clearance capacity of other metabolites and toxins, leading to further neurodegeneration [16, 29]. Expression of genes involved in CSF production were also found to differ in healthy CP and CP of AD patients [29]. In a murine model of AD, implants of CP diminished ABP levels with consequent reduction of neurotoxicity accompanied by a behavior recovery [30].

Given the immune function of the CP, it is also being investigated in inflammatory diseases of the central nervous system. In multiple sclerosis (MS) and in mice with experimental autoimmune encephalitis, an MS animal model, it was suggested that the CP controls brain immune surveillance, especially the passage of immune cells from the blood through the CP into the CSF [28, 31-33].

Xiang et al. [34] discuss the CP as a site of injury during ischemic and hemorrhagic stroke as well as its contribution to the neuroprotective response after the injury. They proposed that there may be an increased secretion of CP born CSF molecules involved in neurogenesis and inflammation. Remarkably, Egorova and colleagues [35] found that there is an increase in volume of the CP on the MRI of patients with ischemic stroke, and Borlogan et al. [36] found that transplantation of CP in rodents with acute stroke had neuroprotective effects.

Following interventricular bleeding or infection, mediators such as Toll-like receptor 4-regulated cytokines might be involved in hypersecretion of CSF by the CP and changes in the glial-lymphatic pathway, thereby causing hydrocephalus [37]. Furthermore, the CP-CSF system could potentially be relevant for drug delivery strategies to improve penetration through the blood-brain barrier, for example, in the context of neonatal and pediatric pharmacology [38].

In view of the many drawbacks of CSF diversion procedures, the motivation to improve treatment of hydrocephalus is comprehensible. However, when considering CPC as an option, we must express some caution to possible deleterious effects.

The physiological functions of CP in neurogenesis and neuroimmunology and its role in diseases, such as AD and MS, should alert to possible as yet to be determined consequences. In ETV-CPC, the CP is only partially reduced and spares the plexus in the 3rd and 4th ventricle; hence, some of the filtering effects may still be present [7, 12]. However, the coagulated CP in the lateral ventricles is in proximity to the SVZ and therefore might influence neurodevelopmental functions.

Yet, no long-term concerns were reported by Pople and Ettles [6] in their 20-year experience of CPC in 104 children and later in 20-year experience of ETV-CPC in infants in the sub-Saharan populations [7, 11, 12]. In particular, in the randomized controlled trial of shunt placement versus ETV-CPC in 100 infants less than 6 months of age, there was no difference in brain growth or developmental outcome within 2 years [12]. Moreover, independent of whether ETV-CPC or VP shunting was performed, brain growth stagnated between the first and second year after surgery in infants with postinfectious hydrocephalus [39]. The comparable pattern of brain growth lead to the assumption that brain growth was related to the primary brain injury associated to the underlying etiology of hydrocephalus rather than hydrocephalus itself or the type of its surgical treatment [39]. These observations suggest that CPC does not have a negative impact on brain growth and development in the first 2 years of life, the period of most rapid brain development, and support the safety of the procedure.

Notwithstanding the fact that there was no increased risk of shunt infection in patients who had failed ETV-CPC with subsequent VP shunt placement compared to those with primary VP shunt placement [40], other neuroimmunological effects were not ruled out. Lim et al. [41] also remind, depending on the etiology of hydrocephalus, of the better cost-effectiveness in particular of ETV but also of ETV-CPC in the treatment of pediatric hydrocephalus compared to VP shunts.

A meta-analysis of Ellenbogen et al. [42] did not find increased efficiency of combined ETV-CPC compared to sole ETV in the treatment for pediatric hydrocephalus, which supports the need for further investigations. Clinical studies on the outcome of ETV-CPC emphasize the requirement of secondary CSF diversion and not the potential impact on the CP physiology [12, 40, 42]. Thus, studies, both in children and in adults, are needed not only on the success in hydrodynamic stabilization of hydrocephalus but also on the long-term outcome, especially premature neurodegeneration and inflammatory changes and on compensatory metabolic mechanisms.

When debating on the current trend to reintroduce ETV-CPC, its value for treatment of hydrocephalus in medically underserved areas should be remembered. Yet, when alternative treatment options are available, we cannot responsibly advocate against or for the use of CPC. Therefore, perhaps, a more detailed discussion of risks and benefits of a ETV-CPC with parents would be best to include the possible implications in brain development and function.

This literature review is based exclusively on published literature.

The authors have no conflicts of interest to declare.

Thanks goes to the Philhuman Foundation, Vaduz, Liechtenstein, for their generous financial support.

Sarah Stricker, Raphael Guzman, Thomas Blauwblomme, and Moise Danielpour all contributed to the outline and writing of the text.

All data that support the findings of this study are included in this review article. Further inquiries can be directed to the corresponding author.

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