Hydrocephalus: historical analysis and considerations for treatment

Abstract

Hydrocephalus is a serious condition that affects patients of all ages, resulting from a multitude of causes. While the etiologies of hydrocephalus are numerous, many of the acute and chronic symptoms of the condition are shared. These symptoms include disorientation and pain (headaches), cognitive and developmental changes, vision and sleep disturbances, and gait abnormalities. This collective group of symptoms combined with the effectiveness of CSF diversion as a surgical intervention for many types of the condition suggest that the various etiologies may share common cellular and molecular dysfunctions. The incidence rate of pediatric hydrocephalus is approximately 0.1-0.6% of live births, making it as common as Down syndrome in infants. Diagnosis and treatment of various forms of adult hydrocephalus remain understudied and underreported. Surgical interventions to treat hydrocephalus, though lifesaving, have a high incidence of failure. Previously tested pharmacotherapies for the treatment of hydrocephalus have resulted in net zero or negative outcomes for patients potentially due to the lack of understanding of the cellular and molecular mechanisms that contribute to the development of hydrocephalus. Very few well-validated drug targets have been proposed for therapy; most of these have been within the last 5 years. Within the last 50 years, there have been only incremental improvements in surgical treatments for hydrocephalus, and there has been little progress made towards prevention or cure. This demonstrates the need to develop nonsurgical interventions for the treatment of hydrocephalus regardless of etiology. The development of new treatment paradigms relies heavily on investment in researching the common molecular mechanisms that contribute to all of the forms of hydrocephalus, and requires the concerted support of patient advocacy organizations, government- and private-funded research, biotechnology and pharmaceutical companies, the medical device industry, and the vast network of healthcare professionals.

Keywords: Cerebrospinal fluid; Drug development; Hydrocephalus; Mechanisms; Pathophysiology; Preclinical research.

Fig. 1

Pathophysiology of hydrocephalus and emerging therapeutic mechanisms. CSF cerebrospinal fluid; SVZ  subventricular zone; AQP4  aquaporin 4. Figure created in BioRender

Fig. 2

Convergent intracellular signaling in inflammation-related hydrocephalus pathophysiology. Epo erythropoietin, PI3K phosphoinositide 3-kinase, AKT Ak strain transforming kinase / protein kinase B, SGK1 serum- and glucocorticoid-induced kinase 1, WNK with no lysine kinase, TRPV4 transient receptor potential vanilloid 4, NKCC1 sodium potassium 2-chloride cotransporter, NF-kB nuclear factor kappa-light-chain-enhancer of activated B cells, SPAK SPS1-related proline/alanine-rich kinase, TLR4 toll-like receptor 4, TAK1 transforming growth factor beta-activated kinase 1, TGF-β transforming growth factor beta. Figure created in BioRender

Fig. 3

Proposed mechanism of action of preclinical targets. CSF cerebrospinal fluid, SPAK SPS1-related proline/alanine-rich kinase, TLR4 toll-like receptor 4, TRPV4 transient receptor potential vanilloid 4, NKCC1 sodium potassium 2-chloride cotransporter 1. Figure created in BioRender

Fig. 4

Summary of targets in preclinical stages. *Diamox indicates Diamox treatment for iNPH. TRPV4 transient receptor potential vanilloid 4, NKCC1 sodium potassium 2-chloride cotransporter, SPAK SPS1-related proline/alanine-rich kinase, TLR4 toll-like receptor 4, POC proof-of-concept, POM proof-of-mechanism. Figure created in BioRender