Hydrocephalus, despite its heterogeneous causes, is ultimately a disease of disordered CSF homeostasis that results in pathological expansion of the cerebral ventricles. Our current understanding of the pathophysiology of hydrocephalus is inadequate but evolving. Over this past century, the majority of hydrocephalus cases has been explained by functional or anatomical obstructions to bulk CSF flow. More recently, hydrodynamic models of hydrocephalus have emphasized the role of abnormal intracranial pulsations in disease pathogenesis. Here, the authors review the molecular mechanisms of CSF secretion by the choroid plexus epithelium, the most efficient and actively secreting epithelium in the human body, and provide experimental and clinical evidence for the role of increased CSF production in hydrocephalus. Although the choroid plexus epithelium might have only an indirect influence on the pathogenesis of many types of pediatric hydrocephalus, the ability to modify CSF secretion with drugs newer than acetazolamide or furosemide would be an invaluable component of future therapies to alleviate permanent shunt dependence. Investigation into the human genetics of developmental hydrocephalus and choroid plexus hyperplasia, and the molecular physiology of the ion channels and transporters responsible for CSF secretion, might yield novel targets that could be exploited for pharmacotherapeutic intervention.
Keywords: AE2 = anion exchanger 2; AQP = aquaporin; BIF = brain interstitial fluid; CA = carbonic anhydrase; CPC = choroid plexus cauterization; CPE = choroid plexus epithelium; CPH = choroid plexus hyperplasia; CPP = choroid plexus papilloma; ETV = endoscopic third ventriculostomy; EVD = external ventricular drain; KCC = K+-Cl− cotransporter; NBCe2 = Na+-HCO3− cotransporter; NCBE = Na+-HCO3− exchanger; NKCC1; NKCC1 = Na+-K+-2Cl− cotransporter; SPAK = Ste20/SPS1-related proline-alanine-rich protein kinase; cerebrospinal fluid; choroid plexus; epithelia; ion transport; pediatric hydrocephalus.