Abstract:

In this Review, Karimy et al. discuss the mechanisms by which inflammation can contribute to the pathogenesis of acquired hydrocephalus and highlight targets for therapeutic intervention. Hydrocephalus is the most common neurosurgical disorder worldwide and is characterized by enlargement of the cerebrospinal fluid (CSF)-filled brain ventricles resulting from failed CSF homeostasis. Since the 1840s, physicians have observed inflammation in the brain and the CSF spaces in both posthaemorrhagic hydrocephalus (PHH) and postinfectious hydrocephalus (PIH). Reparative inflammation is an important protective response that eliminates foreign organisms, damaged cells and physical irritants; however, inappropriately triggered or sustained inflammation can respectively initiate or propagate disease. Recent data have begun to uncover the molecular mechanisms by which inflammation — driven by Toll-like receptor 4-regulated cytokines, immune cells and signalling pathways — contributes to the pathogenesis of hydrocephalus. We propose that therapeutic approaches that target inflammatory mediators in both PHH and PIH could address the multiple drivers of disease, including choroid plexus CSF hypersecretion, ependymal denudation, and damage and scarring of intraventricular and parenchymal (glia–lymphatic) CSF pathways. Here, we review the evidence for a prominent role of inflammation in the pathogenic mechanism of PHH and PIH and highlight promising targets for therapeutic intervention. Focusing research efforts on inflammation could shift our view of hydrocephalus from that of a lifelong neurosurgical disorder to that of a preventable neuroinflammatory condition. Hydrocephalus, that is, the enlargement of brain ventricles associated with failed cerebrospinal fluid (CSF) homeostasis, is the most common neurosurgical disorder and is treated mainly by neurosurgical CSF diversion procedures with high rates of morbidity and failure. Posthaemorrhagic hydrocephalus and postinfectious hydrocephalus are the most common causes of hydrocephalus and are both characterized by inflammation in the brain tissue and CSF space. Recent data have begun to uncover the molecular mechanisms by which inflammation, driven by activation of Toll-like receptor 4, contributes to the pathogenesis of hydrocephalus. Pharmacotherapeutic approaches that target inflammation have the potential to address multiple drivers of posthaemorrhagic hydrocephalus and postinfectious hydrocephalus, including acute hypersecretion of CSF by the choroid plexus epithelium and scarring of CSF drainage pathways.