Glymphatic system in health and disease: a narrative review

The main functional parts of the glymphatic system are perivascular spaces and surrounding astrocytes. Cerebrospinal fluid enters the brain parenchyma from subarachnoid cisterns through perivascular Virchow-Robin spaces and passes into the interstitium through aquaporin channels in astrocytes. Then, cerebrospinal fluid removes metabolic products and mixes with interstitial fluid. Outflow of cerebrospinal fluid with metabolic products from the brain parenchyma occurs in three ways. The first route is periarterial through intermuscular spaces in the middle layer of cerebral arteries. The second route is perivenous. The third route is lymphatic through meningeal or sinus-associated lymphatic vessels. They provide drainage of macromolecules and immunocompetent cells from the brain to the cervical lymph nodes. Gliomas are accompanied by inhibition of normal cerebrospinal fluid outflow pathways, mainly due to additional intracranial tissue, and compensatory cerebrospinal fluid outflow along the spinal cord. Reduced cerebrospinal fluid release with impaired outflow contribute to accumulation of toxic metabolic products, proinflammatory cytokines and chemokines. Transport of antigens to lymph nodes is inhibited that disrupts antitumor immunity. Impaired cerebrospinal fluid circulation also reduces the effectiveness of intracranial drug delivery. One of the mechanisms of pathogenesis of glioma metastasis is based on migration of tumor cells along classical and meningeal lymphatic pathways. Damage to the latter contributes to metastasis.