Bulat-Klarica-Oreskovic Hypothesis: A Comprehensive Review

Classical theories of cerebrospinal fluid (CSF) production and flow are taught throughout medical education. The idea that CSF is produced and/or filtered by the choroid plexus and flows in one direction throughout the ventricular system has been a largely accepted thesis. However, modern studies have called into question the validity of this hypothesis, suggesting that CSF does not move unidirectionally but rather is driven by microvessel contractions in a to-and-fro manner throughout the cerebrospinal system. Moreover, new insights suggest that in addition to CSF production, the exchange of fluids and proteins between the cortical vasculature and the interstitium may function as the brain's version of a lymphatic system. This comprehensive review provides evidence for a different framework of CSF flow. One that includes perivascular pulsations that push CSF back and forth, allowing exchange between the CSF and interstitium, and with CSF production occurring throughout the cerebrospinal system. These findings could be revolutionary in understanding the pathophysiology of CSF flow and in the treatment of pathologies such as intracranial hypertension, hydrocephalus, Alzheimer's disease, and many others.