The term 'papilledema' is used to describe swelling of the optic disc that is thought or known to be associated with increased intracranial pressure (ICP) transmitted to the subarachnoid space (SAS) surrounding the optic nerve (ON). In most cases, the diagnosis of increased ICP is confirmed by lumbar puncture, the results of which are believed to represent the pressure in all of the cerebrospinal fluid (CSF) spaces. Until recently, all CSF spaces were thought to communicate freely and that CSF pressure and composition in one location were the same throughout the central nervous system (CNS) unless there was an acquired structural disturbance. However, the concept of continuous CSF flow and pressure throughout the CNS does not explain why some patients with elevated ICP do not develop papilledema, why some patients have highly asymmetrical papilledema, or why some patients with papilledema have normal ICP during 24-hour monitoring. In addition, CSF sampling during lumbar puncture and during ON sheath fenestration demonstrates an increased concentration of lipocalin-like prostaglandin D synthase, a substance toxic to astrocytes, in the SAS of the ON compared with that in the lumbar CSF space, and also a difference in CSF dynamics between the lumbar and ON SAS in some patients with papilledema. We therefore suggest that papilledema does not result from raised ICP alone but in some cases by compartmentation of the SAS of the ON, leading to a toxic milieu around the nerve.