High altitude cerebral edema - its own entity or end-stage acute mountain sickness?

High-altitude cerebral edema (HACE) and acute mountain sickness (AMS) are neuro-pathologies associated with rapid exposure to hypoxia. However, speculation remains regarding the exact etiology of both HACE and AMS and whether or not they share a common mechanistic pathology. This mini-review outlines the basic principles of HACE development, highlighting how edema could develop from 1) a progression from cytotoxic swelling to ionic edema, or 2) permeation of the blood brain barrier (BBB) with or without ionic edema. Thereafter, discussion turns to the available neuroimaging literature in the context of cytotoxic, ionic or vasogenic edema in both HACE and AMS. While HACE is clearly caused by an increase in brain water of ionic and/or vasogenic origin, there is very little evidence that this type of edema is present when AMS develops. However, cerebral vasodilation, increased intracranial blood volume and concomitant intracranial fluid shifts from the extracellular to the intracellular space, as interpreted from changes in diffusion indices within white matter, are observed consistently in persons acutely exposed to hypoxia and with AMS. Therefore, herein we explore the idea that intracellular swelling occurs alongside AMS, and is a critical pre-cursor to extracellular ionic edema formation. We propose that this process produces a subtle modulation of the BBB, which either together with or independent of vasogenic edema provides a transvascular segue from the end-stage of AMS to HACE. Ultimately, this mini-review seeks to shed light on the possible processes underlying HACE pathophysiology, and thus highlight potential avenues for future prevention and treatment.