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

J Appl Physiol (1985). 2021 Jul 1;131(1):313-325. doi: 10.1152/japplphysiol.00861.2019. Epub 2021 Apr 15.


High-altitude cerebral edema (HACE) and acute mountain sickness (AMS) are neuropathologies associated with rapid exposure to hypoxia. However, speculation remains regarding the exact etiology of both HACE and AMS and whether they share a common mechanistic pathology. This 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. Although 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 precursor 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 review seeks to shed light on the possible processes underlying HACE pathophysiology, and thus highlights potential avenues for future prevention and treatment.

Keywords: acute mountain sickness; gliovascular homeostasis; high-altitude cerebral edema; interstitial edema; magnetic resonance imaging.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Altitude
  • Altitude Sickness*
  • Blood-Brain Barrier
  • Brain
  • Brain Edema* / etiology
  • Humans