Abstract
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.
Highlights
This review summarizes critical issues pertaining to the origin and mechanisms of the neuropathophysiology of highaltitude cerebral edema (HACE) and whether it is the end stage of the less severe condition, acute mountain sickness (AMS)
Despite excellent research efforts to better define and clinically assess these neurological syndromes [1, 2], research involving both human participants and animal models have failed to clearly identify the exact etiology of all three syndromes or if specific physiological processes associated with AMS precede a more severe HACE diagnosis
This controversy likely arises from the subjective reporting of clinical symptoms, the complexity surrounding the measurement and quantification of cerebral pathophysiology, and contradictory clinical observations in persons with HACE [3,4,5]
Summary
This review summarizes critical issues pertaining to the origin and mechanisms of the neuropathophysiology of highaltitude cerebral edema (HACE) and whether it is the end stage of the less severe condition, acute mountain sickness (AMS). In a limited number of individuals, the newly established osmotic pressure gradient across the BBB (Na þ , K þ , and/or ClÀ movement into the cells), plus a later activation of alternative secondary cotransporters due to initial cellular energy depletion [92], is proposed to draw water into the brain forming extracellular ionic edema This subtle mechanistic development, in addition to further membrane destabilization and breakdown of the BBB mediated by hydrostatic or inflammatory processes, could further compromise the intracranial compartment leading to vasogenic edema and severe HACE symptomology (Fig. 3). An increase in intracellular or extracellular fluid may buffer excess neurotransmitters or false neurotransmitters, protecting neurons from tonic activation
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
