Magnetic Resonance Imaging Evidence of Cytotoxic Cerebral Edema in Acute Mountain Sickness

Abstract

The present study applied T2- and diffusion-weighted magnetic resonance imaging to examine if mild cerebral edema and subsequent brain swelling are implicated in the pathophysiology of acute mountain sickness (AMS). Twenty-two subjects were examined in normoxia (21% O2), after 16 hours passive exposure to normobaric hypoxia (12% O2) corresponding to a simulated altitude of 4,500 m and after 6 hours recovery in normoxia. Clinical AMS was diagnosed in 50% of subjects during hypoxia and corresponding headache scores were markedly elevated (P<0.05 versus non-AMS). Hypoxia was associated with a mild increase in brain volume (+7.0+/-4.8 ml, P<0.05 versus pre-exposure baseline) that resolved during normoxic recovery. Hypoxia was also associated with an increased T2 relaxation time (T2rt) and a general trend toward an increased apparent diffusion coefficient (ADC). During the normoxic recovery, brain volume and T2rt recovered to pre-exposure baseline values, whereas a more marked reduction in ADC in the splenium of the corpus callosum (SCC) was observed (P<0.05). While changes in brain volume and T2rt were not selectively different in AMS, ADC values were consistently lower (P<0.05 versus non-AMS) and associated with the severity of neurologic symptoms. Acute mountain sickness was also characterized by an increased brain to intracranial volume ratio (P<0.05 versus non-AMS). These findings indicate that mild extracellular vasogenic edema contributes to the generalized brain swelling observed at high altitude, independent of AMS. In contrast, intracellular cytotoxic edema combined with an anatomic predisposition to a 'tight-fit' brain may prove of pathophysiologic significance, although the increase in brain volume in hypoxia was only about 0.5% of total brain volume.

Acute high-altitude sickness

“…Laboratory investigations of the brain in AMS show that all subjects exposed to altitudes of 4500 m had normal lumbar cerebrospinal fluid pressure and a small increase of brain volume assessed using MRI (<1%, ∼7-10 mL) after 16 h, independent of presence or absence of AMS [14]. The volume increase can partly be attributed to increased blood volume and partly to cell swelling [14,15]. A recent study demonstrated swelling of white matter correlating with AMS scores after 22 h [16].…”

“…However, in AMS, lumbar punctures reveal an intact blood-brain barrier for large molecular weight proteins [38]. Furthermore, there are no significant associations of peripheral oedema [39], slight increase in brain volume [14], albuminuria [40] and leakage of fluorescent dye from retinal vessels [41] with AMS. Thus, the slight tissue swelling in the body in hypoxia is not different between those with and without AMS.…”

“…Furthermore, a lower ventilatory drive in hypoxia might contribute to more severe hypoxaemia in AMS, at least in some individuals [12,13]. Laboratory investigations of the brain in AMS show that all subjects exposed to altitudes of 4500 m had normal lumbar cerebrospinal fluid pressure and a small increase of brain volume assessed using MRI (<1%, ∼7-10 mL) after 16 h, independent of presence or absence of AMS [14]. The volume increase can partly be attributed to increased blood volume and partly to cell swelling [14,15].…”

Cerebral Volumetric Changes Induced by Prolonged Hypoxic Exposure and Whole-Body Exercise

“…Two MRI studies provided evidence for brain swelling in the white matter after 6 to 16 hours of passive exposure to normobaric hypoxia (inspiratory O 2 fraction, FiO 2 = 0.12). 3,4 Changes in apparent diffusion coefficient (ADC, characterizing the selfdiffusion of water in tissue) of the gray matter 5 and an increase in the total brain parenchyma volume 6 have also been reported within minutes (o 40 minutes) of hypoxia. The kinetics of cerebral volume changes and their relationships with alteration in ADC and cerebral blood flow (CBF) in hypoxia remain to be clarified.…”

“…2,7 Although the 'tight-fit' hypothesis suggests that increased brain volume and subsequent enhanced intracranial pressure may underlie AMS symptoms, 7 the link between changes in brain volumes, signs of cerebral edema, and symptoms of AMS typically developing over the first 6 to 12 hours of hypoxic exposure remains controversial. 3,4,[8][9][10] Some reports suggest that performing physical activity during the first hours of hypoxic exposure may accentuate symptoms of AMS. [11][12][13] Only one recent study compared the effects of hypoxic exposure for 8 hours associated or not with physical exercise (3 times 30 minutes of moderate intensity exercise) on brain volume and cerebral edema.…”