Elsevier

The Lancet Neurology

Volume 8, Issue 2, February 2009, Pages 175-191
The Lancet Neurology

Review
The cerebral effects of ascent to high altitudes

https://doi.org/10.1016/S1474-4422(09)70014-6Get rights and content

Summary

Cellular hypoxia is the common final pathway of brain injury that occurs not just after asphyxia, but also when cerebral perfusion is impaired directly (eg, embolic stroke) or indirectly (eg, raised intracranial pressure after head injury). We Review recent advances in the understanding of neurological clinical syndromes that occur on exposure to high altitudes, including high altitude headache (HAH), acute mountain sickness (AMS), and high altitude cerebral oedema (HACE), and the genetics, molecular mechanisms, and physiology that underpin them. We also present the vasogenic and cytotoxic bases for HACE and explore venous hypertension as a possible contributory factor. Although the factors that control susceptibility to HACE are poorly understood, the effects of exposure to altitude (and thus hypobaric hypoxia) might provide a reproducible model for the study of cerebral cellular hypoxia in healthy individuals. The effects of hypobaric hypoxia might also provide new insights into the understanding of hypoxia in the clinical setting.

Introduction

As air travel provides easier access to mountains, and the demand for adventurous holidays increases, millions of people now travel to high altitudes each year to ski, trek, climb, and work (eg, soldiers, astronomers, miners, and guides). Consequently, acute mountain sickness (AMS) has become a common complaint. Owing to differences in the definition of AMS and in the ascent profiles among studies, the reported prevalence of AMS varies widely, but about half of trekkers who ascend to 5000 m will develop AMS.1 For example, with the rapid expansion of lowland Chinese populations into Tibet in recent years, AMS and high-altitude cerebral oedema (HACE) have become occupational hazards for the workers on the Qinghai–Tibetan Railway, with overall incidences for AMS and HACE of 45–95% and 0·49%, respectively.2, 3 As more people visit high altitude, an awareness of the presentations, knowledge of the syndromes, and treatments for altitude-related illness are increasingly important to the clinical neurologist.

Previous reviews have covered the epidemiology and features of the management of high-altitude illnesses.4, 5 Here, we Review recent advances in understanding the neurological clinical syndromes and the underlying pathophysiological changes in cerebral perfusion and oedema formation that occur on ascent to high altitudes. We also discuss the possible molecular and genetic mechanisms involved and the neuropsychological sequelae.

Section snippets

Neurological effects of hypobaric hypoxia

Although barometric pressure decreases exponentially as altitude is gained, the percentage of each gas component of air is constant up to 12 000 m. Therefore, although the proportion of oxygen remains unchanged at 20·93%, increases in altitude result in a lower partial pressure of oxygen in the inspired air. This reduction in the driving gradient on the oxygen cascade can compromise the supply of adequate oxygen to the tissues.

The first detailed clinical descriptions of the consequences of too

Neuropsychological effects of hypobaric hypoxia

Several studies have shown impairment in arithmetic,59 memory and metamemory,60, 61 language, perception, learning, cognitive flexibility, and psychomotor skills51, 62 during ascent to high altitudes. Increases in reaction time,9, 63 auditory evoked-potential P300 latency,64 and a slowing of pupil constriction65 have also been seen, and these are indicative of a fundamental slowing of neuronal processing. As with other symptoms, the neuropsychological changes were related to the rate of ascent

Evidence of long-term brain injury

Anooshiravani and coauthors78 did not detect functional or structural alterations with MRI in eight climbers who reached the summit of a 6000 m peak. However, Paola and coauthors79 have recently shown that ascents to extreme altitude are associated with reduced white matter density and volume in areas related to the left motor cortex. Garrido and coauthors80 have shown increased signal intensity in the periventricular, posterior parietal, and occipital cortices in five of nine climbers who

Genetic predisposition to AMS

The study of genetophysiology, in particular the genetics behind hypoxic adaptation, is one of the most rapidly developing areas in high-altitude research.82 Because of the polygenic nature of the human response to hypobaric hypoxia, several genetic loci, each with a small contribution, probably define phenotype.83 The available studies can be divided into those that investigate a population's adaptation to high altitude and those that look for associations between polymorphic variations and

Current pathophysiological theories

Other than a previous occurrence of altitude illness, there are no obvious predisposing factors that identify one individual as being at higher risk of AMS than another when ascending to the same altitude at the same rate. The indiscriminate nature of AMS led Ross98 to write of “the random nature of cerebral mountain sickness”. He proposed that interindividual variation in neuroaxis compliance (ie, the inability of some to cope with brain swelling compared with others) accounted for the

Imaging changes in patients with AMS

CT scans done on climbers with HAPE and neurological dysfunction have shown small ventricles, cisterns, and the disappearance of sulci.134 MRI enables improved assessment of oedema and, although it does not measure intracranial pressure, can infer changes in intracranial pressure from changes in brain volume (eg, loss of ventricular space or sulci effacement). MRI has been used in several studies where the participants have developed AMS, and there are clinical reports of MRI findings in

AMS and HACE at the level of the vessels

The intracranial pressure, cerebrovascular, and MRI studies have given us a greater understanding of gross changes with hypobaric hypoxia but much is unknown about the mechanisms of these changes at the vascular and cellular levels. Figure 7 summarises current knowledge.

Conclusions

The brain is the most oxygen-dependent organ in the body and many pathophysiological processes either cause or result in an interruption to its oxygen supply. Insights into cerebral cellular hypoxia will help with the management of many acute neurological conditions.

The controlled study of brain injury is difficult because injuries vary by mechanism (eg, gunshot, subarachnoid haemorrhage, and ischaemia), location (eg, frontal or parietal), and patient characteristics (old or young). Given that

Search Strategy and selection criteria

References for this Review were identified through a search of PubMed from 1969 to November, 2008, with the term “brain” in conjunction with “altitude”, “hypoxia”, “cerebral blood flow”, “acute mountain sickness”, “high altitude cerebral oedema”, and “neuropsychology” form the basis for this Review. Abstracts from recent international scientific meetings were also included. Priority was given to recent publications, particularly those published since 2005.

References (184)

  • K Suzuki et al.

    Genetic variation in hypoxia-inducible factor 1alpha and its possible association with high altitude adaptation in Sherpas

    Med Hypotheses

    (2003)
  • Y Droma et al.

    Adaptation to high altitude in Sherpas: association with the insertion/deletion polymorphism in the angiotensin-converting enzyme gene

    Wilderness Environ Med

    (2008)
  • C Rajput et al.

    Predominance of interaction among wild-type alleles of CYP11B2 in Himalayan natives associates with high-altitude adaptation

    Biochem Biophys Res Commun

    (2006)
  • M Wilson et al.

    Impact of genetic factors on outcome from brain injury

    Br J Anaesth

    (2007)
  • RT Ross

    The random nature of cerebral mountain sickness

    Lancet

    (1985)
  • J Vardy et al.

    Acute mountain sickness and ascent rates in trekkers above 2500 m in the Nepali Himalaya

    Aviat Space Environ Med

    (2006)
  • TY Wu et al.

    Who should not go high: chronic disease and work at altitude during construction of the Qinghai–Tibet railroad

    High Alt Med Biol

    (2007)
  • T Wu et al.

    Ataxia: an early indicator in high altitude cerebral edema

    High Alt Med Biol

    (2006)
  • PH Hackett et al.

    High-altitude illness

    N Engl J Med

    (2001)
  • JB West

    T H Ravenhill and his contributions to mountain sickness

    J Appl Physiol

    (1996)
  • TH Ravenhill

    Some experiences of mountain sickness in the Andes

    Journal of Tropical Medicine and Hygiene

    (1913)
  • JB West et al.
  • AF Kramer et al.

    Cognitive function at high altitude

    Hum Factors

    (1993)
  • M Nelson

    Psychological testing at high altitudes

    Aviat Space Environ Med

    (1982)
  • DT Berry et al.

    Isocapnic hypoxemia and neuropsychological functioning

    J Clin Exp Neuropsychol

    (1989)
  • B Fowler et al.

    The threshold for hypoxia effects on perceptual-motor performance

    Hum Factors

    (1987)

  • The International Classification of Headache Disorders, 2nd edn

    Cephalalgia

    (2004)
  • RC Roach et al.

    Lake Louise AMS Scoring Consensus Committee. The Lake Louise acute mountain sickness scoring system

  • JB Sampson et al.

    Procedures for the measurement of acute mountain sickness

    Aviat Space Environ Med

    (1983)
  • CK Grissom et al.

    Acetazolamide in the treatment of acute mountain sickness: clinical efficacy and effect on gas exchange

    Ann Intern Med

    (1992)
  • AR Bradwell et al.

    Acetazolamide and high altitude diseases

    Int J Sports Med

    (1992)
  • B Basnyat et al.

    Efficacy of low-dose acetazolamide (125 mg BID) for the prophylaxis of acute mountain sickness: a prospective, double-blind, randomized, placebo-controlled trial

    High Alt Med Biol

    (2003)
  • P Bartsch et al.

    Pharmacological prevention of acute mountain sickness. Same ascent rates must be used to assess effectiveness of different doses of acetazolamide

    BMJ

    (2001)
  • B Basnyat et al.

    Acetazolamide 125 mg BD is not significantly different from 375 mg BD in the prevention of acute mountain sickness: the prophylactic acetazolamide dosage comparison for efficacy (PACE) trial

    High Alt Med Biol

    (2006)
  • J Vuyk et al.

    Acetazolamide improves cerebral oxygenation during exercise at high altitude

    High Alt Med Biol

    (2006)
  • PH Hackett et al.

    Dexamethasone for prevention and treatment of acute mountain sickness

    Aviat Space Environ Med

    (1988)
  • TS Johnson et al.

    Prevention of acute mountain sickness by dexamethasone

    N Engl J Med

    (1984)
  • M Basu et al.

    Glucocorticoids as prophylaxis against acute mountain sickness

    Clin Endocrinol

    (2002)
  • JP Roncin et al.

    EGb 761 in control of acute mountain sickness and vascular reactivity to cold exposure

    Aviat Space Environ Med

    (1996)
  • JH Gertsch et al.

    Randomised, double blind, placebo controlled comparison of ginkgo biloba and acetazolamide for prevention of acute mountain sickness among Himalayan trekkers: the prevention of high altitude illness trial (PHAIT)

    BMJ

    (2004)
  • DM Bailey et al.

    Acute mountain sickness; prophylactic benefits of antioxidant vitamin supplementation at high altitude

    High Alt Med Biol

    (2001)
  • P Bartsch et al.

    Prevention of high-altitude pulmonary edema by nifedipine

    N Engl J Med

    (1991)
  • CW Chan et al.

    Effect of sildenafil and acclimatization on cerebral oxygenation at altitude

    Clin Sci

    (2005)
  • M Maggiorini et al.

    Both tadalafil and dexamethasone may reduce the incidence of high-altitude pulmonary edema: a randomized trial

    Ann Intern Med

    (2006)
  • PH Hackett et al.

    High altitude cerebral edema

    High Alt Med Biol

    (2004)
  • B Basnyat et al.

    Neurological conditions at altitude that fall outside the usual definition of altitude sickness

    High Alt Med Biol

    (2004)
  • C Clarke

    Acute mountain sickness: medical problems associated with acute and subacute exposure to hypobaric hypoxia

    Postgrad Med J

    (2006)
  • J Dickinson et al.

    Altitude-related deaths in seven trekkers in the Himalayas

    Thorax

    (1983)
  • SY Song et al.

    Cerebral thrombosis at altitude: its pathogenesis and the problems of prevention and treatment

    Aviat Space Environ Med

    (1986)
  • XD Zhou

    Transient ischemic attack in young people at high altitude

    Qinghai Med J

    (1984)

    • Cited by (0)

    View full text
    Copyright © 2009 Elsevier Ltd. All rights reserved.