Curr Pain Headache Rep (2013) 17:383
DOI 10.1007/s11916-013-0383-2
UNCOMMON HEADACHE SYNDROME (J AILANI, SECTION EDITOR)
Altitude Headache
J. Ivan Lopez & Ashley Holdridge & Jorge E. Mendizabal
Published online: 31 October 2013
# Springer Science+Business Media New York 2013
Abstract High altitude headache (HAH) has been defined by
the International Headache Society as a headache that appears
within 24 hours after ascent to 2,500 m or higher [1••]. The
headache can appear in isolation or as part of acute mountain
sickness (AMS), which has more dramatic symptoms than the
headache alone. If symptoms are ignored, more serious
conditions such as high altitude cerebral edema (HACE), high
altitude pulmonary edema (HAPE), or even death may ensue.
While there is no definitive understanding of the underlying
pathophysiologic mechanism, it is speculated that HAH occurs
from the combination of hypoxemia-induced intracranial
vasodilation and subsequent cerebral edema. There are a
number of preventive measures that can be adopted prior to
ascending, including acclimatization and various medications.
A variety of pharmacological interventions are also available to
clinicians to treat this extremely widespread condition.
Keywords High altitude headache . Acute mountain
sickness . HAH . AMS . Treatment . Prevention
Introduction
High altitude headache (HAH) is an extremely prevalent
condition, affecting up to 80 % of individuals who ascend
above 2,500 m [1••]. Whether for work or leisure, more and
This article is part of the Topical Collection on Uncommon Headache
Syndrome
J. I. Lopez (*)
University of Nevada School of Medicine, Reno, Nevada
e-mail: jlopez@renown.org
A. Holdridge
University of Alabama at Birmingham, Birmingham, Alabama
J. E. Mendizabal
Corpus Christi Neurology, Corpus Christi, Texas
more individuals find themselves at altitudes higher than 2,
500 m and therefore are at risk of developing HAH. The
purpose of this paper is to provide an update as to the
epidemiology, clinical features, pathophysiology, diagnosis,
treatment, and prevention of HAH.
The International Classification of Headache Disorders
II has developed diagnostic criteria to better define this
condition [2•]:
A. Headache with at least two of the following characteristics
and fulfilling criteria C and D:
1. Bilateral
2. Frontal or frontotemporal
3. Dull or pressing quality
4. Mild or moderate intensity
5. Aggravated by exertion, movement, straining,
coughing, or bending
B. Ascent to altitude above 2,500 m
C. Headache develops within 24 hours after ascent
D. Headache resolves within 8 hours after descent
Epidemiology
It is estimated that 8 out of every 10 climbers will experience
some form of headache during their trek. Development of
HAH is correlated to both the degree as well as the length of
time of the ascent. Approximately 25 % of individuals who
ascend to 2,500 m above sea level develop HAH. Upon
further ascent to greater than 4,900 m, the incidence increases
to 47–62 %. Almost 100 % of individuals who climb above 4,
500 m will develop some form of headache [3–5].
Clinical Characteristics
HAH can appear in isolation or as part of AMS. Headache is
the most frequent and pervasive symptom in AMS and
constitutes the key clinical feature (6). The distinguishing
383, Page 2 of 5
feature between the two is the presence of additional
symptomsin AMS. The Lake Louise AMS scoring system
defines AMS as the presence of headache plus one or more
of the following symptoms: anorexia, nausea, vomiting,
insomnia, fatigue, dizziness, and/or vertigo in an
unacclimatized person who ascends rapidly to above 2,
500 m [1••, 5]. Typically, the symptoms develop between 6
and 24 hours after ascending, but they can develop as early as
1 hour [5] after ascent. Headaches in both HAH and AMS are
described as dull, steady, throbbing, and stabbing in nature [6,
7]. While headaches in both conditions tend to be bilateral and
frontal, occipital headaches tend to be a clinical feature of
AMS. In a cross-sectional study by Alizadeh et al., 100 % of
the participants who climbed Mount Damavand developed
occipital headaches fulfilling criteria for AMS [5].
If AMS progresses, HACE may develop, with the onset of
ataxia, altered consciousness, or both. Clinically, HACE is the
end stage of AMS, with findings such as papilledema, retinal
hemorrhage, cranial-nerve palsies, and global encephalopathy
[5, 6]. If allowed to progress, brain herniation from increased
intracranial pressure will result. In cases where a person
suffers from HAPE, the progression from AMS to HACE
may be rapid [5, 6].
Risk Factors
Acknowledging risk factors prior to ascent is imperative in the
prevention of HAH. The main risk factor for developing HAH
is a rapid ascent to greater than 2500 m above sea level,
particularly at a speed greater than 300–500 m/day in the
acclimatization period [8•]. Other risk factors include individual
susceptibility, previous episodes of HAH or AMS, residing at
below 900 m above sea level, strenuous exercise, dehydration,
obesity, young age, history of cardiovascular disease, female
gender, and a history of headaches, particularly migraine with
or without aura [3, 8•]. The symptoms of HAH may worsen
with exercise, physical activity, or head movement. HAH can
appear upon awakening or can awaken the individual during
the night. The headache appears to be worse in female subjects
and in those individuals with a history of headaches prior to
ascending to a high altitude [9].
In a cohort study performed in young Chinese men, Bian et al.
found that anxiety can contribute to the appearance of HAH [10].
Although good physical fitness does not seem to prevent HAH, a
study performed by Richalet et al. found an association between
low ventilatory response to hypoxia with exercise and the risk of
developing severe high altitude-related illnesses [11].
Anatomical and Physiologic Considerations
On an anatomical level, the pain-sensitive structures of the
head include blood vessels and meninges [12]. To understand
the role of altitude in the genesis of headaches, clinicians must
Curr Pain Headache Rep (2013) 17:383
understand the relationship between altitude, arterial oxygen
pressure, and atmospheric pressure. There is an inverse
relation between altitude/atmospheric pressure and altitude/
arterial oxygen pressure. Upon ascent, the chemoreceptors of
the carotid body detect a decrease in arterial oxygen pressure.
At rest, the brain receives approximately 14 % of the cardiac
output, around 700 ml per minute. The average adult male
intracranial volume (including brain and cerebrospinal fluid)
is only twice this (1,473 ml). Hypoxia would increase this
volume by the mechanism explained above [13]. The decrease
in partial pressure of oxygen at high altitudes reduces the supply
of oxygen in the brain and results in up to 26 % increased blood
flow in the brain [14]. Cerebral autoregulation, the process by
which cerebral perfusion is maintained and sustained, is
affected by hypoxia in individuals that suffer from acute
mountain sickness (AMS) and HAH [3, 15•].
Pathophysiology
At present, no mechanism has yet been definitively determined
to cause HAH or headache associated with AMS, although
many theories exist . In one theory, it is thought that hypoxia
provokes a neurohumoral and a hemodynamic response, with
release of inflammatory mediators that lead to an increase in the
capillary pressure by overperfusion and vasodilation, resulting
in cerebral edema and headache [4]. The brain edema causes
traction of the meninges and blood vessels and irritation of the
mechanoreceptors, producing pain [3, 10, 16]. Another
version suggests that hypoxia induces disruption of the
blood-brain barrier (BBB), resulting in vasogenic edema.
Proinflammatory mediators can directly weaken the tight
junctions between cerebral endothelial cells, decreasing the
effectiveness of the BBB and increasing the potential for
capillary leak [17].
A popular theory proposed by Ross in 1985 is known as the
“tight-fit hypothesis.” This theory suggests that increased
brain volume with hypoxia elevates intracranial pressure,
leading to swelling of the brain. Those with a greater ratio of
cranial cerebrospinal fluid to brain volume are able to
compensate for the displacement of the cerebrospinal fluid
and will be less likely to develop AMS [5, 7].
Yet another explanation involves pathophysiology similar
to that of the migraine. The hypoxia is thought to produce
activation of the trigeminovascular system and sensitization of
intracranial pain receptors [3]. As occurs in the migraine, the
trigeminovascular system activates the release of calcitonin
gene-related peptide (CGRP), substance P, and neurokinin A.
The vessels will dilate, and plasma protein extravasation
occurs, resulting in head pain [18]. The headache is most
likely a consequence of edema and vasodilation [3].
Wilson et al. postulate that HAH is a result of a “mismatch
phenomenon.” Given that hypoxia increases cerebral
perfusion, in turn increasing venous drainage, which requires
Curr Pain Headache Rep (2013) 17:383
greater venous pressure, a phenomenon that decreases venous
outflow will cause venous congestion to occur [13]. At high
altitudes, retinal veins become distended, which may mirror
the engorgement of cerebral veins [7]. Wilson et al. performed
ophthalmological examination in 24 subjects at high altitude.
Twelve of these subjects, who ascended to 5,300 m,
additionally underwent magnetic resonance imaging.
Headache burden correlated with retinal venous distension
and narrowing of transverse venous sinuses. The researchers
concluded that intracranial pressure may rise in the presence
of anatomical restrictions to venous drainage, thus leading to
headache [7] (Fig. 1).
Diagnosis and Differential Diagnosis
The diagnosis of HAH requires that the onset of pain develop
once the individual reaches 2,500 m above sea level and that
the headache is not attributable to any other condition. A
complete history and neurological exam will help the clinician
distinguish between primary and secondary headaches.
Adherence to the diagnostic criteria as laid out by the
International Headache Society in the ICHD-II [2•) will go a
long way in helping the clinician determine whether the
headache can be treated up in the mountains or whether the
patient needs to descend and seek different care.
Comorbid factors such as dehydration, low blood glucose,
and electrolyte disturbances can provoke headache at both low
and high altitudes and should be taken into account [1••]. One
must consider other causes for the headache, including
migraine, infections, alcohol or drug use, carbon monoxide
intoxication, brain tumors, and arteriovenous malformation. A
case report by Shrestha et al. describes a climber returning from
a trek involving an ascent to 5,600 m with complaints of sudden
headache, right visual field impairment, and aphasia. She was
later found to have a cerebral venous sinus thrombosis, possibly
triggered by high altitude and dehydration, along with factor V
mutation and decreased protein S levels [19]. This case
highlights the importance of a thorough history and physical
examination, as not all headaches at high altitude are what they
appear to be.
Fig. 1 Various proposed mechanisms for HAH
Page 3 of 5, 383
Treatment
HAH is a self- limiting condition that typically will resolve
within 2–3 days [3]. If symptoms persist, descent to a lower
altitude is recommended. Descending even 500–1,000 m has
been found to resolve the headache [5]. For acute
management, breathing oxygen at 2 to 4 liters/min has been
found to reduce headache within 15 to 30 minutes [3, 20]. A
positive response to oxygen will help differentiate HAH from
migraine. No pharmacologic protocol exists for acute
interventions, but prostaglandin inhibitors are effective in
relieving symptoms. In two studies, a single dose of 400 mg
or 600 mg of ibuprofen resolved the headache [5]. Aspirin at a
dose of 325 mg three times per day has been shown to be
successful. Acetaminophen at a dose of 500–1,000 mg has
been successful as well [3]. In cases where symptoms persist
despite the above therapies, dexamethasone 8 mg divided into
four doses exerts its effect by reducing the release of cytokines
and reducing capillary permeability [3].
Prevention
The most important preventive measure for HAH is
acclimatization. Ascent to more than 2,438.4 m without proper
acclimatization can result not only in headache, but life-
threatening conditions [21]. Low-altitude residents can induce
some degree of altitude acclimatization by ascending to
moderate (>1,500 m) or higher altitudes during either
continuous or intermittent altitude pre-exposures [9, 21]. A
moderate ascent rate of 300 m/day has been advocated by some
as the mainstay of prevention [22]. Other sources recommend a
3-stage protocol. The first stage (>2,700–3,600 m) consists of
6 days of graded activity; the second stage (>3,600–5,400 m)
consists of 4 additional days of routine activity; and the third
stage (>5,400 m), another 4 days of increasing activity [21].
In terms of pharmacologic prophylaxis, the use of
acetazolamide – an inhibitor of the carbonic anhydrase – prior
to ascent has been studied extensively. Acetazolamide is a
synthetic non-bacteriostatic sulfonamide, and doses of 125 mg
BID have been used [23]. In a study published by Leshem
383, Page 4 of 5
et al. [24], tadalafil 20 mg/day plus acetazolamide 125 mg
BID showed superiority over acetazolamide alone in the
prevention of altitude illness in 51 subjects. Tadalafil, a
PDE5 inhibitor, acts by blocking the breakdown of cyclic
GMP, an intracellular mediator of the nitric oxide vasodilatory
effects. This, in turn, inhibits hypoxia-mediated edema,
thought to be partially responsible for HAH [3].
Burtscher et al. [25] found a beneficial prophylactic effect
of aspirin in a randomized double-blind placebo-controlled
study. Study subjects were first examined at low altitude
(600 m) and were then transported to high altitude (3,
480 m). Subjects in the active treatment arm received
320 mg of aspirin every 4 hours, for a total dose of 960 mg.
The effect of aspirin was independent from its effect on arterial
oxygenation. The authors theorized that aspirin exerts its
effect by reducing prostaglandin concentrations, thus
effectively reducing prostaglandin-mediated ergoreceptor
activation and accompanying sympathetic stimulation.
Prophylaxis with Gingko biloba and spironolactone has not
been shown to be beneficial [3, 26]. Interestingly, iron
supplementation has shown some promise. Talbot et al.
studied 24 healthy volunteers with normal iron status at
baseline prior to ascending to high altitude (4,340 m). They
randomly administered either IV iron supplementation or NS
to the subjects [27]. The incidence of headache was higher in
individuals who received placebo. Although the number of
subjects was small, this double-blinded placebo-controlled
study unlocks the possibility of using IV iron supplementation
as a preventive measure against HAH in healthy individuals.
Other considerations that have been suggested include
avoiding dehydration by drinking five 8-ounce glasses of
water prior to ascent to a higher altitude, descending to lower
elevations for sleeping , as well as ensuring adequate rest [28].
Conclusion
HAH is an extremely prevalent condition affecting thousands of
people each year. HAH can appear in isolation after ascent to 2,
500 m or higher, but more frequently it appears in combination
with other symptoms as part of AMS. There is currently no
consensus regarding the underlying pathophysiologic
mechanism of HAH, as there is a multitude of contributing
factors. Similar therapeutic and preventive measures can be used
equally in both HAH and AMS. This review has attempted to
provide an update regarding the pathophysiology, anatomical
considerations, clinical features, and most recent diagnostic,
therapeutic, and preventive measures in the management of this
highly prevalent condition. It appears that a continuum exists
between HAH and AMS. The clinician who provides care to
individuals at high altitudes needs to be aware of this condition
and must keep abreast of the latest developments in order to
provide the best treatments available.
Curr Pain Headache Rep (2013) 17:383
Compliance with Ethics Guidelines
Conflict of Interest Dr. J. Ivan Lopez, Dr. Ashley Holdridge, and Dr.
Jorge E. Mendizabal all reported no potential conflicts of interest relevant
to this article.
Human and Animal Rights and Informed Consent This article does
not contain any studies with human or animal subjects performed by any
of the authors.
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Papers of particular interest, published recently, have been
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• Of importance
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