Headaches at High Altitudes: How Does the Brain React to Increased Elevations Both Acutely and Chronically?

Abstracts & Commentary

By Dara G. Jamieson, MD, Associate Professor, Clinical Neurology, Weill Medical, College, Cornell University. Dr. Jamieson is a consultant for Boehringer Ingelheim and Merck, and is on the speaker's bureau for Boehringer Ingelheim, Merck, Ortho-McNeil, and Pfizer.

Synopsis: Headache triggered acutely at high elevations may be migraine or the development of cerebral edema with progression to acute mountain sickness. Decreased ATPase gene expression seen in chronic headache sufferers dwelling at high altitudes may elucidate the neurobiology of migraine in general.

Sources: Serrano-Duenas M. High Altitude Headache. A Prospective Study of Its Clinical Characteristics. Cephalalgia. 2005;25:1110-1116; Appenzeller O, et al. Migraine in the Andes and Headache at Sea Level. Cephalalgia. 2005;25:1117-1121.

Visitors who travel to areas of elevated altitudes may suffer from a high altitude headache which can progress to acute mountain sickness (AMS) or high-altitude cerebral edema. The Lake Louise Consensus Group has defined AMS as headache, in an un-acclimatized person who has recently arrived at an altitude greater than 2500 meters, accompanied by gastro-intestinal symptoms, insomnia, dizziness, or fatigue. The symptoms begin within the first 12 hours of ascent and, without descent or treatment with oxygen, dexamethasone, or acetazolamide, may lead to ataxia and altered level of consciousness from cerebral edema. Sleeping at high altitude predisposes to headache development, and sleep aggravates symptoms of AMS with intracranial vasodilatation, particularly during REM sleep. The etiology of the headache is proposed to be hypoxia-induced cerebral vasodilation, with activation of the trigeminovascular system. Increase in cerebral blood volume and flow, with impaired autoregulation and increased capillary pressure, leads to vasogenic edema.1

Recognition of the high altitude headache, which may herald the development of more serious neurological symptoms, is crucial in order to prevent neurological worsening. M. Serrano-Duenas (2005) conducted a prospective study of the symptoms of high altitude headache in the Ecuadorian Andes. A questionnaire describing the headache characteristics was prepared and presented to 63 men and 35 women (mean age, 26 years, with a mean of 9 years climbing experience) who had experienced headache during organized snow and ice mountain climbing courses. During the 4-day course, they ascended the Chimborazo Mountain (6310 m) by day 3, with headache evaluations at different stages of the ascent and descent. The headaches associated with increased elevation were described as holocranial (66%), with pulsatile-burst type pain (75%) and an oscillating evolution (37%). The headaches increased with exercise (50%) and were relieved with rest in 42%. Accompanying symptoms included anorexia, irritability, pessimism, and anxiety. M. Serrano-Duenas points out some of the inconsistencies of the current criteria for the designation of altitude headache, and proposes that this description be used to formulate new a definition.

Migraine may be triggered by high altitude, with sea-level dwellers developing migraines related to the mechanisms proposed in altitude headache. However, chronic headache disorders are more common in inhabitants of high-elevations who may develop a syndrome of mal-adaptation known as chronic mountain sickness (CMS). CMS is characterized by profound hypoxia and polycythemia, as well as neurological symptoms and signs including migraine. Appenzeller and colleagues in 20032 noted that 47% of the inhabitants of Cerro de Pasco, Peru (altitude 4338 m) reported headaches. Twenty-four percent of men in the region had migraine with aura, with an average of 65 attacks a day. In a study of male inhabitants of Ceru de Pasco, some with CMS, middle cerebral artery vasodilatation in response to CO2 and to NO, as measured by transcranial Doppler, was defective both at their usual elevated altitudes and when they were measured at sea level in Lima. Appenzeller et al proposed that the susceptibility to migraine, in the setting of chronic hypoxia, might be related to altered gene expression of vascular growth factors, which could affect vascular reactivity.

In the paper published by Appenzeller et al in 2005, gene expression of the ATP1A1 subunit of Na+/K+ ATPase was assayed in 30 men, natives of Cerro de Pasco. ATPase has been implicated in the pathogenesis of familial hemiplegic migraine, as impaired function of the enzyme may make the cortex susceptible to cortical spreading depression. Andean men with CMS had significantly lower expression of the ATP1A1 subunit of ATPase (P = 0.008) than did Andean men without CMS. An increase in the level of expression was seen within one hour of arrival at sea level in Lima. A low level of expression of the ATP1A1 subunit of ATPase predicted low oxygen saturation, disturbed sleep, and a high likelihood of CMS. Appenzeller et al postulated that the low expression of the ATP1A1 subunit of Na+/K+ ATPase in the high Andes may trigger headache by causing trigeminal perivascular nerve depolarization, leading to cortical activation and pain. This study of secondary migraine in the high Andes may lead to better understanding of the neurobiology of migraine and to therapy for migraine sufferers at lower elevations as well.

References

1. Hackett PH, Roach RC. High-Altitude Illness. N Engl J Med. 2001;345:107-114.

2. Appenzeller O, et al. Cerebral Vasoreactivity in Andeans and Headache at Sea Level. J Neurol Sci. 2004;219:101-106.