Curr Pain Headache Rep (2015) 19:9 DOI 10.1007/s11916-015-0483-2
UNCOMMON AND/OR UNUSUAL HEADACHES AND SYNDROMES (J AILANI, SECTION EDITOR)
High-Altitude Headache Michael J. Marmura & Pablo Bandres Hernandez
# Springer Science+Business Media New York 2015
Abstract High-altitude headache is one of many neurological symptoms associated with the ascent to high altitudes. Cellular hypoxia due to decreased barometric pressure seems to be the common final pathway for headache as altitude increases. Susceptibility to high-altitude headache depends on genetic factors, history of migraine, and acclimatization, but symptoms of acute mountain sickness are universal at very high altitudes. This review summarizes the pathophysiology of acute mountain sickness and high-altitude headache as well as the evidence for treatment and prevention with different drugs and devices which may be useful for regular and novice mountaineers. This includes an examination of other headache disorders which may mimic high-altitude headache. Keywords High-altitude headache . Acute mountain sickness . Hypoxia . Pathophysiology
Introduction Headache is a very common symptom resulting from travel to high-altitude destinations, and high-altitude headache (HAH) This article is part of the Topical Collection on Uncommon and/or Unusual Headaches and Syndromes M. J. Marmura Department of Neurology, Thomas Jefferson University, Philadelphia, PA, USA P. B. Hernandez Department of Neurology, Hospital Fundación Alcorcón, Madrid, Spain M. J. Marmura (*) Jefferson Headache Center, Jefferson Hospital for Neuroscience, 900 Walnut Street, Suite 200, Philadelphia, PA 19107, USA e-mail: [email protected]
is a recognized headache disorder [1]. About 80 % of persons report headache as a symptom with ascent to high altitudes, especially with rapid ascent and very high altitude [2]. At altitudes over 4500 m, headache is extremely common [2]. HAH is part of the syndrome of altitude or mountain sickness, which may also include shortness of breath, sleep disturbance, fatigue, anorexia, nausea, and dizziness [3]. HAH is considered a disorder of homoeostasis by the International Headache Society in the International Classification of Headache Disorders (ICHD-3β). ICHD-3β defines HAH as a headache which develops in association with ascent to altitudes of at least 2500 m and resolves within 24 h of descent to less than 2500 m. To meet these criteria, the headache should have two or three characteristics: bilateral location, mild-moderate intensity, and aggravation by exertion, movement, straining, and/or bending. Like migraine, HAH may be associated with irritability, nausea, and anorexia, but other migraine features such as unilateral location, photophobia, and phonophobia are atypical for pure HAH. A Bpulsatile-burst type quality^ and Boscillating evolution^ are common descriptors [4]. Risk factors for headache in mountaineers include low oxygen saturation, poor fluid intake, exertion, and a personal history of migraine [5•, 6]. Given that migraine is a risk factor for HAH, and that high altitude can be a trigger for migraine, there can be considerable clinical overlap. A single case report described high altitude as a trigger for cluster headache in a 40-year-old woman with a prior history of episodic cluster which responded to oxygen treatment [7]. Retinal venous distension on ophthalmologic exam and radiographic narrowing of transverse sinus may predict hypoxemia and risk of HAH [2, 8]. Oral contraceptive use, which decreases circulating progesterone levels, may also increase HAH risk [9]. Preacclimatized individuals are much less likely to develop HAH [10].
9
Curr Pain Headache Rep (2015) 19:9
Page 2 of 7
Pathophysiology
Table 1 Definitions of altitude illness from the 1991 International Hypoxia Symposium
Although the percentage of oxygen in air remains the same at higher altitudes (about 21 %), HAH is caused by decreased barometric pressure, resulting in a lower percentage of oxygen molecules per breath. At 3600 m, barometric pressure is only 480 mmHg, compared with 760 mmHg at sea level. This reduction of the partial pressure of oxygen in inspired air, especially with coughing or bending, compromises the supply of oxygen to the tissues resulting in HAH and mountain sickness. The body acclimates to higher altitudes by increasing respiration, producing more red blood cells to carry oxygen, and increasing pressure in pulmonary capillaries [2]. Erythropoietin-induced polycythemia and increased cerebral blood flow may also occur. The length of time required to acclimate varies from person to person, and a slower rate of ascent can prevent HAH. Ethnic groups with a long history of living at high altitudes such as Sherpas frequently have genetic adaptations such as angiotensin-converting enzyme gene polymorphisms which allow better performance at high altitude [11]. Biomarkers suggest anti-inflammatory and anti-permeability to bloodbrain barrier factors are protective in persons less prone to developing HAH [12]. Experienced mountaineers are also less likely to develop symptoms [13]. Acute mountain sickness (AMS) is a syndrome, defined as the presence of headache in an unacclimatized person who has recently arrived at an altitude above 2500 m plus the presence of one or more of the following: gastrointestinal symptoms (anorexia, nausea, or vomiting), insomnia, dizziness, lightheadedness, or fatigue. Symptoms could present as early as 1 h after ascent but usually develop within 6 to 10 h after ascent. The Lake Louise Consensus Group also established a scoring system to evaluate AMS and establish severity of illness [14]. Table 1 reviews the basic categories of altitude sickness. Mild AMS presents headache with nausea, dizziness, and fatigue during the first 12 h after rapid ascent (above 2500 m). Moderate AMS presents moderate-to-severe headache with marked nausea, dizziness or lightheadedness, insomnia, and fluid retention at high altitude for 12 h or more. The brain is very sensitive to hypoxia, and the most severe symptoms of AMS are neurologic. High-altitude cerebral edema is the end stage of AMS and presents with varying degrees of confusion, gait ataxia, psychiatric changes, and disturbances of consciousness that could progress to deep coma. Other significant neurologic disturbances may include the following [2]:
Diagnosis
Criteriaa
Acute mountain sickness (AMS)
Headache and at least one of the following: (1) Anorexia, nausea, or vomiting; fatigue or weakness (2) Dizziness or lightheadedness (3) Difficulty sleeping A change in mental status and/or ataxia in a person with AMS or Both mental status changes and ataxia in a person without AMS Symptoms—at least two of the following: (1) Dyspnea at rest (2) Cough (3) Weakness or decreased exercise performance (4) Chest tightness or congestion Signs—at least two of the following: (1) Crackles or wheezing in at least one lung field (2) Central cyanosis (3) Tachypnea (4) Tachycardia
&
Transient ischemic attacks (TIA), possibly related to vasospasm or hypoxia. Persons with a history of recent TIA or stroke within 90 days should not travel to high altitudes [15].
High-altitude cerebral edema
High-altitude pulmonary edema
a
All of the following must occur in the setting of a recent gain in altitude
&
Stroke related to right-to-left shunting, with secondary increased risk of embolism if there is patient foramen ovale. This is more commonly reported in association with decompression sickness in divers [16]. Transient global amnesia [17, 18]. Cerebral venous thrombosis as a result of volume depletion and polycythemia. Hypercoagulable disorders such as hyperhomocysteinemia and protein C or S deficiency may increase risk [19–21]. Seizures due to hyperventilatory hypocapnia and hypoxia or cerebral edema [22]. High-altitude syncope, due to a vasovagal phenomenon. Heart rates remain elevated after 2 weeks at high altitude [23]. Cranial nerve palsies, being the sixth cranial nerve most commonly affected (also facial and hypoglossal nerve palsies reported) [24]. Ophthalmological disturbances, such as retinal hemorrhages, amaurosis fugax, and cortical blindness. Optic nerve swelling at very high altitudes is common [25]. Sleep disturbances.
& &
& & & & &
Chronic mountain sickness (CMS), also known as Monge’s disease, can develop after living at high altitudes for a long time and is characterized by polycythemia, headache, dizziness, tinnitus, breathlessness, sleep disturbance, fatigue, and mental confusion. Pulmonary hypertension and stroke due to polycythemia are a few of the most serious manifestations. Genetic factors likely explain the increased incidence in certain populations [26].
Curr Pain Headache Rep (2015) 19:9
Treatment Mild HAH should resolve with analgesics, such as acetaminophen and ibuprofen, but further management consists of hydration and halting the ascent and descent if there are no signs of improvement. HAH should resolve after 10 to 15 min of supplementary oxygen, or spontaneously 24 h after descent [1]. Avoiding medications which can decrease respiratory drive such as opioids, barbiturates, or benzodiazepines and sedating medications is recommended for HAH [27]. Mild AMS management may consist of halting the ascent or a descent of 500 m or more, acclimatizing for 24 h, or rapid acclimatization with acetazolamide (125 to 250 mg twice daily) as well as treating the symptoms with a combination of analgesics and antiemetics [28]. Ibuprofen is likely effective based on a placebo-controlled study [29]. Another study noted no difference between ibuprofen 400 mg and acetaminophen 1000 mg [30]. Aspirin, with a dose of 320 mg given every 4 h beginning 2 h before ascent, is more effective than placebo in preventing HAH [5•]. Moderate AMS treatment includes also descending 300 to 500 m with acetaminophen, ibuprofen, dexamethasone, and acetazolamide (125 to 250 mg twice daily). Specific treatments are discussed below. Acetazolamide Acetazolamide (125–250 mg twice per day) is effective for AMS therapy and prophylaxis. Acetazolamide causes bicarbonate diuresis with consequent metabolic acidosis and increase of ventilation by inhibiting renal carbonic anhydrase. Other non-carbonic anhydrase mechanisms are also likely important such as reductions in the production of CSF and promotion of ion transport across blood-brain barrier [28]. In animal models of chronic mountain sickness, acetazolamide appears to decrease blood viscosity and alter pulmonary vascular resistance and erythropoiesis [29]. Acetazolamide is effective in improving cerebral tissue oxygenation, even in persons with obstructive sleep apnea [30]. Acetazolamide commonly produces alterations in taste and paresthesia and less commonly nausea, polyuria, or diarrhea. Acute kidney injury is a rare complication [31]. The effectiveness of acetazolamide for prevention and treatment of AMS has been evaluated in multiple randomized placebo-controlled trials. The number needed to treat to prevent one case of AMS with acetazolamide varies from two to eight persons depending on the rate of ascent (lower for more rapid ascents) and dose [32]. The lowest effective daily dose appears to be 250 mg and, in one study, was equally effective as 750 mg/day [33••, 34]. There is less evidence that acetazolamide is effective for HAH. One study reported ibuprofen prophylaxis with 600 mg three times daily was equally effective for prevention of HAH and AMS; some experts question it as the definitive acute treatment of
Page 3 of 7 9
choice for HAH and AMS [35•, 36]. For CMS, however, a low dose of 250 mg/day appears to be very effective with relatively few side effects [37]. One study suggested that combination treatment with the phosphodiesterase type 5 inhibitor, tadalafil, was more effective than acetazolamide alone. Another study found that the acetylsalicylic acid analog calcium carbasalate was not effective compared to acetazolamide 500 mg/day [38, 39]. Acetazolamide may not be effective in decreasing pulmonary artery pressures and treating highaltitude pulmonary edema [40]. Dexamethasone Dexamethasone is a corticosteroid which acts by reducing the release of cytokines and capillary permeability, which is especially useful in the treatment of high-altitude cerebral edema. Dexamethasone is a known effective treatment for cerebral edema from tumors or other medical illnesses such as hepatic failure [41]. Dexamethasone is particularly useful due to its effects on both osmotic cell swelling and its inhibition of angiogenesis [42]. Significant side effects may occur, especially with longer-term use, such as gastrointestinal bleeding, rash, avascular necrosis, and adrenal crisis [43]. A clinical trial of soldiers being transported from sea level to up to 4400 m found that 4 mg dexamethasone (either oral or intramuscular) every 6 h starting 48 h prior to decompression or ascent was more effective than low doses or placebo for preventive AMS [44]. Another study found dexamethasone 4 mg every 6 h to be more effective than placebo for both AMS and symptoms such as HAH [45]. A randomized trial of climbers with rapid ascent (from 500 to 5000 m) found that both dexamethasone and tadalafil were both effective in the prevention of highaltitude pulmonary edema, although there was a trend for better efficacy with dexamethasone [46]. A separate trial, however, suggested that dexamethasone was more effective for improving exercise capacity at altitude than tadalafil [47]. Nifedipine Nifedipine is a calcium channel blocker which reduces pulmonary-artery pressure and is a vasodilator and is used in the treatment of hypertension, angina, and Raynaud’s phenomenon, among other disorders. Its effectiveness in preventing AMS and high-altitude pulmonary edema is likely related to pulmonary vascular changes. These effects may be seen with other vasodilators such as hydralazine or phentolamine which have not been studied for AMS [48]. Common side effects of nifedipine include bradycardia or tachycardia (often with initial doses) and hypotension [49]. Nifedipine is effective in prevention of high-altitude pulmonary edema in susceptible individuals at doses of 20 mg or greater. In one trial, a 20-mg extended release preparation of nifedipine was more effective than placebo in preventing high-altitude
9
Curr Pain Headache Rep (2015) 19:9
Page 4 of 7
pulmonary edema subjects with a proven history of the disorder. Nifedipine was superior in terms of symptom score, pulmonary-artery pressure, and alveolar-arterial pressure gradient [50]. The effectiveness of nifedipine for HAH, AMS, or the acute treatment of high-altitude pulmonary edema is less clear, although it is often used [51]. In one trial of persons with established AMS already receiving supplemental oxygen therapy and bed rest, nifedipine was not superior to placebo [52].
Oxygen Along with slow acclimatization and descent, oxygen is a standard and proven treatment for HAH and AMS. Hyperbaric oxygen, along with supplemental oxygen, is effective for AMS and other complications of high altitude [63]. Portable hyperbaric chambers, also known as Gamow Bags, are effective for the elimination of carboxyhemoglobin in the emergency department and for AMS and cerebral or pulmonary edema at high altitude [64–66].
Phosphodiesterase Type 5 Inhibitors Phosphodiesterase type 5 inhibitors, including sildenafil and tadalafil, are oral medications used for the treatment of erectile dysfunction. Common side effects include headache and severe hypotension in persons taking concurrent nitric oxide donors. Phosphodiesterase type 5 inhibitors prevent the action of cGMP-specific phosphodiesterase type 5 on cyclic GMP in the smooth muscle cells, including the lungs, suggesting they may be effective as a treatment for pulmonary hypertension [53]. Reducing pulmonary hypertension, leading to increased cerebral and peripheral oxygenation, is a goal in the treatment of highaltitude pulmonary edema. Multiple trials have shown that these medications lower systolic pulmonary artery pressure more than controls [54•]. In one trial, sildenafil 50 mg increased exercise capacity and arterial oxygen saturation. Two patients noted HAH with treatment [55]. Sildenafil 40 mg three times daily also lowered oxygen consumption and systolic pulmonary artery pressure in another study of 12 subjects at high altitude [56]. The effectiveness of tadalafil for AMS and high-altitude pulmonary edema has been evaluated in comparative trials with dexamethasone [46, 47]. Sildenafil may also be effective in the treatment of CMS [57].
Furosemide Furosemide is a loop diuretic which produces rapid diuresis and is occasionally used for the treatment of cerebral edema [58]. A few small studies have suggested furosemide 40– 80 mg as a treatment for both AMS and either high-altitude pulmonary or cerebral edema based on its diuretic effect, changes in platelet function and blood viscosity [59, 60]. Interestingly, exposure to high altitude appears to increase in the free fraction of furosemide and possibly its effectiveness [61]. The most common side effect of furosemide is diuresis which may potentially lead to dehydration. Therefore, furosemide is used as an acute treatment along with other measures for AMS and pulmonary or cerebral edema, rather than a preventive measure. The diuretic spironolactone at 100 mg/day does not appear effective against AMS [62].
Others A small study found that Ginkgo biloba at a dose of 80 mg every 12 h starting 24 h before ascent was effective in preventing AMS in inexperienced hikers [67]. Two other studies using different Ginko formulations failed to demonstrate superiority or placebo and were inferior to acetazolamide [68, 69]. In another study, the anticonvulsant gabapentin 300 mg improved HAH severity and headache-free time and reduced need for additional analgesics compared to placebo [70]. There is conflicting evidence regarding the effectiveness of sumatriptan, a selective serotonin agonist for migraine, in HAH or AMS. A small study found a non-significant trend favoring ibuprofen 600 mg as superior to sumatriptan 100 mg for acute treatment HAH and AMS [71]. Another report noted only mild differences between sumatriptan 100 mg and placebo for HAH [72]. In a preventive trial, subjects using sumatriptan 50 mg prior to ascent were less likely to develop either HAH or AMS [73]. Theophylline is a methyl xanthine drug used for asthma and chronic obstructive pulmonary disease which relaxes bronchial smooth muscle and blocks the action of adenosine. A small study of 17 subjects randomized to either theophylline 300 mg daily for 5 days prior to and during ascent or placebo reported significantly reduced symptoms of AMS and oxygen desaturations at 4559 m in the theophylline group [74].
Other Related Headache Disorders Headache attributed to airplane travel is described as a severe, unilateral, and periocular headache without autonomic symptoms which occurs exclusively during airplane travel [1]. Airplane headache is most likely to happen during descent prior to landing or less commonly during initial ascent after takeoff. The location is usually unilateral, orbitofrontal but parietal spread may occur. Commonly, it is a jabbing or stabbing headache but pulsation may also occur. The headache usually improves spontaneously 30 min after landing [75]. Unlike HAH, airplane headache is felt to be related to individual
Curr Pain Headache Rep (2015) 19:9
abnormalities of sinus cavities and the Bvacuum effect^ triggered by decreased oxygen saturations [76]. Other headache disorders may be precipitated by hypoxia and/or hypercapnia. Diving headache, triggered by diving below 10 m in the absence of decompression illness, is an example of headache essentially due to hypercapnia. Symptoms mimic those of carbon dioxide intoxication including mental confusion, lightheadedness, motor incoordination, dyspnea, and facial flushing [1]. A partial pressure of carbon dioxide in arterial blood over 50 mmHg is known to cause smooth muscle relaxation and consequent intracranial vasodilatation with increased intracranial pressure. It is unclear if the mechanism of sleep apnea headache is related to hypoxia, hypercapnia, or disturbance in sleep. Sleep apnea headache is usually characterized by a bilateral morning headache of less than 4 h which resolves with successful treatment of the sleep apnea [1]. The pain quality is usually pressing and may present with concurrent nausea, photophobia, or phonophobia.
Page 5 of 7 9
References Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance 1. 2. 3. 4.
5.•
6.
7.
Conclusion HAH is a common symptom in those travelling to high altitude, especially persons with no prior acclimatization and rapid ascent, as part of AMS. Allowing extra time for ascent and preventive treatment with analgesics or acetazolamide may prevent the development of HAH and AMS. For acute treatment of HAH, oxygen, halting ascent, or descending to lower altitudes is effective. Simple analgesics and dexamethasone are likely effective in the treatment of HAH. Dexamethasone appears to be effective in both the acute and preventive treatment of HAH and AMS. Nifedipine or phosphodiesterase type 5 inhibitors may prevent AMS and cerebral or pulmonary edema, but there is no evidence for their use to treat HAH. Sumatriptan may not be effective for HAH but may be considered in patients with concurrent migraine.
8.
9.
10.
11.
12.
13.
14.
Acknowledgments Thanks to Gail Iannarella for assistance in preparing this manuscript.
15.
Compliance with Ethics Guidelines
16.
Conflict of Interest Dr. Michael J. Marmura reports royalties from Cambridge, Demos Medical, and Medlink Neurology. Dr. Pablo Bandres Hernandez declares no potential conflicts of interest.
17.
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.
18. 19.
Olesen J. ICHD-3 beta is published. Use it immediately. Cephalalgia. 2013;33:627–8. Wilson MH, Newman S, Imray CH. The cerebral effects of ascent to high altitudes. Lancet Neurol. 2009;8:175–91. Porcelli MJ, Gugelchuk GM. A trek to the top: a review of acute mountain sickness. J Am Osteopath Assoc. 1995;95:718–20. Serrano-Duenas M. High altitude headache. A prospective study of its clinical characteristics. Cephalalgia. 2005;25: 1110–6. Burtscher M, Mairer K, Wille M, et al. Risk factors for high-altitude headache in mountaineers. Cephalalgia. 2011;31:706–11. Overview of important risk factors for headache in those travelling to high altitudes. Arregui A, Cabrera J, Leon-Velarde F, et al. High prevalence of migraine in a high-altitude population. Neurology. 1991;41:1668– 9. Mampreso E, Maggioni F, Viaro F, et al. Efficacy of oxygen inhalation in sumatriptan refractory Bhigh altitude^ cluster headache attacks. J Headache Pain. 2009;10:465–7. Wilson MH, Davagnanam I, Holland G, et al. Cerebral venous system and anatomical predisposition to high-altitude headache. Ann Neurol. 2013;73:381–9. Harrison MF, Anderson P, Miller A, et al. Oral contraceptive use and acute mountain sickness in South Pole workers. Aviat Space Environ Med. 2013;84:1166–71. Jackson SJ, Varley J, Sellers C, et al. Incidence and predictors of acute mountain sickness among trekkers on Mount Kilimanjaro. High Alt Med Biol. 2010;11:217–22. Droma Y, Hanaoka M, Basnyat B, et al. Adaptation to high altitude in Sherpas: association with the insertion/deletion polymorphism in the angiotensin-converting enzyme gene. Wilderness Environ Med. 2008;19:22–9. Julian CG, Subudhi AW, Wilson MJ, et al. Acute mountain sickness, inflammation, and permeability: new insights from a blood biomarker study. J Appl Physiol (1985). 2011;111:392–9. Mairer K, Wille M, Burtscher M. The prevalence of and risk factors for acute mountain sickness in the Eastern and Western Alps. High Alt Med Biol. 2010;11:343–8. Sutton JR, Coates G, Houston CS. The Lake Louise consensus on the definition and quantification of altitude illness. In: Sutton JR, Coates G, Houston CS, editors. Hypoxia and mountain medicine. Burlington: Queen City Printers; 1992. Baumgartner RW, Siegel AM, Hackett PH. Going high with preexisting neurological conditions. High Alt Med Biol. 2007;8: 108–16. Saary MJ, Gray GW. A review of the relationship between patent foramen ovale and type II decompression sickness. Aviat Space Environ Med. 2001;72:1113–20. Litch JA, Bishop RA. Transient global amnesia at high altitude. N Engl J Med. 1999;340:1444. Bucuk M, Tomic Z, Tuskan-Mohar L, et al. Recurrent transient global amnesia at high altitude. High Alt Med Biol. 2008;9:239–40. Fujimaki T, Matsutani M, Asai A, et al. Cerebral venous thrombosis due to high-altitude polycythemia. Case report. J Neurosurg. 1986;64:148–50.
9 20.
Curr Pain Headache Rep (2015) 19:9
Page 6 of 7
Boulos P, Kouroukis C, Blake G. Superior sagittal sinus thrombosis occurring at high altitude associated with protein C deficiency. Acta Haematol. 1999;102:104–6. 21. Hassan KM, Kumar D. Reversible diencephalic dysfunction as presentation of deep cerebral venous thrombosis due to hyperhomocysteinemia and protein S deficiency: documentation of a case. J Neurosci Rural Pract. 2013;4:193–6. 22. Daleau P, Morgado DC, Iriarte CA, et al. New epilepsy seizure at high altitude without signs of acute mountain sickness or high altitude cerebral edema. High Alt Med Biol. 2006;7:81–3. 23. Thomas KN, Burgess KR, Basnyat R, et al. Initial orthostatic hypotension at high altitude. High Alt Med Biol. 2010;11:163–7. 24. Virmani SK, Swamy AS. Cranial nerve palsy at high altitude. J Assoc Physicians India. 1993;41:460. 25. Bosch MM, Barthelmes D, Merz TM, et al. High incidence of optic disc swelling at very high altitudes. Arch Ophthalmol. 2008;126: 644–50. 26. Ronen R, Zhou D, Bafna V, et al. The genetic basis of chronic mountain sickness. Physiology (Bethesda). 2014;29:403–12. 27. Hackett PH, Roach RC. High-altitude illness. N Engl J Med. 2001;345:107–14. 28. Swenson ER. Carbonic anhydrase inhibitors and high altitude illnesses. Subcell Biochem. 2014;75:361–86. 29. Pichon A, Connes P, Quidu P, et al. Acetazolamide and chronic h y p o x i a : e ff e c t s o n h a e m o r h e o l o g y a n d p u l m o n a r y haemodynamics. Eur Respir J. 2012;40:1401–9. 30. Ulrich S, Nussbaumer-Ochsner Y, Vasic I, et al. Cerebral oxygenation in patients with OSA: effects of hypoxia at altitude and impact of acetazolamide. Chest. 2014;146:299–308. 31. Neyra JA, Alvarez-Maza JC, Novak JE. Anuric acute kidney injury induced by acute mountain sickness prophylaxis with acetazolamide. J Investig Med High Impact Case Rep. 2014;2: 2324709614530559. 32. Kayser B, Dumont L, Lysakowski C, et al. Reappraisal of acetazolamide for the prevention of acute mountain sickness: a systematic review and meta-analysis. High Alt Med Biol. 2012;13:82–92. 33.•• Low EV, Avery AJ, Gupta V, et al. Identifying the lowest effective dose of acetazolamide for the prophylaxis of acute mountain sickness: systematic review and meta-analysis. BMJ. 2012;345:e6779. Overview of evidence supporting acetazolamine in preventing mountain sickness from decades of clinical trials. 34. Basnyat B, Gertsch JH, Holck PS, 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;7: 17–27. 35.• Gertsch JH, Lipman GS, Holck PS, et al. Prospective, double-blind, randomized, placebo-controlled comparison of acetazolamide versus ibuprofen for prophylaxis against high altitude headache: the Headache Evaluation at Altitude Trial (HEAT). Wilderness Environ Med. 2010;21:236–43. One of a few comparative studies in the treatment of acute altitude related headache. 36. Penninga L, Wetterslev J, Penninga EI, et al. Acetazolamide for the prevention of acute mountain sickness: time to move on. High Alt Med Biol. 2013;14:85–6. 37. Richalet JP, Rivera-Ch M, Maignan M, et al. Acetazolamide for Monge’s disease: efficiency and tolerance of 6-month treatment. Am J Respir Crit Care Med. 2008;177:1370–6. 38. Leshem E, Caine Y, Rosenberg E, et al. Tadalafil and acetazolamide versus acetazolamide for the prevention of severe high-altitude illness. J Travel Med. 2012;19:308–10. 39. Kayser B, Hulsebosch R, Bosch F. Low-dose acetylsalicylic acid analog and acetazolamide for prevention of acute mountain sickness. High Alt Med Biol. 2008;9:15–23.
40.
41.
42.
43. 44.
45. 46.
47.
48.
49. 50. 51. 52.
53.
54.•
55.
56. 57.
58. 59.
60. 61.
62.
Basnyat B, Hargrove J, Holck PS, et al. Acetazolamide fails to decrease pulmonary artery pressure at high altitude in partially acclimatized humans. High Alt Med Biol. 2008;9:209–16. Canalese J, Gimson AE, Davis C, et al. Controlled trial of dexamethasone and mannitol for the cerebral oedema of fulminant hepatic failure. Gut. 1982;23:625–9. Severinghaus JW. Hypothetical roles of angiogenesis, osmotic swelling, and ischemia in high-altitude cerebral edema. J Appl Physiol (1985). 1995;79:375–9. Subedi BH, Pokharel J, Goodman TL, et al. Complications of steroid use on Mt. Everest. Wilderness Environ Med. 2010;21:345–8. Hackett PH, Roach RC, Wood RA, et al. Dexamethasone for prevention and treatment of acute mountain sickness. Aviat Space Environ Med. 1988;59:950–4. Johnson TS, Rock PB, Fulco CS, et al. Prevention of acute mountain sickness by dexamethasone. N Engl J Med. 1984;310:683–6. Maggiorini M, Brunner-La Rocca HP, Peth S, et al. Both tadalafil and dexamethasone may reduce the incidence of high-altitude pulmonary edema: a randomized trial. Ann Intern Med. 2006;145: 497–506. Fischler M, Maggiorini M, Dorschner L, et al. Dexamethasone but not tadalafil improves exercise capacity in adults prone to highaltitude pulmonary edema. Am J Respir Crit Care Med. 2009;180:346–52. Hackett PH, Roach RC, Hartig GS, et al. The effect of vasodilators on pulmonary hemodynamics in high altitude pulmonary edema: a comparison. Int J Sports Med. 1992;13 Suppl 1:S68–71. Terry RW. Nifedipine therapy in angina pectoris: evaluation of safety and side effects. Am Heart J. 1982;104:681–9. Bartsch P, Maggiorini M, Ritter M, et al. Prevention of high-altitude pulmonary edema by nifedipine. N Engl J Med. 1991;325:1284–9. Koul PA, Khan UH, Hussain T, et al. High altitude pulmonary edema among BAmarnath Yatris^. Lung India. 2013;30:193–8. Deshwal R, Iqbal M, Basnet S. Nifedipine for the treatment of high altitude pulmonary edema. Wilderness Environ Med. 2012;23:7– 10. Archer SL, Michelakis ED. Phosphodiesterase type 5 inhibitors for pulmonary arterial hypertension. N Engl J Med. 2009;361:1864– 71. Jin B, Luo XP, Ni HC, et al. Phosphodiesterase type 5 inhibitors for high-altitude pulmonary hypertension: a meta-analysis. Clin Drug Investig. 2010;30:259–65. Excellent review of clinical trials and rationale for the use of these newer treatments for mountain sickness and pulmonary hypertension. Ghofrani HA, Reichenberger F, Kohstall MG, et al. Sildenafil increased exercise capacity during hypoxia at low altitudes and at Mount Everest base camp: a randomized, double-blind, placebocontrolled crossover trial. Ann Intern Med. 2004;141:169–77. Perimenis P. Sildenafil for the treatment of altitude-induced hypoxaemia. Expert Opin Pharmacother. 2005;6:835–7. Ge RL, Helun G. Current concept of chronic mountain sickness: pulmonary hypertension-related high-altitude heart disease. Wilderness Environ Med. 2001;12:190–4. Rabinstein AA. Treatment of cerebral edema. Neurologist. 2006;12:59–73. Singh I, Chohan IS. Reversal of abnormal fibrinolytic activity, blood coagulation factors and platelet function in high-altitude pulmonary oedema with frusemide. Int J Biometeorol. 1973;17:73–81. Hultgren HN. Letter: furosemide for high altitude pulmonary edema. JAMA. 1975;234:589–90. Arancibia A, Nella GM, Paulos C, et al. Effects of high altitude exposure on the pharmacokinetics of furosemide in healthy volunteers. Int J Clin Pharmacol Ther. 2004;42:314–20. Basnyat B, Holck PS, Pun M, et al. Spironolactone does not prevent acute mountain sickness: a prospective, double-blind, randomized, placebo-controlled trial by SPACE Trial Group (spironolactone and
Curr Pain Headache Rep (2015) 19:9 acetazolamide trial in the prevention of acute mountain sickness group). Wilderness Environ Med. 2011;22:15–22. 63. Rodway GW, Windsor JS, Hart ND. Supplemental oxygen and hyperbaric treatment at high altitude: cardiac and respiratory response. Aviat Space Environ Med. 2007;78:613–7. 64. Jay GD, Tetz DJ, Hartigan CF, et al. Portable hyperbaric oxygen therapy in the emergency department with the modified Gamow bag. Ann Emerg Med. 1995;26:707–11. 65. Butler GJ, Al-Waili N, Passano DV, et al. Altitude mountain sickness among tourist populations: a review and pathophysiology supporting management with hyperbaric oxygen. J Med Eng Technol. 2011;35:197–207. 66. Freeman K, Shalit M, Stroh G. Use of the Gamow Bag by EMTbasic park rangers for treatment of high-altitude pulmonary edema and high-altitude cerebral edema. Wilderness Environ Med. 2004;15:198–201. 67. Moraga FA, Flores A, Serra J, et al. Ginkgo biloba decreases acute mountain sickness in people ascending to high altitude at Ollague (3696 m) in northern Chile. Wilderness Environ Med. 2007;18:251–7. 68. Chow T, Browne V, Heileson HL, et al. Ginkgo biloba and acetazolamide prophylaxis for acute mountain sickness: a randomized, placebo-controlled trial. Arch Intern Med. 2005;165:296–301. 69. Gertsch JH, Basnyat B, Johnson EW, et al. Randomised, double blind, placebo controlled comparison of Ginkgo biloba and
Page 7 of 7 9 acetazolamide for prevention of acute mountain sickness among Himalayan trekkers: the Prevention of High Altitude Illness Trial (PHAIT). BMJ. 2004;328:797. 70. Jafarian S, Gorouhi F, Salimi S, et al. Low-dose gabapentin in treatment of high-altitude headache. Cephalalgia. 2007;27: 1274–7. 71. Burtscher M, Likar R, Nachbauer W, et al. Ibuprofen versus sumatriptan for high-altitude headache. Lancet. 1995;346:254–5. 72. Utiger D, Eichenberger U, Bernasch D, et al. Transient minor improvement of high altitude headache by sumatriptan. High Alt Med Biol. 2002;3:387–93. 73. Jafarian S, Gorouhi F, Salimi S, et al. Sumatriptan for prevention of acute mountain sickness: randomized clinical trial. Ann Neurol. 2007;62:273–7. 74. Kupper TE, Strohl KP, Hoefer M, et al. Low-dose theophylline reduces symptoms of acute mountain sickness. J Travel Med. 2008;15:307–14. 75. Berilgen MS, Mungen B. A new type of headache, headache associated with airplane travel: preliminary diagnostic criteria and possible mechanisms of aetiopathogenesis. Cephalalgia. 2011;31: 1266–73. 76. Pfund Z, Trauninger A, Szanyi I, et al. Long-lasting airplane headache in a patient with chronic rhinosinusitis. Cephalalgia. 2010;30: 493–5.
UNCOMMON AND/OR UNUSUAL HEADACHES AND SYNDROMES (J AILANI, SECTION EDITOR)
High-Altitude Headache Michael J. Marmura & Pablo Bandres Hernandez
# Springer Science+Business Media New York 2015
Abstract High-altitude headache is one of many neurological symptoms associated with the ascent to high altitudes. Cellular hypoxia due to decreased barometric pressure seems to be the common final pathway for headache as altitude increases. Susceptibility to high-altitude headache depends on genetic factors, history of migraine, and acclimatization, but symptoms of acute mountain sickness are universal at very high altitudes. This review summarizes the pathophysiology of acute mountain sickness and high-altitude headache as well as the evidence for treatment and prevention with different drugs and devices which may be useful for regular and novice mountaineers. This includes an examination of other headache disorders which may mimic high-altitude headache. Keywords High-altitude headache . Acute mountain sickness . Hypoxia . Pathophysiology
Introduction Headache is a very common symptom resulting from travel to high-altitude destinations, and high-altitude headache (HAH) This article is part of the Topical Collection on Uncommon and/or Unusual Headaches and Syndromes M. J. Marmura Department of Neurology, Thomas Jefferson University, Philadelphia, PA, USA P. B. Hernandez Department of Neurology, Hospital Fundación Alcorcón, Madrid, Spain M. J. Marmura (*) Jefferson Headache Center, Jefferson Hospital for Neuroscience, 900 Walnut Street, Suite 200, Philadelphia, PA 19107, USA e-mail: [email protected]
is a recognized headache disorder [1]. About 80 % of persons report headache as a symptom with ascent to high altitudes, especially with rapid ascent and very high altitude [2]. At altitudes over 4500 m, headache is extremely common [2]. HAH is part of the syndrome of altitude or mountain sickness, which may also include shortness of breath, sleep disturbance, fatigue, anorexia, nausea, and dizziness [3]. HAH is considered a disorder of homoeostasis by the International Headache Society in the International Classification of Headache Disorders (ICHD-3β). ICHD-3β defines HAH as a headache which develops in association with ascent to altitudes of at least 2500 m and resolves within 24 h of descent to less than 2500 m. To meet these criteria, the headache should have two or three characteristics: bilateral location, mild-moderate intensity, and aggravation by exertion, movement, straining, and/or bending. Like migraine, HAH may be associated with irritability, nausea, and anorexia, but other migraine features such as unilateral location, photophobia, and phonophobia are atypical for pure HAH. A Bpulsatile-burst type quality^ and Boscillating evolution^ are common descriptors [4]. Risk factors for headache in mountaineers include low oxygen saturation, poor fluid intake, exertion, and a personal history of migraine [5•, 6]. Given that migraine is a risk factor for HAH, and that high altitude can be a trigger for migraine, there can be considerable clinical overlap. A single case report described high altitude as a trigger for cluster headache in a 40-year-old woman with a prior history of episodic cluster which responded to oxygen treatment [7]. Retinal venous distension on ophthalmologic exam and radiographic narrowing of transverse sinus may predict hypoxemia and risk of HAH [2, 8]. Oral contraceptive use, which decreases circulating progesterone levels, may also increase HAH risk [9]. Preacclimatized individuals are much less likely to develop HAH [10].
9
Curr Pain Headache Rep (2015) 19:9
Page 2 of 7
Pathophysiology
Table 1 Definitions of altitude illness from the 1991 International Hypoxia Symposium
Although the percentage of oxygen in air remains the same at higher altitudes (about 21 %), HAH is caused by decreased barometric pressure, resulting in a lower percentage of oxygen molecules per breath. At 3600 m, barometric pressure is only 480 mmHg, compared with 760 mmHg at sea level. This reduction of the partial pressure of oxygen in inspired air, especially with coughing or bending, compromises the supply of oxygen to the tissues resulting in HAH and mountain sickness. The body acclimates to higher altitudes by increasing respiration, producing more red blood cells to carry oxygen, and increasing pressure in pulmonary capillaries [2]. Erythropoietin-induced polycythemia and increased cerebral blood flow may also occur. The length of time required to acclimate varies from person to person, and a slower rate of ascent can prevent HAH. Ethnic groups with a long history of living at high altitudes such as Sherpas frequently have genetic adaptations such as angiotensin-converting enzyme gene polymorphisms which allow better performance at high altitude [11]. Biomarkers suggest anti-inflammatory and anti-permeability to bloodbrain barrier factors are protective in persons less prone to developing HAH [12]. Experienced mountaineers are also less likely to develop symptoms [13]. Acute mountain sickness (AMS) is a syndrome, defined as the presence of headache in an unacclimatized person who has recently arrived at an altitude above 2500 m plus the presence of one or more of the following: gastrointestinal symptoms (anorexia, nausea, or vomiting), insomnia, dizziness, lightheadedness, or fatigue. Symptoms could present as early as 1 h after ascent but usually develop within 6 to 10 h after ascent. The Lake Louise Consensus Group also established a scoring system to evaluate AMS and establish severity of illness [14]. Table 1 reviews the basic categories of altitude sickness. Mild AMS presents headache with nausea, dizziness, and fatigue during the first 12 h after rapid ascent (above 2500 m). Moderate AMS presents moderate-to-severe headache with marked nausea, dizziness or lightheadedness, insomnia, and fluid retention at high altitude for 12 h or more. The brain is very sensitive to hypoxia, and the most severe symptoms of AMS are neurologic. High-altitude cerebral edema is the end stage of AMS and presents with varying degrees of confusion, gait ataxia, psychiatric changes, and disturbances of consciousness that could progress to deep coma. Other significant neurologic disturbances may include the following [2]:
Diagnosis
Criteriaa
Acute mountain sickness (AMS)
Headache and at least one of the following: (1) Anorexia, nausea, or vomiting; fatigue or weakness (2) Dizziness or lightheadedness (3) Difficulty sleeping A change in mental status and/or ataxia in a person with AMS or Both mental status changes and ataxia in a person without AMS Symptoms—at least two of the following: (1) Dyspnea at rest (2) Cough (3) Weakness or decreased exercise performance (4) Chest tightness or congestion Signs—at least two of the following: (1) Crackles or wheezing in at least one lung field (2) Central cyanosis (3) Tachypnea (4) Tachycardia
&
Transient ischemic attacks (TIA), possibly related to vasospasm or hypoxia. Persons with a history of recent TIA or stroke within 90 days should not travel to high altitudes [15].
High-altitude cerebral edema
High-altitude pulmonary edema
a
All of the following must occur in the setting of a recent gain in altitude
&
Stroke related to right-to-left shunting, with secondary increased risk of embolism if there is patient foramen ovale. This is more commonly reported in association with decompression sickness in divers [16]. Transient global amnesia [17, 18]. Cerebral venous thrombosis as a result of volume depletion and polycythemia. Hypercoagulable disorders such as hyperhomocysteinemia and protein C or S deficiency may increase risk [19–21]. Seizures due to hyperventilatory hypocapnia and hypoxia or cerebral edema [22]. High-altitude syncope, due to a vasovagal phenomenon. Heart rates remain elevated after 2 weeks at high altitude [23]. Cranial nerve palsies, being the sixth cranial nerve most commonly affected (also facial and hypoglossal nerve palsies reported) [24]. Ophthalmological disturbances, such as retinal hemorrhages, amaurosis fugax, and cortical blindness. Optic nerve swelling at very high altitudes is common [25]. Sleep disturbances.
& &
& & & & &
Chronic mountain sickness (CMS), also known as Monge’s disease, can develop after living at high altitudes for a long time and is characterized by polycythemia, headache, dizziness, tinnitus, breathlessness, sleep disturbance, fatigue, and mental confusion. Pulmonary hypertension and stroke due to polycythemia are a few of the most serious manifestations. Genetic factors likely explain the increased incidence in certain populations [26].
Curr Pain Headache Rep (2015) 19:9
Treatment Mild HAH should resolve with analgesics, such as acetaminophen and ibuprofen, but further management consists of hydration and halting the ascent and descent if there are no signs of improvement. HAH should resolve after 10 to 15 min of supplementary oxygen, or spontaneously 24 h after descent [1]. Avoiding medications which can decrease respiratory drive such as opioids, barbiturates, or benzodiazepines and sedating medications is recommended for HAH [27]. Mild AMS management may consist of halting the ascent or a descent of 500 m or more, acclimatizing for 24 h, or rapid acclimatization with acetazolamide (125 to 250 mg twice daily) as well as treating the symptoms with a combination of analgesics and antiemetics [28]. Ibuprofen is likely effective based on a placebo-controlled study [29]. Another study noted no difference between ibuprofen 400 mg and acetaminophen 1000 mg [30]. Aspirin, with a dose of 320 mg given every 4 h beginning 2 h before ascent, is more effective than placebo in preventing HAH [5•]. Moderate AMS treatment includes also descending 300 to 500 m with acetaminophen, ibuprofen, dexamethasone, and acetazolamide (125 to 250 mg twice daily). Specific treatments are discussed below. Acetazolamide Acetazolamide (125–250 mg twice per day) is effective for AMS therapy and prophylaxis. Acetazolamide causes bicarbonate diuresis with consequent metabolic acidosis and increase of ventilation by inhibiting renal carbonic anhydrase. Other non-carbonic anhydrase mechanisms are also likely important such as reductions in the production of CSF and promotion of ion transport across blood-brain barrier [28]. In animal models of chronic mountain sickness, acetazolamide appears to decrease blood viscosity and alter pulmonary vascular resistance and erythropoiesis [29]. Acetazolamide is effective in improving cerebral tissue oxygenation, even in persons with obstructive sleep apnea [30]. Acetazolamide commonly produces alterations in taste and paresthesia and less commonly nausea, polyuria, or diarrhea. Acute kidney injury is a rare complication [31]. The effectiveness of acetazolamide for prevention and treatment of AMS has been evaluated in multiple randomized placebo-controlled trials. The number needed to treat to prevent one case of AMS with acetazolamide varies from two to eight persons depending on the rate of ascent (lower for more rapid ascents) and dose [32]. The lowest effective daily dose appears to be 250 mg and, in one study, was equally effective as 750 mg/day [33••, 34]. There is less evidence that acetazolamide is effective for HAH. One study reported ibuprofen prophylaxis with 600 mg three times daily was equally effective for prevention of HAH and AMS; some experts question it as the definitive acute treatment of
Page 3 of 7 9
choice for HAH and AMS [35•, 36]. For CMS, however, a low dose of 250 mg/day appears to be very effective with relatively few side effects [37]. One study suggested that combination treatment with the phosphodiesterase type 5 inhibitor, tadalafil, was more effective than acetazolamide alone. Another study found that the acetylsalicylic acid analog calcium carbasalate was not effective compared to acetazolamide 500 mg/day [38, 39]. Acetazolamide may not be effective in decreasing pulmonary artery pressures and treating highaltitude pulmonary edema [40]. Dexamethasone Dexamethasone is a corticosteroid which acts by reducing the release of cytokines and capillary permeability, which is especially useful in the treatment of high-altitude cerebral edema. Dexamethasone is a known effective treatment for cerebral edema from tumors or other medical illnesses such as hepatic failure [41]. Dexamethasone is particularly useful due to its effects on both osmotic cell swelling and its inhibition of angiogenesis [42]. Significant side effects may occur, especially with longer-term use, such as gastrointestinal bleeding, rash, avascular necrosis, and adrenal crisis [43]. A clinical trial of soldiers being transported from sea level to up to 4400 m found that 4 mg dexamethasone (either oral or intramuscular) every 6 h starting 48 h prior to decompression or ascent was more effective than low doses or placebo for preventive AMS [44]. Another study found dexamethasone 4 mg every 6 h to be more effective than placebo for both AMS and symptoms such as HAH [45]. A randomized trial of climbers with rapid ascent (from 500 to 5000 m) found that both dexamethasone and tadalafil were both effective in the prevention of highaltitude pulmonary edema, although there was a trend for better efficacy with dexamethasone [46]. A separate trial, however, suggested that dexamethasone was more effective for improving exercise capacity at altitude than tadalafil [47]. Nifedipine Nifedipine is a calcium channel blocker which reduces pulmonary-artery pressure and is a vasodilator and is used in the treatment of hypertension, angina, and Raynaud’s phenomenon, among other disorders. Its effectiveness in preventing AMS and high-altitude pulmonary edema is likely related to pulmonary vascular changes. These effects may be seen with other vasodilators such as hydralazine or phentolamine which have not been studied for AMS [48]. Common side effects of nifedipine include bradycardia or tachycardia (often with initial doses) and hypotension [49]. Nifedipine is effective in prevention of high-altitude pulmonary edema in susceptible individuals at doses of 20 mg or greater. In one trial, a 20-mg extended release preparation of nifedipine was more effective than placebo in preventing high-altitude
9
Curr Pain Headache Rep (2015) 19:9
Page 4 of 7
pulmonary edema subjects with a proven history of the disorder. Nifedipine was superior in terms of symptom score, pulmonary-artery pressure, and alveolar-arterial pressure gradient [50]. The effectiveness of nifedipine for HAH, AMS, or the acute treatment of high-altitude pulmonary edema is less clear, although it is often used [51]. In one trial of persons with established AMS already receiving supplemental oxygen therapy and bed rest, nifedipine was not superior to placebo [52].
Oxygen Along with slow acclimatization and descent, oxygen is a standard and proven treatment for HAH and AMS. Hyperbaric oxygen, along with supplemental oxygen, is effective for AMS and other complications of high altitude [63]. Portable hyperbaric chambers, also known as Gamow Bags, are effective for the elimination of carboxyhemoglobin in the emergency department and for AMS and cerebral or pulmonary edema at high altitude [64–66].
Phosphodiesterase Type 5 Inhibitors Phosphodiesterase type 5 inhibitors, including sildenafil and tadalafil, are oral medications used for the treatment of erectile dysfunction. Common side effects include headache and severe hypotension in persons taking concurrent nitric oxide donors. Phosphodiesterase type 5 inhibitors prevent the action of cGMP-specific phosphodiesterase type 5 on cyclic GMP in the smooth muscle cells, including the lungs, suggesting they may be effective as a treatment for pulmonary hypertension [53]. Reducing pulmonary hypertension, leading to increased cerebral and peripheral oxygenation, is a goal in the treatment of highaltitude pulmonary edema. Multiple trials have shown that these medications lower systolic pulmonary artery pressure more than controls [54•]. In one trial, sildenafil 50 mg increased exercise capacity and arterial oxygen saturation. Two patients noted HAH with treatment [55]. Sildenafil 40 mg three times daily also lowered oxygen consumption and systolic pulmonary artery pressure in another study of 12 subjects at high altitude [56]. The effectiveness of tadalafil for AMS and high-altitude pulmonary edema has been evaluated in comparative trials with dexamethasone [46, 47]. Sildenafil may also be effective in the treatment of CMS [57].
Furosemide Furosemide is a loop diuretic which produces rapid diuresis and is occasionally used for the treatment of cerebral edema [58]. A few small studies have suggested furosemide 40– 80 mg as a treatment for both AMS and either high-altitude pulmonary or cerebral edema based on its diuretic effect, changes in platelet function and blood viscosity [59, 60]. Interestingly, exposure to high altitude appears to increase in the free fraction of furosemide and possibly its effectiveness [61]. The most common side effect of furosemide is diuresis which may potentially lead to dehydration. Therefore, furosemide is used as an acute treatment along with other measures for AMS and pulmonary or cerebral edema, rather than a preventive measure. The diuretic spironolactone at 100 mg/day does not appear effective against AMS [62].
Others A small study found that Ginkgo biloba at a dose of 80 mg every 12 h starting 24 h before ascent was effective in preventing AMS in inexperienced hikers [67]. Two other studies using different Ginko formulations failed to demonstrate superiority or placebo and were inferior to acetazolamide [68, 69]. In another study, the anticonvulsant gabapentin 300 mg improved HAH severity and headache-free time and reduced need for additional analgesics compared to placebo [70]. There is conflicting evidence regarding the effectiveness of sumatriptan, a selective serotonin agonist for migraine, in HAH or AMS. A small study found a non-significant trend favoring ibuprofen 600 mg as superior to sumatriptan 100 mg for acute treatment HAH and AMS [71]. Another report noted only mild differences between sumatriptan 100 mg and placebo for HAH [72]. In a preventive trial, subjects using sumatriptan 50 mg prior to ascent were less likely to develop either HAH or AMS [73]. Theophylline is a methyl xanthine drug used for asthma and chronic obstructive pulmonary disease which relaxes bronchial smooth muscle and blocks the action of adenosine. A small study of 17 subjects randomized to either theophylline 300 mg daily for 5 days prior to and during ascent or placebo reported significantly reduced symptoms of AMS and oxygen desaturations at 4559 m in the theophylline group [74].
Other Related Headache Disorders Headache attributed to airplane travel is described as a severe, unilateral, and periocular headache without autonomic symptoms which occurs exclusively during airplane travel [1]. Airplane headache is most likely to happen during descent prior to landing or less commonly during initial ascent after takeoff. The location is usually unilateral, orbitofrontal but parietal spread may occur. Commonly, it is a jabbing or stabbing headache but pulsation may also occur. The headache usually improves spontaneously 30 min after landing [75]. Unlike HAH, airplane headache is felt to be related to individual
Curr Pain Headache Rep (2015) 19:9
abnormalities of sinus cavities and the Bvacuum effect^ triggered by decreased oxygen saturations [76]. Other headache disorders may be precipitated by hypoxia and/or hypercapnia. Diving headache, triggered by diving below 10 m in the absence of decompression illness, is an example of headache essentially due to hypercapnia. Symptoms mimic those of carbon dioxide intoxication including mental confusion, lightheadedness, motor incoordination, dyspnea, and facial flushing [1]. A partial pressure of carbon dioxide in arterial blood over 50 mmHg is known to cause smooth muscle relaxation and consequent intracranial vasodilatation with increased intracranial pressure. It is unclear if the mechanism of sleep apnea headache is related to hypoxia, hypercapnia, or disturbance in sleep. Sleep apnea headache is usually characterized by a bilateral morning headache of less than 4 h which resolves with successful treatment of the sleep apnea [1]. The pain quality is usually pressing and may present with concurrent nausea, photophobia, or phonophobia.
Page 5 of 7 9
References Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance 1. 2. 3. 4.
5.•
6.
7.
Conclusion HAH is a common symptom in those travelling to high altitude, especially persons with no prior acclimatization and rapid ascent, as part of AMS. Allowing extra time for ascent and preventive treatment with analgesics or acetazolamide may prevent the development of HAH and AMS. For acute treatment of HAH, oxygen, halting ascent, or descending to lower altitudes is effective. Simple analgesics and dexamethasone are likely effective in the treatment of HAH. Dexamethasone appears to be effective in both the acute and preventive treatment of HAH and AMS. Nifedipine or phosphodiesterase type 5 inhibitors may prevent AMS and cerebral or pulmonary edema, but there is no evidence for their use to treat HAH. Sumatriptan may not be effective for HAH but may be considered in patients with concurrent migraine.
8.
9.
10.
11.
12.
13.
14.
Acknowledgments Thanks to Gail Iannarella for assistance in preparing this manuscript.
15.
Compliance with Ethics Guidelines
16.
Conflict of Interest Dr. Michael J. Marmura reports royalties from Cambridge, Demos Medical, and Medlink Neurology. Dr. Pablo Bandres Hernandez declares no potential conflicts of interest.
17.
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.
18. 19.
Olesen J. ICHD-3 beta is published. Use it immediately. Cephalalgia. 2013;33:627–8. Wilson MH, Newman S, Imray CH. The cerebral effects of ascent to high altitudes. Lancet Neurol. 2009;8:175–91. Porcelli MJ, Gugelchuk GM. A trek to the top: a review of acute mountain sickness. J Am Osteopath Assoc. 1995;95:718–20. Serrano-Duenas M. High altitude headache. A prospective study of its clinical characteristics. Cephalalgia. 2005;25: 1110–6. Burtscher M, Mairer K, Wille M, et al. Risk factors for high-altitude headache in mountaineers. Cephalalgia. 2011;31:706–11. Overview of important risk factors for headache in those travelling to high altitudes. Arregui A, Cabrera J, Leon-Velarde F, et al. High prevalence of migraine in a high-altitude population. Neurology. 1991;41:1668– 9. Mampreso E, Maggioni F, Viaro F, et al. Efficacy of oxygen inhalation in sumatriptan refractory Bhigh altitude^ cluster headache attacks. J Headache Pain. 2009;10:465–7. Wilson MH, Davagnanam I, Holland G, et al. Cerebral venous system and anatomical predisposition to high-altitude headache. Ann Neurol. 2013;73:381–9. Harrison MF, Anderson P, Miller A, et al. Oral contraceptive use and acute mountain sickness in South Pole workers. Aviat Space Environ Med. 2013;84:1166–71. Jackson SJ, Varley J, Sellers C, et al. Incidence and predictors of acute mountain sickness among trekkers on Mount Kilimanjaro. High Alt Med Biol. 2010;11:217–22. Droma Y, Hanaoka M, Basnyat B, et al. Adaptation to high altitude in Sherpas: association with the insertion/deletion polymorphism in the angiotensin-converting enzyme gene. Wilderness Environ Med. 2008;19:22–9. Julian CG, Subudhi AW, Wilson MJ, et al. Acute mountain sickness, inflammation, and permeability: new insights from a blood biomarker study. J Appl Physiol (1985). 2011;111:392–9. Mairer K, Wille M, Burtscher M. The prevalence of and risk factors for acute mountain sickness in the Eastern and Western Alps. High Alt Med Biol. 2010;11:343–8. Sutton JR, Coates G, Houston CS. The Lake Louise consensus on the definition and quantification of altitude illness. In: Sutton JR, Coates G, Houston CS, editors. Hypoxia and mountain medicine. Burlington: Queen City Printers; 1992. Baumgartner RW, Siegel AM, Hackett PH. Going high with preexisting neurological conditions. High Alt Med Biol. 2007;8: 108–16. Saary MJ, Gray GW. A review of the relationship between patent foramen ovale and type II decompression sickness. Aviat Space Environ Med. 2001;72:1113–20. Litch JA, Bishop RA. Transient global amnesia at high altitude. N Engl J Med. 1999;340:1444. Bucuk M, Tomic Z, Tuskan-Mohar L, et al. Recurrent transient global amnesia at high altitude. High Alt Med Biol. 2008;9:239–40. Fujimaki T, Matsutani M, Asai A, et al. Cerebral venous thrombosis due to high-altitude polycythemia. Case report. J Neurosurg. 1986;64:148–50.
9 20.
Curr Pain Headache Rep (2015) 19:9
Page 6 of 7
Boulos P, Kouroukis C, Blake G. Superior sagittal sinus thrombosis occurring at high altitude associated with protein C deficiency. Acta Haematol. 1999;102:104–6. 21. Hassan KM, Kumar D. Reversible diencephalic dysfunction as presentation of deep cerebral venous thrombosis due to hyperhomocysteinemia and protein S deficiency: documentation of a case. J Neurosci Rural Pract. 2013;4:193–6. 22. Daleau P, Morgado DC, Iriarte CA, et al. New epilepsy seizure at high altitude without signs of acute mountain sickness or high altitude cerebral edema. High Alt Med Biol. 2006;7:81–3. 23. Thomas KN, Burgess KR, Basnyat R, et al. Initial orthostatic hypotension at high altitude. High Alt Med Biol. 2010;11:163–7. 24. Virmani SK, Swamy AS. Cranial nerve palsy at high altitude. J Assoc Physicians India. 1993;41:460. 25. Bosch MM, Barthelmes D, Merz TM, et al. High incidence of optic disc swelling at very high altitudes. Arch Ophthalmol. 2008;126: 644–50. 26. Ronen R, Zhou D, Bafna V, et al. The genetic basis of chronic mountain sickness. Physiology (Bethesda). 2014;29:403–12. 27. Hackett PH, Roach RC. High-altitude illness. N Engl J Med. 2001;345:107–14. 28. Swenson ER. Carbonic anhydrase inhibitors and high altitude illnesses. Subcell Biochem. 2014;75:361–86. 29. Pichon A, Connes P, Quidu P, et al. Acetazolamide and chronic h y p o x i a : e ff e c t s o n h a e m o r h e o l o g y a n d p u l m o n a r y haemodynamics. Eur Respir J. 2012;40:1401–9. 30. Ulrich S, Nussbaumer-Ochsner Y, Vasic I, et al. Cerebral oxygenation in patients with OSA: effects of hypoxia at altitude and impact of acetazolamide. Chest. 2014;146:299–308. 31. Neyra JA, Alvarez-Maza JC, Novak JE. Anuric acute kidney injury induced by acute mountain sickness prophylaxis with acetazolamide. J Investig Med High Impact Case Rep. 2014;2: 2324709614530559. 32. Kayser B, Dumont L, Lysakowski C, et al. Reappraisal of acetazolamide for the prevention of acute mountain sickness: a systematic review and meta-analysis. High Alt Med Biol. 2012;13:82–92. 33.•• Low EV, Avery AJ, Gupta V, et al. Identifying the lowest effective dose of acetazolamide for the prophylaxis of acute mountain sickness: systematic review and meta-analysis. BMJ. 2012;345:e6779. Overview of evidence supporting acetazolamine in preventing mountain sickness from decades of clinical trials. 34. Basnyat B, Gertsch JH, Holck PS, 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;7: 17–27. 35.• Gertsch JH, Lipman GS, Holck PS, et al. Prospective, double-blind, randomized, placebo-controlled comparison of acetazolamide versus ibuprofen for prophylaxis against high altitude headache: the Headache Evaluation at Altitude Trial (HEAT). Wilderness Environ Med. 2010;21:236–43. One of a few comparative studies in the treatment of acute altitude related headache. 36. Penninga L, Wetterslev J, Penninga EI, et al. Acetazolamide for the prevention of acute mountain sickness: time to move on. High Alt Med Biol. 2013;14:85–6. 37. Richalet JP, Rivera-Ch M, Maignan M, et al. Acetazolamide for Monge’s disease: efficiency and tolerance of 6-month treatment. Am J Respir Crit Care Med. 2008;177:1370–6. 38. Leshem E, Caine Y, Rosenberg E, et al. Tadalafil and acetazolamide versus acetazolamide for the prevention of severe high-altitude illness. J Travel Med. 2012;19:308–10. 39. Kayser B, Hulsebosch R, Bosch F. Low-dose acetylsalicylic acid analog and acetazolamide for prevention of acute mountain sickness. High Alt Med Biol. 2008;9:15–23.
40.
41.
42.
43. 44.
45. 46.
47.
48.
49. 50. 51. 52.
53.
54.•
55.
56. 57.
58. 59.
60. 61.
62.
Basnyat B, Hargrove J, Holck PS, et al. Acetazolamide fails to decrease pulmonary artery pressure at high altitude in partially acclimatized humans. High Alt Med Biol. 2008;9:209–16. Canalese J, Gimson AE, Davis C, et al. Controlled trial of dexamethasone and mannitol for the cerebral oedema of fulminant hepatic failure. Gut. 1982;23:625–9. Severinghaus JW. Hypothetical roles of angiogenesis, osmotic swelling, and ischemia in high-altitude cerebral edema. J Appl Physiol (1985). 1995;79:375–9. Subedi BH, Pokharel J, Goodman TL, et al. Complications of steroid use on Mt. Everest. Wilderness Environ Med. 2010;21:345–8. Hackett PH, Roach RC, Wood RA, et al. Dexamethasone for prevention and treatment of acute mountain sickness. Aviat Space Environ Med. 1988;59:950–4. Johnson TS, Rock PB, Fulco CS, et al. Prevention of acute mountain sickness by dexamethasone. N Engl J Med. 1984;310:683–6. Maggiorini M, Brunner-La Rocca HP, Peth S, et al. Both tadalafil and dexamethasone may reduce the incidence of high-altitude pulmonary edema: a randomized trial. Ann Intern Med. 2006;145: 497–506. Fischler M, Maggiorini M, Dorschner L, et al. Dexamethasone but not tadalafil improves exercise capacity in adults prone to highaltitude pulmonary edema. Am J Respir Crit Care Med. 2009;180:346–52. Hackett PH, Roach RC, Hartig GS, et al. The effect of vasodilators on pulmonary hemodynamics in high altitude pulmonary edema: a comparison. Int J Sports Med. 1992;13 Suppl 1:S68–71. Terry RW. Nifedipine therapy in angina pectoris: evaluation of safety and side effects. Am Heart J. 1982;104:681–9. Bartsch P, Maggiorini M, Ritter M, et al. Prevention of high-altitude pulmonary edema by nifedipine. N Engl J Med. 1991;325:1284–9. Koul PA, Khan UH, Hussain T, et al. High altitude pulmonary edema among BAmarnath Yatris^. Lung India. 2013;30:193–8. Deshwal R, Iqbal M, Basnet S. Nifedipine for the treatment of high altitude pulmonary edema. Wilderness Environ Med. 2012;23:7– 10. Archer SL, Michelakis ED. Phosphodiesterase type 5 inhibitors for pulmonary arterial hypertension. N Engl J Med. 2009;361:1864– 71. Jin B, Luo XP, Ni HC, et al. Phosphodiesterase type 5 inhibitors for high-altitude pulmonary hypertension: a meta-analysis. Clin Drug Investig. 2010;30:259–65. Excellent review of clinical trials and rationale for the use of these newer treatments for mountain sickness and pulmonary hypertension. Ghofrani HA, Reichenberger F, Kohstall MG, et al. Sildenafil increased exercise capacity during hypoxia at low altitudes and at Mount Everest base camp: a randomized, double-blind, placebocontrolled crossover trial. Ann Intern Med. 2004;141:169–77. Perimenis P. Sildenafil for the treatment of altitude-induced hypoxaemia. Expert Opin Pharmacother. 2005;6:835–7. Ge RL, Helun G. Current concept of chronic mountain sickness: pulmonary hypertension-related high-altitude heart disease. Wilderness Environ Med. 2001;12:190–4. Rabinstein AA. Treatment of cerebral edema. Neurologist. 2006;12:59–73. Singh I, Chohan IS. Reversal of abnormal fibrinolytic activity, blood coagulation factors and platelet function in high-altitude pulmonary oedema with frusemide. Int J Biometeorol. 1973;17:73–81. Hultgren HN. Letter: furosemide for high altitude pulmonary edema. JAMA. 1975;234:589–90. Arancibia A, Nella GM, Paulos C, et al. Effects of high altitude exposure on the pharmacokinetics of furosemide in healthy volunteers. Int J Clin Pharmacol Ther. 2004;42:314–20. Basnyat B, Holck PS, Pun M, et al. Spironolactone does not prevent acute mountain sickness: a prospective, double-blind, randomized, placebo-controlled trial by SPACE Trial Group (spironolactone and
Curr Pain Headache Rep (2015) 19:9 acetazolamide trial in the prevention of acute mountain sickness group). Wilderness Environ Med. 2011;22:15–22. 63. Rodway GW, Windsor JS, Hart ND. Supplemental oxygen and hyperbaric treatment at high altitude: cardiac and respiratory response. Aviat Space Environ Med. 2007;78:613–7. 64. Jay GD, Tetz DJ, Hartigan CF, et al. Portable hyperbaric oxygen therapy in the emergency department with the modified Gamow bag. Ann Emerg Med. 1995;26:707–11. 65. Butler GJ, Al-Waili N, Passano DV, et al. Altitude mountain sickness among tourist populations: a review and pathophysiology supporting management with hyperbaric oxygen. J Med Eng Technol. 2011;35:197–207. 66. Freeman K, Shalit M, Stroh G. Use of the Gamow Bag by EMTbasic park rangers for treatment of high-altitude pulmonary edema and high-altitude cerebral edema. Wilderness Environ Med. 2004;15:198–201. 67. Moraga FA, Flores A, Serra J, et al. Ginkgo biloba decreases acute mountain sickness in people ascending to high altitude at Ollague (3696 m) in northern Chile. Wilderness Environ Med. 2007;18:251–7. 68. Chow T, Browne V, Heileson HL, et al. Ginkgo biloba and acetazolamide prophylaxis for acute mountain sickness: a randomized, placebo-controlled trial. Arch Intern Med. 2005;165:296–301. 69. Gertsch JH, Basnyat B, Johnson EW, et al. Randomised, double blind, placebo controlled comparison of Ginkgo biloba and
Page 7 of 7 9 acetazolamide for prevention of acute mountain sickness among Himalayan trekkers: the Prevention of High Altitude Illness Trial (PHAIT). BMJ. 2004;328:797. 70. Jafarian S, Gorouhi F, Salimi S, et al. Low-dose gabapentin in treatment of high-altitude headache. Cephalalgia. 2007;27: 1274–7. 71. Burtscher M, Likar R, Nachbauer W, et al. Ibuprofen versus sumatriptan for high-altitude headache. Lancet. 1995;346:254–5. 72. Utiger D, Eichenberger U, Bernasch D, et al. Transient minor improvement of high altitude headache by sumatriptan. High Alt Med Biol. 2002;3:387–93. 73. Jafarian S, Gorouhi F, Salimi S, et al. Sumatriptan for prevention of acute mountain sickness: randomized clinical trial. Ann Neurol. 2007;62:273–7. 74. Kupper TE, Strohl KP, Hoefer M, et al. Low-dose theophylline reduces symptoms of acute mountain sickness. J Travel Med. 2008;15:307–14. 75. Berilgen MS, Mungen B. A new type of headache, headache associated with airplane travel: preliminary diagnostic criteria and possible mechanisms of aetiopathogenesis. Cephalalgia. 2011;31: 1266–73. 76. Pfund Z, Trauninger A, Szanyi I, et al. Long-lasting airplane headache in a patient with chronic rhinosinusitis. Cephalalgia. 2010;30: 493–5.
