In this systematic review, 39 articles were included. The authors decided to include all types of articles as the literature within AH is very limited. Therefore, the main purpose was to present and discuss the current evidence on diagnosis, pathophysiology, and treatment of AH. However, a restriction was made in the literature search strategy where only English articles were included. Articles that have not been indexed in PubMed, Scopus and Embase, may have not been included in this review. Despite of this, our systematic review presents 275 AH-patients, which, together give a stereotypical clinical picture of AH.
The cumulative analysis in this review revealed that 127 females (46%) and 148 males (54%) have suffered from AH (275 patients in total). At present, it is difficult to conclude whether gender affects the development of AH. By instance, there was a predominance of males in few studies [4, 6, 26], whereas there was a predominance of females in the study by Bui et al. . Gender difference in some primary headaches has been documented [41, 42], and if similar difference is identified in AH, it will provide knowledge of which particular gender is more susceptible to AH. The mean diagnosis age for AH was 28.7 ± 4.8 years (n = 275/275), while the age at first AH-attack was 26.4 ± 3.8 years (reported by 163/275 patients). These data may indicate that the diagnosis age of AH and the first AH-attack may occur in a relatively young age regardless of gender. There is no explanation on association of age with AH. This needs further investigation to identify whether it is related to pathophysiology of AH or demographic characteristics of travelers.
The stereotypical clinical symptom of AH is an intense unilateral pain locating in the fronto-orbital region. The pain is very severe and is often described as 8–10 on a pain scale from 0 to 10, where 0 is no pain and 10 is the worst imaginable pain [2, 4, 6, 9, 25, 35, 40]. The pain disappears within 30 min in most cases, where it seems that the AH duration might correspond to the duration of take-off and landing. However, there is a smaller group of AH passengers who experience a second-phase headache, which is a mild headache that may last hours to days; but, it may not be considered as a direct continuation of the intense headache that occurs within the airplane.
Onset of AH was found mostly during the descending phase in 210 patients (n = 210/275), followed by ascending phase in 33 patients (n = 33/275) [2, 4, 6, 7, 9, 11, 15–17, 19, 21, 25–28, 35–37, 39, 40], and only 18 patients (n = 18/275) were found to report it both during descending and ascending phase [2, 4, 5, 7, 11, 13, 26]. Based on the findings, AH was found to occur in 138 patients (n = 138/275) [5, 15, 17, 19, 28, 35–37] since their first flight experience.
AH is experienced without accompanying symptoms in almost all cases; but, there are few cases that cannot be considered as part of the stereotypical clinical symptoms of AH [13, 18]. In the current literature, there are 54 patients suffering from migraine [2, 4, 6, 7, 18]. Although there are many who suffer from migraine, it does not indicate that there is a direct link between migraine and AH . In addition, these migraine patients have reported that they experienced AH and not migraine attacks (2,4,6,7,18). Furthermore, 22 patients suffering from tension type headache, did also report a pure AH-attack and not a tension type headache-attack [6, 12, 21]. In relation to sinus infections, only few cases have been reported, where there was an active sinus infection in the passengers who experienced AH . This indicates that AH is a separate headache that is not associated with other headaches and conditions; but, it is currently unclear whether certain headaches or conditions (such as stress and anxiety) are potential risk factors for developing AH.
In 2013, AH was formally classified by IHS, where diagnostic criteria for AH were established . This makes it possible for future studies to use the diagnostic criteria for harmonizing the research within this field (e.g. Bui et al. [2, 25]). It will also make it easier for doctors to diagnose AH at clinic as the criteria can be used identically.
Berilgen et al.  were the first to suggest “sinus barotrauma” as a potential mechanism underlying AH, which has been a key element in the subsequent discussion for AH mechanisms [2–5, 9–14, 18–21, 24–27, 32, 35, 39, 40]. It is well known that imbalance between atmospheric pressure changes and pressure inside the sinuses can cause tissue damage [43–45]. This means, for example, that the pressure in the sinuses is lower than the cabin pressure during the landing [6, 26]. At take-off, the cabin pressure is lower than the sinuses [6, 26]. It has also been shown that the cabin pressure changes during a flight travel, where the cabin pressure will decrease with around by 8 hPa for every 300 m the airplane increases in altitude . The normal altitude for airplanes is 2500 m with a stabilized cabin pressure at 846 hPa .
Berilgen et al.  suggest that the first-degree sinus barotrauma is the key mechanism underlying AH. During the first-degree sinus barotrauma, nerve endings in the ethmoid sinuses, which are invaded by the trigeminal nerve , are affected. This causes pain in the fronto-orbital region [7, 48], which explains that the pain is mainly experienced in the orbital region [2, 4–13, 15–18, 21, 25–28, 35]. The proposal of first-degree sinus barotrauma may be reasonable as it is explained by the fact that neurological examinations, such as CT, MRI, MRA and ENT, have shown normal sinus conditions in several studies [5, 7–13, 15, 17, 18, 21, 26, 35]. However, few studies have shown cases of thickened nasal mucosa among 2 AH-patients with allergy and chronic rhinosinusitis [16, 19]. The patient with allergy was treated with antihistamines and subsequently experienced headache-free flight travels . Data from these studies indicate that thickened nasal mucosa resulted from the allergy and chronic rhinosinusitis and not as a result of the flight travels. Coutinho et al.  suggest that MRI should be used to rule out other conditions including sinus barotrauma. This indicates that Coutinho et al.  have not taken into account the degrees of sinus barotrauma as those are only the second-degree and third-degree that show thickened nasal mucosa . Relative to the pain of AH, the pain usually disappears within 30 min [2, 5–13, 15–19, 21, 25–27, 35], which is consistent with the short-term pain at the first-degree sinus barotraume . However, neurological examinations were not performed on all the presented 275 AH-patients in this review and this should be considered in the future for proper diagnosis of AH at clinic.
It is still unknown which specific substances play a role in the mechanism of AH. Bui et al. have speculated that vasodilation may occur in the cerebral arteries during an AH-attack . One of the substances investigated in that study was PGE2, where PGE2 levels were significantly higher in a group of AH-patients compared with healthy subjects during a simulated flight in a pressure chamber . Wienecke et al. have shown that PGE2 can induce vasodilation in the cerebral arteries and headache in healthy subjects by infusion of PGE2 . Authors suggested that PGE2-induced headache might be due to activation and sensitization of cranial perivascular sensory afferents . As local inflammation may occur in the sinuses during an AH-attack [2–7, 9–14, 18–21, 24–27, 32, 35, 39, 40], it may be reasonable to consider that PGE2 increases as a consequence of this inflammatory condition . This makes PGE2 an interesting potential biomarker for AH and infusion of PGE2 in AH-patients in future studies may provide knowledge whether PGE2 play a role in the AH mechanism.
The theoretical mechanism of AH is mainly based on barotrauma [2–7, 9–14, 18–21, 24–27, 32, 35, 39, 40] and possibly vasodilation in the cerebral arteries . A study by Hiraga et al.  considers the opposite. The authors point out that vasoconstriction may be the cause of AH. The female patient in their study experienced a headache, which lasted for several hours and days when they performed a neurological examination and contraction of her cerebral arteries was seen. Mainardi et al. , however, proposed that patient’s symptoms do not match with the diagnostic criteria for AH and hence it is unclear whether vasoconstriction in the cerebral arteries can be a cause or a consequence of AH. For future studies, it would be valuable to use imaging techniques during a real or simulated flight travel to investigate whether vasoconstriction or vasodilation occurs in the cerebral arteries during an AH-attack.
It has been shown that cortisol levels were significantly higher before and during a simulated flight in a small group of AH-patients compared with a healthy matched group tested in a pressure chamber . Some AH-patients reported that they felt stressed and had anxiety during the simulated flight . In addition, Kararizou et al.  has also presented an AH-patient with anxiety. This might indicate that psychological aspects can also contribute in AH [12, 25]. However, flight passengers frequently present stress and anxiety in dealing with the flight and in most of cases they do not complain of AH. On the contrary, patients who do not have any negative emotional impact may start to present anxiety and stress when they experience AH. Therefore, stress and anxiety could be considered as a consequence of the fearing to develop AH instead of being one of principal pathogenetic mechanisms of AH. If anxiety and stress did have a predominant role in the pathogenesis of AH, then it should be expected that AH may occur in almost every flight, which is not the case.
It may be difficult to run experiments during a real-time flight travel both from practical points and also safety issues. However, an experimental model might be a reasonable alternative that can be used to induce AH, which allows investigating more physiological aspects of AH. Bui et al.  used a pressure chamber to study AH under controlled experimental conditions. In the chamber, pressure changes, which correspond to the changes during take-off and landing, are applied. This study presented occurrence of AH during simulated flight in those who suffer from this condition but not healthy controls . The clinical symptoms of the simulated AH were found similar to the symptoms of the real-time AH-attacks . This indicated that it is possible to use the pressure chamber as a platform experimental model to induce AH and to investigate AH under fully controlled conditions. Furthermore, it can also be used to investigate whether AH is associated with risk factors or comorbidities in future studies.
There is no specific treatment plan for AH, that might be due to the fact that this headache is considered short lasting and terminated after the flight travel is over. However, evidences in the literature demonstrate that some passengers suffering from AH, have been required to take medications to subside the headache. This systematic review, only focused on pharmacological treatment, although there have been cases of non-pharmacological treatments .
Several flight passengers have been self-medicated in order to relieve AH, where only ibuprofen, naproxen, and triptans have been found the most effective [2, 6, 9, 11, 16, 17, 26, 35]. Only Berilgen et al.  have prescribed naproxen to their 21 subjects and all subjects experienced no headache after intake of naproxen before the start of their flights. Today, the effects of ibuprofen, naproxen, and triptans are based on the patient’s own narratives [2, 6, 9, 11, 16, 17, 26, 35]. Therefore, future studies seem necessary to provide a clear guideline as whether or not medications are actually needed and which patient will get the best benefit. Since most studies are based on case series and case reports, it is reasonable to perform future randomized controlled trials (RCTs) on pharmacological treatments of AH. Setting up a double blind RCT, where a control group is given placebo, and the other group, medication (ibuprofen, naproxen or triptans), can reveal the actual effect of medications on AH.
Based on the finding of this review, 6 flight passengers have taken ibuprofen, where 4 of those have experienced a relieving effect [6, 9, 16]. For the naproxen, 24 flight passengers have taken this medication with all experiencing a relieving effect [17, 26, 35]. If PGE2 has a central role in the mechanism of AH, then ibuprofen and naproxen seem reasonable choices, as these medications inhibit COX, reduce elevated levels of PGE2 during an AH-attack, and can abort headaches [25, 50].
Ipekdal et al.  performed a study in 2011 and included 5 patients who took triptans 30 min before flight travels and this prevented development of AH completely . Cumulative findings of this systematic review showed that 12 patients have taken triptans in order to relieve AH [2, 4, 11]. Triptans are a class of drugs developed for abortion of migraine headaches [11, 51–53]. In relation to AH, Ipekdal et al.  have suggested that triptans may cause vasospasms during an AH-attack and thereby prevent it. There is, however, no evidence to present a mechanism-based explanation for use of triptans for AH.
Calcitonin gene-related peptide (CGRP) and vasoactive intestinal peptide (VIP) are believed to play a role in vasodilation in the cerebral arteries leading to development of migraine attacks . Bellamy et al. have shown that CGRP and VIP levels are significantly reduced when patients take triptans during a migraine attack , which is associated with a significant relief of headache . Future studies are required to investigate whether CGRP and VIP also play a role in development of AH. If AH is a result of vasodilation in the cerebral arteries, elevated levels of CGRP and VIP might be seen in AH and triptans that have shown some benefits for AH may act on these headache biomarkers.
The frequencies of AH-attacks are relatively high; 42 flight passengers experience AH in every flight travels and 39 flight passengers experience AH in more than 50% of the flight travels [4–6, 12, 19, 21, 27, 39, 40]. For the rest of 194 AH-patients presented in this systematic review it is not known how often AH occurs. Clinical trials, such as RCTs, seem necessary for better understanding of AH and the value of considering strategic plans for treatment or prevention of AH.