Acute mountain sickness, high-altitude cerebral edema, and high-altitude pulmonary edema are some of the well-documented complications of rapid ascent to high altitude. Cerebrovascular diseases have also been reported at high-altitude, mostly in the form of small descriptive studies, though there are more published data related to cerebral venous thrombosis (CVT) as compared to stroke [67,68,69,70]. Altitudes are categorized into six levels: low (less than 1500 m), intermediate (1500–2500 m), high (2500–3500 m), very high (3500–5800 m), extreme high (above 5800 m), and the “death zone” (above 8000 m) [71].

Studies reporting the impact of higher altitudes on stroke have yielded inconsistent findings. One of the reasons for inconsistency is the limited stroke epidemiological data of the long-term high-altitude inhabitants, even though >5% of the worldwide population lives above 1500 m and millions of people are chronically exposed to hypobaric hypoxia. Cerebral autoregulation is compromised at high altitudes, affecting not only individuals residing chronically at high altitudes but also newcomers to such environments [72]. High altitudes also lead to various physiological adaptations in the human body, including, but not limited to, elevated hemoglobin and hematocrit levels, lung volume changes, and heightened orthostatic tolerance [73].

Several studies have reported an increased risk of thrombosis and ischemic stroke at high altitudes, mostly above 2500 m [74,75,76,77,78,79]. These patients living at high altitudes with ischemic stroke were predominantly male and were of younger age, with a mean age of 40 years at the time of stroke diagnosis [74,75,77,78,79,80]. A study by Lu et al. in 2020, comparing patients with acute ischemic stroke (AIS) in Tibet (higher altitude of 3650 m) and Beijing (lower altitude of 40 m), found that the patients diagnosed with AIS in Tibet were generally younger than those in Beijing (58.19 vs. 65.10 years; p < 0.001) [79]. One study specifically looking at the radiologically proven strokes found that among 4000 high-altitude residents under 40 years, there were 10 radiologically proven strokes, compared to only 1 among 4000 low-altitude residents of the same age group [74]. There are multiple plausible explanations for these effects. A decrease in atmospheric pressure at high altitudes causes hypoxia that may result in compensatory hyperventilation, tachycardia, vasoconstriction, erythrocytosis, and increased blood viscosity increasing the risk for thromboembolic complications [79].

On the other hand, a Swiss ecological study in 2009 reported decreased stroke mortality at higher altitudes (259–1960 m), with a 12% decreased stroke mortality per 1000 m gained in elevation. These results were statistically significant even after adjusting for potential vascular confounders [81]. Additionally, three separate ecological studies from the United States, Austria, and Ecuador, respectively, also reported similar results that living at moderately high altitudes (<3500 m) have a beneficial effect on ischemic heart disease and stroke mortality [82,83,84]. The protective effects were more pronounced within the altitude range of 2000 to 3500 m [84]. An observational study in sub-himalayan region of India also reported a reduction in stroke incidence among hospitalized patients at a moderate altitude of 2000 m [85]. The possible explanations for these effects could be a better adaptation to hypoxia and the involvement of hypoxia-inducible factor (HIF), which is a transcription factor and has been found to provide resistance against ischemia and improve cardiac function. HIF senses cellular hypoxia and helps cells adapt and survive in a hypoxic environment by upregulating erythropoietin, promoting angiogenesis, and increasing glycolysis [86].

Air travel is now a common occurrence, with nearly 2 billion people traveling annually [87]. Fortunately, flight-related strokes are rare. Commercial planes typically fly at an average peak altitude ranging from 33,000 to 42,000 feet (~10,000 to 12,800 m), while still maintaining the intra-cabin air pressure [88]. However, flights have been associated with an increased risk of deep venous thrombosis and pulmonary embolism, a connection often referred to as the “economy class syndrome” [87,89]. This is thought to be due to paradoxical embolism through a patent foramen ovale (PFO) [89], although the role of PFO in ischemic stroke even in the general population remains unclear. Humaidan et al. published a case series of 42 patients with flight-related strokes and found paradoxical embolism in only 17% of cases, a figure lower than expected. They observed a wide range of etiologies similar to those seen in general stroke patients [87]. Another case series of 44 patients (32 with AIS, 12 with Transient Ischemic Attacks) revealed paradoxical emboli in 18% of their patients. They also noted a higher frequency of high-grade carotid stenosis and occlusion in their cohort (12 patients, 27%). Furthermore, 67% of the strokes linked to high-grade carotid stenosis or occlusion occurred on longer flights (>4 h) [90]. It is hypothesized that in individuals with already compromised carotid perfusion, the combination of dehydration and a decrease in cabin air pressure leading to hypoxemia may increase the risk of stroke [90].

The present knowledge about altitude and stroke indicates that high altitudes of >3500 m increase the risk of ischemic stroke but when people reside between 1500 to 2500 m, there appears to be a protective effect for stroke, possibly due to better adaptation to hypoxia [82,83,84,91]. However, it is unclear at what point this protective effect turns into a risk factor. It is also important to note that the observed differences between residents of high and low altitudes could potentially be influenced by genetic variations. In conclusion, the association between high altitude and stroke is complex and elusive. Researchers need large-scale studies to firmly establish the connection between altitude and stroke.