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(Ophthalmic) Space Oddity

Ask spaceflight professionals what the biggest risk of space travel is and you’ll hear a range of answers – radiation, circulation, muscle atrophy. But one leading health concern that’s often overlooked is the risk of visual deterioration. And as technology advances, mankind is increasingly looking to the skies, with astronauts heading to the International Space Station, to asteroids, and to look for evidence of life on Mars – so it’s important to understand all of the health factors that could potentially hold them back.

In 2011, Mader et al. described an array of visual aberrations affecting astronauts after long-duration spaceflight (1). Persistent reports of vision changes prompted NASA to institute the Vision Impairment and Intracranial Pressure (VIIP) program (2), which involves multiple extensive eye examinations before and after each mission – at which point seven astronauts demonstrated ophthalmic anomalies including optic disc edema, globe flattening, choroidal folds, cotton wool spots, retinal nerve fiber layer thickening and reduced near vision (see Table 1). The authors concluded that a potential cause for the changes might be cephalad fluid shift (the upward shift of blood in the body) resulting from prolonged microgravity exposure and causing intracranial hypertension; alternatively, optic nerve sheath compartment syndrome or a combination of the two factors might be at fault. What they didn’t analyze, though, was the initial population. What made those seven astronauts stand out from the approximately 300 whose eyes were examined? Why were they different?

Table 1. Pathologic ophthalmic changes observed and the percentages of astronauts experiencing each change.
Ophthalmic outcome Percentage of astronauts experiencing outcome
Choroidal folds 13% (n=48)
Cotton wool spots 13% (n=39)
Globe flattening 65% (n=34)
Optic disc edema 19% (n=48)
Refractive change (≥0.5 D) 59% (n=32)

Human beings aren’t designed for space, and the plethora of medical issues astronauts still face makes that abundantly clear. Each spaceflight candidate must pass a rigorous battery of tests to ensure not only that they’re in good enough health for the launch, but also that they’re unlikely to encounter any unexpected problems while in a microgravity environment. Although the examinations currently take up to 10 days (3), they don’t include genetic screening – a practice that may one day change as we gain a better understanding of the hereditary factors behind potential problems astronauts may encounter while in space. A recent study involving 49 International Space Station crewmembers has identified a number of those factors and shed light on the genetic reasons some astronauts experience significant vision alterations in space.

In 2012, Sara Zwart and colleagues analyzed the blood and urine of astronauts during and after flight (4). They discovered metabolic differences – in particular, in the folate- and vitamin B12-dependent one-carbon transfer pathway – in those whose vision was most severely affected. Those differences were present even before flight, suggesting that they are a natural variation, rather than an effect of long-term space travel. But these differences constitute only circumstantial evidence – and the researchers needed proof. So, to understand what differences in DNA might be driving both the metabolic and ophthalmic changes, they looked at single nucleotide polymorphisms (SNPs) in the genes of the one-carbon transfer pathway (see Table 2). In addition, because intracranial hypertension in earthbound patients is sometimes associated with high concentrations of androgen hormones, the authors examined the astronauts’ androgen levels and performed non-targeted metabolomics analyses as well (5).

Table 2. One-carbon transfer pathway SNPs investigated during the study. These SNPs were chosen because of their documented effect on circulating concentrations of the pathway metabolite homocysteine, known to be increased in astronauts with ophthalmic ch
SNP Gene Protein Function Number of subjects homozygous Number of subjects heterozygous
MTRR A66G MTRR Methionine synthase reductase Assists the function of the enzyme methionine synthase 10 25
MTHFR A1298C MTHFR Methylenetetrahydrofolate reductase Converts one form of folate into another 6 16
MTHFR C677T       6 19
SHMT C1420T SHMT Serine hydroxymethyltransferase Converts one form of folate into another; converts serine to glycine 3 16
CBS 844ins68 CBS Cystathionine β-synthase Converts homocysteine and serine to cystathionine   8

Eight women and 41 men, each of whom had spent between 52 and 382 total days in space, were examined for the study. Statistical models showed that SNP status had a strong predictive effect on the likelihood of pathologic ophthalmic changes – and that, in some cases (like globe flattening and refractive change), B-vitamin nutritional status formed a further missing piece of the puzzle. But when they broke down the genetic data, the authors found that only two of the SNPs were significantly associated with the vision changes. The G allele of MTRR occurred in 67 percent of choroidal fold cases (vs. 43 percent of those without) and 80 percent of cotton wool spot cases (vs. 46 percent of those without; the C allele of SMHT occurred in 94 percent of optic disc edema cases (vs. 75 percent of those without). Androgens mattered, too; crewmembers with higher pre-flight DHEA were more likely to experience cotton wool spots or refractive changes, and those with elevated in-flight testosterone had a higher likelihood of cotton wool spots. Interestingly, these and several of the astronauts’ other symptoms (increased homocysteine levels, optic disc edema, and retinal nerve fiber layer thickness) correspond with a well-known condition on earth: polycystic ovary syndrome (PCOS). The main difference between the two is that PCOS by its nature affects only women – whereas the astronauts experiencing ophthalmic changes after spaceflight have all been men.

Obviously, the study had its limitations, chief among them the fact that only 49 subjects were investigated. Given the requirements for inclusion, though – namely the need to have spent a significant amount of time on the International Space Station – it’s unlikely that a much larger sample will be possible in the near future. But there are other ways forward, like expanding the pool of tested SNPs to include all genes involved in the one-carbon transfer pathway, or investigating the population-level derivations of the risk alleles. In the meantime, using known differences in SNPs and androgen levels to elucidate the mechanisms behind these vision changes could allow researchers to prevent or treat them in at-risk astronauts – and perhaps even yield better treatments for similar conditions in people on Earth.

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  1. TH Mader et al., “Optic disc edema, globe flattening, choroidal folds, and hyperopic shifts observed in astronauts after long-duration space flight”, Ophthalmology, 118, 2058–2069 (2011). PMID: 21849212.
  2. M Hillen, “VIIP: A space odyssey”, The Ophthalmologist, 11, 30–34 (2014). Available at:
  3. European Space Agency, “Psychological and medical selection process” (2008). Available at: Accessed January 14, 2016.
  4. SR Zwart et al., “Vision changes after spaceflight are related to alterations in folate- and vitamin B-12-dependent one-carbon metabolism”, J Nutr, 142, 427–431 (2012). PMID: 22298570.
  5. SR Zwart et al., “Genotype, B-vitamin status, and androgens affect spaceflight-induced ophthalmic changes”, FASEB J, 30, 141–148 (2016). PMID: 26316272.
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