NASA research progresses toward understanding ocular consequences of long-duration spaceflights

Although the causes of ocular functional and anatomical changes in astronauts of long-duration spaceflights remain largely unknown, recent studies by NASA are gathering new data. The latest evolutions in OCT technology have brought insights to this research, and substantial efforts are being made to investigate countermeasures to preserve the eye health of crew members.

“Our goal is to determine what causes these changes by investigating weightlessness-induced headward fluid shifts, possible changes in intracranial pressure (ICP), and possible impact of CO₂ concentration, radiation, exercise, diet and genetic predisposition. In addition, our studies investigate why some crew members develop these signs and why some do not,” Michael B. Stenger, PhD, lead of the Cardiovascular and Vision Laboratory at Johnson Space Center, said.

Another part of the research focuses on how to prevent changes.

“Not an easy task, since we don’t know exactly what causes these changes. But we have identified possible contributing factors, for example the headward fluid shift, and therefore can start testing if countermeasures proven to stress the cardiovascular system during spaceflight affect the eye,” he said.

Spaceflight-associated neuro-ocular syndrome

The term spaceflight-associated neuro-ocular syndrome (SANS) has been adopted to describe the neuro-ocular responses to long-duration spaceflight. The former term, visual impairment and intracranial pressure (VIIP) syndrome, was abandoned because the technical definition of vision impairment, that is, best corrected visual acuity of 20/40 or worse in the better eye, did not apply to any of the astronauts.

Source: NASA

“None of the astronauts coming back to Earth were any worse than 20/20 BCVA, so if you go by the letter, there is no vision impairment in astronauts,” Tyson Brunstetter, OD, PhD, a Navy aerospace optometrist who works with astronauts at Johnson Space Center, said.

Evidence that ICP plays a dominant role remains inconclusive.

“We changed the name to SANS to be more inclusive. It encompasses all the signs that we know at this point in time and is open to include other possible factors,” Brunstetter said.

By strict definition, SANS is characterized by the presence of clinically significant disc edema by fundoscopy, which restricts the incidence of SANS in astronauts to 15%. However, new evidence based on OCT shows that most, if not all, long-duration crew members have some level of optic disc edema, which may not appear on fundoscopy.

Disc edema is the most concerning sign because it can potentially lead to permanent vision loss. Other changes may occur, including choroidal folds, cotton wool spots, global flattening with hyperopic shift and retinal hemorrhages in some cases.

“Optic disc edema is the basis for the definition of SANS, but about 60% of long-duration astronauts have at least one of these signs,” Brunstetter said.

Many of the signs disappear when astronauts come back to Earth, but some may persist for years. There have been cases of globe flattening and refractive error persisting for more than 12 years, and there are astronauts who were on long-duration spaceflights decades ago and are still showing choroidal folds today.

“We did not have OCT years ago, but we can say these signs are likely associated with spaceflights. Choroidal folds and hyperopic shift are not something you normally see in a typical terrestrial clinic,” Brunstetter said.

Variables

Some individuals seem to be more susceptible to develop SANS than others, but more data are needed to draw a definitive conclusion. In addition, more testing needs to be conducted in specific groups, such as women, to find out if they are affected in the same way as men. Another group to consider is space-naive astronauts who have not previously flown in space, Brunstetter said.

“This would remove some of the confounding variables, such as the cumulative effects in astronauts who have flown multiple times. Preliminary data suggest that space-naive crew members might have the same incidence of SANS signs as the other crew members,” he said.

There is some evidence that mission duration has a role. One crew member who was in space for 340 days would not have been diagnosed with disc edema if he had been on a typical 6-month mission. At about 200 days, during a medical examination, disc edema was found in the right eye.

“It is important that we understand how duration impacts morphological changes and how persistent disc edema may impact on the visual field. The Mars mission is 3 years, and currently we do not know how this length of time will affect the eye and vision later in life. We are trying to collect as much data as we can to be able to understand and predict these ocular changes during longer missions,” Stenger said.

The Lunar Orbit Platform-Gateway, formerly known as the Deep Space Gateway, is a space station that will be put in orbit around the moon. Unlike the International Space Station, it will be outside of the Earth’s magnetic field, which protects from space radiation.

“Data we collect at this lunar orbit platform may answer our questions on the impact of space radiation. It could be an inflammatory response of the eye and optic nerve, but we don’t have data to support this at the moment,” Stenger said.

Ongoing studies

Flight-induced headward fluid shift, which occurs in absence of gravity, is one of the most likely causes of the alterations that lead to SANS. The NASA Fluid Shifts Study uses noninvasive techniques to evaluate the effects of headward fluid shift on the blood circulation system, eye structures and IOP, as well as ICP. Some research approaches include testing in the seated, supine and 15° whole body head-down position. These test conditions enable researchers to compare the fluid shifts that occur in space to that which occur on the ground during different body posture to determine if spaceflight is like laying down. Also, it might enable researchers to predict who will get SANS by monitoring an astronaut’s response to posture changes.

“Tests so far seem to indicate that elevated ICP is not the issue, as we first thought. But we do see changes in the jugular vein volume and pressure, which may not cause a significant increase in ICP, but there are definitely ocular effects that are likely related. We see choroidal engorgement and retinal thickness changes in most cases, likely due to a venous congestion rather than ICP,” Stenger said.

The study is also investigating how lower-body negative pressure has an effect on ocular variables, with the aim of developing effective mitigation strategies.

The Ocular Health Study is a comprehensive prospective study that gathers data from space missions to assess crew members’ visual health, ocular changes and associated factors, such as cardiovascular state and central nervous system changes.

“One of our early findings is an increase in total retinal thickness near the optic nerve head, which is greater than preflight levels as early as flight day 10 and seems to be persistent in most of the crew members assessed in this project. Choroidal engorgement also occurs frequently,” Brandon Macias, PhD, senior scientist in the Cardiovascular and Vision Laboratory and principal investigator of the Ocular Health Study, said.

Some more recent, intriguing data show a decrease in the axial length and anterior chamber depth.

“Preliminary results had shown that the posterior segment is affected, but it appears that there are small but significant changes also in the anterior part of the eye. We are beginning to understand how these structural modifications impact refraction change and vision, explaining some of the anecdotal reports of blurry vision when looking at objects close up,” he said.

Genetics

Research being led by the Nutritional Biochemistry Laboratory team at the NASA Johnson Space Center is investigating what may predispose some astronauts to develop eye problems while others are less affected.

“In 2012, we published a paper documenting that astronauts who were affected had different blood biochemistry, and these differences existed before flight. We followed that up with a genetic study where we looked at a small number of single nucleotide polymorphisms. In 2016, we published evidence that genetics and B vitamin status were significant predictors of the ophthalmic outcomes,” Scott M. Smith, PhD, lead for the Nutritional Biochemistry Laboratory, said.

While the overall statistical modeling identified genetics and B vitamin status as significant predictors of ophthalmic outcomes, there were also specific gene variants associated with specific ocular changes: the GG form of the MTRR A66G SNP with choroidal folds and cotton wool spots, and the CC variant of C1420T SNP of the gene for the enzyme SHMT1 with optic disc edema. An association was also identified between testosterone response and refractive changes.

“The genetic pathways we have focused on are associated with one-carbon metabolism, which involves several enzymes and B vitamins, including vitamin B12, vitamin B6, folate and riboflavin. Affected astronauts had higher concentrations of four metabolites in this pathway, namely homocysteine, cystathionine, 2-methylcitric acid and methylmalonic acid, and they also had lower serum folate concentrations — all before (and during) flight,” Smith said. “Our follow-on hypothesis paper in 2017 highlighted the fact that genetics and vitamin B status play a key role in a multifactorial phenomenon leading to ocular changes in some astronauts.”

Understanding these processes will provide opportunities for developing prevention strategies, such as B vitamin supplementation of astronauts.

“From a nutrition perspective, we maintain that B vitamin supplementation might be a way to mitigate these effects by improving nitric oxide synthesis and endothelial function, and for now we are trying to gather more background data to support our initial findings and this hypothesis,” Smith said.

Terrestrial analogues of SANS

One way of studying spaceflight-related conditions is by looking at similarities with pathologies that occur on Earth. Interestingly, many of the characteristics of astronauts with ophthalmic changes are shared by women with polycystic ovary syndrome (PCOS).

“We feel that women with PCOS may be an analogous population to study in order to understand how their cerebrovascular system is affected by their genetics, and may be the key to understanding why some astronauts develop these eye issues. In collaboration with the Mayo Clinic, we are studying women with PCOS and women with intracranial hypertension to help establish the genetic link,” Smith said.

Conditions in space are unique, and there are no perfect terrestrial analogues that can be used as disease models, Brunstetter said.

The classic comparison has been with idiopathic intracranial hypertension (IIH), but there are critical differences. Both IIH and SANS produce optic disc edema in many cases, but IIH has a female-to-male ratio of 9-to-1, while no women have been officially diagnosed with SANS when defined by a fundoscopic optic disc edema finding.

“We have more men in space missions, but for sure the rate is not a 9-to-1 female-to-male ratio for SANS. In addition, IIH women are typically obese, whereas SANS astronauts are healthy, athletic individuals,” Brunstetter said.

IIH is also associated with significant symptoms, the main one being clinical headaches in more than 90% of cases, but in SANS the incidence seems to be the same as on the ground. Also, there are no symptoms other than decreased near vision, which is thought to be associated with globe flattening.

“If you keep in mind that most of our astronauts are in their mid to late 40s, some even older, it is obvious that they cannot accommodate to overtake that hyperopic shift. Otherwise, there are no symptoms like headaches or transient vision obscuration or tinnitus, like you oftentimes have with IIH,” Brunstetter said.

Finally, in IIH, retinal folds outnumber choroidal folds whereas for SANS it is the opposite, which may reflect a different pathogenesis.

Countermeasures

The exact cause of SANS is unknown and could be multifactorial, involving CO₂, radiation and potentially other factors in addition to fluid shift.

“The only evidence we have at present is that fluid shift occurs in weightlessness or microgravity, and taking the best we know, NASA is investing on the development of countermeasures,” Alex Huang, MD, PhD, clinical scientist at the Doheny Eye Institute and UCLA, said.

His research on aqueous angiography and the development of the flex arm, which allows using the Spectralis OCT (Heidelberg Engineering) in different body positions, raised the interest of NASA scientists who asked him to get involved in their projects, specifically working at countermeasures.

“In the past, many have worked on countermeasures. One important research tool was the Chibis lower-body negative pressure device, used to reverse headward fluid shift by placing a vacuum on the lower extremities. It is a good countermeasure for fluid shifts, but it is big, expensive and does not allow freedom of movement,” Huang said.

Thigh cuffs, tied on each leg and pumped up at 60 mm Hg to compress the femoral vein, have shown efficacy in mitigating headward fluid shift. A ground-based study tested this countermeasure in 20 healthy participants at Doheny and UCLA. They were studied for 10 minutes in the sitting position, supine position and 15° head-down posture and then for 10 minutes in the 15° head-down posture with thigh cuffs.

“We looked at IOP using pneumotonometry and subfoveal choroidal thickness by OCT using the Spectralis Flex module. IOP significantly increased from upright to supine and further to head-down, but dropped significantly when the thigh cuffs were applied. During head-down tilt, we also observed an increase in [subfoveal choroidal thickness], then reversed with thigh cuffs,” Huang said.

The cuffs used in the study were inflated by a pneumatic pump plugged to a wall outlet for electricity. A newer prototype uses macro- and micromanipulators, similar to those used to tie ski boots. It allows freedom of movement and has already been shown to be similarly effective in another 20 subjects.

“Further studies will look at retinal function by measuring ERG, PERG and VEP,” Huang said.

There are other countermeasures some research propose. One of them is Balance Goggles (Equinox), which are meant to be worn by astronauts during sleep to potentially balance out IOP and ICP. Another one is an impedance threshold breathing device, which lowers the intrathoracic pressure in every respiratory cycle, thus reducing venous congestion in the neck and preventing fluid from accumulating toward the head.

“It will be important to test potential SANS countermeasures during spaceflight during 6-month to 1-year missions,” Macias said.

“Another criticism is that we work with acute stressors to reverse acute changes in the eye, but what we are dealing with in real life is a chronic disease. In other words, we are working on an entity that does not really occur on Earth,” Huang said.

Upcoming study designs will look at longer exposure to microgravity and larger magnitude of exposure to countermeasures. One of them is the Artificial Gravity Study in which gravitational force is simulated by rotation.

“With the head positioned at the center and the feet at the end, by spinning the body at a particular rate, you can create g-force from head to feet. Depending on the rate you spin, you have different levels of stress,” Macias said.

The study is investigating continuous 1 g exposure at the center of mass, which results in about double the amount at the level of the feet. Time of exposure is 30 minutes every day for 60 days at bed-rest position.

Because it is expensive and difficult to bring most of the countermeasures to space, testing them on Earth in acute situations is a first step toward developing more targeted devices.

“Ultimately, once those steps are done, these countermeasures will have to be tested in space,” Huang said.

The role of OCT

Among technologies that assist in preventing, diagnosing and monitoring SANS, OCT has a primary role. The devices used by NASA are often modifications of technologies already in use. For OCT, the addition of a flexible arm to the Spectralis has been instrumental in allowing experiments with the astronauts in supine and head-down body positions.

“This OCT platform has revolutionized our understanding and quantification of eye anatomy during 6-month missions and hopefully future 1-year missions,” Macias said. “Later this year, NASA will acquire an upgraded OCT device that we expect will be able to image deeper into the tissue, helping us to better characterize structural changes.”

OCT angiography will also create new opportunities for investigating how the microvascular structures of the eye might be affected, he said.

“Fundoscopy is vital to the diagnosis of SANS, but OCT has enabled us to see more. Our definition of SANS is likely to evolve over the upcoming years because OCT is providing us with critical, objective, higher-resolution data,” Brunstetter said.

The Spectralis OCT is already used also in the International Space Station. Astronauts are trained to use it and are connected with specialists at Johnson Space Center who guide them in the process and read the images.

“We have great communication capabilities. However, during missions to Mars, the communication lag will be tremendous, up to 40 minutes, and that’s a bridge we have to cross,” Brunstetter said.

Complementary to OCT, devices for functional assessment such as visual field measures or retinal electrophysiology should be measured during spaceflight. It is unclear how these structural changes may impact visual function later in life. – by Michela Cimberle

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• For more information:
• Tyson Brunstetter, OD, PhD, Brandon Macias, PhD, Scott M. Smith, PhD, and Michael B. Stenger, PhD, can be reached at 2101 NASA Parkway, Houston, TX 77058; email: isidro.r.reyna@nasa.gov.
• Alex Huang, MD, PhD, can be reached at Doheny Eye Center, 625 S. Fair Oaks Ave., Suite 285, Pasadena, CA 91105; email: ahuang@doheny.org.

Disclosures: Brunstetter reports he is a Navy aerospace optometrist at Johnson Space Center. Huang reports he is a consultant for Aerie Pharmaceuticals and receives research support from Heidelberg Engineering, Glaukos and Diagnosys. Macias reports he is senior scientist in the Cardiovascular and Vision Laboratory. Smith reports he is lead for the Nutritional Biochemistry Laboratory. Stenger reports he is lead of the Cardiovascular and Vision Laboratory at Johnson Space Center.

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