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Monitoring long-term effects on vision in microgravity a priority for NASA’s future flight to Mars

Issue: June 25, 2015

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NASA is banding together with thought leaders in ophthalmology and industry to try to remedy vision problems encountered by astronauts in space for lengthy periods of time. The hope is that in-flight monitoring and treatments will counter the detrimental effects of living in essentially a gravity-free environment.

“When you are in space, you do not have gravity like we do on Earth,” OSN Chief Medical Editor Richard L. Lindstrom, MD, said. “In the head, gravity assists blood return to the heart. But in weightlessness, not only is this assist absent, but up to 2 L of fluid shifts headward from the lower body. The core etiology is probably related to elevated venous pressure, which then causes an elevated cerebral spinal fluid pressure. This can result in disc edema and choroidal swelling.”

Lindstrom is one of a handful of ophthalmologists and industry leaders with diverse backgrounds who convened twice last fall as part of a special advisory group to the National Space Biomedical Research Institute (NSBRI) in Houston, a NASA-funded consortium.

“After 8 to 12 weeks in space, some astronauts start to shift hyperopic, developing blurry vision at distance,” Lindstrom said.

The cause is swelling of the choroid, flattening of the globe shortening the axial length of the eye and sometimes associated disc edema. “This presents additional requirements for corrective lenses inflight for astronauts as they try to do their work,” Lindstrom said.

German astronaut Alexander Gerst using the Spectralis OCT on board the International Space Station.

Source: NASA

Some astronauts who have experienced disc edema have also had suggestive mild transient visual field defects. However, after returning to Earth, “they do not demonstrate any permanent vision loss, at least so far,” Lindstrom said. Returning to space a second time may exacerbate the situation.

NASA’s Journey to Mars is targeted to get underway around 2030, with the roundtrip journey taking up to 950 days. With such a long flight, there is concern that the astronauts’ vision might progress to severe visual loss or even blindness. “To date, there have been no solutions,” Lindstrom said.

Richard L. Lindstrom

Through a literature search, Lindstrom and others have found rare instances of a similar syndrome on Earth with progressive hyperopic shift, papilledema and choroidal swelling. The condition is called “idiopathic benign progressive hyperopia with choroidal folds and papilledema” and has been reported in a small number of patients not exposed to space travel. The cause of this condition is unknown, but this Earth-bound syndrome and the space-induced changes seem similar.

Overall, it appears men are more prone to developing vision problems in space. NASA medical researchers have found that the cardiovascular risk profile among male astronauts, although clinically normal, is higher compared with female astronauts, suggesting that men may have slightly stiffer blood vessels that may contribute to higher cerebral spinal fluid pressure in space.

Unique technologies

In addition to NASA medical monitoring and a significant research effort in ocular health, NASA has asked the NSBRI to participate in this ocular research effort. NSBRI began in 1997, but it has only been since October 2014 that the institute emphasized ocular health, starting with its Vision for Mars Challenge to accelerate unique technologies for both space and terrestrial applications. In addition to funding by NSBRI for three selected companies, money was earmarked for medical community education, including a workshop, for a total of close to $500,000 to date, according to Dorit B. Donoviel, PhD, deputy chief scientist and industry forum lead at NSBRI. The grants awarded were matched at 100% by private funds, creating a unique public-private partnership.

“I would say, next to radiation, vision in space is one of the highest risks for human health, specifically space flight-induced intracranial hypertension with vision alterations,” Donoviel said.

The first published paper to report this new ocular syndrome in astronauts and suggest there is an elevation of intracranial pressure leading to papilledema appeared in Ophthalmology in 2011, in which the authors state “that the optic nerve and ocular changes we describe may result from cephalad fluid shifts brought about by prolonged microgravity exposure.”

Donoviel is optimistic that this syndrome can be effectively addressed.

“We are trying to develop mechanical countermeasures to what we believe is a major contributing factor: fluid shifts that occur in the microgravity environment,” she said. “The fluids move upward toward the head. We feel that is affecting some of the ocular structures in a negative way.”

NSBRI is developing mechanical ways to redistribute fluid, such as with garments and devices, plus investigating mechanically adjusting pressure in the eye itself.

One of the three company awards is to Annidis in Grandville, Mich., for its RHA multispectral ophthalmoscope, which is already on the market.

“Frankly, this device appears to me, and others agree as well, the best-kept secret in ophthalmology,” Donoviel said. “You are provided very precise images of every layer of the retina, from front to back. In addition, the Annidis RHA is likely to detect a retinal pathology, due to a fluid shift, much earlier than OCT.”

At the moment, though, the ophthalmoscope would likely not be used in space, but rather before and after flight. “We do not really understand what these incredible resolutions mean clinically, so we funded Annidis to do a clinical study comparing OCT and RHA in patients at risk for papilledema,” Donoviel said.

Another award was given to Web Vision Centers Group LLC of South Jordan, Utah, led by Bob Main. The company is partnering with a variety of vision lens manufacturers to provide astronauts with prescription-adjustable lenses for space.

“It turns out that because of these fluid shifts, your vision changes in the space environment,” Donoviel said. Several options will be developed by the company and evaluated by NSBRI’s astronaut advisers. “Electronic glasses is one example, in which a computer will change the prisms in the lenses, which will alter the prescription,” Donoviel said. Magnetic lenses that can be physically switched out is another possibility.

John P. Berdahl, MD, is the founder and CEO of Equinox LLC in Sioux Falls, S.D. Started in 2014, Equinox received the third NSBRI grant for Balance Goggles, which are environmental chambers designed to control the pressure inside the eye.

John P. Berdahl

“We are basically trying to balance out intraocular pressure and intracranial pressure,” Berdahl said. “By manipulating the IOP up or down, we can balance that to whatever the intracranial pressure is.”

The device is in the preclinical stage with some proof-of-concept work.

“I think there is a real chance that these goggles can benefit astronauts going to Mars,” Berdahl said. “But presently, we have to ask the right questions and do the right science to see if we are right.”

Some versions of the goggles will be specifically designed for astronaut use and available in about 2 years. A commercial product launch, however, is likely 3 to 4 years away. If successful, the proposal would be for astronauts to wear Balance Goggles while sleeping, for about 8 hours of daily wear.

“When the first man or woman steps on Mars, it is going to be a defining moment for the human race,” Berdahl said. “We are hoping to play a small role in that. Perhaps our technology can also spur other ideas.”

In addition to the $100,000 from NSBRI, Equinox has raised in a seed round from angel investors and prize money from competitions enough money to develop and test early prototypes. The technology might also be used on Earth to treat diseases of the optic nerve, such as glaucoma and intracranial hypertension.

Berdahl is the lead author of a 2012 article on the translaminar pressure gradient in sustained zero gravity, idiopathic intracranial hypertension and glaucoma that appeared in Medical Hypotheses.

“This paper is a review of what we think is going on for the physiology of the eye in space,” he said. “It is generally believed that it takes roughly 3 months in space before vision problems occur, although some individuals will start to show signs and symptoms before then.”

Some astronauts, though, have been in space for a full 6 months without any ocular adverse events.

VIIP

To date, there have been 48 U.S. astronauts who have flown on the International Space Station, according to Christian A. Otto, MD, MMSc, the lead scientist for the NASA Vision Impairment and Intracranial Pressure (VIIP) Risk program. Of those 48 astronauts, 33 have so far been classified via refractive change, MRI of the brain, OCT of the retina, funduscopy and ocular ultrasound. Among these 33 individuals, 22 have been confirmed as having signs and symptoms of VIIP, whereas 11 have been designated as non-cases. The astronauts with VIIP have been further classified, with roughly one-third expressing the most severe manifestation, which is optic disc edema.

“We are calling it disc edema because we have not measured intracranial pressure in flight,” Otto said.

Clinical findings for VIIP include hyperopic shift, choroidal folds, optic nerve sheath distention, globe flattening and edema of the optical disc.

Christian A. Otto

“The most common manifestation of the VIIP syndrome is hyperopic shift, caused likely by engorgement of the choroid,” Otto said. “We have also had seven cases of disc edema and three cases of cotton wool spots.”

All of the astronauts so far have been corrected back to 20/20 upon return to the ground.

“Only a handful of astronauts have had permanent refractive changes.” Otto, senior scientist at the Universities Space Research Association in Houston, said.

“NASA is planning missions to Mars lasting up to 3 years, so the concern is that if this disc edema is allowed to persist, the result may be visual field deficits,” he said.

One mechanical countermeasure used by the Russians, which may also be used to prevent vision change, is a calibrated tourniquet applied to the proximal thigh to partially occlude the venous flow.

“This sequesters volume in the lower limbs that would otherwise move toward the head,” Otto said. “We think that elevated intracranial pressure may be contributing to these vision problems.”

VIIP also shares many of the symptoms of idiopathic intracranial hypertension, which is primarily treated by Diamox (acetazolamide, Duramed Pharmaceuticals) to decrease cerebrospinal fluid production, so both conditions might be treated with the same medication.

“In fact, NASA has the drug on the International Space Station for potential treatment of severe cases of VIIP,” Otto said.

Otto and colleagues believe that the signs and symptoms of VIIP may be ameliorated by selecting individuals for space flight who may be less susceptible to this particular syndrome, decreasing the likelihood of severe vision impairment on longer missions.

Ocular instruments in space

Jane E. Rady, divisional vice president of business development at Abbott Medical Optics, is one of the industry representatives to NSBRI.

“In my business development role, I screen and evaluate a lot of different technologies and small companies, from both a licensing and acquisition perspective,” she said. “So I was able to introduce to NSBRI smaller companies that might provide technologies amenable to the space program.”

Although Abbott Medical Optics does not specifically design or develop technologies for space travel, “that does not preclude future applications for space,” she said.

“The key issue, medically, is that we need to understand how disease progresses in space and then understand when to do treatment and intervention,” Rady said.

For example, astronauts are trained to use Tono-Pens (Reichert Technologies) to measure one another’s IOP while in flight.

In the Prospective Observational Study of Ocular Health in ISS Crews, for which Otto is lead investigator, real-time video downlink enables data sharing with medical operations on the ground. According to the protocol, the following in-flight measurements are made at regular time intervals: funduscopy, OCT, visual acuity, Amsler grid, contrast sensitivity, tonometry with blood pressure, ocular ultrasound, cardiac ultrasound and transcranial Doppler imaging with blood pressure measurement. Pre-flight and post-flight only testing includes refraction, threshold visual field, pupil reflex, extraocular muscle balance, MRI, slit lamp biomicroscopy and high-resolution retinal photography.

Ali A. Tafreshi

“OCT is the technology that has proved most useful for precise, objective, in-flight measurement of retinal structures responsible for vision,” according to Ali A. Tafreshi, medical science liaison for Heidelberg Engineering, which makes the commercially available Spectralis OCT that is used on the International Space Station. The Spectralis system includes a rescan feature that automatically places follow-up scans in precisely the same location, thus bypassing operator variability, according to Tafreshi.

“NASA’s OCT studies have detected minute nerve fiber layer thickening not observable by any other means,” Tafreshi said. “This thickening may represent the first observable pathologic change during space flight, and precise measurement of these changes may be instrumental in the early recognition of microgravity-induced eye and optic nerve changes.”

OCT could be an on-board early-warning system, according to Tafreshi.

“NASA researchers have reported that subtle changes have been documented with Spectralis within the first week in space,” he said.

Although the exact mechanisms of vision changes and susceptibility factors to visual impairment are currently unknown, “there is an expectation that structural imaging of the eye with OCT, along with intracranial pressure (ICP) measurements, can provide the information needed that will pave the way for mitigation strategies,” Tafreshi said. “The same principles can be applied to clinical monitoring of this phenomenon.”

Direct measurements of ICP continuously during space flight “would elicit critical information correlating pressure changes with other adaptive milestones of the body,” Tafreshi said. Even though ICP dynamics are unknown, understanding more about rising and falling pressure “would enable correlation with other body adaptations, such as vascular volume, cardiac output and neurovestibular functions. Several ICP measurement tools are currently in development,” he said.

Terrestrial applications

The Ocular Health study will provide insight regarding structural changes in eyes as well as the nervous system, potentially providing data that may be used to help patients with a range of ocular diseases or with brain disease.

“The difference in IOP and ICP may be very important in the pathogenesis of diseases of the optic nerve, especially glaucoma,” Tafreshi said. “If the translaminar pressure difference is the cause of optic nerve head edema in astronauts subjected to prolonged zero gravity, raising IOP and/or orbital pressure may treat the condition and protect astronauts in future space travels from the effect of zero gravity on the optic nerve head.”

The use of OCT in space has further potential in telemedicine, according to Lindstrom — for example, patient self-monitoring at home of retinal disease such as diabetic macular edema or wet age-related macular degeneration.

“This would be for people who live far, far away from ophthalmologists and retina doctors. These patients might know when to come back for an anti-VEGF injection, for instance,” Lindstrom said.

Donoviel predicted that the ophthalmoscope from Annidis could eventually replace OCT.

“It shows you metabolic activity that right now normally requires injection and more invasive imaging,” she said. “The ophthalmoscope also includes near-infrared light to distinguish oxygenated tissues from non-oxygenated tissues, which you cannot currently do with OCT.”

Donoviel is also enthused about Balance Goggles being used on Earth.

“A lot of patients currently are not fully regulated for their intraocular pressures in glaucoma,” she said. “With Balance Goggles, the pressure can be set and guarantee that the patient will be regulated, at least over a nighttime period, by decreasing pressure and relieving some of the pressure on the eye.”

In addition, the interchangeable lenses and autorefractors from Web Vision Centers Group would be particularly useful to patients with diabetes, “whose prescription changes through the day,” Donoviel said. Ocular surgery patients might also benefit because of varying vision postoperatively.

“Space is a harsh environment,” Berdahl said. “Bone demineralization and ionizing radiation are legitimate concerns. And although there are other long-term health care issues, the immediate concern is that you need to be able to see well while you are in space to do the job you need to do. Solving this problem should be a top priority for ophthalmology and is a top priority for NASA and its teams.” – by Bob Kronemyer

Would prior corneal refractive treatments substantially affect the accuracy of IOP measurement data obtained by astronaut peers using hand-held applanation tonometry during long-term space flight?

Measurements affected but not IOP itself

Refractive surgery does not affect IOP; it only affects the measurement of IOP. That said, the measurement by applanation tonometry can be affected by laser vision correction, whether the measurement is performed here on Earth or in space under microgravity.

Steven C. Schallhorn

The way we measure IOP is not directly measuring the intraocular pressure. It is an indirect measure of IOP, even in space. Applanation tonometry approximates the IOP by measuring the force necessary to flatten a small area of the cornea and is the most commonly used method to assess IOP.

Two eyes with the same actual IOP will have two different applanation tonometry IOP measurements if their corneal thickness is significantly different. Removing a small amount of central tissue from the cornea to correct nearsightedness, for example, can impact how the cornea responds when applanated. In addition, the LASIK flap can alter the biomechanical properties of the eye and also affect the measurement.

Space travel can change IOP, as well as the measurement of IOP, and many now think this is due to fluid shifts in the body. Refractive surgery will change the measurement a bit, but it will not change the IOP.

Steven C. Schallhorn, MD, is a professor of ophthalmology at the University of California, San Francisco. Disclosure: Schallhorn reports no relevant financial disclosures.

Applanation precise in microgravity

This situation brings up the distinction between accuracy and precision in measurements. Accuracy is how close a measurement is to the real value, and precision is how reproducible the measurements are from one to another. Measuring tools can be either one or both. Ideally they are both accurate and precise.

Savak Teymoorian

In this case, hand-held applanation tonometry would be precise but not accurate in the setting of microgravity. It is not, however, the microgravity environment that causes this inaccuracy. The fundamental premise for applanation is the ability to flatten the cornea. As long as the globe and associated cornea remain relatively unchanged going from Earth to space, then the measurements should be precise or reproducible. The trouble with obtaining IOP measurements of the eye in patients with refractive surgery is that the augmentation of the cornea decreases the accuracy of the readings. This augmentation should not significantly change in astronauts who have had prior refractive surgery once they are in space. We would expect to the see the same amount of accuracy, or actually lack of it, on Earth or in space.

If we depend on this amount of accuracy on Earth and anticipate the precision to remain the same in space, then hand-held tonometry should be used in this environment. Remember that IOP in real-life is actually a range of values and not one number. When evaluating glaucoma patients, we take readings on each visit, sometimes more than once on a particular visit, to get a better understanding of this range. If there is not a significant change in the properties of the globe or cornea in space, then the IOP of astronauts should stay near the range measured on Earth. Ultimately, a subtle change in IOP for most patients would not make for a change in treatment.

Savak “Sev” Teymoorian, MD, MBA, is an associate at Harvard Eye Associates in Laguna Hills, Calif. Disclosure: Teymoorian reports no relevant financial disclosures.