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Optic Disc Edema after 30 Days ofStrict Head-down Tilt Bed Rest

As of 2017, optic disc edema has been identified from funduscopyimages in 10 of 68 astronauts (15%) flying long-duration missions tothe International Space Station (ISS).1 Optic disc edema is one of theocular findings that characterizes the spaceflight-associated neuro-ocular syndrome (SANS); however, it has notmanifested during priorexperiments using the spaceflight analog 6� head-down tilt bed rest(HDTBR).2 To more closely replicate the ISS environment, westudied 11 subjects (5 women) before and after 30 days of strictHDTBR in a mild hypercapnic environment (3.8 mmHg ambientpartial pressure of carbon dioxide [PCO2]). Subjects remained inthe strict head-down tilt position 24 hours per day and wereinstructed to not lift their heador raise onto an elbowduringmeals anduse of a standard pillow was prohibited. After approval by theInstitutional Review Boards at the National Aeronautics and SpaceAdministration’s (NASA) Johnson Space Center and the Institute forAerospace Medicine at the German Aerospace Center, opticalcoherence tomography (OCT) (Spectralis Flex Module OCT2, Hei-delberg Engineering, Heidelberg, Germany) images (20��20�, 25lines, ART¼ 25, HR mode) were obtained in seated subjects beforeHDTBR and on the first day of recovery approximately 2 to 3 hoursafter assuming upright posture. The Early Treatment Diabetic Reti-nopathy Study analysis grid was manually centered over the opticdisc and total retinal thickness (TRT) from each quadrant surround-ing the central 1-mm disc was measured, as previously described.2

Based on preliminary review of OCT images, undilated fundusimages were obtained in 5 subjects suspected of ocular structuralchanges. For the first time, we report the development of optic discedema using an Earth-based spaceflight analog. Four subjects werediagnosed with a Modified Frisén Scale grade3 of 1, and 1 subjectwas diagnosed with a grade of 2; the edema was observedbilaterally. Analysis of OCT images provided evidence of asignificant increase in peripapillary TRT from pre- to post-HDTBR in all quadrants. The mean change (95% confidence in-terval) for each quadrant for all subjects was as follows: inferior, 39(18e60) mm; superior, 53 (26e79) mm; nasal, 42 (14e70) mm; andtemporal, 22 (11e33) mm. This increase in TRT is approximately 4to 5 times greater than that observed after the 70-day HDTBRstudy when standard pillow use was permitted and a mild hyper-capnic environment was not used (Fig 1).

This study design of strict HDTBR and a mild hypercapnicenvironment was chosen by NASA to most closely match condi-tions on the ISS to develop a model of SANS using an Earth-basedanalog. As a result, the study design was not intended to differ-entiate which factor(s) were responsible for the outcomes describedhere. We speculate that strict head-down tilt and the associatedhydrostatic pressure gradient at the level of the eye contributed tothe optic disc edema. Data from patients with Ommaya reservoirsdemonstrate that placing the head on a pillow while supineconsistently reduced intracranial pressure (ICP) from 14 to

10 mmHg.4 This finding suggests that previous HDTBR studiesthat allowed subjects use of a standard pillow during dailyactivities, and allowed them to lift the upper torso during meals,may have temporarily relieved the cephalad venous congestionand lowered ICP, thus mitigating the development of optic discedema. Accordingly, because astronauts are unable to “lift theirhead or stand up” while in weightlessness, the impacts of thesustained headward fluid shift may underlie the development ofoptic disc edema during spaceflight. When subjects in this studymaintained a strict head-down tilt position without use of a stan-dard pillow and were not allowed to lift their head and upper bodyto eat during meals, they too demonstrated optic disc edema. Futurestudies should be conducted to differentiate the effects of the stricthead-down tilt from the mild increase in ambient PCO2.

The direct role of a mild increase in ambient PCO2 on the devel-opment of optic disc edema in astronauts on ISS is unexplored.Arterial blood gas measurements have not been conducted duringspaceflight. However, end-tidal PCO2 (PETCO2) measurementsacquired in astronauts during spaceflight,when the ambient PCO2wassimilar to that used in this study (3.8 mmHg), were similar to PETCO2

measured in the supine position on Earth before and after spaceflightwhen breathing room air.5 Similarly, in the current study PETCO2

measured in the 6� head-down tilt position before and on the finalday of bed rest (mean� standard deviation)was 42.1�3.3mmHg and41.7�3.4 mmHg, respectively. These data indicate that our space-flight analog did not alter arterial PCO2 levels, which would likely benecessary for the hypercapnic environment to contribute to thedevelopment of optic disc edema. Comparison of arterialized and/orPETCO2 values throughout HDTBR in control subjects not breathingelevated ambient PCO2 is necessary to confirm these observations.

We observed Frisén Grade edema in w45% of our subjectsafter 30 days of HDTBR, which is higher than the 15% reported inastronauts after ISS missions.1 Both during weightlessness andafter 24 hours of HDTBR, jugular vein area increases without acorresponding increase in ICP,4 suggesting a potential directeffect on venous drainage of the eye. Conversely, the hydrostaticpressure column during 24 hours of HDTBR leads to a sustainedICP similar to supine posture, but weightlessness causes ICP todecrease in the supine posture.4 Whether these factorscontributed to differences in edema incidence between HDTBRand weightlessness, or to the lack of other SANS symptomsobserved here, requires further investigation.

We document the development of optic disc edema and quan-tified peripapillary TRT after 30 days of strict HDTBR in a mildlyhypercapnic environment, suggesting that this novel spaceflightanalog may lead to retinal structure changes similar to SANS. Thismodel should be considered for testing possible countermeasureson Earth that this may prevent or reverse these findings. Whetherlonger-duration HDTBR studies will lead to the development ofadditional ocular changes associated with SANS, or to a greaterincidence or magnitude of change, is unknown. This model ofexperimentally induced optic disc edema in human subjects

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Figure 1. Optic disc edema and increased total retinal thickness. Funduscopic images of the retina and optic disc from both eyes from A, the single subjectdiagnosed with Frisén grade 2 and B, one of the other subjects who received a diagnosis of Frisén grade 1 in both eyes (and a choroidal nevus in the righteye). A, The Frisén grade 2 was classified based on the grayish circumferential halo observed completely around the optic disc, while (B) the Frisén grade 1was classified based on the grayish C-shaped halo with a temporal gap.3 C, Change in global total retinal thickness (TRT) from pre- to post-6� head-downtilt bed rest (HDTBR). Means and 95% confidence intervals are plotted for each peripapillary quadrant from the current and previous studies. Data from thecurrent study in which subjects maintained strict head-down tilt and were in a mild hypercapnic environment are plotted at 30 days of HDTBR (filledsymbols). Data plotted at 14 days and 70 days of HDTBR (open symbols) were from subjects that did not maintain strict head-down tilt and were in anormocapnic environment. Note: Data from each study were collected after exactly 14, 30, and 70 days, respectively, and the symbols have been shifted toprevent overlap and improve visualization. Data from 14 and 70 days of HDTBR are adapted from Taibbi et al.2

Ophthalmology Volume 126, Number 3, March 2019Author's Personal Copy

provides new opportunities to investigate the pathophysiology andpotential treatment options for optic disc edema, both for NASAand for patients on Earth.

STEVEN S. LAURIE, PHD1

BRANDON R. MACIAS, PHD1

JOCELYN T. DUNN, PHD1

MILLENNIA YOUNG, PHD2

CLAUDIA STERN, MD3

STUART M.C. LEE, PHD1

MICHAEL B. STENGER, PHD2

1KBRwyle, Houston, Texas; 2NASA Johnson Space Center, Houston,Texas; 3German Aerospace Center Institute of Aerospace Medicine,Köln, Germany

Financial Disclosures: The authors made the following disclosures:National Aeronautics and Space Administration Human Research Pro-gram grant no. NNJ14ZSA001N (S.S.L.).

HUMAN SUBJECTS: Human subjects were part of this study protocol.The study was approved by the Institutional Review Boards at NASAJohnson Space Center and the Institute for Aerospace Medicine at theGerman Aerospace Center and adhered to the tenets of the Declarationof Helsinki; informed consent was obtained from all subjects.

No animal subjects were included in this study.

Author Contributions:Conception and design: Laurie, Macias, Young, Stern, Lee, StengerData collection: Laurie, Macias, Dunn, Stern, Lee, StengerAnalysis and interpretation: Laurie, Macias, Dunn, Young, Stern, Lee,StengerObtained funding: Laurie, Macias, Lee, StengerOverall responsibility: Laurie, Macias, Dunn, Young, Stern, Lee, Stenger

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Abbreviations and Acronyms:HDTBR ¼ 6� head-down tilt bed rest; ICP ¼ intracranial pressure;ISS ¼ International Space Station; NASA ¼ National Aeronautics andSpace Administration; OCT ¼ optical coherence tomography;PCO2 ¼ partial pressure of carbon dioxide; PETCO2 ¼ end-tidal partialpressure of carbon dioxide; SANS¼ spaceflight-associated neuro-ocularsyndrome; TRT ¼ total retinal thickness.

Correspondence:Steven S. Laurie, PhD, KBRwyle, 2400 NASA Pkwy, Houston, TX77058. E-mail: steven.laurie@nasa.gov.

References

1. Stenger MB, Tarver WJ, Brunstetter T, et al. NASAHuman Research Program Evidence Report: Risk of Space-flight Associated Neuro-ocular Syndrome (SANS). NASAJohnson Space Center; 2017. Available at https://human-researchroadmap.nasa.gov/evidence/reports/SANS.pdf?rnd¼0.434276635495143. Accessed February 15, 2018.

2. Taibbi G, Cromwell RL, Zanello SB, et al. Ocular outcomescomparison between 14- and 70-day head-down-tilt bed rest.Invest Ophthalmol Vis Sci. 2016;57:495e501.

3. Scott CJ, Kardon RH, Lee AG, et al. Diagnosis and grading ofpapilledema in patients with raised intracranial pressure usingoptical coherence tomography vs clinical expert assessment usinga clinical staging scale. Arch Ophthalmol. 2010;128:705e711.

4. Lawley JS, Petersen LG, Howden EJ, et al. Effect of gravity andmicrogravity on intracranial pressure. J Physiol. 2017;595:2115e2127.

5. PriskGK,Fine JM,CooperTK,West JB.Vital capacity, respiratorymuscle strength, and pulmonary gas exchange during long-durationexposure to microgravity. J Appl Physiol. 2006;101:439e447.