Development of optic disc edema during 30 days of hypercapnic head-down tilt bed rest is associated with short sleep duration and blunted temperature amplitude.

Sleep and circadian temperature disturbances occur with spaceflight and may, in part, result from the chronically elevated carbon dioxide (CO2) levels on the international space station. Impaired sleep may contribute to decreased glymphatic clearance and, when combined with the chronic headward fluid shift during actual spaceflight or the spaceflight analog head-down tilt bed rest (HDTBR), may contribute to the development of optic disc edema. We determined if strict HDTBR combined with mildly elevated CO2 levels influenced sleep and core temperature and was associated with the development of optic disc edema. Healthy participants (5 females) aged 25-50 yr, underwent 30 days of strict 6° HDTBR with ambient Pco2 = 4 mmHg. Measures of sleep, 24-h core temperature, overnight transcutaneous CO2, and Frisén grade edema were made pre-HDTBR, on HDTBR days 4, 17, 28, and post-HDTBR days 4 and 10. During all HDTBR time points, sleep, core temperature, and overnight transcutaneous CO2 were not different than the pre-HDTBR measurements. However, independent of the HDTBR intervention, the odds ratios {mean [95% confidence interval (CI)]} for developing Frisén grade optic disc edema were statistically significant for each hour below the mean total sleep time (2.2 [1.1-4.4]) and stage 2 nonrapid eye movement (NREM) sleep (4.8 [1.3-18.6]), and above the mean for wake after sleep onset (3.6 [1.2-10.6]) and for each 0.1°C decrease in core temperature amplitude below the mean (4.0 [1.4-11.7]). These data suggest that optic disc edema occurring during HDTBR was more likely to occur in those with short sleep duration and/or blunted temperature amplitude.NEW & NOTEWORTHY We determined that sleep and 24-h core body temperature were unaltered by 30 days exposure to the spaceflight analog strict 6° head-down tilt bed rest (HDTBR) in a 0.5% CO2 environment. However, shorter sleep duration, greater wake after sleep onset, and lower core temperature amplitude present throughout the study were associated with the development of optic disc edema, a key finding of spaceflight-associated neuro-ocular syndrome.

Eye-brain axis in microgravity and its implications for Spaceflight Associated Neuro-ocular Syndrome.

Long-duration human spaceflight can lead to changes in both the eye and the brain, which have been referred to as Spaceflight Associated Neuro-ocular Syndrome (SANS). These changes may manifest as a constellation of symptoms, which can include optic disc edema, optic nerve sheath distension, choroidal folds, globe flattening, hyperopic shift, and cotton wool spots. Although the underpinning mechanisms for SANS are not yet known, contributors may include intracranial interstitial fluid accumulation following microgravity induced headward fluid shift. Development and validation of SANS countermeasures contribute to our understanding of etiology and accelerate new technology including exercise modalities, Lower Body Negative Pressure suits, venous thigh cuffs, and Impedance Threshold Devices. However, significant knowledge gaps remain including biomarkers, a full set of countermeasures and/or treatment regimes, and finally reliable ground based analogs to accelerate the research. This review from the European Space Agency SANS expert group summarizes past research and current knowledge on SANS, potential countermeasures, and key knowledge gaps, to further our understanding, prevention, and treatment of SANS both during human spaceflight and future extraterrestrial surface exploration.

Evaluation of Optic Disc Edema in Long-Duration Spaceflight Crewmembers Using Retinal Photography.

BACKGROUND: Long-duration spaceflight crewmembers are at risk for spaceflight-associated neuro-ocular syndrome (SANS). One of the earliest manifestations of SANS is optic disc edema (ODE), which could be missed using the subjective Frisén scale. The primary objective of this study is to determine the inter-rater and intrarater reliability of Frisén grade for SANS-induced ODE among a trained observer cohort. The secondary objective is to propose a standardized evaluation process for SANS-induced ODE across International Space Station Partner Agencies. METHODS: Retrospective, double-blinded diagnostic study. Preflight and postflight fundus photographs were presented to subject matter experts who identified and graded ODE. Pairs of images were also compared side-by-side for disc ranking. Grader concordance was assessed for Frisén grading and disc ranking. RESULTS: Expert graders identified Grade 1 ODE in 17.35% of images from 62 crewmembers (9 female, mean [SD] age, 47.81 [5.19] years). Grades 2 and 3 were identified less than 2% of the time. Concordance in Frisén grades among pairs of graders was 70.99%. Graders identified a difference in preflight and postflight fundus photographs 17.21% of the time when using disc ranking. Pairs of graders had complete concordance in disc ranking 79.79% of the time. Perfect intrarater agreement between Frisén grade and disc ranking occurred 77.7% of the time. CONCLUSIONS: These findings demonstrate intergrader and intragrader variability when using the Frisén scale to identify SANS-induced ODE, which is typically milder in presentation than terrestrial cases of idiopathic intracranial hypertension. It is possible to miss early ODE on fundoscopy alone, making it insufficient as a sole criterion for the diagnosis of SANS. A more sensitive and objective method of surveillance is necessary to monitor international crewmembers for ODE, perhaps using a multimodal approach that includes technology such as optical coherence tomography.

Optic disc edema during strict 6° head-down tilt bed rest is related to one-carbon metabolism pathway genetics and optic cup volume.

Some astronauts on International Space Station missions experience neuroophthalmological pathologies as part of spaceflight associated neuro-ocular syndrome (SANS). Strict head-down tilt bed rest (HDTBR) is a spaceflight analog that replicates SANS findings and those who had 3-4 risk alleles (G and C alleles from the methionine synthase reductase [MTRR] A66G and serine hydroxymethyltransferase [SHMT1] C1420T, respectively) as compared to 1-2 risk alleles, had a greater increase in total retinal thickness (TRT). The objective of this study was to identify factors that contribute to the individual variability of the development of SANS in a 60 d HDTBR at the German Aerospace Center's:envihab facility, Cologne Germany. 22 of 24 subjects who participated in the HDTBR study provided blood samples for genetic analysis. Total retinal thickness and optic cup volume were measured before and after bed rest. Subjects with 3-4 versus 0-2 risk alleles had greater ΔTRT during and after bed rest, and the model improved with the addition of baseline optic cup volume. This bed rest study confirms that variants of MTRR and SHMT1 are associated with ocular pathologies. Subjects with more risk alleles had the greatest HDTBR-induced ΔTRT, reaffirming that genetics predispose some individuals to developing SANS. Preflight optic cup volume and genetics better predict ΔTRT than either one alone. Whether nutritional supplements can override the genetic influences on biochemistry, physiology, and pathophysiology remains to be tested. These findings have significant implications for both aerospace and terrestrial medicine.

Assessing the effects of artificial gravity in an analog of long-duration spaceflight: The protocol and implementation of the AGBRESA bed rest study.

A comprehensive strategy is required to mitigate risks to astronauts' health, well-being, and performance. This strategy includes developing countermeasures to prevent or reduce adverse responses to the stressors astronauts encounter during spaceflight, such as weightlessness. Because artificial gravity (AG) by centrifugation simultaneously affects all physiological systems, AG could mitigate the effects of weightlessness in multiple systems. In 2019, NASA and the German Aerospace Center conducted a 60-days Artificial Gravity Bed Rest Study with the European Space Agency (AGBRESA). The objectives of this study were to 1) determine if 30 min of AG daily is protective during head down bed rest, and 2) compare the protective effects of a single daily bout (30 min) of AG versus multiple daily bouts (6 × 5 min) of AG (1 Gz at the center of mass) on physiological functions that are affected by weightlessness and by head-down tilt bed rest. The AGBRESA study involved a comprehensive suite of standard and innovative technologies to characterize changes in a broad spectrum of physiological systems. The current article is intended to provide a detailed overview of the methods used during AGBRESA.

Future research directions to identify risks and mitigation strategies for neurostructural, ocular, and behavioral changes induced by human spaceflight: A NASA-ESA expert group consensus report.

A team of experts on the effects of the spaceflight environment on the brain and eye (SANS: Spaceflight-Associated Neuro-ocular Syndrome) was convened by NASA and ESA to (1) review spaceflight-associated structural and functional changes of the human brain and eye, and any interactions between the two; and (2) identify critical future research directions in this area to help characterize the risk and identify possible countermeasures and strategies to mitigate the spaceflight-induced brain and eye alterations. The experts identified 14 critical future research directions that would substantially advance our knowledge of the effects of spending prolonged periods of time in the spaceflight environment on SANS, as well as brain structure and function. They used a paired comparison approach to rank the relative importance of these 14 recommendations, which are discussed in detail in the main report and are summarized briefly below.

Optic disc edema and chorioretinal folds develop during strict 6° head-down tilt bed rest with or without artificial gravity.

Spaceflight associated neuro-ocular syndrome (SANS) is hypothesized to develop as a consequence of the chronic headward fluid shift that occurs in sustained weightlessness. We exposed healthy subjects (n = 24) to strict 6° head-down tilt bed rest (HDTBR), an analog of weightlessness that generates a sustained headward fluid shift, and we monitored for ocular changes similar to findings that develop in SANS. Two-thirds of the subjects received a daily 30-min exposure to artificial gravity (AG, 1 g at center of mass, ~0.3 g at eye level) during HDTBR by either continuous (cAG, n = 8) or intermittent (iAG, n = 8) short-arm centrifugation to investigate whether this intervention would attenuate headward fluid shift-induced ocular changes. Optical coherence tomography images were acquired to quantify changes in peripapillary total retinal thickness (TRT), retinal nerve fiber layer thickness, and choroidal thickness, and to detect chorioretinal folds. Intraocular pressure (IOP), optical biometry, and standard automated perimetry data were collected. TRT increased by 35.9 µm (95% CI, 19.9-51.9 µm, p < 0.0001), 36.5 µm (95% CI, 4.7-68.2 µm, p = 0.01), and 27.6 µm (95% CI, 8.8-46.3 µm, p = 0.0005) at HDTBR day 58 in the control, cAG, and iAG groups, respectively. Chorioretinal folds developed in six subjects across the groups, despite small increases in IOP. Visual function outcomes did not change. These findings validate strict HDTBR without elevated ambient CO2 as a model for investigating SANS and suggest that a fluid shift reversal of longer duration and/or greater magnitude at the eye may be required to prevent or mitigate SANS.

Potential Involvement of the Ocular Glymphatic System in Optic Disc Edema in Astronauts.

INTRODUCTION: A significant proportion of the astronauts who spend extended periods in microgravity develop ophthalmic abnormalities, including optic disc edema, optic nerve sheath distention, globe flattening, chorioretinal folds, hyperopic refractive error shifts, and nerve fiber layer infarcts. A constellation of these neuro-ophthalmic findings has been termed spaceflight-associated neuro-ocular syndrome. An increased understanding of factors contributing to this syndrome is one of the top priorities for ESA and NASA because the length of missions is expected to increase substantially in the future. As discussed in the present article, the very recent discovery of an ocular glymphatic clearance system can potentially help to unlock mechanisms underlying microgravity-induced optic disc edema. Observations pertaining to the ocular glymphatic pathway provide supporting evidence for the hypothesis, originally proposed by our group, suggesting that the glymphatic outflow from the eye into the optic nerve may be impeded under prolonged microgravity conditions, leading to optic disc edema.Wostyn P, De Winne F, Stern C, Mader TH, Gibson CR, De Deyn PP. Potential involvement of the ocular glymphatic system in optic disc edema in astronauts. Aerosp Med Hum Perform. 2020; 91(12):975977.

Optic Disc Edema and Choroidal Engorgement in Astronauts During Spaceflight and Individuals Exposed to Bed Rest.

Importance: Optic disc edema develops in astronauts during long-duration spaceflight and is a risk for all future astronauts during spaceflight. Having a ground-based analogue of weightlessness that reproduces critical features of spaceflight-associated neuro-ocular syndrome will facilitate understanding, preventing, and/or treating this syndrome. Objective: To determine whether the ocular changes in individuals exposed to an analogue of weightlessness are similar to the ocular changes in astronauts exposed to a duration of spaceflight comparable to this analogue of weightlessness. Design, Setting, and Participants: This cohort study, conducted from 2012 to 2018, investigated 11 healthy test participants before, during, and after 30 days of strict 6° head-down tilt bed rest as well as 20 astronauts before and during approximately 30 days of spaceflight. Data were collected at NASA Johnson Space Center, the German Aerospace Center, and on board the International Space Station. Statistical analysis was performed from February 13 to April 24, 2019. Main Outcomes and Measures: Peripapillary total retinal thickness and peripapillary choroid thickness quantified from optical coherence tomography images. Results: Peripapillary total retinal thickness increased to a greater degree among 11 individuals (6 men and 5 women; mean [SD] age, 33.4 [8.0 years]) exposed to bed rest than among 20 astronauts (17 men and 3 women; mean [SD] age, 46.0 [6.0] years), with a mean difference between groups of 37 µm (95% CI, 13-61 µm; P = .005). Conversely, choroid thickness did not increase among the individuals exposed to bed rest but increased among the astronauts, resulting in a mean difference between groups of 27 µm (95% CI, 14-41 µm; P < .001). Conclusions and Relevance: These findings suggest that strict head-down tilt bed rest produces a different magnitude of edema than occurs after a similar duration of spaceflight, and no change in choroid thickness. It is possible that a mild, long-term elevation in intracranial pressure experienced by individuals exposed to bed rest is greater than the intracranial pressure experienced by astronauts during spaceflight, which may explain the different severity of optic disc edema between the cohorts. Gravitational gradients that remain present during bed rest may explain the lack of increase in choroid thickness during bed rest, which differs from the lack of gravitational gradients during spaceflight. Despite the possibility that different mechanisms may underlie optic disc edema development in modeled and real spaceflight, use of this terrestrial model of spaceflight-associated neuro-ocular syndrome will be assistive in the development of effective countermeasures that will protect the eyes of astronauts during future space missions.

Dilated Prelaminar Paravascular Spaces as a Possible Mechanism for Optic Disc Edema in Astronauts.

INTRODUCTION: A number of ophthalmic abnormalities, including optic disc edema, have been reported in several astronauts involved in long-duration spaceflights. An increased understanding of factors contributing to this syndrome, initially designated visual impairment and intracranial pressure syndrome and recently renamed spaceflight-associated neuro-ocular syndrome, has become a high priority for ESA and NASA, especially in view of future long-duration missions, including trips to Mars. The underlying pathophysiological mechanisms of this syndrome are still not well understood. In the present paper, we propose that optic disc edema in astronauts may occur, at least in part, as a result of retention of interstitial fluid in distended paravascular spaces at the prelaminar region of the optic nerve head. Preflight, in-flight, and postflight analysis of the optic nerve head and surrounding structures by optical coherence tomography in long-duration International Space Station crewmembers could provide important structural information in this respect.Wostyn P, De Winne F, Stern C, De Deyn PP. Dilated prelaminar paravascular spaces as a possible mechanism for optic disc edema in astronauts. Aerosp Med Hum Perform. 2018; 89(12):1089-1091.

Intracranial and Intraocular Pressure During Various Degrees of Head-Down Tilt.

BACKGROUND: More than half of astronauts develop ophthalmic changes during long-duration spaceflight consistent with an abnormal intraocular and intracranial pressure (IOP, ICP) difference. The aim of our study was to assess IOP and ICP during head-down tilt (HDT) and the additive or attenuating effects of 1% CO2 and lower body negative pressure (LBNP). METHODS: In Experiment I, IOP and ICP were measured in nine healthy subjects after 3.5 h HDT in five conditions: -6°, -12°, and -18° HDT, -12° with 1% CO2, and -12° with -20 mmHg LBNP. In Experiment II, IOP was measured in 16 healthy subjects after 5 min tilt at +12°, 0°, -6°, -12°, -18°, and -24°, with and without -40 mmHg LBNP. RESULTS: ICP was only found to increase from supine baseline during -18° HDT (9.2 ± 0.9 and 14.4 ± 1 mmHg, respectively), whereas IOP increased from 15.7 ± 0.3 mmHg at 0° to 17.9 ± 0.4 mmHg during -12° HDT and from 15.3 ± 0.4 mmHg at 0° to 18.7 ± 0.4 mmHg during -18° HDT. The addition of -20 mmHg LBNP or 1% CO2 had no further effects on ICP or IOP. However, the use of -40 mmHg LBNP during HDT lowered IOP back to baseline values, except at -24° HDT. DISCUSSION: A small, posterior intraocular-intracranial pressure difference (IOP > ICP) is maintained during HDT, and a sustained or further decreased difference may lead to structural changes in the eye in real and simulated microgravity.Marshall-Goebel K, Mulder E, Bershad E, Laing C, Eklund A, Malm J, Stern C, Rittweger J. Intracranial and intraocular pressure during various degrees of head-down tilt. Aerosp Med Hum Perform. 2017; 88(1):10-16.

Optic disc edema, globe flattening, choroidal folds, and hyperopic shifts observed in astronauts after long-duration space flight.

PURPOSE: To describe the history, clinical findings, and possible etiologies of ophthalmic findings discovered in 7 astronauts after long-duration space flight, and document vision changes in approximately 300 additional astronauts. DESIGN: Retrospective, observational examination of ophthalmic findings in 7 astronauts and analysis of postflight questionnaires regarding in-flight vision changes in approximately 300 additional astronauts. PARTICIPANTS: Seven astronauts with ophthalmic anomalies upon return from long-duration space missions to the International Space Station and 300 additional astronauts who completed postflight questionnaires regarding in-flight vision changes. METHODS: Before and after long-duration space flight, all 7 subjects underwent complete eye examinations, including cycloplegic and/or manifest refraction and fundus photography. Six underwent postmission optical coherence tomography (OCT) and magnetic resonance imaging (MRI); 4 had lumbar punctures (LP). Approximately 300 astronauts were queried regarding visual changes during space missions. MAIN OUTCOME MEASURES: Refractive change, fundus photograph examination, retina OCT, orbital MRI, LP opening pressures, and examination of visual acuity data. RESULTS: After 6 months of space flight, 7 astronauts had ophthalmic findings, consisting of disc edema in 5, globe flattening in 5, choroidal folds in 5, cotton wool spots (CWS) in 3, nerve fiber layer thickening by OCT in 6, and decreased near vision in 6 astronauts. Five of 7 with near vision complaints had a hyperopic shift ≥+0.50 diopters (D) between pre/postmission spherical equivalent refraction in 1 or both eyes (range, +0.50 to +1.75 D). These 5 showed globe flattening on MRI. Lumbar punctures performed in the 4 with disc edema documented opening pressures of 22, 21, 28, and 28.5 cm H(2)O performed 60, 19, 12, and 57 days postmission, respectively. The 300 postflight questionnaires documented that approximately 29% and 60% of astronauts on short and long-duration missions, respectively, experienced a degradation in distant and near visual acuity. Some of these vision changes remain unresolved years after flight. CONCLUSIONS: We hypothesize that the optic nerve and ocular changes we describe may result from cephalad fluid shifts brought about by prolonged microgravity exposure. The findings we report may represent parts of a spectrum of ocular and cerebral responses to extended microgravity exposure. FINANCIAL DISCLOSURE(S): The authors have no proprietary or commercial interest in any of the materials discussed in this article.