Persistent Globe Flattening in Astronauts following Long-Duration Spaceflight.

Posterior globe flattening has been well-documented in astronauts both during and after long-duration space flight (LDSF) and has been observed as early as 10 days into a mission on the International Space Station. Globe flattening (GF) is thought to be caused by the disc centred anterior forces created by elevated volume and/or pressure within the optic nerve sheath (ONS). This might be the result of increased intracranial pressure, increased intraorbital ONS pressure from compartmentalisation or a combination of these mechanisms. We report posterior GF in three astronauts that has persisted for 7 years or more following their return from LDSFs suggesting that permanent scleral remodelling may have occurred.

Astronaut ophthalmic syndrome.

During and after missions on the International Space Station, some astronauts experience ophthalmic changes, including choroidal folds, optic disc edema, cotton-wool spots, globe flattening, and refraction changes. Astronauts with ophthalmic issues had significantly higher plasma concentrations of metabolites that are associated with the 1-carbon metabolic pathway than those without ophthalmic issues. We hypothesized that genetic differences might explain the metabolite differences. Indeed, genetics and B vitamin status were significant predictors of ophthalmic issues. We now have developed a hypothesis regarding the mechanisms that link 1-carbon pathway genetics and the condition that we suggest calling, "astronaut ophthalmic syndrome." We maintain that this condition is genetically predisposed and is associated with endothelial dysfunction that is induced by oxidative stress. Subsequent edema can hinder cerebrospinal fluid efflux and can lead to locally increased pressures in the subarachnoid space within the orbit, which impinges on the optic nerve and/or eye in affected individuals. Confirming this hypothesis will help characterize the genetics of 1-carbon pathway metabolism, homocysteine, oxidative stress, endothelial dysfunction, and cardiovascular and potentially other diseases.-Zwart, S. R., Gibson, C. R., Gregory, J. F., Mader, T. H., Stover, P. J., Zeisel, S. H., Smith, S. M. Astronaut ophthalmic syndrome.

Genotype, B-vitamin status, and androgens affect spaceflight-induced ophthalmic changes.

Ophthalmic changes have occurred in a subset of astronauts on International Space Station missions. Visual deterioration is considered the greatest human health risk of spaceflight. Affected astronauts exhibit higher concentrations of 1-carbon metabolites (e.g., homocysteine) before flight. We hypothesized that genetic variations in 1-carbon metabolism genes contribute to susceptibility to ophthalmic changes in astronauts. We investigated 5 polymorphisms in the methionine synthase reductase (MTRR), methylenetetrahydrofolate reductase (MTHFR), serine hydroxymethyltransferase (SHMT), and cystathionine ß-synthase (CBS) genes and their association with ophthalmic changes after flight in 49 astronauts. The number of G alleles of MTRR 66 and C alleles of SHMT1 1420 both contributed to the odds of visual disturbances. Preflight dehydroepiandrosterone was positively associated with cotton wool spots, and serum testosterone response during flight was associated with refractive change. Block regression showed that B-vitamin status and genetics were significant predictors of many of the ophthalmic outcomes that we observed. In one example, genetics trended toward improving (P = 0.10) and B-vitamin status significantly improved (P < 0.001) the predictive model for refractive change after flight. We document an association between MTRR 66 and SHMT1 1420 polymorphisms and spaceflight-induced vision changes. This line of research could lead to therapeutic options for both space travelers and terrestrial patients.

Persistent Asymmetric Optic Disc Swelling After Long-Duration Space Flight: Implications for Pathogenesis.

BACKGROUND: Several ophthalmic findings including optic disc swelling, globe flattening and choroidal folds have been observed in astronauts following long-duration space flight. The authors now report asymmetric choroidal expansion, disc swelling and optic disc morphologic changes in a 45-year-old astronaut which occurred during long-duration space flight and persisted following his space mission. METHODS: Case study of ocular findings in an astronaut documented during and after a long-duration space flight of approximately 6 months. Before, during and after his spaceflight, he underwent complete eye examination, including fundus photography, ultrasound, and optical coherence tomography. RESULTS: We documented asymmetric choroidal expansion inflight that largely resolved by 30 days postflight, asymmetric disc swelling observed inflight that persisted for over 180 days postflight, asymmetric optic disc morphologic changes documented inflight by OCT that persisted for 630 days postflight and asymmetric globe flattening that began inflight and continued 660 days postflight. Lumbar puncture opening pressures obtained at 7 and 365 days post-mission were 22 and 16 cm H20 respectively. CONCLUSION: The persistent asymmetric findings noted above, coupled with the lumbar puncture opening pressures, suggest that prolonged microgravity exposure may have produced asymmetric pressure changes within the perioptic subarachnoid space.

Neuro-Ophthalmology of Space Flight.

BACKGROUND: To describe the history, clinical findings, and possible pathogenic etiologies of the constellation of neuro-ophthalmic findings discovered in astronauts after long-duration space flight and to discuss the terrestrial implications of such findings. EVIDENCE ACQUISITION: Retrospective review of published observational, longitudinal examination of neuro-ophthalmic findings in astronauts after long-duration space flight; analysis of postflight questionnaires regarding in-flight vision changes in approximately 300 additional astronauts; and hypothesis generating for developing possible future countermeasures and potential implications for neuro-ophthalmic disorders on Earth. Astronauts with neuro-ophthalmic findings, which were not present at the start of a space flight mission and only seen on return from long-duration space missions to the International Space Station, will be discussed. RESULTS: After 6 months of space flight, 7 astronauts had ophthalmic findings consisting of optic disc edema in 5, globe flattening in 5, choroidal folds in 5, cotton-wool spots in 3, nerve fiber layer thickening detected by optical coherence tomography in 6, and decreased near vision in 6. Five of 7 astronauts with near vision complaints had a hyperopic shift ≥+0.50 diopters (D) between pre-/post-mission spherical equivalent refraction in 1 or both eyes (range, +0.50 to +1.75 D). These 5 astronauts showed globe flattening on magnetic resonance imaging. A total of 6 lumbar punctures have been performed to date (4 in the originally described cohort) and documented opening pressures of 18, 22, 21, 21.5, 28, and 28.5 cm H2O. These were performed at 8, 66, 19, 7, 12, and 57 days after mission, respectively. The 300 postflight questionnaires documented that approximately 29% and 60% of astronauts on short-duration and long-duration missions, respectively, experienced a degradation in distant and near visual acuity. Some of these vision changes remain unresolved for years after flight. Several possible pathogenic mechanisms, as well as potential countermeasures and discussion of possible terrestrial implications, are described. CONCLUSIONS: We previously hypothesized that the optic nerve and ocular changes that we described in astronauts may be the result of orbital and cranial cephalad fluid shifts brought about by prolonged microgravity exposure. The findings we reported previously and continue to see in astronauts may represent parts of a spectrum of ocular and cerebral responses to extended microgravity exposure. Future investigations hopefully will lead to countermeasures that can be used to eliminate or lessen the magnitude of these potentially harmful findings before long-duration space flight including the possibility of a manned mission to Mars.

Photorefractive Keratectomy and Laser-Assisted In Situ Keratomileusis on 6-Month Space Missions.

BACKGROUND: This article documents the stability of photorefractive keratectomy (PRK) and laser-assisted in situ keratomileusis (LASIK) in two astronauts during 6-mo missions to the International Space Station.CASE REPORTS: Ocular examinations including visual acuity, cycloplegic refraction, slit lamp examination, corneal topography, central corneal thickness, optical biometry (axial length/keratometry), applanation tonometry, and dilated fundus examination were performed on each astronaut before and after their missions, and in-flight visual acuity testing was done on flight day 30, 90, and R-30 (30 d before return). They were also questioned regarding visual changes during flight.DISCUSSION: We documented stable vision in both PRK and LASIK astronauts during liftoff, entry into microgravity, 6 mo on the International Space Station, descent, and landing. Our results suggest that both PRK and LASIK are stable and well tolerated during long-duration spaceflight.Gibson CR, Mader TH, Lipsky W, Schallhorn SC, Tarver WJ, Suresh R, Hauge TN, Brunstetter TJ. Photorefractive keratectomy and laser-assisted in situ keratomileusis on 6-month space missions. Aerosp Med Hum Perform. 2024; 95(5):278-281.

Optic disc edema in an astronaut after repeat long-duration space flight.

BACKGROUND: A number of ophthalmic findings including optic disc edema, globe flattening, and choroidal folds have been observed in several astronauts after long-duration space flights. The authors report the first astronaut with previously documented postflight ophthalmic abnormalities who developed new pathological changes after a repeat long-duration mission. METHODS: A case study of an astronaut with 2 long-duration (6 months) exposures to microgravity. Before and after his first long-duration space flight, he underwent complete eye examination, including fundus photography. Before and after his second flight, 9 years later, he underwent fundus photography, optical coherence tomography, ocular ultrasonography, and brain magnetic resonance imaging, as well as in-flight fundus photography and ultrasound. RESULTS: After his first long-duration mission, the astronaut was documented to have eye findings limited to unilateral choroidal folds and a single cotton wool spot. During a subsequent 6-month mission, he developed more widespread choroidal folds and new onset of optic disc edema in the same eye. CONCLUSION: Microgravity-induced anatomical changes that occurred during the first mission may have set the stage for recurrent or additional changes when the astronaut was subjected to physiological stress of repeat space flight.

Spaceflight associated neuro-ocular syndrome (SANS): an update on potential microgravity-based pathophysiology and mitigation development.

Long-duration spaceflight is associated with neurologic and ophthalmic clinical and imaging findings in astronauts termed spaceflight associated neuro-ocular syndrome (SANS). These microgravity-induced findings have been well documented by the National Aeronautics and Space Administration (NASA) and are clearly a potential risk for future human space exploration. The underlying pathogenesis of SANS is not well understood, although multiple hypotheses have emerged. Terrestrial analogues and potential countermeasures have also been studied to further understand and potentially mitigate SANS. In this manuscript, we review the current understanding of SANS, discuss the prevailing hypotheses for pathogenesis, and describe current developments in terrestrial analogues and potential countermeasures for SANS.

Implantable Collamer Lens Use in a Spaceflight Participant During Short Duration Spaceflight.

BACKGROUND: The purpose of this report is to document the first use of a single piece, posterior chamber phakic implantable collamer lens (ICL) with a central port in the right eye (OD) of a spaceflight participant (SFP) during a 12-d Soyuz mission to the International Space Station (ISS). We also briefly document the stability of a pre-existing pachychoroid pigment epitheliopathy (PPE) in the macula of his left eye (OS) during this mission.CASE REPORT: Ocular examination, including refraction, slit lamp examination, macular examination by optical coherence tomography (OCT), and tonometry were performed before and after his mission and he was questioned regarding visual changes during each portion of his flight.DISCUSSION: We documented no change in ICL position during his spaceflight. He reported stable vision during liftoff, entry into microgravity, 12 d on the ISS, descent, and landing. Our results suggest that the modern ICL with a central port is stable, effective, and well tolerated during short duration spaceflight. His PPE also remained stable during this mission as documented by OCT.Gibson CR, Mader TH, Lipsky W, Brown DM, Jennings R, Law J, Sargsyan A, Brunstetter T, Danilichev SN, Maezawa Y. Implantable collamer lens use in a spaceflight participant during short duration spaceflight. Aerosp Med Hum Perform. 2023; 94(1):48-50.

Vision changes after spaceflight are related to alterations in folate- and vitamin B-12-dependent one-carbon metabolism.

Approximately 20% (7 of 38) of astronauts on International Space Station (ISS) missions have developed measurable ophthalmic changes after flight. This study was conducted to determine if the folate- and vitamin B-12-dependent 1-carbon metabolic pathway is altered in these individuals. Since 2006, we have conducted experiments on the ISS to evaluate nutritional status and related biochemical indices of astronauts before, during, and after flight. Data were modeled to evaluate differences between individuals with ophthalmic changes (n = 5) and those without them (n = 15), all of whom were on ISS missions of 48-215 d. We also determined whether mean preflight serum concentrations of the 1-carbon metabolites and changes in measured cycloplegic refraction after flight were associated. Serum homocysteine (Hcy), cystathionine, 2-methylcitric acid (2MCA), and methylmalonic acid concentrations were 25-45% higher (P < 0.001) in astronauts with ophthalmic changes than in those without them. These differences existed before, during, and after flight. Preflight serum concentrations of Hcy and cystathionine, and mean in-flight serum folate, were correlated with change (postflight relative to preflight) values in refraction (P < 0.05), and preflight serum concentrations of 2MCA tended to be associated (P = 0.06) with ophthalmic changes. The biochemical differences observed in crewmembers with vision issues strongly suggest that their folate- and vitamin B-12-dependent 1-carbon transfer metabolism was affected before and during flight. The consistent differences in markers of 1-carbon metabolism between those who did and those who did not develop changes in vision suggest that polymorphisms in enzymes of this pathway may interact with microgravity to cause these pathophysiologic changes.

The odyssey of the ocular and cerebrospinal fluids during a mission to Mars: the "ocular glymphatic system" under pressure.

A significant proportion of the astronauts who spend extended periods in microgravity develop ophthalmic abnormalities including optic disc edema, globe flattening, chorioretinal folds, and hyperopic refractive error shifts. A constellation of these neuro-ophthalmic findings has been termed "spaceflight-associated neuro-ocular syndrome". Understanding this syndrome is currently a top priority for NASA, especially in view of future long-duration missions (e.g., Mars missions). The recent discovery of an "ocular glymphatic system" can potentially help to unlock mechanisms underlying microgravity-induced optic disc edema. Indeed, a major paradigm shift is currently occurring in our understanding of transport of fluids and solutes through the optic nerve following the recent discovery of an optic nerve glymphatic pathway for influx of cerebrospinal fluid. In addition, the recent identification of an entirely new glymphatic pathway for efflux of ocular fluid may have profound implications for fluid dynamics in the eye. Observations pertaining to this ocular glymphatic pathway provide critical new insights into how intracranial pressure can alter basic fluid transport in the eye. We believe that these novel findings have the potential to be game changers in our understanding of the pathogenesis of optic disc edema in astronauts. In the present review, we integrate these new insights with findings on the intracranial and neuro-ophthalmologic effects of microgravity in one coherent conceptual framework. Further studies in this area of investigation could not only provide exciting new insights into the mechanisms underlying microgravity-induced optic disc edema but also offer opportunities to develop countermeasure strategies.

Optic Disc Edema in Astronauts from a Choroidal Point of View.

INTRODUCTION: Optic disc edema has been well documented in astronauts both during and after long-duration spaceflight and is hypothesized to largely result from increased pressure within the orbital subarachnoid space brought about by a generalized rise in intracranial pressure or from sequestration of cerebrospinal fluid within the orbital subarachnoid space with locally elevated optic nerve sheath pressure. In addition, a recent prospective study documented substantial spaceflight-associated peripapillary choroidal thickening, which may be a contributing factor in spaceflight-associated neuro-ocular syndrome. In the present article, based on the above, we offer a new perspective on the pathogenesis of microgravity-induced optic disc edema from a choroidal point of view. We propose that prolonged microgravity exposure may result in the transudation of fluid from the choroidal vasculature, which, in turn, may reach the optic nerve head, and ultimately may lead to fluid stasis within the prelaminar region secondary to impaired ocular glymphatic outflow. If confirmed, this viewpoint would shed new light on the development of optic disc edema in astronauts.Wostyn P, Gibson CR, Mader TH. Optic disc edema in astronauts from a choroidal point of view. Aerosp Med Hum Perform. 2022; 93(4):396-398.

Does Long-Duration Exposure to Microgravity Lead to Dysregulation of the Brain and Ocular Glymphatic Systems?

Spaceflight-associated neuro-ocular syndrome (SANS) has been well documented in astronauts both during and after long-duration spaceflight and is characterized by the development of optic disc edema, globe flattening, choroidal folds, and hyperopic refractive error shifts. The exact mechanisms underlying these ophthalmic abnormalities remain unclear. New findings regarding spaceflight-associated alterations in cerebrospinal fluid spaces, specifically perivascular spaces, may shed more light on the pathophysiology of SANS. The preliminary results of a recent brain magnetic resonance imaging study show that perivascular spaces enlarge under prolonged microgravity conditions, and that the amount of fluid in perivascular spaces is linked to SANS. The exact pathophysiological mechanisms underlying enlargement of perivascular spaces in space crews are currently unclear. Here, we speculate that the dilation of perivascular spaces observed in long-duration space travelers may result from impaired cerebral venous outflow and compromised cerebrospinal fluid resorption, leading to obstruction of glymphatic perivenous outflow and increased periarterial cerebrospinal fluid inflow, respectively. Further, we provide a possible explanation for how dilated perivascular spaces can be associated with SANS. Given that enlarged perivascular spaces in space crews may be a marker of altered venous hemodynamics and reduced cerebrospinal fluid outflow, at the level of the optic nerve and eye, these disturbances may contribute to SANS. If confirmed by further studies, brain glymphatic dysfunction in space crews could potentially be considered a risk factor for the development of neurodegenerative diseases, such as Alzheimer's disease. Furthermore, long-duration exposure to microgravity might contribute to SANS through dysregulation of the ocular glymphatic system. If prolonged spaceflight exposure causes disruption of the glymphatic systems, this might affect the ability to conduct future exploration missions, for example, to Mars. The considerations outlined in the present paper further stress the crucial need to develop effective long-term countermeasures to mitigate SANS-related physiologic changes during long-duration spaceflight.

Optic nerve sheath diameter and spaceflight: defining shortcomings and future directions.

Neuro-ocular changes during long-duration space flight are known as spaceflight-associated neuro-ocular syndrome (SANS). The ability to detect, monitor, and prevent SANS is a priority of current space medicine research efforts. Optic nerve sheath diameter (ONSD) measurement has been used both terrestrially and in microgravity as a proxy for measurements of elevated intracranial pressure. ONSD shows promise as a potential method of identifying and quantitating neuro-ocular changes during space flight. This review examines 13 studies measuring ONSD and its relationship to microgravity exposure or ground-based analogs, including head-down tilt, dry immersion, or animal models. The goal of this correspondence is to describe heterogeneity in the use of ONSD in the current SANS literature and make recommendations to reduce heterogeneity in future studies through standardization of imaging modalities, measurement techniques, and other aspects of study design.