Incidence and Progression of Chorioretinal Folds During Long-Duration Spaceflight

This cohort study assesses the incidence and presentation of chorioretinal folds in long-duration International Space Station crew members and objectively quantifies the progression of choroidal folds during spaceflight.

Key Points

Question

What is the incidence, presentation, and progression of chorioretinal fold development during long-duration spaceflight missions to the International Space Station?

Findings

In this analysis of 36 long-duration crew members, 6 (17%) developed chorioretinal folds; presentation of folds in crew members differed from that reported in patients with idiopathic intracranial hypertension. Quantitative analysis revealed that the earliest appearance of choroidal folds varied among individuals and that both macular and peripapillary choroidal folds worsened with flight durations up to 1 year.

Meaning

Chorioretinal fold progression is a concern for present International Space Station missions and future longer-duration exploration missions to the Moon and Mars.

Abstract

Importance

The primary contributing factor for development of chorioretinal folds during spaceflight is unknown. Characterizing fold types that develop and tracking their progression may provide insight into the pathophysiology of spaceflight-associated neuro-ocular syndrome and elucidate the risk of fold progression for future exploration-class missions exceeding 12 months in duration.

Objective

To determine the incidence and presentation of chorioretinal folds in long-duration International Space Station crew members and objectively quantify the progression of choroidal folds during spaceflight.

Design, Setting, and Participants

In this retrospective cohort study, optical coherence tomography scans of the optic nerve head and macula of crew members completing long-duration spaceflight missions were obtained on Earth prior to spaceflight and during flight. A panel of experts examined the scans for the qualitative presence of chorioretinal folds. Peripapillary total retinal thickness was calculated to identify eyes with optic disc edema, and choroidal folds were quantified based on surface roughness within macular and peripapillary regions of interest.

Interventions or Exposures

Spaceflight missions ranging 6 to 12 months.

Main Outcomes and Measures

Incidence of peripapillary wrinkles, retinal folds, and choroidal folds; peripapillary total retinal thickness; and Bruch membrane surface roughness.

Results

A total of 36 crew members were analyzed (mean [SD] age, 46 [6] years; 7 [19%] female). Chorioretinal folds were observed in 12 of 72 eyes (17%; 6 crew members). In eyes with early signs of disc edema, 10 of 42 (24%) had choroidal folds, 4 of 42 (10%) had inner retinal folds, and 2 of 42 (5%) had peripapillary wrinkles. Choroidal folds were observed in all eyes with retinal folds and peripapillary wrinkles. Macular choroidal folds developed in 7 of 12 eyes (4 of 6 crew members) with folds and progressed with mission duration; these folds extended into the fovea in 6 eyes. Circumpapillary choroidal folds developed predominantly superior, nasal, and inferior to the optic nerve head and increased in prevalence and severity with mission duration.

Conclusions and Relevance

Choroidal folds were the most common fold type to develop during spaceflight; this differs from reports in idiopathic intracranial hypertension, suggesting differences in the mechanisms underlying fold formation. Quantitative measures demonstrate the development and progression of choroidal folds during weightlessness, and these metrics may help to assess the efficacy of spaceflight-associated neuro-ocular syndrome countermeasures.

Introduction

Spaceflight-associated neuro-ocular syndrome (SANS) was first described in a case series with 5 of 7 astronauts presenting with optic disc edema and 5 of 7 with choroidal folds after return from long-duration missions to the International Space Station (ISS).¹ Following these initial findings, additional reports documented development of retinal and choroidal folds during spaceflight and their persistence after return to Earth,^2,3,4 including a retrospective analysis that identified signs of choroidal folds in 6 of 15 participants (40%).⁵ Subsequently, quantitative evidence from optical coherence tomography (OCT) images revealed development and progression of optic disc edema in approximately 70% of ISS crew members flying 6-month missions⁶ and that choroidal folds progressively worsened during a 1-year spaceflight mission in a single crew member with Frisén grade 1 optic disc edema.⁷ Development of chorioretinal folds at or near the macula has the potential to affect vision during spaceflight and impact visual function late in life if not resolved, yet the primary factor contributing to development and progression of chorioretinal folds remains unclear.

Folds are not common in terrestrial pathologies but have been associated with acquired hyperopia, hypotony, ocular inflammatory disorders, and intracranial hypertension.^8,9,10,11,12 Prior to each mission, crew members undergo examinations to rule out inflammatory disorders, systemic disease, abnormal intraocular pressure, and use of medication that could produce intracranial hypertension. On rare occasions, low intraocular pressure can lead to choroidal folds, for example following surgery¹³; however, evidence suggests intraocular pressure is not decreased during long-duration spaceflight.^14,15 The presence of choroidal folds, retinal folds, or peripapillary wrinkles in terrestrial patients with optic disc edema may indicate elevated intracranial pressure (ICP) when other known causes such as orbital disease, tumor, posterior scleritis, and hypotony are ruled out.^16,17

Folds develop within the retina due to changes in mechanical loading conditions and biomechanical tissue properties.^8,18 Thus, the timing, location, orientation, and pattern of fold presentation within the retina may provide insight into the underlying pathophysiology.^8,10,18,19 OCT imaging enables 3-dimensional visualization and quantification of fold morphology compared with more traditional forms of ophthalmic imaging and has led to the classification of choroidal folds, outer retinal folds and creases, inner retinal folds, and peripapillary wrinkles in patients with papilledema resulting from idiopathic intracranial hypertension (IIH).^10,20 The purpose of this study was to objectively document and quantify the prevalence and progression of choroidal folds, retinal folds, and peripapillary wrinkles in crew members flying long-duration spaceflight missions to the ISS. We hypothesized that the prevalence of chorioretinal folds in ISS crew members with optic disc edema would be similar in proportion to previous reports in patients with IIH and that folds would worsen with greater spaceflight mission duration.

Methods

Thirty-six crew members, including astronauts and cosmonauts, participated in spaceflight missions with mean (SD) duration of 189 (60) days onboard the ISS. Data were obtained during research studies approved by the NASA Johnson Space Center Institutional Review and Human Research Multilateral Review Boards. Participants provided written informed consent consistent with the Declaration of Helsinki²¹ and did not receive a stipend or incentives to participate. Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline was followed except reporting of study dates due to attributability concerns.

Bilateral OCT images were acquired with Spectralis OCT1 or OCT2 systems (Heidelberg Engineering) before, during, and after long-duration spaceflight.⁶ For crew members with prior spaceflight experience, only images from the most recent spaceflight mission were analyzed. While scan placement was consistent within each individual before, during, and after spaceflight and across all crew members in this cohort, scan density and size were updated as the Spectralis OCT2 system became available for use on the ISS. All participants were imaged with a circle pattern (3.5 mm or 12°, 100 automatic real-time tracking [ART] levels) centered over the optic nerve head (ONH). Crew members were scanned with a 20°, 12-line, 16 ART (OCT1) or a 15°, 48-line, 25 ART (OCT2) radial scan pattern centered over the ONH. Similarly, a 20° × 20° (6 × 6-mm) vertical raster scan pattern centered on the fovea was acquired using a 25-line, 16 ART (OCT1) or 193-line, 16 ART (OCT2) pattern.

Automated segmentations of the internal limiting membrane, retinal nerve fiber layer, and Bruch membrane were manually corrected, verified by an additional expert grader (C.R.F.), and processed in MATLAB (MathWorks). Global peripapillary total retinal thickness (TRT) was calculated from the radial scans in an annular zone circumscribing the ONH within 250 μm of Bruch membrane opening.^5,6 The choroidal-scleral interface was manually delineated on circular scans. Mean retinal nerve fiber layer and choroid thickness were calculated from the circle scan pattern except in 1 crew member with poor scan quality.^6,22 A panel of 4 experts (T.J.B., C.R.G., S.S.L., S.S.M.) jointly inspected all OCT images for peripapillary wrinkles, retinal folds, and choroidal folds following the classification criteria in the OCT Substudy of the Idiopathic Intracranial Hypertension Treatment Trial^10,20 and arrived at a consensus for each scan. The prevalence of chorioretinal folds in ISS crew member eyes demonstrating optic disc edema based on TRT increase of 19.4 μm or more²² was compared with the previously reported prevalence of folds in patients with IIH with papilledema.^10,20

Surface roughness quantification improves on the peak shape analysis methodology previously reported in 1 ISS crew member completing a 1-year spaceflight mission.⁷ Due to the limited number of crew members who developed folds during spaceflight and the greater prevalence of choroidal folds in the spaceflight cohort relative to peripapillary wrinkles and retinal folds, surface roughness data are presented for Bruch membrane only. Bruch membrane surface layer was aligned to a reference plane using singular value decomposition and polynomial curve fitting to remove scan tilt and curvature. The aligned surface layer was used to generate a topographical height map to aid visualization of the pattern and orientation of choroidal folds (Figure 1).

Figure 1. Quantification of Bruch Membrane Surface Roughness.

Bruch membrane surface layer was used to visualize and quantify the development of choroidal folds and their progression during spaceflight. Bruch membrane layer (red) and internal limiting membrane (blue) were manually segmented on optical coherence tomography images from the vertical block scan centered over the fovea (A) and the radial scan centered over the optic nerve head (B). Inner retinal folds (white arrowhead) and choroidal folds (yellow arrowheads) are marked on each transverse optical coherence tomography image. The subtle retinal folds indicated in panel A are extensions of the prominent inner retinal folds observed in the same crew member in Figure 2B. Bruch membrane surface layer colored height maps were generated to better visualize the pattern and orientation of macular (C) and peripapillary choroidal folds (D) during spaceflight: teal represents no change, while dark blue and yellow represent posterior and anterior displacement, respectively. The change in Bruch membrane macular surface roughness was quantified within 3 adjacent 1 × 5-mm regions to track the successive progression of choroidal folds spanning from the peripapillary region (C: fovea–2 mm ROI) toward the fovea region (C: fovea ROI) during spaceflight. Peripapillary surface roughness was calculated within the nasal, superior, temporal, and inferior quadrants of an elliptical region of interest within 500 to 1000 μm of Bruch membrane opening (D).

Bruch membrane root mean square surface roughness²³ was measured in 3 adjacent 1 × 5-mm rectangular regions of interest (ROI) on the vertical raster scan pattern (Figure 1C). To measure progression of macular choroidal folds toward the fovea, the first and second rectangular ROIs were located between the fovea and ONH (Figure 1C: fovea–2 mm and fovea–1 mm). The third ROI was centered on the fovea (Figure 1C: fovea). One crew member who developed macular choroidal folds in the right eye during spaceflight was scanned with a 20° × 10° (6 × 3 mm) raster pattern, which limited coverage to the fovea–1 mm and fovea ROIs. In 2 crew members scanned with the 193-line 20° × 20° (6 × 6 mm) vertical raster pattern, a subset of 38 equally spaced lines of the 193 total lines were analyzed. Using the ONH radial scan pattern, the change in peripapillary Bruch membrane surface roughness was measured within the superior, temporal, nasal, and inferior quadrants of an annular region corresponding to Bruch membrane opening + 500 to 1000 μm (Figure 1D).

Surface roughness precision testing was performed on a separate cohort of novice astronauts with normal healthy retinas studied in Laurie et al.²² The statistical distribution of these measures was modeled with a bayesian hierarchical model incorporating random effects for each source of variation (individual, session, analyzer, residual error) following previously published methodology used for precision analysis of TRT and choroidal thickness change.²² Under the assumption of a normal test-retest distribution, a change in surface roughness within a peripapillary or macular ROI of more than 2.8 or 2.3 μm, respectively (2 SDs), would have a less than 5% chance of being observed due to sampling error or normal physiological variability. Therefore, a change in surface roughness greater than these values would be considered evidence of new or progressed fold. Analysis took place between March 2020 and March 2022.

Results

Six of 36 crew members demonstrated at least 1 type of fold during spaceflight (12 of 72 study eyes [17%]). Bilateral choroidal folds were identified in all 6 crew members. One of 6 crew members presented with bilateral peripapillary and macular choroidal folds before the present spaceflight mission. Examples of choroidal folds, inner retinal folds, peripapillary wrinkles, and the distribution within this cohort are shown in Figure 2. There was no meaningful difference in age (4 years [95% CI, −1 to 9]; P = .09), body mass index (calculated as weight in kilograms divided by height in meters squared) (1.9 [95% CI, −0.5 to 4.4]; P = .12), or mission duration (46 days [95% CI, −12 to 104]; P = .11) between crew members who developed or did not develop folds (Table). Overall, 7 crew members (19%) were female, 2 of which developed chorioretinal folds. Two of 36 crew members (6%), both within the folds group, were diagnosed with bilateral Frisén grade 1 optic disc edema based on fundus photography. Optic disc edema assessed by an increase in TRT of 19.4 μm or more²² was observed in 25 of 36 crew members (69%) or 42 of 72 study eyes (58%). The folds group demonstrated a greater change in global peripapillary TRT (54.6 µm [95% CI, 7.1-102.1]; P = .03) and circumpapillary retinal nerve fiber layer thickness (6.5 µm [95% CI, 0.6-12.5]; P = .03) during spaceflight than those without folds (Table). The increase in global choroid thickness that developed during weightlessness was not different between groups (−2.4 µm [95% CI, −23.2 to 18.3]; P = .81).

Figure 2. Distribution of Choroidal Folds, Retinal Folds, and Peripapillary Wrinkles in International Space Station (ISS) Crew Members.

A, Example optical coherence tomography (OCT) image indicating a region of peripapillary wrinkles (white arrowheads). B, Example OCT image indicating region of inner retinal folds (white arrowhead) and choroidal folds (yellow arrowhead). In panels A and B, the infrared image includes the OCT scan pattern location (green lines) with the bold line representing the OCT image to the right. C, Of the 36 participants in this study, all 6 individuals who presented with folds during spaceflight demonstrated bilateral choroidal folds. Within these 6 individuals, 8 eyes had only choroidal folds, 2 eyes had both choroidal folds and inner retinal folds, and 2 eyes had choroidal folds, inner retinal folds, and peripapillary wrinkles. D, The prevalence of each fold type within ISS crew member eyes demonstrating the earliest signs of optic disc edema (data presented here) differed from the prevalence of each fold type within eyes of patients with idiopathic intracranial hypertension (IIH) demonstrating papilledema.^10,22 Within the 42 eyes that showed signs of developing optic disc edema during spaceflight, 2 eyes (5%) had peripapillary wrinkles, 4 (10%) had inner retinal folds, and 10 (24%) had choroidal folds. As reported by Sibony et al,^10,20 of 125 study eyes with papilledema, 58 (46%) had peripapillary wrinkles, 59 (47%) had inner retinal folds, 25 (20%) had outer retinal folds, and 13 (10%) had choroidal folds. TRT indicates total retinal thickness.

Table. International Space Station Crew Member Demographics and Ocular Structural Changes^a.

Variable	Mean (95% CI)			P value
	Group		Difference between groups
	No folds	Folds
No. of crew members
Male	25	4	NA	NA
Female	5	2
Age, y	46 (44 to 48)	50 (46 to 54)	4 (–1 to 9)	.09
BMI	25.2 (24.3 to 26.1)	27.1 (24.8 to 29.4)	1.9 (–0.5 to 4.4)	.12
Mission duration, d	182 (161 to 202)	228 (174 to 282)	46 (–12 to 104)	.11
Change in TRT, BMO to 250 μm, μm	25.8 (19.7 to 32.0)	80.4 (33.3 to 127.5)	54.6 (7.1 to 102.1)	.03b
Change in RNFL thickness, circle scan, μm	1.1 (0.0 to 1.2)	7.6 (1.7 to 13.5)	6.5 (0.6 to 12.5)	.03c
Change in choroid thickness, circle scan, μm	32.9 (25.2 to 40.6)	30.5 (11.2 to 49.7)	–2.4 (–23.2 to 18.3)	.81d

Abbreviations: BMI, body mass index (calculated as weight in kilograms divided by height in meters squared); BMO, Bruch membrane opening; NA, not applicable; RNFL, retinal nerve fiber layer thickness; TRT, total retinal thickness.

^a Crew members were assigned to the folds group based on presence of peripapillary wrinkles, retinal folds, or choroidal folds at any time during spaceflight. Crew members with no evidence of peripapillary wrinkles, retinal folds, or choroidal folds during spaceflight were assigned to the no folds group. Generalized estimating equation models were used to derive marginal means and 95% CIs for each group and difference between groups. Changes in total retinal thickness, retinal nerve fiber layer thickness, and choroid thickness were quantified as the difference between preflight (seated) and flight day 150, accounting for eyes nested within individuals and repeated measures over time. Two-sided P values are provided for each comparison between groups. Because retinal nerve fiber layer thickness comprises a portion of total retinal thickness, these measures are not independent of each other.

^b Benjamini-Hochberg–adjusted P = .045.

^c Benjamini-Hochberg–adjusted P = .045.

^d Benjamini-Hochberg–adjusted P = .81.

The prevalence of fold type observed in the subset of 42 spaceflight study eyes that demonstrated the earliest signs of optic disc edema (change in TRT ≥19.4 μm) was compared with the prevalence of fold type reported in the IIH Treatment Trial (Figure 2D).^10,20 One crew member who developed bilateral choroidal folds during this spaceflight mission did not develop edema by any definition and was excluded from this comparison. Choroidal folds were most common in ISS crew members (10 of 42 [24%]) but were the least common fold type in patients with IIH (13 of 125 eyes [10%]).¹⁰ Conversely, inner retinal folds and peripapillary wrinkles were observed least often in ISS crew members (4 of 42 eyes [10%] and 2 of 42 eyes [5%], respectively) but were the most common fold type observed in patients with IIH (59 of 125 eyes [47%] and 58 of 125 eyes [46%], respectively).¹⁰ Outer retinal folds were present in 25 of 125 eyes (20%) of patients with IIH²⁰ but were not observed in ISS crew members. In 2 crew members with Frisén grade 1 optic disc edema and chorioretinal folds, lumbar puncture opening pressure measured 22 cm H₂O 7 days postflight²⁴ and 19.4 cm H₂O 9 days postflight respectively.

Macular choroidal folds were observed in 7 study eyes of 4 crew members during spaceflight. One of the 4 crew members demonstrated bilateral macular choroidal folds before the present mission, a finding that was attributed to previous long-duration spaceflight. In all 7 eyes with macular choroidal folds, Bruch membrane surface roughness increased in the macular region as mission duration progressed (Figure 3). An increase in surface roughness at flight day (FD) 26 in the fovea–2 mm and fovea–1 mm region of interest preceded the increase in the fovea sector between FD26 and FD63 in 1 eye from 1 crew member (Figure 3: right eye, orange square). One crew member demonstrated a meaningful increase in surface roughness (+4.8 μm) in the fovea–2 mm sector of their right eye between FD160 and FD266 while there was no change in the fovea–1 mm and fovea sectors (Figure 3: right eye, orange triangle). The crew member with preexisting bilateral macular choroidal folds demonstrated a meaningful increase in surface roughness in the fovea sector between FD28 and FD83 in both the right (+2.8 μm) and left (+4.9 μm) eye (Figure 3: fovea, circles).

Figure 3. Progression of Macular Choroidal Folds in International Space Station Crew Members During Spaceflight.

Compared with preflight, macular Bruch membrane surface roughness increases with spaceflight duration in crew members with macular choroidal folds. Seven study eyes from 4 individual crew members demonstrated choroidal folds in the 3 macular regions of interest (see Figure 1C for locations) during spaceflight. Each individual crew member is represented by a different symbol, which are consistent across figures. Orange symbols represent data from the right eye and blue symbols represent data from the left eye. A meaningful increase in surface roughness was determined when the change compared with preflight exceeded a 2.3-μm threshold (shaded region).

Peripapillary choroidal folds were observed bilaterally in all 6 crew members, although severity was variable between eyes within each crew member (Figure 4; eFigure 1 in Supplement 1). In 8 of 12 eyes with folds, peripapillary surface roughness increased during spaceflight within the nasal, superior, and inferior sectors, ranging from +2.8 to +13.4 μm, while minimal changes were observed in the temporal sector (Figure 4). In the right eye of 1 crew member (Figure 4: orange diamond), choroidal folds that began in the superior quadrant progressed to the temporal region after 120 days of spaceflight (+3.9 μm) and persisted for the remainder of the mission.

Figure 4. Progression of Peripapillary Choroidal Folds in International Space Station Crew Members During Spaceflight.

Peripapillary Bruch membrane surface roughness increased nasal, superior, and inferior to the optic nerve head but not temporally. Mean Bruch membrane surface roughness was quantified in an annular region circumscribing the optic nerve head within 500 μm to 1000 μm of Bruch membrane opening. Each individual crew member is represented by a different symbol which are consistent across figures. Orange symbols represent data from the right eye and blue symbols represent data from the left eye. A meaningful increase in surface roughness was determined when the change compared with preflight exceeded a 2.8-μm threshold (shaded region).

Discussion

The present study documents choroidal folds as the most common type of fold to develop during long-duration spaceflight in ISS crew members, occurring more than twice as frequently as retinal folds and peripapillary wrinkles. This finding contrasts with the distribution of fold types observed in patients with IIH, suggesting the underlying mechanism(s) causing folds differs between these populations. Macular and peripapillary choroidal folds developed as early as FD26 and as late as FD266 and continued to worsen throughout 6 to 12 months of spaceflight. Progression of macular folds within the foveal region is of particular concern due to the potential to disrupt vision.

Peripapillary TRT increased more in crew members with folds, suggesting magnitude of optic disc edema may be associated with development of folds or wrinkles. However, it remains to be determined if edema is the primary contributing factor. In 1 crew member, choroidal fold development without a meaningful increase in TRT may indicate involvement of other mechanisms, likely associated with the spaceflight-induced headward fluid shift and venous congestion. While choroidal engorgement may contribute to the development of folds, we observed a similar increase in choroid thickness in eyes with or without chorioretinal folds. In some eyes, localized choroidal expansion coincided with structural changes in Bruch membrane layer (eFigure 2 in Supplement 1), but the association of these observations requires further investigation.

Overlapping signs with IIH, including optic disc edema, chorioretinal folds, and globe flattening, led to the hypothesis that pathologically elevated ICP may have been the primary contributing factor to SANS.¹ However, direct measurements of ICP during brief periods of weightlessness induced by parabolic flight²⁵ and noninvasive estimates during spaceflight²⁴ suggest ICP does not reach levels observed in terrestrial pathologies such as IIH. In the initial report of eye changes after long-duration spaceflight,¹ 1 of 2 crew members without folds had a lumbar puncture opening pressure of 21 cm H₂O 19 days after return to Earth, while 3 of 5 with folds demonstrated pressures of 28, 28.5, and 22 cm H₂O at 12, 57, and 66 days after return to Earth, respectively. In the current study, 2 additional crew members with chorioretinal folds had a lumbar puncture opening pressure of 22²⁴ and 19.4 cm H₂O at 7 and 9 days after return to Earth, respectively. Mild chronic elevation of ICP throughout long-duration spaceflight could be sufficient to contribute to the development of chorioretinal folds, but further investigation during spaceflight is needed to determine the role of ICP in individual SANS cases.

If increased ICP were the primary factor influencing the development of chorioretinal folds in spaceflight, individuals with SANS and IIH might presumably have similar proportions of each fold type. The reduced frequency of peripapillary wrinkle and retinal fold development in SANS compared with IIH could be explained by the relatively mild level of disc edema that develops in most individuals during spaceflight. However, peripapillary wrinkles and inner retinal folds are more common than choroidal folds in strict head-down tilt bed rest where the magnitude of optic disc edema is comparable with spaceflight.²⁶ While folds in IIH may predominantly result from mechanical indentation due to elevated ICP,^1,10 effects of the headward fluid shift and venous congestion associated with spaceflight may alter the loading conditions of ocular structures in SANS.^24,27,28 Globe flattening at the ONH,²⁹ decreased axial length and hyperopic shift,⁶ choroidal expansion,^6,14 and interstitial edema²⁷ may contribute to choroidal fold formation during spaceflight, although the magnitude of each individual contribution is unclear.

Data collected before the development of SANS provide unique insights not typically afforded in terrestrial patients with folds. Surface roughness quantification provides the ability to detect development of choroidal folds and objectively measure their progression. Analyses presented here demonstrate choroidal fold development as early as 26 days in weightlessness and continued progression throughout mission durations up to 1 year in both peripapillary and macular regions. Fold pattern schematics (eFigure 1 in Supplement 1) indicate similar presentation of choroidal folds among crew members: concentric, circumpapillary folds in the superior, nasal, and/or inferior quadrants accompanied by horizontal linear choroidal folds extending from the temporal periphery of the ONH into the macula. This pattern may reflect asymmetric shape deformation in SANS consistent with radial mechanical compression of Bruch membrane layer nasal and tension temporal to the ONH.

Macular choroidal folds directly involved the fovea in 6 eyes from 4 crew members (eFigure 1 in Supplement 1). Despite these structural changes, each of the 4 crew members demonstrated best-corrected visual acuity of 20/15 or better with normal visual fields and Amsler grid findings within 4 days postflight. However, disruption of the foveal photoreceptor layer could pose a vision concern for future extended-duration missions. Choroidal folds have been reported to persist more than 5 years postflight in some crew members^1,4 and long-term effects on ocular health and vision remain to be fully explored. Bruch membrane surface roughness quantification could present an objective approach to predict a threshold of deformation past which folds do not fully resolve after return to Earth.

While most long-duration ISS crew members are affected by early signs of disc edema,^6,30 a smaller proportion develop chorioretinal folds (17% in this cohort). In this study, there was no consistent bias in development or progression of folds for the right or left eye or in either sex. Individual anatomical differences, for example in choroidal anatomy, may play a role in the development of choroidal folds.^1,8 Although 2 of the 6 crew members with folds documented in this report were novice fliers, cumulative effects of optic disc edema, choroidal expansion, and globe flattening across repeated long-duration spaceflight missions may alter mechanical properties of the ONH and retina and increase propensity for structural change. Quantitative monitoring of choroidal folds, retinal folds, and peripapillary wrinkles will help characterize vision risk on future exploration-class missions.

Limitations

While this study reflects the available evidence to date, the total number of study individuals is small and requires future research to confirm these findings. Interpretation of the results presented could have been influenced by the orientation of available scans relative to the orientation of the folds being measured; however, the number of scans used in this analysis should provide sufficient resolution to minimize this source of error.

Conclusions

We present a novel approach to objectively track choroidal fold development and demonstrate continued worsening of folds throughout spaceflight missions up to 1 year in duration. Differences in prevalence of fold types between SANS and IIH provide further evidence that elevated ICP is not likely the sole contributing factor to choroidal fold development during spaceflight. Quantitative measures provide a sensitive method for detecting and tracking folds over time and may highlight a vision concern for extended exploration missions. Future applications of the surface roughness metric should be considered to assess efficacy of SANS countermeasures.

Supplement 1.

eFigure 1. Peripapillary and Macular Choroidal Fold Pattern Schematic in the Right and Left Eye of each Crewmember with Choroidal Folds

eFigure 2. Localized Choroidal Vessel Expansion Coincides with Choroidal Fold Development in the Right Eye of One Crewmember

Supplement 2.

Data sharing statement