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Chorioretinal folds in astronauts: risk of chorioretinal fold-related maculopathy and terrestrial staging of disease

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
, last revision on July 21, 2023
Chorioretinal Folds in Astronauts: Risk of Chorioretinal Fold-Related
Maculopathy and Terrestrial Staging of Disease
 !"#$%&&&!'()*
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-.%&%/
"-.%-
+&01-
23!3&#/00
01-
40/000
1-5
63!377$
7'87'8-5
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-5
:-.101-5
;1<1-5
,3!3-./'0/'
/'-5
5
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'()*
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3!3&#/00
646,>24,
0?99,+,
$29;'4
@'AA7A*A
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, last revision on July 21, 2023
%
BC3
'3)D.
3%.)
773.
%.)/3.
3%.
)BC533.
3)D!3
B!C/B/C
%3.33
.3).E
33DD
3'31)
2

, last revision on July 21, 2023
333
BCD%'3.
3&F33%33BG#C
%.3)5'53
D5%
)1%'
E'%")
E%355.
5")
.3%'
33
'").33.%
&F33%
33%'")
.33.
3)
)+'+6
6B9HC.BC)$
.E.3.3
B*C)
3

, last revision on July 21, 2023
3B7CE
'E.)2437
3%.)6
3..%%3
73%'*3)!
)"%33'
3%3%.)D
3+BC%I
AB"C%'
33BG#CAB+C.DB7JC
BC)"+
3.
3D37)
!)"D3)0'.
.%%/B/C)
3B!C'",:
.%33/)9!%..
33.):
333%D%D
);!3%%
37*
'3)
4

, last revision on July 21, 2023
/3
'
I%)
5

, last revision on July 21, 2023

) (&#&KE()
3G.)Clin Ophthalmol)
",",A2+2,++2,;),)"29I!G0)"2,,"
") !$GL'7J**&&38)
)American Journal of
Ophthalmology)",2A49B4C,+:,29)),),6IL)L)",2),"),"
+) G*G*)/G
*)JAMA Ophthalmol)G%
 4","+),),,IL33)","")46:
2) $%#! *()$!#3
.3)JAMA Ophthalmol)G%6
","+),),,IL33)","+),+,+
4) ! .M37).
33
3)npj Microgravity)",""A:BC+9),),+:I24"6,"",,"""9
6) $%#! @3)D
%3
'..')Journal of Applied Physiology)
","+A+2BC4,4),)4"IL),,929)",""
9) *(0(%)3
B7C33..'
)npj Microgravity)",",A6BC9),),+:I24"6,",,,;9;
:) $%#(L3)-
3.)American Journal of Ophthalmology
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... SANS is a complex collection of ocular changes observed in astronauts during and after long-duration space missions [1]. Initially identified through post-flight examinations, SANS includes symptoms such as globe flattening [2], choroidal folds [3], and optic disc oedema [4]. The proposed mechanisms underpinning SANS pathophysiology are not fully clear yet, but include cephalad brain and orbital fluid shift [5,6], increased levels of radiation [7], intracranial pressure changes, vascular dysregulation, mitochondrial dysfunction [8] and shifts in cerebrospinal fluid dynamics, which collectively may contribute to the ocular changes documented [9]. ...
... implicated in cataract development, [7,8] and potentially age-related macular degeneration and choroidal folds. [9,10] Further efforts must also be made to teach populations UV-protective behaviors to reduce these risks. The general public should also be aware of the importance of sunglasses to reduce UV radiation exposure to the eye. ...
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The negative impact of climate change on human health is well documented but under-recognized (e.g., air pollution, malnutrition, water-source contamination, and altered vector and waterborne transmission of infectious disease). The impact of climate change on eye health remains significantly underappreciated, whereas climate change impacts every country, lower and lesser-income countries will be disproportionately affected further exacerbating global health inequalities. In this manuscript, we examine the potential effects of climate changes on ocular health on our planet.
... Spaceflight-associated neuro-ocular syndrome (SANS) is a syndrome know to affect a significant proportion of astronauts during long-duration spaceflight (LDSF). SANS is characterized by optic disc edema [1], hyperopic shifts [2], chorioretinal folds [3] and globe flattening [4]. While the precise etiology of SANS remains incompletely understood, it is hypothesized to be as a result of the unique conditions encountered in the microgravity environment characteristic of LDSF, and heightened radiation exposure [5]. ...
... This work is a component of our NASA-funded endeavour to monitor and uphold astronaut vision during LDSF . Currently spaceflight associated neuro-ocular syndrome (SANS) is considered to be the greatest ocular risk during long-duration spaceflight, and its pathophysiology is not yet fully understood (Masalkhi et al., 2023a;Soares et al., 2024;Waisberg, Ong, Masalkhi, Mao, et al., 2024;. Other components of our related research include developing visual assessments that can be performed in space, as well as developing countermeasures to improve astronaut vision Waisberg, Ong, Zaman, et al., 2022), and detecting structural vision changes (Kamran et al., 2024;Masalkhi et al, 2023b;Waisberg, Ong, Kamran, et al., 2023). ...
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Empty space myopia is a phenomenon that has been observed in pilots when flying in the open sky. Previous research has been conducted to develop training biofeedback devices to help pilot visual accommodation in empty skies. During future long-duration spaceflight, astronauts may also experience empty space myopia due to prolonged periods of time in vast space. Extended reality is a relatively novel technology that has emerged as a powerful tool for tracking ocular movements. Extended reality with auditory feedback may serve as a low-cost, easily applicable method to improve ciliary muscle control and vision during long-duration spaceflight to combat empty space myopia. In this paper, we review the effects of empty field myopia in space and report on the novel development of extended reality with auditory biofeedback as a potential astronaut training tool.
... The results from SANS-CNN demonstrate a robust detection of SANS findings with lightweight CNNs compared to state-of-the-art pre-trained architectures. Given that prolonged optic disc edema and chorioretinal folds have been observed to lead to potential significant visual impairment terrestrially (e.g., chorioretinal folds-related maculopathy or idiopathic intracranial hypertension) [37][38][39][40] , the automatic evaluation of SANS for immediate insight to onboard members is critical for deep space exploration. As mitigation strategies continue to develop for SANS, there is a necessity for guidance on how long astronauts should employ these countermeasures during spaceflight. ...
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Spaceflight associated neuro-ocular syndrome (SANS) is one of the largest physiologic barriers to spaceflight and requires evaluation and mitigation for future planetary missions. As the spaceflight environment is a clinically limited environment, the purpose of this research is to provide automated, early detection and prognosis of SANS with a machine learning model trained and validated on astronaut SANS optical coherence tomography (OCT) images. In this study, we present a lightweight convolutional neural network (CNN) incorporating an EfficientNet encoder for detecting SANS from OCT images titled “SANS-CNN.” We used 6303 OCT B-scan images for training/validation (80%/20% split) and 945 for testing with a combination of terrestrial images and astronaut SANS images for both testing and validation. SANS-CNN was validated with SANS images labeled by NASA to evaluate accuracy, specificity, and sensitivity. To evaluate real-world outcomes, two state-of-the-art pre-trained architectures were also employed on this dataset. We use GRAD-CAM to visualize activation maps of intermediate layers to test the interpretability of SANS-CNN’s prediction. SANS-CNN achieved 84.2% accuracy on the test set with an 85.6% specificity, 82.8% sensitivity, and 84.1% F1-score. Moreover, SANS-CNN outperforms two other state-of-the-art pre-trained architectures, ResNet50-v2 and MobileNet-v2, in accuracy by 21.4% and 13.1%, respectively. We also apply two class-activation map techniques to visualize critical SANS features perceived by the model. SANS-CNN represents a CNN model trained and validated with real astronaut OCT images, enabling fast and efficient prediction of SANS-like conditions for spaceflight missions beyond Earth’s orbit in which clinical and computational resources are extremely limited.
... Spaceflight Associated Neuro-Ocular Syndrome (SANS) refers to a range of neuro-ocular changes experienced by astronauts during long duration space flight (LDSF) missions. The findings in SANS include optic disc edema [1], globe flattening [2], choroidal folds [3], and refractive error shift [4]. Although the exact etiology of SANS is not fully understood it may be multifactorial, involving alterations in cephalad intraorbital, intraocular, and intracranial fluid shifts and secondary changes in tissue and fluid dynamics due to microgravity. ...
... Terrestrially, chronic choroidal folds have been observed to develop into a maculopathy termed chorioretinal fold-related maculopathy. 12,14 Fluorescein angiography has been able to detect choroidal folds on Earth and following injection the peaks are observed to become bright (hyperfluorescent) while the troughs of choroidal folds remain dark (hypofluorescent). 13 Olsen et al 12 classified chorioretinal folds-related maculopathy into 3 stages with FA by observing areas of hypofluorescence and leakage areas. ...
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Purpose To provide automated system for synthesizing fluorescein angiography (FA) images from color fundus (CF) photographs for averting risks associated with fluorescein dye and extend its future application to Space-associated neuro-ocular syndrome (SANS) detection in spaceflight where resources are limited. Design Development and validation of a novel conditional generative adversarial network (GAN) trained on limited amount of fluorescein angiography and color fundus images with diabetic retinopathy and control cases. Participants Color fundus and fluorescein angiography paired images for unique patients were collected from a publicly available study. Methods FA4SANS-GAN was trained to generate fluorescein angiography images from color fundus photographs using two multi-scale generators coupled with two patch-GAN discriminators. 850 CF and FA images were utilized for training by augmenting images from 17 unique patients. The model was evaluated on 56 fluorescein images collected from 14 unique patients. In addition, it was compared with three other GAN architectures trained on the same dataset. Furthermore, we test the robustness of the models against acquisition noise and retaining structural information when introduced to artificially created biological markers. Main Outcome Measure For GAN synthesis metric Fréchet Inception Distance (FID) and Kernel Inception Distance (KID). Also, two one-sided tests (TOST) based on Welch's t-test for measuring statistical significance. Results On test FA images, mean FID for FA4SANS-GAN was 39.8 (SD 9.9), which is better than GANgio model’s mean of 43.2 (SD 13.7), Pix2PixHD’s mean of 57.3 (SD 11.5) and Pix2Pix’s mean of 67.5 (SD 11.7). Similarly for KID, FA4SANS-GAN achieved mean of 0.00278 (SD 0.00167) which is better than other three model’s mean KID of 0.00303 (SD 0.00216), 0.00609 (SD 0.00238), 0.00784 (SD 0.00218). For TOST measurement, FA4SANS-GAN has proven to be statistically significant vs. GANgio (p = 0.006); vs Pix2PixHD (p < 0.00001); and vs. Pix2Pix (p < 0.00001). Conclusion Our study has shown FA4SANS-GAN to be statistically significant for two GAN synthesis metrics. Moreover, it is robust against acquisition noise, and can retain clear biological markers compared to the other three GAN architectures. This deployment of this model can be crucial in International Space Station (ISS) for detecting Spaceflight-associated neuro-ocular syndrome (SANS).
... Spaceflight-associated neuro-ocular syndrome (SANS) is a condition affecting astronauts during long-duration spaceflight (LDSF). SANS is characterized by hyperopic refractive shifts [1], optic disc edema [2], globe flattening, and chorioretinal folds [3]. With the commercialization of human spaceflight, the amount of space travelers experiencing LDSF will grow exponentially over the coming years, and there may be a potential increase in cases of SANS. ...
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Long-duration spaceflight (LDSF) is associated with unique hazards and linked with numerous human health risks including Spaceflight Associated Neuro-ocular Syndrome (SANS). The proposed mechanisms for SANS include microgravity induced cephalad fluid shift and increased Intracranial Pressure (ICP). SANS is a disorder seen only after LDSF and has no direct terrestrial pathologic counterpart as the zero G environment cannot be completely replicated on Earth. Head-down tilt, bed rest studies however have been used as a terrestrial analog and produce the cephalad fluid shift. Some proposed countermeasures for SANS include vasoconstrictive thigh cuffs and lower body negative pressure. Another potential researched countermeasure is the impedance threshold device (ITD) which can reduce ICP. We review the mechanisms of the ITD and its potential use as a countermeasure for SANS.
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The neuro-ocular effects of long-duration spaceflight have been termed Spaceflight Associated Neuro-Ocular Syndrome (SANS) and are a potential challenge for future, human space exploration. The underlying pathogenesis of SANS remains ill-defined, but several emerging translational applications of terrestrial head-mounted, visual assessment technology and machine learning frameworks are being studied for potential use in SANS. To develop such technology requires close consideration of the spaceflight environment which is limited in medical resources and imaging modalities. This austere environment necessitates the utilization of low mass, low footprint technology to build a visual assessment system that is comprehensive, accessible, and efficient. In this paper, we discuss the unique considerations for developing this technology for SANS and translational applications on Earth. Several key limitations observed in the austere spaceflight environment share similarities to barriers to care for underserved areas on Earth. We discuss common terrestrial ophthalmic diseases and how machine learning and visual assessment technology for SANS can help increase screening for early intervention. The foundational developments with this novel system may help protect the visual health of both astronauts and individuals on Earth.
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Purpose To present a case of atypical unilateral developmental retinal vascular anomaly. Observations A 10-year-old girl presented to her paediatrician after an absent red reflex was noted in a photograph. She had right anisometropic amblyopia and right iris heterochromia, but was otherwise healthy, with no visual complaints. Fundus examination revealed abnormal right retinal vasculature in keeping with an arteriovenous malformation (AVM). OCTA performed at age 16, showed large aberrant veins in the right eye, whereas OCTA B-Scans showed that the same eye had significantly higher retinal blood perfusion than the unaffected eye. Conclusions and Importance OCTA is a valuable, non-invasive emerging method of evaluating patients with AVMs, with this patient having a unique unilateral presentation of a developmental anomaly, without evidence of progression or other vessel malformation. OCTA allowed assessment of flow between the affected and non-affected eye, quantifying the greater blood perfusion in the affected eye due to the AVM.
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Chorioretinal folds (CRFs) are undulations of the choroid and overlying Bruch’s membrane, retinal pigment epithelium and neurosensory retina. CRFs represent a clinical sign that is mandatory to investigate assuming their association with several ocular and extra-ocular disorders. Recent advances in retinal imaging have improved the characterization of CRFs. More importantly, retinal imaging may be useful to detect ocular complications secondary to chronic CRFs, including the development of choroidal neovascularization.
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Prolonged microgravity exposure during long-duration spaceflight (LDSF) produces unusual physiologic and pathologic neuro-ophthalmic findings in astronauts. These microgravity associated findings collectively define the “Spaceflight Associated Neuro-ocular Syndrome” (SANS). We compare and contrast prior published work on SANS by the National Aeronautics and Space Administration’s (NASA) Space Medicine Operations Division with retrospective and prospective studies from other research groups. In this manuscript, we update and review the clinical manifestations of SANS including: unilateral and bilateral optic disc edema, globe flattening, choroidal and retinal folds, hyperopic refractive error shifts, and focal areas of ischemic retina (i.e., cotton wool spots). We also discuss the knowledge gaps for in-flight and terrestrial human research including potential countermeasures for future study. We recommend that NASA and its research partners continue to study SANS in preparation for future longer duration manned space missions.
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Purpose: To report 3 cases of ocular chorioretinal folds from different etiologies and their aspect with the new imaging technology of optical coherence tomography (OCT) angiography (OCT-A). Methods: Baseline data, investigational process on etiology, and follow-up data of patients referred for chorioretinal folds to the Medical Retina & Imaging Unit of San Raffaele Hospital in the period January-March 2016 were collected. Multimodal imaging evaluation, comprehensive of infrared, fundus autofluorescence, multicolor, spectral-domain OCT, and OCT-A, was performed on all patients. Results: Four eyes of 3 men, 65, 46, and 50 years of age, showed chorioretinal folds secondary to central serous chorioretinopathy, postoperative hypotony (after deep sclerectomy), and anisometropia with unilateral hyperopia, respectively. In all cases, OCT-A imaging showed a signal reduction in the choriocapillaris layer in correspondence of the folds. Due to this signal reduction, the en face reconstruction of choriocapillaris layer showed, in all cases, a peculiar tigroid aspect. The aspect of the folds at OCT-A remained unchanged during the 3-month follow-up in all patients. Conclusions: Optical coherence tomography angiography shows a typical linear signal reduction in the choriocapillaris layer in correspondence of the fold with a tigroid pattern. We hypothesize this aspect could be explained by blood flow alteration at the choriocapillaris level in correspondence of the fold.
Article
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.
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To describe a series of chorioretinal folds represent a clinical sign that may be associated with multiple systemic, orbital and ophthalmologic disorders. We report both the associations with systemic disease and describe three stages of a chorioretinal fold-related maculopathy. Observational, retrospective case series. We reviewed fifty-seven affected eyes from 40 patients with the clinical sign of CRF from one of two academic institutions. A careful review of the medical histories and systemic diagnostic evaluations were conducted. Imaging studies were conducted. The mean age at diagnosis was 64 ± 17 years. Most eyes (18) were hyperopic (+2.60 ± +2.90 diopters). There were 20 patients (50%) with some form of autoimmune disorder. Overall, the mean presenting visual acuity was 20/50, declining slightly to 20/60 over 19 ± 30 months. Ten eyes had stage 3 CRF related maculopathy, more common in older individuals with more chronic CRFs. Four stage 3 eyes had associated choroidal neovascularization (CNV) and these eyes presented with 20/60 visual acuity and dropped to 20/100 over approximately 1.5 years. Stage 3 eyes without CNV, had a mean presenting visual acuity of 20/40 and decreased to 20/65 over 2.1 years. Chorioretinal folds are associated with numerous ophthalmic and systemic disorders. A careful medical history and evaluation is essential. We describe three stages of a unique chorioretinal fold-related maculopathy. Stage 3 resembles occult CNV, occurs primarily in older individuals with chronic chorioretinal folds and is accompanied by a slow deterioration in central acuity.