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.

Original Contribution Section Editors: Clare Fraser, MD Susan Mollan, MD Evaluation of Optic Disc Edema in Long-Duration Spaceflight Crewmembers Using Retinal Photography William E. Valencia, MD, Sara S. Mason, BS, Tyson J. Brunstetter, OD, PhD, Ashot E. Sargsyan, MD, Caroline M. Schaefer, MPH, William J. Tarver, MD, Mary G. Van Baalen, PhD, Charles R. Gibson, OD, Andrew G. Lee, MD, Sergey N. Danilichev, MD, Patricia V. Hinton, MD, Igor A. Makarov, MD, PhD, Vladimir P. Matveev, MD, Claudia H. Stern, MD, PhD, Ari Taniguchi-Shinojima, MD, PhD, Steven E. Feldon, MD 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 The University of Texas Medical Branch at Galveston (WV), Galveston, Texas; MEI Technologies Inc (SM), Houston, Texas; NASA Johnson Space Center (TB, WT, MVB), Houston, Texas; KBR (AS), Houston, Texas; The University of Texas Health Science Center at Houston School of Public Health (CS), Houston, Texas; Coastal Eye Associates (CG), Webster, Texas; Department of Ophthalmology (AL), Houston Methodist Hospital, Houston, Texas; Gagarin Research and Test Cosmonaut Training Center (SD, VM), Star City, Russian Federation; Canadian Space Agency (PH), Chapman Space Centre, Longueuil, Canada; Institute of Biomedical Problems (IM), Russian Academy of Science, Moscow, Russian Federation; German Aerospace Center (CS), Cologne, Germany; Department of Ophthalmology (AT-S), Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan; and School of Medicine and Dentistry (SF), Flaum Eye Institute, University of Rochester, Rochester, New York. The authors report no conflicts of interest. Address correspondence to William Valencia, MD, The University of Texas Medical Branch at Galveston, University Boulevard, Rt 1110, Galveston, TX 77555; E-mail: [e-mail] 364 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. Journal of Neuro-Ophthalmology 2023;43:364–369 doi: 10.1097/WNO.0000000000001787 © 2023 by North American Neuro-Ophthalmology Society M ader et al described combinations of optic disc edema (ODE), globe flattening, choroidal folds, retinal nerve fiber layer (RNFL) infarcts, optic nerve sheath distention, and hyperopic shifts in refraction in a subset of 7 International Space Station (ISS) crewmembers (1). Structural and functional ocular changes in long-duration spaceflight (LDSF) crewmembers have since been widely reported in the literature. This spectrum of clinical findings associated with sustained microgravity exposure is currently termed spaceflight-associated neuro-ocular syndrome (SANS) (2). The challenging mission profiles of future interplanetary travel warrant efforts to elucidate SANS pathophysiology and develop evidence-based strategies for its prevention and management. Among the diverse elements of SANS, ODE is of utmost interest because of the concerns related to its origin and consequences. The terrestrial gold standard for evaluating ODE is fundoscopy using the Frisén scale (3,4), a subjective test with variability among graders (5,6). The use of Frisén Grade 1 or higher ODE as a requisite criterion to define and diagnose SANS had resulted in an overall incidence of 16% among the U.S. Operating Segment (USOS) LDSF crew (7). A more inclusive SANS case definition using other available measures would undoubtedly produce higher incidence figures. In a survey of 300 astronauts, 23% of short duration mission crewmembers reported a degradation in near vision, as did almost half of LDSF crewmembers (1). In a study involving 16 Russian cosmonauts who flew long-duration missions, 8 Valencia et al: J Neuro-Ophthalmol 2023; 43: 364-369 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution were found to have ODE on landing day (8). To better understand the pathogenesis of SANS and respective countermeasures, an objective, internationally standardized approach for evaluating the status of the disc should be encouraged. The astronaut cohort is mostly asymptomatic and differs in many ways from any terrestrial patient population with ODE including idiopathic intracranial hypertension (IIH), an imperfect terrestrial analog for SANS. IIH typically presents with severe headache, pulsatile tinnitus, and other characteristic symptoms of raised intracranial pressure that are lacking in astronauts with SANS (2,9). Cephalad fluid shift in microgravity is hypothesized to be a causative factor for ocular structural changes, including those within the optic nerve head (1,2,10,11). At the same time, it remains unclear whether true papilledema from increased intracranial pressure is occurring in parallel to contribute to ODE. Fundoscopy is the primary data source in diagnosis and follow-up of papilledema associated with IIH (6,12). The inter-rater reproducibility of the Frisén scale for IIH has been evaluated (5), and Grade 1 ODE is the most difficult to recognize (13). No similar evaluations are available for SANS. The low sensitivity and subjective nature of fundoscopy are its obvious limitations, which allow us to question the validity of Frisén grading as a primary method for diagnosing and monitoring SANS. In contrast to relevant terrestrial conditions, SANS presents in the milder part of the ODE spectrum, where the Frisén scale lacks sufficient gradation. In addition to fundoscopy, SANS has been evaluated with ocular coherence tomography (OCT), orbital and cranial MRI, ocular ultrasound, and lumbar puncture (1,2,9,10,14). The International Fundoscopy Evaluation of Crewmembers (IFEC) is the first project in a series of collaborative SANS data analysis efforts. The aim of this study was to determine the inter-rater and intrarater reliability for defining Frisén grade of SANS-induced ODE among a trained observer cohort. This was accomplished by conducting a retrospective, blinded evaluation of pre and postflight funduscopic images for ODE using a standardized method (Frisén scale) to identify and grade ODE in a population of LDSF crewmembers of ISS. The secondary goal of this study is to propose a standardized evaluation process for SANS-induced ODE across ISS Partner Agencies—the Canadian Space Agency (CSA), the European Space Agency (ESA), Japan Aerospace Exploration Agency (JAXA), the State Corporation Roscosmos (Roscosmos), and the National Aeronautics and Space Administration (NASA). METHODS Participants In this retrospective study, fundoscopy data were obtained from both eyes of 62 international crewmembers across all ISS Partner Agencies: CSA (N = 2), ESA (N = 10), JAXA (N = 6), NASA (N = 33), and Roscosmos (N = 11). Table 1 shows a summary of crewmember characteristics. Fundus Photography ISS Partner Agencies provided a preflight (baseline) and postflight cycloplegic fundus photograph for both eyes of crewmembers of approximately 6-month long missions. These data were collected routinely for clinical and occupational surveillance purposes. If a preflight image was not available for a crewmember, the postflight image was only included in the single image comparisons, not the paired assessments. Because of confidentiality, no images were cross analyzed for repeat fliers. NASA, CSA, and JAXA used the following cameras to capture fundus images: Topcon TRC-NW6S (Tokyo, Japan), Topcon TRC-50EX (Tokyo, Japan), and Canon CR-2 Plus AF (Tokyo, Japan); ESA used Zeiss Visucam (Oberkochen, Germany); and Roscosmos used Zeiss FF450 Plus (Oberkochen, Germany). TIFF and JPEG images were collected with a 50° field of view and de-identified before being provided to NASA’s Lifetime Surveillance of Astronaut Health (LSAH) team of epidemiologists. All images were cropped to a circular mask using Adobe Photoshop (San Jose, CA). For each subject, images were superimposed by setting their opacity down to ½, placing them in different layers, and achieving best possible alignment by mutual rotation and translation. After applying the overlying circle mask, each layer was exported to a separate image with opacity set back to 1. Ophthalmologists from Roscosmos, ESA, JAXA, and NASA met in Houston, Texas and received training on standardized optic disc evaluation using the Frisén scale (3) conducted by S.F., Neuro-Ophthalmologist and Director of the Photographic Reading Center, using a training dataset of fundus images centered on the optic disc. The training dataset included images of defining characteristics of each stage of papilledema, similar to the one used in the Idiopathic Intracranial Hypertension Treatment Trial (IIHTT) (6). In Phase 1 of IFEC image review, observers were shown all optic disc photographs, sequentially and in random order, and were asked to grade the disc appearance using the standard TABLE 1. Crewmember characteristics Person mission Age at launch, mean (SD) F M CSA ESA JAXA NASA Roscosmos Total 2 54.54 (1.75) 0 2 10 44.86 (6.74) 1 9 7 45.33 (3.01) 0 7 37 48.61 (4.94) 8 29 11 48.15 (4.35) 0 11 67 47.81 (5.19) 9 58 CSA, Canadian Space Agency; ESA, European Space Agency; JAXA, Japan Aerospace Exploration Agency; NASA, National Aeronautics and Space Administration; Roscosmos, State Corporation Roscosmos. Valencia et al: J Neuro-Ophthalmol 2023; 43: 364-369 365 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution Frisén scale. Images were displayed in their native resolution for 30 seconds each using Microsoft PowerPoint (Redmond, WA). Each of the 4 subject-matter experts and S.F. provided Frisén grading for each individual image in a mutually blinded fashion. In Phase 2, the grading team reviewed image pairs of each individual side-by-side for 30 seconds. The observers were asked to assess differences in disc appearance and choose the disc with less edema, or to label them no change or unable to compare. Statistical Analysis The development of algorithms and data analysis was performed between 2017 and 2019. Interobserver reliability was evaluated using the approach described by Sinclair et al. (5) For “Phase 1,” agreement was evaluated among all observers in assessing the level of disc edema. Second, the probability of pairs of observers agreeing on disc classification was examined by analyzing all possible pairings of reviewers. The extent of disagreement was also noted (1, 2, or 3 Frisén grades). For “Phase 2,” pairs of images were presented to graders, who were asked to identify which image had more edema or if there was no difference. The probability of pairs of observers agreeing on disc ranking was examined. Finally, intrarater agreement between Frisén grading and disc ranking was assessed. Statistical analyses were performed using SAS/ STAT 15.1 (Cary, NC). As described in the study by Sinclair et al (5), variables were analyzed using descriptive statistics. RESULTS Phase 1: Frisén Grading A total of 284 single images were assessed by the 5 expert graders. Five of the images were not scored by any of the graders because of image quality. Figure 1 illustrates the frequency of Frisén grades given by each observer. Grade 0 was recorded for most images (1,105; 80.89%) and Grade 1 was the second most frequent (237; 17.35%). Grades 2 and 3 were scarcely reported, combining for less than 2% of the graded images (22, 2; 1.61%, 0.15%, respectively). There were 29 instances where a grader did not provide a grade because of various reasons (e.g., over-exposed image or out-of-focus blur). All 5 graders agreed for 107 of the images (38.4%), all of which were attributed Grade 0. There was agreement for 4 of the 5 graders for 94 images (33.7%); 90 were Grade 0, 3 were Grade 1, and 1 was Grade 2. The difference in grades or agreement between pairs of readers was assessed. There was complete agreement for 1,906 pairs (71%). For the 779 pairs that did not agree, 737 (27%) differed by one grade (minor disagreement) and 42 (2%) differed by 2 grades (major disagreement). Table 2 compares our findings with results from other studies evaluating inter-rater or intrarater agreement. Phase 2: Disc Ranking A total of 136 pairs of images were shown to graders, positioned randomly side by side. The frequency that each observer detected a difference is illustrated in Figure 2. All 5 graders agreed on 74 pairs of images (54.41%), 71 of which agreed to no difference and 3 picked the same image with more edema. Forty-four pairs had agreement among 4 of the 5 graders, 41 of which were assigned no difference and 3 where the graders picked the same image with more edema. Four of the pairs of images had conflicting choices. Pairs of graders were compared and of the 1,326 pairs, 1,058 (79.79%) completely agreed, 262 (19.76%) FIG. 1. Frequency of Frisén grades by grader. Grade 0 was recorded for most images (1,105; 80.89%) and Grade 1 was the second most frequent (237; 17.35%). Grades 2 and 3 were scarcely reported. All 5 graders agreed for 107 of the images (38.4%), all of which were attributed Grade 0. 366 Valencia et al: J Neuro-Ophthalmol 2023; 43: 364-369 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution TABLE 2. Frisén Grade Agreement Study Assessment Complete Agreement Within 1 Grade Two or More Grade Difference Number of Comparisons IFEC Sinclair et al (5) Frisén (3) Fischer et al (6) Inter-rater Inter-rater Inter-rater Intrarater 71% 36% 49% 55%–73% 98% 82% 86% $93% 2% 18% 14% #7% 2,685 2,820 78 58–116 IFEC, International Fundoscopy Evaluation of Crewmembers. had minor disagreement, and 6 (0.45%) had major disagreement (Table 3). Agreement Between Frisén Grading and Disc Ranking Perfect agreement occurred when a grader gave 2 individual images the same score and also noted that there was no difference between the paired images or the grader gave one image a higher score when rated individually and also stated that that image was worse when the 2 images were compared. Of the 642 assessable comparisons, 499 (77.7%) had perfect agreement (Table 4). There were 56 (8.7%) instances in which the grader gave 2 images the same score when viewed individually, but stated that one image was worse than the other when shown side-by-side. 76 (11.8%) times a grader gave 1 of the 2 images a higher score when shown individually, but stated that there was no difference between the images when observed together. Finally, there were 11 (1.7%) instances of major disagreement in which a grader gave one image a higher score when shown individually, but stated that the opposing image was worse when the 2 images were compared together. CONCLUSION This study marks the first collaborative effort among ISS Space Agencies to analyze data for SANS-induced ODE. Our results show that there is wide inter-rater variability using the Frisén scale to identify ODE in LDSF crewmembers. Most cases identified as having ODE were graded as one on the Frisén scale, the most difficult grade to recognize (13). Improved surveillance requires updated, uniform methods and parameters to detect early signs of SANS. In the IIHTT, systematically trained lay observers identified the exact same Frisén grade in 55%–73% of reads, but graded at least 93% of the reads within one grade (6), similar to our findings. Sinclair et al (5) found that expert observers rarely came to a complete agreement, but reached 82% agreement within one grade. However, despite reasonable intrarater and inter-rater concordance within one grade, the Frisén scale lacks enough accuracy to consistently identify incipient levels of ODE. Patients with IIH tend to have moderate or severe papilledema at presentation (4,15,16), thus offering easier-to-identify pathology on fundoscopy. In contrast, SANS-induced ODE is Grade 1 in 90% of cases. The recent SANS definition, de facto, forces a FIG. 2. Paired comparisons by grader. No difference was recorded by the 5 graders for 563 (82.79%) paired images and a difference was identified in 117 pairs of images (17.21%). Valencia et al: J Neuro-Ophthalmol 2023; 43: 364-369 367 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution TABLE 3. Disc ranking, grader pairs Concordance Between Graders Number of Comparisons (%) Complete agreement Minor disagreement* Major disagreement† 1,058 (79.79) 262 (19.76) 6 (0.45) *One grader identified a difference while the other classified the pair as the same or unable to compare. † The pair picked different images as “worse.” binary decision at the lowermost end of the Frisén scale (between 0 and 1), based on subjective assessment of subtle indicators of edema, and this happens in conditions of natural anatomical variability, flattened image presentation by nonstandardized optical equipment, and other confounding factors. Our study also found that disagreement between Frisén grading and disc ranking occurred about 22% of the time, which seems to be another weakness of the Frisén classification—a relatively modest reliability for ODE follow-up compared with instantaneous disc ranking (5). Advanced objective methods to identify and characterize ODE are readily available in terrestrial and space settings. A spectral-domain Spectralis OCT system (Heidelberg Engineering, Germany) has been flown on the ISS medical suite since 2013, and was recently replaced by a new model, Spectralis OCT2 (Heidelberg Engineering, Germany) while maintaining the data continuity. Earlier studies (17,18) used OCT to identify papilledema and ODE by measuring the RNFL. Although helpful for the diagnosis and management of IIH patients, OCT measurement of the RNFL alone can miss mild cases of papilledema (19). Measuring peripapillary total retinal thickness (TRT) is more sensitive compared with RNFL measurement (20). Using a model incorporating random effects of measurements, Laurie et al (21) determined that a change in peripapillary TRT of more than 19.4 mm would have less than 5% chance of being observed because of sampling error or physiologic variability. Future studies aiming to understand the pathophysiology of SANS require the use of well-delineated parameters that can be measured reliably. Based on results from the IFEC project, the TABLE 4. Intragrader concordance between Frisén grade and disc ranking Concordance Within Grader Complete agreement Minor disagreement* Major disagreement† Number of Comparisons (%) 499 (77.7) 132 (20.6) 11 (1.7) *Grader identified a difference in Frisén grade, but not in ranking or vice versa. † Grader gave one image a higher grade when shown individually, but ranked the opposing picture worse when the images were compared together. 368 ISS International Partners acknowledged that an update was required in how SANS ODE is described and diagnosed, and how SANS is defined. In 2020, the “earliest indication of SANS” definition was established and is diagnosed whenever one or more of the following signs are detected in at least one eye of a crewmember, during or following LDSF: ODE (i.e., $20 mm increase in peripapillary TRT as measured by OCT), chorioretinal folds, globe flattening, and a hyperopic refractive error shift of $0.75 diopters. Based on this definition, the earliest signs of SANS are detected in approximately 69% of LDSF crewmembers. A case definition for the “pathological threshold of SANS” has not yet been established, but is being pursued. It was further acknowledged that OCT technology significantly increases the sensitivity to detect early changes associated with SANS and may be applied in an objective, continuous measure that allows for more helpful applications than the ordinal Frisén scale. Using OCT, countermeasures such as lower body negative pressure (LBNP), which helps to shift fluids to the lower extremities (22), can undergo robust evaluation for effectiveness against SANS. Our study had limitations. The retrospective design relied on clinical data previously gathered across 5 different international partners, and multiple variables limited our ability to provide a dataset of uniform quality, such as different fundoscopes, photographers, and file formats. We did ensure that all international partners used cameras that met clinical standards of care. Graders may have been biased toward higher Frisén grading to meet their personal expectations of a high incidence of SANS in LDSF crewmembers. This study did not account for countermeasures, nor did it control for age of our participants. This article launches a multilateral effort to critically reexamine and standardize surveillance of ocular changes in spaceflight crewmembers. We find that the use of fundoscopy is probably not sufficient as the sole method to characterize SANS-induced ODE; an ordinal measure such as the Frisén grade is unsatisfactory as a primary criterion to define, diagnose, and classify SANS. A multimodality approach to ocular surveillance with the use of consistently applied continuous variables is essential for advancing our understanding of SANS and for developing effective countermeasures. STATEMENT OF AUTHORSHIP Conception and design: T. Brunstetter, S. Mason, W. Valencia, S. Feldon; Acquisition of data: S. Mason, W. Tarver, M. Van Baalen, C. Gibson, A. Lee, S. Danilichev, P. Hinton, I. Makrov, V. Matveev, C. Stern, A. Taniguchi-Shinojima; Analysis and interpretation of data: S. Mason, C. Schaefer. Drafting the manuscript: W. Valencia, S. Mason, T. Brunstetter, A. Sargsyan, C. Schaefer, W. Tarver, M. Van Baalen, A. Lee, P. Hinton, C. Stern, A. Taniguchi-Shinojima, S. Feldon; Revising the manuscript for intellectual content: M. Van Baalen. Final approval of the completed manuscript: W. Valencia, S. Mason, T. Brunstetter, A. Sargasyan, C. Schaefer, W. Tarver, M. Van Baalen, C. Gibson, A. Lee, S. Danilichev, P. Hinton, I. Makrov, V. Matveev, C. Stern, A. Taniguchi-Shinojima, S. Feldon. Valencia et al: J Neuro-Ophthalmol 2023; 43: 364-369 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution REFERENCES 1. 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