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

Retinal and optic disc perfusion in nonarteritic anterior ischemic optic neuropathy (NAION) is incompletely understood. Our aim was to investigate the characteristics of the microvascular structures at the peripapillary area and optic disc, and their associations with retinal structure and function in patients with NAION. We conducted a prospective, observational case series study. Thirty-four eyes, consisting of 15 NAION eyes and 19 normal eyes, were included. Optical coherence tomography (OCT) angiography was used to measure the vessel densities in the peripapillary superficial retina and whole-depth mode inside the optic disc. Measurement of circumpapillary retinal nerve fiber layer (cpRNFL) thickness was performed using OCT. Sectorial division analysis of cpRNFL was performed by eliminating the influences of the difference in disc rotation between OCT images and OCT angiography images. The vessel densities of peripapillary retina and inside the optic disc were significantly reduced in the NAION compared to the normal (both P < 0.001). Both the severity of visual field defect and cpRNFL thinning were significantly associated with the peripapillary vessel density (P = 0.006, P = 0.046), but not with the optic disc vessel density (P = 0.981, P = 0.856). cpRNFL and peripapillary vessel density showed reduction predominantly in the superior sectors, corresponding to the visual field defect. However, the correlations showed discrepancy of the sectors. The microvascular structures in the peripapillary retina and optic disc were reduced, but the cpRNFL thinning was associated with vessel density only in the peripapillary retina, indicating that the vessel densities in the peripapillary retina and optic disc may be differently affected in the pathological process of NAION.

Original Contribution Persistent Asymmetric Optic Disc Swelling After LongDuration Space Flight: Implications for Pathogenesis Thomas H. Mader, MD, C. Robert Gibson, OD, Christian A. Otto, MD, Ashot E. Sargsyan, MD, Neil R. Miller, MD, Prem S. Subramanian, MD, PhD, Stephen F. Hart, MD, William Lipsky, MD, Nimesh B. Patel, OD, PhD, Andrew G. Lee, MD 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. Journal of Neuro-Ophthalmology 2017;37:133-139 doi: 10.1097/WNO.0000000000000467 © 2016 by North American Neuro-Ophthalmology Society COL(R) US Army (THM), Cooper Landing, Alaska; Coastal Eye Associates (CRG), Webster, Texas; Department of Medicine (CAO), Baylor College of Medicine, Houston, Texas; KBRWyle (AES), Houston, Texas; Wilmer Eye Institute (NRM), Baltimore, Maryland; Department of Ophthalmology (PSS), University of Colorado, Denver, Colorado; Life Sciences Division (SFH), NASA, Houston, Texas; Coastal Eye Associates (WL), Houston, Texas; Department of Vision Science (NBP), University of Houston, Houston, Texas; and Department of Ophthalmology (AGL), Methodist Hospital, Houston, Texas. The authors report no conflicts of interest. Address correspondence to Thomas H. Mader, MD, Box 610, Cooper Landing, AK 99572; E-mail: [e-mail] Mader et al: J Neuro-Ophthalmol 2017; 37: 133-139 I n 2011 the National Aeronautics and Space Administration (NASA) Space Medicine Division documented ophthalmic abnormalities in 7 astronauts after long-duration space flight (LDSF) including optic disc swelling, optic nerve sheath (ONS) distention, globe flattening, choroidal folds, hyperopic shifts in refraction, and cotton-wool spots (CWS) (1). The optic disc swelling gradually resolved, usually within weeks, after their return to Earth. We now report asymmetric changes in the choroid, optic discs, retinal nerve fiber layer, and globe that persisted in an astronaut long after his return to Earth. These persistent findings suggest that prolonged microgravity exposure may have produced chronic asymmetric pressure changes in the perioptic subarachnoid space (SAS) and an asymmetric increase in choroidal volume. CASE REPORT A healthy 45-year-old male astronaut, on no medications, worked on the International Space Station (ISS) between 2013-2014 for approximately 6 months. His premission eye examination was normal including intraocular pressure (IOP) measurements, retinal photography (Topcon TRC 50EX, Tokyo, Japan) (Fig. 1), optical coherence tomography (OCT) (Heidelberg Engineering: Heidelberg Spectralis, Heidelberg, Germany), and automated visual fields (Humphrey SITA-Standard 24-2). He had prominent baseline ONSs on brain and orbital MRI and orbital ultrasound (US). His preflight cycloplegic refraction was: 22.25-0.75 · 090, right eye, and 22.00-1.00 · 094, left eye, correcting acuity to 20/15 bilaterally. The astronaut was launched on a Russian built Soyuz spacecraft from Baikonur Cosmodrome in Kazakhstan. His 6-hour (4 orbit) transit to the ISS was uneventful. His mission included Extravehicular Activities (EVAs) lasting 13 hours in total. Launch plus 10-day (L+10) US showed minimal bilateral globe flattening and increased 133 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution FIG. 1. Preflight appearance of the right and left optic discs. ONS diameters from baseline. At L+21, OCT (Heidelberg Spectralis; Heidelberg, Germany) documented mild choroidal thickening in each eye that became asymmetric thereafter (Fig. 2A), and increases in minimum rim width (MRW) (Fig. 2B) and total retinal thickness (TRT) (Fig. 2C) with insufficient data in the left eye. L+30 US revealed mild bilateral globe flattening with stable ONS diameters and normal fundus photographs (OIS EyeScan; Chicago, IL). IOP measurements starting at L+10 were normal and symmetric during the mission. Fundus photographs of the left eye, including disc appearance, remained normal throughout the mission. L+90 OCT confirmed mild disc swelling R . L and choroidal folds in the right eye (Fig. 3). L+90 fundus photographs of the right eye documented mild optic disc swelling and moderate choroidal folds (Fig. 4). Although the clinical appearance of the left optic disc was normal, OCT detected mild disc swelling (Fig. 2B, C; Fig. 3). L+90 US revealed moderate globe flattening (R . L) and continued ONS enlargement (R . L), which persisted at L+140. The astronaut reported occasional mild headaches during the mission which were successfully treated with ibuprofen. He denied transient visual obscurations, diplopia, or pulsesynchronous tinnitus. Uncorrected distance visual acuity in the right eye improved from 20/60 preflight to 20/25 at L +90 and in the left eye improved from 20/60 preflight to 20/30 on L+120 suggesting asymmetric hyperopic shifts. After a normal landing, the astronaut's R+4 cycloplegic refraction was 21.50-0.75 · 090, right eye, and 21.75- 1.00 · 095, left eye, correctable to 20/15 bilaterally. Visual fields were normal. Retinal photography and ophthalmoscopy of the right eye documented continued mild optic disc swelling with moderate choroidal folds (Fig. 5), which also was detected on OCT (Fig. 6). The left fundus, including the optic disc, appeared normal, but OCT still showed mild bilateral disc swelling (R . L) (Fig. 2B, C). Orbital 3T MRI confirmed bilateral globe flattening (R . L) with increased optic nerve sheath diameter in both eyes (Fig. 7) compared with preflight values but less than inflight peak diameters. Postflight optical biometry (IOLMaster 500; Zeiss USA, San Diego, CA) detected a reduction in axial length from baseline of 0.53 mm, right eye, and 0.29 mm, left eye. US revealed diffuse optic disc elevation in the right eye and minimal ele134 vation of the left optic disc. This result was similar to the last inflight study performed at L+140. R+7 opening pressure on lumbar puncture (LP) was 22 cm H2O. Although the choroidal thickening in each eye was largely resolved by R+30 in the right eye and R+4 in the left eye, residual thickening in the right eye was still present on OCT at R+90 (Fig. 2A). R+90 retinal photography confirmed no change from R+4. At R+180 there was a new CWS surrounded by a superficial retinal hemorrhage in the right eye and no change in optic disc swelling (Fig. 8). At the time of this finding, the astronaut was in good health and his blood pressure remained normal. Repeat MRI revealed persistent globe flattening R . L and optical biometry documented a reduction in axial length from preflight of 0.41 mm, right eye, and 0.20 mm, left eye. US confirmed globe flattening with continued disc elevation. Visual fields remained normal. Serial OCTs demonstrated a gradual decrease in both MRW and TRT in each eye after landing (Fig. 2B, C). R+365 opening pressure on LP was 16 cm H2O with normal composition. R+360 US showed persistent mild right globe flattening without disc protrusion, whereas ONS diameters had returned to preflight values in both eyes. R+365 MRW and TRT were near baseline in the left eye. In the right eye, MRW showed mild elevation, and TRT remained elevated (Fig. 2C). Biometry revealed a 0.39 mm, right eye, and 0.16 mm, left eye, reduction in axial lengths from preflight. At R+600 (20 months), funduscopy was normal bilaterally. At R+630 (21 months), OCT demonstrated continued optic disc asymmetry and persistent morphologic change from baseline (Fig. 3). At R+660 (22 months) US showed no change from R+365. R+630 cycloplegic refraction was 21.25-1.25 · 085, right eye, and 21.50-1.00 · 100, left eye. R+630 MRW and TRT in each eye were unchanged from R+365 (Fig. 2B, C). R+630 OCT documented persistent right choroidal folds (Fig. 3). R+660 visual fields were normal and biometry revealed a 0.36 mm, right eye, and 0.17, left eye, decrease from preflight measurements. DISCUSSION Both unilateral and bilateral optic disc swelling have been documented in astronauts during and after LDSF (1,2). Mader et al: J Neuro-Ophthalmol 2017; 37: 133-139 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution FIG. 2. Optical coherence tomography. A. Circumpapillary choroid thickness quantified using a circular scan centered on the optic nerve head (ONH). B. Minimum rim width (MRW) calculated using 12 radial scans through the ONH. C. Total retinal thickness (TRT) from Bruch membrane opening to 250 mm. Preflight (L2, days before launch); inflight (L+, mission day); postflight (R+, days after return to Earth). Mader et al: J Neuro-Ophthalmol 2017; 37: 133-139 Typically, there is a slow progression during flight and a gradual resolution postflight. The etiology of the disc swelling is unclear but two main potential mechanisms have been proposed (1-3). They are not mutually exclusive. First, optic disc swelling may result from a rise in intracranial pressure (ICP) from cephalad fluid shifts during LDSF leading to venous stasis in the head and neck (1-6). This stasis could cause impairment of cerebrospinal fluid (CSF) drainage into the venous system and cerebral venous congestion, leading to elevated ICP. This could result in ONS distention, globe flattening, and stasis of axoplasmic flow with optic disc swelling similar to what occurs in patients with terrestrial primary pseudotumor cerebri (PTC) (1,7,8). Although inflight CSF pressures have never been measured, lumbar puncture opening pressures (LPOP) of 28 and 28.5 cm H2O were documented in astronauts at 12 and 57 days, respectively, after LDSF and may have been higher during the mission (1). After LDSF, MRI changes in other astronauts suggestive of increased ICP include pituitary concavity, empty sella, and changes in pituitary stalk configuration (9). Other possible factors contributing to ICP elevation during LDSF include defects in the vitamin B12-dependent 1-carbon transfer pathways (10), high carbon dioxide levels, rigorous resistive exercise, and high-salt ISS diets. However, in the astronaut we report, many findings cast doubt on raised ICP as the cause of optic disc edema. Neither the LPOP of 22 cm H2O at R+7 nor the LPOP of 16 cm H2O at R+365 was sufficiently high to cause or maintain papilledema. If elevated ICP and disc swelling result from microgravity-induced venous stasis, they should have resolved on return to Earth. In contrast to the affected astronauts, most terrestrial papilledema is bilateral and symmetric. Furthermore, our subject reported only occasional mild headaches inflight and no additional symptoms of increased ICP. In contrast, moderate to severe headache is reported by .90% of all patients with terrestrial primary PTC (7) and 79% of men (11). Therefore, mechanisms of disc swelling other than increased ICP must be considered. The second possible mechanism of optic disc swelling, at least in this astronaut, is compartmentation of CSF in the orbital SAS (1-3). There is thought to be homogeneity of pressure and chemical composition throughout the SAS of the brain and orbit (12). However, the tightly confined, densely septated cul-de-sac-like anatomic connection between the intracranial SAS and the SAS surrounding the ON creates a fragile flow equilibrium that may lead to asymmetric pressure levels in the perioptic SAS (12-16). This anatomy, coupled with the cephalad fluid shifts of prolonged microgravity, may inhibit CSF absorption within the orbit through venous and lymphatic mechanisms leading to sequestration of CSF surrounding the orbital portion of the ON (1,13,17). This sequestration may produce locally elevated ONS 135 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution FIG. 3. Serial preflight, inflight, and postflight radial OCT scans through the optic nerve head show persistent asymmetric optic disc morphologic change from baseline. OCT, optical coherence tomography; OD, right eye; OS, left eye. pressures, and the accumulation of toxic substances (2,15,16) that could cause disc swelling and associated findings (e.g., choroidal folds, globe flattening) with or without a rise in ICP (1). CSF sampling from LPs and during ONS fenestration in some patients with PTC have demonstrated an increased concentration of lipocalin-like prostaglandin D synthase (L-PGDS) in the SAS of the ON compared with that of the lumbar CSF space (15). L-PGDS is a brain-derived protein that is toxic to astrocytes. It is also a prostaglandin synthase that in increased concentrations can augment the production of prostaglandins and cause vasoconstriction. This could potentially cause FIG. 4. Inflight (L+90 days) fundus photographs of right and left eye. Note the presence of mild right optic disc swelling (arrowhead) and horizontal choroidal folds (arrow) superior to the disc. 136 Mader et al: J Neuro-Ophthalmol 2017; 37: 133-139 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution FIG. 5. Postflight (R+4 days) fundus examination demonstrates continued optic disc swelling (arrowhead) and choroidal folds (arrow) in the right eye. The left fundus appears unremarkable. a local microinfarct in the retinal nerve fiber layer manifesting as a CWS. Small anatomic differences between the ONSs, although insignificant on Earth, could cause unequal changes in CSF outflow facility and corresponding asymmetric optic disc edema. In our current report, we documented mild clinical right disc swelling 90 days into the mission, with a normalappearing left disc. This disc swelling persisted for at least 180 days postmission in conjunction with elevated TRT values in the right eye at 630 days (21 months) postmission. Optic nerve head OCT at R+630 also demonstrated persistent asymmetric disc morphologic changes from baseline (Fig. 3). Imaging modalities performed from L+90 through R+630 documented globe flattening (R . L) from baseline as did biometry. This long-standing optic disc and globe asymmetry despite LPOPs of 22 and 16 cm H2O, at 1 week and 1 year, respectively, strongly suggest that increased ICP alone was not the cause of this astronaut's ocular findings. In further support of this hypothesis, in a previous longduration astronaut, we documented asymmetric disc swelling in conjunction with a normal LPOP 1 week after space flight (2) and the unilateral loss of previously visible spontaneous venous pulsations during space flight in the eye with the disc swelling that continued to be absent on his most recent examination 21 months after his return to Earth (18). Asymmetric, chronic ONS pressure elevations possibly in conjunction with toxic metabolites within the ONS may have set the stage for tissue remodeling of the optic nerve head and posterior sclera. It is possible that space radiation may have impacted our findings. Previous studies suggest that relatively low-dose space radiation may predispose astronauts to an increased incidence of cataracts (19,20). In animal models, radiationinduced chronic oxidative stress and inflammation can FIG. 6. Postflight (R+4 days) scanning laser ophthalmoscopy and optical coherence tomography of the right eye reveals disc swelling and chorioretinal folds. Green arrows indicate location and direction of line scans. Mader et al: J Neuro-Ophthalmol 2017; 37: 133-139 137 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution FIG. 7. Preflight and postflight axial T2 magnetic resonance imaging shows postflight globe flattening (R . L) with increased optic nerve sheath diameter bilaterally. OD, right eye; OS, left eye. cause tissue injury (21-23). During LDSF, the entire CNS is subjected to higher rates of ionizing radiation than terrestrially. Perhaps in the brain and spinal cord, with free flow of CSF, the potential inflammatory effects of radiation are diluted compared with the rather stagnant ONS CSF. It has been suggested that even mild inflammatory stimuli on Earth may produce arachnoiditis and trabeculitis with secondary fibrosis as well as closing of the arachnoid apertures that drain CSF into the meningeal lymphatics, thus adding to CSF compartmentation (12). The delayed onset of the CWS after this space mission is also consistent with radiation exposure. CWSs are a wellknown side effect of radiation therapy, and there can be a time delay of months to years between the radiation exposure and their appearance (24). CWSs after radiation therapy are observed after comparatively short bursts of high-dose radiation far exceeding the magnitude of the prolonged low dose encountered by astronauts. Radiation therapy may produce multiple large CWSs and extensive retinal hemorrhage. In contrast, the one small CWS and hemorrhage in this astronaut may represent the end result of a comparatively low but prolonged radiation dose. Postmission CWSs also were documented in 4 other long-duration astronauts 3 of whom had EVAs during their missions (NASA Lifetime Surveillance of Astronaut Health). As the EVA suits provide less shielding than the ISS, the dose rate during EVA is consistently higher. We used OCT technology on the ISS to document asymmetric choroidal expansion during the mission (Fig. 2A). Head-down (4), parabolic flight (5), and space shuttle (6) studies have documented sudden, transient IOP increases thought to be caused by choroidal expansion. As the choroid is drained by the vortex veins and lacks autoregulation, elevated venous pressure from cephalad fluid shifts could inhibit choroidal drainage, causing sudden choroidal inflation and a concomitant IOP spike (4). An OCT study confirmed increased choroidal thickness during head-down tilt (25) and residual choroidal folds have been documented in astronauts years after space flight (1,2). Since we documented choroidal expansion during his flight with no long-term increase in IOP this suggests that, as previously hypothesized (4), a compensatory decrease in anterior chamber volume may have occurred. We also documented persistent choroidal folding by OCT at R+630. Although choroidal folding in terrestrial primary PTC is associated with higher levels of ICP (26), this may not be the case in astronauts (27). STATEMENT OF AUTHORSHIP Category 1: a. Conception and design: T. H. Mader, C. R. Gibson, C. A. Otto, A. Sargsyan, N. R. Miller, P. S. Subramanian, S. F. Hart, W. Lipsky, N. B. Patel, and A. G. Lee; b. Acquisition of data: C. R. Gibson, A. Sargsyan, and N. B. Patel; c. Analysis and interpretation of data: T. H. Mader, C. R. Gibson, C. A. Otto, A. Sargsyan, N. R. Miller, P. S. Subramanian, S. F. Hart, W. Lipsky, N. B. Patel, and A. G. Lee. Category 2: a. Drafting the manuscript: T. H. Mader, C. R. Gibson, C. A. Otto, A. Sargsyan, N. R. Miller, P. S. Subramanian, S. F. Hart, W. Lipsky, N. B. Patel, and A. G. Lee; b. Revising it for intellectual content: T. H. Mader, C. R. Gibson, C. A. Otto, A. Sargsyan, N. R. Miller, P. S. Subramanian, S. F. Hart, W. Lipsky, N. B. Patel, and A. G. Lee. Category 3: a. Final approval of the completed manuscript: T. H. Mader, C. R. Gibson, C. A. Otto, A. Sargsyan, N. R. Miller, P. S. Subramanian, S. F. Hart, W. Lipsky, N. B. Patel, and A. G. Lee. ACKNOWLEDGMENTS FIG. 8. Postflight (R+180 days) appearance of the right eye demonstrates persistent optic disc swelling of the superior disc margin (arrow), absence of previously visible choroidal folds, and a new cotton-wool spot surrounded by a superficial retinal hemorrhage (arrowhead). 138 This case report has been approved by the NASA institutional review board. Because of the relative likelihood of attributability of these data, the subject has provided written informed consent. 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