Neuro-Ophthalmology of Space Flight

State-of-the-Art Review rie Biousse, MD Section Editors: Vale Steven Galetta, MD Neuro-Ophthalmology of Space Flight Andrew G. Lee, MD, William J. Tarver, MD, Thomas H. Mader, MD, Col (R), Charles Robert Gibson, OD, Stephen F. Hart, MD, Christian A. Otto, MD, MMSc Background: To describe the history, clinical findings, and possible pathogenic etiologies of the constellation of neuro-ophthalmic findings discovered in astronauts after long-duration space flight and to discuss the terrestrial implications of such findings. Evidence Acquisition: Retrospective review of published observational, longitudinal examination of neuro-ophthalmic findings in astronauts after long-duration space flight; analysis of postflight questionnaires regarding in-flight vision changes in approximately 300 additional astronauts; and hypothesis generating for developing possible future countermeasures and potential implications for neuro-ophthalmic disorders on Earth. Astronauts with neuro-ophthalmic findings, which were not present at the start of a space flight mission and only seen on return from long-duration space missions to the International Space Station, will be discussed. Department of Ophthalmology (AGL, CRB), Houston Methodist Hospital, Houston, Texas; Department of Ophthalmology (AGL), Baylor College of Medicine, Houston, Texas; Departments of Ophthalmology, Neurology, and Neurosurgery (AGL), Weill Cornell Medical College, New York, New York; Department of Ophthalmology (AGL), The University of Texas Medical Branch, Galveston, Texas; Department of Ophthalmology (AGL), The University of Iowa Hospitals and Clinics, Iowa City, Iowa; Section of Ophthalmology (AGL), The University of Texas MD Anderson Cancer Center, Houston, Texas; Space Medicine Division (WJT, SFH), National Aeronautics and Space Administration, Washington, DC; US Army (THM), Cooper Landing, Alaska; Coastal Eye Associates (CRG), Webster, Texas; and Universities Space Research Association (CO), National Aeronautics and Space Administration, Washington, DC. Presented in part at the 41st Annual NANOS Meeting, February 21- 26, 2015, at the Hotel del Coronado in San Diego, CA. Although the authors have served as employees or consultants for NASA, the contents of this specific manuscript were vetted and reviewed by Lifetime Surveillance of Astronaut Health (LSAH) at the National Aeronautics and Space Administration (NASA). The views and opinions represented here are those of the authors as well as content already within the public domain, and thus do not necessarily represent the views of the space agency (NASA) or the US government. The authors report no conflict of interest. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the full text and PDF versions of this article on the journal's Web site (www. jneuro-ophthalmology.com). Address correspondence to Andrew G. Lee, MD, The Department of Ophthalmology, Blanton Eye Institute, Houston Methodist Hospital, 6560 Fannin Street, Scurlock 450, Houston, TX 77030; E-mail: aglee@ houstonmethodist.org Lee et al: J Neuro-Ophthalmol 2016; 36: 85-91 Results: After 6 months of space flight, 7 astronauts had ophthalmic findings consisting of optic disc edema in 5, globe flattening in 5, choroidal folds in 5, cotton-wool spots in 3, nerve fiber layer thickening detected by optical coherence tomography in 6, and decreased near vision in 6. Five of 7 astronauts with near vision complaints had a hyperopic shift $+0.50 diopters (D) between pre-/post-mission spherical equivalent refraction in 1 or both eyes (range, +0.50 to +1.75 D). These 5 astronauts showed globe flattening on magnetic resonance imaging. A total of 6 lumbar punctures have been performed to date (4 in the originally described cohort) and documented opening pressures of 18, 22, 21, 21.5, 28, and 28.5 cm H2O. These were performed at 8, 66, 19, 7, 12, and 57 days after mission, respectively. The 300 postflight questionnaires documented that approximately 29% and 60% of astronauts on short-duration and long-duration missions, respectively, experienced a degradation in distant and near visual acuity. Some of these vision changes remain unresolved for years after flight. Several possible pathogenic mechanisms, as well as potential countermeasures and discussion of possible terrestrial implications, are described. Conclusions: We previously hypothesized that the optic nerve and ocular changes that we described in astronauts may be the result of orbital and cranial cephalad fluid shifts brought about by prolonged microgravity exposure. The findings we reported previously and continue to see in astronauts may represent parts of a spectrum of ocular and cerebral responses to extended microgravity exposure. Future investigations hopefully will lead to countermeasures that can be used to eliminate or lessen the magnitude of these potentially harmful findings before long-duration space flight including the possibility of a manned mission to Mars. Journal of Neuro-Ophthalmology 2016;36:85-91 doi: 10.1097/WNO.0000000000000334 © 2016 by North American Neuro-Ophthalmology Society NEURO-OPHTHALMIC PHYSIOLOGIC AND PATHOLOGIC RESPONSES IN OUTER SPACE P hysiologic and pathologic systemic responses and novel but dramatic ocular changes are known to occur in the microgravity environment of outer space. The precise effects of the long-duration space flight environment on the human 85 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. State-of-the-Art Review eye and brain remain ill-defined, but over the last decade, the US National Aeronautics and Space Administration's (NASA) Space Medicine Division has documented varying degrees of optic disc edema, globe flattening, choroidal folds, hyperopic refractive error shifts, and cotton-wool spots (CWSs) in astronauts during and after long-duration space flight. In addition, optical coherence tomographic (OCT), ultrasonographic, and neuroimaging findings have demonstrated structural correlates to the clinical findings experienced by our long-duration space flyers. These correlates have been seen with choroidal folds, flattening of the posterior globe, optic disc edema, and increased cerebrospinal fluid (CSF) signal in the optic nerve sheaths. Although there have been some similarities between these imaging and clinical findings with terrestrial idiopathic intracranial hypertension (IIH), there have also been clear and surprising differences. The clinical features of this unique patient cohort during space travel suggest specific neuro-ophthalmologic responses that might be inherent to long-duration exposure to the microgravity space environment. We previously described our clinical findings and proposed that these neuro-ophthalmic changes may represent pathologic processes within the eye, optic nerve, orbit, vascular system, or cranial cavity (1). In addition, there may be a cephalad fluid shift experienced by affected astronauts during microgravity exposure that might be the key to the underlying pathogenesis. Alternatively, increased intracranial pressure (ICP), translaminar pressure differences between intraocular pressure (IOP) and ICP, or alterations in the cardiovascular or cerebrovascular systems also have been proposed as potential alternative but not necessarily mutually exclusive pathogenic mechanisms. The objectives of this review include: 1) to describe the neuro-ophthalmic changes seen in astronauts after longduration space flight; 2) to present hypotheses to explain these neuro-ophthalmic abnormalities; 3) to compare and contrast terrestrial IIH and postoperative ischemic optic neuropathy (ION) with the findings in long-duration space flyers; and (4) to discuss the possible implications of the space flight findings for these terrestrial neuro-ophthalmic disorders. In 2011, Mader et al (1) reported the historical, clinical, and imaging findings in an astronaut cohort after longduration space flight to the International Space Station (ISS), and reviewed possible etiologies for the ophthalmic abnormalities. The retrospective observational report of Mader et al described the neuro-ophthalmic findings in 7 astronauts and an analysis of postflight questionnaires about in-flight vision changes in approximately 300 additional astronauts. The 7 subjects underwent complete eye examinations before and after their ISS mission, including cycloplegic and/or manifest refraction and fundus photography. 86 Six underwent postmission OCT and magnetic resonance imaging (MRI); 4 had lumbar punctures (LPs). After 6 months of space flight, the 7 astronauts had the following: optic disc edema in 5, globe flattening in 5, choroidal folds in 5, CWS in 3, nerve fiber layer thickening by OCT in 6, and decreased near vision in 6. Five of 7 astronauts with near vision complaints had a hyperopic shift of +0.50 diopters (D) or greater between before and after mission spherical equivalent refraction in 1 or both eyes (range: +0.50 to +1.75 D). These 5 individuals also showed a structural correlate of globe flattening (axial hyperopic shortening) on orbital MRI and ultrasound imaging. In our original report, LP performed in 6 total cases (4 in the initial cohort) documented opening pressures (OPs) of 22, 21, 28, and 28.5 cm H2O performed 66, 19, 12, and 57 days after mission, respectively. The 300 postflight questionnaires documented that approximately 29% of short (space shuttle) duration and 60% of long-duration mission flyers on ISS had experienced a degradation in distant and near visual acuity. Although the visual changes were reversible or correctible to 20/20, some subjective and self-reported refractive error changes remained persistent even years after flight. Supplemental Digital Content, Table E1, http://links.lww.com/ WNO/A193, summarizes the neuro-ophthalmic findings in 7 ISS crew members. In addition, NASA follows longitudinally the health of the astronaut corps in the Lifetime Surveillance of Astronaut Health (LSAH) program. Supplemental Digital Content, Table E2, http://links. lww.com/WNO/A194, demonstrates the in-flight and postflight refractive changes from shuttle and ISS flyers in the LSAH. Figure 1 is an example of preflight and postflight development of optic disc edema in 1 long-duration space flyer. The severity of the disc edema in this astronaut was not representative of the typical disc edema in most cases (Frisen grade 1 or less). Figure 2 demonstrates flattening of the posterior globe, increased CSF in the optic nerve sheath, and an elevated optic disc. Figure 3 shows bilateral choroidal folds in a long-duration flyer after flight, which were not present in preflight fundus photographs. Since our initial report, new longitudinal observational data has revealed additional affected individuals including female and international astronauts. The findings have revealed a range of severity with additional cases developing disc edema, anatomical changes on ultrasound and MRI, and refractive changes. PROPOSED PATHOGENIC MECHANISMS Although optic disc edema, globe flattening, choroidal folds, and hyperopic shifts have been reported in terrestrial IIH, the neuro-ophthalmic findings in these long-duration space flyers seem to have unique and somewhat perplexing clinical and neuroimaging differences when compared with IIH (1-12). First, our affected space flyers did not report the typical and classic symptoms of increased ICP seen in Lee et al: J Neuro-Ophthalmol 2016; 36: 85-91 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. State-of-the-Art Review FIG. 1. Preflight and postflight appearance of the optic discs demonstrates edema after long-duration space flight (Reprinted with permission from [1]). terrestrial IIH (e.g., chronic headache, pulse synchronous tinnitus, or diplopia) (1). Reported headaches were mild and not sufficiently severe to interrupt mission activities on ISS. They have been reported especially early in flight in our astronauts, but the headaches were not severe and did not have qualities of increased ICP. None of our astronauts were taking any medications that are associated with elevated ICP. Second, although choroidal folds and hyperopic shifts are sometimes seen in terrestrial IIH, these findings seem to be a more common finding in our astronauts. Third, retinal CWSs are also not a typical component of IIH and yet they were present in our cohort. Finally, although several reports have described the ultrasonography, OCT, MRI, and CT findings in IIH that include flattening of the posterior globe and prominent CSF in the perioptic subarachnoid space (SAS), these structural findings seem more pronounced (especially relative to the lack of symptoms) in our astronauts than in typical IIH (2,4,5,8,10,13). In IIH, the elevated subarachnoid CSF pressure caused by IIH is believed to be directly transmitted from the intracranial compartment to the intraorbital compartments through the perioptic SAS (8,11). This increased ICP causes an unfolding of the ON sheaths and pressure on the retrolaminar optic nerve head. This leads to axoplasmic statis with axonal swelling and resultant bilateral optic disc edema, which is described as papilledema on Earth (8,12). In remains unclear whether the optic disc edema seen in astronauts after long-duration space flight actually repreLee et al: J Neuro-Ophthalmol 2016; 36: 85-91 sents true papilledema. LP OP (admittedly performed days to weeks after return to Earth) has been borderline high but uniformly unimpressive as compared with the elevated ICP typically seen in IIH. Elevated intrasheath CSF pressure is believed to cause the subarachnoid compartment to exert an anterior force that indents the posterior sclera resulting in posterior globe flattening, redundancy and folding of the choroid, and axial shortening of the globe with a hyperopic shift. Increased CSF fluid pressure within the optic nerve sheath may account for MRI findings of both terrestrial IIH and the findings in these astronauts. Since the end of the US space shuttle program, NASA astronauts must now make the return to Earth from the ISS by the Russian Soyuz. This return in Kazakhstan (in the former Union of Soviet Socialists Republics [USSR]) makes the political and operational logistics from measuring OP on LP in our astronauts immediately on landing or even within a few days more problematic. We have reported elevated OP measurements of 28.5 and 28 cm H2O at 57 and 12 days, respectively, in astronauts after returning to Earth. Although these pressures were only mildly elevated, these LP results could represent the downslope of a CSF pressure spike that may have existed during microgravity exposure. It should be noted that we have no experience with and essentially no capability for performing an LP in space. We have no spinal needles on ISS and have no substitute for the standard manometry column, which is gravity dependent on Earth. 87 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. State-of-the-Art Review FIG. 2. Axial orbital T2 magnetic resonance imaging in the optic nerve (long arrow) and flattening (short arrows) of the posterior glove (Reprinted with permission from [1]). The possible mechanisms of an IIH-like syndrome in our astronauts may involve a rise in cephalad-orbital venous volume and/or pressure brought about by microgravity fluid shifts. Previous head-down and microgravity studies have documented that cerebral arterial diameter and blood flow velocity are autoregulated and do not change significantly during space flight (14,15) but microgravity fluid shifts have been documented to cause jugular vein distension (16-19), possibly implicating cerebral venous congestion as a mechanism. The traditional understanding of ICP regulation on Earth assumes that CSF is largely produced in the choroid plexus and drainage depends on the pressure difference between the CSF and the venous system (20-22). Perhaps, venous stasis in the head and neck (valveless veins as opposed to valves in the lower extremity veins preventing flow against gravity), produced by cephalad fluid shifts during space flight, might cause of reduction of CSF, lymphatic, or cerebral venous outflow or congestion, which could increase ICP (23). An alternate hypothesis is that the rate of CSF formation and absorption (outflow) is a balance between hyperosmolar plasma in high-pressure capillaries, and the subsequent absorption of the formed hypo-osmolar interstitial fluid by the low-pressure venules that are in anatomic proximity to the high-pressure capillaries (1,24). Thus, in a microgravity environment, interstitial venous stasis at the level of lowpressure CSF venules and a subsequent decrease in the osmotic drive toward absorption may occur. Yet another possible explanation is that the optic disc edema may not be ICP-related papilledema. Instead, it may be that the intraocular and intraorbital findings are the result of localized CSF events occurring at the level of the intraorbital ON with or without a rise in CSF pressure in the entire CSF system (1). This might explain the lack of significantly elevated ICP on LP and also the lack of typical symptoms of increased ICP in our astronauts as compared with terrestrial IIH (25). The OP on LP is assumed to be equal throughout the CSF system, but this may not necessarily be the case. In addition, impaired exchange of CSF between the intracranial and perioptic SAS may explain persistent papilledema and visual loss in patients with terrestrial IIH despite a functioning lumboperitoneal shunt. This also might be the explanation for "normal or nearnormal" OP in some patients who clearly have clinical IIH (26-29). The role of CSF stasis rather than elevation of ICP is also an intriguing hypothesis. It has been proposed that CSF is constantly produced and absorbed in the entire CSF system as a consequence of filtration and reabsorption of water volume through the capillary walls into the surrounding brain tissue (24). This implies that the CSF exchange between each portion of the CSF system and the surrounding tissue may depend on pathophysiologic conditions that predominate locally within those compartments. Animal studies also have documented a potential role of lymphatic drainage of CSF through the extracranial lymphatic system (30), and there may be analogous lymphatic drainage pathway in the dura of the CSF outflow pathway of the optic nerve in the orbit (27). This potentially important CSF FIG. 3. Macular choroidal folds (arrows) are present in each eye (Reprinted with permission from [1]). 88 Lee et al: J Neuro-Ophthalmol 2016; 36: 85-91 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. State-of-the-Art Review absorption pathway is beyond the scope of our review and further study is necessary to clarify the potential role of this system in both terrestrial IIH and perhaps in affected astronauts in microgravity in space. We also have seen impaired olfactory function in terrestrial IIH and in the head-down tilt position (perhaps analogous to the cephalad fluid shift seen in our astronauts) and this might support the hypothesis of a role for lymphatic drainage outflow abnormalities at the level of the olfactory system and cribriform plate (31). Thus, these orbital ON lymphatic drainage systems may be affected by initial cephalad directed flow and then persistent microgravity exposure could lead to secondary lymph stasis, which could produce increase in ON sheath pressures within the unique cul de sac-like anatomically closed system. Killer et al (27) have proposed such a theory of a terrestrial IIH compartment syndrome with a bottleneck in CSF passage between the orbit and optic canal and this may be a compelling hypothesis for the findings that we see in our astronaut cohort. Theoretically ocular hypotony could produce similar findings to our cases (e.g., choroidal folds and optic disc edema), but we do not believe that hypotony is at play in our astronauts. Although there is an initial spike in IOP on exposure to microgravity, this is followed by a decrease in IOP over a period of days (32). In-flight data from the ISS have shown that IOP remains clinically normal, approximating baseline measurements. In fact, IOP values have been so unimpressive that it is no longer routinely collected. Head-down bed rest studies suggest that the initial spike in IOP is followed by a leveling (33) or lowering (34,35) of IOP over a period of days. The initial spike in IOP supports the hypothesis that there is choroidal expansion brought about by cephalad fluid shifts (33,36). The subsequent decrease in IOP after the initial IOP spike may be the result of a compensatory decrease in aqueous volume. We are not aware of any evidence supporting IOP as the causative factor in microgravity/space flight related optic disc edema (33,37,38). Likewise, the etiology of the hyperopic shift supports the cephalad fluid shift hypothesis. The phenomenon of hyperopic shift is so common that NASA astronauts older than 40 years are routinely offered the use of adjustable spectacle mounted plus lens "space anticipation glasses" preflight should they experience a hyperopic shift during the mission. The hyperopic shift usually occurs after weeks or months in space, has a gradual onset, is variable in magnitude and may persist for months to years after return to the 1-G Earth environment. Although 1 long-duration study demonstrated a decrease in near visual acuity after 4-5 days of head-down tilt (39), another similar study noted no visual changes (40). As postulated previously, choroidal expansion coupled with normal age-related presbyopia in those flyers older than 40 years may lead to a progressive shortening of the axial length that could cause a hyperopic Lee et al: J Neuro-Ophthalmol 2016; 36: 85-91 shift (41). Although changes in corneal refractive power after exposure to changes in atmospheric pressure and oxygen partial pressure could be another possibility, although previous reports have shown that normal nonpostrefractive surgery corneas are not subject to refractive changes during exposure to changing environmental conditions of space flight (42-44). Likewise, we do not believe that intraocular fluid shifts are producing any lenticular changes as the etiology of the hyperopic shift. Instead, we hypothesize that choroidal expansion at least partially accounts for the hyperopic shift. The spongy highly vascular choroid is normally approximately 0.3 mm in thickness, drains into the vortex veins which are sensitive to impaired outflow produced by microgravity and cephalad fluid shifts. Choroidal volume changes in microgravity also may be responsible for the abrupt increase in IOP (within 30 seconds) in orbital and parabolic aircraft flights (e.g., Boeing KC-135 airplane) and head-down studies (33,36,45). The cephalad fluid shift also could cause venous congestion in the neck and head that might lead to a rise in vortex vein pressure (33,36) and perhaps decreased choroidal drainage and stagnation or pooling of blood in the choroid (46). Choroidal vasculature alterations have been reported in highly myopic eyes (47) on Earth. A shortening of the distance between the macula and the lens of 0.33 mm anteriorly at the macula would lead to a 1D shift toward hyperopia. For patients with permanent refractive error change, this pooling may gradually expand the delicate collagen lamella of the choroid beyond its normal anatomic structural boundaries such that the choroid becomes permanently distended even on return to Earth and in the presence of normal venous backpressure (1). The choroidal folds that we see might be the structural marker of this change. Newell (48) hypothesized that visible choroid folds may occur as a result of a combination of variable anatomic attachments of the choroid to Bruch membrane and other factors that cause congestion in the choriocapillaris. COTTON-WOOL SPOTS CWSs have been noted in 3 astronauts after exposure to extended microgravity. CWSs are believed to be accumulations of cytoplasmic debris caused by focal obstruction of axoplasmic transport (29). They may leave a subtle visual field defect (49,50) and are believed to reflect precapillary arteriolar closure (50,51). CWSs are known to occur in a number of conditions including diabetes mellitus, HIV retinopathy, Purtscher retinopathy, high-altitude retinopathy, and hypertensive retinopathy (52-56). None of these disorders offer insight into why these findings occur in our astronauts. It has been postulated that perhaps local asymmetric microgravity-related changes in CSF flow within the intraorbital ON may lead to a biochemically altered CSF that may cause a metabolic toxicity to the ON and set the 89 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. State-of-the-Art Review stage for focal arteriolar closure in the retina. The role of radiation exposure including cosmic rays in space, solar flare activity, or during extravehicular activity outside the ISS remains unknown. Retrospective review of solar flare activity and extravehicular activity did not reveal any difference however between astronauts with or without CWS although the sample size was very small. We described an astronaut with 2 long-duration (6 months) exposures to microgravity (57). Before and after his first long-duration space flight, he underwent complete eye examination, including fundus photography. Before and after his second flight, 9 years later, he underwent preflight fundus photography, OCT, ocular ultrasonography, brain MRI, and then in-flight fundus photography and ultrasound. After his first long-duration mission, the astronaut was documented to have eye findings limited to unilateral choroidal folds and a single CWS. During the subsequent 6-month mission, he developed more widespread choroidal folds and new onset of optic disc edema in the same eye. This bothersome finding suggests that the effects of repeated exposure to space flight and microgravity might be cumulative. Newer findings continue to add pieces to the puzzle of this long-duration space flight related neuro-ophthalmic findings including loss of spontaneous venous pulsations (58), developing additional terrestrial-based models of hydrostatic pressure changes on the eye (59) and additional hypothesis on microgravity-related changes (60), which deserve further exploration. CONCLUSIONS AND FUTURE CONSIDERATIONS Finally, the findings in our astronauts might also have some bearing on further understanding of the pathogenesis or treatment of terrestrial IIH and another condition with cephalad fluid shift as a risk factor, ION after spine surgery. Spine surgery in the prone position produces a similar morphologic change in the head, face, and neck (postoperative facial edema) as the cephalad fluid shift experienced by astronauts. In terrestrial patients who have lost vision due to ION after spine surgery, the impaired venous return in the orbit has been speculated as a potential risk factor. Likewise, in our head-down tilt studies, similar hypotheses about cephalad fluid shift as a pathogenic mechanism have been proposed. This raises additional questions about possible mechanisms for optic disc edema in terrestrial causes of disc edema without elevated ICP. Further study is necessary to determine the etiology for the findings in our long-duration space flyers. It is hoped that we will be able to document a single or predominant mechanism and propose specific countermeasures in preparation for a return to longer duration space flight including the possibility of future missions to 90 ISS or to asteroids, a return trip to the moon, or perhaps a future manned mission to Mars. STATEMENT OF AUTHORSHIP Category 1: a. Conception and design: A. G. Lee, W. J. Tarver, T. H. Mader, C. R. Gibson, S. F. Hart, and C. Otto; b. Acquisition of data: W. J. Tarver, T. H. Mader, C. R. Gibson, S. F. Hart, and C. Otto; c. Analysis and interpretation of data: A. G. Lee, W. J. Tarver, T. H. 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