Origins of Cerebral Edema: Implications for Spaceflight-Associated Neuro-Ocular Syndrome

Background: Spaceflight-associated neuro-ocular syndrome (SANS) was first described in 2011 and is associated with structural ocular changes found to occur in astronauts after long-duration missions. Despite multiple insufficient potential terrestrial models, an understanding of the etiology has yet to be described. Evidence acquisition: A systematic review was conducted on literature published about the pathophysiology of cerebral edema. Databases searched include PubMed, Scopus, and the Texas Medical Center Online Library. This information was then applied to create theories on mechanisms on SANS etiology. Results: Cerebral edema occurs through 2 general mechanisms: redistribution of ions and water intracellularly and displacement of ions and water from the vascular compartment to the brain parenchyma. These processes occur through interconnected endocrine and inflammatory pathways and involve mediators such as cytokines, matrix metalloproteases, nitric oxide, and free radicals. The pathways ultimately lead to a violation of cellular membrane ionic gradients and blood-brain barrier degradation. By applying the principles of cerebral edema pathophysiology to the optic disc edema (ODE) see in SANS, several theories regarding its etiology can be formed. Venous stasis may lead to ODE through venous and capillary distension and leak, as well as relative hypoxia and insufficient ATP substrate delivery causing axoplasmic flow stasis and local oxidative stress. Conclusions: Using the pathophysiology of cerebral edema as a model, hypotheses can be inferred as to the etiology of ODE in SANS. Further studies are needed to determine the presence and contribution of local vascular stasis and resulting inflammation and oxidative stress to the pathophysiology of SANS.

State-of-the-Art Review Section Editors: Fiona Costello, MD, FRCP(C) Sashank Prasad, MD Origins of Cerebral Edema: Implications for SpaceflightAssociated Neuro-Ocular Syndrome Laura A. Galdamez, MD, FAWM, Tyson J. Brunstetter, OD, PhD, Andrew G. Lee, MD, William J. Tarver, MD, MPH Background: Spaceflight-associated neuro-ocular syndrome (SANS) was first described in 2011 and is associated with structural ocular changes found to occur in astronauts after long-duration missions. Despite multiple insufficient potential terrestrial models, an understanding of the etiology has yet to be described. Evidence Acquisition: A systematic review was conducted on literature published about the pathophysiology of cerebral edema. Databases searched include PubMed, Scopus, and the Texas Medical Center Online Library. This information was then applied to create theories on mechanisms on SANS etiology. Results: Cerebral edema occurs through 2 general mechanisms: redistribution of ions and water intracellularly and displacement of ions and water from the vascular compartment to the brain parenchyma. These processes occur through interconnected endocrine and inflammatory pathways and involve mediators such as cytokines, matrix metalloproteases, nitric oxide, and free radicals. The pathways ultimately lead to a violation of cellular membrane ionic gradients and blood–brain barrier degradation. By applying the principles of cerebral edema pathophysiology to the optic disc edema (ODE) see in SANS, several theories regarding its etiology can be formed. Venous stasis may lead to ODE through venous and capillary distension and leak, as well as relative hypoxia and insufficient ATP substrate delivery causing axoplasmic flow stasis and local oxidative stress. Department of Emergency Medicine (LAG), Baylor College of Medicine, Houston, Texas; United States Navy detailed to NASA Johnson Space Center (TJB), Houston, Texas; Department of Ophthalmology (AGL), Blanton Eye Institute, Houston Methodist Hospital, Houston, Texas; Department of Ophthalmology (AGL), Baylor College of Medicine, Houston, Texas; Department of Ophthalmology, Neurology, and Neurosurgery (AGL), Weill Cornell Medicine, New York, New York; Department of Ophthalmology (AGL), University of Texas Medical Branch (UTMB), Galveston, Texas; Department of Ophthalmology (AGL), University of Iowa Hospitals and Clinics, Iowa City, Iowa; University of Texas Maryland Anderson Cancer Center (AGL), Houston, Texas; and NASA Johnson Space Center (WJT), Houston, Texas. The authors report no conflicts of interest. Address correspondence to Laura A. Galdamez, MD, FAWM, Baylor College of Medicine, 8402 Westerbrook Lane, Humble, TX 77396; E-mail: [e-mail] 84 Conclusions: Using the pathophysiology of cerebral edema as a model, hypotheses can be inferred as to the etiology of ODE in SANS. Further studies are needed to determine the presence and contribution of local vascular stasis and resulting inflammation and oxidative stress to the pathophysiology of SANS. Journal of Neuro-Ophthalmology 2020;40:84–91 doi: 10.1097/WNO.0000000000000852 © 2019 by North American Neuro-Ophthalmology Society I n 2011, Mader et al (1) published the first report on the neuro-ocular structural changes found in 7 longduration International Space Station crewmembers. The findings included optic disc edema (ODE), choroidal folds, cotton wool spots, globe flattening, and hyperopic refractive shift (2). Of these, the Human Systems Risk Board of the National Aeronautics and Space Administration (NASA) deemed ODE to be the primary metric for this new syndrome, now termed spaceflight-associated neuro-ocular syndrome (SANS) (2). The etiology for SANS is unknown, and terrestrial analogs do not sufficiently align with the findings in SANS to determine a singular, terrestrially reproducible causative factor (2). Cerebral edema occurs in a variety of brain injury and ischemic disorders; however, the molecular physiology behind edema formation is relatively consistent (3). Exploring these principles may allow us to better understand and develop hypotheses for the physiologic processes leading to ODE observed in SANS. METHODS A systematic review was conducted on currently available information and published literature regarding the pathogenesis of cerebral edema observed in a variety of disorders. Databases searched include PubMed, Scopus, and the Texas Medical Center Online Library. Search terms were “cerebral edema,” “neuronal edema,” “neuronal swelling,” and Galdamez et al: J Neuro-Ophthalmol 2020; 40: 84-91 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. State-of-the-Art Review “neural swelling” in combination with “pathophysiology.” Initially, all disorders associated with cerebral edema were investigated for relevance; however, articles that focused on glial cell swelling were excluded in an effort to obtain only the most relevant data. The last date the search was accomplished was August 15, 2018. The initial search yielded 7,432 articles. These were scanned for repeat titles and primary English language or available translation. The remaining 6,446 titles and/or abstracts were scanned for relevance, leaving 170 publications that were read and analyzed in their entirety. The references of these articles were scanned for further publications that were applicable or required additional verification for accuracy. Final literature used included review articles, primary research articles, book chapters, and technical reports. RESULTS Cerebral Edema Brain tissue is classically divided into 4 compartments: intracellular, cerebrospinal fluid (CSF), intravascular, and interstitial (3). Cerebral edema is described in 2 categories: intracellular fluid accumulation (i.e., cytotoxic edema) and extracellular fluid accumulation (i.e., vasogenic edema) (3). Cytotoxic edema refers to redistribution of ions and water into cells from the extracellular space (3–8). It is the main mechanism behind edema formation in early ischemic stroke and hepatic encephalopathy (9). Normally, negatively charged intracellular proteins attract positively charged sodium ions into the cytoplasm, and the energydependent Na+/K+ ATPase pump extrudes sodium to maintain low intracellular levels (4,10–12). In ischemic central nervous system processes, this pump is inhibited through both energy depletion and directly by free radicals (4,10,13). Quiescent sodium channels and transporters are formed or activated leading to increased intracellular sodium flow (10). The sequestered sodium sets up a new gradient facilitating ion flow across the blood–brain barrier (BBB), priming the tissue for transcapillary fluid movement (6,8). Vasogenic edema refers to movement of water from the intravascular space into the interstitial space, increasing overall tissue water volume (3). It is the primary mechanism of cerebral edema formation in neuroinflammatory disorders and malignancies (12,14). The BBB comprises vascular endothelial cells connected by tight junction proteins surrounded by a basement membrane (12,15–17). The BBB tightly regulates transcellular transport of large, lipophobic molecules, and water permeability is one-tenth that of peripheral blood vessels (12,16). Initially, increased sodium accumulation in endothelial cells leads to cell swelling (3,5,6,11,12,18,19). Stressed endothelial cells produce inflammatory cytokines and extracellular adhesion moleGaldamez et al: J Neuro-Ophthalmol 2020; 40: 84-91 cules to recruit leukocytes (12,13,20). Recruited neutrophils and activated microglia release products including free radicals, nitric oxide synthetase, and matrix metalloproteases (MMP) (12,20). In models of intracranial hemorrhage and ischemic stroke, edema formation decreases with depletion of circulating neutrophils or microglia inhibition (20,21). Nitrous oxide synthetase augments inflammatory cytokines and activates MMP-9, and its inhibition leads to reduced cerebral edema in ischemic stroke models (3,13,22,23). MMP-9 is a proteolytic enzyme which degrades proteins of the basement membrane and tight junctions to help remodel the extracellular matrix (12,13,24). MMP-9 expression is increased pathologically by cytokines, free radicals, and vascular endothelial growth factor (6,12,16,25). Hypoxia exposure increases expression of active MMP-9 in brain and retinal pigment epithelial (RPE) cells (17,26). Hypoxia inducible factor (HIF-1a) (upregulated in hypoxia and ischemia) is temporally associated with sodium channel formation, leukocyte recruitment/activation, cytokine release, MMP-9 activation, and BBB breakdown (3,22,27). Free radicals form in normal metabolic processes, but are upregulated in ischemic injury (13,28). They are typically neutralized through several pathways, but when those pathways are saturated, they can accumulate and have deleterious effects on BBB integrity (29). Most pathologic cerebral edema forms from a combination of cytotoxic and vasogenic mechanisms. In high-energy traumatic brain injury, cerebral edema forms through mechanical deformation vs. low-energy traumatic brain injury which causes edema through oxidative stress and inflammation. Hydrostatic pressure from acute hypertensive episodes or venous stasis causes a similar cascade and vessel injury continues after decreased intraluminal pressure secondary to leukocyte recruitment/activation and release of inflammatory biomarkers and free radicals (30,31). In intracerebral hemorrhage, heme degradation products promote microglia activation, inflammatory cytokine release, free radical generation, and BBB breakdown (3,20,32). Optic Disc Edema Of the 7 astronauts described by Mader et al (1), 5 demonstrated ODE after returning from a 6-month, longduration space flight (Fig. 1). Several theories exist regarding the etiology of ODE in terrestrial disorders including venous compression, ocular hypotension, capillary stasis in the circle of Zinn, central retinal vein occlusion, and inflammation (33). The etiology of ODE in SANS is unknown, but the principles of cerebral edema can be used to hypothesize possible mechanisms. The optic nerve head (ONH) is a transition area where unmyelinated retinal ganglion axons turn 90° to traverse through the lamina cribrosa and form the optic nerve (34,35). Nerve fibers passing through the collagenous 85 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. State-of-the-Art Review FIG. 1. Optic disc edema in returned long-duration astronaut. Fundoscopy view of the right eye of a US astronaut after returning from a long-duration spaceflight. Optic disc edema extends from 10 o’clock to 6 o’clock. matrix of the lamina cribrosa are unmyelinated, putting them at higher risk of injury from mechanical forces and increasing their ATP utilization (34,35). This immense energy utilization is supported by a high concentration of mitochondria clustered in the ONH (34). The short posterior ciliary arteries branch to form the choroidal network and anastomose to form a ring of vessels around the ONH (circle of Zinn), which supply axons in the prelaminar and laminar areas (33,34,36). Choroidal blood flow lacks autoregulation, and choroidal blood volume increases during body inversion (2). The choroid is organized with the smaller capillaries approximating the RPE cells, and the vessel diameter increases to larger venules farther away (34,36). The choroidal veins drain through the ophthalmic vein (2). The blood–retinal barrier (BRB) is analogous to the BBB intracranially and is separated into an inner BRB and outer BRB (37). The inner BRB refers to the nonfenestrated capillaries that penetrate into the retina and ONH and is identical to the BBB (37). The outer BRB refers to the RPE cells connected by tight junctions that sit on the Bruch membrane and separate the fenestrated capillaries of the choroid from the hyperosmolar retinal space (37). The RPE is not attached to the retina, but the constant active transport of ions and water from the retinal space to the choroid keeps the 2 layers adjoined (37,38). Venous Stasis During spaceflight, cerebral venous stasis is hypothesized to occur secondary to the cephalic fluid shift that results from microgravity (2). Increased internal jugular vein pressure has 86 been demonstrated in parabolic flight models and engorgement of the central veins that occurs in spaceflight can persist up to 6 months after return (2). Cephalic venous congestion described in dialysis patients (due to stenosed central veins or retrograde flow from grafts) has been associated with ODE in the nasal distribution of the optic disc, similar to SANS (39–41). Venous stasis likely leads to ODE through venous and capillary distension and leakage (42). Although occlusion of the ophthalmic vein leads to ODE, occlusion of the central retinal vein alone does not (33,35,36,42). Most commonly, ophthalmic venous drainage occurs through the cavernous sinus in the anterior-posterior direction; however, variability of outflow patterns (i.e., posterior-anterior or reverse flow) within the superior ophthalmic vein has been noted in astronauts both on-orbit and on the ground (A. Sargsyan, personal communication, March 13, 2019). Venous stasis in the ophthalmic vein could lead to capillary and choroidal circulatory stasis, causing insufficient delivery of substrate for ATP production in the ONH (38). Acute intracranial pressure (ICP) elevation can also cause ophthalmic vein stasis leading to ONH axonal edema (35,42). Tracer studies in ODE models have shown delayed filling and tracer leakage in the choroid, prelaminar area, and lamina cribrosa (which normally fill before retinal arteries), demonstrating relative circulatory stasis in these areas (33,35,42). Increased capillary permeability is also demonstrated in terrestrial models of long-duration bed rest (2). Unlike brain tissue, local ischemia of retinal tissues primarily leads to swelling of nerves, not support cells (38). Anatomical variations (i.e., incomplete anastomoses and stenosis of arterioles supplying the ONH) may predispose some individuals to this metabolic imbalance (34,36). Local ischemia may lead to H+ ion accumulation, which directly causes choroid vasodilation (37). The larger venules of the choroid would likely dilate first and largest, further compressing the smaller capillaries closer to the RPE, worsening the local ischemia (37). This may lead to retinal nerve fiber layer ischemia which could, in part, underlie the axoplasmic stasis that presents as cotton wool spots described in SANS. Vascular stasis also leads to increased intraluminal hydrostatic pressure. In hypertension and central serous chorioretinopathy, intravascular hydrostatic pressure compromises choroidal circulation causing serous retinal separation through oxidative stress (37,43). One study found increased levels of MMP-9 in patients with increased jugular vein pressure and decreased cerebral venous outflow (30). Hydrostatic pressure may stress the endothelial cells of the BRB, causing inflammatory biomarker release, BRB breakdown, and water translocation into the subretinal space and ONH interstitium (30). This mechanism may place astronauts on long-duration missions at hypothetical risk of serous retinal separation. Venous stasis may underlie many pathologic changes seen in SANS through circulatory compromise in the Galdamez et al: J Neuro-Ophthalmol 2020; 40: 84-91 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. State-of-the-Art Review choroid and ONH leading to ATP depletion in a highly energy-dependent area, failure of the cytoskeletal motor proteins leading to axoplasmic flow stasis, collapse of the ion gradient with redistribution of sodium and water intracellularly, and local release of inflammatory cytokines and free radicals by stressed cells leading to BRB breakdown. Inflammatory Response and Free Radical Formation Immune system dysregulation occurs in microgravity (44). Most inflammatory cytokines have short half-lives and low plasma concentrations, but increased levels of cytokines and chemokines involved in inflammatory cell recruitment and activation were demonstrated in long-duration spaceflight crew as well as terrestrial analogs (prolonged bedrest and rodent hind limb unloading) (44). These crewmembers’ baseline inflammatory cytokine levels were minimally detectable, and samples were collected during low-stress mission phases (44). Total white blood cell count and granulocyte levels increased in spaceflight (45). Cytokine production secondary to T-cell stimulation decreases initially in spaceflight, and while most stayed depressed throughout the long-duration mission, some trended up toward normal production levels in late flight (45). If inflammatory mediators play a primary role in SANS, this decrease and slow trend back toward normal production levels might explain the delayed presentation. A state of low-level inflammation would exacerbate the immune response to venous stasis and local ischemia outlined above. This could worsen inner BRB breakdown (already highly sensitive to oxygen deprivation) leading to increased fluid extravasation within the ONH. If the Na+/ K+ ATPase is not functioning secondary to energy depletion, this extra fluid could be taken up from the interstitial space into the neurons, causing local axonal edema (37,46). Outer BRB breakdown may lead to increased fluid extravasation into the hyperosmotic retinal space. The choroidal folds noted in SANS are more consistent with neuro-ocular inflammatory disorders, such as Vogt– Koyanagi–Harada disease which manifests as optic disc swelling secondary to inflammation and choroidal thickening and folding (43,47). Unilateral edema of the disc is another rare inflammatory disorder demonstrating asymmetric papilledema and marked engorgement of retinal vessels secondary to venous stasis (36). Oxidative stress occurs secondary to local inflammation. Mice exposed to short-duration spaceflight have demonstrated upregulation of genes associated with oxidative stress in the retina and optic nerve (2). These free radicals directly inhibit Na+/K+ ATPase, activate MMP-9 and inhibit axoplasmic flow (13,48). In addition, astronauts with altered 1carbon metabolism leading to higher concentrations of free radical inducers were far more likely to have ophthalmologic changes (2,49). This may help explain the partial protection Galdamez et al: J Neuro-Ophthalmol 2020; 40: 84-91 for female astronauts as estrogens are potent antioxidants; specifically, 17b-estradiol has been found to protect retinal glial cells from oxidative stress (50). Local Energy Depletion and Axoplasmic Stasis Organelles are made in the neural cell body and require active transport to distribute to the distal axon (48). Axoplasmic flow requires ATP-dependent motor proteins, ATP, and a cytoskeleton for the motor proteins to move along. Axoplasmic flow stasis occurs in glaucoma, increased ICP, ONH ischemia, and venous stasis (33,48,51,52). Mitochondria normally accumulate in the ONH to support the energy demand, but in axoplasmic flow stasis, a buildup of giant mitochondria occurs (33). Motor proteins and mitochondria accumulate at the ONH in glaucoma models (48). Tracer studies in increased ICP demonstrate poor axon flow with accumulation and swelling in the lamina cribrosa and anterior prelaminar area, demonstrating obstruction at the lamina cribrosa (33). Axoplasmic flow stasis can occur due to inhibition of the energy-dependent motor proteins either directly through oxidative stress, or indirectly from circulatory stasis and local ATP depletion. The progressive ODE may be due to continued stasis of active transport or subsequent disruption of passive transport (48). Passive transport is slower and may explain the delayed presentation of ODE. As mitochondria accumulate, the loss of optimal mitochondrial distribution along the axon may further worsen the axoplasmic flow stasis. It may take time to perceive the detrimental effects of this progression given the lower energy demand of the myelinated retrolaminar nerve (48). Axoplasmic flow stasis may also occur secondary to actin cytoskeleton disruption. The 90⁰ turn of the axons at the ONH increases their susceptibility to impaired transport, and the collagenous lamina cribrosa is subject to tissue deformation, increasing the likelihood of mechanical stress on the axons (48). Models of increased IOP demonstrate cytoskeletal injury at the lamina cribrosa including decreased number of microtubules in the area of accumulated organelles (48). Increased myelin sheath pressure from increased ICP can alter microtubule structure, and derangements may persist beyond ICP normalization (48). Increased Intracranial Pressure Initially believed to be the etiology of SANS, increased ICP has met criticism as the major determinant as it is unclear whether ICP is chronically increased in microgravity (2,33). Invasive ICP measurements have not been performed in humans in microgravity, but postflight lumbar punctures have demonstrated only mild ICP elevations (2). Invasive monitoring of a macaque monkey in spaceflight demonstrated return to average preflight ICP within 6–9 days in microgravity (2). The initial ICP increase in the macaque 87 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. State-of-the-Art Review was mild and less than if lying supine terrestrially (2). Terrestrial idiopathic intracranial hypertension (IIH) is now deemed an unlikely SANS model as astronauts do not share key symptoms and signs (2). The pattern of ODE is also different between IIH and SANS; IIH models demonstrate anterior, intraocular swelling, but both anterior and posterior disc swelling is seen in SANS (53). Also, IIH patients have mainly retinal folds, whereas in SANS, there are significantly more choroidal folds compared with retinal folds (43,54). Astronauts demonstrate indirect evidence of increased ICP with ONS distension (2). Sustained ICP elevation causes axonal swelling from axoplasmic stasis (2,33,42,51). Sustained ICP elevation is correlated with increased HIF-1a in the retinal ganglion cell layer, and models have demonstrated breakdown of the BRB with vascular leak into the interstitial space of the ONH (33,51). There are discrepancies with pure increased ICP models in explaining SANS etiology, but an acute episode of increased ICP that resolves may set into motion a cascade of local inflammation and oxidative stress that continues. One hypothesis to explain increased ONS pressure is altered flow dynamics between the intracranial and ONS subarachnoid spaces. Impaired outflow from the ONS compartment could lead to CSF sequestration and increased ONS pressure (55). Models of IIH and asymmetric papilledema have demonstrated evidence of such a compartment syndrome (56). TABLE 1. Pathophysiologic mechanisms hypothesized to cause optic disc edema in SANS Inciting Event Mechanisms of Optic Disc Edema Supporting Evidence Venous stasis Hydrostatic pressure causes capillary leak and inflammatory/oxidative stress Circle of Zinn engorgement compresses axons and capillaries in optic nerve Cephalic venous stasis in dialysis patients leads to ODE (40–42) Hydrostatic pressure causes serous retinal separation in central serous chorioretinopathy (38,51) Increased retinal HIF-1a in ICP models (38,44) Occlusion of ophthalmic vein leads to ODE; variability of flow in ophthalmic vein noted in some astronauts (34,36,37,43) Mitochondrial and motor proteins accumulate in high energy-dependent areas (i.e. ONH and LC) (34,49) ODE in SANS mainly neuronal; retinal ischemia causes neuronal swelling (39) Increased inflammatory cells, cytokines, and chemokines in astronauts (45,46) Choroidal folding observed in inflammatory disorders more than in increased ICP models (48,51) Increased MMP-9 in patients with increased internal jugular venous pressure (26) Mice from short-duration missions have upregulation of oxidative stress genes in the retina and optic nerve (2) Astronauts with genes predisposing to free radical formation are more prone to ophthalmologic changes (2,50) Females may have lower SANS prevalence; estrogens are potent antioxidants (52) Delayed vascular filling in choroid and lamina cribrosa in increased ICP models (34,36,43) Motor proteins and mitochondria accumulate at ONH and LC in glaucoma and increased ICP models (34,49) Increased IOP models demonstrate cytoskeletal derangement in LC (49) Local circulatory stasis in ONH and choroid Local ATP depletion in ONH Anaerobic metabolism leads to choroid dilation; choroidal veins compress capillaries Energy-dependent axon motor protein dysfunction Activation of inflammatory cascade Ion gradient dysfunction; intracellular sequestering of sodium and water Outer BRB breakdown causing fluid extravasation into subretinal space Inner BRB breakdown causing interstitial fluid leak, local neurons uptake Increased oxidative stress Ion gradient disruption through Na+/K+ ATPase inhibition Oxidative stress disrupts motor proteins directly, leading to axonal stasis Increased optic nerve sheath pressure Axoplasmic stasis leads to local swelling, capillary compression Mitochondria accumulate in ONH Axon cytoskeleton disruption through mechanical stress ATP, adenosine triphosphate; BRB, blood-retinal barrier; HIF-1a, hypoxia inducible factor; ICP, intracranial pressure; LC, lamina cribrosa; MMP, matrix metalloprotease; ODE, optic disc edema; ONH, optic nerve head; SANS, spaceflight-associated neuro-ocular syndrome. 88 Galdamez et al: J Neuro-Ophthalmol 2020; 40: 84-91 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. State-of-the-Art Review FIG. 2. Hypotheses of pathophysiologic mechanism for SANS findings. ATP, adenosine triphosphate; BRB, blood–retinal barrier; ICP, intracranial pressure; O2, oxygen; TJ, tight junction. CONCLUSION Using the pathophysiology of cerebral edema as a model, several hypotheses can be inferred as to the causes of ODE in SANS. Venous and local circulatory stasis in the ONH may lead to increased hydrostatic pressure and local ATP depletion resulting in increased oxidative stress and inflammation leading to both cellular ion gradient dysfunction and BRB breakdown (Table 1 and Fig. 2). The new generation of optical coherence tomography recently installed on the International Space Station will allow for better characterization of the choroid plexus and evaluate the hypothesized venous distension and capillary compression in microgravity. Local ATP depletion and increased ONS pressure could contribute to axoplasmic stasis and result in cytoskeleton disruption, local mitochondrial accumulation in the ONH, and local capillary compression that positively reinforce local vascular stasis (Table 1 and Fig. 2). Increased ONS pressure secondary to globally increased ICP has not been well supported. However, regional increases in ICP secondary to local CSF and extracellular free water redistribution, as described in recent MRI studies, may contribute (57,58). Characterizing patterns of redistribution in SANS vs. nonSANS cases may help further elucidate this contribution. Increased ONS pressure may also occur through mechanisms of ocular nerve compartment syndrome secondary to altered flow dynamics of CSF between the intracranial subarachnoid space and optic nerve subarachnoid space. Such a mechanism has been described in cases of papilledema due to a variety of causes and has been used to create a potential explanation for unilateral papilledema (56,59). This mechanism could be investigated using CT cisternography or MRI diffusion imaging to evaluate CSF flow Galdamez et al: J Neuro-Ophthalmol 2020; 40: 84-91 through the ONS on return from long-duration spaceflight. This could also provide information on the potential utility or disutility of measuring cytokines within the CSF fluid of returned long-duration astronauts, as impaired communication between these 2 spaces likely means concentrations of such substances would not be equal. This could also provide information on the potential effect of attempting to alter the translaminar pressure gradient through increased IOP proposed by Scott et al (60) (JAMA Ophthalmology 2019), as without viable communication between the 2 compartments this strategy may not achieve the intended goal. The mentioned theorized mechanisms could lead to both vasogenic and cytotoxic edema that may underlie not just ODE, but also the other clinical findings noted in SANS (Fig. 2). Further studies are needed to determine the presence and contribution of local vascular stasis and resulting inflammation and oxidative stress to the pathophysiology of SANS. STATEMENT OF AUTHORSHIP Category 1: a. Conception and design: L. A. Galdamez, T. J. Brunstetter, and W. J. Tarver; b. Acquisition of data: L. A. Galdamez and T. J. Brunstetter; c. Analysis and interpretation of data: L. A. Galdamez and T. J. Brunstetter. Category 2: a. Drafting the manuscript: L. A. Galdamez and T. J. Brunstetter, A. G. Lee; b. Revising it for intellectual content: L. A. Galdamez, T. J. Brunstetter, and A. G. Lee. Category 3: a. Final approval of the completed manuscript: L. A. Galdamez, T. J. Brunstetter, W. J. Tarver, and A. G. Lee. REFERENCES 1. 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