State-of-the-Art Review
Section Editors: Fiona Costello, MD, FRCP(C)
Origins of Cerebral Edema: Implications for Spaceflight-
Associated 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 poten-
tial 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 cere-
bral edema. Databases searched include PubMed, Scopus,
and the Texas Medical Center Online Library. This informa-
tion was then applied to create theories on mechanisms on
SANS etiology.
Results: Cerebral edema occurs through 2 general mecha-
nisms: redistribution of ions and water intracellularly and
displacement of ions and water from the vascular compart-
ment to the brain parenchyma. These processes occur
through interconnected endocrine and inflammatory path-
ways and involve mediators such as cytokines, matrix
metalloproteases, nitric oxide, and free radicals. The path-
ways 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 sub-
strate 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 Oph-
thalmology (AGL), Blanton Eye Institute, Houston Methodist Hos-
pital, Houston, Texas; Department of Ophthalmology (AGL), Baylor
College of Medicine, Houston, Texas; Department of Ophthalmol-
ogy, Neurology, and Neurosurgery (AGL), Weill Cornell Medicine,
New York, New York; Department of Ophthalmology (AGL), Uni-
versity 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: lgalda8896@gmail.com
Galdamez et al: J Neuro-Ophthalmol 2019; 00: 1-8
Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited.
Sashank Prasad, MD
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 patho-
physiology of SANS.
Journal of Neuro-Ophthalmology 2019;00:1–8
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 long-
duration 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 syn-
drome, now termed spaceflight-associated neuro-ocular syn-
drome (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). Explor-
ing 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 patho-
genesis 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
1
 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 accom-
plished 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 publica-
tions 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, nega-
tively charged intracellular proteins attract positively
charged sodium ions into the cytoplasm, and the energy-
dependent Na+/K+ ATPase pump extrudes sodium to main-
tain 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 disor-
ders and malignancies (12,14). The BBB comprises vascular
endothelial cells connected by tight junction proteins sur-
rounded 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 mole-
2 Galdamez et al: J Neuro-Ophthalmol 2019; 00: 1-8
Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited.
cules to recruit leukocytes (12,13,20). Recruited neutro-
phils and activated microglia release products including
free radicals, nitric oxide synthetase, and matrix metallopro-
teases (MMP) (12,20). In models of intracranial hemor-
rhage and ischemic stroke, edema formation decreases
with depletion of circulating neutrophils or microglia inhi-
bition (20,21). Nitrous oxide synthetase augments inflam-
matory 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 de-
grades proteins of the basement membrane and tight junc-
tions 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 associ-
ated with sodium channel formation, leukocyte
recruitment/activation, cytokine release, MMP-9 activation,
and BBB breakdown (3,22,27). Free radicals form in nor-
mal metabolic processes, but are upregulated in ischemic
injury (13,28). They are typically neutralized through sev-
eral pathways, but when those pathways are saturated, they
can accumulate and have deleterious effects on BBB integ-
rity (29).
Most pathologic cerebral edema forms from a combina-
tion 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 pro-
mote 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 dem-
onstrated ODE after returning from a 6-month, long-
duration space flight (Fig. 1). Several theories exist regard-
ing the etiology of ODE in terrestrial disorders including
venous compression, ocular hypotension, capillary stasis in
the circle of Zinn, central retinal vein occlusion, and inflam-
mation (33). The etiology of ODE in SANS is unknown,
but the principles of cerebral edema can be used to hypoth-
esize 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

FIG. 1. Optic disc edema in returned long-duration astro-
naut. 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 vol-
ume 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 trans-
port 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
Galdamez et al: J Neuro-Ophthalmol 2019; 00: 1-8
Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited.
State-of-the-Art Review
been demonstrated in parabolic flight models and engorge-
ment 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 asso-
ciated 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 leak-
age 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 sup-
plying the ONH) may predispose some individuals to this
metabolic imbalance (34,36). Local ischemia may lead to
H+ ion accumulation, which directly causes choroid vaso-
dilation (37). The larger venules of the choroid would likely
dilate first and largest, further compressing the smaller capil-
laries 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 com-
promises choroidal circulation causing serous retinal sepa-
ration through oxidative stress (37,43). One study found
increased levels of MMP-9 in patients with increased jugu-
lar 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
3
 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 intracel-
lularly, 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 gran-
ulocyte levels increased in spaceflight (45). Cytokine pro-
duction 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 medi-
ators 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 deple-
tion, 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 thick-
ening and folding (43,47). Unilateral edema of the disc is
another rare inflammatory disorder demonstrating asym-
metric 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 demon-
strated 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 axo-
plasmic flow (13,48). In addition, astronauts with altered 1-
carbon 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
4 Galdamez et al: J Neuro-Ophthalmol 2019; 00: 1-8
Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited.
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). Axo-
plasmic 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). Mito-
chondria 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 sub-
sequent disruption of passive transport (48). Passive trans-
port 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 accumu-
lated organelles (48). Increased myelin sheath pressure from
increased ICP can alter microtubule structure, and derange-
ments 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 demon-
strated return to average preflight ICP within 6–9 days in
microgravity (2). The initial ICP increase in the macaque
 State-of-the-Art Review

was mild and less than if lying supine terrestrially (2). Ter-
restrial 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 poste-
rior disc swelling is seen in SANS (53). Also, IIH patients
have mainly retinal folds, whereas in SANS, there are sig-
nificantly 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 subarach-
noid spaces. Impaired outflow from the ONS compartment
could lead to CSF sequestration and increased ONS pres-
sure (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
Local circulatory stasis
in ONH and choroid
Activation of
inflammatory cascade
Increased oxidative
stress
Increased optic nerve
sheath pressure
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.
Hydrostatic pressure causes capillary leak and
inflammatory/oxidative stress
Circle of Zinn engorgement compresses axons
and capillaries in optic nerve
Local ATP depletion in ONH
Anaerobic metabolism leads to choroid
dilation; choroidal veins compress
capillaries
Energy-dependent axon motor protein
dysfunction
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
Ion gradient disruption through Na+/K+ ATPase
inhibition
Oxidative stress disrupts motor proteins
directly, leading to axonal stasis
Axoplasmic stasis leads to local swelling,
capillary compression
Mitochondria accumulate in ONH
Axon cytoskeleton disruption through
mechanical stress
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)

Galdamez et al: J Neuro-Ophthalmol 2019; 00: 1-8 5

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 inflam-
mation leading to both cellular ion gradient dysfunction
and BRB breakdown (Table 1 and Fig. 2). The new gen-
eration 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 second-
ary 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. non-
SANS cases may help further elucidate this contribution.
Increased ONS pressure may also occur through mecha-
nisms 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 papillede-
ma 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 cisternog-
raphy or MRI diffusion imaging to evaluate CSF flow
6 Galdamez et al: J Neuro-Ophthalmol 2019; 00: 1-8
Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited.
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 communica-
tion 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 pro-
posed by Scott et al (60) (JAMA Ophthalmology 2019), as
without viable communication between the 2 compart-
ments 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 result-
ing inflammation and oxidative stress to the pathophysiol-
ogy 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.
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