State-of-the-Art Review

Section Editors: Fiona Costello, MD, FRCP(C)

Sashank Prasad, MD

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 Conclusions: Using the pathophysiology of cerebral edema
(SANS) was first described in 2011 and is associated with as a model, hypotheses can be inferred as to the etiology of
structural ocular changes found to occur in astronauts after ODE in SANS. Further studies are needed to determine the
long-duration missions. Despite multiple insufficient poten- presence and contribution of local vascular stasis and
tial terrestrial models, an understanding of the etiology has resulting inflammation and oxidative stress to the patho-
yet to be described. physiology of SANS.
Evidence Acquisition: A systematic review was conducted
on literature published about the pathophysiology of cere- Journal of Neuro-Ophthalmology 2019;00:1–8
bral edema. Databases searched include PubMed, Scopus, doi: 10.1097/WNO.0000000000000852
and the Texas Medical Center Online Library. This informa- © 2019 by North American Neuro-Ophthalmology Society
tion was then applied to create theories on mechanisms on
SANS etiology.

I n 2011, Mader et al (1) published the first report on the

Results: Cerebral edema occurs through 2 general mecha-
nisms: redistribution of ions and water intracellularly and neuro-ocular structural changes found in 7 long-
displacement of ions and water from the vascular compart-
ment to the brain parenchyma. These processes occur duration International Space Station crewmembers. The
through interconnected endocrine and inflammatory path- findings included optic disc edema (ODE), choroidal folds,
ways and involve mediators such as cytokines, matrix cotton wool spots, globe flattening, and hyperopic refractive
metalloproteases, nitric oxide, and free radicals. The path- shift (2). Of these, the Human Systems Risk Board of the
ways ultimately lead to a violation of cellular membrane National Aeronautics and Space Administration (NASA)
ionic gradients and blood–brain barrier degradation. By
applying the principles of cerebral edema pathophysiology deemed ODE to be the primary metric for this new syn-
to the optic disc edema (ODE) see in SANS, several theories drome, now termed spaceflight-associated neuro-ocular syn-
regarding its etiology can be formed. Venous stasis may drome (SANS) (2). The etiology for SANS is unknown, and
lead to ODE through venous and capillary distension and terrestrial analogs do not sufficiently align with the findings
leak, as well as relative hypoxia and insufficient ATP sub- in SANS to determine a singular, terrestrially reproducible
strate delivery causing axoplasmic flow stasis and local
oxidative stress. causative factor (2).
Cerebral edema occurs in a variety of brain injury and
ischemic disorders; however, the molecular physiology
Department of Emergency Medicine (LAG), Baylor College of behind edema formation is relatively consistent (3). Explor-
Medicine, Houston, Texas; United States Navy detailed to NASA
Johnson Space Center (TJB), Houston, Texas; Department of Oph- ing these principles may allow us to better understand and
thalmology (AGL), Blanton Eye Institute, Houston Methodist Hos- develop hypotheses for the physiologic processes leading to
pital, Houston, Texas; Department of Ophthalmology (AGL), Baylor ODE observed in SANS.
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; METHODS
Department of Ophthalmology (AGL), University of Iowa Hospitals
and Clinics, Iowa City, Iowa; University of Texas Maryland Anderson A systematic review was conducted on currently available
Cancer Center (AGL), Houston, Texas; and NASA Johnson Space information and published literature regarding the patho-
Center (WJT), Houston, Texas.
genesis of cerebral edema observed in a variety of disorders.
The authors report no conflicts of interest.
Databases searched include PubMed, Scopus, and the Texas
Address correspondence to Laura A. Galdamez, MD, FAWM, Baylor
College of Medicine, 8402 Westerbrook Lane, Humble, TX 77396; Medical Center Online Library. Search terms were “cerebral
E-mail: [email protected] edema,” “neuronal edema,” “neuronal swelling,” and

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

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 State-of-the-Art Review

“neural swelling” in combination with “pathophysiology.” cules to recruit leukocytes (12,13,20). Recruited neutro-
Initially, all disorders associated with cerebral edema were phils and activated microglia release products including
investigated for relevance; however, articles that focused on free radicals, nitric oxide synthetase, and matrix metallopro-
glial cell swelling were excluded in an effort to obtain only teases (MMP) (12,20). In models of intracranial hemor-
the most relevant data. The last date the search was accom- rhage and ischemic stroke, edema formation decreases
plished was August 15, 2018. with depletion of circulating neutrophils or microglia inhi-
The initial search yielded 7,432 articles. These were bition (20,21). Nitrous oxide synthetase augments inflam-
scanned for repeat titles and primary English language or matory cytokines and activates MMP-9, and its inhibition
available translation. The remaining 6,446 titles and/or leads to reduced cerebral edema in ischemic stroke models
abstracts were scanned for relevance, leaving 170 publica- (3,13,22,23). MMP-9 is a proteolytic enzyme which de-
tions that were read and analyzed in their entirety. The grades proteins of the basement membrane and tight junc-
references of these articles were scanned for further tions to help remodel the extracellular matrix (12,13,24).
publications that were applicable or required additional MMP-9 expression is increased pathologically by cytokines,
verification for accuracy. Final literature used included free radicals, and vascular endothelial growth factor
review articles, primary research articles, book chapters, (6,12,16,25). Hypoxia exposure increases expression of
and technical reports. active MMP-9 in brain and retinal pigment epithelial
(RPE) cells (17,26). Hypoxia inducible factor (HIF-1a)
RESULTS (upregulated in hypoxia and ischemia) is temporally associ-
ated with sodium channel formation, leukocyte
Cerebral Edema recruitment/activation, cytokine release, MMP-9 activation,
and BBB breakdown (3,22,27). Free radicals form in nor-
Brain tissue is classically divided into 4 compartments:
mal metabolic processes, but are upregulated in ischemic
intracellular, cerebrospinal fluid (CSF), intravascular, and
injury (13,28). They are typically neutralized through sev-
interstitial (3). Cerebral edema is described in 2 categories:
eral pathways, but when those pathways are saturated, they
intracellular fluid accumulation (i.e., cytotoxic edema) and
can accumulate and have deleterious effects on BBB integ-
extracellular fluid accumulation (i.e., vasogenic edema) (3).
rity (29).
Cytotoxic edema refers to redistribution of ions and
Most pathologic cerebral edema forms from a combina-
water into cells from the extracellular space (3–8). It is the
tion of cytotoxic and vasogenic mechanisms. In high-energy
main mechanism behind edema formation in early ischemic
traumatic brain injury, cerebral edema forms through
stroke and hepatic encephalopathy (9). Normally, nega-
mechanical deformation vs. low-energy traumatic brain
tively charged intracellular proteins attract positively
charged sodium ions into the cytoplasm, and the energy- injury which causes edema through oxidative stress and
dependent Na+/K+ ATPase pump extrudes sodium to main- inflammation. Hydrostatic pressure from acute hypertensive
tain low intracellular levels (4,10–12). In ischemic central episodes or venous stasis causes a similar cascade and vessel
nervous system processes, this pump is inhibited through injury continues after decreased intraluminal pressure
both energy depletion and directly by free radicals secondary to leukocyte recruitment/activation and release
(4,10,13). Quiescent sodium channels and transporters of inflammatory biomarkers and free radicals (30,31). In
are formed or activated leading to increased intracellular intracerebral hemorrhage, heme degradation products pro-
sodium flow (10). The sequestered sodium sets up a new mote microglia activation, inflammatory cytokine release,
gradient facilitating ion flow across the blood–brain barrier free radical generation, and BBB breakdown (3,20,32).
(BBB), priming the tissue for transcapillary fluid movement
(6,8). Optic Disc Edema
Vasogenic edema refers to movement of water from the Of the 7 astronauts described by Mader et al (1), 5 dem-
intravascular space into the interstitial space, increasing onstrated ODE after returning from a 6-month, long-
overall tissue water volume (3). It is the primary mechanism duration space flight (Fig. 1). Several theories exist regard-
of cerebral edema formation in neuroinflammatory disor- ing the etiology of ODE in terrestrial disorders including
ders and malignancies (12,14). The BBB comprises vascular venous compression, ocular hypotension, capillary stasis in
endothelial cells connected by tight junction proteins sur- the circle of Zinn, central retinal vein occlusion, and inflam-
rounded by a basement membrane (12,15–17). The BBB mation (33). The etiology of ODE in SANS is unknown,
tightly regulates transcellular transport of large, lipophobic but the principles of cerebral edema can be used to hypoth-
molecules, and water permeability is one-tenth that of esize possible mechanisms.
peripheral blood vessels (12,16). Initially, increased sodium The optic nerve head (ONH) is a transition area where
accumulation in endothelial cells leads to cell swelling unmyelinated retinal ganglion axons turn 90° to traverse
(3,5,6,11,12,18,19). Stressed endothelial cells produce through the lamina cribrosa and form the optic nerve
inflammatory cytokines and extracellular adhesion mole- (34,35). Nerve fibers passing through the collagenous

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 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
FIG. 1. Optic disc edema in returned long-duration astro-
naut. Fundoscopy view of the right eye of a US astronaut pressure (ICP) elevation can also cause ophthalmic vein
after returning from a long-duration spaceflight. Optic disc stasis leading to ONH axonal edema (35,42). Tracer studies
edema extends from 10 o’clock to 6 o’clock. in ODE models have shown delayed filling and tracer leak-
age in the choroid, prelaminar area, and lamina cribrosa
matrix of the lamina cribrosa are unmyelinated, putting (which normally fill before retinal arteries), demonstrating
them at higher risk of injury from mechanical forces and relative circulatory stasis in these areas (33,35,42). Increased
increasing their ATP utilization (34,35). This immense capillary permeability is also demonstrated in terrestrial
energy utilization is supported by a high concentration of models of long-duration bed rest (2). Unlike brain tissue,
mitochondria clustered in the ONH (34). local ischemia of retinal tissues primarily leads to swelling of
The short posterior ciliary arteries branch to form the nerves, not support cells (38). Anatomical variations
choroidal network and anastomose to form a ring of vessels (i.e., incomplete anastomoses and stenosis of arterioles sup-
around the ONH (circle of Zinn), which supply axons in plying the ONH) may predispose some individuals to this
the prelaminar and laminar areas (33,34,36). Choroidal metabolic imbalance (34,36). Local ischemia may lead to
blood flow lacks autoregulation, and choroidal blood vol- H+ ion accumulation, which directly causes choroid vaso-
ume increases during body inversion (2). The choroid is dilation (37). The larger venules of the choroid would likely
organized with the smaller capillaries approximating the dilate first and largest, further compressing the smaller capil-
RPE cells, and the vessel diameter increases to larger venules laries closer to the RPE, worsening the local ischemia (37).
farther away (34,36). The choroidal veins drain through the This may lead to retinal nerve fiber layer ischemia which
ophthalmic vein (2). could, in part, underlie the axoplasmic stasis that presents as
The blood–retinal barrier (BRB) is analogous to the BBB cotton wool spots described in SANS.
intracranially and is separated into an inner BRB and outer Vascular stasis also leads to increased intraluminal
BRB (37). The inner BRB refers to the nonfenestrated hydrostatic pressure. In hypertension and central serous
capillaries that penetrate into the retina and ONH and is chorioretinopathy, intravascular hydrostatic pressure com-
identical to the BBB (37). The outer BRB refers to the RPE promises choroidal circulation causing serous retinal sepa-
cells connected by tight junctions that sit on the Bruch ration through oxidative stress (37,43). One study found
membrane and separate the fenestrated capillaries of the increased levels of MMP-9 in patients with increased jugu-
choroid from the hyperosmolar retinal space (37). The RPE lar vein pressure and decreased cerebral venous outflow
is not attached to the retina, but the constant active trans- (30). Hydrostatic pressure may stress the endothelial cells
port of ions and water from the retinal space to the choroid of the BRB, causing inflammatory biomarker release, BRB
keeps the 2 layers adjoined (37,38). breakdown, and water translocation into the subretinal
space and ONH interstitium (30). This mechanism may
Venous Stasis place astronauts on long-duration missions at hypothetical
During spaceflight, cerebral venous stasis is hypothesized to risk of serous retinal separation.
occur secondary to the cephalic fluid shift that results from Venous stasis may underlie many pathologic changes
microgravity (2). Increased internal jugular vein pressure has seen in SANS through circulatory compromise in the

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 State-of-the-Art Review

choroid and ONH leading to ATP depletion in a highly for female astronauts as estrogens are potent antioxidants;
energy-dependent area, failure of the cytoskeletal motor specifically, 17b-estradiol has been found to protect retinal
proteins leading to axoplasmic flow stasis, collapse of the ion glial cells from oxidative stress (50).
gradient with redistribution of sodium and water intracel-
lularly, and local release of inflammatory cytokines and free Local Energy Depletion and Axoplasmic Stasis
radicals by stressed cells leading to BRB breakdown. Organelles are made in the neural cell body and require
active transport to distribute to the distal axon (48). Axo-
Inflammatory Response and Free Radical plasmic flow requires ATP-dependent motor proteins, ATP,
Formation and a cytoskeleton for the motor proteins to move along.
Immune system dysregulation occurs in microgravity (44). Axoplasmic flow stasis occurs in glaucoma, increased ICP,
Most inflammatory cytokines have short half-lives and low ONH ischemia, and venous stasis (33,48,51,52). Mito-
plasma concentrations, but increased levels of cytokines and chondria normally accumulate in the ONH to support
chemokines involved in inflammatory cell recruitment and the energy demand, but in axoplasmic flow stasis, a buildup
activation were demonstrated in long-duration spaceflight of giant mitochondria occurs (33). Motor proteins and
crew as well as terrestrial analogs (prolonged bedrest and mitochondria accumulate at the ONH in glaucoma models
rodent hind limb unloading) (44). These crewmembers’ (48). Tracer studies in increased ICP demonstrate poor
baseline inflammatory cytokine levels were minimally axon flow with accumulation and swelling in the lamina
detectable, and samples were collected during low-stress cribrosa and anterior prelaminar area, demonstrating
mission phases (44). Total white blood cell count and gran- obstruction at the lamina cribrosa (33).
ulocyte levels increased in spaceflight (45). Cytokine pro- Axoplasmic flow stasis can occur due to inhibition of
duction secondary to T-cell stimulation decreases initially in the energy-dependent motor proteins either directly
spaceflight, and while most stayed depressed throughout the through oxidative stress, or indirectly from circulatory
long-duration mission, some trended up toward normal stasis and local ATP depletion. The progressive ODE may
production levels in late flight (45). If inflammatory medi- be due to continued stasis of active transport or sub-
ators play a primary role in SANS, this decrease and slow sequent disruption of passive transport (48). Passive trans-
trend back toward normal production levels might explain port is slower and may explain the delayed presentation of
the delayed presentation. ODE. As mitochondria accumulate, the loss of optimal
A state of low-level inflammation would exacerbate the mitochondrial distribution along the axon may further
immune response to venous stasis and local ischemia worsen the axoplasmic flow stasis. It may take time to
outlined above. This could worsen inner BRB breakdown perceive the detrimental effects of this progression given
(already highly sensitive to oxygen deprivation) leading to the lower energy demand of the myelinated retrolaminar
increased fluid extravasation within the ONH. If the Na+/ nerve (48).
K+ ATPase is not functioning secondary to energy deple- Axoplasmic flow stasis may also occur secondary to actin
tion, this extra fluid could be taken up from the interstitial cytoskeleton disruption. The 90⁰ turn of the axons at the
space into the neurons, causing local axonal edema (37,46). ONH increases their susceptibility to impaired transport,
Outer BRB breakdown may lead to increased fluid and the collagenous lamina cribrosa is subject to tissue
extravasation into the hyperosmotic retinal space. The deformation, increasing the likelihood of mechanical stress
choroidal folds noted in SANS are more consistent with on the axons (48). Models of increased IOP demonstrate
neuro-ocular inflammatory disorders, such as Vogt– cytoskeletal injury at the lamina cribrosa including
Koyanagi–Harada disease which manifests as optic disc decreased number of microtubules in the area of accumu-
swelling secondary to inflammation and choroidal thick- lated organelles (48). Increased myelin sheath pressure from
ening and folding (43,47). Unilateral edema of the disc is increased ICP can alter microtubule structure, and derange-
another rare inflammatory disorder demonstrating asym- ments may persist beyond ICP normalization (48).
metric papilledema and marked engorgement of retinal
vessels secondary to venous stasis (36). Increased Intracranial Pressure
Oxidative stress occurs secondary to local inflammation. Initially believed to be the etiology of SANS, increased ICP
Mice exposed to short-duration spaceflight have demon- has met criticism as the major determinant as it is unclear
strated upregulation of genes associated with oxidative stress whether ICP is chronically increased in microgravity (2,33).
in the retina and optic nerve (2). These free radicals directly Invasive ICP measurements have not been performed in
inhibit Na+/K+ ATPase, activate MMP-9 and inhibit axo- humans in microgravity, but postflight lumbar punctures
plasmic flow (13,48). In addition, astronauts with altered 1- have demonstrated only mild ICP elevations (2). Invasive
carbon metabolism leading to higher concentrations of free monitoring of a macaque monkey in spaceflight demon-
radical inducers were far more likely to have ophthalmologic strated return to average preflight ICP within 6–9 days in
changes (2,49). This may help explain the partial protection microgravity (2). The initial ICP increase in the macaque

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 State-of-the-Art Review

was mild and less than if lying supine terrestrially (2). Ter- increased HIF-1a in the retinal ganglion cell layer, and
restrial idiopathic intracranial hypertension (IIH) is now models have demonstrated breakdown of the BRB with
deemed an unlikely SANS model as astronauts do not share vascular leak into the interstitial space of the ONH
key symptoms and signs (2). The pattern of ODE is also (33,51). There are discrepancies with pure increased ICP
different between IIH and SANS; IIH models demonstrate models in explaining SANS etiology, but an acute episode
anterior, intraocular swelling, but both anterior and poste- of increased ICP that resolves may set into motion a cascade
rior disc swelling is seen in SANS (53). Also, IIH patients of local inflammation and oxidative stress that continues.
have mainly retinal folds, whereas in SANS, there are sig- One hypothesis to explain increased ONS pressure is altered
nificantly more choroidal folds compared with retinal folds flow dynamics between the intracranial and ONS subarach-
(43,54). noid spaces. Impaired outflow from the ONS compartment
Astronauts demonstrate indirect evidence of increased could lead to CSF sequestration and increased ONS pres-
ICP with ONS distension (2). Sustained ICP elevation sure (55). Models of IIH and asymmetric papilledema have
causes axonal swelling from axoplasmic stasis demonstrated evidence of such a compartment syndrome
(2,33,42,51). Sustained ICP elevation is correlated with (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 Cephalic venous stasis in dialysis patients
inflammatory/oxidative stress leads to ODE (40–42)
Local circulatory stasis Circle of Zinn engorgement compresses axons Hydrostatic pressure causes serous retinal
in ONH and choroid and capillaries in optic nerve separation in central serous
chorioretinopathy (38,51)
Local ATP depletion in ONH Increased retinal HIF-1a in ICP models (38,44)
Anaerobic metabolism leads to choroid Occlusion of ophthalmic vein leads to ODE;
dilation; choroidal veins compress variability of flow in ophthalmic vein noted in
capillaries some astronauts (34,36,37,43)
Energy-dependent axon motor protein Mitochondrial and motor proteins accumulate
dysfunction in high energy-dependent areas (i.e. ONH
and LC) (34,49)
Ion gradient dysfunction; intracellular ODE in SANS mainly neuronal; retinal ischemia
sequestering of sodium and water causes neuronal swelling (39)
Activation of Outer BRB breakdown causing fluid Increased inflammatory cells, cytokines, and
inflammatory cascade extravasation into subretinal space chemokines in astronauts (45,46)
Inner BRB breakdown causing interstitial fluid Choroidal folding observed in inflammatory
leak, local neurons uptake disorders more than in increased ICP
models (48,51)
Increased MMP-9 in patients with increased
internal jugular venous pressure (26)
Increased oxidative Ion gradient disruption through Na+/K+ ATPase Mice from short-duration missions have
stress inhibition upregulation of oxidative stress genes in the
retina and optic nerve (2)
Oxidative stress disrupts motor proteins Astronauts with genes predisposing to free
directly, leading to axonal stasis radical formation are more prone to
ophthalmologic changes (2,50)
Females may have lower SANS prevalence;
estrogens are potent antioxidants (52)
Increased optic nerve Axoplasmic stasis leads to local swelling, Delayed vascular filling in choroid and lamina
sheath pressure capillary compression cribrosa in increased ICP models (34,36,43)
Mitochondria accumulate in ONH Motor proteins and mitochondria accumulate
at ONH and LC in glaucoma and increased
ICP models (34,49)
Axon cytoskeleton disruption through Increased IOP models demonstrate
mechanical stress cytoskeletal derangement in LC (49)
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.

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

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 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 through the ONS on return from long-duration spaceflight.

This could also provide information on the potential utility
Using the pathophysiology of cerebral edema as a model, or disutility of measuring cytokines within the CSF fluid of
several hypotheses can be inferred as to the causes of ODE returned long-duration astronauts, as impaired communica-
in SANS. Venous and local circulatory stasis in the ONH tion between these 2 spaces likely means concentrations of
may lead to increased hydrostatic pressure and local ATP such substances would not be equal. This could also provide
depletion resulting in increased oxidative stress and inflam- information on the potential effect of attempting to alter the
mation leading to both cellular ion gradient dysfunction translaminar pressure gradient through increased IOP pro-
and BRB breakdown (Table 1 and Fig. 2). The new gen- posed by Scott et al (60) (JAMA Ophthalmology 2019), as
eration of optical coherence tomography recently installed without viable communication between the 2 compart-
on the International Space Station will allow for better ments this strategy may not achieve the intended goal.
characterization of the choroid plexus and evaluate the The mentioned theorized mechanisms could lead to
hypothesized venous distension and capillary compression both vasogenic and cytotoxic edema that may underlie not
in microgravity. just ODE, but also the other clinical findings noted in
Local ATP depletion and increased ONS pressure could SANS (Fig. 2). Further studies are needed to determine the
contribute to axoplasmic stasis and result in cytoskeleton presence and contribution of local vascular stasis and result-
disruption, local mitochondrial accumulation in the ONH, ing inflammation and oxidative stress to the pathophysiol-
and local capillary compression that positively reinforce ogy of SANS.
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- STATEMENT OF AUTHORSHIP
ary to local CSF and extracellular free water redistribution, Category 1: a. Conception and design: L. A. Galdamez, T. J.
Brunstetter, and W. J. Tarver; b. Acquisition of data: L. A. Galdamez
as described in recent MRI studies, may contribute (57,58). and T. J. Brunstetter; c. Analysis and interpretation of data: L. A.
Characterizing patterns of redistribution in SANS vs. non- Galdamez and T. J. Brunstetter. Category 2: a. Drafting the
SANS cases may help further elucidate this contribution. manuscript: L. A. Galdamez and T. J. Brunstetter, A. G. Lee; b.
Revising it for intellectual content: L. A. Galdamez, T. J. Brunstetter,
Increased ONS pressure may also occur through mecha- and A. G. Lee. Category 3: a. Final approval of the completed
nisms of ocular nerve compartment syndrome secondary manuscript: L. A. Galdamez, T. J. Brunstetter, W. J. Tarver, and A. G.
to altered flow dynamics of CSF between the intracranial Lee.
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
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 State-of-the-Art Review

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