Spaceflight-Associated Neuro-ocular Syndrome (SANS)

Key Points at a Glance

SANS is a neuro-ophthalmic syndrome that occurs in the microgravity environment of long-duration spaceflight (e.g., ISS) and was previously called VIIP (Visual Impairment and Intracranial Pressure) syndrome.
Main findings include optic disc edema, choroidal folds, cotton wool spots, globe flattening, and hyperopic shift.
Up to 48% of astronauts on long-duration ISS missions report changes in near vision, and up to 45% of those on missions longer than 30 days show ocular abnormalities.
The etiology is multifactorial, with proposed mechanisms including cephalad fluid shift, elevated intracranial pressure, optic nerve sheath compartmentalization, and abnormalities in one-carbon metabolism pathways.
A key distinguishing feature from terrestrial IIH (idiopathic intracranial hypertension) is that classic symptoms such as headache, diplopia, and pulsatile tinnitus are absent in SANS.
Management follows a “countermeasures” rather than “treatment” approach, including supplementation of one-carbon metabolism pathways, swimming goggles, and acetazolamide.
To date, no life-threatening cases or mission interruptions due to SANS have been reported.

1. What is SANS?

SANS (Spaceflight-Associated Neuro-Ocular Syndrome) is a general term for a series of neuro-ophthalmic findings and symptoms observed in astronauts during long-duration spaceflight¹².

Previously called VIIP (Visual Impairment and Intracranial Pressure) syndrome, the name was changed to the current one because it became clear that increased intracranial pressure alone could not explain the pathophysiology¹³.

Epidemiology

The incidence of SANS varies depending on mission duration.

After short shuttle missions: Up to 23% report changes in near visual acuity²
After long-duration ISS missions: Up to 48% report changes in near visual acuity²
Crew members on missions over 30 days: Up to 45% show ocular abnormalities regardless of symptoms¹²

Note that the annual number of astronauts is about 12 (approximately 3 every 3 months), so the statistical sample size is limited.

Q How often does SANS occur?

After long-duration ISS missions, up to 48% of astronauts report changes in near vision, and up to 45% of those on missions over 30 days show ocular abnormalities (even without symptoms). However, the annual number of astronauts is only about 12, limiting the sample size available for analysis.

2. Main Symptoms and Clinical Findings

Subjective Symptoms

Decreased near vision: Appears as a hyperopic shift of up to 1.5 diopters. It can occur as early as 3 weeks after exposure to microgravity ¹².
Scotomas: Partial loss of the visual field.
Decreased distance vision: Occurs due to changes in the shape of the eyeball.
Headache: Reported in some astronauts.

An important difference from IIH is that diplopia, pulsatile tinnitus, transient visual loss, nausea, and vomiting, which are common in IIH, are not seen in SANS.

Clinical Findings (Findings Confirmed by a Physician)

Optic disc edema: May be asymptomatic and can present as asymmetric bilateral edema. Unlike the concentric Paton lines seen in terrestrial IIH, SANS exhibits linear wrinkles ¹².
Choroidal folds: Appear in the posterior pole before retinal folds ¹².
Cotton wool spots: Recognized as ischemic changes in the retina ¹³.
Nerve fiber layer thickening on OCT: The peripapillary retinal nerve fiber layer thickens ¹².
Globe flattening: The posterior pole of the eye flattens, shortening the axial length ¹³.
Hyperopic shift: Confirmed as an increase in hyperopic power on refraction testing ¹³.

In IIH, optic atrophy may remain after treatment, but this finding has not been observed in SANS. Intraocular pressure measurement is not considered a reliable indicator of SANS onset.

Q Do SANS symptoms persist after returning to Earth?

Unlike IIH, optic atrophy has not been reported in SANS to date. However, it is known that some cases continue to show hyperopic shift and ocular flattening after return, and long-term follow-up studies are ongoing.

3. Causes and Risk Factors

Major Risk Factors

Prolonged exposure to microgravity during long-term space missions such as on the ISS is the greatest risk factor, and the risk increases with exposure duration.

High salt intake: Excessive salt associated with space food may affect fluid retention.
Intense resistance exercise: It has been pointed out that it affects intracranial pressure through increased abdominal pressure.
Sensitivity to elevated CO2 levels: The CO2 concentration inside the ISS reaches about 10 times that on the ground, suggesting a contribution to increased intracranial pressure via cerebral vasodilation.
Nutritional deficiencies: Particularly deficiencies in folic acid and vitamin B12 are relevant.
Biochemical abnormalities in one-carbon metabolism: Enzyme polymorphisms in the cyanocobalamin- and folate-dependent metabolic pathway may be predisposing factors.

Association with Biomarkers

In astronauts with ophthalmic symptoms, serum folate levels during flight tend to decrease ⁴⁵. Although no difference is observed in vitamin B12 serum concentrations, those with ophthalmic symptoms have 25-45% higher serum levels of methylmalonic acid, homocysteine, cystathionine, and 2-methylcitric acid after long-duration stays ⁴.

Q Are there characteristics of astronauts who are more likely to develop SANS?

Those with biochemical abnormalities in the one-carbon metabolism pathway, low serum folate levels during flight, or significantly elevated serum methylmalonic acid levels after flight may be at higher risk. Lifestyle and environmental factors such as sensitivity to elevated CO2 levels, high-salt diet, and intense resistance exercise are also thought to be involved.

4. Diagnosis and Examination Methods

The diagnosis of SANS is made by combining multiple modalities. The location and purpose of each examination are shown below.

Examination Method	Location	Main Purpose/Findings
MRI	On the ground (before/after flight)	Optic nerve sheath diameter increase, posterior globe flattening, pituitary gland depression
Orbital ultrasound	Inside ISS	Qualitative detection of globe flattening
OCT and fundus examination	Inside ISS (transmitted to ground)	Confirmation of papilledema, folds, and cotton wool spots
Lumbar puncture	Ground only	CSF opening pressure measurement (normal to borderline)

Details of MRI Findings

MRI performed before and after flight reveals the following findings.

Increased optic nerve sheath diameter, increased optic nerve diameter, and optic nerve kinking
T2 hyperintense signal (observed in 96% of astronauts)
Flattening of the posterior globe, indentation of the pituitary superior margin, posterior displacement of the pituitary stalk, and cephalad shift of the brain

Other Tests

OCT angiography (OCTA): Recently introduced on the ISS. Expected to provide quantitative data on changes in choroidal blood flow.
Refraction test: Quantitatively evaluates the degree of hyperopic shift.
Laboratory tests: Examine enzyme deficiencies in the cyanocobalamin- and folate-dependent one-carbon metabolism pathway.
Lumbar puncture (LP): Only feasible on Earth. CSF opening pressure is often normal to borderline (one case recorded a maximum of 28.5 cmH2O 2 months after landing). Its diagnostic utility is debated.

Notably, NASA’s astronaut health monitoring protocol states that intraocular pressure measurement is not a reliable indicator for the onset of SANS.

5. Standard Treatment

Management of SANS is fundamentally approached as “countermeasures” rather than “treatment” ⁶⁷. Options in the unique space environment are limited, and the following three main countermeasures are used.

Nutritional Supplementation

Folic acid and vitamin B12 supplementation: Nutritional management to compensate for potential enzyme deficiencies in the one-carbon metabolism pathway.

Decreased serum folate levels have been confirmed in astronauts presenting with ophthalmic symptoms, and supplementation is the mainstay of countermeasures.

Goggles

Swim goggles: Used to reduce the translaminar pressure difference (TLPD) across the lamina cribrosa.

Applying positive pressure around the eye reduces the pressure gradient on the optic nerve.

Medication

Acetazolamide: Selectively used to suppress cerebrospinal fluid production.

This does not apply to all cases and is determined based on the individual patient’s condition.

6. Pathophysiology and Detailed Mechanisms

The pathogenesis of SANS is not singular; multiple hypotheses have been proposed. It is currently considered multifactorial, and the contribution of each factor may vary among individual astronauts.

Basic Background

In a microgravity environment, the gravitational excretion function of lymph, CSF, and blood vessels is impaired, causing a cephalad fluid shift to the head, neck, and orbits. This fluid shift is thought to increase hydrostatic pressure within the brain (intracranial pressure) and orbit (optic nerve sheath)¹⁷.

Hypothesis 1: Increased Intracranial Pressure Theory

Cephalad fluid shift → Increased intracranial volume and pressure.

Elevated CSF pressure → Transmitted to the orbit via the optic nerve sheath → Papilledema and globe flattening.

Impaired vortex vein drainage → Choroidal thickening → Axial length shortening and hyperopic shift.

Counterargument: Classic symptoms of IIH (headache, tinnitus, transient visual loss) are absent. In-flight CSF opening pressure data are also lacking, so the “IIH-like” theory remains debated.

Hypothesis 2: Optic Nerve Sheath Compartment Syndrome

CSF physiological changes and individual differences in flow and excretion within the optic nerve sheath overlap.

Check valve-like system: The optic nerve sheath forms a closed compartment, trapping CSF within the sheath without increasing intracranial CSF pressure.

CSF infusion studies: The optic nerve sheath expands linearly to an individual saturation point, which can explain asymmetric findings in IIH and SANS.

Other Pathophysiological Factors

Role of lymphatic drainage: Reduced lymphatic drainage capacity may contribute to edema formation.
Choroidal expansion: Increased choroidal volume contributes to retinal and choroidal folds, flattening of the posterior globe, and hyperopic shift.
High CO₂ environment: CO₂ concentration inside the ISS is about 10 times that on Earth. The contribution to intracranial pressure via cerebral vasodilation should not be underestimated.
Radiation exposure: Deep space missions beyond Earth’s magnetosphere expose astronauts to harmful radiation, potentially causing brain parenchymal inflammation and blood-brain barrier (BBB) disruption, leading to increased intracranial pressure.

Q Is SANS the same condition as idiopathic intracranial hypertension (IIH)?

SANS and IIH share similar findings (e.g., optic disc edema, optic nerve sheath distension), but SANS lacks classic IIH symptoms (e.g., headache, pulsatile tinnitus, transient visual obscurations). In-flight CSF opening pressure data are also lacking, and the “IIH-like” theory is debated. The pathophysiology is thought to involve spaceflight-specific mechanisms such as cephalad fluid shift and optic nerve sheath compartmentalization.

7. Latest Research and Future Prospects (Research Stage Reports)

Advances in Diagnostic Technology Using OCTA and AI

ISS introduction of OCTA: Enables comprehensive and quantitative data acquisition of choroidal blood flow changes, expected to contribute to elucidating the pathophysiology of SANS.
AI (CNN) analysis of OCT images: In-flight OCT image analysis using lightweight convolutional neural networks (CNN) is being attempted, and research is progressing toward automatic detection of SANS-specific changes.

Deep Space Exploration and Radiation Exposure

In deep space exploration beyond Earth’s magnetosphere, such as lunar and Mars missions, exposure to significantly higher radiation levels than on the ISS is expected. Elucidating the relationship between radiation-induced brain parenchymal inflammation, BBB disruption, and the onset of SANS is an important future research topic.

Genetic Polymorphism Screening of One-Carbon Metabolism Pathway

Individual differences in SANS onset suggest the presence of genetic predisposition. An approach to pre-identify high-risk astronauts for SANS through enzyme polymorphism screening of the one-carbon metabolism pathway and provide preventive interventions is being considered ⁴⁵.

Pressure Control Using Swimming Goggles

A novel approach of controlling the translaminar pressure gradient (TLPD) using swimming goggles is also under research. Verification is underway to determine whether applying positive pressure around the eyes can reduce the pressure difference on the optic nerve.

8. References

Lee AG, Mader TH, Gibson CR, Tarver W, Rabiei P, Riascos RF, Galdamez LA, Brunstetter T. Spaceflight associated neuro-ocular syndrome (SANS) and the neuro-ophthalmologic effects of microgravity: a review and an update. NPJ Microgravity. 2020;6:7. PMID: 32047839. doi:10.1038/s41526-020-0097-9 ↩ ↩² ↩³ ↩⁴ ↩⁵ ↩⁶ ↩⁷ ↩⁸ ↩⁹ ↩¹⁰ ↩¹¹
Martin Paez Y, Mudie LI, Subramanian PS. Spaceflight Associated Neuro-Ocular Syndrome (SANS): A Systematic Review and Future Directions. Eye Brain. 2020;12:105-117. PMID: 33117025. doi:10.2147/EB.S234076 ↩ ↩² ↩³ ↩⁴ ↩⁵ ↩⁶ ↩⁷ ↩⁸
Wojcik P, Kini A, Al Othman B, Galdamez LA, Lee AG. Spaceflight associated neuro-ocular syndrome. Curr Opin Neurol. 2020;33(1):62-67. PMID: 31789708. doi:10.1097/WCO.0000000000000778 ↩ ↩² ↩³ ↩⁴
Zwart SR, Gibson CR, Mader TH, Ericson K, Ploutz-Snyder R, Heer M, Smith SM. Vision changes after spaceflight are related to alterations in folate- and vitamin B-12-dependent one-carbon metabolism. J Nutr. 2012;142(3):427-431. PMID: 22298570. doi:10.3945/jn.111.154245 ↩ ↩² ↩³
Brunstetter TJ, Zwart SR, Brandt K, et al. Severe Spaceflight-Associated Neuro-Ocular Syndrome in an Astronaut With 2 Predisposing Factors. JAMA Ophthalmol. 2024;142(9):808-817. PMID: 39052244. doi:10.1001/jamaophthalmol.2024.2385 ↩ ↩²
Nguyen T, Ong J, Brunstetter T, Gibson CR, Macias BR, Laurie S, Mader T, Hargens A, Buckey JC, Lan M, Wostyn P, Kadipasaoglu C, Smith SM, Zwart SR, Frankfort BJ, Aman S, Scott JM, Waisberg E, Masalkhi M, Lee AG. Spaceflight Associated Neuro-ocular Syndrome (SANS) and its countermeasures. Prog Retin Eye Res. 2025;106:101340. PMID: 39971096. doi:10.1016/j.preteyeres.2025.101340 ↩
Ong J, Mader TH, Gibson CR, Mason SS, Lee AG. Spaceflight associated neuro-ocular syndrome (SANS): an update on potential microgravity-based pathophysiology and mitigation development. Eye (Lond). 2023;37(12):2409-2415. PMID: 37072472. doi:10.1038/s41433-023-02522-y ↩ ↩²

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