Spaceflight Associated Neuro-Ocular Syndrome

⚙

Pathophysiology

7

Cephalad Fluid Shift in Microgravity

In microgravity, the absence of hydrostatic pressure gradients causes a redistribution of body fluids toward the head. This cephalad fluid shift increases venous pressure in the head and neck, elevates intracranial pressure, and contributes to optic disc edema and posterior globe flattening.

vascular endothelial cell CL:0000071

cerebrospinal fluid circulation GO:0090660

Show evidence (3 references)

PMID:21849212 SUPPORT Human Clinical

"We hypothesize that the optic nerve and ocular changes we describe may result from cephalad fluid shifts brought about by prolonged microgravity exposure."

The landmark paper describing SANS findings in 7 astronauts proposes cephalad fluid shifts as the primary mechanism.

PMID:39827235 SUPPORT Human Clinical

"several hypotheses have been proposed including increased intracranial pressure, cerebral venous congestion and glymphatic stasis, compartmentalization of CSF within the orbital nerve sheath sub-arachnoid space (SAS), upward brain shift, inflammation, disrupted axoplasmic transport, and..."

This 2025 multifactorial analysis reviews all proposed SANS mechanisms, noting they may be interconnected rather than mutually exclusive.

PMID:33335101 SUPPORT Human Clinical

"A recent in-flight study of 11 astronauts reported that 55% of the crew had stagnant and retrograde blood flow in their IJV"

In-flight ultrasound documented stagnant or retrograde internal jugular vein flow in the majority of a crew, evidencing the cephalad venous congestion that follows the microgravity-induced headward fluid shift.

Elevated Intracranial Pressure

Chronic mildly elevated intracranial pressure during long-duration spaceflight is hypothesized to transmit along the optic nerve sheath, compressing the optic nerve and causing papilledema, globe flattening, and choroidal folds. Unlike terrestrial idiopathic intracranial hypertension, the ICP elevation in SANS is typically mild and not associated with severe headaches.

retinal ganglion cell CL:0000740 retinal astrocyte CL:4033015

cerebrospinal fluid secretion GO:0033326

Show evidence (3 references)

PMID:21849212 SUPPORT Human Clinical

"Lumbar punctures performed in the 4 with disc edema documented opening pressures of 22, 21, 28, and 28.5 cm H(2)O performed 60, 19, 12, and 57 days postmission, respectively."

Direct lumbar puncture measurements in post-flight astronauts demonstrated mildly elevated opening pressures, supporting the elevated ICP hypothesis.

PMID:33117025 SUPPORT Human Clinical

"Two main hypotheses are proposed for the pathophysiology of SANS. The first being elevated intracranial pressure and the second compartmentalization of CSF to the globe. These hypotheses are not mutually exclusive"

This systematic review identifies elevated ICP as one of two primary hypothesized mechanisms, noting the two are not mutually exclusive.

PMID:33335101 SUPPORT Human Clinical

"ICP is not elevated to pathological levels in weightlessness, but rather stabilizes at levels between that of upright and supine terrestrial levels, thus never reaching normal upright levels to unload the brain"

Invasive human ICP measurements support the SANS-specific nuance that microgravity ICP is only borderline/mildly elevated (not pathologically high as in terrestrial IIH); the mechanism is loss of the normal upright ICP-lowering rather than gross intracranial hypertension.

Optic Nerve Sheath Distension

Increased cerebrospinal fluid pressure within the optic nerve sheath leads to sheath distension, which can be visualized on orbital MRI and ocular ultrasound. Terrestrially, ONS distension is associated with increased ICP.

retinal ganglion cell CL:0000740

Downstream

CSF Compartmentalization Optic nerve sheath distension may contribute to compartmentalization of CSF within the orbital subarachnoid space.

Show evidence (2 references)

PMID:33083526 SUPPORT Human Clinical

"potential changes in optic nerve (ON) tortuosity and ON sheath (ONS) distension may indicate altered cerebrospinal fluid dynamics during weightlessness"

Quantitative MRI study of astronauts showing that optic nerve and sheath changes reflect altered CSF dynamics in microgravity.

PMID:33083526 SUPPORT Human Clinical

"a subject diagnosed with optic disc edema (Frisen Grade 1, right eye) displayed increased ONS area post flight, although this increase is relatively small compared to clinical populations with increased ICP"

While one astronaut with optic disc edema showed increased ONS area, the changes were small compared to terrestrial ICP patients, suggesting mechanisms beyond simple ICP elevation.

CSF Compartmentalization

Compartmentalization of CSF within the orbital subarachnoid space may create a pressure differential that contributes to optic disc edema independently of overall ICP elevation. The cul-de-sac anatomy of the optic nerve sheath may act as a one-way valve, trapping CSF and elevating local pressure.

Show evidence (1 reference)

PMID:33117025 SUPPORT Human Clinical

"Two main hypotheses are proposed for the pathophysiology of SANS. The first being elevated intracranial pressure and the second compartmentalization of CSF to the globe. These hypotheses are not mutually exclusive"

Systematic review identifying CSF compartmentalization as one of two primary hypothesized mechanisms for SANS.

Choroidal Engorgement and Vascular Congestion

Microgravity-induced venous congestion leads to choroidal thickening and engorgement. This contributes to hyperopic refractive shifts and choroidal folds observed in affected astronauts. The lack of normal gravitational venous drainage impairs outflow from the orbital and ocular vasculature.

choroidal cell of the eye CL:0000348

Show evidence (2 references)

PMID:32047839 SUPPORT Human Clinical

"decreased choroidal drainage and stagnation or pooling of blood in the choroid, with secondary choroidal expansion as well as globe flattening, and set the stage for choroidal folds"

Review describing how venous congestion in microgravity leads to choroidal blood pooling, expansion, globe flattening, and choroidal folds.

PMID:32047839 SUPPORT Human Clinical

"in-flight OCT has documented choroidal thickening on all tested astronauts compared with pre-flight baseline OCT"

In-flight OCT demonstrates choroidal thickening in every tested astronaut, indicating that microgravity-induced choroidal engorgement/expansion is a near-universal structural change.

Retinal Oxidative Stress

Spaceflight induces oxidative stress-related damage in retinal tissue. Epigenetic alterations and pathway changes associated with retinal disease have been documented in murine models of spaceflight exposure.

retinal ganglion cell CL:0000740

response to oxidative stress GO:0006979

Downstream

Retinal Gene Expression Changes Oxidative stress drives downstream transcriptomic reprogramming in retinal tissue.

Show evidence (2 references)

PMID:34179686 SUPPORT Model Organism

"Several biological pathways involved in retinal diseases such as macular degeneration were significantly altered"

Epigenomic analysis of spaceflight mouse retinas revealed alterations in pathways associated with retinal disease, consistent with oxidative stress-mediated damage.

PMID:31527661 SUPPORT Model Organism

"Immunofluorescence assays showed degradation of cone photoreceptors and increased retinal oxidative stress."

Direct immunofluorescence (4-hydroxynonenal lipid-peroxidation staining) in ISS-flown mouse retinas demonstrated increased retinal oxidative stress and cone photoreceptor degradation, directly supporting the oxidative stress node beyond the pathway-level epigenetic evidence.

Retinal Gene Expression Changes

Spaceflight induces gene expression changes in retinal tissue, with differentially expressed genes enriched for phototransduction and photoreceptor phenotypes. These transcriptomic changes are downstream consequences of oxidative stress and epigenetic alterations.

retinal ganglion cell CL:0000740

phototransduction GO:0007602

Show evidence (1 reference)

PMID:31527661 SUPPORT Model Organism

"RNA sequencing detected 600 differentially expressed genes (DEGs) in murine spaceflight retinas, which were enriched for genes related to visual perception, the phototransduction pathway, and numerous retina and photoreceptor phenotype categories"

Mouse retinas from ISS-flown animals showed significant transcriptomic changes in phototransduction and photoreceptor pathways.

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Pathograph

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Phenotypes

9

Eye 8

Optic Disc Edema VERY_FREQUENT Papilledema HP:0001085

Show evidence (2 references)

PMID:21849212 SUPPORT Human Clinical

"After 6 months of space flight, 7 astronauts had ophthalmic findings, consisting of disc edema in 5, globe flattening in 5, choroidal folds in 5, cotton wool spots (CWS) in 3, nerve fiber layer thickening by OCT in 6, and decreased near vision in 6 astronauts."

Landmark study documenting optic disc edema in 5 of 7 examined astronauts after long-duration spaceflight.

PMID:31162175 SUPPORT Human Clinical

"SANS is currently clinically defined by the development of optic disc edema during prolonged exposure to the weightless (microgravity) environment"

Optic disc edema is considered the defining clinical feature of SANS.

Retinal Nerve Fiber Layer Thickening VERY_FREQUENT Retinal nerve fiber edema HP:0020120

Show evidence (2 references)

PMID:21849212 SUPPORT Human Clinical

"After 6 months of space flight, 7 astronauts had ophthalmic findings, consisting of disc edema in 5, globe flattening in 5, choroidal folds in 5, cotton wool spots (CWS) in 3, nerve fiber layer thickening by OCT in 6, and decreased near vision in 6 astronauts."

Nerve fiber layer thickening on OCT was documented in 6 of 7 astronauts, the most frequent objective imaging finding in the landmark SANS cohort.

PMID:32047839 SUPPORT Human Clinical

"Patel et al. showed an increase in retinal nerve fiber layer (RNFL) thickness and total retinal thickness close to the optic nerve head margin consistent with optic disc edema"

Quantitative OCT comparison of long-duration ISS astronauts with healthy controls confirmed increased RNFL and total retinal thickness near the optic nerve head after microgravity exposure.

Posterior Globe Flattening FREQUENT Abnormal eye morphology HP:0012372

Show evidence (1 reference)

PMID:21849212 SUPPORT Human Clinical

"Five of 7 with near vision complaints had a hyperopic shift ≥+0.50 diopters (D) between pre/postmission spherical equivalent refraction in 1 or both eyes (range, +0.50 to +1.75 D). These 5 showed globe flattening on MRI."

Globe flattening on MRI was documented in 5 of 7 astronauts and correlated with hyperopic refractive shifts.

Choroidal and Retinal Folds FREQUENT Abnormal choroid morphology HP:0000610

Show evidence (2 references)

PMID:21849212 SUPPORT Human Clinical

"After 6 months of space flight, 7 astronauts had ophthalmic findings, consisting of disc edema in 5, globe flattening in 5, choroidal folds in 5, cotton wool spots (CWS) in 3"

Choroidal folds were found in 5 of 7 examined astronauts after long-duration spaceflight.

PMID:32047839 SUPPORT Human Clinical

"the clinical manifestations of SANS including: unilateral and bilateral optic disc edema, globe flattening, choroidal and retinal folds, hyperopic refractive error shifts, and focal areas of ischemic retina (i.e., cotton wool spots)"

Comprehensive review confirming choroidal and retinal folds as core clinical features of SANS.

Cotton Wool Spots OCCASIONAL Retinal cotton wool spot HP:0031606

Show evidence (1 reference)

PMID:21849212 SUPPORT Human Clinical

"After 6 months of space flight, 7 astronauts had ophthalmic findings, consisting of disc edema in 5, globe flattening in 5, choroidal folds in 5, cotton wool spots (CWS) in 3"

Cotton wool spots were found in 3 of 7 examined astronauts.

Hyperopic Refractive Shift FREQUENT Hypermetropia HP:0000540

Show evidence (2 references)

PMID:21849212 SUPPORT Human Clinical

"The 300 postflight questionnaires documented that approximately 29% and 60% of astronauts on short and long-duration missions, respectively, experienced a degradation in distant and near visual acuity."

Large survey documenting high prevalence of visual acuity degradation in astronauts, with higher rates after long-duration missions.

PMID:21849212 SUPPORT Human Clinical

"Five of 7 with near vision complaints had a hyperopic shift ≥+0.50 diopters (D) between pre/postmission spherical equivalent refraction in 1 or both eyes (range, +0.50 to +1.75 D)."

Quantitative measurement of hyperopic shift in astronauts after long-duration spaceflight.

Optic Nerve Sheath Distension FREQUENT Optic nerve sheath dilatation HP:6001281

Show evidence (1 reference)

PMID:33083526 SUPPORT Human Clinical

"Terrestrially, ONS distension is associated with increased ICP; therefore, these results suggest that, on average, ICP was not pathologically elevated immediately after spaceflight"

Quantitative MRI study of 10 astronauts found average ONS area did not increase post-flight, though individual variation was observed in subjects with optic disc edema.

Reduced Visual Acuity OCCASIONAL HP:0007663

Show evidence (2 references)

PMID:21849212 SUPPORT Human Clinical

"Some of these vision changes remain unresolved years after flight."

Documents persistent visual acuity changes in some astronauts even years after return from spaceflight.

PMID:33117025 SUPPORT Human Clinical

"even with persistent anatomic and physiologic neuro-ocular changes, any functional impact has been correctable with spectacles"

Systematic review notes functional visual changes are correctable with spectacles, though structural changes may persist.

Nervous System 1

Mildly Elevated Intracranial Pressure FREQUENT Increased intracranial pressure HP:0002516

Show evidence (2 references)

PMID:21849212 SUPPORT Human Clinical

"Lumbar punctures performed in the 4 with disc edema documented opening pressures of 22, 21, 28, and 28.5 cm H(2)O performed 60, 19, 12, and 57 days postmission, respectively."

Direct measurement of elevated opening pressures in post-flight astronauts. Normal range is typically 7-18 cm H2O.

PMID:30286250 SUPPORT Human Clinical

"Patients with elevated intracranial pressure (ICP) exhibit neuro-ocular symptoms including headache, papilloedema and loss of vision. Some of these symptoms are also present in astronauts during and after prolonged space-flight where lack of gravitational stress prevents daily lowering of ICP..."

Confirms that astronauts exhibit symptoms consistent with elevated ICP due to absence of gravitational unloading during spaceflight.

💊

Medical Actions

2

Lower Body Negative Pressure

Action: lower body negative pressure therapy Ontology label: Therapeutic Procedure NCIT:C49236

Application of negative pressure to the lower body to counteract cephalad fluid shift by drawing blood and fluids toward the legs. LBNP at 20 mmHg has been demonstrated to safely reduce intracranial pressure without impairing cerebral perfusion, and is a leading countermeasure candidate for SANS during spaceflight.

Show evidence (2 references)

PMID:30286250 SUPPORT Human Clinical

"An LBNP of 20 mmHg may be the optimal level to lower ICP without impairing CPP to counteract spaceflight-associated neuro-ocular syndrome in astronauts."

Clinical study demonstrating LBNP effectively lowers ICP in a dose-dependent fashion while maintaining cerebral perfusion pressure.

PMID:33335101 SUPPORT Human Clinical

"Lower body negative pressure (LBNP) can simulate gravitational stress during spaceflight that is likely to counteract SANS and venous thrombosis, but the ideal dose and method of delivery have yet to be determined."

Review supporting LBNP as a promising countermeasure while noting the need to optimize dosing for in-flight use.

Mobile Lower Body Negative Pressure Suit

Action: mobile lower body negative pressure suit Ontology label: Therapeutic Procedure NCIT:C49236

A wearable negative pressure suit that allows astronauts to apply caudal-directed fluid redistribution during normal crew activities, serving as a practical in-flight countermeasure.

Show evidence (1 reference)

PMID:31747995 SUPPORT Human Clinical

"The flexible GravitySuit at 20 mmHg LBNP comfortably induced mechanical loading and desired fluid displacement while maintaining the mobility of hips and knee joints."

The GravitySuit mobile LBNP device induced footward fluid shift and mechanical loading at 20 mmHg without interfering with daily activity, providing a feasible in-flight countermeasure.

🌍

Environmental Factors

2

Microgravity Exposure

Checked ECTO for an exposure_term binding (issue #8430); ECTO has no microgravity, gravity, or weightlessness exposure term of any kind, so left unbound rather than forcing this onto an unrelated broad parent.

Prolonged exposure to microgravity during spaceflight is the primary environmental factor driving SANS. The condition is predominantly seen after missions of 6 months or longer aboard the International Space Station. Over the last 10 years, approximately 1 in 3 astronauts flying long-duration ISS missions have presented with one or more SANS findings.

Show evidence (2 references)

PMID:31162175 SUPPORT Human Clinical

"Over the last 10 years, ~1 in 3 astronauts flying long-duration ISS missions have presented with ≥1 of these ocular findings."

Establishes the epidemiologic association between long-duration microgravity exposure and SANS.

PMID:37072472 SUPPORT Human Clinical

"Long-duration spaceflight is associated with neurologic and ophthalmic clinical and imaging findings in astronauts termed spaceflight associated neuro-ocular syndrome (SANS)."

Confirms the association of SANS specifically with long-duration spaceflight.

Mechanism Target:

TRIGGERS Cephalad Fluid Shift in Microgravity — Microgravity is not a risk factor for this entry, it is the condition without which none of it happens, and the node is named for it. Direct because the step is mechanical rather than biological: removing the hydrostatic gradient redistributes fluid headward, which is what the node describes. The fetched item is the authors' own conclusion and names both ends of this edge.

Show evidence (3 references)

PMID:21849212 SUPPORT Human Clinical

"We hypothesize that the optic nerve and ocular changes we describe may result from cephalad fluid shifts brought about by prolonged microgravity exposure"

Names prolonged microgravity exposure and the cephalad fluid shift in one sentence, which is exactly this edge. Graded support to match this paper's existing grading on this node, though the authors write it as a hypothesis and the word belongs on the record.

PMID:31162175 SUPPORT Human Clinical

"Over the last 10 years, ~1 in 3 astronauts flying long-duration ISS missions have presented with ≥1 of these ocular findings."

Reports that about one in three astronauts on long-duration station missions showed at least one of these ocular findings. It sizes how often the exposure is followed by the disease and says nothing about the fluid shift at this node.

PMID:37072472 SUPPORT Human Clinical

"Long-duration spaceflight is associated with neurologic and ophthalmic clinical and imaging findings in astronauts termed spaceflight associated neuro-ocular syndrome (SANS)."

States that long-duration spaceflight is associated with the neurologic and ophthalmic findings that define the syndrome. An association at the level of the whole disease.

Elevated Ambient Carbon Dioxide

The ISS cabin atmosphere contains CO2 levels higher than terrestrial ambient (typically 2-5 mmHg vs <1 mmHg on Earth). Elevated CO2 causes cerebral vasodilation, which may exacerbate intracranial pressure elevation and contribute to SANS pathology.

Show evidence (1 reference)

PMID:32047839 SUPPORT Human Clinical

"These potential risk factors include high salt diets, rigorous resistive exercise, exposure to elevated ambient CO2 levels and possible defects in the vitamin B12-dependent 1-carbon transfer pathways."

Elevated ambient CO2 on the ISS is identified as a potential risk factor that may augment intracranial pressure during spaceflight.

Mechanism Target:

MODULATES Elevated Intracranial Pressure — The two slots here are deliberately telling different stories, and the difference is the point. The link type is known because the schema asks what the field knows: hypercapnic cerebral vasodilation raising intracranial pressure is well-characterised physiology, and this exposure's own description names that step. The predicate is the weaker one because it answers a different question, whether that edge operates in this population at cabin concentrations, which the source declines to say. Recorded as modulating rather than predisposing on the source's own instruction. The exposure entry describes cabin carbon dioxide raising intracranial pressure through cerebral vasodilation, but the cited review states outright that the physiologic role of carbon dioxide remains ill defined and lists it among its open questions. Both items are carried so the candidate mechanism and the authors' refusal to commit to it travel together, and the predicate matches the weaker of the two.

Show evidence (3 references)

PMID:32047839 SUPPORT Human Clinical

"The ongoing debate has prompted revisiting some of the other risk factors including carbon dioxide and in particular the role of hypercapnia in increased ICP"

Names carbon dioxide and the intracranial pressure at this node in one clause. Partial because it reports a debate being revisited rather than a result, and it is the closest any cited sentence comes to this edge.

PMID:32047839 SUPPORT Human Clinical

"Since astronauts are exposed to these elevated CO2 levels in addition to MG the possible physiologic role of CO2 remains ill defined"

The bound on the claim, in the same paper's words: carbon dioxide is confounded with microgravity because astronauts meet both at once, and its physiologic role is not defined. This is why the link modulates rather than predisposes.

PMID:32047839 SUPPORT Human Clinical

"These potential risk factors include high salt diets, rigorous resistive exercise, exposure to elevated ambient CO2 levels and possible defects in the vitamin B12-dependent 1-carbon transfer pathways."

Lists elevated ambient carbon dioxide among potential risk factors alongside high salt diets, resistive exercise and a vitamin B12 pathway defect. A list of candidates, which names the exposure without stating a mechanism or a magnitude.

📊

Related Datasets

2

Spaceflight causes changes in gene expression, photoreceptor integrity, and oxidative stress-related damage in the murine retina geo:GSE131954

Transcriptomic profiling of retinas from C57BL/6 mice flown aboard the ISS for 35 days, identifying 600 differentially expressed genes enriched for visual perception and phototransduction pathways.

mouse BULK RNA SEQ

PMID:31527661

Illumina NGS RNA-seq and RRBS Sequencing on Spaceflight Mouse Retina geo:GSE159771

Integrated DNA methylome and transcriptome analysis of mouse retinas following 37-day spaceflight, revealing epigenetic clock deceleration and altered pathways involved in retinal disease.

mouse METHYLATION

PMID:34179686

{ }

Source YAML

click to show

name: Spaceflight Associated Neuro-Ocular Syndrome
creation_date: '2026-03-17T00:00:00Z'
category: Complex
parents:
- Neuro-Ophthalmologic Disorder
- Spaceflight-Induced Condition
description: >
  Spaceflight Associated Neuro-Ocular Syndrome (SANS) is a constellation of
  neuro-ophthalmic findings observed in astronauts during and after long-duration
  spaceflight. The syndrome includes optic disc edema, globe flattening,
  choroidal and retinal folds, hyperopic refractive shifts, and cotton wool spots.
  SANS is hypothesized to result from cephalad fluid shifts in microgravity
  leading to elevated intracranial pressure, cerebral venous congestion, and
  compartmentalization of cerebrospinal fluid within the optic nerve sheath.
  It is a major physiologic barrier to future planetary spaceflight missions.
pathophysiology:
- name: Cephalad Fluid Shift in Microgravity
  description: >
    In microgravity, the absence of hydrostatic pressure gradients causes a
    redistribution of body fluids toward the head. This cephalad fluid shift
    increases venous pressure in the head and neck, elevates intracranial
    pressure, and contributes to optic disc edema and posterior globe flattening.
  cell_types:
  - preferred_term: vascular endothelial cell
    term:
      id: CL:0000071
      label: blood vessel endothelial cell
  biological_processes:
  - preferred_term: cerebrospinal fluid circulation
    term:
      id: GO:0090660
      label: cerebrospinal fluid circulation
  evidence:
  - reference: PMID:21849212
    reference_title: "Optic disc edema, globe flattening, choroidal folds, and hyperopic shifts observed in astronauts after long-duration space flight."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We hypothesize that the optic nerve and ocular changes we describe may
      result from cephalad fluid shifts brought about by prolonged microgravity
      exposure.
    explanation: >-
      The landmark paper describing SANS findings in 7 astronauts proposes
      cephalad fluid shifts as the primary mechanism.
  - reference: PMID:39827235
    reference_title: "A multifactorial, evidence-based analysis of pathophysiology in Spaceflight Associated Neuro-Ocular Syndrome (SANS)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      several hypotheses have been proposed including increased intracranial
      pressure, cerebral venous congestion and glymphatic stasis,
      compartmentalization of CSF within the orbital nerve sheath sub-arachnoid
      space (SAS), upward brain shift, inflammation, disrupted axoplasmic
      transport, and radiation exposure
    explanation: >-
      This 2025 multifactorial analysis reviews all proposed SANS mechanisms,
      noting they may be interconnected rather than mutually exclusive.
  - reference: PMID:33335101
    reference_title: "Reviving lower body negative pressure as a countermeasure to prevent pathological vascular and ocular changes in microgravity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A recent in-flight study of 11 astronauts reported that 55% of the crew
      had stagnant and retrograde blood flow in their IJV
    explanation: >-
      In-flight ultrasound documented stagnant or retrograde internal jugular
      vein flow in the majority of a crew, evidencing the cephalad venous
      congestion that follows the microgravity-induced headward fluid shift.
- name: Elevated Intracranial Pressure
  description: >
    Chronic mildly elevated intracranial pressure during long-duration spaceflight
    is hypothesized to transmit along the optic nerve sheath, compressing the optic
    nerve and causing papilledema, globe flattening, and choroidal folds. Unlike
    terrestrial idiopathic intracranial hypertension, the ICP elevation in SANS
    is typically mild and not associated with severe headaches.
  cell_types:
  - preferred_term: retinal ganglion cell
    term:
      id: CL:0000740
      label: retinal ganglion cell
  - preferred_term: retinal astrocyte
    term:
      id: CL:4033015
      label: retinal astrocyte
  biological_processes:
  - preferred_term: cerebrospinal fluid secretion
    term:
      id: GO:0033326
      label: cerebrospinal fluid secretion
  evidence:
  - reference: PMID:21849212
    reference_title: "Optic disc edema, globe flattening, choroidal folds, and hyperopic shifts observed in astronauts after long-duration space flight."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Lumbar punctures performed in the 4 with disc edema documented opening
      pressures of 22, 21, 28, and 28.5 cm H(2)O performed 60, 19, 12, and 57
      days postmission, respectively.
    explanation: >-
      Direct lumbar puncture measurements in post-flight astronauts demonstrated
      mildly elevated opening pressures, supporting the elevated ICP hypothesis.
  - reference: PMID:33117025
    reference_title: "Spaceflight Associated Neuro-Ocular Syndrome (SANS): A Systematic Review and Future Directions."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Two main hypotheses are proposed for the pathophysiology of SANS. The first
      being elevated intracranial pressure and the second compartmentalization of
      CSF to the globe. These hypotheses are not mutually exclusive
    explanation: >-
      This systematic review identifies elevated ICP as one of two primary
      hypothesized mechanisms, noting the two are not mutually exclusive.
  - reference: PMID:33335101
    reference_title: "Reviving lower body negative pressure as a countermeasure to prevent pathological vascular and ocular changes in microgravity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      ICP is not elevated to pathological levels in weightlessness, but rather
      stabilizes at levels between that of upright and supine terrestrial
      levels, thus never reaching normal upright levels to unload the brain
    explanation: >-
      Invasive human ICP measurements support the SANS-specific nuance that
      microgravity ICP is only borderline/mildly elevated (not pathologically
      high as in terrestrial IIH); the mechanism is loss of the normal upright
      ICP-lowering rather than gross intracranial hypertension.
- name: Optic Nerve Sheath Distension
  description: >
    Increased cerebrospinal fluid pressure within the optic nerve sheath leads to
    sheath distension, which can be visualized on orbital MRI and ocular ultrasound.
    Terrestrially, ONS distension is associated with increased ICP.
  cell_types:
  - preferred_term: retinal ganglion cell
    term:
      id: CL:0000740
      label: retinal ganglion cell
  downstream:
  - target: CSF Compartmentalization
    description: >-
      Optic nerve sheath distension may contribute to compartmentalization of CSF
      within the orbital subarachnoid space.
  evidence:
  - reference: PMID:33083526
    reference_title: "Quantitative magnetic resonance image assessment of the optic nerve and surrounding sheath after spaceflight."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      potential changes in optic nerve (ON) tortuosity and ON sheath (ONS)
      distension may indicate altered cerebrospinal fluid dynamics during
      weightlessness
    explanation: >-
      Quantitative MRI study of astronauts showing that optic nerve and sheath
      changes reflect altered CSF dynamics in microgravity.
  - reference: PMID:33083526
    reference_title: "Quantitative magnetic resonance image assessment of the optic nerve and surrounding sheath after spaceflight."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      a subject diagnosed with optic disc edema (Frisen Grade 1, right eye)
      displayed increased ONS area post flight, although this increase is
      relatively small compared to clinical populations with increased ICP
    explanation: >-
      While one astronaut with optic disc edema showed increased ONS area,
      the changes were small compared to terrestrial ICP patients, suggesting
      mechanisms beyond simple ICP elevation.
- name: CSF Compartmentalization
  description: >
    Compartmentalization of CSF within the orbital subarachnoid space may create
    a pressure differential that contributes to optic disc edema independently of
    overall ICP elevation. The cul-de-sac anatomy of the optic nerve sheath may
    act as a one-way valve, trapping CSF and elevating local pressure.
  evidence:
  - reference: PMID:33117025
    reference_title: "Spaceflight Associated Neuro-Ocular Syndrome (SANS): A Systematic Review and Future Directions."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Two main hypotheses are proposed for the pathophysiology of SANS. The first
      being elevated intracranial pressure and the second compartmentalization of
      CSF to the globe. These hypotheses are not mutually exclusive
    explanation: >-
      Systematic review identifying CSF compartmentalization as one of two
      primary hypothesized mechanisms for SANS.
- name: Choroidal Engorgement and Vascular Congestion
  description: >
    Microgravity-induced venous congestion leads to choroidal thickening and
    engorgement. This contributes to hyperopic refractive shifts and choroidal
    folds observed in affected astronauts. The lack of normal gravitational
    venous drainage impairs outflow from the orbital and ocular vasculature.
  cell_types:
  - preferred_term: choroidal cell of the eye
    term:
      id: CL:0000348
      label: choroidal cell of the eye
  evidence:
  - reference: PMID:32047839
    reference_title: "Spaceflight associated neuro-ocular syndrome (SANS) and the neuro-ophthalmologic effects of microgravity: a review and an update."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      decreased choroidal drainage and stagnation or pooling of blood in the
      choroid, with secondary choroidal expansion as well as globe flattening,
      and set the stage for choroidal folds
    explanation: >-
      Review describing how venous congestion in microgravity leads to
      choroidal blood pooling, expansion, globe flattening, and choroidal folds.
  - reference: PMID:32047839
    reference_title: "Spaceflight associated neuro-ocular syndrome (SANS) and the neuro-ophthalmologic effects of microgravity: a review and an update."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      in-flight OCT has documented choroidal thickening on all tested
      astronauts compared with pre-flight baseline OCT
    explanation: >-
      In-flight OCT demonstrates choroidal thickening in every tested
      astronaut, indicating that microgravity-induced choroidal
      engorgement/expansion is a near-universal structural change.
- name: Retinal Oxidative Stress
  description: >
    Spaceflight induces oxidative stress-related damage in retinal tissue.
    Epigenetic alterations and pathway changes associated with retinal disease
    have been documented in murine models of spaceflight exposure.
  cell_types:
  - preferred_term: retinal ganglion cell
    term:
      id: CL:0000740
      label: retinal ganglion cell
  biological_processes:
  - preferred_term: response to oxidative stress
    term:
      id: GO:0006979
      label: response to oxidative stress
  downstream:
  - target: Retinal Gene Expression Changes
    description: >-
      Oxidative stress drives downstream transcriptomic reprogramming in
      retinal tissue.
  evidence:
  - reference: PMID:34179686
    reference_title: "Spaceflight decelerates the epigenetic clock orchestrated with a global alteration in DNA methylome and transcriptome in the mouse retina."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Several biological pathways involved in retinal diseases such as macular
      degeneration were significantly altered
    explanation: >-
      Epigenomic analysis of spaceflight mouse retinas revealed alterations
      in pathways associated with retinal disease, consistent with oxidative
      stress-mediated damage.
  - reference: PMID:31527661
    reference_title: "Spaceflight influences gene expression, photoreceptor integrity, and oxidative stress-related damage in the murine retina."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Immunofluorescence assays showed degradation of cone photoreceptors and
      increased retinal oxidative stress.
    explanation: >-
      Direct immunofluorescence (4-hydroxynonenal lipid-peroxidation staining)
      in ISS-flown mouse retinas demonstrated increased retinal oxidative stress
      and cone photoreceptor degradation, directly supporting the oxidative
      stress node beyond the pathway-level epigenetic evidence.
- name: Retinal Gene Expression Changes
  description: >
    Spaceflight induces gene expression changes in retinal tissue, with
    differentially expressed genes enriched for phototransduction and
    photoreceptor phenotypes. These transcriptomic changes are downstream
    consequences of oxidative stress and epigenetic alterations.
  cell_types:
  - preferred_term: retinal ganglion cell
    term:
      id: CL:0000740
      label: retinal ganglion cell
  biological_processes:
  - preferred_term: phototransduction
    term:
      id: GO:0007602
      label: phototransduction
  evidence:
  - reference: PMID:31527661
    reference_title: "Spaceflight influences gene expression, photoreceptor integrity, and oxidative stress-related damage in the murine retina."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      RNA sequencing detected 600 differentially expressed genes (DEGs) in
      murine spaceflight retinas, which were enriched for genes related to
      visual perception, the phototransduction pathway, and numerous retina and
      photoreceptor phenotype categories
    explanation: >-
      Mouse retinas from ISS-flown animals showed significant transcriptomic
      changes in phototransduction and photoreceptor pathways.
phenotypes:
- category: Ophthalmologic
  name: Optic Disc Edema
  frequency: VERY_FREQUENT
  description: >
    Swelling of the optic disc (papilledema) is the hallmark finding of SANS,
    observed in a significant proportion of astronauts after long-duration
    spaceflight on the International Space Station. Variable Frisén grades
    have been documented.
  phenotype_term:
    preferred_term: Papilledema
    term:
      id: HP:0001085
      label: Papilledema
  evidence:
  - reference: PMID:21849212
    reference_title: "Optic disc edema, globe flattening, choroidal folds, and hyperopic shifts observed in astronauts after long-duration space flight."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      After 6 months of space flight, 7 astronauts had ophthalmic findings,
      consisting of disc edema in 5, globe flattening in 5, choroidal folds in
      5, cotton wool spots (CWS) in 3, nerve fiber layer thickening by OCT in
      6, and decreased near vision in 6 astronauts.
    explanation: >-
      Landmark study documenting optic disc edema in 5 of 7 examined astronauts
      after long-duration spaceflight.
  - reference: PMID:31162175
    reference_title: "Gravitational Influence on Intraocular Pressure: Implications for Spaceflight and Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      SANS is currently clinically defined by the development of optic disc
      edema during prolonged exposure to the weightless (microgravity) environment
    explanation: >-
      Optic disc edema is considered the defining clinical feature of SANS.
- category: Ophthalmologic
  name: Retinal Nerve Fiber Layer Thickening
  frequency: VERY_FREQUENT
  description: >
    Thickening (edema) of the peripapillary retinal nerve fiber layer detected
    on optical coherence tomography (OCT) is among the most sensitive and
    frequent objective findings of SANS, reflecting axoplasmic stasis at the
    optic nerve head. OCT reveals some degree of nerve fiber layer / total
    retinal thickening in nearly all astronauts after long-duration spaceflight,
    often preceding or occurring without clinically apparent optic disc edema.
  phenotype_term:
    preferred_term: Retinal nerve fiber layer thickening
    term:
      id: HP:0020120
      label: Retinal nerve fiber edema
  evidence:
  - reference: PMID:21849212
    reference_title: "Optic disc edema, globe flattening, choroidal folds, and hyperopic shifts observed in astronauts after long-duration space flight."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      After 6 months of space flight, 7 astronauts had ophthalmic findings,
      consisting of disc edema in 5, globe flattening in 5, choroidal folds in
      5, cotton wool spots (CWS) in 3, nerve fiber layer thickening by OCT in
      6, and decreased near vision in 6 astronauts.
    explanation: >-
      Nerve fiber layer thickening on OCT was documented in 6 of 7 astronauts,
      the most frequent objective imaging finding in the landmark SANS cohort.
  - reference: PMID:32047839
    reference_title: "Spaceflight associated neuro-ocular syndrome (SANS) and the neuro-ophthalmologic effects of microgravity: a review and an update."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Patel et al. showed an increase in retinal nerve fiber layer (RNFL)
      thickness and total retinal thickness close to the optic nerve head
      margin consistent with optic disc edema
    explanation: >-
      Quantitative OCT comparison of long-duration ISS astronauts with healthy
      controls confirmed increased RNFL and total retinal thickness near the
      optic nerve head after microgravity exposure.
- category: Ophthalmologic
  name: Posterior Globe Flattening
  frequency: FREQUENT
  description: >
    Flattening of the posterior aspect of the globe, detected on MRI, is a
    characteristic structural change in SANS. It results from increased
    retrobulbar pressure transmitted through the optic nerve sheath and has
    been shown to persist for years after return to Earth.
  phenotype_term:
    preferred_term: Posterior globe flattening
    term:
      id: HP:0012372
      label: Abnormal eye morphology
  evidence:
  - reference: PMID:21849212
    reference_title: "Optic disc edema, globe flattening, choroidal folds, and hyperopic shifts observed in astronauts after long-duration space flight."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Five of 7 with near vision complaints had a hyperopic shift ≥+0.50
      diopters (D) between pre/postmission spherical equivalent refraction in 1
      or both eyes (range, +0.50 to +1.75 D). These 5 showed globe flattening
      on MRI.
    explanation: >-
      Globe flattening on MRI was documented in 5 of 7 astronauts and
      correlated with hyperopic refractive shifts.
- category: Ophthalmologic
  name: Choroidal and Retinal Folds
  frequency: FREQUENT
  description: >
    Folds in the choroid and retina detected on fundoscopy and optical coherence
    tomography, resulting from choroidal engorgement and posterior globe
    deformation in microgravity. These may persist after return to Earth.
  phenotype_term:
    preferred_term: Choroidal folds
    term:
      id: HP:0000610
      label: Abnormal choroid morphology
  evidence:
  - reference: PMID:21849212
    reference_title: "Optic disc edema, globe flattening, choroidal folds, and hyperopic shifts observed in astronauts after long-duration space flight."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      After 6 months of space flight, 7 astronauts had ophthalmic findings,
      consisting of disc edema in 5, globe flattening in 5, choroidal folds in
      5, cotton wool spots (CWS) in 3
    explanation: >-
      Choroidal folds were found in 5 of 7 examined astronauts after
      long-duration spaceflight.
  - reference: PMID:32047839
    reference_title: "Spaceflight associated neuro-ocular syndrome (SANS) and the neuro-ophthalmologic effects of microgravity: a review and an update."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the clinical manifestations of SANS including: unilateral and bilateral
      optic disc edema, globe flattening, choroidal and retinal folds, hyperopic
      refractive error shifts, and focal areas of ischemic retina (i.e., cotton
      wool spots)
    explanation: >-
      Comprehensive review confirming choroidal and retinal folds as core
      clinical features of SANS.
- category: Ophthalmologic
  name: Cotton Wool Spots
  frequency: OCCASIONAL
  description: >
    Retinal cotton wool spots representing focal areas of retinal nerve fiber
    layer ischemia, observed in some astronauts with SANS.
  phenotype_term:
    preferred_term: Retinal cotton wool spots
    term:
      id: HP:0031606
      label: Retinal cotton wool spot
  evidence:
  - reference: PMID:21849212
    reference_title: "Optic disc edema, globe flattening, choroidal folds, and hyperopic shifts observed in astronauts after long-duration space flight."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      After 6 months of space flight, 7 astronauts had ophthalmic findings,
      consisting of disc edema in 5, globe flattening in 5, choroidal folds in
      5, cotton wool spots (CWS) in 3
    explanation: >-
      Cotton wool spots were found in 3 of 7 examined astronauts.
- category: Ophthalmologic
  name: Hyperopic Refractive Shift
  frequency: FREQUENT
  description: >
    A shift toward hyperopia (farsightedness) occurs in affected astronauts,
    likely due to posterior globe flattening shortening the axial length of the
    eye. Approximately 29% of short-duration and 60% of long-duration astronauts
    report degraded visual acuity.
  phenotype_term:
    preferred_term: Hyperopic shift
    term:
      id: HP:0000540
      label: Hypermetropia
  evidence:
  - reference: PMID:21849212
    reference_title: "Optic disc edema, globe flattening, choroidal folds, and hyperopic shifts observed in astronauts after long-duration space flight."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The 300 postflight questionnaires documented that approximately 29% and
      60% of astronauts on short and long-duration missions, respectively,
      experienced a degradation in distant and near visual acuity.
    explanation: >-
      Large survey documenting high prevalence of visual acuity degradation
      in astronauts, with higher rates after long-duration missions.
  - reference: PMID:21849212
    reference_title: "Optic disc edema, globe flattening, choroidal folds, and hyperopic shifts observed in astronauts after long-duration space flight."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Five of 7 with near vision complaints had a hyperopic shift ≥+0.50
      diopters (D) between pre/postmission spherical equivalent refraction in 1
      or both eyes (range, +0.50 to +1.75 D).
    explanation: >-
      Quantitative measurement of hyperopic shift in astronauts after
      long-duration spaceflight.
- category: Ophthalmologic
  name: Optic Nerve Sheath Distension
  frequency: FREQUENT
  description: >
    Distension of the optic nerve sheath with increased cerebrospinal fluid,
    visualized on MRI and ultrasound, reflecting elevated perioptic
    subarachnoid space pressure.
  phenotype_term:
    preferred_term: Optic nerve sheath distension
    term:
      id: HP:6001281
      label: Optic nerve sheath dilatation
  evidence:
  - reference: PMID:33083526
    reference_title: "Quantitative magnetic resonance image assessment of the optic nerve and surrounding sheath after spaceflight."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Terrestrially, ONS distension is associated with increased ICP;
      therefore, these results suggest that, on average, ICP was not
      pathologically elevated immediately after spaceflight
    explanation: >-
      Quantitative MRI study of 10 astronauts found average ONS area did not
      increase post-flight, though individual variation was observed in
      subjects with optic disc edema.
- category: Neurologic
  name: Mildly Elevated Intracranial Pressure
  frequency: FREQUENT
  description: >
    Opening pressures measured via lumbar puncture in post-flight astronauts
    are mildly elevated above the normal terrestrial range. Unlike idiopathic
    intracranial hypertension, severe headaches are not typically prominent.
  phenotype_term:
    preferred_term: Increased intracranial pressure
    term:
      id: HP:0002516
      label: Increased intracranial pressure
  evidence:
  - reference: PMID:21849212
    reference_title: "Optic disc edema, globe flattening, choroidal folds, and hyperopic shifts observed in astronauts after long-duration space flight."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Lumbar punctures performed in the 4 with disc edema documented opening
      pressures of 22, 21, 28, and 28.5 cm H(2)O performed 60, 19, 12, and 57
      days postmission, respectively.
    explanation: >-
      Direct measurement of elevated opening pressures in post-flight
      astronauts. Normal range is typically 7-18 cm H2O.
  - reference: PMID:30286250
    reference_title: "Lower body negative pressure to safely reduce intracranial pressure."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Patients with elevated intracranial pressure (ICP) exhibit neuro-ocular
      symptoms including headache, papilloedema and loss of vision. Some of
      these symptoms are also present in astronauts during and after prolonged
      space-flight where lack of gravitational stress prevents daily lowering
      of ICP associated with upright posture.
    explanation: >-
      Confirms that astronauts exhibit symptoms consistent with elevated ICP
      due to absence of gravitational unloading during spaceflight.
- category: Ophthalmologic
  name: Reduced Visual Acuity
  frequency: OCCASIONAL
  description: >
    Decreased visual acuity has been reported in astronauts during and after
    long-duration spaceflight. Although correctable with spectacles, some
    vision changes remain unresolved years after flight.
  phenotype_term:
    preferred_term: Reduced visual acuity
    term:
      id: HP:0007663
      label: Reduced visual acuity
  evidence:
  - reference: PMID:21849212
    reference_title: "Optic disc edema, globe flattening, choroidal folds, and hyperopic shifts observed in astronauts after long-duration space flight."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Some of these vision changes remain unresolved years after flight.
    explanation: >-
      Documents persistent visual acuity changes in some astronauts even
      years after return from spaceflight.
  - reference: PMID:33117025
    reference_title: "Spaceflight Associated Neuro-Ocular Syndrome (SANS): A Systematic Review and Future Directions."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      even with persistent anatomic and physiologic neuro-ocular changes, any
      functional impact has been correctable with spectacles
    explanation: >-
      Systematic review notes functional visual changes are correctable
      with spectacles, though structural changes may persist.
environmental:
- name: Microgravity Exposure
  influences_mechanisms:
  - target: Cephalad Fluid Shift in Microgravity
    environmental_effect: TRIGGERS
    causal_link_type: DIRECT
    description: >-
      Microgravity is not a risk factor for this entry, it is the condition
      without which none of it happens, and the node is named for it. Direct
      because the step is mechanical rather than biological: removing the
      hydrostatic gradient redistributes fluid headward, which is what the
      node describes. The fetched item is the authors' own conclusion and
      names both ends of this edge.
    evidence:
    - reference: PMID:21849212
      reference_title: "Optic disc edema, globe flattening, choroidal folds, and hyperopic shifts observed in astronauts after long-duration space flight."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "We hypothesize that the optic nerve and ocular changes we describe may result from cephalad fluid shifts brought about by prolonged microgravity exposure"
      explanation: >-
        Names prolonged microgravity exposure and the cephalad fluid shift in
        one sentence, which is exactly this edge. Graded support to match this
        paper's existing grading on this node, though the authors write it as
        a hypothesis and the word belongs on the record.
    - reference: PMID:31162175
      reference_title: "Gravitational Influence on Intraocular Pressure: Implications for Spaceflight and Disease."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Over the last 10 years, ~1 in 3 astronauts flying long-duration ISS missions have presented with ≥1 of these ocular findings."
      explanation: >-
        Reports that about one in three astronauts on long-duration station
        missions showed at least one of these ocular findings. It sizes how
        often the exposure is followed by the disease and says nothing about
        the fluid shift at this node.
    - reference: PMID:37072472
      reference_title: "Spaceflight associated neuro-ocular syndrome (SANS): an update on potential microgravity-based pathophysiology and mitigation development."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Long-duration spaceflight is associated with neurologic and ophthalmic clinical and imaging findings in astronauts termed spaceflight associated neuro-ocular syndrome (SANS)."
      explanation: >-
        States that long-duration spaceflight is associated with the
        neurologic and ophthalmic findings that define the syndrome. An
        association at the level of the whole disease.
  description: >
    Prolonged exposure to microgravity during spaceflight is the primary
    environmental factor driving SANS. The condition is predominantly seen
    after missions of 6 months or longer aboard the International Space Station.
    Over the last 10 years, approximately 1 in 3 astronauts flying long-duration
    ISS missions have presented with one or more SANS findings.
  evidence:
  - reference: PMID:31162175
    reference_title: "Gravitational Influence on Intraocular Pressure: Implications for Spaceflight and Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Over the last 10 years, ~1 in 3 astronauts flying long-duration ISS
      missions have presented with ≥1 of these ocular findings.
    explanation: >-
      Establishes the epidemiologic association between long-duration
      microgravity exposure and SANS.
  - reference: PMID:37072472
    reference_title: "Spaceflight associated neuro-ocular syndrome (SANS): an update on potential microgravity-based pathophysiology and mitigation development."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Long-duration spaceflight is associated with neurologic and ophthalmic
      clinical and imaging findings in astronauts termed spaceflight associated
      neuro-ocular syndrome (SANS).
    explanation: >-
      Confirms the association of SANS specifically with long-duration
      spaceflight.
  notes: >-
    Checked ECTO for an exposure_term binding (issue #8430); ECTO has no
    microgravity, gravity, or weightlessness exposure term of any kind, so
    left unbound rather than forcing this onto an unrelated broad parent.
- name: Elevated Ambient Carbon Dioxide
  influences_mechanisms:
  - target: Elevated Intracranial Pressure
    environmental_effect: MODULATES
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      The two slots here are deliberately telling different stories, and the
      difference is the point. The link type is known because the schema asks
      what the field knows: hypercapnic cerebral vasodilation raising
      intracranial pressure is well-characterised physiology, and this
      exposure's own description names that step. The predicate is the weaker
      one because it answers a different question, whether that edge operates
      in this population at cabin concentrations, which the source declines
      to say. Recorded as modulating rather than predisposing on the source's
      own
      instruction. The exposure entry describes cabin carbon dioxide raising
      intracranial pressure through cerebral vasodilation, but the cited
      review states outright that the physiologic role of carbon dioxide
      remains ill defined and lists it among its open questions. Both items
      are carried so the candidate mechanism and the authors' refusal to
      commit to it travel together, and the predicate matches the weaker of
      the two.
    evidence:
    - reference: PMID:32047839
      reference_title: "Spaceflight associated neuro-ocular syndrome (SANS) and the neuro-ophthalmologic effects of microgravity: a review and an update."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The ongoing debate has prompted revisiting some of the other risk factors including carbon dioxide and in particular the role of hypercapnia in increased ICP"
      explanation: >-
        Names carbon dioxide and the intracranial pressure at this node in one
        clause. Partial because it reports a debate being revisited rather
        than a result, and it is the closest any cited sentence comes to this
        edge.
    - reference: PMID:32047839
      reference_title: "Spaceflight associated neuro-ocular syndrome (SANS) and the neuro-ophthalmologic effects of microgravity: a review and an update."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Since astronauts are exposed to these elevated CO2 levels in addition to MG the possible physiologic role of CO2 remains ill defined"
      explanation: >-
        The bound on the claim, in the same paper's words: carbon dioxide is
        confounded with microgravity because astronauts meet both at once, and
        its physiologic role is not defined. This is why the link modulates
        rather than predisposes.
    - reference: PMID:32047839
      reference_title: "Spaceflight associated neuro-ocular syndrome (SANS) and the neuro-ophthalmologic effects of microgravity: a review and an update."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "These potential risk factors include high salt diets, rigorous resistive exercise, exposure to elevated ambient CO2 levels and possible defects in the vitamin B12-dependent 1-carbon transfer pathways."
      explanation: >-
        Lists elevated ambient carbon dioxide among potential risk factors
        alongside high salt diets, resistive exercise and a vitamin B12
        pathway defect. A list of candidates, which names the exposure without
        stating a mechanism or a magnitude.
  description: >
    The ISS cabin atmosphere contains CO2 levels higher than terrestrial
    ambient (typically 2-5 mmHg vs <1 mmHg on Earth). Elevated CO2 causes
    cerebral vasodilation, which may exacerbate intracranial pressure
    elevation and contribute to SANS pathology.
  exposure_term:
    preferred_term: exposure to elevated ambient carbon dioxide
    term:
      id: ECTO:9000049
      label: exposure to carbon dioxide
  evidence:
  - reference: PMID:32047839
    reference_title: "Spaceflight associated neuro-ocular syndrome (SANS) and the neuro-ophthalmologic effects of microgravity: a review and an update."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These potential risk factors include high salt diets, rigorous resistive
      exercise, exposure to elevated ambient CO2 levels and possible defects in
      the vitamin B12-dependent 1-carbon transfer pathways.
    explanation: >-
      Elevated ambient CO2 on the ISS is identified as a potential risk
      factor that may augment intracranial pressure during spaceflight.
treatments:
- name: Lower Body Negative Pressure
  description: >
    Application of negative pressure to the lower body to counteract cephalad
    fluid shift by drawing blood and fluids toward the legs. LBNP at 20 mmHg
    has been demonstrated to safely reduce intracranial pressure without
    impairing cerebral perfusion, and is a leading countermeasure candidate
    for SANS during spaceflight.
  treatment_term:
    preferred_term: lower body negative pressure therapy
    term:
      id: NCIT:C49236
      label: Therapeutic Procedure
  evidence:
  - reference: PMID:30286250
    reference_title: "Lower body negative pressure to safely reduce intracranial pressure."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      An LBNP of 20 mmHg may be the optimal level to lower ICP without
      impairing CPP to counteract spaceflight-associated neuro-ocular syndrome
      in astronauts.
    explanation: >-
      Clinical study demonstrating LBNP effectively lowers ICP in a
      dose-dependent fashion while maintaining cerebral perfusion pressure.
  - reference: PMID:33335101
    reference_title: "Reviving lower body negative pressure as a countermeasure to prevent pathological vascular and ocular changes in microgravity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Lower body negative pressure (LBNP) can simulate gravitational stress
      during spaceflight that is likely to counteract SANS and venous
      thrombosis, but the ideal dose and method of delivery have yet to be
      determined.
    explanation: >-
      Review supporting LBNP as a promising countermeasure while noting
      the need to optimize dosing for in-flight use.
- name: Mobile Lower Body Negative Pressure Suit
  description: >
    A wearable negative pressure suit that allows astronauts to apply
    caudal-directed fluid redistribution during normal crew activities,
    serving as a practical in-flight countermeasure.
  treatment_term:
    preferred_term: mobile lower body negative pressure suit
    term:
      id: NCIT:C49236
      label: Therapeutic Procedure
  evidence:
  - reference: PMID:31747995
    reference_title: "Mobile Lower Body Negative Pressure Suit as an Integrative Countermeasure for Spaceflight."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The flexible GravitySuit at 20 mmHg LBNP comfortably induced mechanical
      loading and desired fluid displacement while maintaining the mobility of
      hips and knee joints.
    explanation: >-
      The GravitySuit mobile LBNP device induced footward fluid shift and
      mechanical loading at 20 mmHg without interfering with daily activity,
      providing a feasible in-flight countermeasure.
datasets:
- accession: geo:GSE131954
  title: Spaceflight causes changes in gene expression, photoreceptor integrity, and oxidative stress-related damage in the murine retina
  description: >
    Transcriptomic profiling of retinas from C57BL/6 mice flown aboard the ISS
    for 35 days, identifying 600 differentially expressed genes enriched for
    visual perception and phototransduction pathways.
  organism:
    preferred_term: mouse
    term:
      id: NCBITaxon:10090
      label: Mus musculus
  data_type: BULK_RNA_SEQ
  publication: PMID:31527661
- accession: geo:GSE159771
  title: Illumina NGS RNA-seq and RRBS Sequencing on Spaceflight Mouse Retina
  description: >
    Integrated DNA methylome and transcriptome analysis of mouse retinas
    following 37-day spaceflight, revealing epigenetic clock deceleration and
    altered pathways involved in retinal disease.
  organism:
    preferred_term: mouse
    term:
      id: NCBITaxon:10090
      label: Mus musculus
  data_type: METHYLATION
  publication: PMID:34179686

Spaceflight Associated Neuro-Ocular Syndrome

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