Table 2 Results and analysis of the included papers, presenting the studies description, main findings and significance

Description

Analysis of ophthalmic findings in 7 astronauts and of postflight questionnaires about vision changes in 300 astronauts.

Case study of an astronaut with 2 long-duration (6 months) exposures to microgravity, with complete eye examination and brain imaging.

Collection of data on changes in ICP in 4 different conditions (change from sitting to supine position, parabolic flight, prolonged exposure to simulated microgravity with -6° HDT and with hypercapnia), in 8 participants.

Investigation of possible mechanisms for ocular changes, using 6° HDT, in 8 male subjects, during three 1 h conditions (seated, HDT and HDT + CO2).

Main findings

1. After 6 months of spaceflight, all 7 astronauts had ophthalmic findings.

2. The 300 postflight questionnaires documented a significant percentage of astronauts as experiencing a degradation in distant and near visual acuity.

1. After his first long-duration mission, the astronaut was documented as having eye findings limited to unilateral choroidal folds and a single cotton wool spot.

2. During a subsequent 6-month mission, the astronaut developed more widespread choroidal folds and new onset of optic disc edema in the same eye.

1. ICP was lower when seated in the 90 ̊ upright posture compared to lying supine.

2. In the supine posture, central venous pressure and ICP were reduced in acute zero gravity.

3. Prolonged periods of simulated microgravity did not cause progressive elevations in ICP.

4. Complete removal of gravity does not pathologically elevate ICP but does prevent the normal lowering of ICP when upright.

1. Relative to the seated position, IOP, ICP, ONS diameter (ONSD) and subfoveal choroidal thickness increased and TLPD decreased during HDT.

2. During HDT + CO2, IOP increased.

3. Between the HDT conditions, TLPD maintained unchanged.

4. Visual acuity and ocular structures did not change across conditions.

5. Genetic polymorphisms were associated with differences in IOP, ICP and end-tidal PCO2.

Significance

The first study to report neuroocular changes in astronauts after LDSF.

Documents the recurrence of ophthalmological changes in an astronaut after a second LDSF.

First study to measure directly ICP during weightlessness conditions.

Reports that the combination of mild hypercapnia with an acute headward fluid shift (HDT) does not increase cardiovascular outcomes, ICP and TLPD.

Description

Analysis of the effect of exercise, supine posture, -15° HDT and aerobic in 22 participants and the use of swimming goggles in 10 participants, on cerebro-ocular hemodynamic and ICP.

Study to assess and quantify ventricular volume changes in cosmonauts and give an analysis of CSF spaces derived from structural MRI brain scans before, shortly after, and 7 months after LDSF.

This study assesses the effect on IOP of 6° head down prone tilt during rest and exercise, in normocapnic and hypercapnic conditions, in 10 participants.

Systematic review of the literature published about the pathophysiology of cerebral and optic disc edema.

Main findings

1. 15° HDT showed increased IOP and JVP and decreased TLPG.

2. Exercise at −15° HDT presented decreased IOP and TLPG.

3. Both IOP and TLPG were higher in participants who wore swimming goggles compared with those not wearing goggles.

4. Exercise was associated with decreased IOP and estimated translaminar pressure gradient in HDT, while the addition of swimming goggles was associated with increased IOP and TLPG in HDT.

1. Found an increased ventricular CSF volume after spaceflight in supratentorial ventricular structures, while the infratentorial fourth ventricle was not enlarged.

2. Found a progressive enlargement of the subarachnoid CSF space.

3. Periventricular white matter changes might be a direct consequence of transependymal water diffusion from the enlarged ventricles into periventricular structures, due to pressure peaks in a backed-up CSF circulation.

1. In the prone 6° HDT position, IOP increased.

2. Normocapnic isometric exercise caused a significant increase in MAP, with a corresponding increase in IOP.

3. Hypercapnia did not significantly modify the responses of MAP, but increased the IOP response.

4. Substantial individual variation in the IOP response was observed.

1. Cerebral edema occurs through redistribution of ions and water intracellularly and displacement of ions and water from the vascular compartment to the brain parenchyma.

2. Venous and local circulatory stasis in the optic nerve head may lead to increased hydrostatic pressure and local ATP depletion resulting in increased oxidative stress and inflammation, in SANS.

Significance

Establishes a relation between exercise, neuro-ocular changes and ICP.

Study, in first-hand, the ventricular volume changes in cosmonauts, analyzing MRI brain scans.

Uses HDT and exercise, in an environment with CO2 variations, as a countermeasure to study the alterations associated with SANS.

Studies the pathophysiology of cerebral and optic disc edema and its relation to SANS.

Description

This study quantifies changes in ocular structures of 11 astronauts, testing before, during, and up to 1 year after LDSF.

Systematic review of literature contrasting simulation and spaceflight studies, focusing on the pathophysiology of SANS.

Registration of pre- and post- spaceflight MRI scans and generation of representations of the optic nerve, of 22 astronauts.

Report of the long-term follow-up and persistence of globe flattening and hyperopic refractive shifts for 7 years or more following LDSF in 3 of the 7 astronauts described in Mader et al.².

Main findings

1. Optic nerve head rim tissue and peripapillary choroidal thickness increased significantly during spaceflight.

2. Spaceflight induced significant thickening of retinal tissue layers near the optic nerve head and choroidal engorgement early inflight that progressively increased across the mission.

3. Chronic elevation in retrobulbar cerebrospinal fluid pressure and/or engorgement of the choroidal vasculature may directly deform tissues at the optic nerve head.

1. Intracranial filling pressure reflects changes in intracranial tissue volumes.

2. ICP is proportional to the pressure gradient driving CSF flow through the resistance of its anatomical passages and that of the absorptive arachnoid villi.

3. Microgravity prevents circadian variations in ICP, possibly inducing the ophthalmic and ICP changes.

4. Microgravity may alter intraorbital flow dynamics resulting in compartmentalized optic nerve compression, independent of ICP.

1. Optic nerve length increased, reflecting forward optic nerve head displacement.

2. Upward displacement of the optic chiasm was detected, indicative of brain movement, but it was not possible to correlate it with the development of SANS.

1. Report of persistent globe flattening after LDSF.

2. Permanent structural change may result from elevated CSF pressures within the ONS in SANS. 3. Elevated ONS pressures, during LDSF, may create sufficient mechanical stress on the sclera to cause permanent structural change with secondary globe flattening in the absence of persistent orbital subarachnoid space pressure elevation.

Significance

Documents spaceflight-induced optic disc edema and ocular changes, post-flight recovery and the consequences after spaceflight.

Shows that ICP and ophthalmic effects of microgravity increase with duration of exposure.

Establishes a relationship between optic nerve structural alterations, ICP and the development of SANS.

Suggests that pre-existing increased ICP, asymmetric ONS structure or globe flattening may pre-dispose to prominent anatomic changes.

Description

Quantitative analysis of optic nerve and ONS cross-sectional areas, and optic nerve tortuosity, in 10 astronauts before and after spaceflight (6-month missions).

Systematic review of current body of literature surrounding SANS.

Compares cerebral perfusion before, during, and after HDT + CO2 in participants who developed SANS (n = 5) with those who did not (n = 6).

Using a model-based analysis of cerebral blood velocity and arterial blood pressure waveforms, intracranial pressure was estimated noninvasively in 11 astronauts, before and after LDSF.

Main findings

1. Most individuals did not have changes in ONS anatomy after LDSF.

2. The single subject diagnosed with grade 1 optic disc edema had an optic nerve cross-sectional area reduction and displayed the largest increases in ONS cross-sectional area.

3. The degree of optic nerve deviation lacked correlation with ONS cross-sectional area.

4. Optic nerve cross-sectional area tended to decrease in our cohort immediately post-flight.

1. Two major hypotheses exist for SANS: elevated ICP and compartmentalization of CSF to the globe and optic nerve. These are not mutually exclusive.

2. Determination of ICP during LDSF remains a challenge to be met and represents a critical need with respect to understanding SANS pathophysiology and designing interventions.

1. All participants had a decrease in perfusion during HDT + CO2.

2. The SANS group had a reduction in perfusion earlier that the non-SANS group.

3. In contrast, by day 29 of HDT + CO2, the SANS group had significantly higher perfusion than the non-SANS group.

1. Supine nICP decreased or did not change after spaceflight.

2. No link between the change in supine nICP and the development of ocular changes.

3. Mean Cerebral blood velocity in the MCA (MCAv) increased after spaceflight independently of the nICP changes and ocular alterations.

4. Inverse correlation between increased mean MCAv and decreased Hb concentration.

Significance

Establishes a relation between changes in optic nerve tortuosity and ONS distension and cerebrospinal fluid dynamics.

Provides the literature about the pathophysiology of SANS, the technology and potential countermeasures and treatment.

Shows that the combination of strict HDT along with chronic CO2 results in altered cerebral perfusion that is SANS dependent.

Compares ICP values before and after spaceflight.

Description

This study developed non-invasive magnetic resonance imaging-based techniques to quantify ophthalmic structural changes under acute 15° HDT.

Comparison of percent ventricular volume change per year (PVVC/yr) documented on pre- to post-flight MRI in 18 astronauts with two groups who underwent longitudinal MRI.

Analysis of the possible neuroophthalmological impact of microgravity, through a microgravity analog (dry-immersion), in 18 participants.

Quantitative and qualitative assessments of the intracranial venous system on preflight and postflight MR venograms in 12 astronauts.

Main findings

1. Under HDT,

- ONS cross-sectional area and optic nerve deviation increased.

- Optic nerve cross-sectional area remained unchanged.

- Vitreous chamber depth decreased.

2. The significant ONS distension identified in this study, in HDT subjects, potentially supports that HDT could result in a higher ICP than would be expected in microgravity.

1. Concerning total ventricular volume change, astronauts showed a significantly greater increase in PVVC/yr.

2. As the older adults had larger total ventricular volumes at baseline, there was no significant difference in total ventricular volume change per year between both groups.

3. 7 astronauts presented features of SANS following spaceflight. These 7 astronauts had significantly smaller total PVVC/yr.

4. PVVC/yr appeared to be inversely associated with SANS.

1. Higher thickness of the retinal nerve fiber layer (RNFL) in the temporal quadrant was observed after dry-immersion (DI).

2. ONSD increased significantly during DI and remained higher during the recovery phase.

3. IOP did not significantly change during and after DI.

1. Astronauts who presented clinically with SANS had enlargement of the dural venous sinuses consistent with intracranial venous congestion. 2. There was no evidence of intracranial dural venous sinus thrombosis.

Significance

First study to measure optic nerve area during HDT.

Reports that astronauts who were in LDSF experienced an annual rate of ventricular expansion more than three times than expected from normal aging.

Utilizes a microgravity analog to study its impact on IOP and establishes a relation with ICP and SANS.

This study suggests an association between intracranial venous congestion and SANS.