Spaceflight Associated Neuro-Ocular Syndrome (SANS): Comparison
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Spaceflight associated neuro-ocular syndrome (SANS) is a unique neuro-ophthalmic phenomenon that has been observed in astronauts who have undergone long-duration spaceflight. The syndrome is characterized by distinct imaging and clinical findings including optic disc edema, hyperopic refractive shift, posterior globe flattening, and choroidal folds. SANS serves a large barrier to planetary spaceflight such as a mission to Mars and has been noted by the National Aeronautics and Space Administration (NASA) as a high risk based on its likelihood to occur and its severity to human health and mission performance. While it is a large barrier to future spaceflight, the underlying etiology of SANS is not well understood. However, several well-developed hypotheses have been proposed and countermeasures have been developed.

  • spaceflight associated neuro-ocular syndrome
  • artificial intelligence
  • microgravity
  • pathophysiology

1. Introduction

Spaceflight-associated neuro-ocular syndrome (SANS) describes a specific collection of neuro-ophthalmic changes that are observed in astronauts in long-duration spaceflight (LDSF) missions [1]. These findings include optic disc edema (ODE), globe flattening, choroidal folds, and hyperopic shift. SANS is one of the largest physiological barriers for planetary spaceflight with the National Aeronautics and Space Administration (NASA) designating it as a “red” risk based on occurrence likelihood and impact on astronaut health and mission performance [2]. With this designation, there is a high priority to further understand SANS pathogenesis and development of countermeasures for future spaceflight.[3][4] While it is a top priority for mitigation development and a large barrier to future spaceflight, the pathogenesis of SANS is not well understood [1]. The spaceflight environment holds a myriad of limitations, including limited medical and diagnostic capabilities.[5] This austere environment holds various constraints to investigating SANS pathophysiology and subsequent insights into effective countermeasure research.[6] The advent of artificial intelligence (AI) has revolutionized the field of medicine in diverse aspects including disease detection and management [37][48]. The utilization of AI has potential to address several limitations in the spaceflight environment.[9][10][11][12]
Vision is of the utmost importance in astronaut health and mission performance during spaceflight missions. Beginning in 1989, astronauts were asked about visual changes following spaceflight missions, which led to multiple reports of visual changes [513]. Persistent anecdotes of visual changes led to further investigation by NASA, including ophthalmic imaging. These investigations led to the first description of SANS by Mader et al., which examined the various ophthalmic changes recorded in astronauts following spaceflight [513]. Employing a combination of modalities and procedures including optical coherence tomography (OCT), fundus examination, magnetic resonance imaging (MRI), and lumbar puncture, this report identified several core changes, including optic disc edema, posterior globe flattening, retinal nerve fiber layer thickening, cotton wool spots (CWS), and hyperopic refractive shifts following LDSF [513]. Mader et al. explored several etiologies to explain their findings, including localized fluid shifts as the pathogenesis, citing the delicately balanced pathways of flow through the intracranial subarachnoid space (SAS) and the optic nerve SAS. If microgravity altered the flow in these routes, it could impede outflow and cause a buildup of CSF in the optic nerve sheath (ONS). This hypothesis for SANS pathogenesis has since been explored in-depth and will be discussed at length in the below.

2. Proposed Pathophysiology of SANS

Knowledge of SANS and its pathophysiology is constantly evolving. The mechanisms underlying the development of SANS continues to be an area of investigation, and, in line with the multiple manifestations of its presentation, its etiology is likely multifactorial [614][15][716][817].  “Spaceflight-associated neuro-ocular syndrome” was initially termed “Vision Impairment and Intracranial Pressure” (VIIP) because it was thought that elevated intracranial pressure (ICP) was the driving factor of SANS [1][2]. It has been hypothesized that cephalad fluid shifts observed during microgravity may lead to elevated ICP [918][1019]. Under terrestrial gravitational conditions in the standing position, fluid at rest in the body (with a particular focus towards intravascular and cerebrospinal fluid) exerts a hydrostatic pressure downwards [918][1019][1120]. Weightlessness causes this pressure to decrease (P = ρgh where ρ = density, g = gravity, h = height, and there is a reduction in g due to the weightless environment), leading to a fluid shift towards the head. Microgravity has been observed to cause stagnation and even reversal in the internal jugular veins (IJVs) of an LDSF crew [1221]. If similar shifts occur in the ocular veins, their congestion could spur choroidal expansion and CWS formation. Cephalad fluid shifts are thought to impose similar restrictions on cerebral spinal fluid (CSF) flow and drainage, a blockage that poses particular risk to the choroid and optic nerve. In normal physiology, CSF drains from the choroid plexus into the cerebral vasculature, flowing through the brain and ocular system. A loss in hydrostatic pressure may slow CSF flow velocity and decrease its resorption [1322], overwhelming decompression mechanisms. The accumulated CSF may cause swelling and elevated pressure in the optic nerve sheath, which in turn contributes to ODE and globe flattening [513][1423]. In the setting of presumed elevated ICP, VIIP shared similarities with terrestrial idiopathic intracranial hypertension (IIH), primarily ODE in the setting of elevated ICP. Nevertheless, it is worth noting that IIH is additionally distinguished by the occurrence of persistent headaches, double vision (diplopia), and pulsating ringing in the ears (pulsatile tinnitus), which are clinical aspects that have not been extensively documented/reported among SANS astronauts. Moreover, the SANS condition is characterized by the presence of asymmetric or unilateral ODE, while IIH typically manifests with bilateral ODE [1][1524]. Furthermore, opening pressures on post-flight lumbar punctures in astronauts with SANS revealed only mildly elevated postflight ICP of a significant value observed in terrestrial IIH, although no lumbar punctures have been performed during spaceflight to date. [1][513]. Another discrepancy that has also been noted is that if venous pressures were to cause elevated ICP is that intraocular pressure (IOP) should be elevated as well [1625]. Persistent IOP elevation during LDSF has not been observed [1625]. In addition, central venous pressure (CVP) has not been elevated following the observations of multiple missions [1726]. To help uncover and explain these observations, the effects of weightlessness on tissue pressures have been proposed and investigated in its role in SANS pathogenesis [1625][1726][1827]. An interesting observation is that there is a positive relationship between individuals developing SANS and pre-flight body weight [1928], while in microgravity, there is a reduction in tissue compressive forces [1625]. The effect of the removal of the overall tissue compressive forces has been observed to be greater than the weight of an individual [1928][2029]. This reduction of tissue compression leads to reduced venous pressure, and this effect is more pronounced in individuals of larger weight. The reduction in venous pressure leads to a reduction in transmural pressure [1625]. Given that there are no typical postural and diurnal alterations to CVP during spaceflight, this change is more persistent in the microgravity environment. The continued transmural pressure during LDSF may lead to remodeling of the eye over time, which may lead to signs of SANS in astronauts [1625]. In the Studying the Physiological and Anatomical Cerebral Effects of CO2 and Tilt (SPACECOT) study, cerebral blood volume (CBV) was analyzed with near-infrared spectroscopy (NIRS) in subjects undergoing head-down tilt, a terrestrial analog for SANS [2130]. The results from the SPACECOT study observed an increase in CBV in individuals undergoing HDT. The researchers in this research hypothesized that persistent increased CBV pulsatility during LDSF may lead to remodeling of ocular structures [2130]. The remodeling process helps to explain why astronauts continue to have persistent SANS findings even after returning to Earth [2130]. Mechanical shifting of the brain in the upwards direction has been proposed as a contributor to SANS through its subsequent uplifting of the optic chiasm. Evidence of an upward shift of the brain and its effects was observed by Roberts et al. in a study comparing pre- and post-flight MRI images of 34 astronauts’ brains [2231]. The researchers examined anatomical changes in the brain and its CSF spaces, tracking vertical brain displacement, central sulcus volume, ventricle volume, and changes in the volume of CSF spaces at the vertex. Astronauts were grouped based on mission length, resulting in 18 LDSF and 16 short-duration (SD). High-resolution cine MRI clips were generated for 12 astronauts within the LDSF group and 6 in the SD group. In these clips, upward shift of the brain was observed after all LDSF but none of the SD flights. Three of the twelve long-duration astronauts developed ODE; all three of these subjects also exhibited irregular CSF pressure and narrowing of the central sulcus. However, these symptoms also appeared in several other members of the LDSF group who did not develop ODE, indicating that alterations in CSF pressure may not levy sufficiently robust effects to cause ODE. Narrowed CSF spaces, including the central sulcus, occurred often within the LDSF group and were correlated with upward brain shifting. A reduction in volume in these CSF spaces may lead to subsequent ventricle congestion [2231]. These findings are valuable in light of a mathematical model of ONS mechanics composed by Shinojima et al. Their model used optic nerve sheath diameter (ONSD) to calculate CSF pressure, enabling them to monitor CSF pressure in astronauts using only measures of their ONSD. However, during application, the model reported implausibly high CSF pressures for several astronauts [2332]. This result led the researchers to believe that the astronauts’ ONSs had elasticities that differed from the standard measure used in the model. They hypothesized that this degraded elasticity was an effect of the upward shift of the brain, whose consistent backwards pull on the optic nerve could deform the ONS dura. This model reinforces Roberts et al.’s findings, and the studies in conversation with each other lend support to upward brain shifting as a potential mechanism for SANS [2332]. Recent findings have tentatively linked SANS to the ocular glymphatic system. The glymphatic system is a recently discovered network of perivascular pathways within the brain that washes out excess interstitial fluid, clears waste from the brain and central nervous system, and distributes compounds such as lipids, glucose, and amino acids [2433]. It has also been proposed as a primary mechanism for CSF transport [2534]. In this model, CSF flows into the cranial SAS from the choroid plexus, traveling through the brain via perivascular spaces (PVS). It eventually enters the complex brain parenchyma, flushing out waste and interstitial fluid and then draining into the lymphatic system. Cranial glymphatic flow was linked to the ocular system in a 2017 study by Mathieu et al. which observed CSF inflow into the optic nerve spaces [2635]. Additionally, it has been illustrated that ocular fluids are cleared from the eye via perivenous drainage pathways in rodents [2736]. This connection led to the definition of a specialized ocular glymphatic system, one which relies on a delicate balance of pressures, polarization, and venous and arterial functionality. Wostyn et al. discusses the potential mechanisms and consequences of ocular glymphatic dysregulation, focusing specifically on instances of PVS dilation [2534]. They identify two key mechanisms by which spaceflight could induce PVS dilation. The first draws from Marshall-Goebel et al.’s IJV findings, described above. The altered hemodynamics that they describe cause cerebral vein distention. Because an increase in venous volume would necessarily shrink the surrounding perivenous outflow, this vascular congestion could halt glymphatic outflow and drainage. CSF continuing to enter via the periarterial spaces would be unable to move forwards and instead accumulate, causing the observed periarterial dilation. Wostyn et al. further propose that weakened CSF resorption, when combined with the impaired outflow, can cause CSF buildup along the ONS, generating pressure near the optic nerve head and contributing to globe flattening and ODE. This buildup may also contribute to choroidal folds by forcing choroid expansion, increasing its rigidity, and predisposing it to corrugation [2837]. Further research in the ocular glymphatic system during microgravity may provide additional insights into SANS. Along with the physical mechanisms proposed to drive SANS, research suggests that genetics and vitamin status may predispose some astronauts to develop SANS [2938][3039]. Zwart et al. investigated whether astronauts with naturally higher levels of 1-carbon metabolites experienced SANS-associated ophthalmic changes [2938][3039]. 1-carbon metabolite concentration was shown to be correlated with ophthalmic change in several astronauts in 2012 [3140]. The researchers investigated five single-nucleotide polymorphisms (SNPs) within several genes involved in 1-carbon metabolism to assess their potential correlation with these symptoms: globe flattening, choroidal folds, optic disc edema, CWS, and change in diopters. They created three models of association, which tracked the development of SANS against (1) days in space, (2) days + presence of polymorphisms, and (3) days + presence + vitamin B levels. Comparing these models revealed several genetic associations. The MTRR 66 G allele was highly correlated with choroidal folds and CWS; astronauts homozygous for the GG genotype always presented both symptoms, while those homozygous for AA developed none. The SHMT 1 C allele was correlated with ODE, whereas the SHMT 1420 TT allele appeared to provide protection from it as none of the astronauts with the TT allele developed ODE. Although none of the five SNPs were associated with diopters or globe flattening, these findings nonetheless provide strong support for the possibility of genetic predisposition for SANS. Building on their previous work, Zwart et al. published a 2019 study investigating proposed links between 1-carbon metabolic polymorphisms and ODE. The research’s subjects experienced head-down tilt bed rest (HDTBR), a terrestrial analog technique that mimics the hydrostatic pressure of microgravity [3241], under 0.5% elevated CO2 levels for 30 days. To determine the risk of developing ODE, total retinal thickness (TRT) and RNFL thickness were recorded using OCT. Changes in thickness were then analyzed against the participants’ allele types and vitamin B levels. The researchers found that TRT in participants with 3–4 risk alleles increased dramatically more than in those with 0–2, creating a difference of 40 μm. Furthermore, pre-HDTBR TRT for participants with 3–4 risk alleles was 14 μm greater than the low-risk group at baseline. Thus, the risk alleles were both correlated with larger TRT at onset and greater response during exposure to adverse conditions. These findings are striking and offer an intriguing explanation of the differential development of SANS in astronauts (Table 1).
Table 1. Hypotheses for the pathogenesis of spaceflight-associated neuro-ocular syndrome (SANS).
Hypothesis Summary Reference
Cephalad fluid shift and elevated intracranial pressure Drops in hydrostatic pressure cause widespread disruption of cranial fluids. These shifts can cause venous congestion and block cerebrospinal outflow, resulting in excess pressure on the optic nerve sheath (ONS). Congestion in the cranial vascular system and CSF spaces causes ICP to increase. The elevation in overall pressure is transferred to the ocular system via the ONS, which may cause SANS findings. Mader et al., 2011 [513]

Marshall-Goebel et al., 2019 [1221]

Orešcović & Bulat, 1993 [1322]

Martin Paez et al., 2020 [3342]

Zhang et al., 2018 [918]

Zhang et al., 2014 [3443]

Lee et al., 2020 [1]
Brain upward shift Microgravity can cause the brain to shift upwards, retracting the optic nerve and compressing CSF spaces. Reduced CSF space volume results in congestion and a subsequent increase in CSF pressure. Roberts et al., 2017 [2231]

Shinojima et al., 2018 [2332]
Ocular glymphatic dysfunction The ocular glymphatic system is an offshoot of the general glymphatic system, a series of perivascular spaces (PVS) that transport CSF. Altered venous and arterial flows modify these PVS; such changes both increase CSF inflow and impair its outflow and drainage, causing CSF buildup near and along the ONS. Jessen et al., 2015 [2433]

Mathieu et al., 2017 [2635]

Wang et al., 2020 [2736]

Wostyn et al., 2018 [2837]

Wostyn et al., 2022 [2534]
Genetics Several polymorphisms within 1-carbon metabolites have been correlated with increased presentation of SANS symptoms, suggesting that genetic mechanisms could predispose astronauts to developing the syndrome. Zwart et al., 2012 [3140]

Zwart et al., 2016 [2938]

Zwart et al., 2019 [3039]
Vitamin B levels Higher levels of vitamin B have been correlated with lower incidence and magnitude of SANS symptom development. Zwart et al., 2016 [2938]

Zwart et al., 2019 [3039]
Reduction of tissue compressive forces Reduction of tissue compressive forces in microgravity may lead to a reduction in transmural pressure at the posterior aspect of the eye. Persistent transmural reduction may lead to ocular remodeling and SANS. Buckey et al., 2022 [1625]

Buckey et al., 2018 [1928]

Norsk et al., 2020 [1827]
Cerebral blood volume pulsatility Cerebral blood volume pulsatility may be increased during spaceflight. This persistent increase in pulsatility during long-duration spaceflight may affect nearby ocular structures to cause remodeling. Strangman et al., 2017 [2130]

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