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NASA NTRS2010

Visual Impairment and Intracranial Hypertension: An Emerging Spaceflight Risk

What is the risk? Given that astronauts exposed to microgravity experience a cephalad fluid shift, and that both symptomatic and asymptomatic astronauts have exhibited optic nerve sheath edema on MRI, there is a high probability that all astronauts have some degree of increased intracranial pressure (ICP; intracranial hypertension), and that those susceptible (via eye architecture, anatomy, narrow optic disc) have a high likelihood of developing papilledema (optic disc edema, globe flattening), choroidal folds, and/or hyperopic shifts and that the degree of edema may determine long-term or permanent vision impairment or loss. Back to back panels on this topic have been developed to address this emerging risk. The first panel will focus on the 6 clinical cases with emphasis on ophthalmic findings and imaging techniques used pre-, in-, and post-flight. The second panel will discuss the operational mitigation and medical requirements, the potential role of CO2 on ISS, and the research approach being developed. In total these back to back panels will explore what is known about this risk, what has been done immediately to address it, and how an integrated research model is being developed.

Fogarty, Jennifer A.↗
NASA NTRS2010

NASA's Spaceflight Visual Impairment and Intracranial Hypertension Research Plan: An accelerated Research Collaboration

To date six long duration astronauts have experienced in flight visual changes and post flight signs of optic disc edema, globe flattening, choroidal folds, hyperoptic shifts and or raised intracranial pressure. In some cases the changes were transient while in others they are persistent with varying degrees of visual impairment. Given that all astronauts exposed to microgravity experience a cephalad fluid shift, and that both symptomatic and asymptomatic patients have exhibited optic nerve sheath edema on MRI, there is a high probability that all astronauts develop in-flight idiopathic intracranial hypertension to some degree. Those who are susceptible, have an increased likelihood of developing treatment resistant papilledema resulting in visual impairment and possible long-term vision loss. Such an acquired disability would have a profound mission impact and would be detrimental to the long term health of the astronaut. The visual impairment and increased intracranial pressure phenomenon appears to have multiple contributing factors. Consequently, the working "physiological fault bush" with elevated intracranial pressure at its center, is divided into ocular effects, and CNS and other effects. Some of these variables have been documented and or measured through operational data gathering, while others are unknown, undocumented and or hypothetical. Both the complexity of the problem and the urgency to find a solution require that a unique, non-traditional research model be employed such as the Accelerated Research Collaboration(TM) (ARC) model that has been pioneered by the Myelin Repair Foundation. In the ARC model a single entity facilitates and manages all aspects of the basic, translational, and clinical research, providing expert oversight for both scientific and managerial efforts. The result is a comprehensive research plan executed by a multidisciplinary team and the elimination of stove-piped research. The ARC model emphasizes efficient and effective communication between management and investigators; and real-time sharing of scientific discoveries in an effort to solve complex problems.

Otto, Christian↗
NASA NTRS2010

Paroxysmal Atrial Fibrillation in a Mission-Assigned Astronaut

This presentation will explore the clinical and administrative conundrums faced by the flight surgeon upon discovering asymptomatic paroxysmal atrial fibrillation seven months prior to scheduled long duration spaceflight. The presenter will discuss the decision-making process as well as the clinical and operational outcomes.

Bauer, Peter A.↗
NASA NTRS2014

A Guideline for the Management of Renal Stones in Astronauts

There are no specific guidelines for the management of renal stones in astronauts. Given the increased risk for bone loss, hypercalcuria, and stone formation due to microgravity, a clinical practice guideline is needed. Methods An extensive review of the literature and current aeromedical standards for the management of renal stones was done. The NASA Flight Medicine Clinic's electronic medical record and Longitudinal Survey of Astronaut Health were also reviewed. This information was used to create an algorithm for the management of renal stones in astronauts. Results Guidelines are proposed based on accepted standards of care, with consideration to the environment of spaceflight. In a usual medical setting, asymptomatic, small stones less than 7 mm are often observed over time. Given the constraints of schedule, and the risks to crew health and mission, this approach is too liberal. An upper limit of 3 mm stone diameter was adopted before requiring intervention, because this is the largest size that has a significant chance of spontaneous passage on its own. Other specific guidelines were also created. Discussion The spaceflight environment requires more aggressive treatment than would otherwise be found with the usual practice of medicine. A small stone can become a major problem because it may ultimately require medical evacuation from orbit. Thus renal stones are a significant mission threat and should be managed in a systematic way to mitigate risks to crew health and mission success.

Reyes, David↗
NASA NTRS2015

Determination of Roles of Microgravity and Ionizing Radiation on the Reactivation of Epstein-Barr Virus In Vitro

Astronauts experience symptomatic and asymptomatic herpes virus reactivation during spaceflight. We have shown increases in reactivation of Epstein-Barr virus (EBV), cytomegalovirus (CMV) and varicella zoster virus (VZV) and shedding in body fluids (saliva and urine) in astronauts during space travel. Alterations in immunity, increased stress hormone levels, microgravity, increased radiation, and other conditions unique to spaceflight may promote reactivation of latent herpes viruses. Unique mechanico-physico forces associated with spaceflight can have profound effects on cellular function, especially immune cells. In space flight analog studies such as Antarctica, bed rest studies, and NASA's undersea habitat (Aquarius), reactivation of these viruses occurred, but to a lesser extent than spaceflight. Spaceflight analogs model some spaceflight factors, but none of the analogs recreates all factors experienced in space. Most notably, microgravity and radiation are not included in many analogs. Stress, processed through the HPA axis and SAM systems, induces viral reactivation. However, the respective roles of microgravity and increased space radiation levels or if any synergy exists are not known. Therefore, we studied the effect of modeled space radiation and/or microgravity, independent of the immune system on the changes in cellular gene expression that results in viral (EBV) reactivation. The effects of modeled microgravity and low shear on EBV replication and cellular and EBV gene expression were studied in human B-lymphocyte cell cultures. Latently infected B-lymphocytes were propagated in the rotating wall bioreactor and irradiated with the various dosages of gamma irradiation. At specific time intervals following exposure to modeled microgravity, the cells and supernatant were harvested and reactivation of EBV were assessed by measuring EBV and gene expression, DNA methylation, and infectious virus production.

Mehta, Satish K↗
NASA NTRS2016

Analysis of Retinal Vascular Branching in Human Subjects Undergoing 70-Day Head-Down Tilt by NASAs VESGEN Software

Significant risks for visual impairment were discovered recently in astronauts following spaceflight, especially after long-duration missions. We hypothesize that microgravity-induced fluid shifts result in pathological changes within the retinal vasculature that precede visual and other ocular impairments. We therefore are analyzing retinal vessels in healthy subjects before and after head-down tilt (HDT), a ground-based microgravity analog with NASA's VESsel GENeration Analysis (VESGEN) software. Methods. Spectralis® infrared (IR) fundus images were collected from both eyes of 6 subjects before and after 70 days of bed rest at 6 degree HDT (NASA Campaign 11). For our retrospective study, branching patterns in arterial and venous trees are mapped by VESGEN into vessel branching generations (Gx) that are quantified by parameters such as densities of vessel length (Lv), area (Av), number (Nv) and fractal dimension (Df) as described previously for diabetic retinopathy (IOVS 51(1):498). Results are further assigned by VESGEN into groups of large (G1-3), medium (G4-6) and small (G≥7) vessels. Results. All subjects remained asymptomatic throughout duration of HDT. To date, we have analyzed one IR image from each of the 12 eyes. Interestingly, two groups of the masked study population identified by VESGEN are distinguished by the presence or absence of small veins (G≥7). For example, L≥7 and Av≥7 are 2.7+/-1.3 E-4 px/px2 and 7.2+/-3.6 E-4 px2/px2 in 6 retinas, but 0 in the other 6 retinas. Nonetheless, the space-filling properties of the entire venous trees were remarkably uniform by all parameters, such as Df = 1.56+/-0.02 for 6 retinas with G≥7 and 1.55+/-0.02 for retinas without G≥7. No small arteries (G≥7) were detected. Conclusions. For our preliminary masked analysis, two groups of venous trees with and without small veins (G≥7) were clearly revealed by VESGEN. Upon completing all images and unmasking the subject status of before and after HDT, we will determine whether differences in the presence or absence of small veins are important correlates, and perhaps reliable predictors, of other ocular and physiological adaptations to prolonged head-down tilt and microgravity. Clinical methods for examining adaptive microvascular remodeling in the retina to microgravity space flight are not currently established.

Fractal↗
NASA NTRS2018

NASA Screening and Clinical Practice for the Monitoring and Mitigation of Coronary Artery Disease: Application to Terrestrial Practice

Coronary artery disease (CAD) surveillance has led to the development of risk stratification tools that drive clinical mitigation efforts for CAD risk. As common risk assessment tools, including the Framingham Risk Score (FRS) or Pooled Cohort Risk Equations, have insufficient accuracy on an individual level to meet NASA’s stringent screening guidelines, NASA has required new approaches to address the risk of catastrophic cardiovascular (CV) medical events among astronauts. Coronary artery calcium (CAC) scanning has emerged as the current best tool to enhance CV risk assessment in asymptomatic individuals, with risk information incremental to FRS data.

Khera, Amit↗
NASA NTRSDate not supplied

One-Carbon Metabolism and SANS 2022 Update

Spaceflight Associated Neuro-ocular Syndrome, or SANS, affects a subset of astronauts (1, 2), and biochemical evidence has documented differences in those astronauts (3). Specifically, they had higher circulating concentrations of metabolites of the one-carbon metabolic pathway (1C), including homocysteine, and these concentrations were higher before flight (3). After ruling out many potential confounding factors in these otherwise healthy individuals (e.g., sex, kidney function, vitamin status, coffee consumption), a study of genetics was warranted. In an initial pilot effort, we documented a genetic predisposition to develop ophthalmic changes after long-duration space flight (4). That is, from a limited study of 5 single-nucleotide polymorphisms (SNPs), we found that the G allele for the MTRR A66G SNP was associated with a greater risk of choroidal folds and cotton-wool spots after flight, and the C allele for SHMT1 C1420T was protective against optic disc edema (4). These data provide a potential pathway for understanding why some individuals develop SANS, while others do not. The initial pilot study of 5 SNPs yielded striking findings, but the 1C pathway is far more complex. An effort was undertaken to examine more than 500 1C SNPs to see if a broader examination could help illuminate this association. That work is ongoing. The astronaut findings led us to advocate for the inclusion of 1C pathway genetic and biochemistry testing on other SANS-related projects, noting that genetics might help identify responders, non-responders, or outliers. The first such effort yielded evidence of an association of specific forms of the MTRR and SHMT-1 SNPs and vitamin B12 status with end-tidal CO2 after acute carbon dioxide exposure (5). The second such effort led to the identification that individuals exposed to strict head-down tilt and CO2 for 30-d who developed optic disc edema also had risk alleles for the two SNPs described above (6). Additionally, we identified a clinical population with many characteristics either attributed or purported to be involved in the ocular changes seen in affected astronauts: women with polycystic ovary syndrome (PCOS). PCOS is a condition of androgen excess and anovulatory menstrual cycles. The shared characteristics and clinical findings between SANS and PCOS generally include higher circulating homocysteine concentrations, increased retinal nerve fiber layer thickness, increased androgen concentrations (or responses), and altered carbohydrate metabolism. To our knowledge, no study has examined whether women with PCOS have asymptomatic ophthalmic anomalies observed in astronauts with SANS. While researchers have evaluated the one-carbon metabolism pathway polymorphisms of PCOS patients, and initial studies show an association with certain one-carbon polymorphisms, none have looked at the set of SNPs identified in our studies that are associated with ophthalmic changes in astronauts. Accordingly, we designed a study to evaluate the association of one-carbon pathway SNPs and ophthalmic findings in patients with PCOS and/or IIH compared to controls. Subjects provided blood samples for vitamin and one carbon biochemistry analyses, an extensive analysis of >500 SNPs associated with one carbon metabolism and had eye examinations and ocular imaging. Data analysis are underway. The data collected to date have shown associations between one carbon pathway biochemistry and genetics and incidence of SANS. The mechanisms for SANS has yet to be identified, although many hypotheses exist. Based on our data, we have developed (8, 9) and expanded (6) a multi-hit hypothesis for how these seemingly disparate findings could be linked. While intriguing, the hypothesis represents the starting point for further research. We aim to clarify the relationship between B-vitamin status and genetics with regard to the risk of SANS. Ultimately, understanding the mechanism(s) behind this will provide a means to predict, prevent, or treat these ophthalmologic pathologies in astronauts, and terrestrial populations.

S M Smith↗
NASA NTRSDate not supplied

Method Development for In-situ Detection of Latent Herpesvirus DNA from Saliva using Nanopore Sequencing

Research toward latent herpesvirus reactivation has been intensively addressed through Space Shuttle and International Space Station (ISS) investigations. This work has provided the understanding that persistent reactivation of herpesviruses from asymptomatic crew can be detected through viral shedding in saliva, urine, and blood. Occasionally, viral reactivation from the latency stage can pose a threat to crew health (clinical manifestation) before, during, and after flight missions. Furthermore, previous work detailing correlations with immunity indicate that monitoring viral reactivation could be implemented to assess potential immune dysfunction. While in-flight monitoring is desirable, there is no well-established procedure or method for real-time evaluations, and research to date has relied on postflight, ground-based analysis. The development of portable molecular technologies like the miniPCR™ (miniPCR Bio) thermal cycler and the MinION™ sequencer (Oxford Nanopore Technologies) have confirmed that real-time monitoring is possible in extreme and low resource environments. These devices, combined with simple sample preparation methods, have been used to demonstrate bacterial identification onboard the ISS, as well as rapid viral detection in remote locations on Earth. The work here builds upon previous molecular advancements onboard the ISS toward the development and validation of a spaceflight-compatible method for viral detection from crew samples. Several herpesviruses can be detected in saliva, which provides a non-invasive means to collect samples for monitoring. While the basis for this method lies in previous spaceflight investigations, key points for method optimization include DNA extraction from saliva, viral primer selection, and bioinformatic processes for data analysis. To increase viral yield, numerous DNA extraction methods have been evaluated and will be discussed in detail. For initial development and testing, varicella-zoster virus (VZV) is being targeted though open reading frame 51 and 63 (ORF51, ORF63), as the replication origin-binding protein is highly expressed during latency. Optimization of the thermal cycling parameters has resulted in the ability to test the entire process. The full method has been tested with both viral VZV DNA standards and saliva spiked with varying concentrations of VZV. Viral sequence data were mapped to the reference sequence using minimap2. Prior to mapping, DNA sequencing reads were filtered for length and quality, barcodes were removed, and alignment identity calculated. Following further assessments, statistics were compared across multiple sequencing experiments and are being used to determine the success of the protocols. Forward work will include the incorporation of herpes simplex virus 1 (HSV-1) and Epstein-Barr virus (EBV) primers as well as the validation of results to the terrestrial qPCR standard assay. Upon full validation of the developed method, saliva will be collected from 20 healthy subjects and spiked with viral DNA. These samples will be split and assayed with the MinION and standard qPCR assay.

Hang N Nguyen↗
NASA NTRS2022

Dermatitis during Spaceflight Associated with HSV-1 Reactivation

Human alpha herpesviruses herpes simplex virus (HSV-1) and varicella zoster virus (VZV) establish latency in various cranial nerve ganglia and often reactivate in response to stress-associated immune system dysregulation. Reactivation of Epstein Barr virus (EBV), VZV, HSV-1, and cytomegalovirus (CMV) is typically asymptomatic during spaceflight, though live/infectious virus has been recovered and the shedding rate increases with mission duration. The risk of clinical disease, therefore, may increase for astronauts assigned to extended missions (>180 days). Here, we report, for the first time, a case of HSV-1 skin rash (dermatitis) occurring during long-duration spaceflight. The astronaut reported persistent dermatitis during flight, which was treated onboard with oral antihistamines and topical/oral steroids. No HSV-1 DNA was detected in 6-month pre-mission saliva samples, but on flight day 82, a saliva and rash swab both yielded 4.8 copies/ng DNA and 5.3 × 104 copies/ng DNA, respectively. Post-mission saliva samples continued to have a high infectious HSV-1 load (1.67 × 107 copies/ng DNA). HSV-1 from both rash and saliva samples had 99.9% genotype homology. Additional physiological monitoring, including stress biomarkers (cortisol, dehydroepiandrosterone (DHEA), and salivary amylase), immune markers (adaptive regulatory and inflammatory plasma cytokines), and biochemical profile markers, including vitamin/mineral status and bone metabolism, are also presented for this case. These data highlight an atypical presentation of HSV-1 during spaceflight and underscore the importance of viral screening during clinical evaluations of in-flight dermatitis to determine viral etiology and guide treatment.

Satish K. Mehta↗
NASA NTRSDate not supplied

Dermatitis During Spaceflight Associated With HSV-1 Reactivation- A Case Study

Human alpha herpesviruses herpes simplex virus (HSV-1 or -2) and varicella zoster virus (VZV) establish latency in various cranial nerve ganglia, and often reactivate in response to stress-associated immune system dysregulation. Reactivation of Epstein Barr Virus (EBV), VZV, HSV-1 and Cytomegalovirus (CMV) is typically asymptomatic during spaceflight, though live/infectious virus has been recovered and the shedding rate increases with mission duration. The risk of clinical disease, therefore, may increase for astronauts assigned to extended missions (>180 days). Here, we report for the first time, a case of HSV-1 skin rash (dermatitis) occurring during a long duration spaceflight. The astronaut reported persistent dermatitis during flight, which was treated onboard with oral antihistamines and topical/oral steroids. No HSV-1 DNA was detected in 6-month pre-mission saliva samples, but on flight day 82, a saliva and rash swab both yielded 4.8 copies/ng DNA and 5.3×104 copies/ng DNA, respectively. Post-mission saliva samples continued to have high infectious HSV-1 load (1.67×107 copies/ng DNA). HSV-1 from both rash and saliva samples had 99.4% genotype homology. Additional physiological monitoring, including stress biomarkers (cortisol, dehydroepiandrosterone (DHEA), and salivary amylase), immune markers (adaptive regulatory and inflammatory plasma cytokines) and biochemical profile markers including vitamin/mineral status and bone metabolism are also presented for this case. These data highlight an atypical presentation of HSV-1 during spaceflight and underscore the importance of viral screening during clinical evaluations of in-flight dermatitis, to determine viral etiology and guide treatment.

Herpes, Viral Reactivation, Spaceflight, Dermatiti↗
NASA NTRS2022

Optimizing Screening for Preventable Blindness With Head-Mounted Visual Assessment Technology

Age-related macular degeneration (AMD) is a leading cause of blindness and is diagnosed as early-stage or late-stage. Early-stage AMD is usually asymptomatic and entails pigmentary changes of the retina (Ayoub & Patel, 2009). As the disorder progresses, there are atrophic or neovascular changes that distort vision, especially the central visual field (Ayoub & Patel, 2009). There are several genetic and non-genetic risk factors for AMD and no proven therapy to slow or reverse late-stage atrophic AMD, while anti-VEGF has effectively treated late-stage neovascular AMD. Several genes of interest have also been investigated thoroughly thus far in their connection to AMD and the CFH and ARMS2 genes have shown promise in understanding the genetic basis of the disorder (Awh et al., 2013). There are other epigenetic and environmental factors as well including smoking and low antioxidant levels (Cano et al., 2010). Ongoing investigations include antioxidant supplementation and a smoking cessation regimen to reverse early-stage AMD (Cano et al., 2010). Progress in treating AMD as a disorder across its varied stages requires newer therapeutics along with a more detailed understanding of the genetic and cellular pathways of pathophysiology is needed to better counter this prevalent disorder of the eye.

age-related macular degeneration↗
NASA NTRSDate not supplied

Oculometric Detection and Characterization of Sub-Clinical Visual/Visuomotor Impairment

It has long been known that qualitative abnormalities in eye movements can be used to diagnose overt brain pathologies (Diefendorf & Dodge, 1908; Fox & Holmes, 1926; Leigh & Zee, 2015). Here, we will examine the use of a set of quantitative measures of the human behavioral response (oculometrics) in a 5-minute radial ocular tracking task (Krukowski & Stone, 2005) with sufficient temporal, spatial, and directional uncertainty to minimize the contribution of a priori prediction or anticipation, and to emphasize the use of a posteriori visual processing of the stimulus trajectory (Liston & Stone, 2014). The derived oculometrics provide a largely independent, reliable set of metrics that are sensitive enough to detect mild sub-clinical impairment across a range of possible neural loci (Stone et al., 2019) with the pattern of impairment across the set providing specificity as to its nature (Tyson et al., 2023). We will review our earlier findings where oculometrics have been used to detect mild impairment due to traumatic brain injury, sleep loss, and low-dose alcohol (Liston et al., 2017; Stone et al., 2019; Tyson et al., 2021). We will also report on a recent clinical study of asymptomatic patients at risk of retinal pathology (Leung et al., 2022) and show that oculometrics can detect and characterize substantive loss of visual function in the absence of clinical indicators of pathology. We conclude that oculometric testing could be used as a routine non-invasive ophthalmological or neurological tool to aid in the early detection and diagnosis of neural injury, toxicity, or disease.

eye movements↗
NASA NTRS2024

Findings From 9 Years of Renal Stone Surveillance of U.S. Astronauts

INTRODUCTION: Renal stones are thought to be a risk for spaceflight due to urine chemistry changes, induced by microgravity. Asymptomatic stone can have significant medical and mission impact.For9 years astronauts travelling to the International Space Station (ISS) have received pre-and post-flight renal ultrasound, according to a specialized renal ultrasound protocol, to look for renal calcifications or mineralized renal material (MRM).A new ultrasound machine was put in service halfway through the screening program. METHODS: MRM screening data from pre-and post-flight were compared, to look for changes in MRM burden. Pre-and post-flight scans from 42 subjects were compared. Studies were further stratified by old versus new machine. Measures were modeled using the analysis of variance (ANOVA) as defined by the interaction between pre-to postflight, and machine-to-machine. RESULTS: There was no observed statistical change seen in MRM burden pre-to postflight using the new higher-resolution ultrasound machine. DISCUSSION: The new machine gives more precise measurements and allows us to differentiate MRMs from other bright objects seen on ultrasound, such as small blood vessels. These data imply that spaceflight does not increase the risk of renal stone formation, at least out to the length of ISS missions. This data will be used to update NASA’s Human System Risk Board’s risk tracking documents, in-flight Concept of Operations, and our Clinical Practice Guideline.

K Cortez↗
NASA NTRS2025

Potential Health Impacts, Treatments, and Countermeasures of Martian Dust on Future Human Space Exploration

The challenges of human space exploration produce some of humanity’s greatest technological and scientific advances, not excluding innovations in medicine. The microgravity environment causes a whole host of physiological changes, and exposure to dust on the Moon caused considerable pulmonary distress to astronauts during the Apollo missions. As the National Aeronautics and Space Administration (NASA)and other space organizations prepare for long duration exploration missions to Mars, the hazards and consequences of the Martian surface need to be accounted for. This review investigates how substances analogous to the hazardous components of Martian dust have caused disease in people on Earth. Because of the small grain size of Martian dust, dust on Mars is more likely to cause lung irritation, absorb into the bloodstream, and lead to diseases in astronauts. Toxic components of Martian dust to astronaut health include perchlorates, silica, nanophase iron oxides, and gypsum in addition to trace amounts of toxic metals whose abundances are debated: chromium, beryllium, arsenic, and cadmium. Predicted effects of dust exposure ranges from asymptomatic to life threatening, with many substances being carcinogenic and most damage impacting the pulmonary system. The longer transit time for astronauts to return home makes the operations of performing emergency medical treatment more difficult and increases both the likelihood and consequences of developing chronic disease. Exposure mitigation needs to be prioritized; however, supplements may be taken to prevent disease from breakthrough exposures and treatment regimens could lessen morbidity and mortality. Treatments and equipment need to be carefully thought out and transported with the astronauts to be prepared for all possible scenarios.

Justin L Wang↗