Spaceflight associated neuro-ocular syndrome (SANS): an update on potential microgravity-based pathophysiology and mitigation development.

Long-duration spaceflight is associated with neurologic and ophthalmic clinical and imaging findings in astronauts termed spaceflight associated neuro-ocular syndrome (SANS). These microgravity-induced findings have been well documented by the National Aeronautics and Space Administration (NASA) and are clearly a potential risk for future human space exploration. The underlying pathogenesis of SANS is not well understood, although multiple hypotheses have emerged. Terrestrial analogues and potential countermeasures have also been studied to further understand and potentially mitigate SANS. In this manuscript, we review the current understanding of SANS, discuss the prevailing hypotheses for pathogenesis, and describe current developments in terrestrial analogues and potential countermeasures for SANS.

Evaluation of Optic Disc Edema in Long-Duration Spaceflight Crewmembers Using Retinal Photography.

BACKGROUND: Long-duration spaceflight crewmembers are at risk for spaceflight-associated neuro-ocular syndrome (SANS). One of the earliest manifestations of SANS is optic disc edema (ODE), which could be missed using the subjective Frisén scale. The primary objective of this study is to determine the inter-rater and intrarater reliability of Frisén grade for SANS-induced ODE among a trained observer cohort. The secondary objective is to propose a standardized evaluation process for SANS-induced ODE across International Space Station Partner Agencies. METHODS: Retrospective, double-blinded diagnostic study. Preflight and postflight fundus photographs were presented to subject matter experts who identified and graded ODE. Pairs of images were also compared side-by-side for disc ranking. Grader concordance was assessed for Frisén grading and disc ranking. RESULTS: Expert graders identified Grade 1 ODE in 17.35% of images from 62 crewmembers (9 female, mean [SD] age, 47.81 [5.19] years). Grades 2 and 3 were identified less than 2% of the time. Concordance in Frisén grades among pairs of graders was 70.99%. Graders identified a difference in preflight and postflight fundus photographs 17.21% of the time when using disc ranking. Pairs of graders had complete concordance in disc ranking 79.79% of the time. Perfect intrarater agreement between Frisén grade and disc ranking occurred 77.7% of the time. CONCLUSIONS: These findings demonstrate intergrader and intragrader variability when using the Frisén scale to identify SANS-induced ODE, which is typically milder in presentation than terrestrial cases of idiopathic intracranial hypertension. It is possible to miss early ODE on fundoscopy alone, making it insufficient as a sole criterion for the diagnosis of SANS. A more sensitive and objective method of surveillance is necessary to monitor international crewmembers for ODE, perhaps using a multimodal approach that includes technology such as optical coherence tomography.

Spaceflight associated neuro-ocular syndrome: proposed pathogenesis, terrestrial analogues, and emerging countermeasures.

Spaceflight associated neuro-ocular syndrome (SANS) refers to a distinct constellation of ocular, neurological and neuroimaging findings observed in astronauts during and following long duration spaceflight. These ocular findings, to include optic disc oedema, posterior globe flattening, chorioretinal folds and hyperopic shifts, were first described by NASA in 2011. SANS is a potential risk to astronaut health and will likely require mitigation prior to planetary travel with prolonged exposures to microgravity. While the exact pathogenesis of SANS is not completely understood, several hypotheses have been proposed to explain this neuro-ocular phenomenon. In this paper, we briefly discuss the current hypotheses and contributing factors underlying SANS pathophysiology as well as analogues used to study SANS on Earth. We also review emerging potential countermeasures for SANS including lower body negative pressure, nutritional supplementation and translaminar pressure gradient modulation. Ongoing investigation within these fields will likely be instrumental in preparing and protecting astronaut vision for future spaceflight missions including deep space exploration.

Incidence and Progression of Chorioretinal Folds During Long-Duration Spaceflight.

Importance: The primary contributing factor for development of chorioretinal folds during spaceflight is unknown. Characterizing fold types that develop and tracking their progression may provide insight into the pathophysiology of spaceflight-associated neuro-ocular syndrome and elucidate the risk of fold progression for future exploration-class missions exceeding 12 months in duration. Objective: To determine the incidence and presentation of chorioretinal folds in long-duration International Space Station crew members and objectively quantify the progression of choroidal folds during spaceflight. Design, Setting, and Participants: In this retrospective cohort study, optical coherence tomography scans of the optic nerve head and macula of crew members completing long-duration spaceflight missions were obtained on Earth prior to spaceflight and during flight. A panel of experts examined the scans for the qualitative presence of chorioretinal folds. Peripapillary total retinal thickness was calculated to identify eyes with optic disc edema, and choroidal folds were quantified based on surface roughness within macular and peripapillary regions of interest. Interventions or Exposures: Spaceflight missions ranging 6 to 12 months. Main Outcomes and Measures: Incidence of peripapillary wrinkles, retinal folds, and choroidal folds; peripapillary total retinal thickness; and Bruch membrane surface roughness. Results: A total of 36 crew members were analyzed (mean [SD] age, 46 [6] years; 7 [19%] female). Chorioretinal folds were observed in 12 of 72 eyes (17%; 6 crew members). In eyes with early signs of disc edema, 10 of 42 (24%) had choroidal folds, 4 of 42 (10%) had inner retinal folds, and 2 of 42 (5%) had peripapillary wrinkles. Choroidal folds were observed in all eyes with retinal folds and peripapillary wrinkles. Macular choroidal folds developed in 7 of 12 eyes (4 of 6 crew members) with folds and progressed with mission duration; these folds extended into the fovea in 6 eyes. Circumpapillary choroidal folds developed predominantly superior, nasal, and inferior to the optic nerve head and increased in prevalence and severity with mission duration. Conclusions and Relevance: Choroidal folds were the most common fold type to develop during spaceflight; this differs from reports in idiopathic intracranial hypertension, suggesting differences in the mechanisms underlying fold formation. Quantitative measures demonstrate the development and progression of choroidal folds during weightlessness, and these metrics may help to assess the efficacy of spaceflight-associated neuro-ocular syndrome countermeasures.

Opposite response of blood vessels in the retina to 6° head-down tilt and long-duration microgravity.

The Spaceflight Associated Neuro-ocular Syndrome (SANS), associated with the headward fluid shifts incurred in microgravity during long-duration missions, remains a high-priority health and performance risk for human space exploration. To help characterize the pathophysiology of SANS, NASA's VESsel GENeration Analysis (VESGEN) software was used to map and quantify vascular adaptations in the retina before and after 70 days of bed rest at 6-degree Head-Down Tilt (HDT), a well-studied microgravity analog. Results were compared to the retinal vascular response of astronauts following 6-month missions to the International Space Station (ISS). By mixed effects modeling, the trends of vascular response were opposite. Vascular density decreased significantly in the 16 retinas of eight astronauts and in contrast, increased slightly in the ten retinas of five subjects after HDT (although with limited significance). The one astronaut retina diagnosed with SANS displayed the greatest vascular loss. Results suggest that microgravity is a major variable in the retinal mediation of fluid shifts that is not reproduced in this HDT bed rest model.

Decreased Vascular Patterning in the Retinas of Astronaut Crew Members as New Measure of Ocular Damage in Spaceflight-Associated Neuro-ocular Syndrome.

Purpose: Ocular structural and functional changes, collectively termed spaceflight-associated neuro-ocular syndrome (SANS), have been described in astronauts undergoing long-duration missions in the microgravity environment of the International Space Station. We tested the hypothesis that retinal vascular remodeling, particularly by smaller vessels, mediates the chronic headward fluid shifts associated with SANS. Methods: As a retrospective study, arterial and venous patterns extracted from 30° infrared Heidelberg Spectralis retinal images of eight crew members acquired before and after six-month missions were analyzed with NASA's recently released VESsel GENeration Analysis (VESGEN) software. Output parameters included the fractal dimension and overall vessel length density that was further classified into large and small vascular branching generations. Vascular results were compared with SANS-associated clinical ocular measures. Results: Significant postflight decreases in Df, Lv, and in smaller but not larger vessels were quantified in 11 of 16 retinas for arteries and veins (P value for Df, Lv, and smaller vessels in all 16 retinas were ≤0.033). The greatest vascular decreases occurred in the only retina displaying clinical evidence of SANS by choroidal folds and optic disc edema. In the remaining 15 retinas, decreases in vascular density from Df and Lv ranged from minimal to high by a custom Subclinical Vascular Pathology Index. Conclusions: Together with VESGEN, the Subclinical Vascular Pathology Index may represent a new, useful SANS biomarker for advancing the understanding of SANS etiology and developing successful countermeasures for long duration space exploration in microgravity, although further research is required to better characterize retinal microvascular adaptations.

Carbon Dioxide Physiological Training at NASA.

INTRODUCTION: Astronauts undergo CO2 exposure training to recognize their symptoms that can arise acutely both on the ground and in spaceflight. This article describes acute CO2 exposure training at NASA and examines the symptoms reported by astronauts during training. METHODS: In a controlled training environment, astronauts are exposed to up to 8% CO2 (60 mmHg) by a rebreathing apparatus. Symptoms are reported using a standard form. RESULTS: Symptom documentation forms between April 1994 and February 2012 were obtained for 130 astronauts. The number of symptoms reported per session out of the possible 24 was related to age and sex, with those older slightly more likely to report symptoms. Women reported more symptoms on average than men (men: 3.7, women: 4.7). Respiratory symptoms (90%), flushing sensation/sweating (56%), and dizziness/feeling faint/lightheadedness (43%) were the top symptoms. Only headache reached statistical significance in differences between men (13%) and women (37%) after adjustment for multiple testing. Among those with multiple training sessions, respiratory symptoms were the most consistently reported. DISCUSSION: CO2 exposure training is an important tool to educate astronauts about their potential acute CO2 symptoms. Wide interindividual and temporal variations were observed in symptoms reported during astronaut CO2 exposure training. Headache could not be relied on as a marker of acute exposure during testing since fewer than half the subjects reported it. Our results support periodic refresher training since symptoms may change over time. Further study is needed to determine the optimal interval of training to maximize symptom recognition and inform operational decisions.Law J, Young M, Alexander D, Mason SS, Wear ML, Méndez CM, Stanley D, Meyers Ryder V, Van Baalen M. Carbon dioxide physiological training at NASA. Aerosp Med Hum Perform. 2017; 88(10):897-902.

Efficacy, Safety, and Tolerability of Armodafinil Therapy for Hypersomnia Associated with Dementia with Lewy Bodies: A Pilot Study.

BACKGROUND/AIMS: Hypersomnia is common in dementia with Lewy bodies (DLB). We assessed the efficacy, safety, and tolerability of armodafinil for hypersomnia associated with DLB. METHODS: We performed a 12-week pilot trial of armodafinil therapy (125-250 mg orally daily) in DLB outpatients with hypersomnia. The patients underwent neurologic examinations, a neuropsychological battery, laboratory testing, electrocardiography, and polysomnography. Efficacy was assessed at 2, 4, 8, and 12 weeks. Safety assessment included laboratory examinations, QTc interval, and heart rate. Tolerability was assessed by analysis of adverse events. Data were analyzed using the last-observation-carried-forward method. RESULTS: Of 20 participants, 17 completed the protocol. The median age was 72 years, most of the participants were men (80%), and most had spouses as caregivers. The Epworth Sleepiness Scale (p < 0.001), Maintenance of Wakefulness Test (p = 0.003), and Clinical Global Impression of Change (p < 0.001) scores improved at week 12. The Neuropsychiatric Inventory total score (p = 0.003), visual hallucinations (p = 0.003), and agitation (p = 0.02) improved at week 4. Caregiver overall quality of life improved at week 12 (p = 0.004). No adverse events occurred. CONCLUSION: These pilot data suggest improvements in hypersomnia and wakefulness and reasonable safety and tolerability of armodafinil therapy in hypersomnolent patients with DLB. Our findings inform the use of pharmacologic strategies for managing hypersomnolence in these patients.

Relationship between carbon dioxide levels and reported headaches on the international space station.

OBJECTIVE: Because of anecdotal reports of CO(2)-related symptoms onboard the International Space Station (ISS), the relationship between CO(2) and in-flight headaches was analyzed. METHODS: Headache reports and CO(2) measurements were obtained, and arithmetic means and single-point maxima were determined for 24-hour and 7-day periods. Multiple imputation addressed missing data, and logistic regression modeled the relationship between CO(2), headache probability, and covariates. RESULTS: CO(2) level, age at launch, time in-flight, and data source were significantly associated with headache. For each 1-mm Hg increase in CO(2), the odds of a crew member reporting a headache doubled. To keep the risk of headache below 1%, average 7-day CO(2) would need to be maintained below 2.5 mm Hg (current ISS range: 1 to 9 mm Hg). CONCLUSIONS: Although headache incidence was not high, results suggest an increased susceptibility to physiological effects of CO(2) in-flight.

Differential sensitivity to SSRI and tricyclic antidepressants in juvenile and adult mice of three strains.

Clinical studies have shown differential efficacy of several antidepressants in children and adolescents compared to adults, yet few animal studies have sought to characterize this phenomenon. We compared effects of fluoxetine and imipramine in two common behavioral assays that hold high predictive validity for antidepressant activity, tail suspension and forced swim test, using juvenile (5 weeks) and adult (12 weeks) mice from 3 strains. C57BL/6J-Tyr(c-Brd) (C57), hybrid C57BL/6J-Tyr(c-Brd)x129S5/SvEvBrd (F2), and Balb/cAnNTac (Balb/C) mice were tested in forced swim test and tail suspension after i.p. dosing with either fluoxetine or imipramine. Brain tissues were analyzed to evaluate levels of VMAT2, a possible modulator of age-dependent sensitivity to antidepressants. Imipramine had more consistent antidepressant effect across age groups and strains. Imipramine increased struggle in mice of both ages. Fluoxetine did not have an effect on immobility in Balb/C of both ages in tail suspension. Fluoxetine also did not increase forced swim struggle behavior in juvenile mice of all strains, but was effective in increasing struggle in adults. Juvenile mice had higher immobility and lower struggle than adults in forced swim, and juveniles also had higher immobility in tail suspension test for Balb/C and C57. In addition, VMAT2 levels were increased in juveniles. These results confirm that standard antidepressants produce effects in both juveniles and adults but age-related differences were evident in both tests. Further examination of these effects is needed to determine whether it may be related to age-dependent difference in the clinical response to antidepressants of these classes.