| Article Access Statistics|
| Viewed||1653 |
| Printed||42 |
| Emailed||0 |
| PDF Downloaded||27 |
| Comments ||[Add] |
Click on image for details.
|Year : 2019 | Volume
| Issue : 8 | Page : 206-211
An overview of spaceflight-associated neuro-ocular syndrome (SANS)
Thomas H Mader1, C Robert Gibson2, Neil R Miller3, Prem S Subramanian4, Nimesh B Patel5, Andrew G Lee6
1 COL (R) US Army, Moab, Utah; Coastal Eye Associates, Webster, New York, USA
2 Coastal Eye Associates, Webster, New York, USA
3 Wilmer Eye Institute, Baltimore, Maryland, USA
4 Department of Ophthalmology, University of Colorado, Denver, Colorado, USA
5 Department of Vision Science, University of Houston, Houston, Texas, USA
6 Blanton Eye Institute, Department of Ophthalmology, Houston Methodist Hospital, Houston; Departments of Ophthalmology, Neurology, and Neurosurgery, Weill Cornell Medicine, New York City, New York; Department of Ophthalmology, Baylor College of Medicine (BCM) and the BCM Center for Space Medicine, Houston, Texas, and University of Texas Medical Branch (UTMB), Galveston; Texas A and M College of Medicine (College Station, Texas), UT MD Anderson Cancer Center, Houston, Texas; University of Iowa Hospitals and Clinics (Iowa City Iowa), and the University of Buffalo, Buffalo, New York, USA
|Date of Web Publication||24-May-2019|
Dr. Thomas H Mader
3509 Red Rock Drive, Moab, Utah 84532
Source of Support: None, Conflict of Interest: None
Over the last decade, the National Aeronautics and Space Administration's (NASA) Space Medicine Division has documented a variety of unusual physiological and pathological neuro-ophthalmic findings in astronauts during and following long duration space flight. These ndings include optic disc swelling, globe flattening, choroidal folds, and hyperopic shifts in refraction. Cephalad fluid shift has been proposed as a possible unifying etiology, but the specific mechanism responsible for these changes remains obscure. This manuscript reviews the history, clinical findings, and potential neurophysiological etiologies for spaceflight-associated neuro-ocular syndrome.
Keywords: Choroidal folds, globe flattening, hyperopic shift, long-duration spaceflight, microgravity, optic disc swelling, spaceflight-associated neuro-ocular syndrome
Key Message: Physiological and pathological neuro-ophthalmic findings occurring in astronauts during and following long-duration space flight are reviewed.
|How to cite this article:|
Mader TH, Gibson C R, Miller NR, Subramanian PS, Patel NB, Lee AG. An overview of spaceflight-associated neuro-ocular syndrome (SANS). Neurol India 2019;67, Suppl S2:206-11
|How to cite this URL:|
Mader TH, Gibson C R, Miller NR, Subramanian PS, Patel NB, Lee AG. An overview of spaceflight-associated neuro-ocular syndrome (SANS). Neurol India [serial online] 2019 [cited 2020 Feb 18];67, Suppl S2:206-11. Available from: http://www.neurologyindia.com/text.asp?2019/67/8/206/259126
Long-duration spaceflights (LDSF) during low Earth orbit missions to the International Space Station (ISS) or even interplanetary space travel will gradually increase. Our experience with spaceflight-associated neuro-ocular syndrome (SANS) is based on findings in a small number of astronauts who have developed a well-documented spectrum of neuro-ophthalmic changes. When the mission length of space travel increases, neuro-ophthalmic problems may increase. It is imperative that we understand and mitigate these potentially harmful anatomic and physiological changes.
| » Historical Perspective|| |
Beginning in 1989, as part of routine postflight eye examinations, astronauts were asked if they had any visual changes during or after spaceflight. In response to reports of vision changes, NASA began a stepwise process to define the problem and determine the etiology. Pre- and postmission ophthalmic examinations, including cycloplegic refraction, dilated fundus examinations with fundus photos, optical coherence tomography (OCT) of the retinas and optic discs, and magnetic resonance imaging (MRI) of the orbits were carried out. This was implemented in a stepwise fashion over years. These evaluations revealed, unusual, and unique physiological and pathological neuro-ophthalmic findings in seven astronauts who had undergone complete eye examinations prior to and following a 6-month ISS mission. The main ophthalmic findings included the following: optic disc swelling (n = 5), globe flattening (GF) (n = 5), choroidal folds (CF) (n = 5), retinal nerve fiber layer (RNFL) infarcts (n = 3), thickening within the RNFL on OCT (n = 6), and decreased near vision (n = 6). Five of the six astronauts with decreased near vision had a hyperopic (farsighted) shift of + 0.50 diopters (D) or greater spherical equivalent refraction in one or both eyes (range, +0.50 to +1.75 D) from premission to postmission evaluations. In addition, GF (axial hyperopic shortening) was seen in five of six astronauts who underwent postmission MRI. Postmission lumbar punctures were performed in four astronauts, two of whom were found to have slightly elevated intracranial pressure (ICP). The syndrome initially was called visual impairment intracranial pressure as it was thought to be a direct result of elevated ICP related to LDSF. However, due to increasing evidence suggesting other possible mechanisms (e.g., cephalad fluid shift), the syndrome more recently has been termed SANS by NASA.,,,
| » Possible Mechanisms of Neurophysiological Changes|| |
Over the last decade, unilateral and bilateral optic disc swelling has been documented clinically in astronauts as a part of SANS, both during and after LDSF.,,, These clinical observations have been greatly augmented by the addition of high-resolution, spectral domain (Heidelberg Spectralis) OCT performed on board the ISS. These OCT scans have shown early optic nerve (ON) changes during spaceflight before the appearance of ophthalmoscopically detectable anomalies. OCT of the ON head revealed mild increase in minimum rim width and peripapillary total retinal thickness (TRT) in nearly all astronauts who had an OCT during spaceflight. These changes occurred as early as 3 weeks into the LDSF., Some degree of unilateral or bilateral optic disc swelling, as documented by OCT, appears to be a nearly universal finding in astronauts during and after LDSF. Clinically recognizable optic disc swelling by retinal examination and fundus photography has been documented as early as 90 days into space flight. Although the endpoint of optic disc swelling is variable, there is generally a slow progression in the magnitude of swelling over months during LDSF. An increase in optic disc swelling from grade 1 to grade 3 on the Frisen scale has been documented in 10 astronauts; in 50%, the swelling was asymmetric with a predisposition for the right side.,, Though the findings are significant, no permanent visual loss has been documented in SANS.
Two major theories have been proposed to explain the etiology of the optic disc swelling, GF, CF, and hyperopic shifts seen in astronauts with SANS ,,,,,, [Figure 1]. These theories are not mutually exclusive. The true mechanism may be multifactorial. The first theory is that these changes occur from a rise in ICP similar to that which takes place in terrestrial idiopathic intracranial hypertension (IIH).,,,,,, Both head-down (HD) and microgravity (MG) studies document that cerebral blood flow velocity and arterial diameter are autoregulated and do not change significantly during spaceflight.,, In contrast, MG fluid shifts are well documented to cause jugular vein distension, suggesting that cerebral and jugular venous congestion may be present in the MG environment.,,, Cerebrospinal fluid (CSF) is produced largely in the choroid plexus and the drainage from the brain into the venous system is dependent upon the pressure differential between the relatively high-pressure intracranial space and the lower-pressure venous sinuses.,, We hypothesize that venous stasis in the head and neck, produced during spaceflight, inhibits the normal outflow of cerebral CSF and causes cerebral venous congestion, both of which lead to a rise in ICP.,,,,,, This elevated cerebral subarachnoid CSF pressure could be transmitted directly from the intracranial compartment to the intraorbital compartment through the perioptic subarachnoid space (SAS). A rise in orbital CSF pressure could result in ONS distention, secondary GF, and stasis of axoplasmic flow with resultant optic disc swelling, all consistent with the observed findings.
|Figure 1: Postflight imaging of the right eye. (a) Fundus imaging showing the "C" halo of the Frisén Grade 1 disc edema and choroidal folds inferior to the disc. (b) SLO image from the SD- optical coherence tomography with an overlay of the vertical raster scan placement. Note the choroidal folds superior and inferior to the disc visible in the SLO image. (c) The retinal cross-section obtained by the vertical scan just nasal to the disc showing retinal nerve fiber layer thickening and severe choroidal folds. (Reprinted with permission J Neuro-Ophthalmol 2013;33:252)|
Click here to view
Many authors have described similar optic disc swelling as well as ONS expansion, GF, CF, and other findings in terrestrial IIH as documented by MRI, ultrasound (US), and OCT.,,, This supports the increased ICP hypothesis. Second, although in-flight CSF pressures have never been measured, modestly elevated lumbar puncture opening pressures (LPOP) of 28 and 28.5 cm H2O have been documented in two astronauts at 12 and 57 days, respectively, post-LDSF and may have been higher during the mission. These two ICP measurements are above the top normal value of 25 cm H2O and would not be expected in the typical astronaut (fit, nonobese, taking few if any medications). Third, MRI changes in some astronauts following LDSF have included pituitary concavity, empty sella, and changes in pituitary stalk configuration, all of which are suggestive of increased ICP. Other factors that may contribute to SANS include defects in the vitamin B12-dependent 1-carbon transfer pathways, high carbon dioxide levels in the ISS, and rigorous resistive exercise on the ISS. It should be noted that ISS cabin pressure and oxygen levels are maintained at Earth normal, whereas the carbon dioxide level averages around 10 times Earth normal during these missions. The potential role of elevated carbon dioxide levels on the ISS in SANS has not been established. A recent HD study with strict positioning in a CO2-enriched atmosphere for 30 days did demonstrate ocular manifestations of SANS, although there was no comparison group with this strict HD position in a normal atmosphere.
Despite findings that suggest a role for increased ICP in the development of SANS, other findings challenge the notion that ICP alone is the cause of the syndrome. First, chronic severe headaches, transient visual obscurations (from papilledema due to increased ICP), tinnitus (from high flow in stenotic venous sinuses), and diplopia (usually from nonlocalizing sixth nerve palsies), common symptoms in IIH, have not been documented in astronauts during or after LDSF. In terrestrial IIH, moderate to severe chronic and recurrent headache is seen in >90% of all patients  and in 79% of men. Transient visual obscurations are noted in 68%, tinnitus in 58%, photopsia in 54%, retrobulbar pain in 44%, and sixth nerve palsy in 30%.,,,, It should be noted that although some mild-to-moderate headaches do occur in astronauts, these headaches seem to be less severe than those in patients with IIH. The headache in IIH is more likely to be severe, unremitting, and sometimes described as “the worst headache of my life.” The headache in IIH also may be associated with nausea, vomiting, and photophobia. Although Vein  reported that 71% of 17 astronauts (16 male, 1 female) had at least one episode of moderate-to-severe headache during spaceflight, there seems to be a clear difference between the frequency and severity of headache in IIH and the headache in astronauts with SANS. In fact, none of the 10 astronauts with documented optic disc swelling in SANS has reported chronic, severe in-flight headaches in postflight questionnaires. Second, although unilateral or asymmetric optic disc swelling occurs in IIH, it is unusual. In contrast, it is common in SANS. If increased ICP were solely responsible for the changes in astronauts, high-pressure cerebral CSF would be expected to be propagated down the ONS in an equal and bilateral fashion. Third, the degree of disc swelling, ONS expansion, GF, and CF documented in astronauts seems out of proportion to the relatively unimpressive levels of ICP measured on LPOP postmission. These observations suggest that elevated ICP alone is not likely to be the cause of disc swelling and other ocular findings in astronauts during and after LDSF. The differences between IIH and SANS are listed in [Table 1].
|Table 1: Differences between terrestrial idiopathic intracranial hypertension (IIH) and space flight associated neuro-ocular syndrome (SANS) (Reproduced with permission from "Eye 2018;32:1164-1167.")|
Click here to view
The second possible explanation of the optic disc swelling, ONS expansion, and other findings in SANS is that they result from localized events occurring at the level of the intraorbital ON with or without elevated ICP.,,,,,, It is generally assumed that there is a homogeneity of CSF component concentrations and pressure throughout the CSF of the brain and orbit. However, the unique “cul-de-sac”-like anatomic connection between the intracranial SAS and the SAS surrounding the ON may create a fragile flow equilibrium that could be impacted by the MG fluid shifts documented during LDSF.,,,,,, Killer et al., have emphasized that it is difficult to explain the hydrodynamics of how cranial CSF enters the orbital SAS and then reverses its direction of flow against an intracranial volume gradient to exit the orbital ONS.,, Under normal 1-G physiological conditions, CSF flow between the cerebral and orbital SAS is balanced and results in similar CSF pressures in the brain and orbit. However, a poor CSF exchange between the intracranial and orbital CSF has been proposed as a possible mechanism to explain the presence of persistent papilledema and loss of vision in IIH patients despite functioning CSF shunts. Oreskovic proposed that CSF exchange between each portion of the CSF system and the surrounding tissue may depend on the pathophysiological conditions predominating within those compartments. CSF is produced and absorbed throughout the entire CSF system due to filtration and reabsorption of water volume through the capillary walls into the surrounding brain tissue. It is hypothesized that chronic cephalad MG-induced fluid shifts cause changes in intraorbital CSF flow dynamics that lead to a gradual impediment of CSF outflow from the orbital ONS. This would result in a gradual, partial, or complete sequestration of CSF within the ONS causing an ON compartment syndrome with or without elevated ICP.,,,,,, It has been hypothesized that variable ONS elasticity may impact the magnitude of pressure produced within the ONS and influence the degree of GF., Finally, glymphatic flow changes and the unique individual anatomy within the tightly confined, densely septated ONS may create varying degrees of ONS expansion and disc swelling, accounting for the expansion and asymmetric optic disc swelling observed in astronauts during and after LDSF.,
Postmission follow-up LPOPs in astronauts with disc swelling also support the ONS sequestration theory. For example, asymmetric disc swelling was documented in one astronaut, with a normal LPOP 1 week after return from LDSF. This same astronaut also demonstrated the loss of previously visible spontaneous venous pulsations during spaceflight in the eye with disc swelling that persisted for 21 months following his return to Earth. In another report, we documented postmission LPOPs of 22 and 16 cm H2O at 1 week and 1 year, respectively, despite the presence of mild, clinically apparent right disc swelling 90 days into an ISS mission and a normal appearing left disc. The disc swelling continued for at least 180 days following the mission in conjunction with the elevated peripapillary TRT values at 630 days postmission. OCT of the ON head at 630 days postmission documented optic disc morphological changes from baseline. Also, imaging modalities and biometry performed from 90 days into spaceflight through 630 days postflight documented GF (right > left). These chronic asymmetric optic disc and globe changes in conjunction with normal postmission LPOPs suggest that increased ICP alone was not the cause of these findings.
| » Mechanism of Visual Changes during Ldsf|| |
A postflight survey of approximately 300 astronauts documented a reduction in near vision in nearly 25% of short-duration space shuttle astronauts and 53% of astronauts on LDSF ISS missions. These mission-impacting vision changes during spaceflight were the initial tip-off that alerted NASA researchers to look for possible flight-related anatomic and physiologic origins for these changes. A brief examination of the specific mechanism thought to produce these persistent visual anomalies offers insight into how SANS changes may alter the ocular anatomy and directly result in visual changes in some astronauts. As discussed previously, increased pressure within the orbital ONS is thought to result from increased ICP, orbital compartmentalization, or both. Regardless of the specific etiology, this increase in the ONS volume exerts an anterior, disc-centered force on the posterior globe, leading to flattening of this anatomic region and forward movement of the retina.,,,,,, This axial shortening of the eye has been well documented by ultrasound, MRI, and axial length biometry both during and after LDSF.,,,,,, Decreased axial length shortens the distance between the cornea and retina and causes the astronaut to have a far-sighted (hyperopic) shift in vision. These visual changes may be particularly prominent in older presbyopic astronauts who have lost the ability to change their lens shape in order to increase their lens power for near visual tasks. This leads to the sometimes-critical need for plus power “space anticipation glasses” for near vision correction in astronauts over the age of 40.
| » Choroidal Expansion|| |
Choroidal expansion is another common anatomic finding in SANS that may lead to intraocular pressure (IOP) changes as well as persistent structural anomalies within the eye as manifested by CF. The choroid is the spongy, highly vascular space located between the retina and sclera. Sudden choroidal expansion is thought to be responsible for the abrupt increase in IOP documented in HD, parabolic flight, and Space Shuttle studies. An OCT study confirmed the presence of an increased choroidal thickness during HD testing, and choroidal expansion has also been documented during LDSF. Because the choroid is drained by the vortex vein system and lacks autoregulation,,, the elevated venous pressure brought about by cephalad MG fluid shifts may inhibit venous drainage and lead to sudden choroidal expansion and a concomitant spike in IOP., Choroidal expansion during spaceflight may also slightly shorten the distance between the cornea and retina, adding to the previously described hyperopic shift. Specifically, a 0.33-mm anterior displacement of the macula would lead to a 1-diopter hyperopic shift. Prolonged choroidal expansion during LDSF is also thought to be responsible for persistent structural changes within the choroid as manifested by CF.,,, Indeed, CF as documented by retinal photos and OCT have been documented for years following LDSF., Given the anatomic proximity of the choroid to the ON in the posterior globe, it is also possible that chronic choroidal expansion may exert a circumferential pressure on the ON, and thus impact optic disc swelling. It is interesting to note that following an initial rise in IOP during space flight, the IOP gradually returns to the normal range. As the eye is a closed system, this suggests that another volume compartment, likely the anterior chamber, may undergo a compensatory decrease in volume.,
| » Cotton Wool Spots|| |
CWS have been documented in astronauts following LDSF. These localized, microvascular infarcts in the peripapillary RNFL appear clinically as isolated white, feathery-edged lesions indicating areas of retinal ischemia. They are composed of accumulations of cytoplasmic debris extruded from ruptured neurons, resulting from focal obstruction of orthograde and retrograde axoplasmic transport. This may result in permanent retinal defects as documented by both microperimetry and OCT., CWS are hypothesized to develop secondary obstruction of the precapillary retinal arteriole with resultant ischemia., They occur in diabetic, human immunodeficiency virus [HIV], Purtscher's, high altitude, hypertensive, radiation-induced, and other retinopathies but are not commonly associated with increased ICP. In astronauts, they could occur from the toxic effects of chemicals that may accumulate within the ONS during LDSF., Local changes in CSF flow during LDSF may limit the normal cleansing process, leading to accumulation of biochemically altered CSF causing focal arterial closure., In support of this notion, concurrent sampling of CSF from the LPs and the ONS during ONS fenestration in some patients with IIH have documented increased concentrations of prostaglandin D synthase in the SAS surrounding the orbital ON, compared with levels in the lumbar SAS. This substance is a brain-derived protein toxic to astrocytes, which, in increased concentrations, increases the production of prostaglandins, causing vasoconstriction and micro-infarcts in the RNFL, as manifested by CWS. The delayed onset of CWS in some astronauts following a space mission could be due to radiation exposure. The occurrence of CWS is a well-known side effect of radiation therapy and may occur months to years following radiation treatment. Comparatively, high-dose terrestrial radiation therapy usually produces multiple large CWS as well as extensive retinal hemorrhages. We hypothesize that the CWS observed in astronauts may reflect the comparatively low but prolonged dose of radiation associated with LDSF.
| » Summary|| |
In summary, researchers have documented a wide spectrum of unexpected and unique neuro-ophthalmic changes in astronauts during and after LDSF. These findings, which include optic disc swelling, GF, CF, and hyperopic shifts in refraction, are currently described by the term “Spaceflight Associated Neuro-ocular Syndrome”. Cephalad fluid shifts during MG exposure unquestionably set the stage for many of these changes. However, the specific mechanisms causing SANS have not been conclusively confirmed, and we believe that the pathological process may indeed be multifactorial and perhaps somewhat variable from astronaut to astronaut. The increased ICP hypothesis that was originally proposed as the primary mechanism may play a role but elevated orbital ONS pressure with or without increased ICP is also a likely component of these unique spaceflight-induced neuro-anatomic changes. As greater numbers of astronauts prepare for longer-duration missions to the ISS, the Moon, or Mars, it is imperative that we obtain a more complete understanding of mechanisms causing SANS so that we can develop appropriate countermeasures to mitigate these mission-impacting changes.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| » References|| |
Mader TH, Gibson CR, Pass AF, Kramer LA, Lee AG, Fogerty J. Optic disc edema, globe flattening, choroidal folds, and hyperopic shifts observed in astronauts after long-duration space flight. Ophthalmol 2011;118:2058-69.
Lee AG, Tarver WJ, Mader TH, Gibson CR, Hart SF, Otto CA. Neuro-ophthalmology of space flight. J Neuroophthalmol 2016;36:85-91.
Lee AG, Mader TH, Gibson CR, Tarver W. Space flight-associated neuro-ocular syndrome. JAMA Ophthalmol 2017;135:992-4.
Lee AG, Mader TH, Gibson CR, Brunstetter TJ, Tarver WJ. Space flight-associated neuro-ocular syndrome (SANS). Eye (Lond) 2018;32:1164-7.
Lee AG, Mader TH, Gibson CR. Why space flight-associated neuro-ocular syndrome may differ from idiopathic intracranial hypertension. JAMA Ophthalmol 2018;136:452.
Mader TH, Gibson CR, Pass AF, Lee AG, Killer HE, Hansen HC, et al
. Optic disc edema in an astronaut after repeat long-duration space flight. J Neuro Ophthal 2013;33:249-55.
Mader TH, Gibson CR, Otto CA, Sargsyan AE, Miller NR, Subramanian PS, et al
. Persistent asymmetric optic disc swelling after long-duration space flight: Implications for pathogenesis. J Neuroophthal 2017;37:133-9.
Patel N, Pass A, Mason S, Gibson CR, Otto C. Optical coherence tomography analysis of the optic nerve head and surrounding structures in long-duration international space station astronauts. JAMA Ophthalmol 2018;136:193-200.
Iwasaki K, Levine BD, Zhang R, Zuckerman JH, Pawelczyk JA, Diedrich A, et al
. Human cerebral autoregulation before, during and after spaceflight. J Physiol 2007;579:799-810.
Frey MA, Mader TH, Bagian JP, Charles JB, Meehan RT. Cerebral blood velocity and other cardiovascular responses to 2 days of head-down tilt. J Appl Physiol 1993;74:319-25.
Delaey C, Van de Voorde. Regulatory mechanisms in the retina and choroid circulation. Ophthalmic Res 2000;32:249-56.
Thornton WE, Hoffler GW, Rummel JA. Anthropometric changes and fluid shifts. In: Johnston R, Dietlein L, editors. Biomedical Results of Skylab. Washington, DC: Scientific and Technical Information Office, NASA; 1977. p. 330-8.
Arbeille P, Fomina G, Roumy J, Alferova I, Tobal N, Herault S. Adaptation of the left heart, cerebral and femoral arteries, and jugular and femoral veins during short- and long-term head-down tilt and space flights. Eur J Appl Physiol 2001;86:157-68.
Harris BA Jr, Billica RD, Bishop SL, Blackwell T, Layne CS, Harm DL, et al
. Physical examination during space flight. Mayo Clin Proc 1997;72:301-8.
Herault S, Fomina G, Alferova I, Kotovskaya A, Poliakov V, Arbeille P. Cardiac, arterial and venous adaptation to weightlessness during 6-month MIR spaceflights with and without thigh cuffs (bracelets). Eur J Appl Physiol 2000;81:384-90.
Davson H, Domer FR, Hollingsworth JR. The mechanism of drainage of the cerebrospinal fluid. Brain 1973;96:329-36.
Andersson N, Malm J, Eklund A. Dependency of cerebrospinal fluid outflow resistance on intracranial pressure. J Neurosurg 2008;109:918-22.
Alperin N, Lee SH, Mazda M, Hushek SG, Roitberg B, Goddwin J, et al
. Evidence for the importance of extracranial venous flow in patients with idiopathic intracranial hypertension (IIH). Acta Neurochir Suppl 2005;95:129-32.
Lavinsky J, Lavinsky D, Lavinsky F, Frutuoso A. Acquired choroidal folds: A sign of idiopathic intracranial hypertension. Graefes Arch Clin Exp Ophthalmol 2007;245:883-8.
Friedman D. Idiopathic intracranial hypertension. Curr Pain Headache Rep 2007;11:62-8.
Griebel SR, Kosmorsky GS. Choroidal folds associated with increased intracranial pressure. Am J Ophthalmol 2000;129:513-6.
Jacobson DM. Intracranial hypertension and the syndrome of acquired hyperopia with choroidal folds. J Neuroophthalmol 1995;15:178-85.
Kramer LA, Sargsyan AE, Hasan KM, Polk JD, Hamilton DR. Orbital and intracranial effects of microgravity: Findings at 3-TMR imaging. Radiology 2012;263:819-27.
Zwart SR, Gibson CR, Mader TH, Ericson K, Ploutz-Snyder R, Heer M, et al
. Vision changes after spaceflight are related to alterations in folate-and vitamin B-12-dependent one-carbon metabolism. J Nutr 2012;142:427-31.
Law J, Van Baalen M, Foy M, Mason SS, Mendez C, Wear ML, et al
. Relationship between carbon dioxide levels and reported headaches on the international space station. J Occup Environ Med 2014;56:477-83.
Laurie SS, Macias BR, Dunn JT, Young M, Stern C, Lee SMC, et al
. Optic disc edema after 30 days of strict head-down tilt bed rest. Ophthalmol 2019;126:467-8.
Friedman DI. Idiopathic intracranial hypertension. Curr Pain Headache Rep 2007;11:62-8.
Bruce BB, Kedar S, Van Stavern GP, Monaghan D. Idiopathic intracranial hypertension in men. Neurology 2009;72:304-9.
Friedman DI. The pseudotumor cerebri syndrome. Neurol Clin 2014;32:363-96.
Friedman DI, Liu GT, Digre KB. Revised diagnostic criteria for the pseudotumorcerebri syndrome in adults and children. Neurology 2013;24:1159-65.
Giuseffi V, Wall M, Siegel PZ, Rojas PB. Symptoms and disease associations in idiopathic intracranial hypertension (pseudotumorcerebri): A case-control study. Neurology 1991;41:239-44.
Wall, M. Idiopathic intracranial hypertension. Neurol Clin 2010;28:593-617.
Vein AA, Koppen H, Haan J, Terwindt GM, Ferrari MD. Space headache: A new secondary headache. Cephalagia 2009;29:683-6.
Killer HE, Subramanian PS. Compartmentalized cerebral spinal fluid. Int Ophthalmol Clin 2014;54:95-102.
Killer HE. Production and circulation of cerebrospinal fluid with respect to the subarachnoid space of the optic nerve. J Glaucoma 2013;22:8-10.
Killer HE, Jaggi GP, Flammer J, Miller NR, Huber AR, Mironov A. Cerebrospinal fluid dynamics between the intracranial and the subarachnoid space of the optic nerve. Is it always bidirectional? Brain 2007;130:514-20.
Kelman SE, Sergott RC, Cioffi GA, Savino PJ, Bosley TM, Elman MJ. Modified optic nerve decompression in patients with functioning lumboperitoneal shunts and progressive visual loss. Ophthalmology 1991;98:1449-53.
Oreskovic D, Klarica M. The formation of cerebrospinal fluid: Nearly a hundred years of interpretations and misinterpretations. Brain Res Rev 2010;64:241-62.
Wostyn P, De Deyn PP. Optic nerve sheath distention as a protective mechanism against the visual impairment and intracranial pressure syndrome in astronauts. Invest Ophthalmol Vis Sci 2017;58:4601-2.
Mader TH, Gibson CR, Lee AG. Author response: Optic nerve sheath distention as a protective mechanism against the visual impairment and intracranial pressure syndrome in astronauts. Invest Ophthalmol Vis Sci 2017;135:992-4.
Mader TH, Gibson CR, Otto CA, Sargsyan AE, Miller NR, Subramanian PS, et al
. Why a one-way ticket to Mars may result in one-way directional glymphatic flow to the eye. J Neuroophthalmol 2017;37:463-4.
Wostyn P, Killer HE, De Deyn PP. Why a one-way ticket to Mars may result in a one-way directional glymphatic flow to the eye. J Neuroophthalmol 2017;37:462-3.
Mader TH, Gibson CR, Lee AG, Patel NB, Hart SF, Pettit DR. Unilateral loss of spontaneous venous pulsations in an astronaut. J Neuroophthalmol 2015;35:226-7.
Mader TH, Taylor GR, Hunter N, Caputo M, Meehan RT. Intraocular pressure, retinal vascular, and visual acuity changes during 48 hours of 10 degree head-down tilt. Aviat Space Environ Med 1990;61:810-3.
Mader TH, Gibson CR, Caputo M, Hunter N, Taylor G, Charles J, et al
. Intraocular pressure and retinal vascular changes during transient exposure to microgravity. Am J Ophthalmol 1993;115:347-50.
Draeger J, Wirt H. Schwartz R. TOMEX monitoring of intraocular pressure under microG conditions. Naturessenschaften 1986;73:450-2.
Shinojima A, Iwasaki K, Aoki K, Ogawa Y, Yanagida R, Yuzawa M. Subfoveal choroidal thickness and foveal retinal thickness during head-down tilt. Aviat Space Environ Med 2012;83:388-93.
Mader TH, Gibson CR, Lee AG. Choroidal folds in astronauts. Invest Ophthalmol Vis Sci 2016;57:592.
Mader TH, Gibson CR. Early evidence of vision impairment after long-duration spaceflight. In: Macias BR, Liu JHK, Otto C, Hargens AR (editors) Intracranial Pressure and its Effect on Vision in Space and on Earth. Vol. 5. Singapore: World Scientific; 2017. p. 22.
Gomez ML, Mojana F, Bartsch D, Freeman WR. Imaging of long-term retinal damage after resolved cotton wool spots. Ophthalmology 2009;116:2407-14.
Kim JS, Maheshwary AS, Bartsch DU, Cheng L, Gomez ML, Hartmann K, et al
. The microperimetry of resolved cotton-wool spots in eyes of patients with hypertension and diabetes mellitus. Arch Ophthalmol 2011;129:879-84.
Schmidt D. The mystery of cotton-wool spots - a review of recent and historical descriptions. Eur J Med Res 2008;13:231-66.
Matthews DR, Stratton IM, Aldington SJ, Holman RR, Kohner EM; UK Prospective Diabetes Study (UKPDS) Group. Risks of progression of retinopathy and vision loss related to tight blood pressure control in type 2 diabetes mellitus: UKPDS 69. Arch Ophthalmol 2004;122:1631-40.
Berrey MM, Shea T, Corey L. Cotton-wool spots in primary HIV infection. J Acquir Immune Defic Syndr Hum Retrovirol 1998;19:197-8.
Agrawal A, McKibbin M. Purtscher's retinopathy: Epidemiology, clinical features and outcome. Br J Ophthalmol 2007;91:1456-9.
Morris DS, Somner J, Donald MJ, McCormick IJ, Bourne RR, Huang SS, et al
. The eye at altitude. Adv Exp Med Biol 2006;588:249-70.
Wong TY, McIntosh R. Hypertensive retinopathy signs as risk indicators of cardiovascular morbidity and mortality. Br Med Bull 2005;7374:57-70.
Seregard S, Pelayes DE, Singh AD. Radiation therapy: Posterior segment complications. Dev Ophthalmol 2013;52:113-23.