Persistent Globe Flattening in Astronauts following Long-Duration Spaceflight

ABSTRACT

Posterior globe flattening has been well-documented in astronauts both during and after long-duration space flight (LDSF) and has been observed as early as 10 days into a mission on the International Space Station. Globe flattening (GF) is thought to be caused by the disc centred anterior forces created by elevated volume and/or pressure within the optic nerve sheath (ONS). This might be the result of increased intracranial pressure, increased intraorbital ONS pressure from compartmentalisation or a combination of these mechanisms. We report posterior GF in three astronauts that has persisted for 7 years or more following their return from LDSFs suggesting that permanent scleral remodelling may have occurred.

Introduction

In a 2011 report, the United States National Aeronautics and Space Administration (NASA) Space Medicine Division documented neuro-ophthalmic findings in seven astronauts after long duration space flight (LDSF) on the International Space Station (ISS).¹ These findings included optic disc swelling, choroidal folds, posterior globe flattening (GF), cotton wool spots, optic nerve sheath (ONS) distention and hyperopic shifts in refraction. The term, “Space flight Associated Neuro-ocular Syndrome” (SANS) is currently used to describe these findings.² Development of GF has been documented in 12 out of 52 (23%) astronauts following LDSF.³ We previously reported an astronaut with mild bilateral GF, documented by orbital ultrasound, occurring only 10 days into a space flight.⁴

The purpose of this correspondence is to report the long-term follow-up and persistence of GF and hyperopic refractive shifts for 7 years or more following LDSF in three of the original seven astronauts described in the initial cohort in 2011. Compared with previous reports of GF in other settings, this phenomenon suggests permanent scleral remodelling occurs in astronauts during LDSF and that pre-existing ONS anomalies in astronaut eyes may worsen during LDSF. This report describes the long-term persistence of GF in astronauts with prior SANS, a disorder unique to space flight with no terrestrial disease equivalent.

Materials and methods

During longitudinal follow-up of the seven astronauts identified in the 2011 report, we identified three with persistent GF.¹ Before and after LDSF, all seven of these individuals had undergone dilated eye examinations, cycloplegic and/or manifest refractions, fundus photography, orbital magnetic resonance imaging (MRI) and optical coherence tomography (OCT) of the optic nerve head (ONH) and retina. Persistent GF was confirmed by two independent methods. First, we examined MRIs from each of the astronauts, looking for changes in posterior globe contour consistent with post-flight GF. It should be noted that MRI interpretation is largely subjective, and acquisition of early MRI was not standardised. Second, we identified those astronauts with a persistent hyperopic shift in refraction of at least +0.75 D from pre-flight to post-flight and a minimum of 7 years thereafter, as this directly correlates with the degree of ocular shortening. In addition, astronaut 3 had axial length measurements performed preflight, at 56 days and 5 years post-flight, for further confirmation on his axial shortening. Astronauts 1, 2, 3 and 5 had post mission lumbar puncture opening pressures (LPOP) performed in the lateral decubitus position without sedation.

Results

After approximately 6 months of continuous orbital flight, three astronauts (all male; age 50 ± 4 years) were documented to have findings consistent with persistent GF as summarised in Table 1. Figure 1 demonstrates preflight (L-3 years), 30 days post-flight and 7 years post-flight MRI findings in astronaut 1. Figure 2 documents the pre-flight and post-flight MRI findings in astronaut 3 as well as his pre-flight, 56 days post-flight and 5 years post-flight axial length measurements. Astronaut 4 never had any evidence of a hyperopic shift and astronaut 6 experienced only a mild hyperopic shift in one eye (OD) post-flight. Although astronaut 7 had a post-flight hyperopic shift in refraction and GF on MRI, he was not available for follow up measurements. ONS distention was documented by MRI in all astronauts post-flight with the exception of astronaut 4 who did not have MRIs performed.

Table 1.

Summary of Refractions, OCT Scans, and CSF Pressures in Seven Astronauts Following Long-Duration Space Flight. Astronauts 1, 2, and 3 had Persistent Globe Flattening

ISS Astronaut	Refractive Change*				CSF Pressure	Funduscopic Examination
	Pre-flight (1-4 months)	Initial Post-flight	Years Post-flight	OCT (Post-flight)	Post-flight (cmCSF)	Post-flight
1	OD: -0.75 -0.50 x 100	OD: +0.75 -0.50 x 105 at R+10	OD: +1.00 -0.50 x 100 at R+ 3 yrs	cMild RNFL thickening (OD > OS)	28.5 at R + 57 days	Disc oedema OD
			OD: +1.25 -0.75 x 100 at R + 7 yrs		34 at R + 7 yrs	Choroidal Folds OD
	OS: plano -0.50 x 90	OS: +0.75 -0.75 x 090 at R+10 days	OS: +0.50 -0.75 x 092 at R + 3 yrs	Persistent choroidal folds OD
			OS: +0.75 -0.75 x 090 at R + 7 yrs
2	OD: +0.75 sph	OD: +2.00 sph at R+21 days	OD: +1.75 sph at R + 5 yrs	RNFL thickening OU	22 at R + 66 days	Bilateral disc oedema OD > OS
			OD: +2.00 sph at R + 10 yrs	Persistent choroidal folds OU	26 at R + 17 mo	Choroidal folds OD > OS
			OD: +2.25 -0.25 x 090 at R + 12 yrs		22 at R + 19 mo	Cotton wool spot OS
	OS: +0.75 -0.25 x 165	OS: +2.00 -0.50 x 140 at R+21 days	OS: +1.75 sph at R + 5 yrs		23 at R + 5 yrs
			OS: +2.00 sph at R + 10 yrs
			OS: +2.25 -0.50 x 090 at R + 12 yrs
3	OD: +1.25 sph	OD: +2.75 sph at R+3 days	OD: +2.50 -0.50 x 110 at R + 5 yrs	RNFL thickening OU	28 at R + 12 days	Disc oedema OU
			OD: +2.75 -0.50 x 110 at R + 7 yrs	Trace RNFL thickening OU at R + 2 and 5 yrs	19 at R + 56 days (on Acetazolamide)	Choroidal folds OD > OS
	OS: +1.25 sph	OS: +2.50 sph at R+3 days	OS: +2.25 sph at R + 5 yrs	Persistent choroidal folds OU
			OS: +2.00 sph at R +7 yrs
4	OD: -1.50 sph	OD: -1.25 -0.25 x 005 at R+19 days	OD: -1.25-0.25 x 015 at R+3 yrs	Choroidal folds OD (R+>5 yrs)	Not measured	Choroidal folds OD
			OD: -0.75-0.25 x 015 at R+6 yrs			Cotton wool spot OD
	OS: -2.25 -0.25 x 135	OS: -2.50 -0.25 x160 at R+19 days	OS: -2.50-0.25 x 135 at R+3 yrs
			OS: -2.00-0.25 x 135 at R+6yrs
5	OD: -0.50 sph	OD: Plano at R+3 days	OD: -0.25-0.25 x 124 at R+2 yrs	Severe RNFL thickening OD > OS	21 at R + 19 days	Bilateral disc oedema OD > OS
			OD: plano-0.50 x 140 at R+4 yrs			Small haemorrhage OD
	OS: -0.25 sph	OS: Plano at R+3 days	OS: -0.25-0.25 x 060 at R+2 yrs
			OS: Plano-0.50 x 062 at R+4yrs
6	OD: -5.75 -1.25 x 010	OD: -5.00 -1.50 x 015 at R+18 days	OD: -4.50-1.25 x 010 at R+3 yrs	Mild RNFL thickening OD	Not measured	Normal
			OD: -4.75-1.50 x 005 at R+5 yrs	Subclinical disc oedema
	OS: -5.00 -1.50 x 180	OS: -4.75 -1.75 x 170 at R+18 days	OS: -4.25-1.75 x 175 at R+3 yrs
			OS: -4.25-2.25 x 175 at R+5 yrs
7	OD: +0.25 sph	OD: +2.00 -0.50 x 028 at R+21 days	no follow up data	Mild RNFL thickening OD>OS	Not measured	Disc oedema OD
				Choroidal folds OD		Cotton wool spot OS
	OS: +0.25 -0.50 x 152	OS: +1.00 sph at R+21 days

* All refractions performed using a cycloplegic agent except for pre-flight and initial post-flight refractions of astronaut 2.

Post-flight OCT and fundus examinations were performed monthly until stable and annually thereafter.

ISS = International Space Station; OCT = optical coherence tomography; CSF = cerebrospinal fluid; OD = right eye; OS = left eye; yrs = years; RNFL = retinal nerve fibre layer; OU = both eyes; R + = return to Earth (e.g., R + 10 is 10 days after return to Earth); mo = months; sph = sphere.

Figure 1.

Astronaut 1 pre-flight (1a; L-3 years) axial T2 (3 T magnetic resonance imaging) showing pre-existing pre-flight optic nerve sheath (ONS) distention and globe flattening. Figure 1b at R + 30 days demonstrates further post-flight globe flattening (OD>OS), disc swelling (OD) and ONS distention (OD>OS). Figure 1c shows persistent globe flattening and ONS distention, most apparent on the right, at R + 7 years

Figure 2.

Astronaut 3 pre-flight (2a) and post-flight (2b; R + 6 days) axial T2 (3 T magnetic resonance imaging) suggesting post-flight globe flattening OU. This astronaut had a previous short-duration space shuttle mission without baseline magnetic resonance imaging. Pre-flight and post-flight IOL master axial length measurements are consistent with bilateral globe flattening (Bottom)

Case reports

Case 1

Astronaut 1’s (Case 4, 2011 report) pre-flight dilated eye examination and fundus photographs were normal. This astronaut had a pituitary adenoma resected 3 years prior to his LDSF but he had no evidence of recurrent disease on serial clinical or imaging studies. His pre-surgical orbital MRI, performed 3 years prior to any space flights, documented mild posterior GF OD and marked asymmetric ONS distention (OD 9.48 mm, OS 6.00 mm) (Figure 1a). This MRI was not available for review at the time of the 2011 publication but was reported as showing no evidence of recurrent pituitary adenoma. Following LDSF, astronaut 1 had asymmetric GF and more prominent ONS distention (OD 9.93 mm, OS 8.30 mm) (Figure 1b), with unilateral Frisén grade 1 disc swelling OD. Seven years post-flight, the ONS distention persisted and was similar to preflight (OD 9.47 mm, OS 6.49 mm) (Figure 1c). At this time his LPOP was 34 cmCSF. His more prominent post-flight GF OD>OS and hyperopic shift also persisted (Table 1). His last MRI showed no evidence of a recurrent pituitary adenoma and serial automated visual field testing (Humphrey perimeter) was normal.

Case 2

Astronaut 2 (Case 2, 2011 report), had a normal pre-flight dilated eye examination and normal fundus photographs. His pre-flight MRI was normal but not adequate for GF assessment. About 3 months into the space flight mission, he observed that he could only see the Earth clearly while looking through the lower portion of his progressive glasses, consistent with a hyperopic refractive shift.¹ Post-flight he had nearly symmetrical posterior GF, a hyperopic shift and mild ONS distention OU, as documented by orbital MRI, as well as Frisén grade 1 disc swelling OU. He had mild persistent GF and hyperopic shifts at 5, 10 and 12 years post-flight (Table 1).

Case 3

Astronaut 3 (Case 7, 2011 report) had a normal pre-flight dilated eye examination and normal fundus photographs. He had an orbital MRI (Figure 2a) demonstrating pre-ISS mission GF and ONS distention, perhaps related to a prior 2 week Space Shuttle flight. During that short-duration mission, he had noted impaired near vision associated with a persistent +0.75 D post-flight hyperopic shift. Approximately 2 months into his ISS mission he reported a progressive decrease in both near and far visual acuity OU. At about 3 to 4 months into his 6 month mission he noted that his normal “Earth” prescription progressive glasses were no longer strong enough for near vision and he switched to “Space Anticipation Glasses” (+1.25 more plus).¹ This astronaut had more prominent, nearly symmetrical, GF following LDSF (Figure 2b), mildly dilated ONSs OU and Frisén grade 1 disc swelling OU. His GF was still present 7 years following his mission, associated with a bilateral decrease in axial length (Figure 2, bottom).

Clinical optic disc swelling in all three affected astronauts resolved by 6 months post-flight, but the GF persisted. None of these astronauts complained of any symptoms associated with increased intracranial pressure (ICP) and specifically denied any transient visual obscurations, headaches, diplopia, pulsatile tinnitus or vision changes with eye movement during their space missions.

Discussion

We hypothesise that three potential, but not necessarily mutually exclusive, mechanisms might explain persistent GF in these three astronauts. First, it is possible that some degree of sustained ICP elevation during the entire 7 years or more post-flight exerted a sufficient anterior force on the posterior globes to cause and maintain GF. Several findings in our current study support this hypothesis. First, the post-flight, nearly symmetric GF, disc swelling and hyperopic shifts documented in astronauts 2 and 3 are similar to those observed in terrestrial idiopathic intracranial hypertension (IIH).⁵ Second, although we lack baseline ICP measurements, elevated post-flight LPOPs of 28.5, 22 and 28.0 cmCSF were documented in astronauts 1, 2 and 3, respectively, possibly representing downslopes of even higher ICPs on the ISS. Third, although astronaut 1 was asymptomatic, an elevated ICP pressure of 34cmCSF was found during an LP at 7 years post-flight. As noted above, his preflight orbital MRI suggested some degree of pre-existing ONS structural changes and GF or unrecognised elevated ICP that may have worsened during LDSF. It is also possible that his ICP was normal preflight but changes in cerebrospinal fluid (CSF) flow, structure or compliance during LDSF led to elevated ICP that persisted post-flight. Finally, although the optic discs appeared normal on fundus examination, astronaut 3 had trace bilateral retinal nerve fibre layer thickening by OCT at both 2 and 5 years post-flight, suggesting persistent low-grade disc swelling. Thus, a microgravity (MG)-induced elevated ICP that started during LDSF and continued for years post-flight could explain these changes.

Many reports have documented anatomical changes within the brains of astronauts and cosmonauts following LDSF, suggesting a rise in CSF pressure during spaceflight.^6–13Although the precise origin of a possible increase in ICP is unknown, the loss of hydrostatic pressure gradients during MG exposure is thought to play a leading role.¹⁴ However, other factors including defects in the vitamin B₁₂ dependent 1 carbon transfer pathways,^15,16 high cabin carbon dioxide levels,^17,18 rigorous resistive exercise and high-salt ISS diets also may play a role. Lawley suggested that complete removal of gravity may not pathologically elevate ICP but may prevent the normal terrestrial lowering of ICP when the individual is upright.¹⁹ Thus, during LDSF, the pressure in the brain may be slightly, but consistently, above that observed on Earth. It is also likely that variations in ONS distention may impact the degree of pressure elevation within the subarachnoid space (SAS) surrounding the optic nerve and influence the degree of GF.²⁰

Although an MG-induced elevated ICP that started during LDSF and continued for years post-flight could explain the findings described above, several arguments may speak against this mechanism. First, it is unlikely that the ICP would remain elevated in all three astronauts, for several years after return to 1 G where venous stasis, congestion and other MG-induced changes would presumably return to normal. Second, no astronaut complained of chronic headaches, functional impairment or other symptoms commonly associated with terrestrial increased ICP. Third, the lack of long-term, post-flight evidence of optic disc swelling by serial high-magnification slit-lamp examinations in any of the three astronauts is contrary to this mechanism. Finally, we doubt that astronaut 2’s LPOPs of 22, 26, 22 and 23 cmCSF at 2, 17, 19 months and 5 years post-flight, respectively, were sufficiently elevated to cause and maintain GF.

A second possible mechanism for GF in these three astronauts is that it was due to elevated CSF pressure within the perioptic SAS caused by a MG-induced orbital SAS compartmentalisation that persisted for 7 or more years after return to Earth with or without increased ICP.^1,4 The preflight asymmetric ONS expansion and GF in astronaut 1 suggest pre-existing unequal sheath pressures. His post-flight unilateral disc swelling and further asymmetric GF and ONS expansion suggest asymmetric CSF flow, volume and pressure changes within the ONSs that worsened during LDSF. Additionally, variable anatomy and pressure-induced growth of meningothelial cells lining the ONS might lead to asymmetric CSF flow along the ONS cul-de-sac in a one-way, ball-valve-like fashion, thus augmenting orbital SAS pressure elevation.^1,4,21 A prior report of an astronaut who returned from LDSF with an LPOP of 18cmCSF with unilateral disc swelling²² and unilateral loss of spontaneous venous pulsations for more than 2 years in the same eye²³ supports this hypothesis. Another report documented asymmetric disc swelling and GF for 6 months following LDSF with LPOPs of 22 and 16cmCSF performed 7 days and 12 months post-flight, respectively, again suggesting an asymmetric increase in local SAS pressure.⁴ However, normal optic disc and OCT NFL examinations for 7 years post-flight in astronaut 1 argue against long-term local ONS pressure elevation as the mechanism in this astronaut.

The third possible explanation for persistent GF is that elevated ONS pressures during LDSF, from whatever mechanism, created sufficient mechanical stress on the sclera to cause permanent structural change with secondary GF in the absence of persistent orbital SAS pressure elevation. Hansen et al.²⁴ described similar behaviour, known as hysteresis, in an experimental ultrasound study of the human ONS, concluding that the sheath diameter reversibility may be impaired after episodes of prolonged intracranial hypertension. The authors documented a limited capability for retraction of the ONS following decompression from higher levels of SAS pressure. The ONS diameter recovered to baseline only when SAS pressure did not exceed 35 mmHg (47.6 cmCSF). In contrast, when decompression occurred from higher pressure levels (45 mmHg (61.2 cmCSF) and above), a clear residual dilatation remained. Similarly, it is possible that elevated ONS pressures during LDSF could lead to alterations in scleral tissue properties, causing an inability of the sclera to recover from deformation after pressure normalisation. A previous in vitro study using inflation testing to measure the biomechanical response of the human posterior sclera reported that the scleral tissues exhibit a nonlinear, rate-dependent, and time-dependent inflation response, showing creep at constant pressure and hysteresis upon unloading.²⁵ The lack of clinically detectable optic disc swelling on biomicroscopic fundus examination in all three astronauts for 7 years or more after the mission suggests no persistent pathologic CSF pressure elevations within the ONS. In addition, acetazolamide use for 6 months in astronaut 3 did not lessen the degree of GF. It is also possible that metabolites within the SAS that accumulated during LDSF biomechanically altered the sclera, causing permanent anatomic change.^1,4 Although all three astronauts with persistent GF also had optic disc oedema and ONS distention, astronaut 5 had these same findings with no evidence of GF. Again, this suggests that variations in scleral rigidity, ONS composition or other anatomic features may be involved in the determination of the degree of persistent GF. We could not identify any consistent, unique anatomical features present in those astronauts without persistent GF.

In summary, we report persistent GF after LDSF and hypothesise that permanent structural change may result from elevated CSF pressures within the ONSs in SANS that direct a disc-centred anterior force on the posterior globe during and possibly after LDSF.^1,4 This process may occur in conjunction with permanent scleral remodelling. Increased ONS pressure could result from elevated ICP, ONS compartmentalisation or a combination of these mechanisms. Our findings suggest that pre-existing increased ICP, asymmetric ONS structure or GF may pre-dispose some astronauts to prominent and persistent anatomic change during and after LDSF. Future astronauts should anticipate optically correctable, long-term visual changes of unpredictable magnitude, during and after LDSF.