While astronauts are returning from long duration spaceflight with multiple ocular signs that mimic those seen in terrestrial patients with elevated intracranial pressure (ICP), evidence has yet to prove a clinically significant increase in ICP during space.1 Preliminary research evidence may even suggest that ICP decreases in microgravity. Idiopathic intracranial hypertension (IIH) has long been considered the ideal terrestrial analogue to Spaceflight Associated Neuro-ocular Syndrome (SANS).1 However, there are several critical features of SANS that do not complement any reported case of IIH on Earth. These findings mandate a closer look at the accuracy of IIH as a terrestrial SANS analog

Batliwala, Shehzad

Brunstetter, Tyson J.

Clemett, Simon J.

Mason, Sara S.

Nelman-Gonzalez, Mayra A.

Sams, Clarence F.

Tarver, William J.

NASA Technical Reports Server

RE-EVALUATION OF IIH AS THE IDEAL TERRESTRIAL ANALOG FOR SANS: 
IS THERE A BETTER MODEL TO CONSIDER?
Shehzad Batliwala, DO1; Tyson J. Brunstetter, OD, PhD2; Bill J. Tarver, MD2,; Simon J. Clemett2; Mayra A. Nelman2;
Sara S. Mason3; Clarence Sams, PhD2
1Dean McGee Eye Institute, Oklahoma City, OK; 2Nasa Johnson Space Center, Houston, TX; 3KBRWyle, Houston, TX
ONH: optic nerve head
CF: choroidal folds
RF: retinal folds
TLPD: translaminar pressure difference
GF: globe flattening
RS: refractive shift
UPT: unified pressure theory
RPE/BM: retinal pigment epithelium / bruch’s membrane
POAG: primary open angle glaucoma 
References
While astronauts are returning from long duration spaceflight 
with multiple ocular signs that mimic those seen in terrestrial 
patients with elevated intracranial pressure (ICP), evidence has 
yet to prove a clinically significant increase in ICP during 
space.1 Preliminary research evidence may even suggest that 
ICP decreases in microgravity. Idiopathic intracranial 
hypertension (IIH) has long been considered the ideal 
terrestrial analogue to Spaceflight Associated Neuro-ocular 
Syndrome (SANS).1 However, there are several critical 
features of SANS that do not complement any reported case of 
IIH on Earth. These findings mandate a closer look at the 
accuracy of IIH as a terrestrial SANS analog.
Introduction
A retrospective literature review was conducted to discover any 
reported ocular IIH findings that bear resemblance to the 
unique findings observed in SANS. Data were analyzed to 
compare and contrast SANS with IIH cases. Some parameters 
addressed included globe flattening, choroidal and retinal folds, 
choroidal vascular engorgement, and disc edema findings. 
Discussion
Condition IIH SANS
Female/Male Sex Ratio 9/1 0/10
BMI Obese (>90%) Athletic to Normal
Symptoms (HA, TVL, etc.) HA (94%), TVO (68%), VL (30%)
HA (0%), TVO (0%), VL 
(0%)
Asymmetric Papilledema < 4% side predominance Right always worse than left
Anatomic Changes (GF, CF, 
ONSD) Yes Yes, but different
LPOP >25 cm H2O (normal to ~50cm) 16cm – 28.5cm H2O
Results
A
Figure 2:
A) IIH - note that the RPE/BM angle at the 
neural canal border is positive in IIH 
(inward deflection toward vitreous).3
B) SANS – the RPE/BM angle at the neural 
canal border is negative (outward 
deflection away from vitreous).1
Is ICP the culprit?
Table 1: A comparison of demographics, symptoms, and objective ocular and diagnostic 
findings in IIH and SANS. Bidot et al: J Neuro-Ophthalmol 2015; 35: 31-36
HA: headache; TVO: transient visual obscuration; VL: visual loss; GF: globe flattening; CF: 
choroidal folds; ONSD: optic nerve sheath diameter; LPOP: lumbar puncture opening 
pressure
SANS can be associated with several ocular findings with 
varying degrees of severity. These include cotton-wool spots, 
retinal hemorrhages, choroidal and retinal folds, optic disc and 
retinal edema, optic nerve sheath distention, posterior globe 
flattening, and hyperopic shifts. Since optic disc edema is the 
SANS sign most threatening to crewmember health and 
mission effectiveness, it is the basis for diagnosing SANS. 
Currently, the SANS case definition is: optic disc edema of 
Frisen Grade ≥1, based on fundoscopic imagery.
Diagnosis of SANS1
Methods
A B C
E
Figure 1: A SANS case1 with globe flattening is illustrated: A) Pre-flight 
MRI; B) 6 days post-flight; and C) 1 year post-flight. While two IIH cases2
are illustrated in: D) minimal globe flattening and extensive optic nerve 
protrusion; and E) flat globe with minimal nerve protrusion.
D
Comparison of Globe Flattening in SANS vs IIH
SANS IIH
Choroidal Folds 11 (23%) 14 (6%)
Retinal Folds 2 (4%) 87* (39%)
Subjects Tested 47 225
Table 2: Relative prevalence of choroidal and retinal folds in SANS vs IIH 
populations. SANS data obtained from 47 USOS astronauts tested during Exp 1-
48.1 IIH data obtained from 125 eyes studied in the IIH Treatment Trial. 3 * In 
the latter, the majority (79%) of eyes with RF did not have choroid 
involvement. 3
Retinal Pigment Epithelium / Basement Membrane Angles
SANS IIH POAG Ocular HTN HypotonyMaculopathy
ONH Edema Edema Cupping Normal Edema
ICP ??? ↑ Dec ↑ Normal
IOP Normal, after initial increase Normal ↑ ↑ Dec
GF Flat Some No No Flat
CF Yes Some No No Yes
Ref. Shift Hyperopic Rare No No Hyperopic
Time course Long Various Long Long Short
Table 3: Overlap Between SANS and Other Terrestrial Analogues4
Although similarities in ocular signs exist between SANS and IIH, there are noticeable 
differences between the two syndromes that behoove the need to look beyond a 
pathologically elevated intracranial pressure. Table 3 lists several characteristics of ocular 
conditions that overlap with SANS, all of which are consolidated into what is known as the 
unified pressure theory (UPT).4 The dynamic changes occurring at the optic nerve head 
(ONH) due to the translaminar pressure difference (TLPD) is at the crux of this theory. For 
example, the changes occurring at the ONH in POAG may be opposite of SANS. Ocular HTN 
is a model that speculates a higher CSF pressure may be protective and counters the 
impact of an elevated IOP to avoid optic disc cupping.4 Hypotony maculopathy is a 
condition with very low IOP that leads to many of the signs seen in SANS such as GF, CF, 
and hyperopic shift. Treatment is done via raising IOP, which reverses disc edema, GF, CF, 
and the hyperopic refractive error.4 A very similar treatment could potentially be the 
strategy for a SANS countermeasure. A potential limitation of the TLPD model is that its 
supportive literature uses retrospective data where postural differences between ICP and 
IOP measurements were not taken into account.10 Data from the Fluid Shifts Study where 
hydrostatic forces are eliminated when obtaining these measurements will give a more 
accurate representation of the TLPD in 0g. A vascular model is equally important in 
characterizing SANS. Choroid expansion in particular may suggest a vascular origin of the 
choroid folds, since the spongy, malleable choroid tissue lacks autoregulation and thus is 
more susceptible to mechanical folding due to 0g-induced obstruction of venous outflow, 
which could  lead to venous congestion in the eye.1,6 Choroid expansion is not a 
documented finding in IIH, although there is a paucity of information in the literature 
regarding measurement of this parameter in IIH patients.1,9 Furthermore, in some cases of 
IIH, choroidal folds precede the development of optic disc edema and in others they have 
been the only presenting sign of raised ICP.1 On the contrary, 60% of astronauts that have 
disc edema also have choroidal folds, and there are no cases that have choroidal folds 
without the presence of disc edema.1,4,5 If choroid expansion can help explain the presence 
of choroidal folds in SANS, and if disc edema and choroidal folds are relatively tightly 
correlated, then a vascular etiology may play a role in the development of disc edema. 
Furthermore, recent studies have found that impairment in functional cerebrovascular 
hemodynamics and a resulting ocular hypoperfusion may be the underlying cause of 
demyelinating diseases like optic neuritis.8 Specifically, the study reported that choroidal
hypoperfusion is positively correlated with the severity of swelling of rNFL. If 0g-induced 
choroidal engorgement leads to any level of venous stasis and congestion, this can 
contribute to choroidal and papillary vascular hypoperfusion and produce disc swelling 
similar to what is seen in acute optic neuritis. OCT angiography on orbit might be useful as 
a future modality to further define these vascular changes. The UPT along with a focus on 
ocular hemodynamics and perfusion can help researchers gain a broader insight into the 
complex interplay of multiple variables that comprises SANS.
1. Stenger et al. Human Research Program Human Health Countermeasures Element, Evidence Report, Risk of Spaceflight Associated Neuro-ocular Syndrome (SANS). 2017
2. Alperin N, Bagci AM, Lam BL, Sklar E. Automated quantitation of the posterior scleral flattening and optic nerve protrusion by MRI in idiopathic intracranial hypertension. AJNR Am J Neuroradiol. 2013;34(12):2354-9.
3. Sibony PA, Kupersmith MJ, Feldon SE, Wang JK, Garvin M. Retinal and Choroidal Folds in Papilledema. Invest Ophthalmol Vis Sci. 2015;56(10):5670-80.
4. Macias et al. Intracranial Pressure and its Effect on Vision in Space and on Earth: Vision Impairment in Space
5. Lee AG, Mader TH, Gibson CR, Tarver W. Space Flight-Associated Neuro-ocular Syndrome. JAMA Ophthalmol. 2017;135(9):992-994.
6. Kupersmith MJ, Sibony P, Mandel G, Durbin M, Kardon RH. Optical coherence tomography of the swollen optic nerve head: deformation of the peripapillary retinal pigment epithelium layer in papilledema. Invest Ophthalmol Vis 
Sci. 2011;52(9):6558-64.
7. Sibony P, Kupersmith MJ, Honkanen R, Rohlf FJ, Torab-parhiz A. Effects of lowering cerebrospinal fluid pressure on the shape of the peripapillary retina in intracranial hypertension. Invest Ophthalmol Vis Sci. 2014;55(12):8223-31.
8. Chen TC, Yeh CY, Lin CW, et al. Vascular hypoperfusion in acute optic neuritis is a potentially new neurovascular model for demyelinating diseases. PLoS ONE. 2017;12(9):e0184927.
9. Van den bergh R, Dralands G, Crolla D, Van den bergh P. Pseudotumor cerebri due to intracranial arteriovenous malformation. Clin Neurol Neurosurg. 1980;82(2):119-25.
10. Lindén C, Qvarlander S, Jóhannesson G, et al. Normal-Tension Glaucoma Has Normal Intracranial Pressure: A Prospective Study of Intracranial Pressure and Intraocular Pressure in Different Body Positions. Ophthalmology. 2017;
Abbreviations Defined
Table 1 illustrates that astronauts with SANS do not have the typical risk factors for IIH, 
nor do they report the classic symptoms of IIH.1 Figure 1 illustrates that while there are 
variations in the degree of nerve protrusion and globe flattening seen in IIH, these 
changes are usually much more pronounced in SANS cases.3-5 Table 2 shows that the 
prevalence of choroidal folds is much higher in SANS, while the prevalence of retinal folds 
is higher in the IIH population.3 The IIH Treatment Trial also reported that 79% of enrolled 
eyes did not have any choroid involvement.3 Figure 2 illustrates one of the more notable 
differences between SANS and IIH in that the RPE/BM angle is oftentimes deflected 
inwards towards the vitreous in IIH and outwards away from the vitreous in SANS.4,6,7 For 
two diseases in which disc edema is thought to occur from an increased ICP, this finding is 
particularly contradictory. 
https://ntrs.nasa.gov/search.jsp?R=20190000676 2019-08-30T10:12:04+00:00Z


Re-evaluation of IIH as the Ideal Terrestrial Analog for Sans: Is There a Better Model to Consider?

Abstract

Similar works

Full text

Available Versions

NASA Technical Reports Server