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Spaceflight Associated Neuro-ocular Syndrome(SANS)
Michael B. Stenger, Ph.D.
HHC Discipline Scientist
Manager, Cardiovascular & Vision Laboratory
Biomedical Sciences and Environmental Research Division (SK3)
1
Deep Space Gateway Symposium4 Dec 2017
https://ntrs.nasa.gov/search.jsp?R=20180000823 2020-07-13T05:36:17+00:00Z
Choroidal Folds
Normal Globe Flatten Globe
Globe Flattening
“Cotton wool” spots
History
2
Optic Disc Edema
(swelling)
OD
OD
OS
OS
Hyperopic Shifts
-Up to +1.75 diopters
Risk: Visual Impairment/Intracranial Pressure (VIIP)
64 64
47 47 47
107
11 129
0
10
20
30
40
50
60
70
Disc Edema Cotton WoolSpot
Choroidal Folds GlobeFlattening
Refractive Error
Num
ber
of A
str
onauts
Astronauts with Ocular Findings
Tested Occurred
Ocular Findings through 2016*
3*USOS astronauts only
Refractive Error
4
64 64
47 47 47
107
11 129
0
10
20
30
40
50
60
70
Disc Edema Cotton WoolSpot
Choroidal Folds GlobeFlattening
Refractive Error
Num
be
r o
f A
str
on
au
ts
Astronauts with Ocular Findings
Tested Occurred
64 64
47 47 47
107
11 129
0
10
20
30
40
50
60
70
Disc Edema Cotton WoolSpot
Choroidal Folds GlobeFlattening
Refractive Error
Num
ber
of A
str
onauts
Astronauts with Ocular Findings
Tested Occurred
Change ≥0.75D
Globe Flattening
5
64 64
47 47 47
107
11 129
0
10
20
30
40
50
60
70
Disc Edema Cotton WoolSpot
Choroidal Folds GlobeFlattening
Refractive Error
Num
be
r o
f A
str
on
au
ts
Astronauts with Ocular Findings
Tested Occurred
64 64
47 47 47
107
11 129
0
10
20
30
40
50
60
70
Disc Edema Cotton WoolSpot
Choroidal Folds GlobeFlattening
Refractive Error
Num
ber
of A
str
onauts
Astronauts with Ocular Findings
Tested Occurred
Subjective call from
MRI, ultrasound
Terrestrially: Globe flattening is associated with disc
edema resulting from intracranial hypertension.
Pre-flight
MRI
Globe Flattening
6
64 64
47 47 47
107
11 129
0
10
20
30
40
50
60
70
Disc Edema Cotton WoolSpot
Choroidal Folds GlobeFlattening
Refractive Error
Num
be
r o
f A
str
on
au
ts
Astronauts with Ocular Findings
Tested Occurred
64 64
47 47 47
107
11 129
0
10
20
30
40
50
60
70
Disc Edema Cotton WoolSpot
Choroidal Folds GlobeFlattening
Refractive Error
Num
ber
of A
str
onauts
Astronauts with Ocular Findings
Tested Occurred
Subjective call from
MRI, ultrasound
Terrestrially: Globe flattening is associated with disc
edema resulting from intracranial hypertension.
6 days post-flight
MRI
Globe Flattening
7
64 64
47 47 47
107
11 129
0
10
20
30
40
50
60
70
Disc Edema Cotton WoolSpot
Choroidal Folds GlobeFlattening
Refractive Error
Num
be
r o
f A
str
on
au
ts
Astronauts with Ocular Findings
Tested Occurred
64 64
47 47 47
107
11 129
0
10
20
30
40
50
60
70
Disc Edema Cotton WoolSpot
Choroidal Folds GlobeFlattening
Refractive Error
Num
ber
of A
str
onauts
Astronauts with Ocular Findings
Tested Occurred
Subjective call from
MRI, ultrasound
Terrestrially: Globe flattening is associated with disc
edema resulting from intracranial hypertension.
1 year post-flight
MRI
Quantify Globe Flattening
8
Collaboration with Dr. Bryn Martin, University of Idaho
64 64
47 47 47
107
11 129
0
10
20
30
40
50
60
70
Disc Edema Cotton WoolSpot
Choroidal Folds GlobeFlattening
Refractive Error
Num
ber
of A
str
onauts
Astronauts with Ocular Findings
Tested Occurred
Optic Disc Edema
9
• Observation of “fuzzy” optic
disc on retinal fundus image.
• Score: 0-5
• 64 Pre/Post flight pairs of
images
• Observed: Right > Left eye
OCT – Journey to the ISS
Photographs courtesy of ESA
10
OCT on the ISS
Photographs courtesy of NASA
11
Optical Coherence Tomography
12
Optic nerve head. Green lines are
locations of OCT scans.
Preflight (top) and postflight (bottom) OCT
scans through optic nerve head.
Reconstruct thickness map from 24 OCT images to quantify retinal thickness.
Engorgement of Optic Nerve Head
13
ILM
BM
ONH Thickness Map
14
ONH Thickness Map
15
64 64
47 47 47
107
11 129
0
10
20
30
40
50
60
70
Disc Edema Cotton WoolSpot
Choroidal Folds GlobeFlattening
Refractive Error
Num
ber
of A
str
onauts
Astronauts with Ocular Findings
Tested Occurred
Fundus Image vs. OCT
16
Fundus ImagingOCT Imaging
Right Eye
Left Eye
Spaceflight Duration?
17
Frisen Grade Pre-flight 4-6 mo missions 1 year missions Post-flight
Eye L-9/6mos FD30 FD90 FD150 FD270 R-30 R+1/3
Left 0 1 1 1 1 2
Right 0 2 2 2 2 2
Left 0 0 0 0 0 0
Right 0 0 0 0 0 1
Choroidal Folds
18
64 64
47 47 47
107
11 129
0
10
20
30
40
50
60
70
Disc Edema Cotton WoolSpot
Choroidal Folds GlobeFlattening
Refractive Error
Num
ber
of A
str
onauts
Astronauts with Ocular Findings
Tested Occurred
64 64
47 47 47
107
11 129
0
10
20
30
40
50
60
70
Disc Edema Cotton WoolSpot
Choroidal Folds GlobeFlattening
Refractive Error
Num
ber
of A
str
onauts
Astronauts with Ocular Findings
Tested Occurred
Bruch’s membrane
Fundus Image IR Image (OCT Camera)
No Choroidal Folds
19
Pre-flight: Seated FD150
Choroidal Folds
20
Pre-flight: Seated FD150
20
(nasal)
(temporal)
(inferior)
(superior)
Choroidal Fold Progression
21
Choroidal/Retinal Folds
22
(Mader et al., J Neuro-Ophthal, 2016)
Cotton Wool Spot
23
64 64
47 47 47
107
11 129
0
10
20
30
40
50
60
70
Disc Edema Cotton WoolSpot
Choroidal Folds GlobeFlattening
Refractive Error
Num
be
r o
f A
str
on
au
ts
Astronauts with Ocular Findings
Tested Occurred
64 64
47 47 47
107
11 129
0
10
20
30
40
50
60
70
Disc Edema Cotton WoolSpot
Choroidal Folds GlobeFlattening
Refractive Error
Num
ber
of A
str
onauts
Astronauts with Ocular Findings
Tested Occurred
Mader et al., J Neuro-Ophthal, 2016
OCT Angiography
24de Castro-Abeger et al 2015
Fundus Photograph OCT Angiography
Visual Function(Threshold Visual Fields)
25
Humphrey Automated PerimetryNormal
Abnormal
Potential Compact Visual Fields Device for ISS
ERG – Slide here
26Moss H et al
2015
ERG can detect
significant deficits in
Retinal Ganglion Cell
Function in population
of mitochondrial DNA
mutations (some may
be associated with 1C
pathway)
Karanjia R et al 2017
64 64
47 47 47
107
11 129
0
10
20
30
40
50
60
70
Disc Edema Cotton WoolSpot
Choroidal Folds GlobeFlattening
Refractive Error
Num
ber
of A
str
onauts
Astronauts with Ocular Findings
Tested Occurred
Ocular Findings through 2016*
27*USOS astronauts only
What do these findings tell us about the cause/mechanism?
ICP during Space Flight
Trambovetskiĭ et al. 1995. Intracranial pressure in monkeys during the
flight of Cosmos-2229. Aviakosm Ekolog Med.
Flight days
Intr
ac
ran
ial P
res
su
re (
mm
Hg
)
Dark – night
Light – day
Shaded – 24hr avg
Baselin
e
• ICP has never been measured in humans during spaceflight• Russians measured ICP invasively in a Macaque monkey in 1992, during a 10-day
Bion satellite flight, with an intracranial (epidural) probe
• ICP increased as high as 30% compared with preflight measurements
• CO2 did not exceed 1mmHg, ISS mission average=3.56mmHg
0
5
10
15
20
25
30
35
40
0 10 20 30 40 50 60 70
LP
OP
(cm
H2O
)
Days after Spaceflight
Intracranial Pressure
29
Idiopathic Intracranial Hypertension patients: optic disc edema and globe flattening
*USOS crew only
Publication Postion n
Eklund, Ann Neurol, (2016) 80:269-276Supine 11
Supine 11
Berdahl, IOVS, (2008) 49:5412-18Supine 68
Supine 39
Berdahl, Ophthalmology, (2008) 115:763-68 Supine 49
Ren, Ophthalmology, (2010) 117:259-66 Supine 71
Petersen, AJPR, (2015) 310:R100-4 Supine 9
Qvarlander, JAP, (2013) 115:1474-80 Supine 27
Edsbagge, AJPR, (2004) 287:R1450-5 Supine 34
Lawley, J Physiol, (2017) 15(595):2115-2127 Supine 8
0
5
10
15
20
25
30
35
40
0 1 2 3 4 5 6 7 8 9 10
ICP
(cm
H2O
)Study Number
(mean ± SD)
ICP after spaceflight may not be pathologically elevated.
What was ICP during spaceflight?
Direct ICP Measures
30
Lawley JS et al 2017
CCFP & DPOAE
31
-400
-200
0
200
400
Upright Supine HDT Chibis Base Chibis
Preflight FD45
No
n-I
nva
siv
e I
CP
(-n
L)
Tympanic Membrane Displacement: CCFP
(n = 10)
(mean ± standard deviation)
(n = 10)(n = 10) (n = 10) (n = 8) (n = 8)
p < .05 vs. Upright † p < .05 vs. Supine*
*
*†
†
Name change: SANS
33
Spaceflight Associated Neuro-ocular Syndrome
(SANS)
“I only have 2 concerns with the name VIIP. Crew members do not have
“Vision Impairment” and it doesn’t appear that “Intracranial Pressure” is
pathologically elevated.”
- Dr. Bill Tarver, Flight Surgeon
NASA Human Systems Risk Board Presentation
Fluid Shifts
34
+VP
+CSFP
+OVP
+OCSFP
Internal Jugular Vein Area
(n = 10)
(mean ± standard deviation)
(n = 10)(n = 10) (n = 9) (n = 10)
-20
0
20
40
60
80
100
120
140
160
180
200
Upright Supine HDT Chibis Base Chibis
Preflight FD45
Are
a (
mm
²)
(n = 5)35
Internal Jugular Vein Pressure
(n = 5)
(mean ± standard deviation)
(n = 5)(n = 5) (n = 5) (n = 5)
0
5
10
15
20
25
Upright Supine HDT Chibis Base
Preflight FD45
Pre
ssu
re (
mm
Hg
)
36
Fluid Shifts in the Eye
37
Preflight, supineFD150
Fluid Shifts
38
Venous Outflow Restriction
Wilson MH 2016
Cerebrospinal Fluid (CSF)
Ma Q et al 2017
Mathieu E et al 2017
Glymphatics & Lymphatics
Kumar KN et al 2012
Countermeasures Research
LBNP
ITD
AG
Thigh CuffsB vitamins
Carbon Dioxide
40
Modified from: Law, et al. J Occup Environ Med. 56:477-83, 2014
0
1
2
3
4
5
6
Ja
n 2
00
1
Ju
l 20
01
Ja
n 2
00
2
Ju
l 20
02
Ja
n 2
00
3
Ju
l 20
03
Ja
n 2
00
4
Ju
l 20
04
Ja
n 2
00
5
Ju
l 20
05
Ja
n 2
00
6
Ju
l 20
06
Ja
n 2
00
7
Ju
l 20
07
Ja
n 2
00
8
Ju
l 20
08
Ja
n 2
00
9
Ju
l 20
09
Ja
n 2
01
0
Ju
l 20
10
Ja
n 2
01
1
Ju
l 20
11
Ja
n 2
01
2
Ju
l 20
12
7-D
ay A
ve
rag
e C
O2
Le
ve
l (m
mH
g)
DateGreen bars: ppCO2 controlled to 4 mmHg
(Fan, et al. J. Physiol, 2010)
CO2 Cerebrovascular
Reactivity
Sleep
Carbon Dioxide
Genetics
42
Zwart S et al 2017
eNOS
Coupled eNOS
L-Arginine
BH2
L-Citrulline +
NOBH
4DHFR
Vascular
Relaxation
eNOS
Uncoupled
eNOS
L-Arginine
BH2
L-Citrulline + NO
BH4
DHFR
Oxidative Stress
H2O2
O2-
ONOO-
+
Summary
43