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)

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11 129

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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

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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

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47 47 47

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11 129

0

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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

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47 47 47

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11 129

0

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60

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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

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47 47 47

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11 129

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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

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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

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0

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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

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(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

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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

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30

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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