NASA’s Spaceflight Visual Impairment Intracranial
Pressure (VIIP) Risk:
Clinical Correlations & Pathophysiology
Bill Tarver, M.D.
Deputy Chief & Medical Director, NASA Clinical Services Branch
&
Christian Otto, M.D.
VIIP Lead Scientist
Aerospace Medicine Grand Rounds
Page No. 1
May 22, 2012
USRA
Houston, TX
Visual Impairment Intracranial Pressure Risk
 Working Risk Statement:
• "Given that the microgravity environment causes cepahld fluid
shift in astronauts, there is a high probability that all
astronauts have intracranial hypertension (IHT) to some
degree. Presently these symptoms have manifested
themselves as changes in eye structure such as papilledema,
globe flattening, choroidal folds, cotton wool spots (CWS)
increased retinal nerve fiber layer and/or decreased near
vision, along with post mission spinal opening pressures
ranging between 21 - 28.5 cmH20 for symptomatic
astronauts. If the IHT is not treated, there is a risk of damage
to the optic nerve and possible reduced vision capability long
term.”
Page No. 2
Clinical Data Overview:
flight
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in Vision
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Common Characteristics of the Cases
• Approximately 6 month
duration ISS mission
• All had normal preflight eye
examinations
• Past medical history was negative for systemic disease;
and none had used medications before or during their
mission that could increase ICP (e.g., vitamin A,
tetracycline, corticosteroids, or nalidixic acid)
Page No. 4
Common Characteristics
• None experienced losses
in best-corrected visual
acuity, color vision or
stereopsis
• ISS cabin pressure, and
oxygen were at normal
operating levels.
• Elevations in CO2
Page No. 5
Pre & Post Flight Papilledema
[Top Pre Flight]
Fundoscopic images of
the right and left optic
disc.
[Bottom Post Flight]
Fundoscopic images of
the right and left optic
disc showing Grade 3
edema at the right optic
disc and Grade 1 edema
at the left optic disc.
Page No. 6
Pre Flight
OD
OS
Post Flight
OD
OS
Choroidal Folds
Postflight
Postflight
OD OD
Preflight
Inferior
Page No. 7
OS
Superior
Postflight
Inferior
Superior
In Flight B-scan Ultrasound
Page No. 8
Mean ONSD Measurement & ICP
Because of a variable pressure-diameter relationship, the clinical relevance of this
method relies on the demonstration of ongoing enlargement on serial US studies.
Clinically ONSD 5.9mm=20mmHg
Page No. 9
Increased Optic Nerve Sheath Diameter
On-Orbit
OS
OD
12 mm
Page No. 10
MRI Globe Imaging
T1 MRI orbital imaging of the right eye. Pre flight
(left) and Post flight (right) showing flattening of
the posterior globe.
Page No. 11
Flattening of Posterior Wall – and Raised Optic Disk
Elevation of optic
disc
Page No. 12
CONFIDENTIAL
Pre & Post Flight Testing
MRI
2D Ultrasound

L-12/9m and L-6/3m

L-21/18m

R+1/3d

R+1/3d

Combined with training

3T or better using specific ocular
imaging protocols
Vision Exam
Page No. 13
•
Fundoscopy
•
Tonometry
•
OCT
In Flight: L+30 Days & R-30 Days
 Vision Exam (includes L+100d)
 Fundoscopy
 Tonometry
 2D Ultrasound
Page No. 14
Clinical Practice Guideline for SpaceflightInduced Intracranial Hypertension
Page No. 15
VIIP Clinical Practice Guideline
& Case Definition
Case Classification (U.S. ISS Crew) (As of Jan 2012)
 36 U.S. ISS crew flown to date:
• Confirmed non-cases N=2
• Unclassified crew N=19
• CPG Class One N=2
• CPG Class Two N=8
• CPG Class Three N=1
• CPG Class Four N=4
N
Confirmed Non Cases
•
•
Page No. 16
< .50 diopter cycloplegic refractive change
No evidence of papilledema, nerve sheath distention, choroidal folds, globe flattening,
scotoma or cotton wool spots compared to baseline.
2
VIIP Clinical Practice Guideline
& Case Definition
Case Classification (U.S. ISS Crew) (As of Jan 2012)
Un-Classified Crew
•
•
Too little evidence at present for definitive classification
Early ISS flyers with no, or limited testing
Class 1 (repeat OCT and visual acuity in 6 weeks)
•
•
•
Case
Class
19
2
≥ .50 diopter cycloplegic refractive change and/or cotton wool spot
No evidence of papilledema, nerve sheath distention, choroidal folds, globe flattening,
scotoma compared to baseline.
CSF opening pressure (if measured) ≤ 25 cmH2O
Class 2 (repeat OCT, cycloplegic refraction, fundus exam and threshold visual field every 4 -6 weeks
x 6 months, repeat MRI in 6 months) 2/10
•
≥ .50 diopter cycloplegic refractive changes or cotton wool spot
•
Choroidal folds and/or optic nerve sheath distension and/or globe flattening and/or scotoma
•
No evidence of papilledema
•
CSF opening pressure ≤ 25 cm H2O (if measured)
8
17
Page No. 17
VIIP Clinical Practice Guideline
& Case Definition
Case Classification (U.S. ISS Crew) (As of Jan 2012)
Case
Class
Class 3 (repeat OCT, cycloplegic refraction, fundus exam and threshold visual field every 4 -6 weeks
x 6 months, repeat MRI in 6 months)
•
•
•
•
≥ .50 diopter cycloplegic refractive changes and/or cotton wool spot
Optic nerve sheath distension, and/or globe flattening and/or choroidal folds and/or
scotoma
Papilledema of Grade 0-2.
CSF opening pressure ≤ 25 cm H2O
Class 4 (institute treatment protocol as per CPG)
•
•
•
•
•
1
4
≥ .50 diopter cycloplegic refractive changes and/or cotton wool spot
Optic nerve sheath distension, and/or globe flattening and/or choroidal folds and/or
scotoma
Papilledema Grade 2 or above.
Presenting symptoms of new headache, pulsatile tinnitus and/or transient visual
obscurations
CSF opening pressure >25 cm H2O
18
Page No. 18
Impact of Inflight Exacerbating Factors?
Resistive Exercise
Does in-flight resistance
training cause additional
transient elevations in
ICP?
High Oral Sodium Intake
Prepackaged Foods
High in sodium
Up to 5000mg+ per day
Inflight Pharmaceuticals
Effects on VIIP?
Page No. 19
CO2 Levels on ISS
Pressure
Adapted from Alperin et al. Radiology, 2000
 CO2 is an extremely potent vasodilator
• Every 1mmHg increase PaCO2=4%
increase in dilation
• Cerebral blood vessels are already
congested
CO2
X
X
 CO2 mission average=3.56mmHg (0.33%)
• 10x normal sea level atmospheric: 0.0314%
• Average Peak CO2=8.32mmHg (0.7%) (20x)
 CO2 also causes increased CSF production
Page No. 20
Cephalad Fluid Shift
Piecing Together Visual Impairment and
Elevated Intracranial Pressure in Spaceflight
Currently-A Three-Part Story
1. The Vascular System
+
Page No. 21
3. The Eye
2. The Brain
+
A Working Model: Potential Interaction of the
CNS, Vascular, & Ocular System in Microgavity
Interstitial Edema
+ICP
+OCSFP
Cerebral
Venous Blood
+CSFP
+OVP
+VP
X
9.8m/s2
Loss of
Hydrostatic Drainage
Adapted from Rekate
Page No. 22
Vascular Capacitance (dV/dP):
Venous & Arterial
20%=1L
Page No. 23
70-80%=4L
Correlation of BMI with ICP in 71 Non-IIH
Subjects
•
•
Mean age 45.7±11.3
Mean BMI 23.7±2.7 kg/m2
(17.3–29.4)
CSF-P correlated with:
•
Higher BMI (P<0.001; r=0.50)
•
Higher systolic blood pressure
(P=0.04; r=0.24),
•
Higher intraocular pressure
(P<0.001; r=0.76)
Ren et. al. Cerebrospinal fluid pressure correlated with body mass index. Arch Clin Exp Ophthalmol. July 2011
Page No. 24
Why Does Elevated Blood Pressure
and Increased Resistance Matter?
Page No. 25
Decreased Venous Compliance and Elevated
CVP in Hypertensives
 "central venous pressure" A major
determinant of preload
 Normal CVP=2-6mmHg
 A change in CVP is determined by the
change in volume (ΔV) of blood within
the thoracic veins divided by the
compliance of the these veins
according to the following equation:
ΔCVP = ΔV / Cv
 CVP, measured in patients with
essential hypertension is modestly
increased, even in the absence of
congestive heart failure i.e. normal
pumping ability of the heart
 Decreased venous compliance
contributes to the increase in CVP in
hypertensive patients
•
•
•
Olivari et al. Pulmonary hemodynamics and right ventricular function in
hypertension. Circulation 1978;57:1185-1190
Safar et al. Venous system in essential hypertension. Clin Science 1985
Nov;69(5):497-504.
London et al. Hemodynamic effects of head-down tilt in normal subjects and
sustained hypertensive patients Am J Physiol Heart Circ Physiol August 1,
1983 245:(2) H194-H202
Page No. 26
LV Hypertrophy
LV Strain
3mmHg
6mmHg
CVP in Normotensives vs Hypertensives
During 10o HDT

Higher increase in cardiac output in
hypertensive patients due to a higher
change in CVP related to decreased
venous distensibility

A decrease in venous vascular
resistance during tilt among
normotensives: due to inhibition of
vasoconstrictor tone (-SNS +PNS).
This led to partial relief of the
congestion; minimizing the effects of
blood volume distribution.

Hypertensives did not demonstrate a
decrease in venous tone

The absence of this buffering effect of
the veins in the hypertensives may be
responsible for the higher CVP and
CO.
Page No. 27
N=9
N=7
London et al. 1983. Hemodynamic effects of head-down tilt in normal subjects and sustained hypertensive patients. Am J Physiol.
Factors Increasing Venous Tone will Increase
Cerebral Venous Outflow Resistance

Resting Tone of Venous Vessels
Influenced by:
•
(CVP)
SNS tone↑
 Resting Blood Pressure

•
Endothelin↑
•
Nitric oxide↓
•
Inflammatory cytokines ↑
Baseline Stiffness of Arterial Vessels
Influenced by:
•
Serum lipids
•
Serum glucose
•
Homocysteine levels
•
Aerobic fitness & vessel wall stiffness
•
Nitric oxide levels
Page No. 28
Although effects
of tone less on
venous side vs
arterial, volume
is much greater
Med Ops/Research Occupational Data Mining ISS
Crew: Cardiovascular Variables
Data Mining Variable
Significant
Correlation
with CPG
Biochemistry:
LDL
√
HDL
-
Triglycerides
-
Hemoglobin A1c
√
Fasting serum glucose
√
Homocysteine
√
Body Composition:
Body Mass Index
√
Percentage Body Fat
√
Cardiac:
Resting blood pressure (pre-in-post flight)
√
Pulse Pressure (pre-in-post flight)
√
CT Coronary Calcium Score
-
Aerobic Capacity:
Page No. 29
Low Maximal Oxygen Uptake
√
All correlated
factors
adversely
affect vascular
structure &
function
Loss of Hydrostatic Drainage, Fluid
Shift, & Cerebral Venous Congestion
1G
0G
1G Supine
CEPHALAD FLUID SHIFT
X
9.8m/s2
Loss of
Hydrostatic Drainage
Adapted from Rowell, 1988
Adapted from Hargens & Richardson, Respiratory Physiology & Neurobiology. 2009
Page No. 30
Tilt Angle vs ICP & CVP: Positional Fluid
Shifts
ICP 24mmHg
CVP=9mmHg
ICP 9.2mmHg
CVP=5mmHg
ICP-2.3mmHg
CVP=0mmHg
1. Chapman et al. The Relationship between Ventricular Fluid Pressure and Body Position in Normal Subjects with Shunts. Neurosurgery 1990
2. Hemodynamic changes due to Trendelenburg positioning and pneumoperitoneum during laproscopic hysterectomy, Acta Anaesthesiologica
Scandiavica. 1995
Page No. 31
Redistribution of Venous Pressures
From 1G to 0G
ICP = CSFout resistance x CSFformation + SSSpressure
0G
Standing 1G
-2
15-20
7-9
9.8m/s2

Cranium is rigid

Venous congestion

Obligate arterial flow

Transcapillary leak

++ICP~30-40
X
1. Hirvonen et al. Hemodynamic changes due to Trendelenburg positioning and pneumoperitoneum during laproscopic hysterectomy, Acta Anaesthesiologica Scandiavica. 1995
2. Hinghofer-Szalkay Gravity, the hydrorostatic indifference concept and the cardiovascular system. European Journal of Applied Physiology, 2010
Page No. 32
3. Chapman et al. The Relationship between Ventricular Fluid Pressure and Body Position in Normal Subjects with Shunts. Neurosurgery 1990
4. Gisolf et al. Human cerebral outflow pathway depends on posture and central venous pressure. Journal of Physiology, 2004.
In Flight B-scan Ultrasound
Page No. 33
MRI Globe Imaging
T1 MRI orbital imaging of the right eye. Pre flight
(left) and Post flight (right) showing flattening of
the posterior globe.
Page No. 34
MRI Signs of Elevated ICP: IIH vs VIIP
MRI Signs of Elevated ICP: IIH vs VIIP
Imaging Assessment
Present in IIH
(Specificity)
Seen in VIIP
Flattening of Posterior
Globes
100%
Yes
Optic Nerve Protrusion
100%
Yes
Optic Nerve Sheath
Distension
88.4%
Yes
Optic Nerve Tortuosity
86%
Yes
Maralani et al. Accuracy of brain imaging in the diagnosis of idiopathic intracranial hypertension. Clinical Radiology. Dec. 2011.
Page No. 35
Key Brain Areas
CSF Resorbtion
Interstitial fluid
CSF Production
Cranial Volume = Brain + CSF + Blood
Page No. 36
(AG-Venous/Lymphatic)
Venous
Congestion
Normal CSF Diffusion Gradient
Normal SSVP:CSFP= 0.60
Therefore delta driving pressure only~3-5mmHg
Venous Sinus Pressure=5-7mmHg
ICP= 10mmHg
Page No. 37
The Brain as an Expansile Vascular Organ
Within a Rigid Cranium
Page No. 38
Venous Congestion causes Increased
Transcapillary Pressure & Decreased Absorbtion
X
Interstitial edema
Page No. 39
↑Venous
Pressure
Dural Venous Transverse Sinus
Page No. 40
Expanding Brain Parenchyma & Cerebellum
Compresses Transverse Sinus
Page No. 41
MRI Venography of Stenosed
Right Transverse Sigmoid Sinus
Page No. 42
Reversibility of Venous Sinus Obstruction with
Reduction of CSF Pressure
A. ICP 50cmH20
Bilateral Stenosis Transverse
Sinus
B. After Lumbar Puncture
removal of CSF x2 with
resultant reduction in ICP
C. Placement of
Ventriculoperitoneal Shunt
for continuous CSF drainage
and ICP reduction
Page No. 43
CSF Production: Choroid Plexus
Choroid plexus in lateral,
third & fourth ventricle
produces 70-90% of CSF in
brain
Increased filtration?
Page No. 44
Choroidal Cell Responses in MicrogravityAquaporin-1 Expression
Ground
Control 1G
Normal Control Choroid
Cell
0G & Hind Limb
Abnormal 0G Analog
Choroid Cell
Page No. 45
Gabrion et al. Choroidal responses in microgravity. Acta Astronautica. 1995
Immunodetection of AQP1 (in
green) at the apical pole of
choroid plexus,
(A) control rat (homogeneously
covered with long bulbous
apical microvilli, and tufts of
kinocillia)
(C) model simulating cephalad
fluid shift. AQP1 was reduced
64% after 14d spaceflight
(STS-58), by 44% after 14
days HLU, and by 68% after
28d HLU. A net decrease was
noted, suggesting CSF
production was decreased.
Loss of microvilli, failure of
exocytosis, loss of kinocillia
Suggests brain adaptation in
microgravity with a reduction
in CSF secretory activity.
Rat CP After 14 days in Microgravity
Scanning Electron Micrograph Rat
Choroidal Cell -Lateral Ventricle
Transmission Electron Micrograph Rat Choroidal CellApical Pole Microvilli Abnormalities
• Is there a set-point for elevated ICP that triggers a down-regulation of aquaporin 1
expression?
• AQP1 Knockout mice had 20-25% reduction in CSF production (Oshio et al 2005)
• Recent data from hydrocephalic rats (elevated ICP) shows a significant down
regulation of AQP1 in in choroid plexus (Paul et al. 2009)
• Hyrdocephalus seems to be associated with AQP1 downregulation in the choroid
plexus which could be an adaptive mechanism to reduce CSF production and ICP
Page No. 46
Pre & Post Flight Papilledema
[Top Pre Flight]
Fundoscopic images of
the right and left optic
disc.
[Bottom Post Flight]
Fundoscopic images of
the right and left optic
disc showing Grade 3
edema at the right optic
disc and Grade 1 edema
at the left optic disc.
Page No. 47
Pre Flight
OD
OS
Post Flight
OD
OS
The Lamina Cribosa: Barrier Between
the Intraocular Space and SAS
The LC serves as a barrier to separate the intraorbital space, with typically higher pressure, from the subarachnopid
space, with typically lower pressure. The LC therefore prevents orbital contents from leaking into the subarachnoid space
Page No. 48
Lamina Cribosa Structure
•
•
•
•
LC is a series of cribiform plates, with pores that line up to permit nerve axons to pass through
Average adult: 1.2 million axons pass through the lamina cribrosa in approx 250 nerve bundles
All of these axons depend on slow and fast axoplasmic transport for viability and synapses production
LC cores are filled with fibrillar collagen and elastic fibres, during aging these constituents are altered
Page No. 49
TLP Differences & Visual Field Defect
12.5
6.6
1.4
Control group

Normal Pressure
Glaucoma
High Pressure
Glaucoma
The extent of glaucomatous visual field loss 
was negatively correlated with the height of
the CSF-P [as CSFp went down vis field
loss increased] and positively correlated
with the TLP difference [as tlp increased,
visual field loss increased].
Page No. 50
Amount of glaucomatous visual field defect
correlated positively with the TLP pressure
difference (P _ 0.005) r=0.69
Ren et al. 2009. Cerebrospinal Fluid Pressure in Glaucoma
Choroidal Folds
Postflight
Postflight
OD OD
OS
Preflight
Inferior
Page No. 51
Postflight
Superior
Inferior
Superior
Venous Congestion & Elevated ICP:
Transmitted to the Choroid?

Ansari et al. 2003. Measurement of Choroidal blood flow in Zero Gravity KC135
parabolic flight experiment.
•
Choroidal volume and flow increase significantly in low G environment when
compared with the baseline data (1G): 75% increase for volume, and 105% for flow.
P
Transmitted via the
ophthalmic veins
P
P Venous Sinus
Page No. 52
MRI Brain Venogram
Next Steps
 MRI/MRV analysis
 Multivariate analysis of Cardio/CNS & ocular variables
• As “N” grows sensitivity of multivariate analysis increases
• Addition of IP “cases and non-cases will increase “N” 33%
 Data review for dose response effect
 Data collection from Inflight Ocular study
 Inflight ocular study
 Vittamed 205 Malm Pilot in Umea
 6 NRAs awarded
• 3 Inflight (Stenger/Dulchavsky/Hargens)
• 1 Imaging (Roberts)
• 2 Non Invasive ICP (Detinger/Williams)
 Countermeasure evaluation
Page No. 53
NASA’s Spaceflight Visual Impairment Intracranial
Pressure (VIIP) Risk:
Clinical Correlations & Pathophysiology
Bill Tarver, M.D.
Deputy Chief & Medical Director, NASA Clinical Services Branch
&
Christian Otto, M.D.
VIIP Lead Scientist
Aerospace Medicine Grand Rounds
Page No. 54
May 22, 2012
USRA
Houston, TX