Fractional Anisotropic Change in Pilots and Chamber...
Transcript of Fractional Anisotropic Change in Pilots and Chamber...
Distribution A: Approved for public release; distribution is unlimited. Case Number: SAF-2013-0146, 26 Mar 2013
White Matter and Fractional
Anisotropic Change in Pilots
and Chamber Techs
Stephen A. McGuire, M.D.
USAFSAM/FECN
AFMSA/SG9 study grant I-11-10
AFMSA/SG9 study grant I-11-44
Dragon Lady
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Distribution A: Approved for public release; distribution is unlimited. Case Number: SAF-2013-0146, 26 Mar 2013
Co-Investigators
WHASC/SAMMC
Paul Sherman
Len Profenna
Patrick Grogan
John Sladky
Gerald York
Alan Flower
Univ Maryland Baltimore
Peter Kochunov
HJ Foundation
David Tate
AFRL
Joe Wood
Gary Ford
No financial disclosures
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Distribution A: Approved for public release; distribution is unlimited. Case Number: SAF-2013-0146, 26 Mar 2013
MRI Abnormalities in 2 Pilots Without Clinical NDCS
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Distribution A: Approved for public release; distribution is unlimited. Case Number: SAF-2013-0146, 26 Mar 2013
MRI Comparison (1)Clinical vs. Research Sequences
High-resolution 3D FLAIR; clinical 2D FLAIR; clinical 2D T2
White matter hyperintensities (WMH) change readily apparent on high-resolution 3D FLAIR
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Distribution A: Approved for public release; distribution is unlimited. Case Number: SAF-2013-0146, 26 Mar 2013
MRI Comparison (2)Clinical vs. Research Sequences
High-resolution 3D FLAIR; clinical 2D FLAIR; clinical 2D T2
WMH change readily apparent on high-resolution 3D FLAIR
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Distribution A: Approved for public release; distribution is unlimited. Case Number: SAF-2013-0146, 26 Mar 2013
MRI – WMH Lesion Volume(n=12 NDCS; 38 no NDCS)
Significant difference in WMH volume in U-2 pilots with vs. without clinical NDCS
No statistical difference in number of WMH
Apparent focal preference for insular region
McGuire et al. Aviat Space Environ Med 2012;83:1117
McGuire et al. Neurology (in press)
ItemAll U-2 pilots
(mean±SD n=50)NDCS U-2
(mean±SD n=12)No NDCS U-2
(mean±SD n=38)p-value
(1-tailed Mann-Whitney)
Total FLAIR vol 1.05±0.54 cm3 1.37±0.79 cm3 0.95±0.37 cm3 0.026
Subcort FLAIR vol 0.07±0.12 cm3 0.13±0.14 cm3 0.05±0.11 cm3 0.059
Insula lobe vol 0.006±0.021 cm3 0.020±0.038 cm3 0.001±0.005 cm3 0.018
Subcort lesion # 3.76±6.10 7.25±10.66 2.66±2.85 0.149
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Distribution A: Approved for public release; distribution is unlimited. Case Number: SAF-2013-0146, 26 Mar 2013
Comparison of WMH2/10/2013
Significant difference between control (DOC + FSG) and PHY (chamber technicians)
WMH distribution similar in pattern to DCS (U-2 pilots)
No significant difference between PHY vs. DCS
Unrelated to clinical episodes of NDCS
Correlation with exposure hours not yet performed
Item PHY (n=61) DOC+FSG (n=102)p-value
(2-tailed Mann-Whitney)
Subcortical WMH vol 0.1479±0.4656 cm3 0.0358±0.0628 cm3 0.021
Subcortical WMH count 7.10±12.44 2.80±3.83 0.017
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Item PHY (n=61) DCS (n=105)p-value
(2-tailed Mann-Whitney)
Subcortical WMH vol 0.1479±0.4656 cm3 0.1475±0.2957 cm3 0.356
Subcortical WMH count 7.10±12.44 9.67±18.26 0.191
Distribution A: Approved for public release; distribution is unlimited. Case Number: SAF-2013-0146, 26 Mar 2013
Comparison U-2 (all) to Doctorate Normative
Images represent super-positioning of all quantitative measurements
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Distribution A: Approved for public release; distribution is unlimited. Case Number: SAF-2013-0146, 26 Mar 2013
WMH Distribution Pattern
Suggests lesion location directly related to volume of tissue at risk – insula region only exception
Similar preference noted in U-2 ± NDCS
Suggests microembolization (shower) as mechanism
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Distribution A: Approved for public release; distribution is unlimited. Case Number: SAF-2013-0146, 26 Mar 2013
WMH Location2/15/2013
1.8% (3/167) of DCS+PHY cortical margin lesions
0.4% (6/1500 exposures) arterial gas bubble reported in chamber experiments
1/3 reported NDCS symptoms
No cortical margin lesions in DOC+FSG cohort
Suggests microembolization (< 30 μ) is occurring
Possibly gas bubble – possibly thrombin-platelet aggregate
Number of Subjects
Number of WMH Lesions
Number WMH Lesions at Cortical Junction
DCS 106 1015 2 (1.8% subjects; 0.2% WMH)
PHY 61 433 1 (1.6% subjects; 0.2% WMH)
DOC 77 218 0
FSG 26 68 0
Aviat Space Environ Med 1996; 67:1092-6
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Cortical Thickness(n= 99 DCS; 75 DOC+FSG)
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Distribution A: Approved for public release; distribution is unlimited. Case Number: SAF-2013-0146, 26 Mar 2013
Cortical Thickness(n= 52 PHY; 75 DOC+FSG)
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Distribution A: Approved for public release; distribution is unlimited. Case Number: SAF-2013-0146, 26 Mar 2013
Fractional Anisotropy (FA) vs. Age2/18/2013
FA slope vs. age greater in DCS and PHY groups compared to DOC and FSG groups
No correlation to WMH volume
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WMH Volume vs. Average FAAll U-2 Pilots
No correlation between FA and WMH volume
Suggests a more diffuse process than seen by WMH
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Distribution A: Approved for public release; distribution is unlimited. Case Number: SAF-2013-0146, 26 Mar 2013
WMH Volume vs. Average FANDCS vs. no NDCS
FA decreases with increasing WMH volume
Numbers small – caution in interpretation
Possibly a correlation NDCS vs. no NDCS
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Distribution A: Approved for public release; distribution is unlimited. Case Number: SAF-2013-0146, 26 Mar 2013
Case Study – FA
FA change with single exposure – 3 mo recovery
6% FA decline (nl < 3%)
14 mountaineers pre/post MRI
Peak altitude 6206 m (21,000 ft)
Significant FA decrease
Third MRI not reported
Zhang et al. High Alt Med Biol 2012;13(2):118-125
2.5-h exposure
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Distribution A: Approved for public release; distribution is unlimited. Case Number: SAF-2013-0146, 26 Mar 2013
NDCS Hypothesis
Arterial macroembolization relatively uncommon
Microembolization (< 30 μm) dominant mechanism
Venous gas bubbles activate platelets and/or thrombin and/or proinflammatory macroparticles
Randomly distribute to CNS proportional to blood flow
Microemboli possibly gas bubbles or possibly thrombin-platelet aggregates or macroparticles/activated leukocytes
Each exposure activates this mechanism
Degree of FLAIR findings related to intensity of exposure
Reflection of duration/frequency of exposure
Possibly associated with cortical loss and more diffuse axonal injury
Statistical 2nd and 3rd order neurocognitive change
No observed clinical neurocognitive change
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Distribution A: Approved for public release; distribution is unlimited. Case Number: SAF-2013-0146, 26 Mar 2013
Unanswered Questions
Are the implemented mitigation strategies sufficient?
Is 15,000 ft altitude safe? Where is the threshold?
What other populations are at risk?
What is the temporal evolution of FA injury & WMH lesions?
Is compressive therapy treatment sufficient?
Should antithrombotic or antiplatelet therapy be given either prophylactically or therapeutically?
Is there a significant inflammatory component?
What is the WMH lesion volume threshold beyond which significant neurocognitive impairment will occur?
Is this time-dependent or episodic?
Is this a static process or a progressive process following treatment and/or cessation of exposure?
Is there an increased risk of later cognitive impairment?
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Distribution A: Approved for public release; distribution is unlimited. Case Number: SAF-2013-0146, 26 Mar 2013
Questions?
Neurologic DCS
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