April 2018
Volume 59, Issue 5
Open Access
Letters to the Editor  |   April 2018
Author Response: The “Ocular Glymphatic System”: An Important Missing Piece in the Puzzle of Optic Disc Edema in Astronauts?
Author Affiliations & Notes
  • Yeni Yucel
    Keenan Research Centre for Biomedical Science, Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Ontario, Canada;
    Department of Ophthalmology and Vision Sciences, University of Toronto, Toronto, Ontario, Canada;
    Department of Laboratory Medicine & Pathobiology, University of Toronto, Toronto, Ontario, Canada;
    Ophthalmic Pathology Laboratory, Department of Ophthalmology and Vision Sciences, St. Michael's Hospital, University of Toronto, Toronto, Ontario, Canada;
    Department of Physics, Faculty of Science, Ryerson University, Toronto, Ontario, Canada;
    Faculty of Engineering and Architectural Science, Ryerson University, Toronto, Ontario, Canada;
    Institute of Biomedical Engineering, Science and Technology (iBEST), St. Michael's Hospital, Ryerson University, Toronto, Ontario, Canada; and the
  • Emily Mathieu
    Keenan Research Centre for Biomedical Science, Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Ontario, Canada;
    Department of Ophthalmology and Vision Sciences, University of Toronto, Toronto, Ontario, Canada;
    Department of Laboratory Medicine & Pathobiology, University of Toronto, Toronto, Ontario, Canada;
  • Neeru Gupta
    Keenan Research Centre for Biomedical Science, Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Ontario, Canada;
    Department of Ophthalmology and Vision Sciences, University of Toronto, Toronto, Ontario, Canada;
    Department of Laboratory Medicine & Pathobiology, University of Toronto, Toronto, Ontario, Canada;
    Glaucoma Unit, St. Michael's Hospital, Toronto, Ontario, Canada.
Investigative Ophthalmology & Visual Science April 2018, Vol.59, 2092-2093. doi:10.1167/iovs.17-23407
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      Yeni Yucel, Emily Mathieu, Neeru Gupta; Author Response: The “Ocular Glymphatic System”: An Important Missing Piece in the Puzzle of Optic Disc Edema in Astronauts?. Invest. Ophthalmol. Vis. Sci. 2018;59(5):2092-2093. doi: 10.1167/iovs.17-23407.

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      © ARVO (1962-2015); The Authors (2016-present)

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We thank Wostyn and De Deyn1 for their comments regarding the relevance of our work2 to optic disc edema in astronauts. New findings related to lymphatic and glymphatic pathways of the eye have been exciting subjects of discussion with NASA (National Aeronautics and Space Administration)3 and the Canadian Space Agency.4 
Astronauts returning from space flight missions may suffer from transient or persistent impaired vision. The typical cluster of eye findings of papilledema, choroidal folds, and cotton wool spots has recently been coined as space flight-associated neuro-ocular syndrome (SANS).5 Microgravity-associated cephalad fluid shifts are implicated in this condition; however, the exact etiology is unclear.6 The swollen optic disc appearance of papilledema is typically associated with elevated intracranial pressure (ICP),7 and until recently, astronauts were believed to develop high ICP.8,9 Optical coherence tomography of the optic disc after space flight, however, shows microanatomic changes that are not associated with raised cerebrospinal fluid (CSF) pressure.10 The finding that CSF pressure did not go up under microgravity conditions further challenges the role of high ICP in astronauts,11 and the etiology of disc edema in astronauts remains unknown. 
We hypothesize that lymphatic drainage plays an important role in removing excess fluid from and around the optic nerve, related to cephalad fluid shifts during long-duration space flight. Impaired lymphatic function may account for some of the ocular findings and vision impairment observed in astronauts. 
We found CSF entry into the optic nerve along small perforating pial vessels in a size-dependent manner through sleeve-like paravascular spaces between vessel walls and aquaporin-4-positive astrocytic endfeet.2 Just how this fluid moves within the optic nerve interstitial tissue, whether by bulk flow12 or by diffusion,13 still needs to be worked out. Another remaining challenge is to determine how excess fluid leaves the optic nerve. It is possible that lymphatics in the optic nerve sheath14,15 and orbit16 drain excess optic nerve fluid and perioptic nerve CSF to the same cervical nodes that drain CSF.17,18 
Lymphatic drainage may be impeded in microgravity conditions. To test this, ground-based models such as hindlimb unloading in rodents may be useful, given that they mimic bone loss, muscle atrophy, and cardiovascular changes observed in astronauts after space flights.19 In this head-down position model, the active pump of the cervical lymphatic vessels is inhibited.20 Passive lymphatic flow is also likely altered because of changes in gravitational forces and central venous pressure.20,21 
To understand vision impairment faced by astronauts on long-term missions, an interdisciplinary approach combining noninvasive imaging and body fluid-based biomarkers is needed.22 Inflight studies of astronauts may validate biomarkers at point of care and lead to new monitoring tools and countermeasures.23 The lymphatic and glymphatic systems offer exciting opportunities to understand the changes that threaten vision in astronauts, with the potential for new strategies to overcome barriers to human deep space exploration. 
References
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Mathieu E, Gupta N, Ahari A, Zhou X, Hanna J, Yücel YH. Evidence for cerebrospinal fluid entry into the optic nerve via a glymphatic pathway. Invest Ophthalmol Vis Sci. 2017; 58: 4784–4791.
Yucel YH. Lymphatic drainage from the eye: evidence and implications for visual impairment intracranial pressure syndrome. Presented at the Lyndon B. Johnson Space Center, Houston, Texas, United States, October 2, 2015.
Yucel YH. Space, Health and Innovation: Emerging Challenges, New Opportunities and Benefits to Society. Canadian Space Agency Headquarters, John H. Chapman Space Centre, St. Hubert, Montreal, Canada, November 29–30, 2017. Available at: www.asc-csa.gc.ca/eng/events/2017/planning-canada-next-chapter-human-space-exploration-health-and-biomedical-roles.asp.
Lee AG, Mader TH, Gibson CR, Tarver W. Space flight-associated neuro-ocular syndrome. JAMA Ophthalmol. 2017; 135: 992–994.
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Hayreh SS. Pathogenesis of optic disc edema in raised intracranial pressure. Prog Retin Eye Res. 2016; 50: 108–144.
Fogarty JA, Otto C, Kerstman E, Oubre C, Wu J. The Visual Impairment Intracranial Pressure Summit Report. NASA/TP-2011-216160. Lyndon B. Johnson Space Center, Houston, Texas, United States, 2011. Available at: https://spacemedicineassociates.com/userfiles/file/Visual%20Impairment%20Intracranial%20Pressure%20Summit%20Report%20NASA%202011.pdf.
Macias BR, Liu JHK, Otto C, Hargens A. Intracranial Pressure and its Effect on Vision on Space and on Earth. Singapore: World Scientific Publishing Co.; 2017.
Patel N, Pass A, Mason S, Gibson CR, Otto C. Optical coherence tomography analysis of the optic nerve head and surrounding structures in long-duration international space station astronauts. JAMA Ophthalmology. 2018; 136: 193–200.
Lawley JS, Petersen LG, Howden EJ, et al. Effect of gravity and microgravity on intracranial pressure. J Physiol. 2017; 595: 2115–2127.
Iliff JJ, Wang M, Zeppenfeld DM, et al. Cerebral arterial pulsation drives paravascular CSF-interstitial fluid exchange in the murine brain. J Neurosci. 2013; 33: 18190–18199.
Smith AJ, Yao X, Dix JA, Jin BJ, Verkman AS. Test of the ‘glymphatic' hypothesis demonstrates diffusive and aquaporin-4-independent solute transport in rodent brain parenchyma. eLife. 2017; 6: e27679.
Killer HE, Laeng HR, Groscurth P. Lymphatic capillaries in the meninges of the human optic nerve. J Neuroophthalmol. 1999; 19: 222–228.
Gausas RE, Daly T, Fogt F. D2-40 expression demonstrates lymphatic vessel characteristics in the dural portion of the optic nerve sheath. Ophthal Plast Reconstr Surg. 2007; 23: 32–36.
Dickinson AJ, Gausas RE. Orbital lymphatics: do they exist? Eye (Lond). 2006; 20: 1145–1148.
Koh L, Zakharov A, Johnston M. Integration of the subarachnoid space and lymphatics: is it time to embrace a new concept of cerebrospinal fluid absorption? Cerebrospinal Fluid Res. 2005; 2: 6.
Mathieu E, Gupta N, Macdonald RL, Ai J, Yucel YH. In vivo imaging of lymphatic drainage of cerebrospinal fluid in mouse. Fluids Barriers CNS. 2013; 10: 35.
Globus RK, Morey-Holton E. Hindlimb unloading: rodent analog for microgravity. J Appl Physiol. 2016; 120: 1196–1206.
Gashev AA, Delp MD, Zawieja DC. Inhibition of active lymph pump by simulated microgravity in rats. Am J Physiol Heart Circ Physiol. 2006; 290: H2295–H2308.
Shellock FG, Swan HJ, Rubin SA. Early central venous pressure changes in the rat during two different levels of head-down suspension. Aviat Space Environ Med. 1985; 56: 791–795.
Yucel YH, Cardinell K, Khattak S, et al . Fluid drainage from the eye to lymph nodes measured by noninvasive photoacoustic imaging of near-infrared nanoparticles. Invest Ophthalmol Vis Sci. In press.
Hargens AR, Bhattacharya R, Schneider SM. Space physiology VI: exercise, artificial gravity, and countermeasure development for prolonged space flight. Eur J Appl Physiol. 2013; 113: 2183–2192.
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