Re: Wåhlin Et Al.: Optic Nerve Length Before and after Spaceflight (ophthalmology. 2021;128:309–316)

We read the excellent cohort study by Wåhlin et al. The authors investigated postflight optic nerve length changes, as well as displacements of the optic nerve head and optic chiasm and their relation to mission duration and clinical manifestations of spaceflight-associated neuro-ocular syndrome (SANS). Their study included 22 astronauts examined with magnetic resonance imaging before and after a stay at the International Space Station. The authors detected an overall length increase in the optic nerve, primarily reflecting forward optic nerve head displacement. The forward displacement was positively related to mission duration and clinical manifestations of SANS. They also detected upward displacement of the optic chiasm, indicative of brain movement, but this observation could not be linked to mission duration and SANS. The authors concluded that their observations cannot be reconciled with a model where an upward brain displacement leads to SANS, but instead their findings support the notion that SANS is caused by an altered pressure difference across the lamina cribrosa, leading to an anterior push on the posterior part of the eye. In line with this theory, we believe the recent discovery of an “ocular glymphatic system” may provide further clues to mechanisms behind the development and delayed recovery of SANS-associated optic disc edema (ODE). Wåhlin et al discuss a recent OCT study by Macias et al.1Macias B.R. Patel N.B. Gibson C.R. et al.Association of long-duration spaceflight with anterior and posterior ocular structure changes in astronauts and their recovery.JAMA Ophthalmol. 2020; 138: 553-559Crossref PubMed Scopus (32) Google Scholar In this study, the authors quantitated ocular structural changes, including peripapillary retinal thickness, that develop in association with long-duration spaceflight and documented how long these changes persist after landing. They found that long-duration spaceflight was associated with ODE and that between 30 and 90 days were required for the peripapillary retinal tissue thickening to return to values similar to those observed before flight. Macias et al1 further noted that the lack of a retinal–blood barrier in the prelaminar region of the optic nerve head may be associated with a greater extravasation of fluid owing to the headward fluid shift in weightlessness and may be a contributing factor to the retinal thickening quantified at this location. Importantly, observations pertaining to the recent discovery of an ocular glymphatic clearance system provide critical new insights into how intracranial pressure (ICP) can alter basic fluid transport in the eye. As discussed elsewhere in this communication, these recently reported findings can potentially help to unlock mechanisms underlying the development and delayed recovery of microgravity-induced ODE. Wang et al2Wang X. Lou N. Eberhardt A. et al.An ocular glymphatic clearance system removes β-amyloid from the rodent eye.Sci Transl Med. 2020; 12eaaw3210Crossref PubMed Scopus (53) Google Scholar recently identified a novel ocular glymphatic pathway for removal of fluid and metabolites from the intraocular space in rodents. Small tracer molecules like amyloid-beta entered retinal ganglion cell axons and the perivenous spaces of the retina and optic nerve head before being cleared by the anterograde glymphatic pathway.2Wang X. Lou N. Eberhardt A. et al.An ocular glymphatic clearance system removes β-amyloid from the rodent eye.Sci Transl Med. 2020; 12eaaw3210Crossref PubMed Scopus (53) Google Scholar,3Rangroo Thrane V. Hynnekleiv L. Wang X. et al.Twists and turns of ocular glymphatic clearance – new study reveals surprising findings in glaucoma.Acta Ophthalmol. 2021; 99: e283-e284Crossref PubMed Scopus (7) Google Scholar The authors further showed that the trans-lamina cribrosa pressure difference, defined as intraocular pressure minus ICP, is a major driver of ocular glymphatic outflow. Indeed, a high ICP abrogated the intra-axonal tracer movement along the optic nerve, whereas lowering the ICP increased it.2Wang X. Lou N. Eberhardt A. et al.An ocular glymphatic clearance system removes β-amyloid from the rodent eye.Sci Transl Med. 2020; 12eaaw3210Crossref PubMed Scopus (53) Google Scholar,3Rangroo Thrane V. Hynnekleiv L. Wang X. et al.Twists and turns of ocular glymphatic clearance – new study reveals surprising findings in glaucoma.Acta Ophthalmol. 2021; 99: e283-e284Crossref PubMed Scopus (7) Google Scholar Interestingly, these data suggest that a rise in ICP, and thus a rise in orbital cerebrospinal fluid pressure, which is assumed to occur in microgravity, would directly inhibit this ocular glymphatic outflow. These observations, in combination with an increased capillary filtration as proposed by Macias et al,1Macias B.R. Patel N.B. Gibson C.R. et al.Association of long-duration spaceflight with anterior and posterior ocular structure changes in astronauts and their recovery.JAMA Ophthalmol. 2020; 138: 553-559Crossref PubMed Scopus (32) Google Scholar might contribute to the ODE seen in astronauts.4Wostyn P. De Winne F. Stern C. et al.Dilated prelaminar paravascular spaces as a possible mechanism for optic disc edema in astronauts.Aerosp Med Hum Perform. 2018; 89: 1089-1091Crossref PubMed Scopus (14) Google Scholar Also interestingly, Rangroo Thrane et al3Rangroo Thrane V. Hynnekleiv L. Wang X. et al.Twists and turns of ocular glymphatic clearance – new study reveals surprising findings in glaucoma.Acta Ophthalmol. 2021; 99: e283-e284Crossref PubMed Scopus (7) Google Scholar noted that the amount of fluid that exits the eye via the posterior ocular glymphatic clearance route is likely to be orders of magnitude lower than clearance via anteriorly located routes. We propose that this could provide one possible explanation for the slow postflight recovery of astronauts from ODE. Obviously, further research is required to provide additional insight regarding the relative contribution of the ocular glymphatic system to ODE in astronauts. In this light, the existence of an ocular glymphatic clearance path requires further confirmation from primate model studies. In this regard, it is pertinent to note that histologic evidence supports the existence of a perivascular pathway in the human optic nerve,4Wostyn P. De Winne F. Stern C. et al.Dilated prelaminar paravascular spaces as a possible mechanism for optic disc edema in astronauts.Aerosp Med Hum Perform. 2018; 89: 1089-1091Crossref PubMed Scopus (14) Google Scholar and that a recent magnetic resonance imaging study with a cerebrospinal fluid tracer, carried out by Jacobsen et al,5Jacobsen H.H. Ringstad G. Jørstad Ø.K. et al.The human visual pathway communicates directly with the subarachnoid space..Invest Ophthalmol Vis Sci. 2019; 60: 2773-2780Crossref PubMed Scopus (27) Google Scholar supports the idea of a glymphatic system in the human visual pathway including the optic nerve, optic chiasm, optic tract, and primary visual cortex. Optic Nerve Length before and after SpaceflightOphthalmologyVol. 128Issue 2PreviewThe spaceflight-associated neuro–ocular syndrome (SANS) affects astronauts on missions to the International Space Station (ISS). The SANS has blurred vision and ocular changes as typical features. The objective of this study was to investigate if microgravity can create deformations or movements of the eye or optic nerve, and if such changes could be linked to SANS. Full-Text PDF Open AccessReplyOphthalmologyVol. 128Issue 5PreviewWe thank Wostyn et al for their comments regarding our article.1 As our results suggest an altered translamina cribrosa pressure difference between the brain and the eye, we share the view that translamina cribrosa glymphatic outflow from the eye to the optic nerve and optic nerve sheath may be altered in microgravity. As indicated in the animal study by Wang et al, the eye’s glymphatic system is likely involved in removing metabolites from neural activity from the intraocular space through the optic nerve head to the optic nerve subarachnoid space. Full-Text PDF