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Peter Wostyn,1 Hanspeter Esriel Killer2,3 1Department of Psychiatry, PC Sint-Amandus, Beernem, Belgium; 2Department of Biomedicine, University of Basel, Basel, Switzerland; 3Augenärzte Zentrum Aarau, Aarau, SwitzerlandCorrespondence: Peter Wostyn, Department of Psychiatry, PC Sint-Amandus, Reigerlostraat 10, Beernem, 8730, Belgium, Tel +32-472713719, Fax +32-50-819720, Email wostyn.peter@skynet.beAbstract: Glaucoma is one of the main causes of irreversible blindness in the world. The most common form, primary open-angle glaucoma, is an optic neuropathy that is characterized by a progressive loss of retinal ganglion cells and their axons, leading to structural changes in the optic nerve head and associated visual field defects. Elevated intraocular pressure remains the most important modifiable risk factor for primary open-angle glaucoma. However, a significant proportion of patients develop glaucomatous damage in the absence of increased intraocular pressure, a condition known as normal-tension glaucoma (NTG). The pathophysiology underlying NTG remains unclear. Several studies have revealed that vascular and cerebrospinal fluid (CSF) factors may play significant roles in the development of NTG. Vascular failure caused by functional or structural abnormalities, and compartmentation of the optic nerve subarachnoid space with disturbed CSF dynamics have been shown to be associated with NTG. In the present article, based on the concept of the glymphatic system and observations in patients with NTG, we hypothesize that failure of fluid transport via the glymphatic pathway in the optic nerve may be involved in the pathogenesis of some if not many cases of NTG. According to this hypothesis, vascular and CSF factors may share reduced glymphatic transport and perivascular waste clearance in the optic nerve as a final common pathway leading to the development of NTG. In addition, we speculate that some cases of NTG may reflect glymphatic dysfunction in natural brain aging and central nervous system diseases, such as Alzheimer’s disease. Clearly, further studies are needed to gain additional insight into the relative contribution of these factors and conditions to reduced glymphatic transport in the optic nerve.Keywords: cerebrospinal fluid, glymphatic system, normal-tension glaucoma, optic nerve, perivascular spaces, vascular failure

A significant proportion of the astronauts who spend extended periods in microgravity develop ophthalmic abnormalities including optic disc edema, globe flattening, chorioretinal folds, and hyperopic refractive error shifts. A constellation of these neuro-ophthalmic findings has been termed "spaceflight-associated neuro-ocular syndrome". Understanding this syndrome is currently a top priority for NASA, especially in view of future long-duration missions (e.g., Mars missions). The recent discovery of an "ocular glymphatic system" can potentially help to unlock mechanisms underlying microgravity-induced optic disc edema. Indeed, a major paradigm shift is currently occurring in our understanding of transport of fluids and solutes through the optic nerve following the recent discovery of an optic nerve glymphatic pathway for influx of cerebrospinal fluid. In addition, the recent identification of an entirely new glymphatic pathway for efflux of ocular fluid may have profound implications for fluid dynamics in the eye. Observations pertaining to this ocular glymphatic pathway provide critical new insights into how intracranial pressure can alter basic fluid transport in the eye. We believe that these novel findings have the potential to be game changers in our understanding of the pathogenesis of optic disc edema in astronauts. In the present review, we integrate these new insights with findings on the intracranial and neuro-ophthalmologic effects of microgravity in one coherent conceptual framework. Further studies in this area of investigation could not only provide exciting new insights into the mechanisms underlying microgravity-induced optic disc edema but also offer opportunities to develop countermeasure strategies.摘要: 在长时间处于微重力状态的宇航员中, 大部分人会出现视力异常, 包括视盘水肿、眼球扁平、脉膜视网膜皱褶和远视屈光不正。这些神经眼科的发现被称为“太空飞行相关神经眼综合征”。了解这一综合征目前是美国宇航局的首要任务, 特别是考虑到未来的长期任务 (如火星任务等) 。最近发现的“眼淋巴系统”可能有助于解开微重力引起视盘水肿的潜在机制。事实上, 随着最近发现了视神经-淋巴通道, 我们对液体和溶质通过视神经传输的理解正在发生重大的范式转变。此外, 最近发现了一种全新的眼内液体流出的淋巴途径可能对眼液动力学有深远的影响。针对眼部淋巴通路的观察为颅内压如何改变眼内基本液体运输提供了重要的新见解。我们相信, 这些新发现有可能改变我们对宇航员视盘水肿发病机制的理解。在目前的综述中, 我们将这些新的见解与微重力对颅内和神经眼科影响的研究结果整合在一个续贯的概念框架中。该领域的后续研究不仅可以为微重力诱导视盘水肿的机制提供令人兴奋的新见解, 而且也为制定相应的对策提供了机会。.

I enjoyed reading the article by Lee et al. [...]

INTRODUCTION: Optic disc edema has been well documented in astronauts both during and after long-duration spaceflight and is hypothesized to largely result from increased pressure within the orbital subarachnoid space brought about by a generalized rise in intracranial pressure or from sequestration of cerebrospinal fluid within the orbital subarachnoid space with locally elevated optic nerve sheath pressure. In addition, a recent prospective study documented substantial spaceflight-associated peripapillary choroidal thickening, which may be a contributing factor in spaceflight-associated neuro-ocular syndrome. In the present article, based on the above, we offer a new perspective on the pathogenesis of microgravity-induced optic disc edema from a choroidal point of view. We propose that prolonged microgravity exposure may result in the transudation of fluid from the choroidal vasculature, which, in turn, may reach the optic nerve head, and ultimately may lead to fluid stasis within the prelaminar region secondary to impaired ocular glymphatic outflow. If confirmed, this viewpoint would shed new light on the development of optic disc edema in astronauts.Wostyn P, Gibson CR, Mader TH. Optic disc edema in astronauts from a choroidal point of view. Aerosp Med Hum Perform. 2022; 93(4):396–398.

Spaceflight-associated neuro-ocular syndrome (SANS) has been well documented in astronauts both during and after long-duration spaceflight and is characterized by the development of optic disc edema, globe flattening, choroidal folds, and hyperopic refractive error shifts. The exact mechanisms underlying these ophthalmic abnormalities remain unclear. New findings regarding spaceflight-associated alterations in cerebrospinal fluid spaces, specifically perivascular spaces, may shed more light on the pathophysiology of SANS. The preliminary results of a recent brain magnetic resonance imaging study show that perivascular spaces enlarge under prolonged microgravity conditions, and that the amount of fluid in perivascular spaces is linked to SANS. The exact pathophysiological mechanisms underlying enlargement of perivascular spaces in space crews are currently unclear. Here, we speculate that the dilation of perivascular spaces observed in long-duration space travelers may result from impaired cerebral venous outflow and compromised cerebrospinal fluid resorption, leading to obstruction of glymphatic perivenous outflow and increased periarterial cerebrospinal fluid inflow, respectively. Further, we provide a possible explanation for how dilated perivascular spaces can be associated with SANS. Given that enlarged perivascular spaces in space crews may be a marker of altered venous hemodynamics and reduced cerebrospinal fluid outflow, at the level of the optic nerve and eye, these disturbances may contribute to SANS. If confirmed by further studies, brain glymphatic dysfunction in space crews could potentially be considered a risk factor for the development of neurodegenerative diseases, such as Alzheimer’s disease. Furthermore, long-duration exposure to microgravity might contribute to SANS through dysregulation of the ocular glymphatic system. If prolonged spaceflight exposure causes disruption of the glymphatic systems, this might affect the ability to conduct future exploration missions, for example, to Mars. The considerations outlined in the present paper further stress the crucial need to develop effective long-term countermeasures to mitigate SANS-related physiologic changes during long-duration spaceflight.

INTRODUCTION: A significant proportion of the astronauts who spend extended periods in microgravity develop ophthalmic abnormalities, including optic disc edema, optic nerve sheath distention, globe flattening, chorioretinal folds, hyperopic refractive error shifts, and nerve fiber layer infarcts. A constellation of these neuro-ophthalmic findings has been termed spaceflight-associated neuro-ocular syndrome. An increased understanding of factors contributing to this syndrome is one of the top priorities for ESA and NASA because the length of missions is expected to increase substantially in the future. As discussed in the present article, the very recent discovery of an ocular glymphatic clearance system can potentially help to unlock mechanisms underlying microgravity-induced optic disc edema. Observations pertaining to the ocular glymphatic pathway provide supporting evidence for the hypothesis, originally proposed by our group, suggesting that the glymphatic outflow from the eye into the optic nerve may be impeded under prolonged microgravity conditions, leading to optic disc edema.Wostyn P, De Winne F, Stern C, Mader TH, Gibson CR, De Deyn PP. Potential involvement of the ocular glymphatic system in optic disc edema in astronauts. Aerosp Med Hum Perform. 2020; 91(12):975977. ispartof: AEROSPACE MEDICINE AND HUMAN PERFORMANCE vol:91 issue:12 pages:975-977 ispartof: location:United States status: published

Primary open-angle glaucoma is one of the leading causes of irreversible blindness worldwide. Raised intraocular pressure is the most important modifiable risk factor and lowering it remains the mainstay therapeutic approach for slowing optic nerve damage and visual field progression in glaucoma patients. An intriguing finding of clinical retrospective and prospective studies is that intracranial pressure is lower in patients with glaucoma. Furthermore, in a recent study on monkeys subjected to an implantation of a lumboperitoneal cerebrospinal fluid shunt to lower intracranial pressure, chronic reduction in intracranial pressure was associated with the development of glaucoma-like pathology in half of the monkeys. In addition, a very recent study demonstrated that patients whose intracranial pressure has been lowered following ventriculoperitoneal shunt placement, as treatment for normal pressure hydrocephalus, have a significantly increased risk of developing normal-tension glaucoma. These findings suggest that a reduced intracranial pressure may play an important role in the pathogenesis of glaucoma. This may be due to an abnormally high pressure difference across the lamina cribrosa resulting in biomechanical changes of the optic nerve head and/or to a deficient clearance of toxic substances, particularly in the subarachnoid space of the optic nerve and/or in the 'ocular glymphatic system'. The search for drugs or medical devices useful to ameliorate glaucoma by lowering the trans-lamina cribrosa pressure difference and/or by facilitating cerebrospinal fluid circulation may therefore be an important area for future research. In this article, we propose that infusion of artificial cerebrospinal fluid through an implantable pump into the intrathecal space surrounding the spinal cord could be a new promising strategy for the treatment of glaucoma. Although the implantation of such a cerebrospinal fluid pump is a relatively invasive intervention, it seems worthwhile to make every effort to identify new therapies for patients who suffer from this devastating disease, especially given the significant number of patients for whom non-invasive treatment options are ineffective.

The underlying pathophysiology of chronic fatigue syndrome remains incompletely understood and there are no curative treatments for this disorder at present. However, increasing neuroimaging evidence indicates that functional and structural abnormalities exist in the brains of chronic fatigue syndrome patients, suggesting that the central nervous system is involved in this disorder and that at least some chronic fatigue syndrome patients may have an underlying neurological basis for their illness. In the present paper, we speculate that glymphatic dysfunction, causing toxic build up within the central nervous system, may be responsible for at least some cases of chronic fatigue syndrome. We further postulate that cerebrospinal fluid diversion such as lumboperitoneal shunting may be beneficial to this subgroup of patients by restoring glymphatic transport and waste removal from the brain. Although recent evidence indicates that at least some chronic fatigue syndrome patients may benefit from cerebrospinal fluid drainage, further studies are needed to confirm this finding and to determine whether this can be attributed to enhancement of glymphatic fluid flow and interstitial fluid clearance. If confirmed, this could offer promising avenues for the future treatment of chronic fatigue syndrome. Clearly, given the relative invasive nature of cerebrospinal fluid diversion, such procedures should be reserved for chronic fatigue syndrome patients who are severely debilitated, or for those with severe headaches. Anyhow, it seems worthwhile to make every effort to identify new therapies for patients who suffer from this devastating disease, especially given that there are currently no effective treatments for this condition.

Glaucoma is a leading cause of irreversible blindness worldwide. Primary open-angle glaucoma, the most common type, is characterized by progressive degeneration of retinal ganglion cells and their axons in the optic nerve, resulting in progressive deterioration of visual fields. The optic nerve head is generally considered to be the primary site of axonal injury in glaucoma. Although the pathophysiology of glaucomatous optic neuropathy is not well understood, elevated intraocular pressure is considered the most important modifiable risk factor. However, in normal-tension glaucoma, intraocular pressure is not elevated and thus other risk factors must also be involved in the optic neuropathy of primary open-angle glaucoma. Several studies reported significantly lower intracranial pressure in patients with glaucoma compared with healthy subjects, suggesting that low intracranial pressure may result in a high pressure difference across the lamina cribrosa, influencing the physiology and pathophysiology of the optic nerve head by the effect of a mechanical force. Moreover, a rapidly evolving literature suggests the existence of an 'ocular glymphatic system'. This opens up new ways to understand the mechanisms underlying a range of ocular diseases such as glaucoma. In the present paper, I hypothesize that an imbalance between intraocular pressure and intracranial pressure, apart from generating mechanical forces at the lamina cribrosa, may lead to a dangerous interplay between ocular fluid and cerebrospinal fluid resulting in impaired cerebrospinal fluid entry into the optic nerve subarachnoid space and optic nerve perivascular spaces, and the perivascular space surrounding the central retinal artery in particular, thereby inhibiting glymphatic clearance of waste products from the retrobulbar or retrolaminar portion of the optic nerve. Should further research demonstrate that the proposed viewpoint is largely correct, it would hold great potential for our understanding of glaucomatous optic nerve damage and would have important implications for diagnosis and therapy of this devastating disorder.

IMPORTANCE: Long-duration spaceflight induces structural changes in the brain and eye. Identification of an association between cerebral and ocular changes could help determine if there are common or independent causes and inform targeted prevention strategies or treatments. OBJECTIVE: To determine if there is an association between quantitative changes in intracranial compartment volumes and peripapillary total retinal thickness after spaceflight. DESIGN, SETTING, AND PARTICIPANTS: This cohort study included healthy International Space Station crew members before and immediately after long-duration spaceflight. Data on race were not collected. Analysis was conducted from September to November 2020. EXPOSURES: Long-duration spaceflight (mean [SD], 191 [55] days). MAIN OUTCOMES AND MEASURES: Optical coherence tomography–derived peripapillary total retinal thickness as a quantitative assessment and early sign of optic disc edema and magnetic resonance imaging–derived measures of lateral ventricle volume, white matter volume, and whole brain plus cerebrospinal fluid volume. RESULTS: In 19 healthy crew members included in this study (5 women [26.3%], 14 men [73.7%]; mean [SD] age, 45.2 [6.4] years), analyses revealed a positive, although not definitive, association between spaceflight-induced changes in total retinal thickness and lateral ventricle volume (4.7-μm increase in postflight total retinal thickness [95% CI, −1.5 to 10.8 μm; P = .13] per 1-mL postflight increase in lateral ventricle volume). Adjustments for mission duration improved the strength of association (5.1 μm; 95% CI, −0.4 to 10.5 μm; P = .07). No associations were detected between spaceflight-induced changes in total retinal thickness and white matter volume (0.02 μm; 95% CI, −0.5 to 0.5 μm; P = .94) or brain tissue plus cerebrospinal fluid volume, an estimate of intracranial volume (0.02 μm; 95% CI, −0.6 to 0.6 μm; P = .95). CONCLUSIONS AND RELEVANCE: These results help characterize spaceflight-associated neuro-ocular syndrome and the physiologic associations of headward fluid shifts with outcomes during spaceflight on the central nervous system. The possibly weak association between increased total retinal thickness and lateral ventricle volume suggest that while weightlessness-induced fluid redistribution during spaceflight may be a common stressor to the brain and retina, the development of optic disc edema appears to be uncoupled with changes occurring in the intracranial compartment.

A significant proportion of the astronauts who spend extended periods in microgravity develop ophthalmic abnormalities. Understanding this syndrome, called visual impairment and intracranial pressure (VIIP), has become a high priority for National Aeronautics and Space Administration, especially in view of future long-duration missions (e.g., Mars missions). Moreover, to ensure selection of astronaut candidates who will be able to complete long-duration missions with low risk of the VIIP syndrome, it is imperative to identify biomarkers for VIIP risk prediction. Here, we hypothesize that the optic nerve sheath response to alterations in intracranial pressure may be a potential predictive biomarker for optic disc edema in astronauts. If confirmed, this biomarker could be used for preflight identification of astronauts at risk for developing VIIP-associated optic disc edema.

The underlying pathophysiology of primary open-angle glaucoma remains unclear, but the lamina cribrosa seems to be the primary site of injury, and raised intraocular pressure is a major risk factor. In recent years, a decreased intracranial pressure, leading to an abnormally high trans-lamina cribrosa pressure difference, has gained interest as a new risk factor for glaucoma. New research now lends support to the hypothesis that a paravascular transport system is present in the eye analogous to the recently discovered 'glymphatic system' in the brain, which is a functional waste clearance pathway that promotes elimination of interstitial solutes, including β-amyloid, from the brain along paravascular channels. Given that β-amyloid has been reported to increase by chronic elevation of intraocular pressure in glaucomatous animal models and to cause retinal ganglion cell death, the discovery of a paravascular clearance system in the eye may provide powerful new insights into the pathophysiology of primary open-angle glaucoma. In this review, we provide a new conceptual framework for understanding the pathogenesis of primary open-angle glaucoma, present supporting preliminary data from our own post-mortem study and hypothesize that the disease may result from restriction of normal glymphatic flow at the level of the lamina cribrosa owing to a low intracranial pressure and/or a high trans-lamina cribrosa pressure gradient. If confirmed, this viewpoint could offer new perspectives for the development of novel diagnostic and therapeutic strategies for this devastating disorder.

We read with great interest the article recently published in the American Journal of Neuroradiology by Roberts et al,[1][1] and we appreciate the opportunity to make a comment. The authors retrospectively analyzed brain MR imaging scans of National Aeronautics and Space Administration astronauts

Ophthalmic abnormalities including unilateral and bilateral optic disc edema, optic nerve sheath distention, globe flattening, choroidal folds, and hyperopic shifts have been observed in astronauts during and after long-duration spaceflight. An increased understanding of factors contributing to this syndrome, termed spaceflight-associated neuro-ocular syndrome, is currently a top priority for the ESA and NASA, especially since this medical obstacle could impact the visual health of astronauts as well as the success of future missions, including continued trips to the International Space Station, a return to the moon, or a future human mission to Mars. Currently, the exact mechanisms causing this neuro-ocular syndrome are not fully understood. In the present paper, we propose a hypothetical framework by which optic disc edema in astronauts may result, at least partly, from the forcing of perioptic cerebrospinal fluid into the optic nerve and optic disc along perivascular spaces surrounding the central retinal vessels, related to long-standing microgravity fluid shifts and variations in optic nerve sheath anatomy and compliance. Although this hypothesis remains speculative at the present time, future research in this area of investigation could not only provide exciting new insights into the mechanisms underlying microgravity-induced optic disc swelling but also offer opportunities to develop countermeasure strategies.

We read with great interest and enthusiasm the article by Van Ombergen et al. (1) published in PNAS. We would like to congratulate the authors for doing this prospective study with findings of great importance to the field of space health research, and we appreciate the opportunity to make a comment. The authors found an increased ventricular cerebrospinal fluid (CSF) volume after spaceflight in supratentorial ventricular structures (i.e., lateral and the third ventricles) and further hypothesize that the impact on the supratentorial regions is an indicator for the structural compliance and CSF reserve capacity of these ventricles acting as buffers in … [↵][1]1To whom correspondence may be addressed. Email: wostyn.peter{at}skynet.be. [1]: #xref-corresp-1-1

Ophthalmic abnormalities including unilateral and bilateral optic disc edema, optic nerve sheath distention, globe flattening, choroidal folds, and hyperopic shifts have been observed in astronauts during and after long-duration spaceflight. An increased understanding of factors contributing to this syndrome, termed spaceflight-associated neuro-ocular syndrome, is currently a top priority for the ESA and NASA, especially since this medical obstacle could impact the visual health of astronauts as well as the success of future missions, including continued trips to the International Space Station, a return to the moon, or a future human mission to Mars. Currently, the exact mechanisms causing this neuro-ocular syndrome are not fully understood. In the present paper, we propose a hypothetical framework by which optic disc edema in astronauts may result, at least partly, from the forcing of perioptic cerebrospinal fluid into the optic nerve and optic disc along perivascular spaces surrounding the central retinal vessels, related to long-standing microgravity fluid shifts and variations in optic nerve sheath anatomy and compliance. Although this hypothesis remains speculative at the present time, future research in this area of investigation could not only provide exciting new insights into the mechanisms underlying microgravity-induced optic disc swelling but also offer opportunities to develop countermeasure strategies.

There has been concern about possible long-term sequelae resembling myalgic encephalomyelitis/chronic fatigue syndrome in COVID-19 patients. Clarifying the mechanisms underlying such a "post-COVID-19 fatigue syndrome" is essential for the development of preventive and early treatment methods for this syndrome. In the present paper, by integrating insights pertaining to the glymphatic system and the nasal cerebrospinal fluid outflow pathway with findings in patients with chronic fatigue syndrome, idiopathic intracranial hypertension, and COVID-19, I provide a coherent conceptual framework for understanding the pathophysiology of post-COVID-19 fatigue syndrome. According to this hypothesis, this syndrome may result from damage to olfactory sensory neurons, causing reduced outflow of cerebrospinal fluid through the cribriform plate, and further leading to congestion of the glymphatic system with subsequent toxic build-up within the central nervous system. I further postulate that patients with post-COVID-19 fatigue syndrome may benefit from cerebrospinal fluid drainage by restoring glymphatic transport and waste removal from the brain. Obviously, further research is required to provide further evidence for the presence of this post-viral syndrome, and to provide additional insight regarding the relative contribution of the glymphatic-lymphatic system to it. Other mechanisms may also be involved. If confirmed, the glymphatic-lymphatic system could represent a target in combating post-COVID-19 fatigue syndrome. Moreover, further research in this area could also provide new insights into the understanding of chronic fatigue syndrome.

As ocular hypertension refers to a condition in which the intraocular pressure is consistently elevated but without development of glaucoma, study of it may provide important clues to factors that may play a protective role in glaucoma. β-amyloid, one of the key histopathological findings in Alzheimer's disease, has been reported to increase by chronic elevation of intraocular pressure in animals with experimentally induced ocular hypertension and to cause retinal ganglion cell death, pointing to similarities in molecular cell death mechanisms between glaucoma and Alzheimer's disease. On the other hand, recent studies have reported that intracranial pressure is higher in patients with ocular hypertension compared with controls, giving rise to the idea that elevated intracranial pressure may provide a protective effect for the optic nerve by decreasing the trans-lamina cribrosa pressure difference. The speculation that the higher intracranial pressure reported in ocular hypertension patients may protect against glaucoma mainly through a lower trans-lamina cribrosa pressure difference remains at least questionable. Here, we present an alternative viewpoint, according to which the protective effect of higher intracranial pressure could be due, at least in part, to a pressure-independent mechanism, namely faster cerebrospinal fluid production leading to increased cerebrospinal fluid turnover with enhanced removal of potentially neurotoxic waste products that accumulate in the optic nerve. This suggests a new hypothesis for glaucoma, which, just like Alzheimer's disease, may be considered then as an imbalance between production and clearance of neurotoxins, including β-amyloid. If confirmed, then strategies to improve cerebrospinal fluid flow are reasonable and could provide a new therapeutic approach for stopping the neurotoxic β-amyloid pathway in glaucoma.

Pressure and velocity in intraocular and subarachnoid space fluid chambers : an inseparable couple