Why a One-Way Ticket to Mars May Result in a One-Way Directional Glymphatic Flow to the Eye

Letters to the Editor FIG. 3. A. Preoperative cerebral angiogram shows a Type I DAVF (arrow) involving the right sigmoid and transverse sinuses. B. The postoperative cerebral angiogram reveals decreased flow through the DAVF after Onyx embolization. DAVF, dural arteriovenous fistula. REFERENCES 1. Davies JM, Hopkins LN. Neuroendovascular intervention: evolving at the intersection of neurosurgery and neuroophthalmology. J Neuroophthalmol. 2017;37:111-112. 2. Borden JA, Wu JK, Shucart WA. A proposed classification for spinal and cranial dural arteriovenous fistulous malformations and implications for treatment. J Neurosurg. 1995;82:166-179. 3. Cognard C, Gobin YP, Pierot L, Bailly AL, Houdart E, Casasco A, et al. Cerebral dural arteriovenous fistulas: clinical and angiographic correlation with a revised classification of venous drainage. Radiology. 1995;194:671-680. Why a One-Way Ticket to Mars May Result in a One-Way Directional Glymphatic Flow to the Eye W e read with great interest the article by Mader et al (1) entitled "Persistent asymmetric optic disc swelling after long-duration space flight: implications for pathogenesis." Mader et al point out that ophthalmic abnormalities including optic disc swelling, optic nerve sheath distention, globe flattening, and choroidal folds have been reported in astronauts after long-duration space flight. They emphasize 2 potential mechanisms to explain optic disc edema observed in astronauts. The first explanation is that optic disc swelling results from elevated intracranial pressure (ICP) secondary to cephalad fluid shifts. The second is compartmentation of cerebrospinal fluid (CSF) in the orbital subarachnoid space (SAS). We provide a possible additional explanation of how microgravity, at least in part, may cause optic disc edema due to an imbalance between ocular glymphatic inflow and outflow. In 2012, the glymphatic system was discovered in mice by Iliff et al (2). Their findings suggested that a brain-wide network of paravascular pathways along which a large proportion of subarachnoid CSF recirculates through brain parenchyma, 462 4. Cognard C, Casasco A, Toevi M, Houdart E, Chiras J, Merland JJ. Dural arteriovenous fistulas as a cause of intracranial hypertension due to impairment of cranial venous outflow. J Neurol Neurosurg Psychiatry. 1198;65:308-316. 5. Gelwan MJ, Choi IS, Berenstein A, Pile-Spellman JM, Kupersmith MJ. Dural arteriovenous malformations and papilledema. Neurosurgery. 1988;22:1079-1084. 6. Lamas E, Lobato RD, Esperarza J, Escudero L. Dural posterior fossa AVM producing raised sagittal sinus pressure: case report. J Neurosurg. 1977;46:804-810. facilitating the clearance of interstitial solutes, including amyloid-b, from the brain. CSF enters the brain along para-arterial channels to exchange with interstitial fluid which is, in turn, cleared from the brain along paravenous pathways. Intriguingly, other reports (3) together with preliminary data from our own postmortem study (4) suggest that a similar paravascular transport system is present in the human optic nerve and retina. We examined cross-sections of human optic nerves by light microscopy after injecting India ink into the SAS of the optic nerve. Our results showed a striking accumulation of India ink in paravascular spaces around the central retinal artery and vein, whereas the lumens of these vessels and the surrounding axons remained unlabeled. We speculated that a "paravascular communication" may exist between the surroundings of the retinal vascular system and the surroundings of the central retinal vessels in the optic nerve. Such a para-arterial "retino-orbital" pathway would include a paraarterial CSF influx route around the central retinal artery to enter the paravascular spaces of the retina, followed by a paravenous efflux route around the central retinal vein. Normally, intraocular pressure exceeds ICP, and, on average, there is a small force (mean 4 mm Hg) directed posteriorly across the lamina cribrosa (5). This trans-lamina cribrosa pressure difference (TLCPD) would ensure effective paravenous outflow from Letters to the Editor: J Neuro-Ophthalmol 2017; 37: 458-465 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Letters to the Editor the eye. However, in long-duration space flight-induced increased ICP, paravenous outflow may fail to match ocular paraarterial inflow due to the reduction of the normal TLCPD. Ocular paravenous outflow may be completely impeded if there is reversal of the TLCPD. This may result in glymphatic stasis predominantly within the prelaminar region of the optic nerve head, which could contribute to the optic disc edema seen in astronauts. The accumulation of toxic metabolites due to glymphatic stasis then may cause further disc swelling. Although this mechanism is speculative, it is important to note that Denniston et al (6) provided support for the importance of the ocular glymphatic system in the pathogenesis of papilledema secondary to idiopathic intracranial hypertension (IIH). Using spectral domain optical coherence tomography in a cohort of patients with IIH, they demonstrated a number of structural differences not seen in healthy controls, including the presence of perivascular "black holes." This was observed both in the optic nerve head and within the retinal nerve fiber layer, and the authors hypothesized that this represents dilated ocular perivascular glymphatic channels. There seemed to be a relationship between the degree of papilledema and the extent of these changes. In healthy controls, the authors did not detect these features. Given these findings, we believe that our proposed theory deserves further study and may ultimately contribute to the field of space health research. Peter Wostyn, MD Department of Psychiatry, PC Sint-Amandus, Beernem, Belgium Hanspeter Esriel Killer, MD Department of Ophthalmology, Kantonsspital Aarau, Aarau, Switzerland Why a One-Way Ticket to Mars May Result in One-Way Directional Glymphatic Flow to the Eye: Response W e greatly appreciate the opportunity to respond to the comments of Dr. Wostyn et al. Their theory focuses on a glymphatic flow imbalance mechanism at the optic nerve head that may, at least partially, explain the development of optic disc swelling in astronauts during long-duration space flight. This hypothesis would still be dependent on a space-flight induced rise in cerebrospinal fluid (CSF) pressure by some mechanism within the subarachnoid space (SAS) surrounding the optic nerve. Perhaps the effects of increased intracranial pressure, Letters to the Editor: J Neuro-Ophthalmol 2017; 37: 458-465 Peter Paul De Deyn, MD, PhD Laboratory of Neurochemistry and Behavior, Institute Born-Bunge, University of Antwerp, Department of Biomedical Sciences, Antwerp, Belgium Department of Neurology and Alzheimer Research Center, University of Groningen and University Medical Center Groningen, Groningen, the Netherlands Department of Neurology and Memory Clinic, Middelheim General Hospital (ZNA), Antwerp, Belgium The authors report no conflicts of interest. REFERENCES 1. Mader TH, Gibson CR, Otto CA, Sargsyan AE, Miller NR, Subramanian PS, Hart SF, Lipsky W, Patel NB, Lee AG. Persistent asymmetric optic disc swelling after long-duration space flight: implications for pathogenesis. J Neuroophthalmol. 2017;37:133-139. 2. Iliff JJ, Wang M, Liao Y, Plogg BA, Peng W, Gundersen GA, Benveniste H, Vates GE, Deane R, Goldman SA, Nagelhus EA, Nedergaard M. A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid b. Sci Transl Med. 2012;4:147ra111. 3. Hu P, Arfuso F, Madigan MC, Adamson S, Shaw LC, Boulton ME, Grant MB, Chan-Ling T. Evidence for a glymphatic system in human, primate, rat and mouse retina. Invest Ophthalmol Vis Sci. 2016;57. ARVO E-Abstract 996. 4. Wostyn P, Killer HE, De Deyn PP. Glymphatic stasis at the site of the lamina cribrosa as a potential mechanism underlying open-angle glaucoma. Clin Exp Ophthalmol. 2017;45:539-547. 5. Berdahl JP, Allingham RR. Intracranial pressure and glaucoma. Curr Opin Ophthalmol. 2010;21:106-111. 6. Denniston AK, Keane PA, Aojula A, Sinclair AJ, Mollan SP. The ocular glymphatic system and idiopathic intracranial hypertension: author response to "Hypodense holes and the ocular glymphatic system". Invest Ophthalmol Vis Sci. 2017;58:1134-1136. sequestration of CSF within the SAS of the optic nerve or a combination of the 2, acting in conjunction with the authors' 2 proposed mechanisms, may produce varying degrees of optic disc swelling. It also is possible that the contribution of this mechanism to disc swelling is a relatively constant low magnitude finding that occurs with even a small change in the translaminar pressure difference. Continued examination of all space flight crew members, including those without clinically apparent optic disc swelling, may provide additional insight regarding the relative contribution of glymphatic stasis. More measurements of opening pressure on lumbar puncture are needed in astronauts completing longduration space flights. These data, in conjunction with 463 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited.