April 2018
Volume 59, Issue 5
Open Access
Letters to the Editor  |   April 2018
The First Histologic Evidence of a Paravascular Pathway Within the Optic Nerve
Author Affiliations & Notes
  • Peter Wostyn
    Department of Psychiatry, PC Sint-Amandus, Beernem, Belgium;
  • Veva De Groot
    Department of Ophthalmology, Antwerp University Hospital, Antwerp, Belgium;
  • Debby Van Dam
    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;
  • Kurt Audenaert
    Department of Psychiatry, Ghent University Hospital, Ghent, Belgium;
  • Peter Paul De Deyn
    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; and the
  • Hanspeter Esriel Killer
    Department of Ophthalmology, Kantonsspital Aarau, Aarau, Switzerland.
Investigative Ophthalmology & Visual Science April 2018, Vol.59, 1717. doi:10.1167/iovs.17-23119
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      Peter Wostyn, Veva De Groot, Debby Van Dam, Kurt Audenaert, Peter Paul De Deyn, Hanspeter Esriel Killer; The First Histologic Evidence of a Paravascular Pathway Within the Optic Nerve. Invest. Ophthalmol. Vis. Sci. 2018;59(5):1717. doi: 10.1167/iovs.17-23119.

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

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We read with great interest the article by Mathieu et al.1 entitled “Evidence for Cerebrospinal Fluid Entry Into the Optic Nerve via a Glymphatic Pathway,” published recently in Investigative Ophthalmology & Visual Science
First, we congratulate the authors for their excellent work and for their efforts to identify a “glymphatic pathway” within the optic nerve of mice. Elucidation of a paravascular transport system in the eye and optic nerve may help explain many of the puzzling features not of only glaucoma but also of common ocular diseases, such as age-related macular degeneration, which have been proposed to share a common glymphatic background25 and exhibit substantial overlaps as well as co-occurrence with Alzheimer's disease. 
As nicely reported by the authors, cerebrospinal fluid (CSF) enters the optic nerve via spaces surrounding blood vessels, bordered by astrocytic endfeet.1 The authors cited one of our recent full papers,5 providing, to the best of our knowledge, the first histologic evidence for a paravascular pathway within the optic nerve. Evidence supporting the existence of a paravascular pathway in the human optic nerve came from our postmortem study in which we examined cross-sections of human optic nerves by light microscopy after injecting India ink into the subarachnoid space (SAS) of the optic nerve.5,6 In fact, this evidence was first reported in our Letter to the Editor published in 2016 in Investigative Ophthalmology & Visual Science.6 We acknowledge the inherent limitations of our postmortem study, including the fact that we could not rule out artifacts due to changes in optic nerve sheath pressure resulting from injecting India ink into the SAS of the optic nerve, the fact that it was not possible to determine whether a complete glymphatic transport system was present in the optic nerve, and the fact that our observations were based upon a small sample size (only two cases) and thus relied upon anecdotal evidence. However, our study was carried out with human tissue and not with animals. Furthermore, the fact that no tracer was found in the surrounding axons5,6 strongly supports that this finding demonstrates a well-defined anatomical structure, such as a paravascular pathway. Interestingly, Singh and Dass7 performed an extensive study of the central artery of the retina and described “a space around the artery” in their histologic work. They, however, did not apply a tracer and the space they described could also have been an artifact resulting from shrinking tissue. We were therefore delighted to read the study by Mathieu et al.1 providing new support for the existence of a paravascular pathway in the optic nerve and providing the first evidence of CSF entry via these paravascular spaces into the orbital optic nerve. Their study adds support to the notion that a glymphatic system is present in the optic nerve, and we believe that the next years will see a rapid expansion of the field of ocular glymphatic research, with great potential for the development of novel diagnostic and therapeutic strategies for many ocular diseases. 
References
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.
Wostyn P, Van Dam D, Audenaert K, Killer HE, De Deyn PP, De Groot V. A new glaucoma hypothesis: a role of glymphatic system dysfunction. Fluids Barriers CNS. 2015; 12: 16.
Denniston AK, Keane PA. Paravascular pathways in the eye: is there an ‘ocular glymphatic system'? Invest Ophthalmol Vis Sci. 2015; 56: 3955–3956.
Wostyn P, De Groot V, Van Dam D, Audenaert K, Killer HE, De Deyn PP. Age-related macular degeneration, glaucoma and Alzheimer's disease: amyloidogenic diseases with the same glymphatic background? Cell Mol Life Sci. 2016; 73: 4299–4301.
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.
Wostyn P, De Groot V, Van Dam D, Audenaert K, De Deyn PP, Killer HE. The glymphatic system: a new player in ocular diseases? Invest Ophthalmol Vis Sci. 2016; 57: 5426–5427.
Singh S, Dass R. The central artery of the retina. I. Origin and course. Br J Ophthalmol. 1960; 44: 193–212.
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