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Should poor sleep be added to the list of risk factors for normal-tension glaucoma in the future?

Eye volume 39, pages 1233–1234 (2025)Cite this article

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Glaucoma is an optic neuropathy characterized by the progressive degeneration of retinal ganglion cells and structural changes in the optic nerve head, resulting in visual field defects [1, 2]. It is a leading cause of irreversible blindness worldwide [1]. Primary open-angle glaucoma (POAG) is the most common form of glaucoma, with elevated intraocular pressure (IOP) being its most important modifiable risk factor [3, 4]. However, a substantial proportion of patients develop glaucomatous damage despite having IOP within the normal range, a condition known as normal-tension glaucoma (NTG), which is a subset of POAG [4]. Although the exact pathophysiology of NTG remains unclear, several studies suggest that IOP-independent factors, including vascular and cerebrospinal fluid (CSF)-related factors, may contribute to its development [5,6,7]. Growing evidence suggests that not only low CSF pressure [6] but also disturbances in CSF dynamics [7,8,9] may play a role in the pathogenesis of NTG. Based on computed tomographic cisternography studies on NTG, Killer et al. [7] previously suggested that the sequestration of CSF in the subarachnoid space (SAS) surrounding the optic nerve, creating a toxic environment around the nerve, may be involved in the development of NTG. Wostyn et al. [8] subsequently speculated that at least some cases of NTG may be caused by age-related reductions in CSF turnover, leading to diminished clearance of toxic substances in the SAS surrounding the optic nerve. More recently, Wostyn and Killer [9] hypothesized that various vascular and CSF-related factors may share impaired glymphatic fluid transport and metabolic waste clearance in the optic nerve as a final common pathway leading to the development of NTG. As discussed below, new insights into the clearance function of the retrograde ocular glymphatic pathway (directed from the brain towards the eye) may provide a deeper understanding of the pathogenesis of NTG.

In 2012, a team led by Iliff and Nedergaard first described the “glymphatic system” in mice [10]. Their study proposed the existence of a brain-wide perivascular network that plays a crucial role in clearing interstitial solutes, including amyloid-β (Aβ), from the brain. Within this system, CSF flows from the SAS into periarterial channels, where it mixes with interstitial fluid (ISF) in the parenchyma. The resulting CSF/ISF mixture is subsequently drained via perivenous pathways and ultimately exits the brain through meningeal and cervical lymphatic vessels. This process is facilitated by aquaporin-4 (AQP4) water channels, which are specifically expressed in astrocytes, where their localization is highly polarized to endfeet that envelop the cerebral vasculature [10]. A key finding is that the brain glymphatic system is mainly disengaged during wakefulness but becomes highly active during sleep, particularly during non-rapid eye movement slow-wave sleep [11]. Experimental studies in mice have demonstrated a several-fold increase in glymphatic CSF influx and a doubling of Aβ clearance during sleep compared to wakefulness [11, 12]. Additionally, a 60% increase in interstitial volume during sleep has been demonstrated, which reduces resistance to fluid flow, enhancing glymphatic transport [11].

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Authors and Affiliations

  1. Department of Psychiatry, PC Sint-Amandus, Beernem, Belgium

    Peter Wostyn

  2. Center for Translational Neuromedicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

    Maiken Nedergaard

  3. Center for Translational Neuromedicine, University of Rochester Medical Center, Rochester, New York, USA

    Maiken Nedergaard

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  1. Peter Wostyn
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  2. Maiken Nedergaard
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Writing – original draft: PW; Writing – review & editing: MN.

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Correspondence to Peter Wostyn.

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Wostyn, P., Nedergaard, M. Should poor sleep be added to the list of risk factors for normal-tension glaucoma in the future?. Eye 39, 1233–1234 (2025). https://doi.org/10.1038/s41433-025-03748-8

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