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Glaucoma Dialogue IGR 17-3

Comment

Comment by David Fleischman on:

66320 Fast circulation of cerebrospinal fluid: an alternative perspective on the protective role of high intracranial pressure in ocular hypertension, Wostyn P; De Groot V; Van Dam D et al., Clinical and Experimental Optometry, 2016; 99: 213-218

See also comment(s) by Jost Jonas • Peter Wostyn •

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The authors of this hypothesis have contributed considerable work in our understanding of cerebrospinal fluid dynamics and its relationship in glaucoma through many of their prior studies. Further, they have found many convincing pieces of evidence implicating a common pathophysiologic mechanism in Alzheimer's disease and glaucoma. This manuscript offers an interesting theory pertaining to the role of cerebrospinal fluid (CSF) in the pathogenesis of glaucoma. The authors begin by explaining that a reduced cerebrospinal fluid pressure (CSFP) has been associated with glaucoma, as described in retrospective and prospective studies. These same studies also found relatively increased CSFP compared to controls in patients with ocular hypertension (OHT). The concept of the translaminar pressure differential is introduced as the explanation for these findings, whereby a difference between the intraocular pressure (IOP) and CSFP is more important than each variable on its own. The translaminar pressure differential (TLPD) offers a biomechanical explanation for glaucoma and OHT. The authors, however, point out many flaws with this theory. The CSF within the orbit may not be in direct communication with the rest of the neuraxis, and therefore precluding a transitive relationship in the lumbar opening pressure. Another excellent point questions the protective effect of an increased CSFP since the TLPD in OHT patients was in fact higher than controls in the initial retrospective studies by Berdahl and colleagues.

The authors then present their theory of a fast circulation of CSF as the possible protective factor for glaucoma. Higher CSFP is interpreted as an increased rate of production of CSF compared to clearance through the arachnoid villi. The adequate clearance of CSF is vital for the removal of neurotoxic waste products, such as β-amyloid (Aβ). They reference an animal model of optic neuropathy induced by CSF segregation of an optic nerve (Jaggi GP, et al., Br J Ophthalmol 2010). The authors suggest that glaucoma is considered an imbalance between production and clearance of neurotoxins, much like Alzheimer's disease. They present evidence that there is an IOP-sensitive increase in Aβ in glaucoma, and this has been found in the retinal ganglion cells in animal models of glaucoma. As Aβ is an integral component of the senile plaques found in Alzheimer's disease, the authors parlay this into evidence of a pathophysiologic association and mechanistic similarity between the two disorders. The authors conclude this discussion by discussing the overlap of Aβ clearance pathways between the brain and the optic nerve. They briefly mention the plausibility of toxin migration by fluid flow from the vitreous and optic nerve interstitial fluids.

The increased frequency of glaucoma in patients with Alzheimer's disease (AD), and the absence of any cases of ocular hypertension in AD patients implies a susceptibility to IOP-mediated damage, which the authors believe to be due to the reduced rate of metabolite clearance via the CSF.

In summary, the authors present an intriguing alternate hypothesis for the role of cerebrospinal fluid in the pathogenesis of glaucoma, and provide several examples in the pathology of AD to assist their theory. Despite the excellent work by the authors in describing orbital CSF dynamics, there are still many holes in our understanding of CSF movement within the perioptic subarachnoid space. Even more complicated is the relationship of perioptic subarachnoid space pressure to the pressure in the remainder of the neuraxis. This precludes any quantitative discussion pertaining to the TLPD and its role in glaucoma pathogenesis. Similarly, CSFP differences of a few millimeters of mercury, which may or may not be clinically relevant, are difficult to translate over to CSF clearance - in this case the inference that the marginally elevated CSFP in the OHT patients is an indication of fast CSF transport.

That being said, there is as yet insufficient evidence to prove and disprove these theories. However, the theories posed here are not entirely difficult to study - and I look forward to following-up on the work of these investigators. The authors are congratulated for formulating a thoughtful and potentially important theory in the pathogenesis of glaucoma that mirrors the pathogenic mechanisms of Alzheimer's disease.

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