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We would like to acknowledge our appreciation for Prof. Weinreb and the IGR editorial team for paying special attention to our manuscript and for Prof. Fleischman and Prof. Jonas for their thoughtful and generous comments.
In this article, we present a hypothesis according to which the higher cerebrospinal fluid (CSF) pressure reported in ocular hypertension (OHT) patients could protect against glaucoma through its association with a higher rate of CSF formation leading to increased CSF turnover with enhanced removal of potentially neurotoxic waste products that accumulate in the optic nerve. We further postulate that glaucoma may share common ground with Alzheimer's disease, and argue that glaucoma, just like Alzheimer's disease, may occur when there is an imbalance between production and clearance of neurotoxins, including β-amyloid. Although much more work is required to substantiate this view, further elucidation of a common pathophysiological process linking glaucoma and Alzheimer's disease might offer new perspectives for the development of novel diagnostic and therapeutic strategies for both disorders. We therefore wish to encourage further studies and research in this area.
This personal view suggests that the protective role of high intracranial pressure (ICP) in OHT is not exclusively of a biomechanical nature (lower pressure difference across the lamina cribrosa), but also of a biochemical one (increased neurotoxin clearance). We fully agree with the reviewers that many important issues remain to be resolved before these biomechanical and biochemical theories can ultimately be confirmed or refuted. Killer and Pircher1 recently challenged the concept of the trans-lamina cribrosa pressure difference (TLCPD). One of their criticisms was that the retrolaminar pressure is measured during lumbar puncture at a site more than 100 cm away from the lamina cribrosa.1 Indeed, given that it is not possible to measure the retrolaminar pressure clinically, the clinical retrospective2,3 and prospective4 studies of CSF pressure in patients with glaucoma took the lumbar CSF pressure measurement as surrogate for pressure in the orbital CSF space. However, from a biomechanical perspective, it must be acknowledged that it is the optic nerve subarachnoid space pressure (ONSP), and not the ICP, that determines the TLCPD since the ONSP represents the true counter-pressure against the intraocular pressure (IOP) across the lamina cribrosa. Given that the imbalance between IOP and ICP may reflect the imbalance between production and clearance of neurotoxins, our group recently presented an alternative viewpoint according to which the TLCPD, calculated as the difference of IOP minus ICP, may be considered as an index for neurotoxic burden in the anterior part of the optic nerve.5
All these different aspects in the pathophysiology of glaucoma render primary open-angle glaucoma and normal-tension glaucoma rather a syndrome than a disease and it seems that the time has come to pull together these different aspects and to start a collaborate study including all the groups that work on the same syndrome.