Senescent changes in cerebrospinal fluid circulatory physiology and their role in the pathogenesis of normal-tension glaucoma

Authors: Wostyn P, De Groot V, Van Dam D, Audenaert K, De Deyn PP.

PURPOSE: To evaluate the evidence supporting a role for senescent changes in cerebrospinal fluid (CSF) circulatory physiology in the pathogenesis of normal-tension glaucoma (NTG).
DESIGN: Literature review and personal perspective of the authors.
METHODS: Analysis of selected articles in the peer-reviewed literature with interpretation and perspective.
RESULTS: Recent studies have reported that intracranial pressure is lower in patients with NTG when compared with patients with primary open-angle glaucoma and nonglaucomatous control subjects. It has been suggested that a low intracranial pressure in patients with normal intraocular pressure could lead to glaucomatous damage. This low intracranial pressure, leading to an abnormally high trans-lamina cribrosa pressure difference, could result in barotraumatically induced optic nerve damage at the lamina cribrosa. However, several experimental studies do not support the speculation that low intracranial pressure and the resulting pressure-dependent effects cause bowing back of the lamina cribrosa and optic disc cupping. On the other hand, CSF production and turnover have been shown to be decreased in aging and in pathologic conditions, such as Alzheimer disease and normal pressure hydrocephalus. Interestingly, recent studies have revealed that both Alzheimer disease patients and patients with normal pressure hydrocephalus may have a higher risk of developing glaucoma. Therefore, we believe that CSF circulatory failure, ultimately resulting in reduced neurotoxin clearance along the optic nerves, could be an alternative explanation as to why glaucoma develops in patients with low intracranial pressure.
CONCLUSIONS: On the basis of the evidence available from the peer-reviewed literature, our tentative conclusion is that age-related changes in CSF circulatory physiology and the subsequent decrease in CSF turnover, with diminished clearance of toxic substances, can account for, at least in part, the pathogenesis of NTG. It should be stressed that for the moment at least, the present hypothesis remains unproven. Further research will be necessary to determine the possible role of CSF circulatory dysfunction in NTG. If confirmed, this hypothesis could provide new, important insights into the pathogenesis of NTG.

The role of cerebrospinal fluid pressure in glaucoma and other ophthalmic diseases: A review

Authors: Fleischman D, Allingham RR.

Glaucoma is one of the most common causes of blindness in the world. Well-known risk factors include age, race, a positive family history and elevated intraocular pressures. A newly proposed risk factor is decreased cerebrospinal fluid pressure (CSFP). This concept is based on the notion that a pressure differential exists across the lamina cribrosa, which separates the intraocular space from the subarachnoid fluid space. In this construct, an increased translaminar pressure difference will occur with a relative increase in elevated intraocular pressure or a reduction in CSFP. This net change in pressure is proposed to act on the tissues within the optic nerve head, potentially contributing to glaucomatous optic neuropathy. Similarly, patients with ocular hypertension who have elevated CSFPs, would enjoy a relatively protective effect from glaucomatous damage. This review will focus on the current literature pertaining to the role of CSFP in glaucoma. Additionally, the authors examine the relationship between glaucoma and other known CSFP-related ophthalmic disorders.

Intracranial pressure and glaucoma

Authors: Jonas JB, Wang N.

Eyes with normal-tension and high-tension glaucoma can have a similar optic nerve head appearance, which differs markedly from the optic disc appearance in vascular optic neuropathies. Factors in addition to intraocular pressure (IOP) may play a role in the pathogenesis of glaucomatous optic neuropathy. Clinical and experimental studies have shown (1) physiologic associations between cerebrospinal fluid pressure (CSFP), systemic arterial blood pressure, IOP, and body mass index; (2) that a low CSFP was associated with the development of glaucomatous optic nerve damage in cats; and (3) that patients with normal-tension glaucoma had significantly lower CSFP and a higher trans-lamina cribrosa pressure difference when compared to normal subjects. Due to anatomic reasons, the orbital CSFP and the optic nerve tissue pressure (and not the atmospheric pressure) form the retro-laminar counter-pressure against the IOP and are thus part of the trans-lamina cribrosa pressure difference and gradient. Assuming that an elevated trans-lamina cribrosa pressure difference and a steeper trans-lamina cribrosa pressure gradient are important for glaucomatous optic nerve damage, a low orbital CSFP would therefore play a role in the pathogenesis of normal-tension glaucoma. Due to the association between CSFP and blood pressure, a low blood pressure would also be indirectly involved.

The translaminar pressure gradient in sustained zero gravity, idiopathic intracranial hypertension, and glaucoma

Authors: Berdahl JP, Yu DY, Morgan WH.

Papilledema has long been associated with elevated intracranial pressure. Classically, tumors, idiopathic intracranial hypertension, and obstructive hydrocephalus have led to an increase in intracranial pressure causing optic nerve head edema and observable optic nerve swelling. Recent reports describe astronauts returning from prolonged space flight on the International Space Station with papilledema (Mader et al., 2011) . Papilledema has not been observed in shorter duration space flight. Other recent work has shown that the difference in intraocular pressure (IOP) and cerebrospinal fluid pressure (CSFp) may be very important in the pathogenesis of diseases of the optic nerve, especially glaucoma (Berdahl and Allingham, 2009; Berdahl, Allingham, et al., 2008; Berdahl et al., 2008; Ren et al., 2009; Ren et al., 2011) . The difference in IOP and CSFp across the lamina cribrosa is known as the translaminar pressure difference (TLPD). We hypothesize that in zero gravity, CSF no longer pools in the caudal spinal column as it does in the upright position on earth. Instead, CSF diffuses throughout the subarachnoid space resulting in a moderate but persistently elevated cranial CSF pressure, including the region just posterior to the lamina cribrosa known as the optic nerve subarachnoid space (ONSAS). This small but chronically elevated CSFp could lead to papilledema when CSFp is greater than the IOP. If the TLPD is the cause of optic nerve head edema in astronauts subjected to prolonged zero gravity, raising IOP and/or orbital pressure may treat this condition and protect astronauts in future space travels from the effect of zero gravity on the optic nerve head. Additionally, the same TLPD concept may offer a deeper understanding of the pathogenesis and treatment options of idiopathic intracranial hypertension (IIH), glaucoma and other diseases of the optic nerve head.Copyright © 2012 Elsevier Ltd. All rights reserved.

The association between glaucomatous and other causes of optic neuropathy and sleep apnea

Authors: Stein JD, Kim DS, Mundy KM, Talwar N, Nan B, Chervin RD, Musch DC.

PURPOSE: To determine whether an association exists between sleep apnea and open-angle glaucoma, normal-tension glaucoma, nonarteritic ischemic optic neuropathy (NAION), papilledema, or idiopathic intracranial hypertension (IIH) and whether treatment with continuous positive airway pressure affects the development of these conditions.
DESIGN: Retrospective, longitudinal cohort study.
METHODS: Billing records for beneficiaries 40 years of age and older enrolled in a large United States managed care network from 2001 through 2007 were reviewed. Incidence of open-angle glaucoma, normal-tension glaucoma, NAION, papilledema, and IIH were determined for the beneficiaries and were stratified by sleep apnea status. Cox regression analyses determined the hazard of each of these conditions developing among individuals with and without sleep apnea, with adjustment for sociodemographic, ocular, and medical conditions.
RESULTS: Among the 2 259 061 individuals in the study, 156 336 (6.9%) had 1 or more sleep apnea diagnoses. The hazard of open-angle glaucoma was no different among persons with sleep apnea either treated (adjusted hazard ratio , 0.99; 95% confidence interval , 0.82 to 1.18) or untreated with continuous positive airway pressure (HR, 1.01; 95% CI, 0.98 to 1.05) and individuals without sleep apnea. Similar findings were observed when assessing the hazard of normal-tension glaucoma developing (P > .05 for both comparisons). A significantly increased hazard of NAION developing (HR, 1.16; 95% CI, 1.01 to 1.33) and IIH (HR, 2.03; 95% CI, 1.65 to 2.49) was observed among individuals with sleep apnea who were not receiving continuous positive airway pressure therapy as compared with individuals without sleep apnea, although similar increased risks could not be demonstrated among continuous positive airway pressure-treated sleep apnea patients for these conditions (P > .05 for both comparisons).
CONCLUSIONS: Patients with untreated sleep apnea are at increased risk for IIH and NAION. Clinicians should consider appropriate screening for these conditions in sleep apnea patients.

Role of Intracranial Pressure (in Glaucoma)

Authors:  Arthur J. Sit, SM, MD

A better understanding of translaminar pressure differences and pressure gradients may elucidate glaucoma pathogenesis. 

Elevated intraocular pressure (IOP) is the greatest risk factor for glaucoma, but IOP alone is not sufficient to explain glaucoma pathogenesis. It is possible that intracranial pressure (ICP) may play some role.

The optic nerve is subject to a variety of forces, as described by Morgan and colleagues (see Figure 1).1 There is IOP from the anterior side of the optic nerve head; retrolaminar tissue pressure (RLTP) within the optic nerve, just behind the laminar cribrosa; orbital pressure from the sides; and finally, there is the fluid pressure of the optic nerve subarachnoid space (ONSAS) surrounding the optic nerve. The ONSAS is filled with cerebral spinal fluid (CSF), and is in communication with the intracranial cerebral spinal fluid, so presumably the ONSAS pressure is in some way related to ICP.


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