Intraocular pressure (IOP) and age are the most consistent independent risk factors for development and progression of glaucoma seen in all of the major prospective clinical trials, even though IOP has not been shown to increase with age in most populations. Glaucoma is also much more prevalent in persons of African ancestry. Lowering IOP is the only clinical treatment that has been shown to retard the onset and progression of glaucoma, but once damaged, the optic nerve head (ONH) is thought to be more susceptible to further glaucomatous progression even after clinical intervention has lowered mean IOP to `normal' levels. We have previously interpreted these findings to mean that the ONH becomes increasingly vulnerable to glaucomatous injury with age, African ancestry, and prior damage. There is a plausible alternative explanation, however. The ocular coats act as a shock absorber, and eyes with stiffer ocular coats have larger IOP fluctuations for a given perturbation. The ocular coats stiffen with age, stiffen with age more quickly in people of African ancestry, and stiffen after exposure to chronically elevated IOP. From these data, we might conclude that IOP fluctuations will be larger in both the elderly, persons of African ancestry, and in glaucomatous eyes in which the ocular coats have stiffened. We therefore hypothesize there are unknown age- and disease-related components of IOP (such as greater IOP fluctuation) that independently contribute to the onset and progression of glaucoma. The fluctuation hypothesis predicts that IOP and OPP fluctuations are greater in the elderly and in eyes with a history of exposure to elevated IOP even if mean IOP is unchanged, due to remodelling of the ocular coats seen with aging and in response to chronic elevated IOP, and that these effects independently contribute to the risk for glaucomatous onset and progression. Support for the fluctuation hypothesis would lead to an entirely new understanding of the importance of IOP and OPP fluctuation in the increased age- and disease-related susceptibility to glaucoma and provide strong rationale for totally new clinical diagnosis and treatment modalities that employ IOP and OPP fluctuation reduction through modification of ocular coats stiffness or intraocular damping of IOP fluctuations. If our results do not support the fluctuation hypothesis, the knowledge we gain about the natural fluctuations of these variables will redefine the appropriate IOP measurement frequency in patients and inform patient care.

Public Health Relevance

We hypothesize there are unknown age- and disease-related components of IOP and ocular perfusion pressure (such as greater IOP and OPP fluctuation) that independently contribute to the onset and progression of glaucoma. We will test this organizing hypothesis by elucidating the age- and disease-related changes in IOP, ocular perfusion pressure, and their fluctuations as they relate to retinal ganglion cell (RGC) axon loss and scleral shell stiffening.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY024732-02
Application #
9059092
Study Section
Diseases and Pathophysiology of the Visual System Study Section (DPVS)
Program Officer
Liberman, Ellen S
Project Start
2015-05-01
Project End
2018-04-30
Budget Start
2016-05-01
Budget End
2017-04-30
Support Year
2
Fiscal Year
2016
Total Cost
Indirect Cost
Name
University of Alabama Birmingham
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
063690705
City
Birmingham
State
AL
Country
United States
Zip Code
35294
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Downs, J Crawford; Girkin, Christopher A (2017) Lamina cribrosa in glaucoma. Curr Opin Ophthalmol 28:113-119
Jasien, Jessica V; Huisingh, Carrie; Girkin, Christopher A et al. (2017) The Magnitude of Hypotony and Time Course of Intraocular Pressure Recovery Following Anterior Chamber Cannulation in Nonhuman Primates. Invest Ophthalmol Vis Sci 58:3225-3230
Turner, Daniel C; Samuels, Brian C; Huisingh, Carrie et al. (2017) The Magnitude and Time Course of IOP Change in Response to Body Position Change in Nonhuman Primates Measured Using Continuous IOP Telemetry. Invest Ophthalmol Vis Sci 58:6232-6240
Downs, J Crawford (2015) IOP telemetry in the nonhuman primate. Exp Eye Res 141:91-8