Continuous Telemetric Measurement and Chronic Control of Cerebrospinal Fluid Pressure
The pressure inside the eye, or intraocular pressure (IOP), has long been thought to play a dominant role in glaucoma, but recent work suggests that pressure from cerebrospinal fluid surrounding the optic nerve exiting the eye is also involved. These pressures are not easy to measure, so there has been no good way to determine if the pressure around the nerve where it exits the eye is truly important. We have developed a new system to wirelessly measure and record the IOP continuously in research subjects, and we now want to extend that system to measure the pressure around the nerve exiting the eye. Using this system, we can definitively determine if the pressure around the nerve is important in glaucoma, which could lead to new treatment approaches for this blinding disease.
The pressure inside the eye, known as intraocular pressure (IOP) has long been thought to play a dominant role in glaucoma, but recent work suggests that fluid pressure from cerebrospinal fluid surrounding the nerve exiting the eye is also involved. IOP and cerebrospinal fluid pressure (CSFP) counteract each other at the optic nerve head (ONH), which is generally accepted as the site of damage in glaucoma. These pressures are difficult to measure and so there has been no good way to determine if the pressure around the nerve is truly important in glaucoma pathogenesis or progression. We have developed a new system to wirelessly measure and record the pressure in the eye continuously in research subjects, and we now want to extend that system to measure CSFP as well. Using this system, we can definitively determine if CSFP is important in glaucoma, which could lead to new treatment approaches for this blinding disease.
In Aim 1, we propose to develop, implant and validate an implantable CSFP transducer for addition to our existing wireless IOP telemetry system, and to quantify the translaminar pressure difference (IOP-CSFP) with body position and normal activity. To accomplish this, we will develop a CSFP telemetry sensor, implant the wireless system (including unilateral IOP) in four research animals, and test transducer performance via bi-weekly calibration against a gold standard clinical monitor. Once validated, we will measure and quantify baseline CSFP and unilateral IOP near-continuously (200Hz for 12 seconds every 2 minutes, 24 hours per day) for 2 months, and characterize the translaminar pressure difference (IOP - CSFP) in various body positions.
In Aim 2, we propose to lower CSFP to one-third of normal levels for 9 months using an implanted CSF shunt and determine if a CSFP-driven increase in the translaminar pressure difference (IOP-CSFP) induces a glaucoma-like optic neuropathy. Once CSFP is lowered and stable, we will perform bi-weekly imaging of the ONH at a manometer-controlled IOP of 10 mmHg to assess longitudinal change in ONH morphology and retinal nerve fiber layer (RNFL) thickness compared to baseline measurements taken before CSFP lowering. Differences in optic disk appearance, ONH structure, and/or decreases in RNFL thickness will indicate that CSFP is potentially an important contributor to glaucoma or a related optic neuropathy.
The ultimate outcome of this research line, wherein we are monitoring bilateral IOP, CSFP, and ocular blood perfusion pressure (OPP) via radiotelemetry and using experimental interventions to chronically alter CSFP and IOP, is to elucidate the contributions of each of these variables to glaucoma pathogenesis and progression. We know IOP is involved in the disease, and the only clinical treatments for glaucoma are based upon IOP lowering. Many patients continue to progress following maximum IOP lowering and new treatment modalities are desperately needed. Furthermore, the validation of CSFP and/or OPP as proven risk factors would give treating physicians another piece of data upon which to base clinical management decisions. If we can show that low CSFP and/or OPP independently contribute to glaucoma, then we can design therapies to alter these variables as new glaucoma treatments.
About the Researcher
J. Crawford Downs, PhD, is a professor of Ophthalmology, Biomedical Engineering and Computer and Information Sciences, and vice chair of Research for the University of Alabama at Birmingham (UAB) Department of Ophthalmology. Dr. Downs joined the UAB faculty in 2012 as the founding director of the Ocular Biomechanics and Biotransport Program. This program is a multidisciplinary effort to study the underlying disease pathophysiologies of blinding eye conditions through an engineering-based framework of biomechanics, mechanobiology, and biostransport. As part of the program, Dr. Downs’ current research focuses specifically on the impact of IOP, OPP, CSFP, aging, and African heritage on the development and progression of glaucoma. He uses experimental and computational approaches in both human donor eyes and unique animal models of glaucoma equipped with IOP and OPP radiotelemetry to investigate how ocular biomechanics influences glaucoma pathogenesis and progression from the organ scale down to the cellular scale. Dr. Downs is widely published and serves as principal investigator on two active NIH R01 grants and as a co-investigator on several others.
My passion for ocular biomechanics and glaucoma arose when I was a graduate student at Tulane University. Dr. Claude Burgoyne, a noted glaucoma specialist, and Dr. Rich Hart, my PhD supervisor, proposed that I use experimental and computational engineering techniques to measure and model the mechanical forces and deformations in the sclera and ONH as a PhD dissertation project. While IOP-driven ONH biomechanics was thought to be important in glaucoma, very little work had been done in the field. So, it was a wide open problem that no one was working on to my knowledge, and it had the potential to really change how we viewed glaucoma pathogenesis and progression. The project was also incredibly risky, in that failure to secure grant funding and convince the community that ONH and scleral biomechanics were fundamentally important in glaucoma would mean we might not have any impact on human health whatsoever. In the ensuing years, we got an NIH grant, developed several groundbreaking techniques to study ocular biomechanics, and helped establish the field. I continue to study glaucoma with the same passion for discovery that initially drove me to do my PhD work in ocular biomechanics, and we are building the collaborative team necessary to investigate glaucoma in greater breadth and depth than any one investigator could do so alone.
First published on: July 14, 2016
Last modified on: December 31, 2018