Melanie Cole (Host): The pressure inside the eye, or the intraocular pressure, has long been thought to play a dominant role in glaucoma, but recent work suggests that pressure from the cerebrospinal fluid surrounding the optic nerve, exiting the eye, is also involved. My guest today is Dr. Jay Crawford-Downs. He's the Vice-Chair of Research in the Department of Ophthalmology and the Director of Ocular Biomechanics and Biotransport Program at UAB Medicine. Welcome to the show, Dr. Downs. Tell us about some of the earliest evidence that cerebrospinal fluid pressure may play a role in glaucoma.

Dr. Jay Crawford-Downs (Guest): So, I appreciate the opportunity to talk to you guys today. Basically, that evidence comes from retrospective chart reviews, mostly from the electronic medical record system at the Mayo Clinic. What happened is, some researchers from Duke University, John Burdell and Rand Allingham, went back and associated cerebrospinal fluid pressure as it was measured with lumbar puncture with the prevalence of glaucoma and the levels of intraocular pressure that were reported in those glaucoma cases. The bottom line on those studies is that, basically, a reduction in cerebrospinal fluid pressure or a low cerebrospinal fluid pressure reading was associated with normal-tension glaucoma--so glaucoma that occurs at epidemiologically defined, normal levels of IOP; and that higher cerebrospinal fluid pressure measurements were associated with ocular hypertension that had not progressed into glaucoma. So, that seemed to be protected. So, the idea that cerebrospinal fluid pressure is counteracting the effects of intraocular pressure at the optic nerve head, at the site of damaging glaucoma, sort of emerged from those studies.

Melanie: Does the pressure measured by lumbar puncture have any relevance in your studies?

Dr. Downs: I think it does. Lumbar puncture is notoriously difficult in terms of measuring an accurate opening pressure and those are they're erroneous, and we all know that they're difficult to measure, and there's no good non-invasive way to measure cerebrospinal fluid pressure but, that being said, this was a huge data set and so, you know, there is no bias in that data that we know of and so one would assume that those errors, even though they are present, are probably sort of averaged out. So, I think this a very solid result.

Melanie: So, how have you typically been measuring the intraocular pressure?

Dr. Downs: So, intraocular pressure is normally measured with a snapshot technique and that would be Goldmann tonometry, or pneumotonometry. There are several, like Schiotz tonometry, which are not any longer used, and those are snapshot measurements. So, “Mrs. Smith, sit in the chair. Please don't blink or move your eyes, and we're going to measure the intraocular pressure.” And, that's also based on--those measurements of transcorneal pressure—are based on some assumptions about corneal geometry and corneal stiffness, which vary across people with age and racial background and those sorts of things. So, it's thought that these tonometric measurements are not accurate except to about 2mm from mercury either way. But, it is a snapshot measurement that sort of gives you that intraocular pressure, that minute in time, when the person is sitting in the chair in the clinic.

Melanie: So, tell us about your new wireless system and your research grant.

Dr. Downs: So, basically, there have been several attempts to do this in humans in terms of wireless telemetry of some sort of wireless measurement of intraocular pressure, and those efforts have been largely unsuccessful, either because the devices have too much drift, in other words they don't measure accurately over time; or they have surgical complications; or they measure something that is not intraocular pressure, which is something like the triggerfish contact lens sensor which measures circumferential corneal stretch that is presumably linked to IOP, but it is not calibratable within a person. So, you don't know if the measurement that you’re getting of an IOP "rise" is, you know, 1mm from mercury (1mmHg) or 25mm from mercury (25mmHg). So, it's not useful clinically, at least in my opinion. So, we've developed an intraocular pressure telemetry system for use in research animals. And basically, this is an implantable device that allows us to put a small piezoelectric, highly-accurate pressure transducer into the anterior chambers of the eye. So, it's a direct measurement inside the eye. And, it doesn't disrupt the detritus, or the retina, and we can also put a third sensor--we can do that bilaterally--and put a third sensor into the carotid artery, which doesn't block flow. So, it's a nice way to measure ocular perfusion pressure or the blood pressure coming into the eye, as it relates to intraocular pressure. So, that sensor gives us 200 measurement of IOP every second, so highly accurate; it can capture transients from blinks, saccade, tonopen, touches, applanation, eye rubs, anything like that. Obviously, the heartbeat and ocular pulse amplitude, which is the change in intraocular pressure, the transient due to blood coming into the eye with every heartbeat. So, that's the system that we have now, within IH, and we've just been funded to add a cerebrospinal fluid pressure monitor to that system. So, we'll have a four-pressure system running here in the next year or so that will include cerebrospinal fluid pressure in the brain, so a ventricular pressure; bilateral intraocular pressure; and then, ocular perfusion pressure, as well. So, that will be a great system to test out some of these hypotheses about intraocular pressure, transience in intraocular pressure, and ocular perfusion pressure, and cerebrospinal fluid pressure, as well.

Melanie: If a person with elevated intraocular pressure is referred to sort of as a “glaucoma suspect”, who do your foresee will be candidates for this type of implantation?

Dr. Downs: Well, I think that the candidate question is interesting. So, our device right now is not exactly translatable to the clinic in the sense that it requires a subcutaneous battery pack to be implanted into the animal and so to translate this into humans, which you could do, would require some kind of passive powering with the subcutaneous inductive power system, which would be placed in the temple and you'd patch over it or something like this, so it would passively power the system across the skin. So, I do think that type of system is doable, probably in the next 5-7 years, maybe 3-7 years. The candidates would be people it's just extraordinarily difficult to figure out what's really going on with their intraocular pressure. Our studies and our research animals have indicated that intraocular pressure is highly variable and it doesn't maintain the same pattern day-to-day. The best IOP studies that have been done are done with snapshot measurements, at most, every hour over a 24-hour period, and we believe, based on our sort of current continuous measurements, that this is a huge underestimation of the variability. This doesn't capture the variability in IOP and it ignored the transience in IOP completely and our latest data indicate that those IOP transients from blinks, from eye movements, saccades, eye rubs, the ocular pulse amplitude with heartbeat; all those things-- just the transient piece of IOP--is about up to about 15% of the energy, the IOP associated energy, bio-mechanical energy, or pressure energy that the eye has to absorb during the day. And, we believe, also, based on other work showing that the ocular coats stiffen with age and stiffen more rapidly with age in persons of African descent by which it's a big risk factor for glaucoma, that those transients are going to increase with age and increase if you're of African heritage. So, there are some big pieces of the IOP/glaucoma puzzle that we don't understand, and the first applications of this are probably going to be in research subjects that have progressive glaucoma or advancing glaucoma for which we just don't have any answers. In other words, they're already maximally, medically, and surgically controlled in terms of their IOP and they're still getting worse and we need to understand why that is.

Melanie: Dr. Downs, for glaucoma pathogenesis, are there other factors such as age or sex or body mass that have been studied to understand how these affect cerebrospinal fluid pressure?

Dr. Downs: Yes, a little bit. So, cerebrospinal fluid pressure is known to decrease a little bit with age and so people have naturally latched on, you know, glaucoma is an age-related disease. It's also about twice as prevalent in people of African heritage compared to people of European descent, all other things being controlled for in terms of access to health care and socio-economic status, and that sort of thing. So, there's definitely some sort of risk factor there that's endemic to that population of the elderly and/or, even more so, persons of African heritage. So, in terms of cerebrospinal fluid pressure, there is some date that suggests that cerebrospinal fluid pressure decreases with age. I don't know that there's a racial prevalence in that, but we do know that intraocular pressure transience, which would also interact with cerebrospinal fluid pressure, are very likely to increase with age and increase more rapidly with age and persons of African heritage. So, we're kind of thinking that these two variables that are kind of unknown--in other words cerebrospinal fluid pressure and exactly its dynamics and how those CSFP dynamics interact with intraocular pressure dynamics which are also largely unknown--that that's going to sort of clear up some of the unknown links in the pathogenesis of glaucoma in these at-risk populations.

Melanie: So, in just the last few minutes, Dr. Downs, how can a community physician refer a patient to UAB Medicine?

Dr. Downs: So, they can log in through the portal in terms of UAB. They can also go to the Department of Ophthalmology website and there's a whole list of glaucoma specialists there. We have a very large sub-specialty practice in glaucoma--we have one of the largest in the southeast--and also do that directly through UAB Medicine's site.

Melanie: And, tell us about your team. Why is UAB so great to work with?

Dr. Downs: UAB, in fact, I've been at several different institutions, and I think that there are a few things. One is we have a very, very active clinical sub-specialty program and the clinicians are very, very amenable to getting involved in research projects, which is unusual, so that's supported at the departmental level. UAB, as an institution, is also a very highly collaborative place, so you know silos and protecting one's own research program for the sake of maintaining a career is really not looked very kindly on. People feel like we ought to be doing team science and that's something that permeates the institution and the department. We're growing. We have good resources allocated to ophthalmology and so, you know, we've gone up in rank from 40th in the nation in IH funding and we'll be top 15 next year.

Melanie: Thank you so much for being with us today, Dr. Downs. A community physician can refer a patient to UAB Callahan Eye Hospital by calling the 844-UAB-EYES. That's 844-325-8620. You're listening to UAB Medcast. For more information on resources available at UAB Medicine, you can go to uabmedicine.org/physician. That's uabmedicine.org/physician. This is Melanie Cole. Thanks so much for listening.