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GLAUCOMA SPECIALISTS HAVE BEEN RETHINKING THE IMPORTANCE OF TARGET PRESSURE.
An emerging field of research suggests that the variation in pressure readings may hold the key to disease progression.
How important are swings in IOP? Very, say a growing number of glaucoma specialists. These ophthalmologists argue that the variation in IOP readings, referred to in the literature as fluctuation, is an independent risk factor for progression. Forget the law of averages, they say. Smoothing out pressure swings could be as important as—or even more important than—achieving a target pressure. Steady is the way to go.
But what about target pressure? “There has to be a complete rethinking of that,” said Rohit Varma, MD, MPH, professor of ophthalmology and preventive medicine at the University of Southern California. “We’re proposing that it’s not one number that you come up with. You may have a target IOP in mind. We’re not saying, ‘Get rid of that.’ But in addition to target IOP, we now need a target range of IOP variation. In my view, this is just the start of a complete reconceptualization of how we’ll need to look at IOP.”
Sanjay G. Asrani, MD, agreed. The standard practice has been to look at average pressures, said Dr. Asrani, associate professor of ophthalmology at Duke University. “Our emphasis has been, ‘low is better.’ But low average pressure is not necessarily better. Stable is better.”
STILL A DEVELOPING CONCEPT
“Most glaucoma specialists believe large fluctuations are significant, particularly those that raise the pressure,” said Arthur J. Sit, MD, assistant professor of ophthalmology at the Mayo Medical School. However, as he noted, the jury is still out. “We just don’t have the evidence now. There’s a lot more we need to understand about the nature of these fluctuations.”
As an idea, fluctuation is “still nascent,” agreed Jonathan S. Myers, MD, associate attending surgeon in the glaucoma service at Wills Eye Institute. “We don’t understand enough to know if fluctuation accounts for just a subset of progressing patients, or if it’s a big piece of the puzzle.”
And compliance is a confounding variable. “Since we don’t know patients’ compliance, this clouds the entire field. Some people who have higher fluctuation probably are having trouble with compliance,” Dr. Myers said.
Even the time frame is up for grabs. “Are we talking about one day in the office, or 24-hour continuous monitoring, or over a period of months? Or years?” Dr. Myers asked. “Some talk about range; some talk about standard deviation over a number of visits.”
Dr. Varma acknowledged that there is a “lack of clarity in the scientific literature” on what fluctuation means. He prefers thinking in terms of “variation” or “intervisit IOP range” and said that, as a term, fluctuation “is more muddied, as it could refer to diurnal changes in IOP or longer-term swings in IOP. I’m careful not to call it IOP fluctuation.”
“Call it whatever you want,” Dr. Asrani said. “It’s change. You’re talking about change vs. stability.”
RESEARCH GIVES A MIXED PICTURE
More than a decade ago, Dr. Asrani and his team gave home tonometers to 64 patients who successfully measured their IOP five times a day for five days.1 Would IOP readings at multiple times of day shed light on, among other things, why some patients with normal pressures get worse?
The researchers found that the mean office IOP and mean home IOP readings were similar. But when pressures measured at home ranged above 6 mmHg from maximum to minimum, progression followed. Patients who experienced a wider spread of their daily eye pressures were worsening at about six times the rate of those who had more stable pressures, “regardless of their mean pressures as measured in the office,” Dr. Asrani said.
Unfortunately, his study couldn’t be replicated. The FDA refused to approve the tonometer, which required patients to self-administer a topical anesthetic. So researchers went back to the major long-term clinical trials to tease out data on IOP variation.
Their findings were mixed, Dr. Asrani said. The Early Manifest Glaucoma Trial (EMGT), the Ocular Hypertension Study (OHTS) and the EGPS (European Glaucoma Prevention Study) found no relation between IOP variation and progression. But the Advanced Glaucoma Intervention Study (AGIS) and the Collaborative Initial Glaucoma Treatment Study (CIGTS) did find an association.
Why the difference? The EMGT and OHTS looked at early glaucoma and glaucoma suspects, respectively. “Maybe these would have shown an impact of fluctuation if they were running longer,” Dr. Asrani said. “It also is possible that the variations of fluctuation in pressure are not as important in very early glaucoma.” The AGIS and CIGTS looked at advanced and moderate glaucoma, respectively, and “showed definitely an impact of fluctuation,” he said.
The AGIS investigators found on retrospective analysis that long-term variations (IOP changes between visits, over years) were related to visual field progression, especially if the IOP was in the low-normal range.2,3 The OHTS found similar results,4 Dr. Asrani said.
And a retrospective analysis of the CIGTS data found that the most important factor associated with visual field loss was not mean IOP, but peak IOP and variation of IOP over time.5
RETHINKING TREATMENT—OR NOT
“There are people who really think [fluctuation] is going to turn out to be as important as peak pressure, and there are those who have yet to be convinced by the data,” Dr. Myers said.
As it happens, both Drs. Asrani and Varma now factor IOP variation into their treatment plans. In contrast, Dr. Myers is taking a wait-and-see approach. Here’s a look at their approaches.
Focus on the variation. Dr. Varma calculates the difference between the highest IOP reading and the lowest IOP reading (taken during office visits at any time of day). He considers any variation higher than 4 mmHg—and, especially, higher than 6 mmHg—to be a red flag.
While the pressures measured only at office visits may not be as refined as minute-by-minute or second-by-second pressure readings, he said they are all that is clinically feasible today. “I’m looking at a bigger picture. We’re speaking about a chronic disease that lasts years and years. My interest is what happens over the course of days, weeks and months.”
Dr. Varma acknowledged that many things may occur over time to affect changes in IOP. A drug may be ineffective, or the patient may not be compliant. But he warned against jumping to such conclusions. “Any IOP measurement suggesting that the variation is high should be viewed with suspicion and treated as a risk factor for progressive optic nerve damage.”
He noted one caveat: If you change a patient’s treatment plan, you have to start over when calculating the range.
Strive for tight pressure control. Say you want to achieve a pressure at or below 17 mmHg. On the first visit, the treated patient’s pressure is 17 mmHg. At the next visit, the IOP is 10 mmHg without any change in the regimen. The pressure dropped seven points. That’s great, right?
No, said Dr. Asrani. “That is more [difference] than I would accept. It’s not enough to just accept anything under 17 mmHg.” Dr. Asrani would rather maintain a constant pressure at 12, 13 or even 14 mmHg. The point is to avoid the ups and downs. “What we need is that the pressure control remains tight.”
To that end, Dr. Asrani sets targets for both mean pressure and range of fluctuation. Merging the Canadian Ophthalmological Society’s guidelines for target pressure6 with his own calculations, Dr. Asrani has created his own target range for fluctuation to correspond to the severity of the glaucoma.
- Advanced glaucoma: Target IOP is in the low teens. Fluctuation must be less than 3 mmHg.
- Moderate glaucoma: Target IOP is in the mid-teens. An acceptable fluctuation range is 4 mmHg or less.
- Mild glaucoma: Target IOP is in the high teens. An acceptable fluctuation range is 5 mmHg or less.
Stick with peak pressure. Given the dearth of studies comparing peak IOP control to peak fluctuation control, Dr. Myers isn’t ready to tailor treatment to fluctuation. “Treating patients based on pressure still remains the basis of our care and the gold standard by which we base target pressures and by which we judge whether a patient is adequately treated,” he said. Still, he granted that a patient whose pressure is good but is “bouncing up and down” is at risk. “Most people would agree that at the very least, patients who show a greater fluctuation of IOP deserve closer attention.”
For Dr. Myers, the problem is in not knowing how to act on the information. “We’re still not certain what to do from a therapeutic standpoint.” Fortunately, either way, the treatment is similar, he said. “Many patients who have high pressure fluctuations also have higher peak pressures. So clinicians who watch peak pressure are still going to catch most of these patients.”
WHERE WE ARE NOW
At this point in glaucoma management, all of the available treatments help stabilize pressure, Dr. Asrani said. “The same bag of tricks [both] lowers eye pressure and reduces fluctuation. Our ability to stabilize pressures is limited to glaucoma drops, lasers and surgery.”
Then why are we having this discussion? “The emphasis in treatment is different,” Dr. Asrani said. “I will add more meds or add some more laser or, when all else fails, even sometimes do surgery.” He noted that while trabeculectomy is risky and unpredictable, it is known to stabilize pressure “to almost the same level, visit to visit.”
Dr. Sit agreed, noting that laser seems to provide a flatter IOP curve, as does filtering surgery. He added that blebless surgeries probably could smooth the ups and downs, too. And some drugs, depending on when they peak and trough, might stabilize pressure.
One hope is for even better medications. Dr. Sit, for example, is interested in how aqueous humor dynamics contribute to the 24-hour IOP pattern. At ARVO this year, he reported that uveoscleral outflow drops to nearly zero at night.7 “This had never been reported,” he said. “That’s new. It’s a piece of the fluctuation puzzle that could explain why some medications work better during the day than at night.” Perhaps new classes of medications in the pipeline may smooth out fluctuations. For now, he said, the best options would be the prostaglandin analogs and carbonic anhydrase inhibitors.
IN THE PIPELINE: BETTER MONITORS
While a growing number of glaucoma experts agree that fluctuation appears to be an important variable, the implications for glaucoma management are still evolving. “I think there’s enough evidence that if we could easily measure these fluctuations, we would act on them,” said Dr. Sit. Devices that measure IOP over time could shed light on the significance of fluctuation, and the day they become available will be “a watershed moment,” he said.
Such devices could transform glaucoma management the way the field of cardiology changed after “cardiovascular physiologists first got to see the real arterial pressure curve in a higher primate,” said J. Crawford Downs, PhD, associate scientist and research director of the ocular biometrics laboratory at Devers Eye Institute in Portland, Ore. Once a continuous curve of arterial blood pressure could be measured, a new window opened on cardiovascular physiology. Then cardiologists could look at true differences between systolic and diastolic pressure, see what happened in bradycardia and tachycardia and learn how stiffening of arteries led to strokes. That’s the high moment glaucoma specialists are waiting for, Dr. Downs said. Until then, “We don’t have any idea what IOP is at any given moment.”
But that may soon change, as several IOP-tracking devices are in the pipeline:
Contact lens + receiver. Sensimed’s Triggerfish Sensor system, which involves a “smart” contact lens, monitors changes in the corneal curvature at the corneoscleral junction. These changes are thought to correlate to IOP fluctuations.
The Triggerfish is composed of a MEMS (micro-electro-mechanical systems) sensor and a telemetry microprocessor. These are embedded in a single-use silicone contact lens that the patient wears for up to 24 hours, including during sleep. In addition, a circular antenna is taped around the eye, and the antenna is connected to a portable recorder. At the end of a monitoring session, when the patient removes the contact lens, the data are wirelessly transferred from the recorder to the ophthalmologist’s computer, providing a 24-hour record of changes in IOP.
The Triggerfish received the European CE mark in 2009 but is not approved for use in the United States.
Wireless sensors. AcuMEMS is developing three products for wireless IOP sensing. All employ MEMS technology. Two of the devices are implantable and are designed to measure IOP directly. An anterior chamber sensor may be implanted in an outpatient setting; a posterior chamber device is designed to be inserted during intraocular or cataract surgery.
A third sensor, located on a contact lens, is for monitoring patients who are not candidates for surgery—that is, those who are considered glaucoma suspects or have early glaucoma. It provides pressure readings similar to applanation tonometry.
The technology allows the patient to record pressure intermittently or continuously. The data are stored on an iPhone-sized portable reader and can be transmitted electronically to the physician or to any data bank. Feasibility studies are ongoing, both in vivo and in vitro. The first human prototype is expected in two years.
Implantable transducer. Dr. Downs has created an implantable IOP transducer system that measures IOP a minimum of 500 times per second, around the clock, for as long as two years. The sensor is an adaptation of a commercial system that’s been used for drug safety studies in cardiovascular applications. Dr. Downs’ device has only been implanted in non-human primates, but he hopes to be involved in the development of a system for human eyes.
This sensor could confirm an association between the magnitude of high-frequency IOP fluctuation and glaucomatous progression. Dr. Downs is particularly interested in high-frequency fluctuations. “I believe they’re significant. They’re large and frequent,” he said, adding that they get larger in amplitude if the eye is stiff—with age or under elevated pressure, for example.
Home tonometer. Dr. Asrani has given Icare’s rebound home tonometer to 130 patients over the past two years. It gives “pretty reliable readings” and correlates well with Goldmann tonometry, he said.
The handheld, portable tonometer requires no topical anesthetic or specialized skills. In an evaluation of its potential as a home IOP measuring device, Dr. Asrani compared IOP measurements taken with the Icare by 100 patients to Goldmann tonometry measurements taken by experienced technicians.8
Eighty-four percent of the study participants required just one attempt to achieve an error-free measurement using the Icare tonometer, and 13 percent required two attempts. Ninety-four percent of the participants agreed or strongly agreed that they learned to use the tonometer quickly, and 93 percent agreed or strongly agreed that the instrument was simple and easy to use.
The device is FDA-approved for clinic use, but its expense—approximately $3,900—could limit its use, Dr. Asrani said. A new, less-expensive Icare instrument for home use is available in Europe and Australia and is awaiting FDA approval.
THE BOTTOM LINE
Dr. Myers is looking forward to the introduction of one or more of the monitoring devices now in the pipeline. “Sensors may completely validate what we know in terms of the risks of pressure and peak pressure. Or they’ll turn our field upside down and teach us things we didn’t know and likely never thought to question,” he said.
In the meantime, Dr. Myers said, “The field of research is open. The burden of proof as to whether this replaces our traditional conception of the disease remains with the fluctuation people. There are a lot of things we don’t know about pressure.”
And Dr. Varma concluded, “We are looking at a completely novel way of assessing IOP. While we have some good, solid data from clinical trials, we’re going to need to refine this concept as we go along. This is not the last word.”
1 Asrani, S. et al. J Glaucoma 2000;9:134–142.
2 Nouri-Madhavi, K. et al. Ophthalmology 2004;111:1627–1635.
3 Caprioli, J. and A. L. Coleman. Ophthalmology 2008;115:1123–1129.
4 Medeiros, F. et al. Ophthalmology 2008;115:934–940.
5 Musch, D. C. et al. Ophthalmology (forthcoming).
6 Damji, K. et al. Can J Ophthalmol 2003;38:189–197.
7 Sit, A. J. et al. Poster 2072. Presented at ARVO, May 2, 2011.
8 Asrani, S. et al. J Glaucoma 2011;20:74–79.
TRACKING UNDERLYING DAMAGE
IOP is dynamic, changing from second to second, minute to minute, day to day, and week to week.
Dr. Downs, associate scientist and research director of the ocular biomechanics laboratory at Devers Eye Institute, believes that these swings damage the optic nerve head. The damage, he said, could be triggered by sensitivity of the lamina cribrosa to rapid changes in IOP.
Dr. Downs compared the lamina cribrosa, which is the principal load-bearing structure of the ONH, to the fabric on a trampoline. The thick and collagenous sclera, to which it attaches, is like the frame. The IOP is pushing on that fabric all the time and deforming it, he said.
For example, any external compression, even blinking or rubbing the eye, could produce changes in IOP. A rise in IOP stretches the lamina cribrosa and compresses it. The lamina cribrosa contains the capillaries that nourish the retinal ganglion cell axons as they pass through its pores to exit the eye. Thus, this deformation then strains the cells, including adjacent axons, and likely diminishes the blood supply, Dr. Downs said. “So it’s a multifactorial phenomenon driven by a single factor. The single factor is IOP dynamics.”
There are other hypotheses regarding how glaucoma progresses, said Dr. Downs. For instance, some researchers attribute progression to damage of the retinal ganglion cells or to a disease of the lateral geniculate, which is where the retinal ganglion cells interface with the brain. But the bulk of the evidence indicates that the damage happens in the optic nerve head region, Dr. Downs said.
MEET THE EXPERTS
SANJAY G. ASRANI, MD Associate professor of ophthalmology at Duke University and director of education at the Duke University Eye Center. Financial disclosure: None.
J. CRAWFORD DOWNS, PHD Associate scientist and research director of the ocular biomechanics laboratory at Devers Eye Institute in Portland. Financial disclosure: Receives NIH grant support.
JONATHAN S. MYERS, MD Associate attending surgeon in the glaucoma service at Wills Eye Institute. Financial disclosure: None.
ARTHUR J. SIT, MD Assistant professor of ophthalmology at the Mayo Medical School. Financial disclosure: Is an advisor to AcuMEMS.
ROHIT VARMA, MD, MPH Professor of ophthalmology and preventive medicine at the University of Southern California. Financial disclosure: Consults for, receives grant support from and is an equity owner in AqueSys and Replenish. Also consults for Alcon, Allergan, Bausch + Lomb Surgical, Genentech, Merck and Pfizer, and receives grant support from Allergan, Genentech and Pfizer.