Questions and Answers

Questions and Answers

Presiding Physician: Jill Koury, MD

Dr Koury: Fifteen years ago the Vancouver glaucoma team described different patterns of long term visual field loss, episodic, general decay, staggered stepwise loss, any merit to an update being done on this report?

Dr Higginbotham: Yes, that was actually Marc’s question. It’s hard to really know, but it seems most patients are linear, but you can get some variability there.

Dr Koury: Are there any medications you would use, or any medications you would stay away from in patients with low tension glaucoma?

Dr Higginbotham: That’s where I really have to talk with the PCP. Many of these patients have systemic hypertension. We have to make sure that they are not using meds that will drop their blood pressure, such as a systemic beta blocker. I don’t use calcium channel blockers because the data is just not there and they are not easy drugs to use. There are a lot of potential side effects.

Dr Lee: Would you say the same thing about Timoptic?

Dr Higginbotham: I use beta blockers. That’s one of the reasons why I chose not to be part of the Collaborative Normal Tension Glaucoma Study, because I had concerns about not being able to use a topical beta blocker in that trial.

Dr Lieberman: I think one of the major implications of Dr Quigley’s presentation that low tension glaucoma is just part of the primary open angle glaucoma spectrum is that I personally don’t see any reason to exclude any glaucoma medication for patients with low pressures. I think the burden of proof is on Dr Drance and Dr Anderson to prove that timolol is contraindicated in those particular patients. I don’t think there is any evidence for it. If you have a patient with low tension glaucoma and you are used to using a beta blocker, I don’t see any reason why you shouldn’t.

Dr Quigley: Yes, in 1984 when the study was designed, we thought there was a possibility that beta blockers decreased retinal and optic nerve blood flow. We now know almost conclusively that they improve retinal and optic nerve blood flow. Timolol clearly improves retinal blood flow. The second fallacy was that persons with glaucoma at normal pressure had something wrong with their vasculature. I just made the argument for you that there is something wrong with their connective tissue, at least, and they may have something wrong with their vasculature. The

Eye on the Bayou, New Concepts in Glaucoma, Cataract and Neuro-Ophthalmology, pp. 53–57 Transactions of the 54th Annual Symposium of the New Orleans Academy of Ophthalmology, New Orleans, LA, USA, February 18-20, 2005

edited by Jonathan D. Nussdorf

© 2006 Kugler Publications, The Hague, The Netherlands

normal tension glaucoma study could not find anything but migraine that was associated with those who progressed. The large set of risk factor studies I presented earlier do not indicate that major cardiovascular disease and lots of other stuff related to it are in fact related to glaucoma at normal or high pressures.

Dr Lee: Do you even ask about Raynaud’s, migraine?

Dr Higginbotham: In my review of systems I do.

Dr Lee: And what do you do with the information?

Dr Higginbotham: I write it down.

Dr Lieberman: Whenever you go back and look at the criteria, for example in the OHTS study for a history of migraine, they are never using the criteria that the neurologists use, which are rather specific. The ophthalmologists ask “Do you have migraine headaches?” and when people say yes, I have a migraine – to me there is tremendous lack of specificity in that particular question of the history.

Dr Higginbotham: I consider it as part of the thorough historical background of that patient. If a patient demonstrates rapid progression of their disease, then migraine or Raynaud’s may be an important component of their disease.

Dr Koury: Dr Quigley says that low tension glaucoma does not exist. Dr Higginbotham says ethnicity has little to do with glaucoma. Then how do you explain the very high rate of glaucoma with low pressures among people of Japanese ancestry?

Dr Quigley: It’s a very interesting thing. It’s a tonometric artifact. There is considerable information now on the fact that Asian persons by tonometry read lower on average by about a 1.5 - 2 mmHg than do persons who are European or African derived. Paul Foster has written a paper out of his studies in Singapore with cannulation of the eye in the operating room and measuring tonometric eye pressure. There is a systematic under-read on the eye pressure in this Asian population. Almost surely what is going on is that their real eye pressure is 15.5, but is measuring 13.5. Interestingly, this finding is not due to a difference in the cornea thickness distribution in Asian persons compared to European persons. The corneal thickness does not provide you the answer. It’s a difference in corneal bioelasticity.

Of course, if a Japanese group says that the top of the normal pressure curve should be 21, using the European value, and then they apply that to the pressure distribution of Japanese people, instead of 50% having so-called low tension glaucoma, they would have 80% with so-called low tension glaucoma, because it is reading off the wrong scale and using the European cut-off. I have spoken with Yoshiaki Kitazawa, who is one of the godfathers of glaucoma in Japan. I asked, “Yoshi, why don’t you use the so-called 2 standard deviation cut-off for Japanese people, which would be 18?” He said, “Well, I wouldn’t think that any of the major journals, the Archives of Ophthalmology would accept our doing that, because they would think that we were using the wrong scale, because the Europeans dominate everything.”

Dr Higginbotham: It is important to individualize treatment and certainly once you start talking about populations, it is really hard to define what should be the population. Specifically, measure the characteristics of the individual patient and take it from there. Look at the optic nerve, look at the visual field, measure the corneal thickness, and that’s what you need to follow.

Dr Koury: For the treatment of optic neuritis – any reason why oral steroids would be worse than placebo while IV steroids are better?

Dr Lee: Two issues: one is the steroid doses were not equal. The oral prednisone dose in the study was 60 mg to 80 mg of prednisone, which is not the same as 1000 mg of intravenous methylprednisolone. The second issue concerns the route of drug administration. The intravenous route is going to avoid any first pass effects that occur through metabolism in the liver.

Dr Koury: Is there a dosage of oral steroids that will do the same as IV?

Dr Lee: That question has been looked at and the Japanese and European optic neuritis treatment trials used oral steroids at a dose of 500 mg of methylprednisolone, and that dosage did not increase the recurrence rate of optic neuritis. Different drug though. Methylprednisolone, prednisone, not the same thing, different dose, but you could theoretically use oral methylprednisolone at a higher dosage in place of intravenous.

Dr Kellum: I can understand why IV steroids work better than oral steroids; it may be related to the dose, but why would oral steroids, if you put them in a hierarchy, oral steroids, placebo, IV steroids, why would oral steroids have a negative impact?

Dr Lee: I quote Neil Miller on this and Neil says you go out hunting and you are hunting for bear. You shoot the bear, but you don’t kill him; you just wound him with the oral steroids. Which is worse, that you didn’t shoot the bear at all, or that you shot and you missed or you wounded him. A wounded bear comes back angrier and worse. So presumably the oral steroid, whether it is dose effect or route administration, is not sufficient to kill it. It comes back angrier than if you hadn’t gone hunting at all.

Dr Koury: What are normal and abnormal values for ESR and CRP?

Dr Lee: The question concerns values of an abnormal sed rate and abnormal CRP, if you look in your lab it will say ESR 0 to 20 mm/hr. We know that the sed rate is susceptible to all sorts of artifacts induced by the hematocrit. After all, you’re just measuring the rate of sedimentation of red cells. If you have less red cells you’re anemic – that’s going to change the sed rate. In addition, when you get older, your sed rate goes up normally. There are age adjustments that can be done on the sed rate to make up for that and one standard adjustment is age plus ten divided by two, if you are a woman, age over two if you are a man. This doesn’t account for all the other things, like your hematocrit and all the proteins that are floating around your body or whether you have diabetes or renal failure. There is no absolute real number I can give you. But if you say okay, I just want to have a number no matter

what you say, 33 for the sed rate. The CRP is laboratory dependent and it is made worse by the fact that we have high sensitivity CRP, which is a totally different test. That’s for cardiovascular risk factors. In our laboratory, a CRP of less than 0.5 is the normal, but in some laboratories the decimal place is shifted and five is the number. Look at your own individual laboratory.

The real answer to your question concerns the sensitivity and the specificity of the test can change if you set the bar higher or lower. Suppose you set the ‘normal’ sed rate at 100, and you are going to use that cutoff to detect giant cell arteritis. You will detect fewer cases of giant cell arteritis, your sensitivity will be low and the specificity will be high. If you set the sed rate cutoff to 22, then your sensitivity goes up, finding more giant cell arteritis, but the specificity drops.

Dr Koury: Dr Lee, are you saying that we should get a stat sed rate and a C-reactive protein on all patients with anterior ischemic optic neuropathy, or just patients when we have a clinical suspicion for giant cell arteritis, since you can get a false positive elevated ESR, for example in patients with renal failure?

Dr Lee: So this is back to the question, what is the most powerful predictor of the disease actually being present? Pretest likelihood of disease, regardless of the test that you perform. If the pretest likelihood of disease is two percent, the person is 35 years old, has diabetes, hypertension, then don’t order the test, because the chance of that person having giant cell arteritis is low. Even if the test is positive, in this case a sedimentation rate, that doesn’t move the post-test likelihood of disease beyond a threshold that you would consider treatable. Conversely, if you have a 90-year old person with headache and scalp tenderness, jaw claudication, bilateral disc edema and the sed rate comes back too, the pretest likelihood of disease is 95%, and a normal sed rate in that setting only moves the post-test likelihood of disease to like 90%. You are not going to use the lab to kind of make this up or down kind of thing. If you think the person absolutely does not have giant cell arteritis, then you probably could get away with not ordering the sed rate and CRP, but the fact of the matter is, most people are in between. You don’t have any 30-year old person with nonarteritic AION. You have the 52-year old person with nonarteritic AION. You order the test to try and move the post-test likelihood of disease towards one of the diagnostic spectrum. In reality, the pretest likelihood of disease is much more powerful than any lab test.

Dr Koury: With retro-bulbar optic neuritis, is it important to start IV steroids within one week, is any time frame vital for success?

Dr Lee: Intravenous steroid speeds the rate of recovery, but you are talking about speeding the rate of recovery of weeks. If you are already three weeks in, you are not really gaining a lot from intravenous steroids if you are using the treatment to speed rate of recovery. If, however, you believe that intravenous steroids reduce the rate of clinically definite MS, which was shown in the optic neuritis treatment trial at year two, but that effect wore off by year five; or, if you are going to consider the patient for interferon therapy, that is, they have an abnormal MRI scan, then it is probably okay within a two week window or maybe even a little bit more. It just depends on what you are using the intravenous steroid therapy for.

Dr Koury: If an retro-bulbar optic neuritis patient had other episodes, numbness or other symptoms, are IV steroids indicated?

Dr Lee: In the optic neuritis treatment trial and in the CHAMPS study, the monosymptomatic event, those subjective complaints don’t count as an event. Clinically definite multiple sclerosis means you had two documented objective neurologic attacks. Just saying I had numbness for a week when I was in college doesn’t cut it. You should not be using that as a driver for intravenous steroid therapy. What you should be using is their MRI scan. The MRI scan is a much more powerful predictor of multiple sclerosis than whether I had subjective numbness in my right hand in 1972.

Dr Koury: Would you use IV steroids for two or more episodes of retrobulbar neuritis within the first two to three years?

Dr Lee: These are questions that are not answered by the clinical trial. If you have recurrent optic neuritis, that debate is did you have one lesion or two. Multiple sclerosis – multiple lesions separated in space and time, that is, they have to be at different times and they have to be different spaces. If the attack is in the same space, technically that doesn’t count as clinically definite multiple sclerosis. Would you use that as a driver for intravenous steroid therapy? Maybe.

Dr Koury: Someone asked about the reliability of using Tono-Pens in monitoring open angle glaucoma.

Dr Higginbotham: Tono-Pens can be very unreliable and certainly I think we all have experienced that. I have found there to be significant variability. Tono-Pens tend to underestimate the pressure at higher levels and overestimate the pressures at lower levels, that is less than six. You need to have other methods at least available, not including the Schiotz.

Dr Quigley: An experienced observer with a Goldmann applanation tonometer, an experienced observer using a Tono-Pen will find that their variability in the measurement is much lower with Goldmann applanation tonometry. I urge you to use Goldmann applanation tonometry in every situation in which you can. In situations when you have an unusual cornea, a somewhat uncooperative or young person, Tono-Pen becomes very useful.

Dr Lieberman: Dr Palmberg swears by the Tono-Pen and I personally find it is useful for generating lottery numbers, because it is fairly random in my hands. I know that there was a study comparing different tonometers using the same kind of cannulation technique in phaco patients. The pneumotonometer seemed to have the best correlation of actual manometric pressure measurements. The pneumotonometer, which no longer runs on gas canisters but sets you back five grand, is a very sweet way to get accurate pressures with bad corneas and may or may not be independent of this central corneal thickness.